israel journal of
psychiatry
Vol. 51 - Number 4 2014
ISSN: 0333-7308
Special section Substance use and addictive disorders 238
Editorial: Substance use and addictive disorders Shaul Lev-Ran and Arturo G. Lerner
240
Response and attention in smokers Limor Dinur-Klein et al.
248
Substance use in pregnancy Einat Peles et al.
258
Alcohol and adolescent patients Daniel Feingold et al.
262
Adolescent Substance Abuse and Suicidal Behavior Dan Shlosberg et al.
270
Cannabis Withdrawal Gregory Katz et al.
277
Synthetic cannabis abuse and HPPD Arturo G. Lerner et al.
281
Buprenorphine for Opiate Dependence Limor Goren et al.
285
Benzodiazepines in methadone patients Einat Peles et al.
290
Involuntary Admission to a Dual Diagnosis Ward Yael Delayahu et al.
296
Flashbacks and HPPD Arturo G. Lerner et al.
303
HCV Hepatitis and Methadone Stephen Malnick et al.
307
New imagery in LSD Flashbacks Arturo G. Lerner et al.
israel journal of
psychiatry
The Official Publication of the Israel Psychiatric Association Vol. 51 - Number 4 2014
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Special section:
Substance use and addictive disorders
238 > Editorial: Substance use
and addictive disorders
Shaul Lev-Ran and Arturo G. Lerner
240 > Response inhibition and sustained and attention in Heavy smokers versus non-smokers Limor Dinur-Klein, Semion Kertzman, Oded Rosenberg, Moshe Kotler, Abraham Zangen and Pinhas N. Dannon
248 > The Prevalence of Alcohol, Substance and Cigarettes Exposure among Pregnant Women within a General Hospital and the Compliance to Brief Intervention for Exposure Reduction Einat Peles, Anat Sason, Miki Bloch, Sharon Maslovitz, Shaul Dollberg, Ariel Many, Michael J. Kuperminc and Miriam Adelson
258 > Clinical Correlates of Alcohol
Abuse among Adolescent Psychiatric Inpatients in Israel
Daniel Feingold, Uri Nitzan, Gideon Ratzoni and Shaul Lev-Ran
262 > Emerging Issues in the
285 > Benzodiazepine Usage During
19.5 Years in Methadone Maintenance Treatment Patients and its Relation to Long-Term Outcome
Einat Peles, Miriam Adelson and Shaul Schreiber
290 > Evaluating the Clinical Impact of Involuntary Admission to a Specialized Dual Diagnosis Ward
Yael Delayahu, Yael Nehama, Adi Sagi, Yehuda Baruch and David M. Blass
296 > Flashbacks and HPPD:
A Clinical-oriented Concise Review
Arturo G. Lerner, Dmitri Rudinski, Oren Bor and Craig Goodman
303 > A Model for Treating HCV
Hepatitis in Patients Receiving Methadone Maintenance Therapy
Stephen Malnick, Victoria Sheidvasser, Alon Basevitz and Shabtai Levit
307 > LSD Flashbacks – The
Appearance of New Visual Imagery Not Experienced During Initial Intoxication: Two Case Reports
Arturo G. Lerner, Craig Goodman, Dmitri Rudinski and Shaul Lev-Ran Hebrew Section
312
> Abstracts
Relationship Between Adolescent Substance Use and Suicidal Behavior Dan Shlosberg, Gil Zalsman and Gal Shoval
270 > Cannabis Withdrawal – A New Diagnostic Category in DSM-5 Gregory Katz, Tsafrir Lobel, Alex Tetelbaum and Sergey Raskin
277 > Synthetic Cannabis Substances (SPS) Use and Hallucinogen Persisting Perception Disorder (HPPD): Two Case Reports Arturo G. Lerner, Craig Goodman, Oren Bor and Shaul Lev Ran
281 > Buprenorphine for Opiate Dependence: Clinic Based Therapy in Israel Limor Goren, Ziv Carmel and Sergio Marchevsky
Memories Yossi Uziel In the picture are faces that are blurred, like memories whose reconstruction depends on the state of mind of the person recalling them. The identity of the faces remains mysterious and enigmatic, representing the idea that ultimately all is forgotten.
Isr J Psychiatry Relat Sci - Vol. 51 - No 4 (2014)
Editorial: Substance use and addictive disorders This special edition of the Israel Journal of Psychiatry and Related Sciences provides a focus on substance use disorders and addiction. While for most practicing psychiatrists issues pertaining to addiction may not be the preliminary focus of their work, it is nevertheless relevant to their daily practice. Substance use is widespread in the community across all social strata and even more so among psychiatric patients. Moreover, substance use affects the course of illness of many psychiatric disorders and has negative physical impact and consequences in a population which is already at-risk for physical morbidity. Addiction and other psychiatric disorders co-exist at high rates. Though local data is currently lacking, population-based studies from high-income countries indicate that up to 30% of individuals with psychiatric disorders have an additional drug or alcohol use disorder. Inversely, up to 40% of individuals with an alcohol use disorder and more than 50% of those with drug use disorders have an additional psychiatric diagnosis (1). These figures indicate that alongside high rates of substance use disorders, co-occurrence of psychiatric disorders and substance use disorders is extremely common. Unfortunately, from a systems standpoint, there is a crude disparity between general psychiatry and addiction. This is a result of a historical fallacy which patients still pay the price for. Almost five decades of scientific research emphasize the neurobiological basis of addiction (2), with clear indications that like other psychiatric disorders, disturbances in brain functioning manifest in human behavior. Though research has welldemonstrated that the most effective method of treating concurrent psychiatric disorders and substance use disorders (“Dual Diagnosis”) is in an integrative fashion, by the same group of therapists in the same facility, this is rarely the case. Most psychiatric facilities in Israel, both inpatient and particularly outpatient, do not have expert services for this population and most specialized services for addiction do not have standard psychiatric care as a basis for medical treatment. Publication of this special issue coincides, to an extent, with the long-awaited publication of the DSM 5. In the transition from DSM-IV-TR to DSM 5, the chapter title has been changed from “Substance-Related Disorders” to “Substance-Related and Addictive Disorders.” This 238
represents an expansion of addiction to include nonsubstance related behaviors. Currently, only Gambling Disorder is included under this diagnostic category, though additional behavioral addictions, such as Internet Gaming Disorder, have been included under section C (“to be studied further”) of DSM 5. In addition, the abolition of “abuse” and “dependence” in DSM 5 and the new diagnosis of “Substance Use Disorder” represent the understanding that these disorders exist on a continuum. Accordingly, in this special edition the reader will encounter different nomenclatures and terminologies, including “addiction,” “abuse,” “dependence,” “substance use disorders,” etc., a common rooted linguistic multitude in this field. This special edition contains contributions from leading psychiatrists working with substance use and addictive disorders in Israel. These include a wide breadth of substances and ages, sub-populations and concurrent psychiatric disorders. Dinur-Klein et al. (3) address the issue of tobacco dependence, the most common substance use disorder, with alarming high rates within the psychiatric population. Exploring the relationship between tobacco dependence and cognitive function is important in order to better understand the underlying mechanisms as a basis for potential effective interventions in this disorder. Another common substance use disorder, cannabis dependence, is addressed by Katz et al. (4). Their review focuses on cannabis withdrawal symptoms, which are a significant contributor to relapse, and acknowledged in DSM 5 for the first time. Peles et al. (5) report on rates of substance use among pregnant women hospitalized in a general hospital, a population commonly under-diagnosed for substance use disorders in the general medical system in critical phases of fetal development. A portion of manuscripts contributed to this special edition come from researchers and clinicians working in specialized addiction clinics. Peles et al. (6), a group with great experience in studying clinical populations of individuals receiving Methadone Maintenance Treatment (MMT), contribute a study on characteristics of cooccurring MMT and benzodiazepine use. Goren et al. (7) describe a clinical population of individuals treated with buprenorphine in a large private network of clinics in Israel.
Shaul Lev-Ran & Arturo G. Lerner
A number of studies published in this manuscript focus on specific clinical populations, particularly those with “dual diagnosis”: Feingold et al. (8) describe a clinical inpatient population of adolescents with previous alcohol abuse, indicating increased prevalence of Attention Deficit Hyperactivity Disorder and related behavioral problems; Delayahu et al. (9) compare clinical outcomes of coerced vs non-coerced inpatients from a dual diagnosis ward. Finally, Shlosberg et al. (10) provide a focused review on the association between substance use and suicidality in adolescence. From a clinical perspective, a number of case reports and series are included in this special edition. Lerner et al. describe various manifestations of Hallucinogen Persistent Perception Disorder (HPPD), providing both a thorough review of this interesting phenomena (11) as well as a number of relevant case reports (12, 13). The collection of papers included in this special edition not only provides an insight into the work conducted in Israel in the field of addiction and dual diagnosis, it provides an indicative snapshot of topics that advance our knowledge of substance use disorders and of the clinical significance of these disorders in psychiatry. The upcoming reform in mental health in Israel will unfortunately not include treatment of addiction, meaning that these disorders will continue to be treated in specialized centers for substance use disorders run by the Ministry of Health. Though treatment of Dual Diagnosis is planned to be transferred to the Health Maintenance Organizations (HMOs) (“Kupot Cholim”) precise definitions are still unclear. We believe the reform provides a historical opportunity to establish accessible integrative treatment facilities for individuals suffering with Dual Diagnosis. This should include all individuals with a psychiatric disorder across the broad spectrum of disorders (e.g., psychotic, mood, anxiety, personality, etc.) who additionally suffer from a substance use disorder. Providing these services through the HMOs will allow access to treatment to up to hundreds of thousands of people in Israel, and will be cost-effective in the long term. This is a rare opportunity to partially amend the long-standing historical split between these services, and it should not be missed. Indicating that substance use disorders are separate from general medicine and general psychiatry is not only contrary to all available research, it further stigmatizes and marginalizes a very large population suffering from these disorders. We believe inclusion of this
field in general psychiatry is critical, allowing educating clinicians from the medical-school level, through training during residency programs and finally through subspecializing in the field. We hope this special edition will serve as part of this process. References 1. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990;264:2511-2518. Epub 1990/11/21. 2. Leshner AI. Addiction is a brain disease, and it matters. Science 1997; 278:45-47. Epub 1997/10/06. 3. Dinur-Klein L, Kertzman S, Rosenberg O, Kotler M, Zangen A, Dannon PN. Response inhibition and sustained attention in heavy smokers versus non-smokers. Isr J Psychiatry Relat Sci 2014;51:240-247. 4. Katz G, Lobel T, Tetelbaum A, Raskin S. Cannabis withdrawal symptoms – a new diagnostic category in DSM-5. Isr J Psychiatry Relat Sci 2014;51: 270-276. 5. Peles E, Sason A, Bloch M, Maslovitz S, Dolberg S, Many A, et al. The prevalence of alcohol, substance and cigarettes exposure among pregnant women within a general hospital and the compliance to brief intervention for exposure reduction. Isr J Psychiatry Relat Sci 2014;51:248-257. 6. Peles E, Adelson M, Shreiber S. Benzodiazine age during 19.5 years in methadone maintenance treatment patients and its relation to longterm outcoms. Isr J Psychiatry Relat Sci 2014;51:285-289. 7. Goren L, Carmel Z, Marchevsky S. Buprenorphine for opiate dependence: Clinic based therapy in Israel. Isr J Psychiatry Relat Sci 2014;51:281-284. 8. Feingold D, Nitzan U, Ratzoni G, Lev-Ran S. Clinical correlates of alcohol abuse among adolescent psychiatric inpatients in Israel. Isr J Psychiatry Relat Sci 2014;51:258-261. 9. Delayahu Y, Nehama Y, Sagi A, Baruch Y, Blass DM. Clinical Outcomes in hospitalized dual diagnosis patients with emphasis on coercion. Isr J Psychiatry Relat Sci 2014;51:290-295. 10. Shlosberg D, Zalsman G, Shoval G. Emerging issues in the relationship between adolescent substance abuse and suicidal behavior. Isr J Psychiatry Relat Sci 2014;51:262-269. 11. Lerner AG, Rudinski D, Bor O, Goodman C. Flashbacks and HPPD: A clinical-oriented concise review. Isr J Psychiatry Relat Sci 2014;51:296-302. 12. Lerner AG, Goodman C, Bor O, Lev-Ran S. Synthetic Cannabis Substances (SPS) use and Hallucinogen Persisting Perception Disorder (HPPD): Two case reports. Isr J Psychiatry Relat Sci 2014;51:277-280. 13. Lerner AG, Goodman C, Rudinski D, Lev-Ran S. LSD flashbacks – the appearance of new visual imagery not experienced during initial intoxication: Two case reports. Isr J Psychiatry Relat Sci 2014;51:307-309.
Shaul Lev-Ran Addiction Medicine and Dual Diagnosis Services, Department of Psychiatry, Sheba Medical Center shauli.levran@gmail.com
Arturo G. Lerner Dual Diagnosis Ward, Lev Hasharon Mental Health Center alerner@lev-hasharon.co.il
Guest editors
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Isr J Psychiatry Relat Sci - Vol. 51 - No 4 (2014)
Response inhibition and sustained and attention in Heavy smokers versus non-smokers Limor Dinur-Klein, MSc,1 Semion Kertzman, MD,1 Oded Rosenberg, MD,1 Moshe Kotler, MD,1 Abraham Zangen, PhD,2 and Pinhas N. Dannon, MD1 1
Beer Yaakov Mental Health Center affiliated with Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Ben-Gurion University of the Negev, Beersheva, Israel
2
Abstract Background: Repeated nicotine administration induces neuro-adaptations associated with abnormal dopaminergic activity. These neuronal changes may contribute to impaired inhibitory control and attention deficit. However, it remains unclear whether smokers perform worse than non-smokers on tests that involve attention and control of impulsivity. The present study examined response inhibition and sustained attention capacities in a large sample of smokers and non-smokers. Methods: Continuous Performance Test (CPT) and Go/ NoGo computerized tasks were used as a measure of response-inhibition ability and sustained attention. Threeway repeated measures analysis of covariance was used with response time, variability of response time, number of commission errors (inappropriate responses to stimuli) and number of omission errors (missed stimuli) as dependent measures. Main effects were: group (smokers and controls), condition (CPT and Go/NoGo), and block (in each condition); gender, education, and age were used as covariates. Results and Conclusions: Smokers, as compared to the control group, made more errors of commission in the Go/ NoGo task, reflecting impaired inhibition ability. However, we found no significant differences between the groups in our measure of sustained attention. Impaired response inhibition was found to co-occur with heavy smoking and therefore may be a potential target for the development of more effective cessation programs.
Background Tobacco smoking is one of the leading causes of preventable death in the world (1). Tobacco use not only kills approximately 440,000 Americans each year, it also causes serious health problems in the population. According to national surveys, an estimated 70.9 million Americans aged 12 or older reported current use of tobacco (2). Chronic smoking is not merely a destructive habit, but is also widely accepted as an addiction. Most chronic smokers use tobacco because they are addicted to nicotine (2). Addiction to nicotine can be described as a persistent state in which there is diminished capacity to control compulsive drug-seeking, regardless of whether it involves risk of negative consequences (3). In order to improve characterization and treatment of this debilitating addiction, clinicians and researchers are interested in identifying behavioral patterns that may either contribute to or co-occur with smoking (4). The subjective and physiological effects of smoking are caused by the central actions of nicotine (5), the primary constitute of tobacco. The effects of nicotine on neurocognitive function have long been held to play a role in nicotine dependence. Previous studies hypothesized that smoking may be used as a form of self-medication due to beneficial acute effects of nicotine on cognitive functioning. Nicotine has been shown to facilitate sustained attention and inhibitory control (6-9). In a prospective study, poor sustained attention and low inhibition predicted adolescent smoking (10). Nicotine has been shown to enhance visuospatial and sustain attention in both smokers and non-smokers (11-15). Nicotine has also been found to reduce omission errors and response time variability in a continuous performance test (CPT) (16) which assesses the ability to sustain attention (17). In contrast to the findings reporting beneficial acute effects of nicotine, long-term use of nicotine has been associ-
Address for Correspondence: Limor Dinur-Klein, MSc, Beer Yaakov Mental Health Center, POB 1, Beer Yaakov 70350,   Limor.klein@beerness.health.gov.il, limordinur@gmail.com
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Limor Dinur-Klein et al.
ated with poorer performance on a variety of neurocognitive tests (independent of gender, alcohol consumption, baseline cognitive function, age, occupational class and education) (18-20). Repeated nicotine administration induces neuroadaptations associated with abnormal dopaminergic activity in the mesocorticolimbic circuitry, resulting in altered cortical neurotransmission and excitability (21). Altered baseline dopamine levels in addicted individuals may contribute to the often-observed elevation of impulsivity in these populations and may contribute to other dopaminergic abnormalities such as attention deficit (22). To date, several studies have demonstrated higher impulsivity in smokers; however, it is unclear if impulsivity is a consequence of drug use or a risk factor in the development of nicotine dependence. Impulsivity is traditionally defined as acting suddenly and without a plan to satisfy an immediate desire and consists of multiple faces, including risky decision making, response inhibition, and delay-reward discounting (23). Two types of behavioral measures are primarily used to examine impulsivity in humans and animals; Go/NoGo tasks to assess response inhibition and relative preference tasks to assess delay aversion (20). Current literature reported a number of studies measuring delay discounting, in which impulsivity was higher among adult smokers versus non-smokers (24-26). However, the results of studies on response inhibition in smokers have been inconsistent. That is, some studies have found response inhibition during a Go/NoGo task to be impaired in smokers relative to controls (27, 28), whereas other studies did not find this group difference in performance on the Go/NoGo task (29), or on other behavioral tasks measuring response inhibition (30). This inconclusive pattern of results goes beyond impulsivity measures to another critical cognitive domain. Using several attentional tasks under drug-free condition several authors reported no significant performance differences between smokers and non-smokers (3133). Nevertheless, two other studies, based on a young population, report significant performance decrements in smokers compared to non-smokers (28, 34). All in all there seems to be paucity of large sample comparative research reporting performance in cognitive tasks addressing the psychological constructs of impulsivity and sustained attention in chronic heavy smokers. The purpose of this study is to identify behavioral patterns that co-occur with heavy smoking and, therefore, may be potential targets for the development of more effective cessation programs. Our study was designed to compare performance on the CPT and the Go/NoGo task on a
large cohort of non-deprived, heavy smokers versus a group of non-smokers controls. We hypothesized smokers to show worse performance accounted for by both predate neurocognitive characteristics influencing maintenance of smoking, and long-term negative effects of nicotine. Methods Subjects
One hundred fourteen males and females who smoke at least 20 cigarettes per day were included in our study. Subjects were recruited from the general population by advertisement for a clinical trial of smoking cessation intervention and will be the focus of future publications. Exclusion criteria included any psychiatric or neurological disorder, any psychotropic medications, current alcohol dependence or any substance abuse except nicotine, history of significant brain malformation or neoplasm, head injury, cerebral vascular events or prior brain surgery. The study was approved by the Helsinki committee of Beer Yaakov Mental Health Center and the Israeli Ministry of Health. All subjects signed an informed consent. Subjects underwent a clinical interview including full demographics, medical history, and smoking habits information. The computerized neurocognitive test that is the focus of the present report was implemented after the interview and before any intervention. Subjects smoked their last cigarettes prior to the beginning of the testing session within one hour of commencement. The control group included 68 healthy volunteers who were recruited from non-smoking medical personnel and healthy volunteers. The project was approved by the Helsinki Committee of Beer Yaakov Mental Health Center and all subjects gave written informed consent. Inclusion criteria were no current or history of smoking. Exclusion criteria for the control group were the same as for the smokers group. Neuropsychological Assessment
The Go/NoGo task primarily reflects the ability to suppress a very potent (but not yet initiated) response. It has been previously reported that Go/NoGo performance is multidimensional, reflecting various inter-related cognitive and emotional functions (35). In order to investigate pure response-inhibition deficits, we used a simple situation and controlled for confounding factors. We applied a computerized special task that included both the CPT and the go/no-go (AnimaScan Ltd, Ashdod, Israel, 2000) as described herein and previously (28, 36, 37). 241
inhibition and sustained attention in heavy smokers versus non-smokers Isr J PsychiatryResponse Relat Sci - Vol. 51 - No 4 (2014)
Task description
Subjects were requested to respond to red squares (Go event) by immediate button press, but to withhold responses to black squares (NoGo event). To ensure comprehension of the task instructions, participants carried out a practice with 30 stimuli that familiarized them with the task. Also, they were given feedback at the end of the practice session, showing their accuracy of performance. Subjects were trained until they achieved a 100% correct performance level. All stimuli were briefly displayed in random order, against a white background centrally on the computer screen, 100 ms each, at a rate of one stimulus per 2000 ms. A total of 300 stimuli were divided into two successive conditions, each of which contained 150 stimuli. The CPT is a condition with frequent (80%) NoGo events and the subjects were instructed to detect and generate a response to rare Go stimuli (20% frequency). The Go/NoGo is a condition with frequent go (80%) events, and the subjects were instructed to withhold responding to rare NoGo stimuli (20%). The whole experimental task lasts for 10 min, and each condition (either CPT or Go/NoGo) continues for 5 min without a pause between them. The performance of each patient is measured during two blocks in each condition [the CPT condition includes both block 1 (75 stimuli) and block 2 (76–150 stimuli); the Go/NoGo condition includes both block 3 (151–225 stimuli) and block 4 (226–300 stimuli)]. The order of task conditions was constant for each examinee. It was found that this specific construction of the task might help to investigate the inhibition ability in situations involving performance shifting (38, 39) from rare Go stimuli (as in the CPT) to frequent go events (in the Go/NoGo). Task measures
Errors of commission occur when the subject incorrectly responds to black squares; such a response is considered to be a measure of impulsivity. Errors of omission occur when the subject omits pressing the button when a red square appears; such a response is considered to be a measure of inattention. Reaction times to Go events were computed for trials in which the participants responded within 2100 ms of stimulus onset. Failures to respond to a Go event within a period of more than 2100 ms of stimulus onset or implausibly early, i.e., less than 250 ms after red stimuli onset were considered errors of omission. Errors of commission were defined as responses that occurred within 2100 ms of a NoGo stimulus onset. Slow response time or variable response time may be a consequence of 242
distraction by external or internal stimuli resulting in fluctuations in processing speed throughout the task. Performance is measured by both speed and accuracy and the speed-accuracy tradeoff may help to elucidate the impairment of inhibitory function during the task performance. Quick and inaccurate responses may point to an impulsive behavior whereas slow and inaccurate responses may occur due to a lapse in attention. Data Analysis
Data was analyzed using SAS 9.2. T-test, Mann Whitney or X2 were used to compare between smokers and controls on demographic characteristics. Three-way repeated measures ANCOVA was used to evaluate differences between smokers and controls in task performance (omissions, commissions, RT, and RT variability). Main effects were group (smokers and controls), condition (CPT and Go/ NoGo), and block (1-4). Gender, education, and age were used as covariates. Spearman correlations were calculated between response time and errors of omission and errors of commission, correcting for gender, education, and age, in order to examine differences between groups in speedaccuracy trade-off characteristics in each group. Spearman correlations were calculated between errors of omission and errors of commission to distinguish between “attention” and “inhibition” within the study population. Preplanned pairwise comparisons were examined by contrast t-tests. Results Study Population
Table 1 presents descriptive statistics for each study group. Since group differences were present, age, gender, and education were entered as covariate in all analyses. Table 1. Descriptive statistics of smokers and controls Study group Measure
Smokers
Controls
Statistic†
Gender (male/female)
(73/49)
(50/18)
X2=3.58 p=0.058
Age (mean ± STD)
50.1±10.88
37.2±9.36
P<0.0001
Education1 (median)
2
3
P<0.0001
Cigarettes/ Day
29±10.3
NR
Pack Years (mean ± STD)
45±22.7
NR
FTND2 (mean ± STD)
7±1.69
NR
†Chi-square / t-test / Mann-Whitney; 11:Primary education, 2:High-school education, 3:Academic education; 2 Fagerström Test for Nicotine Dependence (n=99)
Limor Dinur-Klein et al.
Fig 1. Adjusted means (and standard errors) of performance on the CPT and the Go/no-go in smokers and controls
Mean reaction time (a), reaction time variability (b), number of commissions (c) and number of omissions (d) (with standard errors) in the CPT task (blocks 1,2) and the Go/NoGo task (blocks 3,4) in smokers compared with controls. All means adjusted for age, gender and education.
Response Time
Mean reaction time was not significantly different between smokers and control (F(1,166)=0.4, p=0.52) (Table 2 and Fig. 1a). However, there was a significant main effect of condition (F(1,510)=123.16, p<0.0001) and block (F(1,510)=15.53, p<0.0001), reflecting a shorter reaction time on the Go/ NoGo task compared with the CPT task and a significant decrease in response time between the second and the first block on each condition.
Significant interactions between group and block (F(1,510)=5.39, p=0.02) and between group and condition (F(1,510)=5.28, p=0.022) were found. Pairwise comparisons revealed a significantly shorter response time for both smokers and controls on the Go/NoGo task compared with the CPT task (t(510)=7.51. p<0.001 and t(510)=8.26, p<0.001 respectively). However, only the control group showed decreased response time between the second and the first block on the Go/NoGo task (t (510)=2.89, p=0.004).
Table 2. Adjusted means (and standard errors) of performance on the CPT and the Go/NoGo in smokers and controls: CPT
Go/NoGo
Test measures
Group
Block1
Block2
Block3
Block4
Reaction time
Smokers
429.01 (15.77)
415.38 (14.98)
372.22 (14.72)
372.6 (14.3)
Controls
462.39 (21.01)
432.41 (19.87)
382.28 (19.5)
360.94 (18.95)
Smokers
79.4 (7.47)
68.83 (7.35)
80.73 (7.35)
81.61 (7.24)
Controls
78.08 (9.9)
73.35 (9.74)
78.48 (9.74)
82.35 (9.59)
Smokers
0.62 (0.11)
0.358 (0.09)
1.64 (0.2)
1.76 (0.15)
Controls
0.35 (0.15)
0.23 (0.13)
0.8 (0.27)
1.18 (0.21)
Smokers
0.1 (0.21)
0.16 (0.24)
1.27 (0.8)
1.72 (1.06)
Controls
0.35 (0.28)
0.94 (0.32)
4.15 (1.11)
5.86 (1.47)
Reaction time variability Errors of commission Errors of omission
F
P
0.41
0.524
0.04
0.96
8.34
0.004*
6.57
0.01*
243
inhibition and sustained attention in heavy smokers versus non-smokers Isr J PsychiatryResponse Relat Sci - Vol. 51 - No 4 (2014)
Variability of Response Time
Variability of reaction time was not statistically different between groups (F(1,166)=0.04, p=0.96) (Table 2 and Fig. 1b). There were no significant main effect of block or for the interactions between group and block and between group and condition. However, there was a significant main effect of condition (F(1,510)=6.05, p=0.01) and a significant interaction between block and condition (F(1,510)=4.97, p=0.02), resulting from a higher variability of the response time in the Go/NoGo task compared with the CPT task. Pairwise comparisons highlighted that there was less variability on the second block of the CPT t(510)=2.26, p=0.02), but no such difference between blocks emerged on the Go/NoGo task. Errors of Commission
The smokers group showed significantly more errors of commissions (F(1,166)=8.34, p=0.004) (Table 2 and Fig. 1c). The interaction between group and condition was significant (F(1,510)=4.79, p=0.029). Pairwise comparisons revealed significantly more errors of commission for the smokers in the Go/NoGo task (t(510)=2.93, p=0.0036) but not in the CPT task (t(510)=1.5, p=0.138). Errors of commission in the Go/NoGo task compared with the CPT task were higher in both groups. The main effect of condition was significant (F(1,510)=67.88, p<0.0001). There was no significant main effect of block and no interaction between group and block. A significant interaction of block with condition (F(1,510)=7.19, p=0.0076), showing a significant decrease in errors of commission for the second block on CPT performance t(510)=2.53, p=0.011) and a non significant increase in errors of commission for the second block on Go/NoGo performance, was present.
group and condition was significant (F(1,510) =4.38, p=0.0369). Pairwise comparisons revealed significantly fewer errors of omission for the smokers in the Go/ NoGo task (t(510)=2.39, p=0.017) but not in the CPT task, although marginally significant (t(510)=1.68, p=0.09). Mean errors of omission in the Go/NoGo task compared with the CPT task was higher in both groups (F(1,510)=15.98, P<0.0001). There was a significant main effect of block (F(1,510)=4.45, p=0.35), showing an increase of errors of omission from the first to the second block on each condition (on the CPT t(510)=3.06, p=0.002; on the Go/NoGo t(510)=1.68, p=0.09). No interaction between group and block and no interaction of block with condition were found. Speed Accuracy Tradeoff
The correlations between number of commissions and reaction time in the Go/NoGo task (on the second block) were different in smokers compared to controls (Table 3). The number of commissions in the Go/NoGo task was negatively correlated with reaction time in both groups on the first block. However, negative correlation was found only in the smokers on the second block. On the CPT task, no correlations were found in both groups. The correlations between number of omissions and mean reaction time in the CPT task (on the second block) were different in the smokers compared to controls. The number of omissions in the CPT task was positively correlated with reaction time in both groups on the first block. However, positive correlation was found on the second block only in smokers. On the Go/NoGo task, no significant correlations were found in both groups (Table 4). Dissociating Sustained Attention and Response Inhibition
The smokers group showed fewer errors of omission. The main effect of group was significant (F(1,166)=6.57, p=0.01). (Table 2 and Fig. 1d) The interaction between
No correlations were found between errors of omission and errors of commission in all blocks in both groups (data not shown), with the exception of block 2 of the CPT in smokers r= 0,29 ; p=0.001. No cross correlations were seen between errors of omission in the CPT
Table 3. Spearman correlations between errors of commission and reaction time in smokers and in controls:
Table 4. Spearman correlations between errors of omission and reaction time in smokers and in controls:
Errors of Omission
Smokers CPT Go/NoGo
244
Controls
Block1
-0.12 (0.2)
0.0008 (0.99)
Block2
-0.04 (0.63)
-0.04 (0.73)
Block3
-0.32 (0.0005)*
-0.288 (0.03)*
Block4
-0.376 (P<0.0001)*
-0.132 (0.33)
CPT Go/NoGo
Smokers
Controls
Block1
0.268 (0.0046)*
0.27 (0.04)*
Block2
0.33 (0.0003)*
-0.047 (0.72)
Block3
0.031 (0.747)
-0.177 (0.19)
Block4
-0.08 (0.389)
-0.18 (0.172)
Limor Dinur-Klein et al.
compared with errors of commission in the Go/NoGo (data not shown). Discussion Our study explored smokers/non-smokers differences in the CPT and Go/NoGo tasks and tested the hypothesis that heavy smokers manifest impairments of sustained attention and response inhibition. Response Inhibition Ability
The Go/NoGo tasks require ability to withhold a response to NoGo stimuli. In this task, the less probable occurrence of NoGo events enhances an expectation that the following stimulus will be a Go stimulus, thereby promoting a tendency toward making a rapid response to Go stimuli. Therefore, this design provides a useful test for evaluation of response inhibition control and action monitoring (40), in which wrong response to the NoGo stimuli (commission error) is assumed to reflect impaired response inhibition ability (41-43). Our results demonstrate that smokers made more commission errors and less omission errors than controls in the Go/NoGo task. Researchers most commonly use errors of commission as indicators of impulsive responding. However, there is a support of using the omission errors as an indication of impulsivity as well. Yechiam et al., in a cognitive analysis of the Go/No-Go task have indicated that a lack of behavioral inhibition is demonstrated by both high rates of commission errors and low rates of omission errors (44). Their results demonstrated that attention to gains is positively associated with commission errors and negatively associated with omission errors. This attentional bias is characteristic of impulsivity (45). In lines with our impulsivity hypothesis we expected smokers to show shorter RT since the time required to respond to a stimulus in impulsive subjects should be shorter (46). Contrary to our expectation, results revealed no group differences in response time or in response time variability in the Go/NoGo task. However, we found a significant negative correlation between errors of commission and reaction time in smokers. Controls exhibited this pattern only in the first Go/NoGo block, that show significant differences in strategy of building speed – accuracy tradeoff. Smokers show fast-inaccurate response style which was found previously as specific for impulsivity concept (47). The speed-accuracy tradeoff may help to elucidate the impairment of inhibitory function during the task
performance (48). Theoretically, impulsive persons would prefer a quick, automatic selection of stimuli for responses without monitoring (49). The commission error is ignored, and the speed of performance is stressed at the expense of accuracy. Therefore, the negative correlation between number of commission errors and response time demonstrate an expression of impulsive reactions. The difference between smokers and controls only in the second block may indicate that smokers’ impulsivity may become prominent over time. Our results are similar to the findings of Yakir et al. (28) and Spinella (27) but in contrast to Dinn et al. (29) and Reynolds et al. (30) who didn’t find impairment in response inhibition. These discrepancies may be related to the differences in terms of sample size (23 smokers or 25 smokers, accordingly), age of subjects (mean of 18.6±1.17 or 14-18, accordingly), and substance intake (average of 5.8 or 8 cigarettes per day, accordingly). It seems feasible that significant neuroadaptations and consequent behavioral changes become evident only in later stages of more substantial nicotine consumption. However, the cross sectional design of our study and of previous studies does not directly address the key issue of whether disinhibition is a consequence of chronic use of nicotine or a risk factor in the development of nicotine dependence. Sustained Attention
The study results demonstrate that smokers made a lower number of errors of omission than controls in the Go/NoGo condition. By contrast, difference in omission errors rate was not observed in the CPT task. The CPT task generally requires the ability to detect and respond to the rare Go stimuli, and missing of the Go stimuli (omission errors) is considered a measure of low vigilance /inattention (40). We expected smokers to manifest impairments of sustained attention and, therefore, to show slower RT and higher RT variability in the CPT. Response time to target stimuli is considered a measure of alertness (50). Slow or variable response time may be a consequence of distraction by external or internal stimuli resulting in fluctuations in processing speed throughout the task. Children with ADHD have been found to have slower response time to target stimuli than normal control in several studies (50). High variability of response time has been described for groups with traumatic brain injury or attention-deficit/hyperactivity disorder (ADHD) and associated with lapses of sustained attention and low level of vigilance (51-53). In our sample, the results did not show higher RT variability or slower RT in smokers 245
inhibition and sustained attention in heavy smokers versus non-smokers Isr J PsychiatryResponse Relat Sci - Vol. 51 - No 4 (2014)
therefore suggesting that smokers do not show impairment in sustained attention. In our population, smokers did not differ from nonsmokers in performance on CPT that assess sustained attention. These findings were in accordance with previous studies (31-33). We extend these previous results, by using a large sample and including a group of older and heavier smokers. Our results are not concordant to some previous findings (28, 34). For example in Foulds et al. (34) smokers were required to abstain from tobacco use 24 hours before the CPT was conducted and, therefore, the difference between smokers and non-smokers could be mainly attributed to the nicotine-withdrawal effect. In Yakir et al. (28) authors reported a diminished sustained attention in young female participants. Discrepancies in results may be attributed to sex-related differences in smoking populations. Another possibility, as the authors suggested, is that the results of the CPT, which was applied last, were confounded when nicotine levels among the smokers had started to decline (28). In contrast to our expectation, the result of our study suggested no negative long-term effects of nicotine on sustained attention. Conclusions The major finding of our study is that heavy smokers, as compared to the control group, show high rate of commission errors in the Go/NoGo task than controls, reflecting impaired inhibition ability. In addition, in contradiction to our hypothesis, smokers did not show higher rate of omission errors on the CPT task than controls, reflecting no differences in sustained attention. Although our study was limited to a cross-sectional study of neurocognitive functions, our findings give indirect evidence that impaired motor response inhibition ability (as measured by the Go/NoGo task) may be associated with the maintenance of smoking. A future neuropsychological prospective cohort study that follows smokers over time may help to clarify the particular brain mechanisms underlying impaired Go/ NoGo performance in smokers. Limitations Several limitations need to be taken into account when considering the patterns obtained here. First, the selection of the study population to include a treatment-seeking population for the smokers group did not match the controls in 246
terms of age, gender and education. Nevertheless it seems implausible the relatively small age and education differences in these factors alone would account for such varied cognitive profile. Second, smoking and/or nicotine levels were not assessed by objective biological means, which could have influenced the results in two ways - a better performance among smokers who experienced high nicotine blood level and/or a worse performance among smokers who experienced low nicotine blood levels. Moreover, secondhand smoking among non-smokers was not assessed subjectively or objectively, and could have influenced performance in the non-smokers group if it exists. Declaration of interests This study is a part of first authorâ&#x20AC;&#x2122;s PhD program, Limor Dinur-Klein receives scholarship from Tel Aviv University. Dr. Kertzman is a share-holder in the Animascan which produces the neurocognitive tests battery. Dr. Rosenberg is the employee of Research Department Beer Yaakov Mental Health Center. Ms Dinur-Klein, Dr. Rosenberg, Profs. Kotler, Zangen & Dannon have no financial interests in the study
References 1. World Health Organization: WHO report on the global tobacco epidemic. Geneva, 2013. 2. National Institute on Drug Abuse: Research Report Series: Tobacco Addiction. Bethesda, Maryland, 2009. 3. Hyman SE, Malenka RC. Addiction and the brain: The neurobiology of compulsion and its persistence. Nat Rev Neurosci 2001; 2: 695-703. 4. Gilbert DG, Crauthers DM, Mooney DK, McClernon JF, Jensen RA. Effects of monetary contingencies on smoking relapse: Influences of trait depression, personality, and habitual nicotine intake. Exp Clin Psychopharmacol 1999; 7: 174-181. 5. Jarvik ME, Madsen DC, Olmstead RE, Iwamoto-Schaap PN, Elins JL, Benowitz NL. Nicotine blood levels and subjective craving for cigarettes. Pharmacol Biochem Behav 2000; 66: 553-558. 6. Newhouse PA, Potter A, Singh A. Effects of nicotine stimulation on cognitive performance. Curr Opin Pharmacol 2004; 4: 36-46. 7. Rezvani AH, Levin ED. Cognitive effects of nicotine. Biol Psychiatry 2001; 49: 258-267. 8. Dawkins L, Powell JH, West R, Powell J, Pickering A. A double-blind placebo-controlled experimental study of nicotine: IIâ&#x20AC;&#x201D;Effects on response inhibition and executive functioning. Psychopharmacology (Berl) 2007; 190: 457-467. 9. Larrison AL, Briand KA, Sereno AB. Nicotine improves antisaccade task performance without affecting prosaccades. Hum Psychopharmacol 2004; 19: 409-419. 10. Harakeh Z, de Sonneville L, van den Eijnden RM, Huizink AC, Reijneveld SA, Ormel J, Vollebergh WM. The association between neurocognitive functioning and smoking in adolescence: The TRAILS study. Neuropsychology 2012; 26: 541-550. 11. Thiel CM, Zilles K, Fink GR. Nicotine modulates reorienting of visuospatial attention and neural activity in human parietal cortex. Neuropsychopharmacology 2005; 30: 810-820. 12. Thiel CM, Fink GR. Effects of the cholinergic agonist nicotine on reorienting of visual spatial attention and top-down attentional control. Neuroscience 2008; 152: 381-390. 13. Vossel S, Thiel CM, Fink GR. Behavioral and neural effects of nicotine on visuospatial attentional reorienting in non-smoking subjects. Neuropsychopharmacology 2008; 33: 731-738.
Limor Dinur-Klein et al.
14. Murphy FC, Klein RM. The effects of nicotine on spatial and nonspatial expectancies in a covert orienting task. Neuropsychologia 1998; 36:1103-1114. 15. Witte EA, Davidson MC, Marrocco RT. Effects of altering brain cholinergic activity on covert orienting of attention: Comparison of monkey and human performance. Psychopharmacology (Berl) 1997; 132: 324-334. 16. Levin ED, Conners CK, Silva D, Hinton SC, Meck WH, March J, Rose JE. Transdermal nicotine effects on attention. Psychopharmacology (Berl) 1998; 140: 135-141. 17. Heishman SJ, Kleykamp BA, Singleton EG. Meta-analysis of the acute effects of nicotine and smoking on human performance. Psychopharmacology (Berl) 2010; 210: 453-469. 18. Hill RD, Nilsson LG, Nyberg L, B채ckman L. Cigarette smoking and cognitive performance. Age Ageing 2003; 32: 548-550. 19. Crevilla JA, Prince M, Mann A. Smoking drinking and incident cognitive impairment: A cohort community based study included in the Gospel Oak project. J. Neurol. Neurosurg. Psychiatry 2000; 68: 622-626. 20. Mitchell SH. Measuring impulsivity and modeling its association with cigarette smoking. Behav Cogn Neurosci Rev 2004; 3: 261-275. 21. Feil J, Zangen A. Brain stimulation in the study and treatment of addiction. Neurosci Biobehav Rev 2010; 34: 559-74. 22. Luijten M, Veltman DJ, Hester R, Smits M, Nijs IM, Pepplinkhuizen L, Franken IH. The role of dopamine in inhibitory control in smokers and non-smokers: A pharmacological fMRI study. Eur Neuropsychopharmacol 2013; 23:1247-1256. 23. Moallem NR, Ray LA. Dimensions of impulsivity among heavy drinkers, smokers, and heavy drinking smokers: Singular and combined effects. Addict Behav 2012; 37: 871-874. 24. Bickel WK, Odum AL, Madden GJ. Impulsivity and cigarette smoking: Delay discounting in current, never, and ex-smokers. Psychopharmacology 1999; 146: 447-454. 25. Heyman G, Gibb S. Delay discounting in college cigarette chippers. Behav Pharmacol 2006; 17: 669-679. 26. Reynolds B, Richards JB, Horn K, Karraker K. Delay discounting and probability discounting as related to cigarette smoking status in adults. Behav Processes 2004; 65: 35-42. 27. Spinella M. Correlations between orbitofrontal dysfunction and tobacco smoking. Addict Biol 2002; 7: 381-384. 28. Yakir A, Rigbi A, Kanyas K, Pollak Y, Kahana G, Karni O, Eitan R, Kertzman S. Lerer B. Why do young women smoke? III. Attention and impulsivity as neurocognitive predisposing factors. Eur Neuropsychopharmacol 2007; 17: 339-351. 29. Dinn WM, Aycicegi A, Harris CL. Cigarette smoking in a student sample. Neurocognitive and clinical correlates. Addict Behav 2004; 29: 107-126. 30. Reynolds B, Patak M, Shroff P, Penfold RB, Melanko S, Duhig AM. Laboratory and self-report assessments of impulsive behavior in adolescent daily smokers and nonsmokers. Exp Clin Psychopharmacol 2007; 15: 264-271. 31. Hahn B, Ross TJ, Yang Y, Kim I, Huestis MA, Stein EA. Nicotine enhances visuospatial attention by deactivating areas of the resting brain default network. J Neurosci 2007; 27: 3477-3489. 32. Hahn B, Ross TJ, Wolkenberg FA, Shakleya M, Huestis MA, Stein EA. Performance effects of nicotine during selective attention, divided attention, and simple stimulus detection: An fMRI study. Cereb Cortex 2009; 19: 1990-2000. 33. Lawrence NS, Ross TJ, Stein EA. Cognitive mechanisms of nicotine on
visual attention. Neuron 2002; 36: 539-548. 34. Foulds J, Stapelton J, Swettenham J, Bell N, McSorley K, Russell MA. Cognitive performance effects of subcutaneous nicotine in smokers and never smokers. Psychopharmacology (Berl) 1996; 127: 31-38. 35. Erickson K, Drevets WC, Clark L, Cannon DM, Bain EE, Zarate CA, Charney DS, Sahakian BJ. Mood congruent bias in affective go/no-go performance of unmedicated patients with major depressive disorder. Am J Psychiatry 2005; 162: 2171-2173. 36. Kertzman S, Lowengrub K, Aizer A, Vainder M, Kotler M, Dannon PN. Go-NoGo performance in pathological gamblers. Psychiatry Res 2008; 161: 1-10. 37. Rigbi A, Kanyas K, Yakir A, Greenbaum L, Pollak Y, Ben-Asher E, Lancet D, Kertzman S, Lerer B. Why do young women smoke? V. Role of direct and interactive effects of nicotinic cholinergic receptor gene variation on neurocognitive function. Genes Brain Behav 2008; 7: 164-172. 38. Koch I, Philipp AM. Effects of response selection on the task repetition benefit in task switching. Mem Cognit 2005; 33: 624-634. 39. Milan EG, Gonzalez A, Sanabria D, Pereda A, Hochel M. The nature of residual cost in regular switch response factors. Acta Psychol (Amst) 2006; 122: 45-57. 40. Menon V, Adleman NE, White CD, Glover GH, Reiss AL. Error-related brain activation during a go/no-go response inhibition task. Hum Brain Mapp 2001; 12: 131-143. 41. Rubia K, Russell T, Overmeyer S, Brammer MJ, Bullmore ET, Sharma, T, Simmons A, Williams SC, Giampietro V, Andrew CM, Taylor E. Mapping motor inhibition: Conjunctive brain activations across different versions of go/no-go and stop tasks. Neuroimage 2001; 13: 250-261. 42. Berwid OG, Curko Kera EA, Marks DJ, Santra A, Bender HA, Halperin, JM. Sustained attention and response inhibition in young children at risk for attention deficit/hyperactivity disorder. J Child Psychol Psychiatry 2005; 46: 1219-1229. 43. Spreen O, Strauss E. A compendium of neuropsychological tests. New York: Oxford University, 1998. 44. Yechiam E, Goodnight J, Bates JE, Busemeyer JR, Dodge KA. A formal cognitive model of the go/no-go discrimination task. Evaluation and implications. Psychol Assess 2006; 18: 239-249. 45. Tullett AM, Inzlicht M. The voice of self-control: Blocking the inner voice increases impulsive responding. Acta Psychologica 2010; 135: 252-256. 46. Moeller FG, Barratt ES, Dougherty DM, Schmitz JM, Swann AC. Psychiatric aspects of impulsivity. Am J Psychiatry 2001; 158: 1783-1793. 47. Barratt ES. The biological basis of impulsiveness. The significance of timing and rhythm disorders. Pers Individ Dif 1983; 4: 387-391. 48. Glickman ME, Gray JR, Morales CJ. Combining speed and accuracy to assess error-free cognitive process. Psychometrika 2005; 70: 405-425. 49. Tzelgov J, Porat Z, Henik A. Automaticity and consciousness: Is perceiving the word necessary for reading it?. Am J Psychol 1997; 110: 429-448. 50. Farrow M, Levy F, Silberstein R. Neurobiology of ADHD. In: Stough C, editor. Neurobiology of exceptionality. New York: Springer, 2005: pp. 143-197. 51. Arcia E, Gualtieri CT. Neurobehavioural performance of adults with closed-head injury, adults with attention deficit, and controls. Brain Inj 1994; 8: 395-404. 52. Collins LF, Long CJ. Visual reaction time and its relationship to neuropsychological test performance. Arch Clin Neuropsychol 1996; 11: 613-623. 53. Lezak MD. Neuropsychological assessment, 3rd ed. Oxford: Oxford University, 1995.
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Isr J Psychiatry Relat Sci - Vol. 51 - No 4 (2014)
The Prevalence of Alcohol, Substance and Cigarettes Exposure among Pregnant Women within a General Hospital and the Compliance to Brief Intervention for Exposure Reduction Einat Peles, PhD,1 Anat Sason, BA,1 Miki Bloch, MD,2 Sharon Maslovitz, MD,3 Shaul Dollberg, MD,4 Ariel Many, MD,3 Michael J. Kuperminc, MD,3 and Miriam Adelson, MD1 1
Dr. Miriam & Sheldon G. Adelson Clinic for Drug Abuse, Treatment & Research, Tel Aviv Sourasky Medical Center, & Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 2 Department of Psychiatry, Tel Aviv Sourasky Medical Center, & Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Department of Obstetrics and Gynecology, Tel Aviv Sourasky Medical Center, & Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 4 Department of Neonatology, Tel Aviv Sourasky Medical Center, & Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Abstract Background: Compliance and impact of a time-limited brief intervention (BI) for reducing exposure to alcohol, psychoactive substances and nicotine among women admitted to the hospital during pregnancy were assessed. Methods: Pregnant women (gestational week ≤30) from a medical center pre-delivery, emergency and high-risk units were interviewed about alcohol (AUDIT and TWEAK questionnaires), smoking (modified Fagerström) and psychoactive substance (modified ASI). All exposed women were invited to participate in a BI and underwent follow-up. Characteristics and rate of exposure were compared to a “standard-group” of non-selected women who arrived to the hospital directly solely to give birth. Results: Forty-six of the 108 study participants (42.6%) were exposed to smoking (85%), alcohol (41%), or drugs (39%), and 41 underwent the BI. Self-report of exposure was reduced significantly following BI but re-elevated post-delivery. Women belonging to the “standardgroup” were better educated, had lower lifetime rates of exposure, and gave birth to newborns with higher birth weights (3254.7±506.9 g vs. 2650.8±785.6 g for the study group).
Conclusion: Compliance of the exposed women to BI was high and contributed to exposure reduction during pregnancy but relapsed following delivery.
Background Nicotine smoking and the use of alcohol and drugs during pregnancy are associated with a significant health risk to the developing fetus. Prenatal alcohol exposure may cause miscarriage, stillbirth, and a range of lifelong disorders, known as Fetal Alcohol Spectrum Disorders (FASD). Illicit substance use during pregnancy also places the fetus and newborn at increased obstetric risk for complications, such as abruption placenta, amnionitis, early pregnancy loss, intrauterine growth retardation, late intrauterine death, placental insufficiency, postpartum hemorrhage, preeclampsia and eclampsia, premature labor, premature rupture of membranes, and septic thrombophlebitis (1). Once fertilization is achieved, nicotine smoking is associated with an increased risk of ectopic pregnancy (RR = 1.8) (2). Women who smoke during pregnancy have an increased risk of premature rupture of membranes associated with premature delivery (<37 weeks’ gestation) (3). Preterm delivery is strongly associated with an increased risk for fetal, neonatal and perinatal mortality (3-6).
Address for Correspondence: Einat Peles, PhD, Adelson Clinic for Drug Abuse, Treatment & Research,Tel Aviv Sourasky Medical Center, 1 Henrietta Szold St., Tel Aviv 64924, Israel. einatp@tlvmc.gov.il
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According to an estimation based on one national survey conducted in 2002 in Israel among pregnant and postpartum women (7), 13% of the pregnant women smoked cigarettes during pregnancy, lower than 18% which is the estimated prevalence among Israeli women (8) or 16% in U.S. women (9). The rate was higher among Jewish women compared to Arab women. Nicotine smoking rates were reduced during pregnancy, but not substantially (from 12.8 to 8% among Jewish women and from 3% to 1.8% among Arab women). Drug abuse rates during pregnancy in Israel have not been reported. In the United States, it is estimated that above 4.4% of pregnant women abuse one or more substances during pregnancy (10), while 1 in 9 pregnant women continues to drink alcohol during pregnancy, and a small percentage of pregnant women continues to binge drink (11). Alcohol consumption during pregnancy in Israel was reported in 14.1% of 3815 women in the post delivery period (12). Studies from other countries report that a strong predictor of alcohol use during pregnancy is the alcohol use level prior to pregnancy (13, 14). Upon confirmation of pregnancy, most women voluntarily reduce their alcohol use (14), however, alcohol use during pregnancy was reported to remain stable at ~12% and binge drinking was between 2-3% during pregnancy. A brief intervention (BI) for both alcohol and nicotine smoking was found to be an important and efficient instrument to reduce alcohol and cigarette use (15-18), while screening alone was also found to be effective among pregnant women. In a study that evaluated if a voucher-based incentive is superior to “usual care” to reduce cigarette smoking and fetal growth (19), while a reduction in smoking was observed in both groups, the intervention was found to be superior. In this study, the staff did not attempt to influence smoking habits and the usual care was an inquiry regarding smoking status and a discussion regarding the advantages of smoking cessation assisted by a smoking cessation pamphlet (20). Less information is available on the efficacy of a BI with respect to substance abuse. For pregnant drug-misusing women, compliance with treatment has been particularly problematic, even in specialized and more intensive treatment programs. One study (21) compared outcome between compliant women (participation in 4 behavioral reinforcement of drug abstinence sessions plus brief motivational therapy) to non-compliant (participated in 0-3 therapy sessions) and found higher birth weights and higher rates of drug-free women at delivery among the
compliant group. Another study compared two models of motivational interviewing plus behavioral incentives for drug abstinence. Although the arm that included a case management component fared better, both intervention models were associated with poor participation (22). Some substance abuse prevention BI techniques employ motivational counseling and are provided by non-specialists in the treatment of alcohol abuse or dependence. The main components of these interventions involve feedback of personal risk, responsibility for personal control, advice regarding behavior modification and strategies to help individuals reduce or stop drinking, an empathetic counseling style, and a declaration of confidence in the individual’s ability to bring about the desired behavioral change. A BI also involves establishing a drinking goal and monitoring the progress, including ongoing support and encouragement. Several trials and reports on alcohol use indicate that both men and women benefit from BIs (14, 23). Some alcohol BI trials found women to benefit more than men (16), possibly reflecting lower initial levels of alcohol use and higher levels of motivation for behavioral changes in women. Furthermore, in the context of a therapeutic situation, women may change their behavior regarding alcohol use (stop or reduce usage) simply in response to questions about their drinking. One study from the U.S. Preventive Services Task Force (USPSTF) review (5) among childbearing-aged women (18–40 years) who screened positive for a drinking problem at study enrollment found that two 15-minute physician-delivered BI sessions resulted in a 20–25% reduction in the number of alcoholic drinks per week and binge drinking episodes that lasted for two years after the BI. Those who became pregnant had the most dramatic decreases in alcohol use (16). Interestingly, in some studies, women who were merely asked about their drinking levels consumed alcohol equally to women in the BI groups, a phenomenon already reported in other populations (24). The official statement released by the USPSTF recommended screening and behavioral counseling interventions to reduce alcohol misuse by adults, including pregnant women, in primary care settings. For example, one BI aimed at nicotine smoking cessation among pregnant women was implemented successfully in Australia (25). Over 65% of current smokers were offered advice about the benefit of quitting, and the rate for stopping the habit was highest at month six of gestation, although women tended to relapse after the birth of their baby (25). In Israel, the preliminary results of a series of health promotion activities for nicotine smoking cessation for pregnant 249
Substance and IsrAlcohol, J Psychiatry Relat Sci - Vol. 51 -Cigarettes No 4 (2014) Exposure in Pregnant Women and Compliance in Brief Intervention
women in prenatal care at four mother and child health clinics in Jerusalem pointed to a positive influence (26), but no additional reports have appeared since then. Interventions aimed at the reduction of alcohol consumption, nicotine smoking, and substance abuse, have been reported with various degrees of success. However, an intervention directed concomitantly at exposure to alcohol, nicotine smoking and substance abuse has never been reported. We reasoned that an individual exposed to alcohol would also be at increased risk for exposure to nicotine smoking and substance abuse since it is well known that most substance abusers are also exposed to nicotine smoking. Given that each exposure can harm a newborn, we designed a BI for reducing them among pregnant women. The current study is a pilot feasibility study of concomitant BI for all harmful exposures among pregnant women who arrived at the hospital during their pregnancy. The BI was tailored to the exposures of each participant based on her responses in a structured interview. Our aims were to evaluate: 1. The rate of exposure to alcohol, nicotine smoking and substance abuse among pregnant women who were admitted to the hospital during pregnancy due to obstetric reasons, as compared to a standard pregnant women population (all pregnant women who arrive at the hospital to deliver), 2. The compliance rate to BI, 3. The effect of BI on exposure reduction at delivery and following three months post-delivery as compared to candidates who refused to participate in the BI, and 4. Newborn outcome and its relation to exposure. Methods The study was approved by the local IRB committee (0292-10). Pregnant Hebrew-speaking women who were admitted to our pre-delivery unit, emergency room (ER) or high-risk unit between June 2011 and January 2012 at gestational week ≤30 were asked to participate in the study (recruitment obtained for about 5 hrs per day, in three random days, every week). All participants filled in structured questionnaires (see below), and those who reported positively for nicotine smoking, alcohol or drugs were defined as the “exposure group.” If they were currently exposed or had stopped just before or during pregnancy, they were invited to participate in a BI. Participants who reported that they stopped any exposure during or just before pregnancy were asked to describe this exposure in detail. In addition, as our study group was recruited within the hospital during pregnancy, we added a control group to enable us to compare the study group’s characteristics 250
to a standard representative pregnant women population. Thus, we recruited a “standard-group” (n = 102) which consisted of all Hebrew-speaking women who arrived at the hospital to give birth during 10 consecutive days (June 4-14, 2012). Unlike the study group which was followed up during pregnancy and after delivery, the “standard-group” was studied only once, immediately following delivery, filling out the same questionnaires about pregnancy habits as did the study group. BrIef intervention (bi) The BI was performed by a single academic female research assistant (AS), an experienced staff member in the addiction treatment clinic. The brief intervention was performed interactively immediately after the initial interview. If a pregnant woman responded positively to inquiries regarding current nicotine smoking, drug use or drinking, she was asked by the interviewer if she would agree to participate in a BI session. If she agreed, the interviewer proceeded to explain the dangers associated with such exposure, and their grave implications for both herself and her unborn child. The discussion was conducted in a nonthreatening atmosphere, with no blame being cast. The interviewer also provided the pregnant woman with newsletters by the Israeli National Anti Drug Authority and Israel Cancer Association which described the implications of exposure to these substances and how to avoid them (especially, during pregnancy). Furthermore, the interviewer also suggested diverse practical tips (i.e., cut cigarette into half ’s, use gums instead, use a plastic cigarette, or cinnamon stick) that may help with the exposure reduction, and encouraged women to find and participate in programs focusing on smoking cessation. The BI group was followed up by phone (once or twice during pregnancy, following delivery and/or three months post delivery) at which points exposure questionnaires were filled out. Due to ethical considerations, the entire “exposure group” was invited to participate in the BI. The BI was directly tailored for the pregnancy period and thus was not suggested to the “exposure group” women from the “standard-group,” who were all studied following delivery. Questionnaires
a. The Alcohol Use Disorders Identification Test (AUDIT) is a 10-item screening tool (27) for identifying individuals with at-risk, hazardous or harmful drinking behavior. We used the AUDIT-C, which includes the
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first three items of the full AUDIT that queries quantity, frequency, and a maximum level of five or more alcoholic drinks on any one occasion, and has been found to be effective in screening for alcohol misuse in women at a cut-off score of ≥3 (28, 29). b. TWEAK is a five-item scale originally developed to screen for risk drinking during pregnancy (30). The utility of its items was demonstrated in studies of obstetric and gynecologic outpatients, and it has been validated among women in that setting (31). It includes questions on tolerance (T), worry (W), eye-openers (E), amnesia (A) and cutting-down (K). c. Fagerström is a nicotine score that is measured with the Modified Fagerström Test for Nicotine Dependence (FTND) (32) and is comprised of six questions. The FTND yields a score of 0 (no or low) to 10 (highest severity of nicotine dependence). d. Information on substance use is acquired by means of the modified addiction severity index (ASI) questionnaire (33). The ASI provides information about the frequency, quantity, and way of administration during the preceding month as well as lifetime use with specific adjustment to pregnancy. Delivery outcome variables
The pregnancy-related outcome variables were neonatal birth weight, gestational age, type of delivery, complications, APGAR 1 and 5 minute scores, referral to the intensive care unit (ICU) and duration of ICU stay, hospitalization duration, and presence of neonatal abstinence syndrome. Statistical analyses
The rate and type of exposure (nicotine smoking, alcohol and psychoactive drugs) were compared between the women who were interviewed in the pre-delivery unit, emergency room (ER) or high-risk unit. Newborn outcome was compared according to the unit from which the women were discharged (i.e., not the one to which they had been originally admitted and where they were interviewed for this study). The change in exposure before BI, during pregnancy and after delivery was studied using repeated measured analyses. Results Study population
Ten of the 118 women who were asked to participate declined, leaving a total of 108 (91.5%) in the study group. Their mean gestational week was 24.6 ± 6.3 (range, 5-30).
Sixty-three were interviewed at the pre-delivery unit, 39 at the ER (one subsequently moved to the pre-delivery unit and 9 to the high-risk unit), and 6 at the high-risk unit. The final analyses were performed according to the place of discharge (64 from the pre-delivery unit, 15 from the high risk unit, and 29 from the ER). The cause for admission to hospital and gestational age differed between the pre-delivery and high-risk units and the ER (Table 1). There were no differences in age, education and pregnancy outcome (newborn weight birth and gestational age). BI group: nicotine smoking, alcohol and substance abuse
Of the 108 participants, 46 (42.6%) met criteria for the “exposure” group. The rate of exposure did not differ according to the three hospital sites (Table 2). Four women had been misclassified (they were all exposed to alcohol drinking that was discontinued before pregnancy) and one woman declined, leaving a total of 41 (97.6%) women who underwent the BI. Sixty-two of the 108 study participants had never smoked, and 46 had smoked in the past or present. Specifically: 7 smoked in the past, and of the rest 39 exposed: 21 stopped during or before pregnancy and 18 were still smoking nicotine at the first evaluation. Alcohol exposure was reported by 10 (24.4%) BI participants, and by another 4 non-BI participants. Lifetime usage of any psychoactive substance was reported by 18 (43.9%) women and it was limited to marijuana (THC) in all but one who also reported having used cocaine and LSD in the past. Comparing the BI and non BI groups (Table 3), the BI group was less educated (48.8% vs. 66.7% had >12years of education respectively, p=0.009), with a trend for a lower rate of being married or in a relationship (85.4% vs. 95.5%, p=0.08) with no other characteristics and outcome differences. BI group follow-up
Nicotine smoking Nicotine smoking severity (Fagerstörm score) and the number of cigarettes were significantly reduced following the BI compared to the pre-BI results (Fagerstörm 3.7±2.0 and 2.8±2.2, F (df=1) 6.1, p = .02; cigarette number 11.0±8.1 and 4.5±6.2, F (df=1)18.7, p < .0005 (included 24 of the 39 exposed women for whom an evaluation was available for nicotine smoking during pregnancy), but elevated again after delivery (Fagerstörm 3.6±2.0 251
Substance and IsrAlcohol, J Psychiatry Relat Sci - Vol. 51 -Cigarettes No 4 (2014) Exposure in Pregnant Women and Compliance in Brief Intervention
Table 1. Comparison of characteristics between the 3 hospital discharge sites and controls
Age at pregnancy (years) Israeli born (%) Education ≥12years (%) Employed (%) Full Part-time job No Married or in relationship (%) Gestational week (at interview) (weeks) Any medication (%) Reason for admission (%) Bleeding Pain Trauma Vomit/ breath/ weakness Low movement / slow fetal growth Uterus: short/contraction /water membrane Others Elective delivery/upper limit of pregnancy due date First pregnancy (%) Pregnancy type (%) Natural IVF Other (injected, IUI) Pregnancy follow-up (%) Hospital high-risk unit Community health services Other Outcome (%) Labor Abortion Lost to follow-up Successfully followed-up (%) Labor in hospital (%) Mode of delivery (%) Vaginal Cesarean Instrumental vaginal Gestational week at delivery (weeks) Spontaneous preterm ≤28 Preterm (28-36 weeks) >36 Unknown Mean birth weight (gram) Birth weight (%) <1500 gram 1500-2500 gram 2500-4000 gram >4000 gram Type of pregnancy (%) Singleton Twins/Triplets Birth weight singleton (gram) Apgar 1 min Apgar 5 min Breastfed (%)
252
ER n (%) 29 (100) 31.9 ± 4.3 22 (75.9) 17 (58.6)
Pre-delivery Unit n (%) 64 (100) 32.6 ± 5.4 52 (81.3) 39 (60.9)
High Risk Unit n (%) 15(100) 29.1±3.2 13 (86.7) 9 (60)
Controls n (%) 102 (100) 32.7 ± 4.9 74 (72.5) 74 (72.5)
20 (69.0) 4 (13.8) 5 (17.2) 27 (93.1) 20.1 ± 8.8 4 (15.4)
48 (75.0) 4 (6.3) 12 (18.8) 57 (89.1) 26.6 ± 3.2 12 (19.7)
6 (40) 3 (20.0) 6 (40) 15 (100) 25.0 ± 6.4 3 (21.4)
89 (87.3) 10 (9.8) 3 (2.9) 94 (92.2) 18 (17.6)
5 (17.2) 6 (20.7) 2 (6.9) 7 (24.1) 4 (13.8) 2 (6.9) 3 (10.3) 0 14 (48.3)
10 (15.6) 3 (4.7) 4 (6.3) 3 (4.7) 7 (10.9) 31 (48.4) 6 (9.4) 0 26 (40.6)
0 (0) 3 (20.0) 1 (6.7) 1 (6.7) 2 (13.3) 4 (26.7) 4 (26.6) 0 4 (26.7)
4 (3.9) 0 (0) 0 (0) 0 (0) 7 (6.9) 70 (68.6) 2 (2) 19 (19.6) 30 (29.4)
25 (86.2) 1 (3.4) 3 (10.3)
50 (78.1) 8 (12.5) 6 (9.4)
126 (80.0) 3 (20.0) 0
94 (92.2) 5 (4.9) 3 (3)
5 (17.2) 23 (79.3) 1 (3.4)
19 (29.7) 44 (68.8) 1 (1.6)
8 (53.3) 6 (40.0) 1 (6.7)
13 (12.7) 89 (87.3) 0
26 (89.7) 1 (4.3) 2 (6.9) 27(93.1) 22 (81.5)
63 (98.4) 0 1 (1.6) 63(98.4) 53 (84.1)
14 (93.3) 0 1 (6.7) 14(93.3) 12 (85.7)
102 (100)
0.4
102 (100)
0.4
17 (65.4) 6 (23.1) 3 (11.5) 37.6±5.1 1 (3.7) 4 (14.8) 22 (81.5) 2 2949±703
31 (49.2) 31 (49.2) 1 (1.6) 36.1±4.1 3 (4.8) 27 (42.9) 33 (52.4) 1 2490±810
7 (50.0) 6 (42.9) 1 (7.1) 37.6±3.1 0 4 (28.6) 10 (71.4) 1 2819±654
3255±507
0 (0) 8 (30.8) 18 (69.2) 0 (0)
8 (12.7) 22 (34.9) 33 (52.4) 0 (0)
2 (7.1) 2 (14.3) 11 (78.6) 0 (0)
1 (1) 4 (2.9) 89 (87.3) 8 (7.8)
26 (96.3) 1 (3.7) 2958.7±715.4 8.6±0.9 9.8±0.5 15(55.6)
47 (74.6) 16 (25.4) 2586.8±879.4 7.9±2.2 9.2±1.2 27(42.9)
11 (78.6) 3 (21.4) 3035.0±418.4 9±0 9.7±0.6 7(50.0)
99 (97.1) 3 (2.9) 3276.7±498.2 8.7±1.4 9.7±1.4 72(70.6)
78 (76.5) 21 (20.6) 3 (2.9) 39.2±1.6 0 5 (4.9) 97 (95.1)
p Value 0.08 0.5 0.5 0.001
0.3 <0.0005 0.9 <0.0005
0.2 0.1
0.001
0.003
0.5 <0.0005
<0.0005
0.001 <0.0005 0.2 0.09 0.004
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Table 2. Comparison of drug, alcohol and nicotine smoking exposure (during and before pregnancy) between the 3 hospital discharge sites and controls ER
Pre-delivery Unit
High-risk Unit
Controls
n (%)
n (%)
n (%)
n (%)
Total
29(100)
64(100)
15(100)
102(100)
Exposure group (%) No Yes – enrolled in a BI Yes - not enrolled in a BI
14(48.3) 14(48.3) 1(3.4)
38(59.4) 22(34.4) 4(6.3)
10(66.7) 5(33.3) 0(0)
76(74.5) 0(0) 26(25.5)
Nicotine groups (%) Current Stopped before/during pregnancy Past Never
6(20.7) 7(24.1) 2(6.9) 14(48.3)
9(14.1) 12(18.8) 4(6.3) 39(60.9)
3(20.0) 2(13.3) 1(6.7) 9(60.0)
4(3.9) 20(19.6) 15(14.7) 63(61.8)
Nicotine dependence (Fagerström score) If cigarette >0
3.3±1.9 n=13
3.5±2.1 n=22
4.8±2.4 n=5
3.2±1.9 n=21
Cigarettes (number)
12.3±8.8
9.1±7.6
12.4±7.7
11.5±8.2
p Value <0.0005
0.1
0.6
Age at nicotine smoking onset (y)
16.9±1.3
18.6±3.8
16.6±2.8
19.3±3.6
0.08
Passive exposure (spouse or partner current smoker) (%)
14(48.3)
24(37.5)
10(66.7)
30(29.4)
0.02
Drinking alcohol (%)
5(17.2)
9(14.1)
0(0)
9(8.8)
0.4
Age at onset of alcohol use (y)*
17.8±1.7
19.4±3.2
-
18.7±2.3
0.6
AUDIT score last month*
2.4±4.3
1.4±2.9
-
0.9±1.2
0.6
AUDIT score before pregnancy*
6.4±4.7
5.2±4.7
-
3.1±1.3
0.3
TWEAK score last month*
0
0.7±1.7
-
0
0.4
TWEAK score before pregnancy*
1.4±2.2
0.9±1.2
-
0.2±0.7
0.3
Lifetime use of drug (THC) (%)
6(20.6)
10(15.7)
2(13.3)
2(2)
0.001
Age at onset of any drug use (y)
20.0±3.6
18.7±3.0
16
19±4.2
0.4
Use of any drug before/during pregnancy
1(3.4)
4(6.3)
0(0)
0(0)
0.005
*Among alcohol drinking only *Among alcohol drinking only **singleton only
and 2.6±2.1 and 3.6±2.4, time effect F(df=2)3.8, p = .01) cigarette (10.7±7.8 and 4.0±5.5 and 7.5±8.3, time effect F(df=2)1.3, p = .3) (n=22). Alcohol Alcohol exposure was followed up among the 10 (24.4%) BI participants. Both the TWEAK and AUDIT scores were low before the BI and during pregnancy and rose following delivery (TWEAK: before 0.2±0.5, during 0.2±0.5, following delivery 0.6±0.9; AUDIT before 0.4±0.9, during 0.4±0.9, following delivery 5.8±5.5). Psychoactive drugs Five women reported using THC before or during pregnancy, and none of them reported its usage during pregnancy after BI. After delivery, 2 of these 5 women reported occasional THC usage and another 2 who had lifetime usage of THC (including the one with cocaine history) reported 1-4 days in the last month of THC usage.
Outcome
Newborn birth weight among the women with singleton births (n = 83) was not related to nicotine smoking status, to education level or to country of birth, but it was significantly related to the location of hospital admission. Comparison between study group and standard-group
The standard-group (a non-selected sample of women who arrived to deliver at the same hospital) (N=102) as compared to the study group (N=108) were more educated (15.4±2.6 vs. 14.6±2.8 years p=0.05 respectively). More of them were working (full time: 87.3%, vs. 68.5%, part time: 9.8% vs. 10.2% not working: 2.9% vs. 21.3%, respectively p<0.0005). More of them had a natural pregnancy (92.2% vs. 80.6%, p=0.03) and were followed up in the community health services (87.3% vs. 67.6%, p=0.001); furthermore, more of them had normal vaginal delivery (76.5% vs. 52.9%, p=0.001), a higher gestational age at delivery (39.2±1.6 vs. 36.7±4.3 253
Substance and IsrAlcohol, J Psychiatry Relat Sci - Vol. 51 -Cigarettes No 4 (2014) Exposure in Pregnant Women and Compliance in Brief Intervention
Table 3. Comparison between BI vs. non BI groups
Age at pregnancy (years) Israeli born (%) Education ≥12years (%) Married or in couple (%) Fagerstrom score Cigarette number Age started nicotine smoking (y) Partner current nicotine smoking (%) Drinking alcohol (%) Age started drinking (y)* AUDIT score last month* AUDIT score before pregnancy* TWEAK last month* TWEAK before pregnancy* Any drug lifetime use (THC) (%) Age started any drug use (y) Any drug during/before pregnancy Pregnancy type (%) Natural IVF Other (injected, IUI) Pregnancy follow-up (%) Hospital high-risk unit Community health services Other Mode of delivery (%) Vaginal Cesarean Instrumental vaginal Gestational week at delivery (weeks) Reason for admission (%) Bleeding Pain Trauma Vomit/ breath/ weakness Low movement / slow fetal growth Uterus: short/contraction /water membrane Others First pregnancy (%) Successful followed-up (%) Gestational week at delivery (weeks) Mean birth weight (gram) Birth weight, n (%) <1500 gram 1500-2500 gram 2500-4000 gram >4000 gram Type of pregnancy (%) Singleton Twins/Triplets Mean birth weight (gram)** Apgar 1 min Apgar 5 min Breastfed (%)
254
BI N (%) 41 (100%) 32.6±4.7 31 (75.6) 20 (48.8) 35 (85.4) 3.5±2.1 10.3±8.1 17.8±3.2 25 (61.0) 10 (24.4) 18.9±2.9 1.3±2.8 5.4±3.9 0.6±1.6 0.3±1.7 18 (43.9) 18.7±3.3 5 (12.2)
Non BI N (%) 66 (100%) 31.5±5.2 55 (83.3) 44 (66.7) 63 (95.5) 22 (33.3) 4 (6.1) 20.5±3.0 3±4.8 6.3±6.6 0±0 0.5±1.0 0 0
30 (73.2) 4 (9.8) 7 (17.0)
56 (84.8) 8 (12.1) 2 (3.0)
13 (31.7) 28 (68.3) 0 (0)
19 (28.8) 44 (66.7) 3 (4.5)
23 (57.5) 13 (32.5) 3 (7.5) 24.1±7.0
32 (50.8) 29 (46.0) 2 (3.2) 25.0±5.9
4 (9.8) 8 (19.5) 1 (2.4) 5 (12.2) 7 (17.1) 11 (26.8) 5 (12.2) 16 (39.0) 39 (95.1) 36.7±4.8 2782.4±727.4
10 (15.2) 4 (6.1) 6 (9.1) 6 (9.1) 6 (9.1) 26 (39.4) 8 (12.1) 27 (40.9) 63 (95.5) 36.6±4.0 2560.2±816.4
3 (7.7) 10 (25.6) 25 (64.1) 1 (2.6)
6 (9.5) 22 (34.9) 35 (55.6) 0 (0)
35 (87.5) 5 (12.5) 2826.9±766.2 8.7±0.8 9.5±1.1 18 (45)
48 (76.2) 15 (23.8) 2699.8±836.9 8.1±2 9.5±1 30 (47.6)
P value 0.3 0.7 0.009 0.08
0.009 0.008 0.4 0.4 0.7 0.1 0.03
0.5
0.2
0.3
0.5 0.2
1 1 0.9 0.7 0.7
0.2 0.2 0.1 1 0.8
Einat Peles et al.
weeks, p<0.0005), a higher birth weight (3255±507 vs. 2651±786 gram, p<0.0005) and a higher Apgar 1 min score (8.7±1.4 vs. 8.2±1.8, p=0.04). In addition, more of the standard-group breastfed (70.6% vs. 47.1%, p=0.001). The standard-group was found to have a significantly lower exposure (25.5% vs. 62% respectively, p<0.0005), including smoking (current 3.9% vs. 16.7%, p=0.001), alcohol AUDIT score life (0.4±0.9 among 9 of standardgroup vs. 1.7±1.5 among 14 of the study group, p=0.03) and psychoactive drug use during /before pregnancy (0 vs. 4.6%, p<0.0005). They were also less exposed to passive smoking exposure (29.4% vs. 44.4%, p=0.03). Discussion In evaluating the rates of exposure to alcohol, nicotine smoking and substance abuse among pregnant women who were admitted to the hospital during pregnancy due to obstetric reasons, we found the most prevalent type of exposure to be nicotine smoking (36.1% of the 108 women). This rate is much higher than had been previously reported among pregnant women in Israel, as well as worldwide, i.e., ranging between 8-20% (7, 34-36). However, unlike previous studies, we recruited pregnant women within a tertiary medical center, and not within the community health care program, who by definition arrived at the hospital during pregnancy due to diverse medical conditions or complications, and should probably be regarded as a selected subgroup that differs from a general population of pregnant women. This finding is novel, and may suggest that pregnant women whose pregnancy is at risk due to any medical reason are at an increased risk for exposure to nicotine smoking, alcohol and/or psychoactive drugs, a characteristic that most likely further (or causally) increases their risk. On the other hand it could be speculated that their medical risk is due to substance exposure. While this may be partially true, the reasons for being admitted to a hospital during pregnancy (i.e., bleeding, pain, trauma, vomiting, respiratory problems, weakness, low movement /slow growth), and women’s medical problems (i.e., cardiac, metabolic, endocrine, oncologic, pulmonary, neurologic, gastrointestinal, urologic, gynecologic, hematologic, psychiatric), are not attributed directly or specifically to nicotine smoking, alcohol, and/or psychoactive drug exposure. Specifically our study group presented with a higher exposure rate to nicotine smoking, alcohol and/or psychoactive drugs (42.6%) compared to 25.5% among our
standard norm group, a non-selected sample of women who arrived to deliver at the same hospital. In addition to their own higher rate of nicotine smoking, the study group was also more exposed to passive nicotine exposure due to a higher proportion of husband/partner smoking compared to the standard-group (44.4% vs. 29.4% respectively). Nicotine smoking is well established as one of the main causes of higher mortality in low socioeconomic classes (37). Furthermore, smoking during pregnancy was reported to be related to a lower education level (38). Indeed our study group was less educated than the standard control group. Lower education may also be related to the lower rate of employment in the study group versus the standard group. However, this could be temporary and associated with their pregnancy-related medical condition. Fewer years of education may also be related to poorer health habits and lifestyles that might have contributed to the pregnancy complications that led them to seek medical care in a hospital setting during pregnancy unlike the reference group who came to the hospital solely to deliver. This possibility was not studied in the current work. Our findings regarding alcohol consumption rates during pregnancy are similar to those previously reported in Israel (12) and in the U.S.A. (14). It has previously been reported (11, 14) that most women voluntarily reduce their alcohol use when they become pregnant. However, one of the problems with drinking is that even a low level of exposure (that may be consumed before becoming aware of being pregnant) is a risk to develop FASD, a disorder that is most likely under-diagnosed in Israel (39). One-quarter of the women in our study group underwent an assisted pregnancy (12 IVF, 9 IUIs). Our observation that half of these women were also exposed to nicotine smoking/ alcohol/ psychoactive drugs during pregnancy (1/3 of those who did IVF) was unexpected. This contradicts finding from Finland that compared singleton births after IVF (n = 5,647) and non-IVF pregnancies (n = 285,357) and found similar rates of exposure in women who became pregnant via IVF compared to women with non-IVF pregnancies (36). The novelty of our BI protocol is that we tailored it to accommodate all types of exposure, namely nicotine smoking and alcohol drinking and psychoactive drugs, unlike other studies on BI that reported on interventions for only one of these exposures. Our rationale was to give all exposed women the opportunity to benefit from the intervention. In addition, we had no data about the prevalence of the diverse exposures among pregnant women within a hospital setting. 255
Substance and IsrAlcohol, J Psychiatry Relat Sci - Vol. 51 -Cigarettes No 4 (2014) Exposure in Pregnant Women and Compliance in Brief Intervention
The compliance rate in the present study was very high (91.5% for participation in the study) and even higher (97.6%) for participating in the BI. Notably, women who agreed to participate in the BI, also responded positively at follows up. At follow up, some of the participating women reported on initiating or participating in diverse available programs for exposure cessation (i.e., smoking). They mentioned that the motivation to initiate diverse programs was due to the BI and newsletters that they got. We believe that these findings imply that exposed pregnant women need and want support, and would cooperate to achieve a healthy pregnancy and a healthy newborn. As a results of our positive finding of a decrease in nicotine consumption in the BI group during pregnancy, we highly recommend the implementation of a BI program during pregnancy. If this is too time consuming or not available in some settings, a screening evaluation would also seem to contribute as well. Moreover, based on our finding and consistent with other reports (25, 40) regarding the resumption or increase in smoking (severity, cigarette number) after delivery, we would suggest additional BI or screening following delivery. As with nicotine smoking, the same pattern was observed for alcohol and psychoactive drugs, but since the rates and level of exposure were very low in our sample, it was not possible for these changes to reach a level of statistical significance. It is possible that with respect to psychoactive drugs, because they are illegal, women may not report their use, and thus their consumption may be underestimated by us. The outcome (i.e., birth weight) of our study group was not related to BI, to nicotine smoking status, to education level or to country of birth, but it was significantly related to the location of hospital admission. This could be expected since the reasons for presenting to the three facilities had different characteristics that were found to be related to newborn weight. Those factors: bleeding (associated with lower birth weight); assisted pregnancy (i.e., in vitro fertilization); pregnancy at high-risk. Only if thousands of cases are studied would it possible to find outcome differences: i.e., the Cochrane database 2009 (18) found that smoking cessation interventions reduced rate of low birth weight (RR 0.83, 95% CI 0.73 to 0.95) and preterm birth (RR 0.86, 95% CI 0.74 to 0.98), and there was a 53.91g (95% CI 10.44 g to 95.38 g) increase in mean birth weight. We did find outcome differences between our study group and the standard norm group (e.g., lower weight birth; 3255±507 g vs. 2651±786 g, respectively), but this is expected based on the substantial characteristics and exposure differences between them. 256
Limitations Because our study included only Hebrew-speaking women and not new immigrants, the rates of the three types of exposure may have been underestimated. The fact that the study was based on self-reported questionnaires is also a drawback in terms of factual accuracy, although the reported relapse after delivery suggests that women’s reports did reflect actual cigarette use. Furthermore, as the protocol did not include a reward or a punishment for nicotine smoking, there is no apparent reason for them not to tell the truth. This is supported by the Cochrane review (17) that found a similar rate of reduction in nicotine smoking in studies using either women’s self reports or objective measures for the nicotine reduction. Finally, our evaluation of newborn outcome measures and their relation to exposure and BI was affected by the low level of exposure to psychoactive drugs and alcohol, while on the other hand, there were many other variables that did have a strong effect on their outcome. It can be assumed that the lack of direct association between a BI and newborn outcomes could be related to our small sample size, because nicotine smoking, which is a known risk factor for low weight birth, was also not found to be related to weight birth in either our study or standard-group. The fact that the BI was performed in a late stage of the pregnancy is also a limitation that most likely reduced its contribution. Conclusion The overall rate of exposure to nicotine smoking, alcohol and substance abuse among pregnant women who are admitted to a hospital during their pregnancy was found to be very high. Women undergoing a BI to reduce substance abuse were highly compliant, and according to women’s self-reports this intervention contributed to significant exposure reduction during pregnancy. As this reduction was lost after delivery, it is highly recommended to implement such a program during pregnancy and following delivery. Acknowledgement Funding for this study was provided by the Bircher Bener Fund, Sackler Faculty of Medicine Tel Aviv University. Many thanks to Esther Eshkol for English editing.
References 1. Finnegan LP, Kendall SR. Maternal and neonatal effects of alcohol and drugs. In Lowinson JH, Ruiz P, Millman RB, editors. Substance abuse: A comprehensive textbook (Third Edition). Baltimore, Md.: Williams
Einat Peles et al.
& Wilkins, 1997: pp 513-534. 2. Saraiya M, Berg CJ, Kendrick JS, Strauss LT, Atrash HK, Ahn YW. Cigarette smoking as a risk factor for ectopic pregnancy. Am J Obstet Gynecol 1998;178:493-498. 3. Castles A, Adams EK, Melvin CL, Kelsch C, Boulton ML. Effects of smoking during pregnancy: Five meta-analyses. Am J Prev Med 1999;16:208-215. 4. WHO Mackay J, Eriksen M. The tobacco atlas. Tobacco Free Initiative. 2003. 5. U.S. Preventive Services Task Force. Screening and behavioral counseling interventions in primary care to reduce alcohol misuse: Recommendation statement. Ann Intern Med 2004;140:554-556. 6. Curtis KM, Savitz DA, Arbuckle TE. Effects of cigarette smoking, caffeine consumption, and alcohol intake on fecundability. Am J Epidemiol 1997;146:32-41. 7. Fisher N, Amitai Y, Haringman M, Meiraz H, Baram N, Leventhal A. The prevalence of smoking among pregnant and postpartum women in Israel: A national survey and review. Health Policy 2005;73:1-9. 8. Ministry of Health, CDC. http://www.old.health.gov.il/download/forms/ a2752_ALL_310705.pdf 9. CDC, USA. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/ adult_data/cig_smoking/ 10. Wendell AD. Overview and epidemiology of substance abuse in pregnancy. Clin Obstet Gynecol 2013;56:91-96. 11. Waterman EH, Pruett D, Caughey AB. Reducing fetal alcohol exposure in the United States. Obstet Gynecol Surv 2013;68:367-378. 12. Senecky Y, Weiss N, Shalev SA, Peleg D, Inbar D, Chodick G, Nachum Z, Bar-Hamburger R, Shuper A. Alcohol consumption during pregnancy among women in Israel. J Popul Ther Clin Pharmacol 2011;18:e261-272. 13. Day NL, Cottreau CM, Richardson GA. The epidemiology of alcohol, marijuana, and cocaine use among women of childbearing age and pregnant women. Clin Obstet Gynecol 1993;36:232-245. 14. Floyd RL, Decouflé P, Hungerford DW. Alcohol use prior to pregnancy recognition. Am J Prev Med 1999;12:101-107. 15. Floyd RL, Weber MK, Denny C, O’Connor MJ. Prevention of fetal alcohol spectrum disorders. Dev Disabil Res Rev 2009;15:193-199. 16. Manwell LB, Fleming MF, Mundt MP, Stauffacher EA, Barry KL. Treatment of problem alcohol use in women of childbearing age: Results of a brief intervention trial. Alcohol Clin Exp Res 2000;24:1517-1524. 17. Lumley J, Oliver SS, Chamberlain C, Oakley L. Interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev 2004;(4):CD001055. 18. Lumley J, Chamberlain C, Dowswell T, Oliver S, Oakley L, Watson L. Interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev 2009;(3):CD001055. doi: 10.1002/14651858. CD001055.pub3. 19. Heil SH, Higgins ST, Bernstein IM, Solomon LJ, Rogers RE, Thomas CS, Badger GJ, Lynch ME. Effects of voucher-based incentives on abstinence from cigarette smoking and fetal growth among pregnant women. Addiction 2008;103:1009-1018. 20. Secker-Walker RH, Solomon LJ, Flynn BS, Skelly JM, Mead PB. Reducing smoking during pregnancy and postpartum: Physician’s advice supported by individual counseling. Prev Med 1998; 27: 422-430. 21. Jones HE, Svikis DS, Tran G. Patient compliance and maternal/infant outcomes in pregnant drug-using women. Subst Use Misuse 2002; 37:1411-1422. 22. Jones HE, Svikis D, Rosado J, Tuten M, Kulstad JL. What if they do not want treatment?: Lessons learned from intervention studies of non-treatmentseeking, drug-using pregnant women. Am J Addict 2004;13:342-357.
23. Schaus JF, Sole ML, McCoy TP, Mullett N, O’Brien MC. Alcohol screening and brief intervention in a college student health center: A randomized controlled trial. J Stud Alcohol Drugs Suppl 2009;16:131-141. 24. Kaner EF, Beyer F, Dickinson HO, Pienaar E, Campbell F, Schlesinger C, Heather N, et al. Effectiveness of brief alcohol interventions in primary care populations. Cochrane Database Syst Rev2007; CD004148. 25. Bowden JA, Oag DA, Smith KL. An integrated brief intervention to address smoking in pregnancy. Acta Obstet Gynecol Scand 2010;89:496-504. 26. Gofin J, Fox C. Smoking cessation program for pregnant women: Minimal input intervention. Harefuah 1990;18:525-527 (in Hebrew). 27. Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption--II. Addiction 1993;88:791-804. 28. Dawson DA, Grant BF, Stinson FS, Zhou Y. Effectiveness of the derived Alcohol Use Disorders Identification Test (AUDIT-C) in screening for alcohol use disorders and risk drinking in the US general population. Alcohol Clin Exp Res 2005;29:844-854. 29. Bradley KA, DeBenedetti AF, Volk RJ, Williams EC, Frank D, Kivlahan DR. AUDIT-C as a brief screen for alcohol misuse in primary care. Alcohol Clin Exp Res 2007;31:1208-1217. 30. Russell, M, Bigler L. Screening for alcohol-related problems in an outpatient obstetric-gynecologic clinic. Am J Obstet Gynecol 1979;134:4-12. 31. Russell M, Chan AWK, Mudar P. Gender and screening for alcoholrelated problems, Gender and alcohol: Individual and social perspectives. In Wilsnack RW, Wilsnack SC, editors. Piscataway, N.J.: Rutgers Center of Alcohol Studies, 1997: pp. 417-444. 32. Fagerstrom KO. Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav 1978; 3;235-241. 33. McLellan AT, Luborsky L, O’Brien CP, Barr HL, Evans F . The Addiction Severity Index in three different populations. NIDA Res Monogr 1984;55:217-223. 34. Aurrekoetxea JJ, Murcia M, Rebagliato M, López MJ, Castilla AM, SantaMarina L, Guxens M, Fernández-Somoano A, Espada M, Lertxundi A, Tardón A, Ballester F. Determinants of self-reported smoking and misclassification during pregnancy, and analysis of optimal cut-off points for urinary cotinine: A cross-sectional study. BMJ Open 2013 Jan 24:3(1). 35. Wojtyła C, Głuszek Ł, Biliński P, Paprzycki P, Warzocha K. Smoking during pregnancy-hematological observations in pregnant women and their newborns after delivery. Ann Agric Environ Med 2012;19:836-841. 36. Räisänen S, Randell K, Nielsen HS, Gissler M, Kramer MR, Klemetti R, Heinonen S. Socioeconomic status affects the prevalence, but not the perinatal outcomes, of in vitro fertilization pregnancies. Hum Reprod 2013 ;28:3118-3125. 37. Jha P, Peto R, Zatonski W, Boreham J, Jarvis MJ, Lopez AD. Social inequalities in male mortality, and in male mortality from smoking: Indirect estimation from national death rates in England and Wales, Poland, and North America. Lancet 2006;368:367-370. 38. Lanting CI, Buitendijk SE, Crone MR, Segaar D, Bennebroek GJ, van Wouwe JP. Clustering of socioeconomic, behavioural, and neonatal risk factors for infant health in pregnant smokers. PLoS One 2009; 4: e8363. 39. Tenenbaum A, Hertz P, Dor T, Castiel Y, Sapir A, Wexler ID. Fetal alcohol spectrum disorder in Israel: Increased prevalence in an at-risk population. Isr Med Assoc J 2011;13:725-729. 40. CDCP 2002: Centers for Disease Control and Prevention. Women and smoking: A report of the Surgeon General (Executive Summary). Morbidity and Mortality Weekly Report 51 (No. RR-12), 2002.
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Clinical Correlates of Alcohol Abuse among Adolescent Psychiatric Inpatients in Israel Daniel Feingold, MA,1 Uri Nitzan, MD,2,3 Gideon Ratzoni, MD,2,3 and Shaul Lev-Ran, MD1,4 1
Addiction Medicine Services, Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel Shalvata Mental Health Center, Hod Hasharon, Israel 3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 4 Social and Epidemiologic Research Department, Centre for Addiction and Mental Health, Toronto, Ontario, Canada 2
Abstract Background: Recent epidemiological studies have reported a world-wide increase in the rates of alcohol use among adolescents. Research has shown a strong link between alcohol abuse and psychiatric disorders. This study explored the clinical and demographic correlates of adolescents with a history of alcohol abuse (AA) compared to adolescents with no history of alcohol abuse (NAA) among a group of adolescent psychiatric inpatients in Israel. Method: Two hundred and thirty-eight subjects were screened, all were patients consecutively admitted to an adolescent inpatient unit at a university-affiliated mental health center in Israel during a 4-year period Result: Patients in the AA group were more prone to have a history of suicide attempts and self-injury compared to patients in the NAA group. Prevalence of attentiondeficit disruptive behavior disorders was more common in the AA group, and these patients were more prone to have a history of criminal activity and drug use. Median length of hospitalization was greater in the NAA group. Limitations: Limitations concerning attribution of causality due to the cross-sectional nature of this study. Conclusion: Higher prevalence of criminal behavior, selfinjury and suicide attempts associated with alcohol abuse may be related to higher levels of impulsivity, indicated by higher prevalence of attention-deficit disruptive behavior disorders. Alcohol-related disorders should be carefully screened and addressed in adolescent psychiatric units and in consequent ambulatory treatment settings.
Introduction In recent years, research has shown a strong link between psychopathology and the excessive use of psychoactive substances. This is particularly true in adolescence, a critical period for the development of various psychological and social skills, which may be impaired by recurrent substance use (1). Within the general population, consistent findings show an association between alcohol use disorders and psychopathology, including mood disorders, conduct disorders and suicide attempts (2-4). There have been reports focusing on clinical samples of inpatient adolescents linking alcohol abuse and dependence with increased prevalence of mood and conduct disorders (5-7), yet additional clinical correlates of alcohol use disorders among psychiatric inpatient adolescents have not been reported. Moreover, there are currently no reports on the rates of alcohol abuse among adolescent psychiatric inpatients in Israel. As rates of alcohol use are lower in Israel compared to other highincome countries (8), exploring the prevalence of alcohol abuse in the Israeli inpatient adolescent population and the clinical characteristics of this population is important Methods Participants included 238 patients (57% girls, 43% boys) admitted to the adolescent inpatient unit at a universityaffiliated mental health center in Israel during a 4-year period. The mean age at admission was 15.8 (±4.3) years and the median duration of hospitalization was 64.5 days. The study was approved by the Institute’s Ethics Review Board. Disclosure of interest S. L. has received speaking fees from Jansen-Cilag and Reckitt-Benckiser, and consulting fees from Lundbeck.
Address for Correspondence: Daniel Feingold, Addiction Medicine Services, Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel rd.y.feingold@gmail.com
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Data regarding participants’ demographic and clinical status was collected using the hospital’s electronic medical record. Diagnoses referred to diagnosis at discharge. All diagnoses at discharge were based on criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (9). Diagnoses were based on several assessments, including primary structured psychiatric interview upon admission, additional biweekly assessments, as well as recurrent clinical team discussions. Final diagnosis was confirmed and signed by the unit director (G.R.), a certified child and adolescent psychiatrist, prior to discharge. Similar diagnostic procedure has been previously used and reported by the authors (10). Independent sample t-test was used for comparing parametric variables of alcohol abusers (AA) and non alcohol abusers (NAA). Though we focused on alcohol use disorders (i.e., abuse or dependence), the category of alcohol abusers was used since none of the subjects were diagnosed with alcohol dependence. Mann-Whitney test was used for comparing median length of hospitalization. Non-parametric variables were compared using Chi-square analyses. Fisher’s exact test was used when appropriate.
mon diagnosis at discharge among individuals in the NAA group (34.6%), which tended to be higher than that in the AA group (18.2%, [χ2(1, 238)=3.52, P=0.06]). Table 1. Sociodemographic and clinical correlates of adolescents with alcohol abuse (AA) compared to adolescents with no alcohol abuse (NAA) in an inpatient adolescent psychiatric ward. Non alcohol abusers (n=205)
P-Value
22 (66.7%)
15 (7.3%)
<0.001
13 (39.4%)
62 (30.2%)
0.29
11 (33.3%)
10 (4.9%)
<0.001
8 (24.2%)
31 (15.1%)
0.19
17 (51.6%)
60 (29.3%)
0.01
12 (36.4%)
33 (16.1%)
0.006
3 (9.1%)
10 (4.9%)
0.40a
19 (57.6%)
124 (60.5)
0.75
10 (30.3%)
65 (31.7%)
0.87
6 (18.2%)
37 (18.0%)
0.98
1 (3%)
17 (8.3%)
0.48a
6 (18.2%)
71 (34.6%)
0.06
7 (21.2%)
58 (28.3%)
0.78
4 (12.1%)
37 (18%)
0.61a
9 (27.3%)
23 (11.2%)
0.012
7 (21.2%)
26 (12.7)
0.19
Drug Abuse Yes History of Violence Yes History of Criminal Acts Yes History of Childhood Trauma Yes Suicide Attempts Yes Self-injurious behavior Yes
Results No significant differences were found in sociodemographic variables and age at admission between individuals in the AA group and those in the NAA group. Alcohol abuse was not documented as a cause for admission in any of the cases. The mean age at admission was 16.0 in the AA group and 15.8 in the NAA group [t(236)=-0.21 ,P=0.83]. A Mann-Whitney test revealed a significant difference between the median length of hospitalization in the AA group (39 days) and the NAA group (79 days), [U=2506, P<0.05]. Among individuals in the AA group, 51.6% reported a history of suicide attempts compared to 29.3% of the NAA patients [χ2(1, 238)=6.43, P<0.05], and 36.4% of individuals in the AA group reported history of self-injurious acts compared to 16.1% in the NAA group [χ2(1, 238)=7.61, P<0.01] (Table 1). Among individuals in the AA group, 33.3% reported history of criminal acts compared to 4.9% in the NAA group [χ2(1, 238)=28.61, P<0.001], and 66.7% of the AA group reported history of drug abuse vs. 7.3% of the NAA group [χ2(1, 238)=76.26, P<0.001]. The most common diagnosis in the AA group was attention-deficit and disruptive behavior disorder, with a prevalence rate of 27.3% compared to 11.2% among NAA patients [χ2(1, 238)=6.29, P<0.05]. Psychotic disorder was the most com-
Alcohol abusers (n=33)
Previous Admissions Yes Prescribed antipsychotics Yes Prescribed antidepressants Yes Prescribed Mood Stabilizers Yes Prescribed ADHD Medication Yes Psychotic disorder at discharge Yes Mood disorder at discharge Yes Anxiety Disorder at discharge Yes Attention deficit and disruptive disorder at discharge Yes Other Diagnosis at discharge Yes
ADHD: attention deficit and hyperactivity disorder. a Fisher’s exact test.
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Discussion Alcohol abuse among adolescents is a major health concern and significant associations with psychiatric problems are well known. In this study we focused on a specific population of adolescents hospitalized in a psychiatric unit. Alcohol abuse was found to be significantly associated with suicide attempts, self-injury, criminal acts and drug abuse. Prevalence of alcohol abuse among adolescent psychiatric inpatients in this study was roughly 14%. These rates are lower than those reported on hospitalized adolescents in studies from other highincome countries (11). As rates of alcohol use among adolescents in the general population in Israel are lower than those reported world-wide (12), our findings should be understood in this context. Individuals in the AA group were significantly more prone to receive a diagnosis of attention-deficit and disruptive behavior disorder at discharge. It has been suggested that of all core symptoms of both attention-deficit and disruptive behavior disorders, impulsivity level has the strongest correlation with alcohol dependence (13). Higher levels of impulsive cognition and behavior may increase the risk of alcohol abuse, while excessive consumption of alcohol, in turn, may contribute to impulsive behavior. Notably, individuals in the AA group were also prone to report history of criminal acts, suicide attempts and self-injurious behavior, all strongly associated with impulsive behavior (14, 15). Analysis revealed that patients in the AA group were hospitalized for a significantly shorter period of time than those in the NAA group. This finding may have an implication for health care policy. As adolescent inpatients suffering from alcohol abuse are released more rapidly from psychiatric hospitalization, their potential drinking problem should be carefully screened for in psychiatric adolescent units and properly addressed by ambulatory services. This may imply that health care services in the community should be available to treat adolescents with alcohol-related disorders. Particularly, this would require competency on the part of the physician (e.g., pediatrician, psychiatrist) to recognize and treat these disorders. Recent reports show low levels of self-reported competency in this field by physicians in Israel (16). Ultimately, as a medical disorder requiring a biopsychosocial approach the diagnosis and treatment of alcohol abuse among individuals suffering from psychiatric disorders should be conducted in the medical system, as opposed to a solely psychosocial approach 260
which is currently the predominant mode in the treatment of substance use disorders in Israel. Limitations of this study should be recognized. First, the relatively small number of participants in the AA group suggests caution regarding generalization of the results. Second, due to its retrospective nature, the data reported is correlative and thus hold limitations concerning attribution of causality (17). This study explored the clinical correlates of alcohol abuse among Israeli adolescent inpatients. Rates of alcohol abuse in this population were lower than reported among psychiatric adolescent inpatients from other high-income countries, a finding which is in line with lower rates of alcohol abuse in the general population in Israel compared to high-income countries. A history of alcohol abuse was found to be associated with higher rates of attentiondeficit and disruptive behaviors, as well as higher rates of suicide attempts, self-injury and criminal acts, all of which may be associated with an underlying tendency towards impulsive behavior. As alcohol abuse was also associated with shorter hospitalizations, this suggests careful screening for alcohol-related problems in psychiatric adolescent units, and particularly appropriate referral to continuous treatment in ambulatory services. Given the various links between alcohol abuse and psychopathology among adolescents, both problems should be addressed in an integrative manner. Psychiatric follow-up services for adolescents should be proficient in treating co-occurring psychiatric disorders and alcohol use disorders. Contribution of authors: 1. Daniel Feingold: Analysis and interpretation of data, drafting. 2. Uri Nitzan: Conception and design, final approval. 3. Gideon Ratzoni: Conception and design, final approval. 4. Shaul Lev-Ran: Conception and design, critical revision, final approval.
References 1. Johns A. Psychiatric effects of cannabis. Br J Psychiatry 2001;178:116-122. 2. Clark DB, Bukstein OG. Psychopathology in adolescent alcohol abuse and dependence. Alcohol Res Health 1998;22:117-121, 126. 3. Fidalgo TM, da Silveira ED, da Silveira DX. Psychiatric comorbidity related to alcohol use among adolescents. Am J Drug Alcohol Abuse 2008;34:83-89. 4. Hibell B, Guttormsson U, Ahlstrรถm S, Balakireva O, Bjarnason T, Kokkevi A, et al. The 2011 ESPAD Report: substance use Among students in 36 European countries. Stockholm: The Swedish Council for Information on Alcohol and Other Drugs, 2011. 5. Esposito-Smythers C, Spirito A. Adolescent substance use and suicidal behavior: A review with implications for treatment research. Alcohol Clin Exp Res 2004;28:77S-88S. 6. Ribeiro SN, Jennen-Steinmetz C, Schmidt MH, Becker K. Nicotine and alcohol use in adolescent psychiatric inpatients: Associations with diagnoses, psychosocial factors, gender and age. Nord J Psychiatry 2008;62:315-321.
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7. King CA, Hill EM, Naylor M, Evans T, Shain B. Alcohol consumption in relation to other predictors of suicidality among adolescent inpatient girls. J Am Acad Child Adolesc Psychiatry 1993;32:82-88. 8. World Health Organization. Global status report on alcohol and health. Geneva: World Health Organization, 2011. 9. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, Fourth edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association, 2000. 10. Lev-Ran S, Aviram A, Braw Y, Nitzan U, Ratzoni G, Fennig S. Clinical correlates of cannabis use among adolescent psychiatric inpatients. Eur Psychiatry 2012;27:470-475. 11. Niethammer O, Frank R. Prevalence of use, abuse and dependence on legal and illegal psychotropic substances in an adolescent inpatient psychiatric population. Eur Child Adolesc Psychiatry 2007;16:254-259. 12. Bar-Hamburger R, Ezrahi Y, Rosiner I, Nirel R. Illegal use of drugs and alcohol in Israel 2009: Seventh national epidemiological survey.
Jerusalem: The Israeli anti-drug authority, 2009. 13. Edwards AC, Kendler KS. Twin study of the relationship between adolescent attention-deficit/hyperactivity disorder and adult alcohol dependence. J Stud Alcohol Drugs 2012;73:185-194. 14. Gvion Y, Apter A. Aggression, impulsivity, and suicide behavior: A review of the literature. Arch Suicide Res 2011;15:93-112. 15. Loeber R, Menting B, Lynam DR, Moffitt TE, Stouthamer-Loeber M, Stallings R, et al. Findings from the Pittsburgh Youth Study: Cognitive impulsivity and intelligence as predictors of the age-crime curve. J Am Acad Child Adolesc Psychiatry 2012;51:1136-1149. 16. Lev-Ran S, Adler L, Nitzan U, Fennig S. Attitudes towards nicotine, alcohol and drug dependence among physicians in Israel. J Subst Abuse Treat 2013;44:84-89. 17. Weaver MF, Dupre MA, Cropsey KL, Koch JR, Sood BA, Wiley JL, et al. Addiction epidemiology in adolescents receiving inpatient psychiatric treatment. Addict Behav 2007;32:3107-3113.
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Emerging Issues in the Relationship Between Adolescent Substance Use and Suicidal Behavior Dan Shlosberg, MD, PhD,1,2 Gil Zalsman, MD,1,2,3 and Gal Shoval, MD1,2 1
Child and Adolescent Division, Geha Mental Health Center, Petah Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Division of Molecular Imaging and Neuropathology, Department of Psychiatry, Columbia University, New York, N.Y., U.S.A. 2
Abstract Adolescent suicidal behavior poses a major global public health concern as it is highly prevalent and associated with mortality and morbidity worldwide. Substanceuse disorders are also an issue of increasing concern among adolescents and have been shown to increase the risk for suicidal behaviors. In this review we address emerging issues in the relationship between adolescent substance use disorders and suicidal behaviors. We focus on common hazardous patterns of substance abuse such as binge drinking and poly-substance abuse and point out developing patterns of substance preferences as evidenced by the contemporary widespread use of synthetic cannabinoids. We address these issues in the context of vulnerable populations such as sexual-minority adolescents and youth with co-occurring mental-disorder diagnoses. Finally, we relate to the present and future challenges presented by these issues to implement effective anti-suicidal treatment and prevention strategies in adolescents with substance use disorders.
Methods Papers relating to substance abuse and suicidal behavior in adolescents from the past 10 years were searched in Pubmed by using the terms “adolescent,” “youth,” “teenage,” matched with “substance use/ abuse/ dependence,”, “suicide ideation /plan /attempt /completion. . From the resultant papers, those relating to the relationship between substance use disorders and suicidal behavior in adolescents were read and searched for further relevant references. After reviewing the chosen material, Address for Correspondence:
262
we highlighted several issues which are the focus of this review and chose papers relating to these subjects in order to compile them into a “non-systematic” review. Internet web sites were either individually picked and accessed or referred to from paper references; internet pages relevant to the subject of this review are cited. Introduction Suicidal behavior (SB) is a broad term encompassing a wide scope of self-injurious behaviors with at least a partial intent to die, ranging from ideation to active self-inflicted death. Adolescent SB poses a major global public-health concern since it is highly prevalent and associated with mortality and morbidity. Suicide is currently the third leading cause of death among adolescents in the United States and second in Europe (1, 2). Recent data indicate an alarming rise in adolescent suicide attempts during the past two years (3) although there are conflicting reports regarding adolescent completed suicide attempts mainly due to high cultural and inter-country variability (4). Regardless of the obvious consequences of completed and non-completed suicide attempts, adolescent suicidal ideation by itself has been shown to increase the risk for compromised adult functioning and future psychiatric morbidity (5). Many risk factors associated with adolescent SB have been described (6-8), and the interplay between them as well as other moderators has been thoroughly studied. In the last two decades many studies have shown substance-use disorders (SUD) to be one of the most prominent risk factors associated with adolescent SB and increased mortality (9-12). On an average day in the U.S. alone about half a million adolescents aged 12 to 17 drink alcohol and an equal number use cannabis (13), and these drug-using teenagers report increased rates of sadness or hopelessness and SB (14).
Gal Shoval, MD, POB 102, Petah Tikva 49100, Israel
shovgal@tau.ac.il
Dan Shlosberg et al.
Adolescent SUD as well as SB are both central issues in child and adolescent psychiatry and the relationship between them has been thoroughly and systematically described elsewhere (15-17). Nevertheless, several emerging issues regarding this relationship have most recently generated high interest among care-givers from educational, social and health related services in the community as well as the clinical setting, yielding a substantial amount of data which may be used to formulate targeted intervention plans. In this review we will address these emerging issues and offer future perspectives. Patterns of Adolescent Substance Use and Abuse Apart from tobacco, alcohol and cannabinoid-based substances are by far the most widely used (13) and studied abused substances worldwide. Both have been shown in many studies to be associated with elevated rates and increased risk for adolescent SB (16,18,19) and may be associated with increased suicide attempt lethality (20). In this context it is worth mentioning that a wide variability in the temporal patterns of abuse exist prior to the emergence of SB, ranging from acute intoxication (21) adjacent to a suicidal act (i.e., facilitating factor) to chronic abuse that can predate SB by several years (22). It is evident today that the impact of alcohol and other substance abuse on SB is more complex than was previously thought and is related not only to the amount of substance consumed (light vs. heavy use) but also, and maybe even more so, to the different patterns of substance abuse as detailed below for both alcohol and other substances abused. Binge drinking Many adolescents display a pattern of excessive alcohol consumption termed “binge drinking,” defined as the consumption of five or more standard alcoholic drinks within less than two hours (23). This pattern is highly prevalent, particularly among youth worldwide (24, 25), and is associated with increased risks for suicidal thoughts and attempts (26). This holds true even when comparing binge drinkers to current alcohol drinkers who do not binge drink (27). Binge drinkers also tend to pursue the concurrent use of other substances of abuse, thus increasing the risk for SB. For instance, a significant correlation with the lifetime use of cannabis has been described for binge drinkers (24), with an elevated risk (OR=5) for concurrent
cannabis use as compared to non-binging alcohol users (27). Binge drinkers who co-abuse cannabis display severe patterns of heavy drinking including increased binge drinking instances as well as elevated alcohol consumption on each drinking occasion (28) both of which are associated with increased risks for suicide attempts (27). Poly-substance abuse Recent epidemiological studies reveal that adolescent poly-substance consumption is a widespread phenomenon and has become the rule rather than the exception (29). This may hold true even for early adolescent drug abusers as data gathered from youths aged 12-14 admitted to substance-abuse treatment programs in the U.S. reveal that 46% of them were poly-substance abusers (30). Polysubstance use is highly correlated with increased risk for suicide attempts (31) and a strong correlation appears also between the number of substances abused to the probability of a reported suicide attempt (19). In this context, the lifetime number of substances used by itself constitutes an important risk factor for SB (32). Since cannabinoids are perceived as “gateway drugs” to the future use of other illicit substances (33), knowledge of their use by adolescents should warrant questioning regarding the consumption of other substances. Furthermore, regarding adolescents with SUD, some studies even suggest that it may not be cannabis use per se that increases the risk of self-directed injurious behavior, but more so the use of other illicit drugs that may follow the initial use of cannabis (34). Co-occurring Substance Abuse and Other Mental Disorders Psychiatric morbidity and mood disorders in particular are highly associated with increased SB rates among adolescents (35). A recent nationally representative study presenting data on principal diagnoses for hospital stays in the U.S., reported that in 2010 mood disorders were the most common principal diagnosis for all hospital stays among children and adolescents (1-17 years old), and the rate of hospital stays for mood disorders had increased by 80% from 1997 to 2010 (36). Since mood disorders and particularly depression are highly prevalent among adolescents (37) they can be taken as good examples when setting out to describe how mental disorders affect the connection between SUD and SB. Although depression is the strongest known risk factor for adolescent suicide (11, 38-40), an ongoing debate exists 263
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among clinicians regarding the overall effect that antidepressant drugs have on youth SB (41). This may be in part due to other confounding variables that affect depression, SB or both in an unpredicted manner. One possible explanation for the complex effect of antidepressant medication on adolescent SB is the concurrent use of psychoactive substances which may very well complicate the resolution of a depressive state or the diminution of SB regardless of the therapeutic regimen. Adolescent depression displays high co-morbidity with alcohol and substance abuse (42, 43) and adolescents suffering from major depressive episodes (MDE) are about twice as likely to be using illicit drugs or to be heavy alcohol consumers (37) than non-depressed peers. Epidemiologic research shows that among adolescents with SUD having a co-occurring diagnosis of other mental disorders, and in particular mood disorders, are the norm rather than the exception. This diagnostic entity is otherwise referred to as “dual diagnosis” or “co-occurring disorders” (COD). Data from 6,886 people presenting to substance abuse treatment in the U.S., of them 4,939 adolescents, revealed that the majority suffered from COD with young adults/late adolescents (aged 18-25) appearing to be the most vulnerable age group (44). In this study, about 90% of early adolescent below 15y of age had suffered at least one mental health problem in the past year and more than half of these reported symptoms of depression (44). The combination of mood disorders and substance abuse has been shown to elevate the risk for adolescent SB (45, 46) including suicide completion (38). Recent evidence further suggests that increased levels of severity of co-occurring disorders in adolescents lead to a heightened risk for a suicide attempt (47). Some studies reveal an additive and even a synergistic effect when COD occurs. For instance, the combination of depression and alcohol abuse in adolescents has been shown to be associated with an additive effect on the lifetime probability for suicide attempts in adolescent girls and a synergistic effect for adolescent boys (48). Interestingly, this combined effect may disappear in the transition to adulthood since a recent report suggested that in adults with MDE, alcohol-dependence may not significantly affect the risk for SB (49), although it should be stressed that other reports suggest otherwise (50). In studies of adolescents suffering from bipolar disorder, subjects with SUD demonstrated a significantly greater lifetime prevalence of suicide attempts as compared to those without SUD (51) and those who concomitantly performed a suicidal attempt were more likely to be abusing alcohol or to have SUD as compared to those who did not attempt suicide (52). 264
Large-scale prospective studies are needed in order to address the causative relationship between substance abuse, depression and SB since current research faces many methodological challenges (17) . Pioneering studies such as the Course and Outcome of Bipolar Youth (COBY) (53) may lay the foundations for the clarification of this intricate relationship and lead to the formulation of effective evidence-based treatment plans. An interesting question in this regard is whether early treatment of mood disorders will be efficacious in decreasing future SUD by alleviating the patients’ need to “self-medicate” in a similar fashion as was previously demonstrated in ADHD patients (54). Another interesting question is whether early treatment of SUD decreases the occurrence and severity of future affective disorders. Several barriers exist that hinder the effective treatment of adolescent COD (55). In the latter comprehensive review, the author suggested that the historical separation of the mental health and substance abuse fields should be abolished since both disorders are psychiatric conditions with established neurobiological pathologies that share developmental etiologies and clinical trajectories. The high rates of COD evidenced today and the increased risk for SB that entails this morbidity indeed demands the provision of integrated substance-abuse and mental-health services in the same program. SUD and SB in Sexual Minorities Sexual minorities, also referred to as lesbian-gay-bisexual (LGB), suffer from increased rates of social stress and rejection across all age groups (56). However, the assessment of data relating specifically to sexual minorities in the adolescent age group is not a simple task. Most LGBs do not quite openly present themselves as such and a significant portion of them have doubts regarding their sexual preferences. Furthermore, many of them may change their sexual orientation throughout this transitional period (57). Such an assessment is made even harder when trying to retrospectively gauge whether same-gender sexual affiliation was present, requiring the differentiation of self-defined sexual orientation from practiced sexual relationships which may or may not be similar to their sexual affiliation. Nevertheless, it is estimated that LGBs account for at least 5% of adolescents (58, 59), whereas up to an additional 5% present themselves as unsure of their sexual orientation (58) and do not necessarily share similar behavioral patterns as the LGB group. Several studies report that sexual minority youths are subject to increased rates of social isolation, harassment and
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victimization (60, 61). Stressful events such as these may translate into increased rates of mental disorders and most notably depression (62) as well as SB (63, 64). Adolescent sexual minorities compared to their heterosexual peers display increased SB (OR=2.9) and the level of disparity is correlated to the severity of SB observed (OR=1.96 , 2.2 , 3.18 , 4.17 for suicidal ideation, intent, attempt and serious attempt accordingly) (65). Data from the ongoing Youth Risk Behavior Survey (YRBS), a large-scale U.S. national school-based survey, report the prevalence of students having attempted suicide to be 6.4%, 25.8%, and 28% for heterosexual, gay/lesbian or bisexual students respectively (58): these rates are exceedingly high relative to the general population. Adolescent sexual minorities also display an elevated risk for SUD including lifetime use of alcohol (OR=2.23) and cannabis (OR=2.58) (66), earlier initiation of alcohol consumption (67) and a higher prevalence of binge drinking (58, 67). Since sexual minority adolescents display both increased SB rates and SUD prevalence, one may speculate that the causal relationship between these two behavioral states will be more pronounced in members of this population. Quite contrarily, it has been shown that problem alcohol and drug use was more strongly associated with suicidal ideation and attempts in non-LGB adolescents as compared to LGB adolescents (63). The authors of the former study stressed the importance of elucidating specific suicidal risk-factors relevant to LGB adolescents other than the generally perceived leading risk factors which may be more relevant to non-LGB adolescents. Yet one must interpret these results cautiously given the relatively older age (1826yrs) of the participants of this study as these results may not be applicable to earlier stages of adolescence (12-19yrs) in which the risk for SB emergence is greatest when compared to non-LGB counterparts (68). Until these results are replicated or refuted it will be safer to assume such a connection exists given the higher prevalence of both phenomena in this population while other specific risk factors for SB are sought for. A large longitudinal study following a cohort of over 1,000 children from birth to age 21, in which the sexual orientation from age 16 until 21 was retrospectively studied, found a 5-fold increased risk for SB and almost a 2-fold risk for substance dependence among LGBs through the cohort period (69). The prospective nature of the study allowed for the evaluation of social and familial backgrounds of the subjects and indeed some differences were found between LGBs and other cohort members in their familial background, suggesting a more troubled childhood for LGBs.
However, reanalyzing the results after controlling for these differences produced similar results with negligible effects on the unadjusted ones (69). One may speculate that other risk factors such as developmental and behavioral factors should be sought to account for the increased rates of SB in the LGB population. Additional prospective studies are sorely needed to facilitate the identification of distinct attributes and risk factors concerned with SB in the LGB population through their transition into adulthood and maturation of sexual preference. The Emergence of New “Designer Drugs” From ongoing efforts to monitor adolescent drug-abuse habits, it is evident that temporal preference trends in adolescent substance use exist. For instance, the abuse of non-medical analgesic opioids has become second in prevalence to cannabis usage, surpassing the use of inhalants and hallucinogens (70). Recently, the rise in adolescents’ usage of synthetic cannabinoids (SC) and cathinones, also termed “new designer drugs,” “spice products” or “legal highs,” has become a source of major concern due to high rates of reported usage and relative ease of availability. In Israel, for instance, dozens of “spice delivery services” exist, responding to real-time phone calls or online internet orders promising the delivery of a wide variety of “spice” products within an hour, thus offering their clients maximal discretion and surpassing the need to expose oneself in the process of substance acquisition. Off-shore orders and practically all urban corner shops provide other convenient alternatives for fast and easy access to these substances. The prevalence of adolescent SC use worldwide is not yet clear due to a limited amount of large scale epidemiological studies available, although initial reports from select populations displayed lifetime prevalence rates of 8-9% (71, 72). Since 2011, questions addressing the use of SC have been added to U.S. national drug monitoring questionnaires. The first results obtained from these large scale surveys were dramatic ; apart from alcohol and tobacco, SC were the second most widely abused substances among 10th and 12th graders (after cannabis) and third among 8th graders (after inhalants), with a two-year stable result of past-12-months prevalence rates among 12th graders of 11.3% (25). Also, the highest rate of emergency department visits involving SC use was within the 12-17 years age group (73). These high prevalence rates are alarming considering the intensive worldwide legislative efforts administered to prohibit the sale and distribution of SC (74, 75). Apart from a few case-reports (76), no studies have yet reported a direct 265
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association between SB and SC usage in adolescents. Our group is currently designing such a study among adolescent psychiatric inpatients, as the rapid growth of the use and harm of SC is already clinically evident. The military setting offers another challenging front in the struggle against adolescent SC abuse. Late adolescents joining the armed forces comprise the age group in the military which is most prone to be drug abusers, as most (75%) of military personnel with SUD are under 25 years old (77). In some armies such as the Israeli Defence Force (IDF), most of the soldiers are aged 18-21 years and therefore in that setting the problem of SC is even more relevant. In one case series almost 10% of 155 U.S. army personnel admitted to military hospitals suspected of or admitting to the use of illegal substances were found positive for SC and most of these were under 24 years old (78). Many factors contribute to the increased prevalence of SC among military personnel (e.g., ease of availability, low detectability, vagueness of legality and questionable prosecution liability). Unfortunately, other factors such as increased access to firearms and stressful life events, which are associated with military service, also contribute to increased suicidal attempts, which in the military are more likely than in the general population to result in death (79). The evident increase in SC usage in a setting of chronic stress coupled with a direct access to firearms should warrant an examination of the possible association of SC with the prevalence and outcome of suicide attempts in the military setting, this association has not yet been explored despite a clear association previously found among military personnel between completed suicides and alcohol or other substance use (80). An array of suicide prevention programs, a â&#x20AC;&#x153;mutual responsibilityâ&#x20AC;? gatekeeper program, was recently employed in the IDF to encourage soldiers to report alcohol and substance abuse including SC in their units, aiming at decreasing these behaviors and possibly the associated SB. Legislative initiatives coupled to strict and timely law enforcement activity to reduce SC retailing should be encouraged. Judging by the number of calls made to nationwide U.S. poison centers consequent to SC exposures during the first half of 2013, the number of exposures has more than halved compared to the corresponding period in 2012. This offers circumstantial evidence for the success of such legislative actions (81). Conclusions Although recent data reveal an encouraging decrease in adolescent suicide attempts and death rates during the 266
past decade (2, 3), suicide in this age group remains by and large a major public-health concern. Adolescent substance abuse has also become a heavy burden on society and the need for its successful management poses many challenges on healthcare, psycho-social, and educational caregivers. The association of adolescent SUD with SB has been substantiated for more than two decades, yet global efforts to reduce substance abuse or SB have displayed a relative lack of success. There are almost no prospective randomized controlled trials from which one can devise and implement evidence based treatment plans specific for adolescents with SUD and SB. Data derived largely from adult studies suggest that interventions schemes that rely on or integrate cognitive behavioral treatment (CBT) techniques may be efficacious in reducing both suicidal behavior as well as substance use among adolescents with co-occurring problems (82). Reductions in suicide attempts, binge drinking and cannabis use were all considered part of the 21 critical national health objectives prioritized by the Healthy People 2010 initiative (HP2010), devised to improve the health and well being of U.S. adolescents and young adults. Although an improvement was reported in all these objectives during the decade in which these were to be achieved, none of the declared target rates were ultimately reached (83). In order for these goals, set by policy makers and guided by expert consultants, to be attained, novel strategies and policies clearly have yet to be formulated. Emerging patterns and norms of substance abuse such as poly-substance abuse and binge drinking emphasize the need to rely on real-time research which may assist in the formulation of time and place-relevant prevention plans and treatment options. Recent studies highlight specified populations with increased risk for both SB and SUD, such as LGB and COD adolescents, the latter displaying a stronger association between the two phenomena. These may suffer from increased vulnerability or decreased resilience to the perilous effects of SUD, social stress or genetic predisposition for mental pathologies. Healthcare personnel should pay heightened attention to observed SB when encountered in LGB youth, even when they are most subtly presented. They should aspire to initiate a suicidality-assessment as soon as possible since the increased risk for LGB SB does not dissipate through sexual identity maturation but rather tends to persist through the transition into adulthood (84). Many adolescents suffering from psychiatric conditions do not turn to treatment (85). Only a minority of completed adolescent suicides are diagnosed with mental problems and many of these go untreated for such problems prior to the
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suicidal act (86). SUD are most common among adolescents with psychiatric morbidity (87, 88) and increasingly often patients are diagnosed as suffering from “dual diagnosis” or COD. Unfortunately, for most of these patients this does not translate into an integrated treatment plan and a duality in treatment focus invariably exists. This is evident in all the treatments’ levels such as its setting, the professional training of the caregivers (i.e., psychiatry vs. drug rehabilitation) and the type and duration of treatment administered. In an editorial published by Bertolote et al. (89) they wrote: “Effective treatment for chronic conditions requires a transformation of health care systems, away from delivery focused on episodic care in response to acute illness, and towards a comprehensive system of care that is designed to meet the long-term needs of patients.” We propose that it is high time to end the artificial dichotomy between psychiatric and substance-abuse directed healthcares and to focus on the adolescent patient as suffering from a chronic illness that has the potential to manifest itself in either direction at a given time and under different circumstances. The rapid emergence and spread of new “designer drugs,” such as hundreds of SC products, offers new challenges to health systems. Legislative efforts to ban these substances should ideally be easy to implement by law enforcement agencies and have a generalized formulation so as to capture a wide range of substances in their legal definition. Despite the paucity of current data relating to the connection between SC use and SB, it is at least prudent to assume such a connection exists until tested, given the shared neuronal target-receptor profile with cannabis and relying on clinical data from cannabis users which firmly establish this connection. Other factors may influence the success of suicide prevention plans in adolescents with SUD. For instance, adolescents are highly peer-influenced and follow the norms of their birth cohort and it has been recently shown that members of birth cohorts with more restrictive social norms regarding alcohol use have a lower likelihood to be abusing alcohol (90). This stresses the potential utility of adolescenttargeted as opposed to population-targeted prevention plans and restrictive measures regarding substance use and may also hold true for SB as well, given the “contagious” effect of suicide in youth (91). In this regard, the timing of prevention plan initiation may be critical. It has been shown that about a third of early adolescent admissions to rehabilitation centers report using their primary substance of abuse at age 11 or younger and many of these are CODs (28). Most recently it was reported that at 12 years of age there is a marked increase in the prevalence of SB (92)
and that most of the transitions from suicide ideation to plan or attempt and also from plan to attempt, occur in adolescents within the first year of onset of ideation or of developing the plan (92) as was previously shown for adults (93). Since differences in rates of SB among adolescents with substance use as compared to those without are apparent by age 13 years and become more pronounced thereafter (22), it may therefore be wise to target the implementation of anti-suicidality and SUD prevention and intervention plans to the junior- high school age group. In addition, agerestriction legislative acts, such as increasing the minimum legal alcohol drinking age from 18 to 21, have been shown to reduce completed suicides among 18-23 years old (94), suggesting that postponement of exposure to potentially harmful substances by early educational initiatives coupled to age-limiting legislative acts should be an integral part of adolescent anti-suicidality strategies. Reference 1. CDC. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, accessed April 10, 2014http://www.cdc. gov/injury/wisqars/index.html 2. European Commission, Eurostat, accessed July 1, 2013http://epp.eurostat. ec.europa.eu/tgm/table.do?tab=table&init=1&plugin=1&language=en &pcode=tsdph240. 3. Eaton DK, Kann L, Kinchen S, Shanklin S, Flint KH, Hawkins J, et al. Youth risk behavior surveillance - United States, 2011. MMWR Surveill Summ 2012; 61: 1-162. 4. OECD Family database, accessed April 10, 2014 http://www.oecd.org/ els/family/48968307.pdf 5. Reinherz HZ, Tanner JL, Berger SR, Beardslee WR, Fitzmaurice GM. Adolescent suicidal ideation as predictive of psychopathology, suicidal behavior, and compromised functioning at age 30. Am J Psychiatry 2006; 163: 1226-1232. 6. Bursztein C, Apter A. Adolescent suicide. Curr Opin Psychiatry 2009; 22: 1-6. 7. Cash SJ, Bridge JA. Epidemiology of youth suicide and suicidal behavior. Curr Opin Pediatr 2009; 21: 613-9. 8. Zalsman G. Genetics of suicidal behavior in children and adolescents. In: Dwivedi Y, editor. The neurobiological basis of suicide. Boca Raton, Florida: CRC, 2012. 9. Wilcox HC. Epidemiological evidence on the link between drug use and suicidal behaviors among adolescents. Can Child Adolesc Psychiatr Rev 2004; 13: 27-30. 10. Swahn MH, Ali B, Bossarte RM, Van DM, Crosby A, Jones AC, et al. Self-harm and suicide attempts among high-risk, urban youth in the U.S.: Shared and unique risk and protective factors. Int J Environ Res Public Health 2012; 9: 178-191. 11. Wolitzky-Taylor KB, Ruggiero KJ, McCart MR, Smith DW, Hanson RF, Resnick HS, et al. Has adolescent suicidality decreased in the United States? Data from two national samples of adolescents interviewed in 1995 and 2005. J Clin Child Adolesc Psychol 2010; 39: 64-76. 12. Pompili M, Serafini G, Innamorati M, Biondi M, Siracusano A, Di GM, et al. Substance abuse and suicide risk among adolescents. Eur Arch Psychiatry Clin Neurosci 2012; 262: 469-485. 13. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. (April 29, 2010). The OAS Report: A Day in the Life of American Adolescents: Substance Use Facts Update. Rockville, Maryland, 2010.
267
Emerging Between Adolescent Substance Use and Suicidal Behavior Isr J Psychiatry RelatIssues Sci - Vol.in51the - No Relationship 4 (2014)
14. Kaley S, Messias E, Mancino M. Sadness,suicide and drug misuse: Results from the youth risk behavior survey 2011. Abstract, presented in American Psychiatric Association 166th Annual Meeting, San Francisco, Cal. , 2013. 15. Rowan AB. Adolescent substance abuse and suicide. Depress Anxiety 2001; 14: 186-191. 16. Esposito-Smythers C, Spirito A. Adolescent substance use and suicidal behavior: A review with implications for treatment research. Alcohol Clin Exp Res 2004; 28: S77-88. 17. Galaif ER, Sussman S, Newcomb MD, Locke TF. Suicidality, depression, and alcohol use among adolescents: A review of empirical findings. Int J Adolesc Med Health 2007; 19: 27-35. 18. Borowsky IW, Ireland M, Resnick MD. Adolescent suicide attempts: Risks and protectors. Pediatrics 2001; 107: 485-493. 19. Kokkevi A, Richardson C, Olszewski D, Matias J, Monshouwer K, Bjarnason T. Multiple substance use and self-reported suicide attempts by adolescents in 16 European countries. Eur Child Adolesc Psychiatry 2012; 21: 443-450. 20. McManama O’Brien KH, Berzin SC. Examining the impact of psychiatric diagnosis and comorbidity on the medical lethality of adolescent suicide attempts. Suicide Life Threat Behav 2012; 42: 437-444. 21. Kaplan MS, McFarland BH, Huguet N, Conner K, Caetano R, Giesbrecht N, et al. Acute alcohol intoxication and suicide: A gender-stratified analysis of the National Violent Death Reporting System. Inj Prev 2013; 19: 38-43. 22. Miller M, Borges G, Orozco R, Mukamal K, Rimm EB, Benjet C, et al. Exposure to alcohol, drugs and tobacco and the risk of subsequent suicidality: Findings from the Mexican Adolescent Mental Health Survey. Drug Alcohol Depend 2011; 113: 110-117. 23. National Institute of Alcohol Abuse and Alcoholism. NIAAA council approves definition of binge drinking. NIAAA Newsletter 2004; 3:3. 24. Hibell B, Guttormsson U, Ahlström S, Balakireva O, Bjarnason T, Kokkevi A, et al. The 2011 ESPAD Report - Substance Use Among Students in 36 European Countries , 2011. http://www.espad.org/ 25. Johnston LD, O’Malley PM, Schulenberg JE. Monitoring the future national results on drug use: 2012 Overview, Key Findings on Adolescent Drug Use. Ann Arbor: Institute for Social Research, University of Michigan, 2013. 26. Schilling EA, Aseltine RH, Jr., Glanovsky JL, James A, Jacobs D. Adolescent alcohol use, suicidal ideation, and suicide attempts. J Adolesc Health 2009; 44: 335-341. 27. Miller JW, Naimi TS, Brewer RD, Jones SE. Binge drinking and associated health risk behaviors among high school students. Pediatrics 2007; 119: 76-85. 28. Chun TH, Spirito A, Hernandez L, Fairlie AM, Sindelar-Manning H, Eaton CA, et al. The significance of marijuana use among alcohol-using adolescent emergency department patients. Acad Emerg Med 2010; 17: 63-71. 29. EMCDDA. Selected issue, Polydrug use: Patterns and responses, European Monitoring Centre for Drugs and Drug Addiction, Lisbon. accessed April 10, 2014 http://www.emcdda.europa.eu/publications/ selected-issues/polydrug-use. 30. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (May 3, 2011). The TEDS Report: Substance Abuse Treatment Admissions Aged 12 to 14. Rockville, Maryland, 2011. 31. Reyes JC, Robles RR, Colon HM, Negron JL, Matos TD, Calderon JM. Polydrug use and attempted suicide among Hispanic adolescents in Puerto Rico. Arch Suicide Res 2011; 15: 151-159. 32. Wong SS, Zhou B, Goebert D, Hishinuma ES. The risk of adolescent suicide across patterns of drug use: A nationally representative study of high school students in the United States from 1999 to 2009. Soc Psychiatry Psychiatr Epidemiol 2013; 48: 1611-1620. 33. Fergusson DM, Horwood LJ, Swain-Campbell N. Cannabis use and psychosocial adjustment in adolescence and young adulthood. Addiction 2002; 97: 1123-1135. 34. Rasic D, Weerasinghe S, Asbridge M, Langille DB. Longitudinal associations
268
of cannabis and illicit drug use with depression, suicidal ideation and suicidal attempts among Nova Scotia high school students. Drug Alcohol Depend 2013; 129: 49-53. 35. Hawton K, Saunders KE, O’Connor RC. Self-harm and suicide in adolescents. Lancet 2012; 379: 2373-2382. 36. Pfuntner A, Wier LM, Stocks C. Most frequent conditions in U.S. hospitals, 2010: Statistical Brief #148. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville, Maryland: Agency for Health Care Policy and Research (U.S.), 2006. http://www.ncbi.nlm. nih.gov/books/NBK127490/ 37. Substance Abuse and Mental Health Services Administration, Results from the 2011 National Survey on Drug Use and Health: Mental Health Findings, NSDUH Series H-45, HHS Publication No. (SMA) 12-4725. Rockville, Maryland: Substance Abuse and Mental Health Services Administration, 2011. 38. Brent DA, Perper JA, Moritz G, Allman C, Friend A, Roth C, et al. Psychiatric risk factors for adolescent suicide: A case-control study. J Am Acad Child Adolesc Psychiatry 1993; 32: 521-529. 39. Asarnow JR, Baraff LJ, Berk M, Grob C, Devich-Navarro M, Suddath R, et al. Pediatric emergency department suicidal patients: Two-site evaluation of suicide ideators, single attempters, and repeat attempters. J Am Acad Child Adolesc Psychiatry 2008; 47: 958-966. 40. Shaffer D, Gould MS, Fisher P, Trautman P, Moreau D, Kleinman M, et al. Psychiatric diagnosis in child and adolescent suicide. Arch Gen Psychiatry 1996; 53: 339-348. 41. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: A meta-analysis of randomized controlled trials. JAMA 2007; 297: 1683-1696. 42. Armstrong TD, Costello EJ. Community studies on adolescent substance use, abuse, or dependence and psychiatric comorbidity. J Consult Clin Psychol 2002; 70: 1224-1239. 43. Sher L, Zalsman G. Alcohol and adolescent suicide. Int J Adolesc Med Health 2005; 17: 197-203. 44. Chan YF, Dennis ML, Funk RR. Prevalence and comorbidity of major internalizing and externalizing problems among adolescents and adults presenting to substance abuse treatment. J Subst Abuse Treat 2008; 34: 14-24. 45. Levy JC, Deykin EY. Suicidality, depression, and substance abuse in adolescence. Am J Psychiatry 1989; 146: 1462-1467. 46. Kovacs M, Goldston D, Gatsonis C. Suicidal behaviors and childhoodonset depressive disorders: A longitudinal investigation. J Am Acad Child Adolesc Psychiatry 1993; 32: 8-20. 47. Effinger JM, Stewart DG. Classification of co-occurring depression and substance abuse symptoms predicts suicide attempts in adolescents. Suicide Life Threat Behav 2012; 42: 353-358. 48. Windle RC, Windle M. An investigation of adolescents’ substance use behaviors, depressed affect, and suicidal behaviors. J Child Psychol Psychiatry 1997; 38: 921-929. 49. Shoval G, Shmulewitz D, Wall MM, Aharonovich E, Spivak B, Weizman A, et al. Alcohol dependence and suicide-related ideation/behaviors in an Israeli household sample, with and without major depression. Alcohol Clin Exp Res 2014;38:820-825. 50. Brière FN, Rohde P, Seeley JR, Klein D, Lewinsohn PM.Comorbidity between major depression and alcohol use disorder from adolescence to adulthood. Compr Psychiatry 2014;55:526-533. 51. Goldstein BI, Strober MA, Birmaher B, Axelson DA, Esposito-Smythers C, Goldstein TR, et al. Substance use disorders among adolescents with bipolar spectrum disorders. Bipolar Disord 2008; 10: 469-478. 52. Goldstein TR, Ha W, Axelson DA, Goldstein BI, Liao F, Gill MK, et al. Predictors of prospectively examined suicide attempts among youth with bipolar disorder. Arch Gen Psychiatry 2012; 69: 1113-1122. 53. Birmaher B, Axelson D, Goldstein B, Strober M, Gill MK, Hunt J, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: The Course and Outcome of Bipolar Youth (COBY)
Dan Shlosberg et al.
study. Am J Psychiatry 2009; 166: 795-804. 54. Biederman J, Wilens T, Mick E, Spencer T, Faraone SV. Pharmacotherapy of attention-deficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics 1999; 104: e20. 55. Hawkins EH. A tale of two systems: Co-occurring mental health and substance abuse disorders treatment for adolescents. Annu Rev Psychol 2009; 60: 197-227. 56. Meyer IH. Prejudice, social stress, and mental health in lesbian, gay, and bisexual populations: Conceptual issues and research evidence. Psychol Bull 2003; 129: 674-697. 57. Needham BL. Sexual attraction and trajectories of mental health and substance use during the transition from adolescence to adulthood. J Youth Adolesc 2012; 41: 179-190. 58. Kann L, Olsen E, McManus T, Kinchen S, Chyen D, Harris W, et al. Centers for disease control and prevention. Sexual identity, sex of sexual contacts, and health-risk behaviors among students in grades 9–12. Youth risk behavior surveillance, selected sites, United States, 2001–2009. MMWR Surveill Summ 2011; 60: 1-134. 59. Hatzenbuehler ML. The social environment and suicide attempts in lesbian, gay, and bisexual youth. Pediatrics 2011; 127: 896-903. 60. Garofalo R, Wolf RC, Kessel S, Palfrey SJ, DuRant RH. The association between health risk behaviors and sexual orientation among a schoolbased sample of adolescents. Pediatrics 1998; 101: 895-902. 61. Robinson JP, Espelage DL, Rivers I. Developmental trends in peer victimization and emotional distress in LGB and heterosexual youth. Pediatrics 2013; 131: 423-430. 62. Mustanski BS, Garofalo R, Emerson EM. Mental health disorders, psychological distress, and suicidality in a diverse sample of lesbian, gay, bisexual, and transgender youths. Am J Public Health 2010; 100: 2426-2432. 63. Silenzio VM, Pena JB, Duberstein PR, Cerel J, Knox KL. Sexual orientation and risk factors for suicidal ideation and suicide attempts among adolescents and young adults. Am J Public Health 2007; 97: 2017-2019. 64. Grossman AH, D’Augelli AR. Transgender youth and life-threatening behaviors. Suicide Life Threat Behav 2007; 37: 527-537. 65. Marshal MP, Dietz LJ, Friedman MS, Stall R, Smith HA, McGinley J, et al. Suicidality and depression disparities between sexual minority and heterosexual youth: A meta-analytic review. J Adolesc Health 2011; 49: 115-123. 66. Marshal MP, Friedman MS, Stall R, King KM, Miles J, Gold MA, et al. Sexual orientation and adolescent substance use: A meta-analysis and methodological review. Addiction 2008; 103: 546-556. 67. Corliss HL, Rosario M, Wypij D, Fisher LB, Austin SB. Sexual orientation disparities in longitudinal alcohol use patterns among adolescents: Findings from the Growing Up Today Study. Arch Pediatr Adolesc Med 2008; 162: 1071-1078. 68. Russell ST, Toomey RB. Men’s sexual orientation and suicide: Evidence for U.S. adolescent-specific risk. Soc Sci Med 2012; 74: 523-529. 69. Fergusson DM, Horwood LJ, Beautrais AL. Is sexual orientation related to mental health problems and suicidality in young people? Arch Gen Psychiatry 1999; 56: 876-880. 70. Wu LT, Woody GE, Yang C, Pan JJ, Blazer DG. Racial/ethnic variations in substance-related disorders among adolescents in the United States. Arch Gen Psychiatry 2011; 68: 1176-1185. 71. Hu X, Primack BA, Barnett TE, Cook RL. College students and use of K2: An emerging drug of abuse in young persons. Subst Abuse Treat Prev Policy 2011; 6: 16. 72. Bretteville-Jensen AL, Tuv SS, Bilgeri OR, Fjeld B, Bachs L. Synthetic cannabinoids and cathinones: Prevalence and markets. Forensic Sci Rev 2013; 25: 7-26. 73. Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. (December 4, 2012). The DAWN Report: Drug-Related Emergency Department Visits Involving Synthetic Cannabinoids. Rockville, Maryland, 2012.
74. National Conference of State Legislators. Synthetic Cannabinoids (a.k.a. “K2” / “Spice”) Enactments. http://www.ncsl.org/issues-research/justice/ synthetic-cannabinoids-enactments.aspx, Accessed July 1, 2013. 75. European Monitoring Centre for Drugs and Drug Addiction. http:// www.emcdda.europa.eu/topics/pods/controlling-new-psychoactivesubstances. Accessed July 1, 2013. 76. Thomas S, Bliss S, Malik M. Suicidal ideation and self-harm following K2 use. J Okla State Med Assoc 2012; 105: 430-433. 77. Servies T, Hu Z, Eick-Cost A, Otto JL. Substance use disorders in the U.S. Armed Forces, 2000-2011. MSMR 2012; 19: 11-16. 78. Berry-Caban CS, Kleinschmidt PE, Rao DS, Jenkins J. Synthetic cannabinoid and cathinone use among U.S. soldiers. US Army Med Dep J 2012; Oct-Dec: 19-24. 79. Anestis MD, Bryan CJ. Means and capacity for suicidal behavior: A comparison of the ratio of suicide attempts and deaths by suicide in the U.S. military and general population. J Affect Disord 2013; 148: 42-47. 80. National Institute On Drug Abuse. Substance Abuse in the Military. http://www.drugabuse.gov/publications/drugfacts/substance-abusein-military. accessed July 1, 2013. 81. American Association of Poison Control Centers. https://aapcc. s3.amazonaws.com/files/library/Synthetic_Marijuana_Data_for_ Website_5.31.2013.pdf , Accessed July 1, 2013 . 82. Esposito-Smythers C, Walsh A, Spirito A, Rizzo C, Goldston DB, Kaminer Y. Working with the suicidal client who also abuses substances. Cogn Behav Pract 2012; 19: 245-255. 83. Jiang N, Kolbe LJ, Seo DC, Kay NS, Brindis CD. Health of adolescents and young adults: Trends in achieving the 21 Critical National Health Objectives by 2010. J Adolesc Health 2011; 49: 124-132. 84. Marshal MP, Dermody SS, Cheong J, Burton CM, Friedman MS, Aranda F, et al. Trajectories of depressive symptoms and suicidality among heterosexual and sexual minority youth. J Youth Adolesc 2013; 42: 1243-1256. 85. Shoval G, Mansbach-Kleinfeld I, Farbstein I, Kanaaneh R, Lubin G, Krivoy A, et al. The use of mental health services by adolescent smokers: A nationwide Israeli study. Eur Psychiatry 2013; 28: 269-275. 86. Perou R, Bitsko RH, Blumberg SJ, Pastor P, Ghandour RM, Gfroerer JC, et al. Mental health surveillance among children - United States, 2005-2011. MMWR Surveill Summ 2013; 62 Suppl 2: 1-35. 87. Shoval G, Zalsman G, Nahshoni E, Weizman A. The use of illicit substances in adolescent schizophrenia inpatients. Int J Adolesc Med Health 2006; 18: 643-648. 88. Shoval G, Sever J, Sher L, Diller R, Apter A, Weizman A, et al. Substance use, suicidality, and adolescent-onset schizophrenia: An Israeli 10-year retrospective study. J Child Adolesc Psychopharmacol 2006; 16: 767-775. 89. Bertolote JM, Fleischmann A, De LD, Wasserman D. Suicide and mental disorders: Do we know enough? Br J Psychiatry 2003; 183: 382-383. 90. Keyes KM, Schulenberg JE, O’Malley PM, Johnston LD, Bachman JG, Li G, et al. Birth cohort effects on adolescent alcohol use: The influence of social norms from 1976 to 2007. Arch Gen Psychiatry 2012; 69: 1304-1313. 91. Swanson SA, Colman I. Association between exposure to suicide and suicidality outcomes in youth. CMAJ 2013; 185: 870-877. 92. Nock MK, Green JG, Hwang I, McLaughlin KA, Sampson NA, Zaslavsky AM, et al. Prevalence, correlates, and treatment of lifetime suicidal behavior among adolescents: Results from the National Comorbidity Survey Replication Adolescent Supplement. JAMA Psychiatry 2013; 70: 300-310. 93. Levinson D, Haklai Z, Stein N, Polakiewicz J, Levav I. Suicide ideation, planning and attempts: Results from the Israel National Health Survey. Isr J Psychiatry Relat Sci 2007; 44: 136-143. 94. Birckmayer J, Hemenway D. Minimum-age drinking laws and youth suicide, 1970-1990. Am J Public Health 1999; 89: 1365-1368.
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Cannabis Withdrawal – A New Diagnostic Category in DSM-5 Gregory Katz, MD, Tsafrir Lobel, MD, Alex Tetelbaum, MD, and Sergey Raskin, MD Jerusalem Mental Health Center, Kfar Shaul Hospital, and Hadassah Medical School, The Hebrew University, Jerusalem, Israel
Abstract Background: Cannabis withdrawal was not formally recognized by the DSM-IV classification but is listed, albeit without diagnostic criteria by ICD-10. The American Psychiatric Association recently has included cannabis withdrawal into DSM-5 classification as part of the “Substance-Related and Addictive Disorders” Section. However, many psychiatrists as well as other medical professionals have very little information, if at all, about the new diagnostic entity. Method: The information was obtained from PubMed (research words: Cannabis, THC, Hashish, Marijuana and Withdrawal). The different clinical symptoms of the phenomena as well as some pathophysiological mechanisms and treatment considerations were summarized and discussed. Results and Conclusions: A substantial amount of scientific data has been obtained in recent years concerning reliability, validity and clinical importance of cannabis withdrawal. The possible influence of cannabis withdrawal on the severity of major psychiatric disturbances is far from being understood and deserves further research. Limitations: The reviewed studies varied in sample size, design and methodology limiting clear conclusions.
Drug abuse among psychiatric patients is a widely recognized problem although the precise extent and the origin of this phenomenon are still unclear. In the large-scale CATIE study in the U.S.A., of the 1,460 participants, 23% used substances and 37% of this group met criteria for
substance use disorder (1). In Israel the comorbidity level is also substantial – among psychiatric inpatients lifetime prevalence of drug abuse is about 24%, active abuse of drugs (during last month) is 17.3% and 28.2% of this group abuse two or more substances (2). After alcohol and nicotine, cannabis is the most abused substance in the general population and among dual-diagnosed patients (3). Cannabis withdrawal was not formally recognized by DSM-IV (4) due to uncertainty of the diagnostic features. It is listed, albeit without diagnostic criteria, in the International Statistical Classification of Diseases and Related Health Problems, tenth revision (5). Prevalence and Symptoms of cannabis withdrawal Budney and colleagues provided clear documentation of the present research that supports a compelling argument for the existence of a clinically important cannabis withdrawal syndrome. In their detailed and comprehensive review (6) the authors stated that “designation of a true withdrawal syndrome requires evidence that the negative abstinence effects 1) occur reliably, 2) are not exceptionally rare, 3) have a specific time course that includes a return to baseline state (i.e., are transient effects), 4) abate with readministration of the drug, 5) are due to deprivation of a specific substance, and 6) are clinically significant” (p. 1967). According to these principals it was proposed that “…the cannabis withdrawal syndrome is reliable, valid, and clinically important and should be included in the next revision of DSM” (p. 1775). Additional evidence has accumulated demonstrating that cannabis withdrawal is not rare in the general population, and indeed is very common in persons seeking treatment for cannabis use problems or among heavy users enrolled in research studies. The studies on the issue used several approaches, including retrospective
Address for Correspondence: Gregory Katz, MD, The Jerusalem Mental Health Center, Kfar Shaul Hospital, Jerusalem 90160 Israel ngkatz60@gmail.com
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self-report (7), prospective out-patient self-report (8, 9), and prospective inpatient observation (10). Two studies (11, 12) examined the prevalence of cannabis withdrawal symptoms using the U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) dataset. The results showed that about 29% of those who used cannabis with minimum frequency of three times per week within the past year reported experiencing at least two cannabis withdrawal symptoms within the past year. Among those who had ever used cannabis more than three times per week within last year, 44% reported experiencing at least two cannabis withdrawal symptoms and 34% reported experiencing at least three symptoms. Another study used retrospective self-report data on subjects’ “most difficult” quit attempt without formal treatment. The sample included 384 adult, non-treatment-seeking lifetime cannabis smokers (13). This study assessed prevalence, time of onset, and peak intensity (5-point Likert scale) for 39 withdrawal symptoms. The results indicated that 40.9% of subjects met the DSM-5 cannabis withdrawal proposed criterion (at least 3 of 7 symptoms); 30.0% met the Budney and Hughes (14) 4-symptom criteria (at least 4 of 11 symptoms); and 57.3% met the Budney et al. (15) 2-symptom criteria (at least 2 of 11 symptoms). Requiring only 2 out of 7 symptoms for DSM-5 cannabis withdrawal increased the proportion of subjects with cannabis withdrawal to 57.3%, while requiring 4 of 7 symptoms reduced the proportion to 28.1%. Reducing the DSM-5 symptoms list to six by dropping physical symptoms (reported by 24.7% of subjects) reduced the proportion of subjects meeting the cannabis withdrawal criterion only slightly, from 40.9% to 38.0%. This study had several limitations. Data were obtained by retrospective self-report with no external corroboration; subjects were living in the community, with access to psychoactive substances other than cannabis. There were no significant associations between decreased use of caffeine, alcohol, or tobacco during the attempts to quit and meeting DSM-5 proposed criteria for cannabis withdrawal. The significance of withdrawal symptoms in risk of relapse into active cannabis use disorders remains unclear. Though cannabis withdrawal has been hypothesized to play a role in maintaining cannabis use in several papers (14, 16), in a follow-up study the results were different (17). Withdrawal symptoms were assessed in 36 subjects seeking treatment for cannabis dependence. Follow-up was performed 26±4 months later, and at this point, the withdrawal symptoms were re-assessed. The
following symptoms were significantly elevated after abstinence compared with follow-up: irritability, anger, depression, restlessness, craving, sleep problems, strange dreams, increased appetite, violent outbursts, sweating, hot flashes, chills, and shakiness. Average withdrawal scores at baseline did not differ with gender, age, treatment type, extent of cannabis use, or a lifetime history of anxiety or affective disorders. The authors concluded that while withdrawal symptoms have consistently been found to follow the cessation of cannabis use among subjects with a history of heavy or daily cannabis use, the symptoms may be of limited clinical importance. Other factors hypothesized to play a significant role in increasing the risk of relapse following attempts to quit: social role participation, personality, psychiatric disorders, and age of onset, level of use, severity of dependence, or other drug use. There were serious limitations in the study. The timeperiod for withdrawal symptoms at baseline was not specified; relapse was assessed 2–3 years after the baseline interview and it might be argued that the potential significance of withdrawal symptoms is unlikely to be detected at such a late point in time. The authors assessed the withdrawal symptoms retrospectively at both baseline and follow-up. These as well as other research studies on cannabis dependence and withdrawal were conducted since the publication of the DSM-IV and supported inclusion of cannabis withdrawal as a disorder. They were followed by the announcement of cannabis dependence criteria in the DSM-5 under the chapter on diagnosis of “Substance-Related and Addictive Disorders” (18). The specific diagnostic criteria are: Inclusion: Requires at least three of the following symptoms, developing within one week of ceasing (or reducing) cannabis use that has been heavy and prolonged. i. Irritability; anger or aggression ii. Nervousness or anxiety iii. Sleep difficulty iv. Decreased appetite or weight loss v. Restlessness vi. Depressed mood vii. Somatic symptoms causing significant discomfort Exclusion: If the symptoms are attributable to another medical condition or better explained by another mental disorder, including intoxication with or withdrawal from another substance, do not make diagnosis. The DSM-5 criteria differ somewhat from several prior proposed diagnostic criteria for cannabis withdrawal 271
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(14, 15, 19). These proposals varied in the content and length of the symptom list and the required number of symptoms. Gorelick and colleagues (13) summarized the differences of proposed symptoms in their comprehensive review. The high diversity of proposed criteria for cannabis withdrawal underlined the need for a more conservative approach. A 15-item version of the Marijuana Withdrawal Checklist (MWC) (20) lists common as well as less frequently observed cannabis-withdrawal symptoms (items: craving for marijuana, depressed mood, decreased appetite, increased aggression, increased anger, headache, irritability, nausea, nervousness/anxiety, restlessness, shakiness, sleep difficulty, stomach pains, strange dreams, and sweating). Participants rate each item on a 0–3 scale (0 = not at all, 1 = mild, 2 = moderate, and 3 = severe) based on their experience the last time they stopped using cannabis. A composite withdrawal discomfort score (WDS) is created by summing the severity ratings of all 15 items. The internal reliability of this measure was proven as high. Possible causes and mechanisms of cannabis withdrawal Non-human studies of cessation of marijuana or cannabinoids have provided evidence of a withdrawal response. Abstinence effects of cannabis in animals included aggression, anorexia, biting, bruxism, irritability, hair-pulling, hyperactivity, increased eye contact and gross motor movement, piloerection, reduction in operant responding for food, scratching, shaking, tooth-baring, yawning, and frequent periods of EEG desynchronization (15). Animal models exhibit both tolerance and dependence following chronic administration of cannabinoids. In rodent brain, downregulation of CB1 (cannabinoid receptor type 1) receptor signaling is thought to underlie tolerance (21). The downregulation is larger and occurs more rapidly in cortical regions, such as hippocampus and cerebellum, than in subcortical regions, such as basal ganglia and midbrain (22). The downregulation is reversible upon abstinence and more rapid in striatum and midbrain than in cortical regions (23). Inhibitors of endocannabinoid-metabolizing enzymes – fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the enzymes responsible for the degradation of the endogenous cannabinoid ligands anandamide and 2-arachidonoylglycerol – reduce precipitated withdrawal responses in tetracannabinol (THC) - dependent mice (24). The study of Huang et al. (25) was the first 272
to demonstrate hyperlocomotion as an explicit sign of precipitated THC abstinence in mice. Animal models demonstrated the high degree of plasticity that occurs at the molecular level in various brain regions following chronic cannabinoid exposure (26). Human research has included laboratory studies of directly observed cannabinoid administration and abstinence. Abstinence from THC causes prominent behavior and affective changes (27). The decrease in mesolimbic dopamine function is considered to play the central role in development of cannabis withdrawal (28). The neuropharmacological mechanism of cannabis dependence may involve interactions of the endocannabinoid system with the dopaminergic and opioid systems (29). Hirvonen et al. (30), using Positron Emission Tomography imaging, showed reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ~4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels. Gorelick and colleagues (31) studied the possibility of development of antagonist-elicited cannabis withdrawal in humans. Ten male daily cannabis smokers received eight days of increasingly frequent 20-mg oral Δ⁹-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the pre-specified withdrawal criteria of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, areaunder-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. The sum-
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mary was that prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These results stand opposite to the results of the above mentioned nonhuman studies (24, 25). This issue remains controversial and needs further clarification. Recently Verweij et al. (32) estimated the role of genetic and environmental influences on individual differences in cannabis withdrawal. The sample included 2,276 lifetime cannabis-using adult Australian twins. Cannabis withdrawal was defined in accordance with criterion B of the proposed DSM-5 revisions. Cannabis abuse/dependence was defined as endorsing one or more DSM-IV criteria of abuse or three or more dependence criteria. The classic twin model was used to estimate the genetic and environmental influences on variation in cannabis withdrawal, along with its co-variation with abuse/ dependence. The results indicated that 11.9% of cannabis users met criteria for cannabis withdrawal. Around 50% of between-individual variation in withdrawal could be attributed to additive genetic variation, and the rest of the variation was mostly due to non-shared environmental influences. Importantly, the genetic influences on cannabis withdrawal almost completely (99%) overlapped with those on abuse/dependence. The researchers concluded that cannabis withdrawal symptoms exist among cannabis users, and that cannabis withdrawal is moderately heritable. Genetic influences on cannabis withdrawal are the same as those affecting abuse/dependence. Treatment A few studies have examined the effects of dronabinol (oral THC) on the symptoms of cannabis withdrawal. Vandrey and colleagues (33) estimated the dronabinolâ&#x20AC;&#x2122;s dose-dependent ability to suppress cannabis withdrawal and cognitive functions. Thirteen daily cannabis smokers completed a within-subject crossover study and received 0, 30, 60 and 120mg dronabinol per day for five consecutive days. Vital signs and subjective ratings of cannabis withdrawal, craving and sleep were obtained daily; outcomes under active dose conditions were compared to those obtained under placebo dosing. On the fifth day of medication maintenance, participants completed a comprehensive cognitive performance battery and then smoked five puffs of cannabis for subjective effects evaluation. Each dronabinol maintenance period occurred in a counterbalanced order and was separated by nine days of ad libitum cannabis use. The results revealed
that dronabinol attenuated cannabis withdrawal in a dose-dependent manner and resulted in few adverse side effects or decrements in cognitive performance. Lofexidine, an agonist at the alpha2-adrenergic receptor that is used to treat opiate withdrawal was tested both alone and in combination with THC in the treatment of cannabis withdrawal (34). The male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for seven days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. The results showed the different effects of THC and lofexidine: reversal of anorexia and weight loss associated with marijuana withdrawal, decrease in subset of withdrawal symptoms, but increase in sleep onset latency, and no decrease in rate of marijuana relapse. Lofexidine was sedating, worsened abstinencerelated anorexia, did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combined use of lofexidine and oral THC was proposed in cases of cannabis withdrawal. Effects of baclofen and mirtazapine on a laboratory model of marijuana withdrawal and relapse were also studied (35). During active marijuana smoking, baclofen decreased craving for tobacco and marijuana in a dose-dependent manner, but had little effect on mood during abstinence and did not decrease relapse. Baclofen worsened cognitive performance regardless of marijuana condition. Mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease marijuana relapse. Overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine showed promise for the potential treatment of marijuana dependence. The efficacy of nefazodone and bupropion-sustained release was also investigated for the treatment of cannabis dependence and withdrawal (36). A double-blind, placebo-controlled, design was employed to assess if nefazodone and bupropion-sustained release increased the probability of abstinence from cannabis and reduced the severity of cannabis dependence and cannabis withdrawal symptoms during a 13-week outpatient treatment program. One-hundred and six participants (mean age= 32 years; females n = 25) were randomized to one of three medication conditions (nefazodone, bupropionsustained release, or placebo) and participated in a weekly, individually based coping skills therapy program. Results 273
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indicated an increased probability of achieving abstinence over the course of treatment and a decrease in the severity of cannabis dependence and the withdrawal symptom of irritability. There were no significant effects demonstrated for nefazodone and bupropion-sustained release on cannabis use or cannabis withdrawal symptoms. The results indicate nefazodone and bupropion-sustained release may have limited efficacy in treating cannabis dependence. The different and promising approach in treatment of cannabis withdrawal was raised by Mason et al. (37) who conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/ GABA modulating drug, gabapentin, for the treatment of cannabis dependence and withdrawal. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted with 50 unpaid treatment-seeking male and female outpatients, aged 18-65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology and by the Timeline Followback Interview. The symptoms as measured by the Marijuana Withdrawal Checklist were also significantly decreased. Overall, gabapentin was associated with significantly greater improvement in overall performance on tests of executive function. This pilot study provided preliminary support for the safety and efficacy of gabapentin for treatment of cannabis withdrawal that merits further study, and provides an alternative conceptual framework of this issue. Cannabis Withdrawal in Patients with Co-Occurring Addictive and Major Mental Disorders Cornelius and co-authors (38) reported that cannabis withdrawal is common among treatment-seeking adolescents with cannabis dependence and major depression, and is associated with rapid relapse to dependence and provides support for the clinical significance of withdrawal among dual diagnosed adolescents. The participants in this study included 170 adolescents and young adults, including 104 with cannabis dependence, 32 with cannabis abuse, and 34 with cannabis use without dependence or abuse. All of these subjects demonstrated current depressive symptoms and cannabis use, and most demonstrated current DSM-IV major depressive disorder and current comorbid cannabis dependence. 274
Most (N=80) of those subjects also demonstrated a current diagnosis of major depressive disorder, and a larger number (N=85) demonstrated a lifetime diagnosis of major depressive disorder. The mean number of cannabis withdrawal symptoms in this cannabis dependent group was 6.0 ± 3.6. The mean self-rated Beck Depression Inventory Score in this group was 20.6 +/− 9.2, and the mean Hamilton Depression score was 16.1±8.7. These subjects had presented for treatment for either of two double-blind, placebo-controlled trials involving fluoxetine. Cannabis withdrawal was the most commonly reported cannabis dependence criterion among the 104 subjects in the sample with cannabis dependence, being noted in 92% of subjects, using a two-symptom cutoff for determination of cannabis withdrawal. The most common withdrawal symptoms among those with cannabis dependence were craving (82%), irritability (76%), restlessness (58%), anxiety (55%), and depression (52%). Cannabis withdrawal (in the N=170 sample) was reported to have been associated with rapid reinstatement of cannabis dependence symptoms (rapid relapse). These findings suggested that cannabis withdrawal should be included as a diagnosis in the DSM-5 and has clinical importance in patients with co-occurring addictive and affective pathology . The main limitation of the study is lack of analysis of influence of cannabis withdrawal on severity and course of depressive symptoms. The data concerning appearance of cannabis withdrawal in patients suffering from schizophrenia are very limited. The only study known to us concerning the dual diagnosed patients (39) has been published recently. One hundred and twenty participants, predominantly African-American (62.5%) and male (76.7%), met inclusion criteria; 20.1% reported that their first regular cannabis use (median age 15 years [range 8-48]) preceded their first psychotic symptoms (20 [4-50] years). Twenty (16.7%) participants met lifetime criteria for cannabis abuse; 98 (81.7%) met surrogate criteria for lifetime cannabis dependence. Withdrawal symptoms were reported by 113 (94.2%) participants, with 74.2% reporting ≥4 symptoms. The most frequently reported withdrawal symptoms were craving for cannabis (59.2%), feeling anxious (52.57%), feeling bored (47.5%), feeling sad or depressed (45.8%), feeling irritable or jumpy (45.0%), feeling restless (43.3%), and trouble falling asleep (33.3%). One hundred and four (92.0%) participants took some action to relieve at least one of their withdrawal symptoms during their index-quit attempt, including 26 (23.0%) participants who reported resuming cannabis use. The conclusion of the study, that
Gregory Katz et al.
cannabis withdrawal is a clinically significant feature of cannabis use among people with schizophrenia, may serve as a negative reinforcer for relapse. The main shortcoming of the study was its uncontrolled design. There is high comorbidity between cannabis abuse and anxiety and mood disorders (40). The prominent overlap between cannabis withdrawal and symptoms of anxiety and affective disorders, however, makes it difficult for proper diagnosis and research. This group usually is treated by different kinds of medications (anxiolytics, antidepressants, neuroleptics) with possible influence on severity of withdrawal symptoms. Therefore, it is unclear whether the existing diagnostic tools are able to diagnose the signs of cannabis withdrawal in comorbid patients. Limitations The reviewed studies were heterogeneous in sample size, design and methodology. The studies on cannabis withdrawal in “dual diagnosis” patients (mainly schizophrenia and bipolar disorder) were scarce with very limited data for analysis. Conclusions The reliability, validity and clinical importance of cannabis withdrawal have been proven in recent years. However, many clinical implications of the phenomena are far from being understood, especially in dual-diagnosed patients. The possible influence of cannabis withdrawal on the severity of major psychiatric disturbances and reaction to treatment in these patients deserves greater attention in research and clinical practice. References 1. Swartz MS, Wagner HR, Swanson JW, Stroup TS, MacEvoy JP, MacGee M, Miller del D, Reimheirr F, Khan A, Canive JM, Liberman JM. Substance use and psychosocial functioning in schizophrenia among new enrollees in the NIMH CATIE study. Psychiatr Serv 2006; 57:1110-1116. 2. Katz G, Durst R, Shufman E, Bar-Hamburger R, Grunhaus L. Substance abuse in hospitalized psychiatric patients. Isr Med Assoc J 2008; 10:672-675. 3. Khan SS, Secades-Villa R, Okuda M, Wang S, Pérez-Fuentes G, Kerridge BT, Blanco C. Gender differences in cannabis use disorders: Results from the National Epidemiologic Survey of Alcohol and Related Conditions. Drug Alcohol Depend 2013;130:101-108. 4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed., text rev.). Washington, DC: 2000. 5. World Health Organization.. The ICD-10 classification of mental and behavioural disorders: Clinical descriptions and diagnostic guidelines. Geneva: World Health Organization, 1992. 6. Budney A, Hughes JR, Moore BA, Vandrey R. A review of the validity and significance of the cannabis withdrawal syndrome. Am J Psychiatry 2004; 161: 1967-1977.
7. Copersino ML, Boyd SJ, Tashkin DP, Huestis MA, Heishman SJ, Dermand JC, Simmons MS, Gorelick DA. Cannabis withdrawal among nontreatment-seeking adult cannabis users. Am J Addict 2006;15:8-14. 8. Budney AJ, Moore BA, Vandrey RG, Hughes JR. The time course and significance of cannabis withdrawal. J Abnorm Psychol 2003;112:393-402. 9. Vandrey RG, Budney AJ, Hughes JR, Liguori A. A within-subject comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and both substances. Drug Alcohol Depend 2008 ;1;92:48-54. 10. Milin R, Manion I, Dare G, Walker S. Prospective assessment of cannabis withdrawal in adolescents with cannabis dependence: A pilot study. J Am Acad Child Adolesc Psychiatry 2008;47:174-178. 11. Agrawal A, Pergadia M, Lynskey M. Is there evidence for symptoms of cannabis withdrawal in the national epidemiologic survey of alcohol and related conditions? Am J Addictions 2008; 17, 199-208. 12. Hasin DS, Keyes KM, Alderson D, Wang S, Aharonovich E, Grant BF. Cannabis withdrawal in the United States: Results from NESARC. J Clin Psychiatry 2008; 69:1354-1363. 13. Gorelick DA, Levin KH, Copersino ML, Heishman SJ, Liu F, Boggs DL, Kelly DL. Diagnostic criteria for cannabis withdrawal syndrome. Drug Alcohol Depend 2012;1:141-147. 14. Budney A, Hughes J. The cannabis withdrawal syndrome. Curr Opin Psychiatry 2006; 19: 233-238. 15. Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 2004; 161:1967-1977. 16. Haney M, Hart CL, Vosburg SK, Nasser J, Bennett A, Zubaran C, Foltin RW. Marijuana withdrawal in humans: Effects of oral THC or divalproex. Neuropsychopharmacology 2004;29:158-170. 17. Arendt M, Rosenberg R, Foldager L, Sher L, Munk-Jørgensen P. Withdrawal symptoms do not predict relapse among subjects treated for cannabis dependence. Am J Addict 2007;16:461-467. 18. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Washington, DC: American Psychiatric Association, 2013. 19. Chung T, Martin CS, Cornelius JR, Clark DB. Cannabis withdrawal predicts severity of cannabis involvement at 1-year follow-up among treated adolescents. Addiction 2008;103:787-799. 20. Budney AJ, Novy P, Hughes JR. Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction 1999; 94:1311-1322. 21. Gonzalez S, Cebeira M, Fernandez-Ruiz J. Cannabinoid tolerance and dependence: A review of studies in laboratory animals. Pharmacol Biochem Behav 2005;81:300-318. 22. Sim-Selley LJ. Regulation of cannabinoid CB1 in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol 2003;15:91-119. 23. Sim-Selley LJ, Schechter NS, Rorrer WK, Dalton GD, Hernandez J, Martin BR, et al. Prolonged recovery rate of CB1 receptor adaptation after cessation of long-term cannabinoid administration. Mol Pharmacol 2006;70:986-996. 24. Schlosburg JE, Carlson BL, Ramesh D, Abdullah RA, Long JZ, Cravatt BF, Lichtman AH. Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. AAPS J 2009;11:342-352. 25. Huang P, Liu-Chen LY, Unterwald EM, Cowan A. Hyperlocomotion and paw tremors are two highly quantifiable signs of SR141716-precipitated withdrawal from delta9-tetrahydrocannabinol in C57BL/6 mice. Neurosci Lett 2009 6;465:66-70. 26. Lichtman AH, Martin BR. Cannabinoid tolerance and dependence. Handb Exp Pharmacol 2005;:691-717. 27. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. Abstinence symptoms following smoked marijuana in humans. Psychopharmacology (Berl) 1999; 141:395-404. 28. Oleson EB, Cheer JF. A brain on cannabinoids: The role of dopamine release in reward seeking. Cold Spring Harb Perspect Med 2012; 1:2.
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29. Weinstein AM, Gorelick DA. Pharmacological treatment of cannabis dependence. Curr Pharm Des 2011;17:1351-1358. 30. Hirvonen J, Goodwin RS, Li CT, Terry GE, Zoghbi SS, Morse C, Pike VW, Volkow ND, Huestis MA, Innis RB. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry 2012;17:642-649. 31. Gorelick DA, Goodwin RS, Schwilke E, Schwope DM, Darwin WD, Kelly DL, McMahon RP, Liu F, Ortemann-Renon C, Bonnet D, Huestis MA. Antagonist-elicited cannabis withdrawal in humans. J Clin Psychopharmacol 2011;31:603-612. 32. Verweij KJ, Agrawal A, Nat NO, Creemers HE, Huizink AC, Martin NG, Lynskey MT. A genetic perspective on the proposed inclusion of cannabis withdrawal in DSM-5. Psychol Med 2012; 30:1-10. 33. Vandrey R, Stitzer ML, Mintzer MZ, Huestis MA, Murray JA, Lee D. The dose effects of short-term dronabinol (oral THC) maintenance in daily cannabis users. Drug Alcohol Depend 2013;128:64-70. 34. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacol 2008;197:157-168. 35. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Cooper ZD, Foltin RW. Effects of baclofen and mirtazapine on a laboratory model
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of marijuana withdrawal and relapse. Psychopharmacology (Berl) 2010;211:233-244. 36. Carpenter KM, McDowell D, Brooks DJ, Cheng WY, Levin FR. A preliminary trial: Double-blind comparison of nefazodone, bupropionSR, and placebo in the treatment of cannabis dependence. Am J Addict 2009; 18:53-64. 37. Mason BJ, Crean R, Goodell V, Light JM, Quello S, Shadan F, Buffkins K, Kyle M, Adusumalli M, Begovic A, Rao S. A proof-of-concept randomized controlled study of gabapentin: Effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology 2012;37:1689-1698. 38. Cornelius J, Chung T, Martin C, Wood DS, Clark DB. Cannabis withdrawal is common among treatment-seeking adolescents with cannabis dependence and major depression, and is associated with rapid relapse to dependence. Addict Behav 2008; 33: 1500-1505. 39. Boggs DL, Kelly DL, Liu F, Linthicum JA, Turner H, Schroeder JR, McMahon RP, Gorelick DA. Cannabis withdrawal in chronic cannabis users with schizophrenia. J Psychiatr Res 2013;47:240-245. 40. Arias F, Szerman N, Vega P, Mesias B, Basurte I, Morant C, Ochoa E, Poyo F, Babin F. Abuse or dependence on cannabis and other psychiatric disorders. Madrid study on dual pathology prevalence. Actas Esp Psiquiatr 2013;41:122-129.
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Arturo G. Lerner et al.
Synthetic Cannabis Substances (SPS) Use and Hallucinogen Persisting Perception Disorder (HPPD): Two Case Reports Arturo G. Lerner, MD,1, 2 Craig Goodman, MD,1 Oren Bor, MD,1 and Shaul Lev Ran, MD1 1
Lev Hasharon Mental Health Medical Center, Pardessya, Israel Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel 3 Sheba Medical Center, Tel Hashomer, Israel 2
Abstract Hallucinogen Persistent Perceptual Disorder (HPPD) is a clinical syndrome characterized by the recurrence of distressing perceptual disturbances which previously emerged during primary hallucinogen intoxication, in the absence of recent use. Here we present two patients who developed HPPD following use of Synthetic Cannabis Substances (SCS), with no prior history of natural-occurring or synthetic hallucinogen use. Both cases had a prior history of cannabis dependence and current tobacco dependence. In both cases patients reported the presence of visual disturbances when smoking SCS and staring at stationary and moving objects. Both patients discontinued SCS use abruptly after suffering from a panic attack under the influence of SCS. Despite cessation of SCS, both patients continued to suffer from HPPD which was accompanied by significant anxiety. Following clonazepam treatment, both subjects reported significant improvement in symptoms and remained with a residual focal visual disturbance which was not accompanied by significant anxiety. To the best of our knowledge these are the first reports of HPPD following SCS use. In light of the increasing use of SCS, clinical psychiatrists should be aware of these perceptual side effects.
INTRODUCTION The use of Natural Cannabis Substances (NCS), which are CB1 receptor partial agonists, has been associated with the appearance of perceptual disturbances during use
and after total cessation (1). Thus it is plausible to expect that the intake of Synthetic Cannabis Substances (SCS) like JWH-018, JWH-073 and HU-210 which are generally CB1 full receptor agonists and were also associated with the appearance of perceptual disturbances during use (2) might affect some predisposed and susceptible users provoking a partial or total recapitulation of the previous perceptual experience in the absence of SCS use. We present the cases of two SCS users with prior history of NCS use who reported the presence of Hallucination Perception Persisting Disorder (HPPD) after stopping SCS consumption. To the best of our knowledge this is the first report of SCS-associated HPPD in the professional literature. Both patients gave informed consent for the publication of their cases. Case 1 Mr. R is a 26-year-old single, male college student who completed compulsory military service and did not have any prior police or criminal records. He had a five year previous history of almost daily “heavy” use of NCS (at least three times per day) (1). He also reported occasional social alcohol drinking and heavy tobacco smoking. He fulfilled DSM-IV-TR full criteria for cannabis and nicotine dependence (3). He denied other substance use including LSD or other natural-occurring or synthetic hallucinogens. He did not report the presence of visual disturbances during NCS use. For the two years prior to his evaluation Mr. R consumed SCS (“Nice Guy” and “Spice”) on an almost daily basis (mainly at evening and night hours), without consuming other substances except tobacco. He explained his SCS use election and
Address for Correspondence: Arturo G. Lerner, MD, Lev Hasharon Mental Health Medical Center, POB 90000, Netanya 42100, Israel alerner@lev-hasharon.co.il; lerneram@internet-zahav.net
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predilection to the availability and affordability of these substances. Mr. R reported common visual disturbances when under the influence of SCS. Perceptual disturbances have appeared when staring at stationary and moving objects. Staring at stationary objects was associated with halos (a circular band of colored light around a light source or object), color intensification (slightly more intensified), color intensification of dimmed color (slightly less intensified), brightness (source appears to be radiating or reflecting light), visual snow (literally visualizing particles of air), positive afterimages (an image continuing to emerge after the exposure to the original image has ceased) and change in texture (physical change of a static surface). Staring at moving objects was associated to illusions of movement (slow motion movement) and trailing phenomena (afterimage-like trail or perception of a series of slow-movement discrete positive afterimages in the wake of moving objects) (4). These visual disturbances were experienced as benign and comfortable, a kind of psychedelic mind-broadening enriching and fruitful experience. They appeared sporadically during his two years of SCS consumption. Following a severe panic attack during consumption of SCS, Mr. R abruptly discontinued SCS use. He described this panic attack as accompanied by visual disturbances and referred to it as being “a horrific trip.” Forty-eight hours following the first panic attack Mr. R re-experienced the return of some of the visual disturbances experienced during SCS use along with anxiety features. Since the initial attack, he reported being continuously bothered by visual disturbances accompanied by anxiety features, and these complaints led to his psychiatric evaluation. On psychiatric examination the patient reported visual occurrences which were similar to those experienced during SCS use and resembled intoxication-associated visual imagery. These almost daily episodes usually lasted between fractions of a second and a few minutes. The perceptual disturbances were sufficiently severe to cause significant distress, anxiety and impairment in social and occupational functioning. Mr. R fulfilled DSM-IV-TR diagnostic full criteria of HPPD (3). There was no previous neurological, ophthalmological or other comorbid medical diseases or co-occurring psychiatric history. A complete physical, neurological (including EEG), and laboratory examination was unremarkable. Uncomplicated outpatient SCS withdrawal was unexpectedly mild and was treated with small doses of clonazepam 278
(5-8). Dosage started at 0.25 mg bid gradually increased to 1 mg bid after two weeks. He reported high motivation for preventing relapse to SCS, and was very reluctant to consume “addictive chemical medications.” During the two weeks following his initial psychiatric evaluation he reported the appearance of two additional panic attacks, milder in severity, accompanied by visual disturbances. Afterwards, no panic attacks were reported, and visual disturbances persisted. These HPPD-Type (HPPD II) (5-8) episodes slowly became more benign and less distressing. His condition dramatically started to improve. He continued taking clonazepam 1mg bid for the next five weeks. After completing two months of treatment, he refused to continue pharmacological treatment stating that he does not need more “chemicals in his body.” He agreed to gradually stop clonazepam. After treatment suspension he continued to report considerable improvement in the frequency of perceptual disturbances and accompanying anxiety. At his six-month evaluation he reported that symptoms had disappeared almost completely. Despite the prominent amelioration, Mr. R continued to complain of focal visual disturbance known as trailing phenomena that remained without accompanying anxiety features. Case 2 Mr. B is a 24-year-old male waiter with a three-year history of previous daily use of NCS. He did not report the presence of visual disturbances during NCS consumption. He also smoked tobacco on a daily basis. He fulfilled DSM-IV-TR full criteria for cannabis and nicotine dependence (3). He denied using other legal or illegal substances including alcohol, LSD or other natural-occurring or synthetic hallucinogens. During the year prior to his psychiatric evaluation he consumed only SCS (“Nice Guy” and “Spice”) on a daily basis mainly during night hours, without consuming additional substances apart from tobacco. He reported visual disturbances when smoking SCS, which were perceived as “amusingly entertaining” and occurred when staring at stationary and moving objects. Staring at stationary objects was associated to halos, visual snow, positive afterimages and dimensional distortion. Staring at moving objects was associated to illusions of movement, black moving spots with open and closed eyes (moving speckles and dots in the peripheral field) and trailing phenomena. On one occasion, while under the influence of SCS, Mr. B suffered from a severe panic attack. The panic attack was interpreted by the patient as a heart attack which was ruled
Arturo G. Lerner et al.
out after an ER examination. Diazepam was prescribed and psychiatric consultation was recommended. The following day Mr. B suffered from an additional panic attack, which was accompanied by visual imagery similar to that experimented during SCS use. Since then, Mr. B suffered from recurrent visual recurrences which were experienced along with anxiety features. These daily episodes usually lasted between fractions of seconds to a few minutes. On psychiatric evaluation Mr. B accurately recognized SCS as the precipitator of his condition (5-8). He reported that the panic attack was so distressing that SCS ingestion was immediately ceased. Disturbances were sufficiently severe to cause significant distress, anxiety and impairment in social and occupational functioning. He fulfilled DSM-IV-TR full criteria of HPPD (3). As in the case of R described above, all examinations revealed no abnormalities Uncomplicated outpatient SCS withdrawal was described as mild and treated with low doses of clonazepam, in a regimen described in the previous case. Mild anxiety features and sleep disturbances accompanied the withdrawal process. The patient was reluctant to be treated with “chemical drugs” (i.e., medications) and only accepted to take medication for a period of one month. He preferred to cope with his condition without medications, psychotherapy or counseling. Mr. B’s episodes of HPPD gradually became more benign and less distressing. His condition dramatically started to improve. After clonazepam suspension he continued to communicate a clear improvement in the frequency of perceptual disturbances. During the following three months symptoms disappeared almost completely. At the end of six months an almost total absence of visual disturbances was reported. Despite the profound reported improvement, he continued to suffer from benign non-distressing perceptual disturbances characterized by black moving spots in his visual fields. DISCUSSION Though HPPD has been well-described and reviewed in the literature following use of various hallucinogenic substances (9), little is known about these phenomena following use of new “designer drugs.” Above we described two cases of HPPD following SCS use. While the exact subjacent mechanism of SCS associated perceptual disturbances is largely unknown, there is some knowledge indicating similarities with those
proposed mechanisms associated with the use of LSD (6) and NCS (1). Serotonin neurotransmission seems to be involved in the origin of both acute and persisting LSD (6) and NCS induced perceptual disturbances (1). The acute short-term effects of LSD seem to be mediated through a 5-HT2A postsynaptic partial agonist activity (10) which may alter and modify how individuals experience their senses and perceptions. Similarly, the acute short-term effects of cannabis appear to be related to serotonergic systems (1). Although the main acute pharmacological effects of cannabis are mediated through cannabinoid receptors (1), it is known that cannabis might severely impair serotonergic neurotransmission (11, 12). This disruption appears be responsible for most of the cannabis effects on cognition and perception (13, 14) and could be linked to the capability of cannabis to produce perceptual aberrations (15, 16) including visual disturbances (1). Chronic long-term effects of LSD, namely FlashbackType or HPPD I and HPPD-Type or HPPD II (5-8) may partially or entirely recapitulate the primary hallucinogenic intoxication, presupposing that a mechanism similar to the original one may be implicated. The cardinal mechanism believed to underlie this condition appears to be a vulnerably or predisposition of LSD consumers continue to centrally process visual imagery after the visualization has been totally eradicated from the visual field (17). Persistence of visual disturbances associated to permanent disinhibtion of visual processors could be triggered by an LSD-engendered intense excessive current (18) or NCS-engendered similar mechanism (1) which might lead and contribute to the destruction or dysfunction of cortical serotonergic inhibitory inter-neurons with GABA-nergic outputs (19). Irreversible destruction or reversible dysfunction may hypothetically be responsible for the distinct types of benign short-term transient or pervasive long-term permanent recurring visual disturbances (1, 5-8). High potency cannabis (20) affecting serotonergic neurotransmission (13, 14), could similarly recapitulate and induce the recurrence of benign short-term transient (1) or pervasive long-term permanent visual disturbances in subjects. The anandamidergic system also seems to be implicated, affecting and impairing areas of visual information processing (21, 22). The function of the endogenous cannabinoid system as well as the CNS on central visual processing is not entirely known and understood and requires further investigation and clarification. 279
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NCS have led to the development of SCS. SCS have been synthesized and produced for biomedical research purposes because they may become promising medications. They constitute a new class of synthetic “designer” cannabinoid-like substances that bind, activate and exert their effects through cannabinoid receptors which indirectly may alter serotonin transmission and modulate anxiety. Chronic activation of CB2 receptors may result in an upregulation of 5HT2A receptor density and function (20, 21). These substances, including their chemical structure, have been extensively reviewed (23). Cannabinoid receptors are part of the intricate endocannabinoid system which is not entirely and clearly understood (23). These substances might show higher potency and affinity for cannabinoid receptors (24) and might exhibit long halflives and active metabolites (25). Therefore, it is plausible and logical to speculate that synthetic cannabis, as observed in natural cannabis (1), might affect serotonin neurotransmission (20, 21) leading to the emergence of HPPD through a mechanism similar to those described as being responsible of the genesis of LSD and NCS visual disturbances (1, 5-8). In both described cases, there was previous use of NCS without associated visual disturbances, followed by initiation and continuous use of SCS. In both cases a panic attack-like “bad trip” accompanied by visual disturbances led to complete and total suspension of any substance consumption. Furthermore, patients continue to suffer from HPPD-Type visual disturbances (HPPD II) (5-8) following discontinuation of SCS. Though significant clinical improvement was noted following treatment with clonazepam, both patients continued to suffer from benign focal visual disturbances (trailing phenomenon and black moving spots) which were not associated with significant anxiety. We propose that in light of the increasing use of SCS, clinical psychiatrists should be aware of these perceptual side effects. References 1. Lerner AG, Goodman C, Rudinski D, Bleich A. Benign and time-limited visual disturbances (flashbacks) in recent abstinent high-potency heavy smokers. Isr J Psychiatry Relat Sci 2011; 48:25-29. 2. Benford DM, Caplan JP. Psychiatric sequelae of Spice, K2, and synthetic cannabinoid receptor agonists. Psychosomatics 2011; 52:295. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington DC: American Psychiatric Association, 2000.
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4. Asher H. “Trailing” phenomenon – A long lasting LSD side effect. Am J Psychiatry 1971; 127:1233-1234. 5. Lerner AG, Gelkopf M, Oyffe I, Finkel B, Katz S, Sigal M, Weizman A. LSD-induced hallucinogen persisting perception disorder (HPPD) treatment with clonidine: An open pilot study. Int Clin Psychopharmacol 2000; 18:35-37. 6. Lerner AG, Gelkopf M, Skladman I, Oyffe I, Finkel B, Sigal M, Weizman A. Flashback and hallucinogen persisting perception disorder: Clinical aspects and pharmacological treatment approach. Isr J Psychiatry Rel Sci 2002;39:92-99. 7. Lerner AG, Gelkopf M, Skalman I, Rudinski R, Nachshon H, Bleich A. Clonazepam treatment of LSD- induced hallucination persisting perception disorder with anxiety features. Int Clin Psychopharmacol 2003;18:101-105. 8. Lerner AG, Rudinski D, Bor O, Goodman C. Flashback and HPPD: A clinical-oriented concise review. Isr J Psychiatry Relat Sci 2014;51:296-302 . 9. Halpern JH, Pope HG .Hallucinogen persisting perception disorder: What do we know after 50 years?. Drug Alcohol Depend 2003; 69: 109-119. 10. Abraham HD, Aldridge AM, Gogia P. The psychopharmacology of hallucinogens. Neuropsychopharmacol 1996;14:285-298. 11. Stanton MD, Mintz J, Franklin RM. Drug flashbacks II: Some additional findings. Int J Addict 1976;11: 53-69. 12. Tunving K. Psychiatric effects of cannabis use. Acta Psychiatr Scand 1985;72: 209-217. 13. Russo EB, Burnett A, Hall B. Parker KK. Agonist properties of cannabidiol at 5-HT 1A receptors. Neurochem Res 2005; 30: 1037-1043. 14. Hill MN, Sun JC, Tse MT, Gorzalka BB. Altered responsiveness of serotonin receptor subtypes following long term cannabinoid treatment. Int J Neuropsychopharmacol 2006;9:277-286. 15. Sierra M. Depersonalization disorder: Pharmacological approaches. Expert Rev Neurother 2008;8:19-16. 16. Mathew RJ, Wilson WH, Humphreys D. Lowe JV, Weithe KE. Depersonalization after marijuana smoking. Biol Psychiatry 1993;33:431441. 17. Young CR. Sertraline treatment of hallucinogen persisting perception disorder. J Clin Psychiatry 1997;58:85. 18. Garrat J, Alreja M, Aghajanian GK. LSD has high efficacy relative to serotonin in enhancing the cationic current Ih: Intracellular studies in rat facial motorneurons. Synapse 1993;13:123-134. 19. Abraham HD. Hallucinogen related disorders. In Kaplan H, Sadock B, editors. Comprehensive textbook of psychiatry, 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2000. 20. Castellanos D, Thornton G. Synthetic cannabioid use: Recognition and management. J Psych Pract 2012; 18:86-93. 21. Leweke FM, Schneider U, Radwan M, Schmidt E, Emrich HM. Different effects of nabilone and cannabidiol on binocular depth inversion in man. Pharmacol Biochem Behav 2000; 66: 175-181. 22. Leweke FM, Schneider U, Thies M, Munt TF, Emrich HM. Effects of synthetic delta 9- tetrahydrocannabinol on binocular depth inversion of natural and artificial objects in man. Psychopharmacology 1999; 142: 230-235. 23. Seely K.A, Lapoint J, Moran JH, Fattore L. Spice drugs are more than harmless herbal blends: A review of the pharmacology and toxicology of synthetic cannabinoids. Prog Neuro-Psychopharmacol Biol Psychiatry 2012; 39: 234-243. 24. Huffman JW, Padgett LW. Recent developments in the medicinal chemistry of cannabinomimetic indoles, pyrroles and indenes. Curr Med Chem 2005; 12: 1395-1411. 25. Brents LK, Gallus-Zawada A, Radominska-Pandya A, Vasiljevik T, Prisinzano TE, Fantegrossi WE, et al. Monohydroxylated metabolites of the K2 synthetic
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Limor Goren et al.
Buprenorphine for Opiate Dependence: Clinic Based Therapy in Israel Limor Goren, MD,1,2 Ziv Carmel, MD,3 and Sergio Marchevsky, MD1,4 1
Hebetim Clinics, Tel Aviv, Israel Lev Hasharon Mental Health Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Shalvata Mental Health Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 4 Beer Yakov Mental Health Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 2
Abstract Background: Opioid dependency is characterized by repeated use of an opioid drug despite physical dependence, behavioral impairments and social dysfunction. Therapeutic approaches for the treatment of opioid dependence are total abstinence and opioid agonist maintenance treatment (OAMT). Opiate agonist maintenance therapy is administered using opioid replacement pharmacological agents, i.e., methadone or buprenorphine. Methadone acts as a full opiate agonist while buprenorphine acts as a partial agonist. Strict supervision is necessary when dispensing methadone, because overdose can be fatal. Buprenorphine associates with opioid receptors slowly but with high affinity, and dissociation from the receptor site is (pseudo) irreversible. It is safer than opioid full agonists such as methadone. Methods: We probed the therapeutic efficacy of buprenorphine using a retrospective evaluation of numerical data in the first private buprenorphine clinic in Israel. Data was collected for all patients attending the clinic in December 2012. Our indicator for treatment success is retention in the program. Results: During the years 2005-2012, 1,399 individuals approached the clinic; 1,224 (87.5%) of them attended the clinic at least twice; treatment adherence in this group was 66.5 % at the end of one year. Conclusions: The success rates of patients who are treated with buprenorphine and are able to eventually return to their families and re-enter the workforce is encouraging. Thus, the community based minimal intervention treatment model using buprenorphine for the treatment of opiate dependence is a viable treatment option in the war against opiate abuse.
Address for Correspondence:
Background Opioid dependency is characterized by repeated use of an opioid drug despite physical dependence, behavioral impairments and social dysfunction. It is also associated with severe social consequences such as delinquency and prostitution and often precipitates the spreading of fatal infectious diseases such as HCV, HIV, HBV (1, 2). The two main therapeutic approaches for the treatment of opioid dependence are total abstinence and opioid agonist maintenance treatment (OAMT). The latter treats addiction as a chronic disease that requires ongoing pharmacotherapy focused on harm reduction (3). As with any chronic illness, the goal of the treatment is to stabilize patients and reduce harm, thereby increasing life expectancy and quality of life (4). Opiate agonist maintenance therapy is administered using one of two available opioid replacement pharmacological agents, methadone or buprenorphine. Methadone acts as a full opiate agonist and buprenorphine acts as a partial agonist. Since the mid-1960s, methadone maintenance has proven successful for the treatment of opioid dependence (1, 5). It decreases drug use, reduces medical comorbidity, decreases transmission of human immunodeficiency virus, reduces mortality and improves social functioning. Strict supervision is necessary when dispensing methadone because overdose can be fatal (2). Israeli methadone treatment centers implement strict rules and regulations. The medication is dispensed in daily doses, during five visits to the treatment center per week. Buprenorphine acts as a partial agonist at the opioid Îź receptor, which mediates analgesia, respiratory depression and reduced gastrointestinal motility. Buprenorphine associates with opioid receptors slowly but with high affinity, and dissociation from the receptor site is (pseudo) irreversible. The half-life of buprenorphine is 24-60 hours (6).
Dr. Limor Goren, Hebetim Clinic, 8 SderotYehudit, Tel Aviv, Israel
â&#x20AC;&#x2020; limor.goren@gmail.com
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It is safer than opioid full agonists such as methadone (7). Buprenorphine is also used as an opioid replacement therapy during pregnancy, causing fewer neonatal abstinence syndrome symptoms than methadone (8). Buprenorphine was approved for opioid dependence in France in 1995, and is currently approved for such use in many countries (9). The U.S. Federal government approved the use of buprenorphine for treating opioid dependent patients in 2000 (6,10). The safety profile of this medication has enabled significant reduction in the supervision required for pharmacological treatment of opioid addiction. Thus, opioid addiction can be treated in community based settings without requiring referral to specialized opioid treatment programs (OTPs), and daily clinic visits are no longer necessary. Buprenorphine is available as buprenorphine pills intended for sublingual use, or Suboxone pills which combine buprenorphine and naloxone. This formulation has the advantage that the medication cannot be misused by crushing and injecting since the naloxone has high bioavailability when taken by this route. This combination pill has become the accepted standard of treatment; however it was only introduced recently to the Israeli market and therefore was not used in the time period of this study. The estimated number of opioid dependent patients in Israel as per the Knesset protocol of 2011 is 15,000 (11). The Israel Ministry of Health approved methadone use in 1975 (12). An estimated 4,500 patients are currently treated with methadone in Israel. Until recently the waiting list for methadone treatment in some clinics was over a year-long. In 2005 the Israel Ministry of Health approved the use of buprenorphine for opioid dependence treatment purposes (13). Publicly funded buprenorphine clinics are scarce. In 2011 only 613 patients received buprenorphine treatment in public clinics in Israel. During that same year the estimated number of private clinic buprenorphine patients was approximately double (personal communication - Ministry of Health sources). Public buprenorphine clinics are generally adjacent to methadone clinics and therefore employ similar administration regimens. Strict supervision of buprenorphine administration is not medically justified, and is counterproductive because it impedes return to normal social functioning owing to the required five visits to the treatment center each week. Private community based buprenorphine clinics were initiated in Israel in 2004 and introduced a new concept of treatment. The aim of the clinic was to make buprenorphine treatment more 282
accessible. For the purpose of this paper, successful treatment is defined as treatment retention that is indicative of the patient being free of illegal opiate use, adherence to follow care including urine tests and willingness to engage in more intensive care when abuse of psychoactive substances is revealed. Working model of the Hebetim clinic
The Hebetim clinic is the first private buprenorphine clinic in Israel, founded in 2004. The clinic is open four days a week from 4:00 p.m. to 7:00 pm. The clinic’s branches are located in office buildings in city centers. Clinic visits focus on interventions including psychoeducation, stabilization and rehabilitation. • Patients are received on a drop-in basis, during treatment hours. • A psychiatrist makes an initial assessment that takes approximately 30 minutes. • Treatment is initiated based on clinical assessment and a urine sample test. • The patient’s urine is tested for opiates/ cocaine/ benzodiazepines/ buprenorphine. • Positive results of opiates and cocaine are followed by weekly instead of monthly prescriptions and recurrent motivational discussions with the psychiatrist or counselor, until stabilization is achieved or referral to public treatment facility. • Patients receive dosages of 2-24 mg per day. The dose is determined by self report of amount of previous drug use. The most common dose is 16 mg/d. • Patients are instructed how to begin therapy at home with “remote supervision” if necessary. (Most new patients who seek treatment have already begun using buprenorphine that they purchased “on the street”). • We are aware of the fact that buprenorphine diversion exists, and that there is demand for it. We address this issue in our clinic by monitoring of urine for buprenorphine traces as a perquisite for the next prescription. We also believe that the fact that there is such a demand for buprenorphine raises the question as to whether accessibility to this drug is sufficient. • Two counselors who are rehabilitated buprenorphine patients mentor clinic patients during treatment including outside of clinic hours. • During the first month patients visit the clinic once a week after which the frequency of visits is reduced to once a month. A full psychosocial evaluation is performed after the first month of treatment. • All medical treatments aside from buprenorphine
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are referred to appropriate medical facilities. When necessary, psychiatrists recommend which treatments or examinations the patients require. • The clinic’s administrative director assists patients in communication with authorities such as the social security office. • The patients pay 1,150 NIS in advance for the first three months of the clinic services, and subsequently 250 NIS per month. The cost of buprenorphine is 1,200 NIS per month for the average dose of 16 mg/d. Methods We probed the therapeutic efficacy of buprenorphine using a retrospective evaluation of numerical data in a naturalistic environment in the Hebetim clinic. We evaluated treatment success as the rate of retention in active treatment. Data were collected for all patients who approached the clinic at any time between January 2005 and December 31, 2012. Our main indicator of treatment success is retention in the program, which implies being free of illegal opioid use. Status of illegal opioid use was determined by self report and random urine tests for non-buprenorphine opiates. Our experience shows that it is rare for patients who are using buprenorphine to concurrently use illegal opiates, since buprenorphine occupies the µ-opiate receptor with higher affinity than other opiates which renders other opiates ineffective. Retention was calculated from first to last visit in clinic. Patients who did not visit the clinic for two months were considered as dropouts from treatment. Patients whose last visit to the clinic was less than two months prior the end of the data collection were defined as right censored, since we do not know when their true last visit to the clinic occurred – it may either have been at the last registered visit or at any time after this visit. For the retention rate calculations, patients who were right censored prior to the defined time points were excluded from the analysis at that time point. This methodology was applied to the calculation of retention rate at the three specified time points (one year, three years or five years) as well as for each time point in the Kaplan Meier curve. Results During the years 2005-2012, 1,399 individuals approached the clinic; 1,224 of them attended the clinic at least twice (87.5%), treatment retention rates for these patients were
calculated as described in the Methods section. One year retention rate was 66.5%, three years retention rate was 46.1% and five years retention rate was 33.5%. The Kaplan Meier curve for retention in treatment is presented in Figure 1. Figure 1. Kaplan Meier curve showing retention rate for all durations up to five years in patients who attended the clinic at least twice during the years 2005-2012. Horizontal dashed lines indicate treatment retention at one, three and five years.
Discussion This retrospective evaluation presents findings from a naturalistic environment that allowed us to probe the therapeutic efficacy of buprenorphine. The clinic offers buprenorphine as the main focus of therapy in a community based opiate rehabilitation treatment clinic. Our findings of 66.5 % treatment adherence at one year of treatment and 46.1% at three years of treatment are comparable to similar treatments models - Alford et al. (14) reported a 49 % treatment retention at one year in collaborative care of opioid-addicted patients in primary care using buprenorphine. One year retention rates at methadone clinics in Israel are currently estimated at 75% (15). Considering the devastating effects of opiate addiction on patients and their families, the increasing success rates of patients who are successfully treated with buprenorphine and are able to eventually return to their families and re-enter the workforce is encouraging. Thus, the community based minimal intervention treatment model using buprenorphine for the treatment of opiate dependence is a viable treatment option in the war against opiate abuse. 283
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References 1. O’Connor PG. Methods of detoxification and their role in treating patients with opioid dependence. JAMA 2005;294:961-963. 2. Mattick RP, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Sys Rev 2008;(2):CD002207. 3. Torrens M, Fonseca F, Castillo C, Domingo-Salvany A. Methadone maintenance treatment in Spain: The success of a harm reduction approach. Bull World Health Organ 2013;91:136-41. 4. Van den Brink W, Haasen C. Evidenced-based treatment of opioiddependent patients. Can J Psychiatry 2006 ;51:635-646. 5. Maremmani I, Pacini M, Pani PP, Popovic D, Romano A, Maremmani AG, Deltito J, Perugi G. Use of street methadone in Italian heroin addicts presenting for opioid agonist treatment. J Addict Dis 2009;28:382-388. 6. Drug Addiction Treatment Act of 2000 (DATA) http://buprenorphine. samhsa.gov/fulllaw.html . Accessed 22.5.13. 7. Working Party, National Medicines Information Centre, St. James’s Hospital. Report to the National Advisory Committee on Drugs on “Use of Buprenorphine as an intervention in the treatment of Opiate Dependence Syndrome” St. James’s Hospital, Dublin 8, 22nd March, 2002. Available at: http://www.drugsandalcohol.ie/5253/1/1221-0964. pdf Accessed May 1, 2013. 8. Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O’Grady KE, Selby P, Martin PR, Fischer G. Neonatal abstinence
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syndrome after methadone or buprenorphine exposure. N Engl J Med 2010;363:2320-2231. 9. Hamza H, Bryson EO. Buprenorphine maintenance therapy in opioidaddicted health care professionals returning to clinical practice: A hidden controversy. Mayo Clin Proc 2012;87:260-267. 10. FDA. Subutex and Suboxone approved to treat opiate dependence T02-38, October 8, 2002, http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/ucm191521. htm. Accessed 20.5.13. 11. Nathan G. Treatment of addiction to hard drugs and alcohol in Israel. Research and Information Dept. Knesset, 20.12.2013, http://www. knesset.gov.il/mmm/data/pdf/m03064.pdf [Hebrew] Accessed 22.5.13. 12. Inter-office committee for the comprehensive treatment of drugs. Comprehensive blueprint for dealing with the problems of drug abuse in the State of Israel (Mann Committee Report), 1983, Jerusalem. 13. Israel Ministry of Health, Department of Treatment of Addictions. Procedures for buprenorphine (Subutex) treatment in approved facilities, Procedure no. 40.009, 2.4.2005. 14. Alford DP, LaBelle CT, Kretsch N, Bergeron A, Winter M, Botticelli M, Samet JH. Collaborative care of opioid-addicted patients in primary care using buprenorphine: Five-year experience. Arch Intern Med 2011;171:425-431. 15. Peles E, Schreiber S, Adelson M. 15-year survival and retention of patients in a general hospital-affiliated methadone maintenance treatment (MMT) center in Israel. Drug Alcohol Depend 2010;107:141-148.
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Benzodiazepine Usage During 19.5 Years in Methadone Maintenance Treatment Patients and its Relation to Long-Term Outcome Einat Peles, PhD,1,2 Miriam Adelson, MD,1 and Shaul Schreiber, MD1,2 1
Dr. Miriam & Sheldon G. Adelson Clinic for Drug Abuse, Treatment & Research, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Department of Psychiatry, Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Abstract Background: Benzodiazepines (BDZs) abuse was found to cause diverse harmful effects among MMT patients. The current study evaluates prevalence rates of BDZ usage during 19.5 years in MMT, and its relation to patients’ long-term retention in treatment. Methods: All 787 opiate addicts who were ever admitted to the Adelson MMT clinic in Tel Aviv between 1993 and 2012 were studied. Observed and random urine results for BDZs usage were taken a few times every month. Positive for BDZ was defined in each month if at least one of the urines tested positive. Long-term retention was studied using Kaplan Meier analyses. Results: BDZ prevalence among the MMT patients (ranged from 26 patients in 1994, and 300 to 350 since 2009) was about 35-40% in the last few years, with a “peak” of 61% followed by low rate of 25.4%. Followed up for up to 19.5 years, those who were negative to BDZ upon admission to MMT stayed longer in treatment (mean 8.5y, 95% Confidence Interval [CI] 7.6-9.4) than those who were positive to BDZ when admitted (mean 6.9y, 95% CI 6.2-7.7) (Kaplan Meier analyses p=0.01). Conclusion: BDZs abuse is highly prevalent among MMT patients. Abuse of BDZ on entry to treatment predicts worse MMT outcome. High and low rates of BDZ abuse may also be attributed to staff tolerance of this abuse; thus, we strongly recommend a strict attitude by staff in order to reduce patients’ harm.
INTRODUCTION The history of the use of sedative drugs in order to treat anxiety and insomnia has its roots in antiquity, and alcohol is the oldest known sedative, used both medically and non-medically. The development of newer sedative medications throughout the ages has promised safety and efficacy, yet time has taught (too often painfully), the dangers of tolerance, dependency and addiction, and the severe potential complications associated with these drugs (intoxication and even death). The main hallmarks over the last two centuries include valerian, the bromides, the barbiturates and meprobamate (for review see 1). Introduced in the early 1960s, benzodiazepines (BDZs) (initially chlordiazepoxide) were described as efficacious, safe and lacking risk of addiction, but life (and experience) taught us differently (2). Furthermore, the sociological phenomenon of a “rush for sedation” of wide populations (mostly women) that accompanied the introduction of this class of medications was evident right after their appearance on the market, and described as early as 1965 in a popular song of the epoch that deals with the darker perspective of the use of tranquilizers among housewives (3). BDZs are positive allosteric modulators of the g-aminobutyric acid type A receptors (GABAARs) (4). GABAARs are ligand-gated chloride-selective ion channels that are physiologically activated by GABA, the major inhibitory neurotransmitter in the brain. GABA also activates GABABRs and GABACRs. GABABRs are metabotropic receptors involved in slow inhibitory neurotransmission (5). GABACRs are ionotropic receptors composed of r (rho) subunits that are both related to and classified by the International Union of Basic and Clinical Pharmacology (IUPHAR) as GABAAR subunits (4).
Address for Correspondence: Einat Peles, PhD, Adelson Clinic for Drug Abuse, Treatment & Research, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel einatp@tlvmc.gov.il
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BDZs are typically categorized according to their pharmacokinetic properties as short-, intermediate- or longacting; they possess anxiolytic, hypnotic, sedative and anti-epileptic properties and are prescribed to obtain one of the following major effects: decrease of sleep latency, reduction of anxiety, suppression of epileptic seizures or relaxation of muscle spasms. In general, BDZs are safe and effective for short-term treatment; however, long-term use is controversial due to the development of tolerance and their liability for physical dependence (2). The prevalence of BDZs usage in the general population was reported as 5.6% in a large survey from Boston Area Community (6), 3.9% in a regional survey from Thailand (7), 3.3% in a Canadian population sample (8), but mostly characterize psychiatric groups, i.e., 25% among U.S. male veterans with PTSD (9); 62.9% among patients with schizophrenia in Taiwan (10) and particularly, among opiate addicts MMT patients, where it ranged between 40 to above 60% (11-13). There are several possible reasons why drug abusers add benzodiazepines to their “cocktail” of street and prescription drugs (14): 1. BDZs induce euphoria (per se, but moreso when snorted): BDZs like other drugs of abuse increase dopamine release in the nucleus accumbens (4). Specifically, BDZs have a stronger impact on GABA neurons than on dopamine neurons. The GABAAR on the interneuron GABA affected by BDZs and the hyper-polarization cause disinhibition on dopamine cell that project to the NA. The GABAAR on the dopamine neuron is less affected by BDZs and thus does not inhibit the dopamine release. 2. BDZs may attenuate intoxication symptoms of “uppers” (e.g., cocaine), or withdrawal symptoms of “downers” (e.g., opiates) or augment the desirable lightheadness induced by alcohol. 3. BDZs may serve as efficacious self-medication/ self-treatment of anxiety, insomnia, other psychiatric illness – or erroneously of depression. Our aims in the current study were to evaluate: 1. prevalence rate of BDZs among MMT patients during the years 1994 and 2012, and 2. the association between BDZs use upon admission and long term retention in treatment (up to 19.5years), and 3. whether it is possible to discontinue BDZs after one year in treatment. METHODS The study was approved by the institutional review board (Helsinki Committee) at TASMC (07-111). All 787 opiate addicts admitted to the Adelson MMT clinic in Tel Aviv between 1993 and 2012 were studied. All MMT patients routinely provide at least one observed 286
random urine test per month (range through years between 1 to 11) lately two per month. BDZ was analyzed using enzyme immunoassay systems (Diagnostic Reagents Inc [DRI ])(15). Each month since admission, each patient was defined as positive to BDZ if at least one of the urine tests was positive, or negative to BDZ if the entire set of tests over the months was negative. The total number of patients in the clinic increased over the years since it was open until having reached full capacity (i.e., 26 patients were tested in 1994, and 300 to 350 since 2009).
®
Statistical Analyses
All analyses were done using the SPSS-19 package. Prevalence of BDZ was calculated for each month since 1994 and until December 2012. Of all the patients who had urine tests (all current patients), we calculated the proportion of those who had at least one positive urine test for BDZ. Duration in treatment from first admission until the patient left treatment or until the end of follow-up (19.5 years) was used for calculating cumulative retention in treatment using survival analyses (Kaplan Meier) with log rank. RESULTS Of all 787 opiate addicts who were ever admitted to the Adelson MMT clinic in Tel Aviv (1993-2012), 58% tested positive to BDZ on entry. Prevalence rate of BDZs
Prevalence of patients with positive urines for BDZ range between 1994 and 2012 years with the highest rate of 61% in 2002 and the lowest rate of 25.4% in 2003. The total number of patients in treatment increased from 26 patients in 1994 to 300 and 350 since 2009, when the clinic reached its full capacity. Since 2008 and up to the present, the rate is consistently around 35-40% (Figure 1). In December 2012, 322 patients were tested. Of them, 209 were negative and 113(35.1%) were positive for BDZ. Figure 1. Benzodiazepine rate (%) by month and years.
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Figure 2. Long term retention in treatment (up to 19.5years) by being positive to BDZ (dashed line, with 141 censored cases) or negative to BDZ (continuous line, with 126 censored cases) on admission to treatment (Kaplan Meier survival analyses, Chi Square 5.7, p 0.01). BDZs on admission
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Cumulative retention (up to 19.5 years) of the 761 patients who were admitted until December 2011 was 6.9y (95% CI 6.2-7.7) for those who tested positive to BDZs on admission, as compared to 8.5y (95% CI 7.6-9.4) for those who tested negative to BDZ (Figure 2). Discontinue BDZs after one year in treatment
Of the 761 who were admitted until December 2011, 76.1% (n=579) remained in treatment at least one year. Of them, 340 (58.7%) were positive and 239 were negative to BDZs on admission. Of the 340 who were positive to BDZ on admission, 36.5% stopped BDZ abuse after one year, but 25.1% of the 239 who were negative on admission started
BDZ abuse during treatment, producing a net reduction of 11.4% in BDZ usage after one year (36.5% minus 25.1%). DISCUSSION We found that abusing BDZs on entry to methadone maintenance treatment predicts shorter retention in treatment. Our previous findings with respect to treatment outcome, retention, survival, hepatitis C sero-conversion and polydrug abuse, support the current finding: positive urine test for BDZs on entry to MMT (urine tested positive during the first month in MMT) is an independent predictor for a shorter retention in treatment, as was already found in a long-term follow-up of up to 10 years (16) and now expanded our follow-up and sample to up to 19 years. Furthermore, in a 287
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study of long-term retention in MMT and survival since admission to MMT (using the Israeli Ministry of Health’s Registry for vital status), we found that BDZs abuse is not just a predictor for lower retention in treatment; it predicted also a shorter survival (17). As most of those who died were not in treatment, and deaths cause were not definitely established (with post-mortem autopsy) in some of the cases, we could not report whether they were abusing BDZs when found dead. However, since they did not stop BDZ use prior to dropping out of treatment, it would be highly unlikely that they managed to stop once they “returned to the street,” the assumption that BDZs were part of the abused drugs at the time of death is plausible. The combination of opiates and BDZs abuse and increased death risk is well established (for review, see 18). BDZ poisoning (based on underlying cause of death) was found to be present among 17% of the opiate deaths in U.S. (19). In 2007, we screened in a random way a sample of our patients for the presence of tricyclic antidepressants (TCAs) (12) and found 15.8% of the patients to abuse amitriptyline. Not surprisingly, logistic regression found that testing positive for amitriptyline was higher in BDZs abusers (Odds Ratio=11.6, 95% CI 4.4-30.7). Such a combination constitutes a potential cardiac hazard (with the prolongation of the QTc interval on ECG, a risk factor for torsades de pointes and sudden death, as one of the cardinal dangers). Due to this hazard, and together with the finding that 12 (7.5%) of the “privileged” group of patients (stabilized patients who, based on their long-standing cessation of any type of street drug abuse and prolonged normative behavior in treatment are granted “take home” methadone doses) were also found to be amitriptyline abusers, we have since then added the TCAs to the routine monitoring in our clinic, a fact that lead to reduction of abuse (about 5% in 2012). About one half of the MMT patients in our clinic are hepatitis C sera positive on admission to treatment. Although they do not differ from others in their overall outcome success, more of them were found to be BDZs abusers after one year in MMT (20). Moreover, among those who are negative for hepatitis C, being positive for BDZ, is associated with increased risk to become hepatitis C sera-positive (of the BDZ abusers as compared to the non-abusers 3.6 patients as compared to 1 patient per 100 person years of follow-up respectively developed hepatitis C p = 0.005) (21). Although there is a high rate of BDZ abuse among MMT patients, BDZ abuse rate tends to decrease after one year in treatment, as is the case with other substances abused on admission (opiates, cocaine, cannabis, amphetamines), 288
although to a lesser extent than the other drugs mentioned. The net reduction (proportion of those who tested positive on admission and stopped it [tested negative] after one year, minus the proportion of those who tested negative on admission but started later on [tested positive] after one year) is small as compared to other substances, mainly because a high proportion of patients tend to start BDZs abuse during treatment – perhaps in an effort to get a “high” sensation that the methadone does not induce. Reviewing the prevalence changes over the years, the high prevalence of BDZs abuse during the years 20012002 period was parallel to the time when some of the clinic policies were less enforced, a fact that probably had a significant influence on patients’ misbehavior. Towards the end of 2002, a strict and clear behavioral program was started (immediate loss of take-home dose privileges for those with positive urines tested to BDZ) and, indeed, in 2003, the rate of BDZs abuse dropped to only 25.4%. This suggests that BDZ abuse may be influenced, in part, by staff attitudes (tolerance or intolerance) towards the phenomenon, and that adhering to the contingency management principles (where “take-home” privileges are the positive incentive) and to the guidelines with no exception may prove beneficial for all. As data from many MMT clinics world-wide indicate that prolonged or total abstinence from BDZs is actually unreachable for many patients (22), the feasibility of an “agonist substitution / maintenance treatment” for BDZs abuse that will follow the principles of the MMT for opioids abuse should be evaluated. However, investigators should avoid the failed trials in the 1990s (when clonazepam was thought to serve as the substitute, and proved to be more problematic in several aspects than the other BDZs abused) (23, 24). Acknowledgement The Adelson family Foundation
References 1. Dell’osso B, Lader M. Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal. Eur Psychiatry 2013; 28: 7-20. 2. Harvey SC. Hypnotics and sedatives. In: Gilman AG, Goodman LS, Rall TW, editors. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, ed 7. New York: Macmillan, 1985: pp. 339-371. 3. Mick Jagger and Keith Richards (The Rolling Stones). Mothers Little Helper. In the album “Aftermath.” 1966. http://www.youtube.com/ watch?v=tfGYSHy1jQs 4. Tan KR, Rudolph U, Lüscher C. Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci 2011;34:188-197. 5. Pinard A, Seddik R, Bettler B. GABAB receptors: Physiological functions and mechanisms of diversity. Adv Pharmacol 2010;58: 231-255. 6. Hall SA, Chiu GR, Kaufman DW, Kelly JP, Link CL, Kupelian V, et al. General exposures to prescription medications by race/ethnicity in a
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population-based sample: Results from the Boston Area Community Health Survey. Pharmacoepidemiol Drug Saf 2010;19:384-392. 7. Puangkot S, Laohasiriwong W, Saengsuwan J, Chiawiriyabunya I. Benzodiazepines misuse: The study community level Thailand. Indian J Psychol Med 2010 ;32:128-130. 8. Esposito E, Barbui C, Patten SB. Patterns of benzodiazepine use in a Canadian population sample. Epidemiol Psichiatr Soc 2009 ;18:248-254. 9. Hawkins EJ, Malte CA, Imel ZE, Saxon AJ, Kivlahan DR. Prevalence and trends of benzodiazepine use among Veterans Affairs patients with posttraumatic stress disorder, 2003-2010. Drug Alcohol Depend 2012 ;124:154-161. 10. Wu CS, Lin YJ, Liu SK. Benzodiazepine use among patients with schizophrenia in Taiwan: A nationwide population-based survey. Psychiatr Serv 2011 ;62:908-914. 11. Kan CC, Hilberink SR, Breteler M. H. Determination of the main risk factors for benzodiazepine dependence using a multivariate and multidimensional approach. Compr Psychiatry 2004; 45: 88-94. 12. Peles E, Schreiber S, Adelson M. Tricyclic antidepressants abuse, with or without benzodiazepines abuse, in former heroin addicts currently in methadone maintenance treatment (MMT). Eur Neuropsychopharmacol 2008;18:188-913. 13. Chen KW, Berger CC, Forde DP, D’Adamo C, Weintraub E, Gandhi D. Benzodiazepine use and misuse among patients in a methadone program. BMC Psychiatry 2011; 11:90. 14. Trudeau DL. Clonazepam prescribing patterns and abuse by methadone patients in a medical center setting. J Addict Dis 1994; 13: 99-107. 15. Hawks RL. Analytical methodology. NIDA Res Monogr 1986;73:30-42. 16. Peles E, Schreiber S, Adelson M. Factors predicting retention in treatment:
10-year experience of a methadone maintenance treatment (MMT) clinic in Israel. Drug Alcohol Depend. 2006;82:211-217. 17. Peles E, Schreiber S, Adelson M. 15-Year survival and retention of patients in a general hospital-affiliated methadone maintenance treatment (MMT) center in Israel. Drug Alcohol Depend 2010;107:141-148. 18. Webster LR, Cochella S, Dasgupta N, Fakata KL, Fine PG, Fishman SM, et al. An analysis of the root causes for opioid-related overdose deaths in the United States. Pain Med 2011;12:S26-S35. 19. Warner M, Chen LH, Makuc DM. Increase in fatal poisonings involving opioid analgesics in the United States, 1999–2006. NCHS Data Brief 2009;22:1-8. 20. Peles E, Rados V, Adelson M. Characterization of former heroin addict patients with Hepatitis C virus antibodies in a methadone maintenance treatment (MMT) clinic in Israel. Subst Use Misuse 2007;42:1477-1484. 21. Peles E, Schreiber S, Rados V, Adelson M. Low risk for hepatitis C seroconversion in methadone maintenance treatment. J Addict Med 2011;5:214-220. 22. Frauger E, Nordmann S, Orleans V, Pradel V, Pauly V, Thirion X, Micallef J; réseau des CEIPs. Which psychoactive prescription drugs are illegally obtained and through which ways of acquisition? About OPPIDUM survey. Fundam Clin Pharmacol 2012; 26: 549-556. 23. Bleich A, Gelkopf M, Weizman T, Adelson M. Benzodiazepine abuse in a methadone maintenance treatment clinic in Israel: Characteristics and a pharmacotherapeutic approach. Isr J Psychiatry Relat Sci 2002; 39 :104-112. 24. Weizman T, Gelkopf M, Melamed Y, Adelson M, Bleich A. Treatment of benzodiazepine dependence in methadone maintenance treatment patients: A comparison of two therapeutic modalities and the role of psychiatric comorbidity. Aust N Z J Psychiatry 2003; 37 :458-463.
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Evaluating the Clinical Impact of Involuntary Admission to a Specialized Dual Diagnosis Ward Yael Delayahu, MD,1,2 Yael Nehama, MD,2,3 Adi Sagi, PhD,1,4 Yehuda Baruch, MD,1,2 and David M. Blass, MD1,5,6 1
Abarbanel Mental Health Center, Bat Yam, Israel Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel 3 Petach Tikva Community Mental Health Center, Petach Tikva, Israel 4 Department of Behavioral Sciences, The Academic College of Tel Aviv- Yaffo, Tel Aviv, Israel 5 Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Baltimore, Maryland, U.S.A. 6 Phoebe Berman Bioethics Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. 2
Abstract Background: We aimed to identify characteristics and outcomes of involuntary and voluntary admissions of dual-diagnosis patients in a single, large mental health center in Israel. Methods: Using a retrospective chart review methodology, 24 patient records were reviewed spanning a period of five years; clinical and demographic variables of voluntary and involuntary admissions were compared. Results: No significant differences were found in sociodemographic characteristics, admission diagnosis and length of hospitalization between the two types of admission. A smaller proportion of patients discharged from involuntary admissions were in remission compared to those discharged from voluntary admission. Nevertheless, involuntary admissions were associated with longer time to next hospitalization. Limitations: The data were based on a small number of patients in a single ward, thus the generalizability of the results is uncertain. Conclusions: The finding of the current study that involuntary admission leads to longer tenure in the community suggests that there may be clinical advantages to involuntary admissions for certain dual diagnosis patients.
Introduction Dual-diagnosis (DD) patients are defined as those having a severe mental illness and a substance abuse disorder (SA) (1). DD comprises an important public health issue as a significant number of patients diagnosed with schizophrenia (47%) or bipolar disorder (61%) also carry a SA diagnosis and vice versa: for those with substance abuse disorders (other than alcohol), more than half (53%) were found to have a psychiatric disorder (2). DD patients comprise a unique patient population who require unique treatment programs (3). Despite the magnitude of this clinical problem, few treatments have been rigorously studied in this patient population. In clinical trials for schizophrenia, bipolar disorder or major depression, active SA is usually an exclusion criterion. Similarly, in trials evaluating treatments for SA, subjects with active psychosis are usually excluded (4, 5). Involuntary hospital admission of general psychiatric patients is a procedure which, despite being somewhat controversial, enjoys wide clinical acceptance (6). It may temporarily reduce patient autonomy, cause discomfort or possibly even a traumatic experience (7), while its benefits have not yet been fully defined. Data about potential long-term effects of involuntary admission of general psychiatric patients are still scarce (8, 9). One systematic review found that when compared with voluntarily-admitted patients, involuntary patients had at least equal or longer hospitalizations and an equal or higher readmission risk (10). Involuntary hospitalizations were not associated with worse clinical outcomes except for lower treatment satisfaction (9). In an Israeli study,
Address for Correspondence: Yael Delayahu, MD, Abarbanel Mental Health Center, Dual-Diagnosis Unit (7A), 15 Keren Kayemet Street, Bat Yam 59100, Israel â&#x20AC;&#x2020; yael.delayahu@abr.health.gov.il
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court-ordered patients had a lower probability for hospital readmission, possibly related to longer length of stay (11). Co-occurring addiction is one of many complex interacting risk factors that are believed to be associated with involuntary admission (10), i.e., the type and severity of psychopathology, socio-demographic factors, social and community support, responsiveness of the health care system, and treatment adherence. Studies to date have been primarily descriptive, focusing on epidemiological aspects (8, 12) and on patient characteristics (6, 13, 14). Among patients being treated specifically for SA, legal coercion was associated with greater readiness for change after controlling for addiction severity, prior treatment history and gender (15). Persons who entered treatment due to legal coercion were over three times more likely to engage in recovery-oriented behavior. A positive association between the length of stay in a rehabilitation program and higher motivation for change was found (16). SA patients who were legally compelled to seek treatment remained in treatment longer, and fared at least as well as those who sought treatment voluntarily (17). In light of the above, the current study was undertaken in order to identify characteristics and outcomes of involuntary hospitalization in the DD population. This study compared clinical and demographic variables between patients who were voluntarily admitted and those who were involuntarily admitted into a DD psychiatric ward. Based on previous findings (9, 10, 11, 17) our hypotheses were: 1) Involuntary hospitalizations would be longer than voluntary ones; 2) patients who were hospitalized involuntarily would have longer time to the next hospitalization (TTNH); and 3) patients who were hospitalized involuntarily would have better clinical outcomes with regard to variables such as cooperation with treatment and clinical status at the time of discharge. Materials and methods Subjects
The study utilized a retrospective chart review design. Inclusion criteria were men aged 18-60 with a major DSM-IV Axis I diagnosis accompanied by an SA diagnosis who were hospitalized in the acute psychiatric DD ward (all male) at a large Mental Health Center (MHC) in Israel. The MHC registry was used to identify all patients admitted from February through March and from May through June 2004 (months were selected randomly). This admission was defined as the “first admission”(FA). Five years of data were collected following the FA (through
July 2009). Demographic data were extracted from the hospital computerized database, and clinical variables were extracted from patient discharge summaries. The study was approved by the Ethics Committee of the MHC and conformed to the provisions of the Declaration of Helsinki. Demographic data collected included: age, marital status, country of origin, religion, years of education, military service, medical history and supportive relationship. The clinical data included: number of previous hospitalizations, time from the previous hospitalization (prior to the FA), substance used, mental status upon admission (specifically suicidal ideations, hallucinations, reality testing and insight), length of hospital stay (LOS), level of cooperation with treatment at the time of discharge, whether or not the discharge was against medical advice (AMA), level of remission at the time of discharge (psychotic, partial remission or complete remission) and TTNH. Data analysis
Three analyses were performed: • Analysis 1: Comparison between patients whose FA was voluntary versus those whose FA was involuntary (between subjects analysis). • Analysis 2: Comparison between the first voluntary admission and the first involuntary admission of the same patient, such that each patient served as his own control (intra-subject analysis). • Analysis 3: Comparison between all voluntary admissions and all involuntary admissions across the entire study sample (between-admissions analysis). Statistical analyses were conducted using SAS version 9.1 (SAS Institute, Cary, North Carolina). The two-sample T-test was applied for testing the statistical significance of the changes in continuous variables, Chi-square test or Fisher’s exact test (as appropriate) were applied for testing the statistical significance of differences between categorical variables. All tests applied were two-tailed; only those which referred to the study hypotheses that emerged from previous studies (9-11, 17) were one-tailed, and the level of significance was set to 0.05. Level of significance between 0.05 – 0.1 was defined as marginal.
®
Results Twenty-four patients were included in the analysis, within the five years follow up they had 108 hospitalizations altogether and among them, 16 patients had both voluntary and involuntary hospitalizations. The socio-demographic and clinical characteristics of the patients are presented in 291
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Table 1. Characteristics of the patient population at first admission Parameter
All
Voluntary
Involuntary
Males, N (%)
24 (100.0)
15 (100.0)
9 (100.0)
Age, mean ± SD (years)
35.3 ± 8.3
33.9 ± 8.1
38.9 ± 7.5
Range
23.0 – 55.0
23.0 – 49.0
31.0 – 55.0
Education, mean ± SD (years)
9.8 ± 2.3
9.6 ± 2.7
10.4 ± 1.5
Marital status, N (%) Single
18 (75.0)
13 (86.7)
7 (77.8)
Divorced
4 (16.7)
2 (13.3)
2 (22.2)
NA
2 (8.3)
Country of origin, N (%) Israel
13 (54.2)
9 (60.0)
5 (55.6)
Russia
8 (33.3)
6 (40.0)
2 (22.2)
Other
2 (8.3)
-
2 (22.2)
NA
1 (4.2)
Religion, N (%) Jewish
19 (79.2)
12 (80.0)
9 (100.0)
Other
3 (12.5)
3 (20.0)
-
NA
2 (8.3)
Military service, N (%)
15 (62.5)
9 (60.0)
7 (77.8)
Supportive relationship, N (%)
2 (8.3)
None
10 (41.7)
8 (53.3)
2 (22.2)
Parents
7 (29.2)
3 (20.0)
5 (55.6)
Parents + Partner
2 (8.3)
1 (6.7)
1 (11.1)
Nuclear family
2 (8.3)
P value t(22)= -1.49
0.151
t(21)= -0.75
0.459
χ2(1)=0.32
0.572
χ2(2)=3.89
0.143
χ2(1)=2.06
0.152
χ2(1)=0.8
0.371
χ2(4)=4.91
0.297
Analysis 3 revealed a trend for a higher proportion of voluntarily admitted patients to have insight (partial or complete) at admission as compared with involuntary patients. There were no significant differences in LOS between admission subtypes in any of the analyses. In analysis 1 and 2 there was no significant difference in the proportion of patients who were discharged AMA or who were cooperative with treatment at the time of discharge between admission subtypes. Analysis 3 revealed a trend for voluntary patients to be more cooperative with treatment at discharge and more likely to be discharged with the consent of the attending staff (not AMA). Analyses 1 and 3 showed that a higher percentage of voluntary patients were in partial or complete remission upon discharge and that more patients discharged from involuntary hospitalizations were in a psychotic state, differences that were not found in analysis 2. All three analyses showed that TTNH in involuntarily-admitted patient tended to be longer than for voluntarily admitted patients. In Analysis 1 and 2 TTNH among voluntarily admitted patients was 7.6 ± 12.2 and 4.7±3.9 months respectively, while for involuntarily admitted patients TTNH was 18.5 ± 19.8 and 10.8 ± 7.7 respectively (p = 0.055 and p = 0.062 respectively). In analysis 3 TTNH in voluntary patients was 6.0 ± 9.1 while in the involuntary group is was 14.6 ± 14.5 (t(26)= -3.13, p = 0.019).
Discussion Many variables may potentially affect hospital Siblings 1 (4.2) 1 (6.7) 1 (11.1) readmission rates and TTNH (18-24). These can NA 2 (8.3) include hospitalization characteristics (e.g., LOS, Additional 13 (54.2) 4 (26.7) 5 (55.6) χ2(1)=2.0 0.157 type of hospitalization and treatment), patient physical characteristics (demographics), clinical variables diagnosis N (%) and characteristics of community care. Our results SD=standard deviation; NA=data not available showed that admission status was associated with TTNH, but not LOS, discharge clinical status, or other demographic and clinical variables. Although these Table 1. There were no statistically significant differences findings do not support our hypothesis that longer LOS found among socio-demographic parameters between would be associated with longer TTNH, they do concur the voluntary and involuntary patient populations. with an earlier report that voluntarily-admitted patients have a higher rate of multiple readmissions compared Clinical variables (Table 2): with patients admitted involuntarily (25). In all three analyses there were no significant differences Our results partially differ from those of a previous in the proportion of patients with suicidal ideation, halIsraeli study that found significantly longer LOS and lucinations or abnormal reality testing at admission. 292
2 (13.3)
-
15 (100.0)
Cooperative at admission
15 (100.0)
12 (80.0)
Hallucinations at admission
Abnormal reality testing at admission
-
13 (86.7) 73.9 ± 78.1
Cooperative with treatment at discharge
Length of stay (days) 57.3 ± 59.6
6 (66.7)
5 (55.6)
3 (33.3)
10 (66.7) 12 (80.0)
partial
Discharge with the consent of the staff
3 (33.3)
4 (26.7) 1 (6.7)
no
3 (33.3)
7 (77.8)
7 (77.8)
5 (55.6)
yes
Insight at admission
2 (13.3) 8 (53.3)
Opiates, Alcohol
Suicidal Ideation at admission
Alcohol, cannabinoids χ2(1)=0.01
0.916
t(22)= 0.54
χ2(1)=1.36,
χ2(1)=1.63
χ2(2)=3.64
χ2(1)=0.017
χ2(1)=3.64
p=0.591
0.243
0.202
0.162
0.897
0.056 (Fisher exact test: p=0.13)
42.5±41.9 (N=16)
14 (87.5)
12 (75.0)
10 (66.7)
1 (6.7)
4 (26.7)
13 (86.7)
15 (100.0)
8 (53.3)
2 (13.3)
3 (20.0)
44.9±49.4 (N=16)
8 (50.0)
10 (62.5)
5 (31.3)
4 (25.0)
7 (43.8)
11 (68.8)
15 (93.8)
11 (68.8)
1 (6.3)
8 (50.0)
4 (25.0)
χ2(1)=0.78
0.3785
0.363
0.0003
8 (11.4)
16 (22.9)
68 (95.8)
paired t-test= -0.15
χ2(3)=3.11
χ2(1)=0.58
χ2(2)=4.26
χ2(1)=0.83
χ2(1)=0.97
0.881
0.374
0.446
0.119
0.361
0.325
40.4 ± 65.8
59 (81.9)
58 (80.6)
53 (74.6)
8 (11.3)
10 (14.1)
56 (78.9)
64 (90.1)
38 (53.5)
10 (14.3)
-
19 (27.1)
16 (22.9)
4 (4.44)
5 (33.3)
χ2(3)=3.19
χ2(1)=12.92
3 (20.0)
-
3 (18.8)
5 (31.3)
3 (20.0)
-
5 (33.3)
15 (100.0)
P value
39.9 ± 50.1
20 (55.6)
22 (62.9)
5 (31.3)
8 (22.9)
16 (45.7)
26 (74.3)
30 (88.2)
17 (50.0)
1 (2.9)
2 (5.9)
16 (47.1)
6 (17.6)
-
3 (8.8)
6 (17.6)
8 (22.9)
Involuntary admissions N=36, N (%)
t(103)= -0.16
χ2(1)=6.24
χ2(1)=3.91
χ2(2)=18.9
χ2(1)=0.08
χ2(1)=0.09
χ2(1)=0.11
χ2(6)=10.82
χ2(1)=57.5
0.877
0.0125
0.048
<0.0001
0.781
0.765
0.735
0.094 (Fisher exact test: p=0.099)
<0.0001
P value
Analysis 3: Both types of all admissions - between admission design Voluntary admissions N=72, N(%)
Cannabinoid + Opiates
1 (11.1)
0.374
0.0003
0.687
Involuntary N=16 N(%)
Opiates, Cannabinoid, Alcohol
2 (2.22)
χ2(4)=4.24
χ2(1)=13.33
t(22)= -0.41
P value
Voluntary N=16 N(%)
1 (1.4)
1 (6.7)
Cannabinoid
2 (2.22)
3 (33.3)
8.0 ± 7.8
Involuntary N=9 N(%)
Analysis 2: Both types of admission intra-subject design
Alcohol
6 (40.0)
Opiates
Type of Drug
6.7 ± 7.1
No. of previous hospitalizations
Voluntary N=15 N(%)
Analysis 1: First admission between subjects design
Yael Delayahu et al.
Table 2. Clinical variables at admission and discharge
* LOS - length of stay ** AMA -Not Against Medical Advice *** TTNH - Time to next hospitalization
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t(26)= -3.13 14.6 ± 14.5 (N=21)
14 (38.9) 45 (62.5)
0.0652 paired t-test= -2.14 10.8 ± 7.7 (N=9)
7 (43.8) 11 (68.8)
0.055 t(21)= -1.64 4 (44.4)
18.5 ± 19.8
10 (66.7)
7.6 ± 12.2
Complete remission
TTNH* (months)
1 (11.1) 5 (33.3) Partial remission
4 (44.4) Psychotic
Mental status on discharge
4.7±3.9 (N=9)
6 (37.5) 4 (25.0)
3 (18.8) 1 (6.3) 0.016 (Fisher exact test: p= 0.0255) χ2(2)=8.25
P value Involuntary N=9 N(%) Voluntary N=15 N(%)
6.0 ± 9.1 (N=62)
9 (25.0) 22 (30.6)
13 (36.1) 5 (6.9) χ2(2)=2.29
0.318
P value Involuntary N=16 N(%) Voluntary N=16 N(%)
Analysis 2: Both types of admission intra-subject design Analysis 1: First admission between subjects design
* TTNH - Time to next hospitalization
294
0.019
0.0006 χ2(2)=14.95
P value Involuntary admissions N=36, N (%) Voluntary admissions N=72, N(%)
Analysis 3: Both types of all admissions - between admission design
Table 2. continuation
TTNH for patients who were involuntarily admitted by court-order, as compared to voluntary admissions. In that study, the authors attributed the longer TTNH to the longer LOS as well as greater improvement in BPRS (11). The authors also suggested that admission status may have influenced the rate of hospital readmission. This suggestion was based on the observation that patients who underwent court-ordered hospitalizations had a comparatively low rate of hospital readmission despite having a clinical profile generally associated with a high risk of hospital readmission (25). In contrast to other studies that showed significantly longer average LOS for involuntary hospitalizations as compared to voluntary ones (23), we did not find such a difference although it is possible that with a larger sample size a difference would have been apparent. Of note, another study found that among acute psychiatric hospitalizations, there was an inverse relationship between the degree of substance abuse and LOS, with DD patients more commonly leaving against medical advice (26). We found that the discharge clinical status of involuntarily admitted patients tended to be worse than that of voluntarily admitted patients. This finding is similar to those from a large U.S. study in which significantly more psychotic symptoms at discharge were found among involuntarily-admitted patients than voluntarily admitted ones (27). The authors attributed their finding to the fact that many involuntarily admitted patients were prematurely discharged prior to resolution of psychotic symptoms once they no longer met criteria for continued involuntary admission. The relationship between LOS and TTNH is complex. Voluntary patients may demand to be released before adequate remission has been achieved, and such premature discharge against medical advice, may result in rapid re-hospitalization (28). Previous studies of general psychiatric inpatients have in fact shown that involuntary admissions are associated with longer TTNH (11). This fact had been previously attributed to longer LOS and to discharge with the staff ’s consent, both of which facilitate patient stabilization and consequent longer TTNH. In the current study of the DD population, involuntary admission tended to be followed by longer TTNH, regardless of the LOS, level of remission, or cooperation with treatment towards discharge. Moreover, there was no significant difference in staff consent to discharge between the two types of admissions. Previous studies of SA patients have found an association between involuntary treatment and greater motiva-
Yael Delayahu et al.
tion for change (15, 17). This finding may help explain our results of longer TTNH in involuntarily admitted DD patients. Limitations of the present study include the fact that it is comprised of a small number of subjects from a single hospital unit, making the generalizability of our results uncertain. The retrospective nature of the study also makes it possible that confounding variables were unaccounted for. Large prospective longitudinal studies are needed to confirm our findings, as well as to evaluate the effect of voluntary and involuntary admissions on additional clinical variables such as readiness for change at discharge and clinical course in the community. Conclusions: Involuntary admission of DD patients leads to longer tenure in the community and thus may have clinical benefits preventing rapid re-hospitalization in this population. Acknowledgements The authors gratefully acknowledge the assistance in text editing from Sharon Furman-Assaf and data collection from Ya’acov Gelber and Natali Cohen.
Author’s contribution Yael Delayahu: conception and design, analysis and interpretation of data, drafting or critical revision Yael Nehama: analysis and interpretation of data, drafting or critical revision Adi Sagi: analysis and interpretation of data, drafting or critical revision Yehuda Baruch: final approval David M. Blass: conception and design, analysis and interpretation of data, drafting or critical revision.
References 1. Drake R, Mercer-McFadden C, Mueser K, et al. Review of integrated mental health and substance abuse treatment for patients with dual diagnosis. Integr Mental Health Subst Abuse 1998; 24:589-605. 2. Regier DA, Farmer ME, Rae DS et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990; 264: 2511-2518. 3. Daley D. Dual disorders recovery counseling. National Institute on Drug Abuse, 2003. 4. Manwani SG, Pardo TB, Albanese MJ, et al. Substance use disorder and other predictors of antidepressant-induced mania: A retrospective chart review. J Clin Psychiatry 2006; 67: 1341-1345. 5. Humphreys K, Weingardt KR, Horst D, et al. Prevalence and predictors of research participant eligibility criteria in alcohol treatment outcome studies, 1970-98. Addiction 2005; 100: 1249-1257. 6. Riecher-Rossler A, Rossler W. Compulsory admission of psychiatric patients in a national and international comparison - incidence and factors of influence. Fortschr Neurol Psychiatr 1992; 60: 375-382.
7. Humble F, Berk M. Pharmacological management of aggression and violence. Hum Psychopharmacol 2003; 18: 423-436. 8. van der Post L, Mulder CL, Bernardt CM, et al. Involuntary admission of emergency psychiatric patients: Report from the Amsterdam Study of Acute Psychiatry. Psychiatr Serv 2009; 60: 1543-1546. 9. Kallert TW, Glockner M, Schutzwohl M. Involuntary vs. voluntary hospital admission. A systematic literature review on outcome diversity. Eur Arch Psychiatry Clin Neurosci 2008; 258: 195-209. 10. Klinkenberg WD, Calsyn RJ. Predictors of receipt of aftercare and recidivism among persons with severe mental illness: A review. Psychiatr Serv 1996; 47: 487-496. 11. Valevski A, Olfson M, Weizman A, Shiloh R. Risk of readmission in compulsorily and voluntarily admitted patients. Soc Psychiatry Psychiatr Epidemiol 2007; 42: 916-922. 12. Priebe S, Badesconyi A, Fioritti A, et al. Reinstitutionalisation in mental health care: Comparison of data on service provision from six European countries. BMJ 2005; 330: 123-126. 13. Becker I, Vazquez-Barquero JL. The European perspective of psychiatric reform. Acta Psychiatr Scand Suppl 2001; 8-14. 14. Munk-Jorgensen P. Has deinstitutionalization gone too far? Eur Arch Psychiatry Clin Neurosci 1999; 249: 136-143. 15. Gregoire TK, Burke AC. The relationship of legal coercion to readiness to change among adults with alcohol and other drug problems. J Subst Abuse Treat 2004; 26: 337-343. 16. Prochaska JO, DiClemente CC. Stages of change in the modification of problem behaviors. Prog Behav Modif 1992; 28: 183-218. 17. Collins JJ, Allison M. Legal coercion and retention in drug abuse treatment. Hosp Community Psychiatry 1983; 34: 1145-1149. 18. Fisher WH, Geller JL, Altaffer F, Bennett MB. The relationship between community resources and state hospital recidivism. Am J Psychiatry 1992;149:385-390. 19. Goodpastor WA, Hare BK. Factors associated with multiple readmissions to an urban public psychiatric hospital. Hosp Community Psychiatry 1991; 42: 85-87. 20. Green JH. Frequent rehospitalization and noncompliance with treatment. Hosp Community Psychiatry 1988; 39: 963-966. 21. Haywood TW, Kravitz HM, Grossman LS, et al. Predicting the “revolving door” phenomenon among patients with schizophrenic, schizoaffective, and affective disorders. Am J Psychiatry 1995; 152: 856-861. 22. Ledoux Y, Minner P. Occasional and frequent repeaters in a psychiatric emergency room. Soc Psychiatry Psychiatr Epidemiol 2006; 41: 115-121. 23. Rosca P, Bauer A, Grinshpoon A, et al. Rehospitalizations among psychiatric patients whose first admission was involuntary: A 10-year follow-up. Isr J Psychiatry Relat Sci 2006; 43: 57-64. 24. Weiden P, Glazer W. Assessment and treatment selection for “revolving door” inpatients with schizophrenia. Psychiatr Q 1997; 68: 377-392. 25. Kastrup M. The use of a psychiatric register in predicting the outcome “revolving door patient.” A nation-wide cohort of first time admitted psychiatric patients. Acta Psychiatr Scand 1987; 76: 552-560. 26. Ries RK, Yuodelis-Flores C, Roy-Byrne PP, et al. Addiction and suicidal behavior in acute psychiatric inpatients. Compr Psychiatry 2009; 50: 93-99. 27. Craw J, Compton MT. Characteristics associated with involuntary versus voluntary legal status at admission and discharge among psychiatric inpatients. Soc Psychiatry Psychiatr Epidemiol 2006; 41: 981-988 28. Dalrymple AJ, Fata M. Cross-validating factors associated with discharges against medical advice. Can J Psychiatry 1993; 38: 285-289.
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Flashbacks and HPPD: A Clinical-oriented Concise Review Arturo G. Lerner, MD,1-2 Dmitri Rudinski, MD,1 Oren Bor, MD,1 and Craig Goodman, PhD1 1
Lev Hasharon Mental Health Medical Center, Pardessya, Israel Sackler School Of Medicine, Tel Aviv University, Ramat Aviv, Israel
2
Abstract A unique characteristic of LSD, LSD-like and substances with hallucinogenic properties is the recurrence of some or all the hallucinogenic symptoms which had appeared during the intoxication after the immediate effects of the substance had worn off. This recurring syndrome, mainly visual, is not clearly understood. The terms Flashback and Hallucinogen Persisting Perception Disorder (HPPD) have been used interchangeably in the professional literature. We have observed at least two different recurrent syndromes, the first Flashback Type we refer to as HPPD I, a generally short-term, non-distressing, benign and reversible state accompanied by a pleasant affect. In contrast, the second HPPD Type we refer to as HPPD II, a generally long-term, distressing, pervasive, either slowly reversible or irreversible, non-benign state accompanied by an unpleasant affect. HPPD I and II appear to be part of a broad spectrum of non-psychopathological and psychopathological states reported by hallucinogen users. HPPD I and II may be clinically characterized by prodromal symptoms, onset, content of visual imagery, precipitators, frequency, duration and intensity of perceptual recurrences, severity, course, differential diagnosis, accompanying mood and affect, insight and remission. Pharmacological therapy with or without preceding or following co-occurring psychiatric disorders have been shown to ameliorate this syndrome. A large variety of medications may be utilized to alleviate this condition, but with differential results suggesting several subtypes. The purpose of this manuscript is to provide a clinical-oriented, comprehensive and concise review to treating psychiatrists.
Introduction Hallucinogens encompass a group of naturally occurring and synthetic substances (1) which may trigger a transient and generally reversible state of intoxication characterized by perceptual disturbances primarily visual in nature, often referred to as “trips” (2, 3). A unique characteristic of LSD (lysergic acid diethylamide) and LSD-like substances is the total or partial recurrence of perceptual disturbances which appeared during previous intoxication and reappeared in the absence of voluntarily or involuntarily recent use (1-3). This syndrome is still poorly understood (2, 3). LSD is the prototype of synthetic hallucinogenic substances and it is probably the most investigated hallucinogen associated with the etiology of this condition. Other substances that have been associated with the development of this condition include: psilocybin (Magic Mushrooms or Shrooms) (4), mescaline (San Pedro and Peyote Hallucinogenic Cacti) (5), cannabis (6), 5-MeO-DiPT (Synthetic Hallucinogen) (7), Ecstasy (MDMA) (8), Phencyclidine (PCP) (9, 10), dextromethorphan (11) and ketamine (12). Datura, salvia divinorum, ayahuasca, ibogaine, synthetic cannabis and inhalants also appeared to be implicated (13). Recurrent visual disturbances attributed to this syndrome are geometric hallucinations, false perception of movement in the peripheral visual fields, flashes of colors, intensified colors, trails of images of moving objects, positive afterimages, halos around objects, macropsia and micropsia (9). A variety of distinct visual disturbances that are reminiscent of those generated by the previous use of substances have been widely reported and described by patients. Etiology LSD’s acute effects seem to emerge through a 5-HT2 postsynaptic partial agonist activity (14). Recurrent imagery
Address for Correspondence: Arturo G. Lerner, MD, Lev Hasharon Mental Health Medical Center, POB: 90000, Netanya, 42100, Israel lerneram@internet-zahav.net and alerner@lev-hasharon.co.il
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may partially or totally look like the previously experienced “trip,” indicating that a mechanism similar to the original intoxication may be implicated. The basic mechanism underlying this syndrome appears to affect vulnerable LSD users who develop chronic disinhibition of visual processors and consequent dysfunction in CNS function (3,15-17). This disinhibition might be associated with an LSD-generated intense current (18) that led to the destruction or dysfunction of cortical serotonergic inhibitory interneurons with GABA-nergic outputs mechanisms which are involved with sensory filtering process of unnecessary stimuli in certain brain areas (16, 18). Investigations of HPPD patients with qEEG mapping indicate that the disorder is represented by disinhibition in the cerebral cortex (15). Thus, an unsuccessful defective sensory gating mechanism may be involved in the pathogenesis of this syndrome (19), facilitating the continuation of the central process of visual imagery after the image has been removed from the visual field (20). It has also been postulated that reverse tolerance or sensitization that had originated after LSD exposure may explain the flashbacks after the stimulus has been removed (21). There may also be a familial and genetic basis as well (2). These processes might play a role in benign transient or pervasive persistence of the visual imagery and associated features (22, 23). HPPD is still poorly understood due to great variability of recurrent perceptual disturbances and different subtypes associated with various psychotropic substances, and may suggest that multiple mechanisms are involved in the etiology (22, 23). Clinical Syndromes Nomenclature used to describe this multi-faceted phenomenon can be confusing and requires clarification (23). Primarily, two subtypes of substance-use associated recurrent perceptual disturbances have been described, including benign Flashback Type or “free trips” (22-24) referred to as HPPD I, and non-benign HPPD Type (2224) referred to as HPPD II. One additional subtype is the return of visual disturbances accompanied by newly generated visual imagery which was not experienced during the original “trip.” Distinct substances may lead to similar but not identical subtypes of visual recurrences, and may vary greatly for different substances. Flashback type or HPPD I
It is a generally transient, recurrent, trigger-precipitated or spontaneous, reversible and visually benign experience (22-24). It is typically a condition in which the re-
experiencing of one or more perceptual symptoms may not produce significant distress or impairment in individual, familial, social, occupational or other important areas of functioning. Experienced LSD users view and relate to these re-occurrences as a “free trip,” an innocuous and trivial aspect of the broad psychedelic dimension, and do not generally seek psychiatric assistance after experiencing these perceptual episodes. Certain individuals may experience the reiterative recurrence of the same single flashback, or a variety of them (22-24). Hallucinogen persisting perception disorder type or HPPD II
It is a typically chronic, recurrent, trigger-precipitated or spontaneous, slowly reversible or irreversible and highly distressing visually pervasive experience (22-24). It is a radically different condition in which the re-experiencing of one or more perceptual symptoms may produce significant distress or impairment in individual, familial, social, occupational or other important areas of functioning. Users are certainly aware of these severe, intruding and disabling consequences of substance consumption and generally actively seek psychiatric help (22-24). Individuals suffering from HPPD II regularly stop the ingestion of these substances including cannabis derivatives, synthetic cannabis and alcohol. HPPD II appears to be an underreported, misdiagnosed or under-diagnosed disruptive side effect (22-24). Additional factors that may contribute to this lack of accurate reports and diagnoses may include patient guilt, relatively ineffective treatments and poor awareness of the disorder in the medical community. HPPD II may be more common and frequent than generally considered. The principal difference between these two conditions rests on the patient’s perception of impairment and disability. HPPD I is perceived as a benign pleasant state whereas HPPD II is perceived as a severe, unpleasant state. HPPD I is typically perceived as a short-term benign condition although it may be long-term in duration. HPPD II is generally a more severe, unpleasant long-term condition. The individual’s subjective experience determines the seriousness of HPPD I and HPPD II, and widely varies from one person to another (22-25). HPPD I and HPPD II may be clinically characterized by prodromal symptoms, onset, content of visual imagery, precipitators, frequency, duration and intensity of perceptual recurrences, severity, course, differential diagnosis, accompanying mood and affect, insight and remission (23). 297
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Prodromal symptoms
HPPD I onset may be preceded by prodromal symptoms which could encompass typical “auras,” slight and surprising feelings of self-detachment, depersonalization, derealization and a mild sense of strangeness or disconnection (23). HPPD II onset could also include bursting “auras,” feelings of self-detachment, a grave sense of imminent, irreversible and uncontrollable changes, sharp depersonalization-derealization and a severe sense of strangeness (23). Prodromal symptoms are more frequently reported in HPPD II (23).
different tonalities) (23), intense fragmentation of still or moving objects, recurrent synesthesia (stimulation of one sensory pathway leads to automatic, involuntary reactions or experiences in a second sensory pathway) (26), geometric phosphenes (non-specific luminous perceptions that occur when the eyes are closed and may originate from entopic stimuli arising from within the eye itself) and imagistic phosphenes (unbidden formed images without geometric patterns generated on closing an eye and pressing it with a finger), acquired dyslexia and aeropsia or visual snow (virtually seeing particles of air) (2).
Onset
Precipitators
HPPD I may slowly commence whereas HPPD II might abruptly erupt. Episodes of HPPD I and II may spontaneously emerge or be precipitated by identified triggers. Episodes may be continuous, intermittent or suddenly paroxysmal. Duration of episodes may range from one long-lasting experience, e.g., “to be stuck,” to multiple episodes lasting from almost imperceptible fractions of seconds to longer periods of time. Duration between episodes may be shorter for HPPD I than HPPD II. Episodes may immediately or gradually disappear (23). HPPD I and II onsets may be preceded by already preexisting mental disorders such as anxiety, mood, somatoform, sleep and dissociative disorders or severe mental illnesses like schizophrenia, but may also contribute to the development of these disorders acting as a trigger (23). HPPD I onset may occur unaccompanied by any prominent additional psychiatric disorder appearing to be a sole, unique and independent condition. The clear clinical association between HPPD I and HPPD II with preceding or subsequent psychiatric disorders should be clinically approached, pharmacologically medicated and comprehensively treated as genuine co-occurring psychiatric disorders. Content of visual imagery
Contents vary widely, only a few of which have been described in DSM-IV-TR (9). Some of the visual disturbances may include floaters (a spot or spots that appear to drift in front of the eye), visualizations of dots, mottles or specks when entering a darkened room, fractals (selfsimilarity perception or small parts seen having the same and identical shape as the whole), repetition of still or moving patterns, sharpness of color contrasts, pareidolia (an image within an image), superimposition of geometric patterns (6), distorted perception of distance (objects seen slightly closer or more distant) (6), monochromatic vision (the visual perception of different colors as one color with 298
A number of triggers of HPPD I and II have been reported. Some reported triggers are: entering a dark environment, intention and sexual intercourse (2); exercise and exposure to noise (23); pregnancy, delivery and post-partum depression (23); photophobia, police car flashing lights, neon lights, monotonous activities and tobacco smoking (23), use of phenothiazines (2) and risperidone (25), as well as ECT treatment in patients with a past history of LSD use (27). Additional precipitators include smoking cannabis products including synthetic cannabis or by listening to acid or trance music when participating in parties (6, 23). Patients may be generally able to accurately point out the specific substance or specific trigger responsible for the syndrome from among the many substances they had consumed or triggers to which they have been previously exposed (23). Frequency, duration and intensity of perceptual recurrences
After HPPD I onset, episodes tend to occur with less frequency, duration and intensity. Past substance users may voluntarily elicit visual imagery with or without known precipitators (2, 23). After HPPD II onset, episodes tend to occur more in frequency, duration and intensity. Individuals might feel a partial or complete lose of control, where the condition may trigger or be accompanied by severe mental illness. A sense of helplessness, advancing general impairment, increasing limitation, functioning incapability, deterioration, debilitation, treatment resistance and slow or partial remission might convert HPPD II into a serious and severe mental disorder. Severity
Patients with HPPD I usually relate to their condition as a mild, benign and transitory hallucinogenic experience. Patients presenting with HPPD II typically relate to their condition as being moderately or severely disturbing.
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Course
The syndrome’s course can be related to both “good” or “bad” trips of the previous intoxication. When the hallucinogenic experience stops, a latent period may precede the onset of the return of the visual imagery. This latent period may last from hours or days up to years and re-emerge as either HPPD I or II with or without any recognized trigger. If the individual’s primary hallucinogenic intoxication continues beyond the subjectively expected time the effects should last (23), this experience is generally accompanied by anxiety (GAD-like or Panic Disorder-like) or depressive features and a threatening feeling of loss of control (22, 23). This clinical status might predict the onset of HPPD II. HPPD I has a generally short-term, reversible and benign course, conversely HPPD II has a generally long-term, irreversible or slowly reversible and pervasive course. Differential diagnosis
It is essential to rule out any organic diseases (9). A comprehensive physical and laboratory examination is mandatory. A complete ophthalmological and neurological evaluation should be conducted. EEG, CT and MRI are on occasion also recommended (23). Accompanying mood and affect
Following HPPD I onset, accompanying mood and affect may be pleasant. Occasionally visual imagery appearing at inappropriate settings may elicit negative mood and affect and disturb functioning (23). HPPD II onset is usually associated with negative mood and affect. Anxiety and depressive features may frequently augment during every new episode. Anxiety might transform into panic attack. Anticipatory anxiety may precede every future additional visual imagery episode and avoidant behavior may entirely limit normal functioning. It may resemble a panic disorder (23). Insight
Following HPPD I and II onset, full insight, reality testing and judgment are maintained before, during and after new episodes. Individuals reporting continuous, persisting and unremitting visual imagery episodes might show reality testing and judgment partially and transiently impaired (23). Remission
Pharmacologically treated or untreated HPPD I, in the absence of additional aggravating precipitators like ongoing substance use, tends to gradually fade away and disappear (22-24). HPPD I rarely transforms into HPPD II.
Pharmacologically treated HPPD II, despite administered treatment, tends sometimes to be chronic in nature. Inexplicably, sometimes disturbing HPPD II may slowly transform into innocuous HPPD I (22-24). HPPD I and II appear to be part of an abundant large spectrum of nonpsychopathological and psychopathological experiences reported by users (23). Pharmacological Treatment Stemming from the still unclear pathogenesis, the numerous substances associated with the genesis of this condition, the myriad of reported perceptual-visual disturbances, the various HPPD subtypes and the preceding or following co-occurring psychiatric disorders, distinct medications have been used toward different targets with different outcomes. No single or multiple medications seem to be completely effective but some of them may lead to clinical improvement (23). Subjects who experience HPPD I do not usually seek pharmacological treatment. Those who actively do so generally present with HPPD II. The professional literature on the effectiveness of pharmacological treatment is debatable and mainly rests on open label studies and case studies. There is an ample non-professional reported information based on individual substance experimentation. The absence of double blind investigations stems from methodological problems in controlling random variables when designing controlled research (23). Clinical studies can be difficult to carry out. The academic literature regarding this condition, although limited, has been comprehensively reviewed (5). Pharmacological agents have been used targeting visual disturbances, anxiety, depression and paroxysmal visual seizures-like episodes (23). Some mechanisms of action can be hypothetically explained whereas others might remain obscure and difficult to explicate. Visual disturbances without co-occurring psychiatric disorders may require pharmacological treatment generally based on one starting medication. Visual disturbances with preceding or following co-occurring psychiatric disorders may require treatment generally based on a polypharmacy approach. Challenging patients are those presenting with HPPD I and II who are already receiving concomitant medication for co-occurring psychiatry disorders. Benzodiazepines
Benzodiazepines appear effective in alleviating but not eradicating this condition (1), and effectiveness may be related to activity at cortical serotonergic inhibitory inter299
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neurons with GABA-nergic outputs (1, 3). Oxazepam (5-10 mg/day) and Lorazepam (0.5-1 mg/day) at low doses have shown little efficacy (28), Clorazepate (5-10 mg/day) seems to be helpful in some cases (13), Alprazolam 0.25-0.75 mg/ day) has been used with some success (29) and Clonazepam (0.5-1.5 mg/day) appears to be the most effective (22, 28). It is suggested that Clonazepam may have effects on serotonergic systems enhancing transmission (30), and leading to improvement in patients (28). Benzodiazepines appear to play a central role as a suggested primary treatment for a large number of patients, but their abuse potential might be inconvenient and bothersome for some subjects with a past history of substance use (2, 22, 23, 28). A carefully monitored prescription of Clonazepam or Alprazolam can help avoid this (23, 29). Sympatholytic centrally acting α2 presynaptic adrenergic agonists
Clonidine is an optional treatment for individuals with a past history of substance-related disorders due to its low profile of abuse and dependence. Improvement has been observed in some patients (24). Effectiveness may be based on the evidence that clonidine may increase plasma GABA levels in humans (31) having a benzodiazepine-like effect. Clonidine may also reduce locus ceruleus activity and decrease adrenergic activity (32), reduction which can be effective in the treatment of PTSD (33). Then, as in PTSD-related flashbacks, some visual disturbances could be associated with excessive sympathetic nervous activity that may be alleviated by Clonidine (24). It is recommended to start treatment with small doses of Clonidine (0.050–0.075 mg/day) which is well tolerated, has minimal side effects and no abuse potential (24). Lofexidine, another sympatholytic centrally acting α2 presynaptic adrenergic agonist similar to Clonidine, also appears to be effective in some cases (13). Serotonin dopamine receptor antagonists
Risperidone was considered a reasonable treatment for visual disturbances due to its proven efficiency in the treatment of hallucinations in schizophrenia. LSD appears to act mainly as a partial agonist at postsynaptic serotonin receptors, thus Risperidone which is a highly potent antagonist of both postsynaptic 5-HT2 and D2 receptors was expected to be useful. In contrast to this conjecture, Risperidone at recommended (34) and low doses (35) aggravated visual disturbances and related anxiety. This worsening was later imputed to a Risperidone alpha 2 presynaptic antagonism and noradrenaline release (36). In addition, Risperidone was associated with the re-experiencing of visual disturbances 300
in some patients suffering from schizophrenia with a past history of LSD use (25). Some patients have found low dosages of atypical antipsychotics to be beneficial, for instance: Olanzapine (5–7.5 mg/day), Quetiapine (up to 25–75 mg/day) and Amisulpride (300–600 mg /day) (13). Low doses of Aripiprazole and Asenapine seem to be effective in some cases (13). Dopamine receptor antagonists
Haloperidol (37) and Trifluoperazine (38) have been previously reported to be helpful in treatment. Currently, these agents are largely not prescribed and are no longer recommended. There are only a few agents in this family which are still used, including Perphenazine in small doses (4-8 mg/day) (23, 29) and Zuclopenthixol (2-10 mg/day) (23). These treatments at low doses are well tolerated and may be an effective treatment among the dopamine receptor antagonists. These patients appear to be more sensitive to dopamine receptor agonists even at low doses, requiring monitoring of extra-pyramidal side effects. Antiepileptic agents
Visual disturbances with paroxysmal onset have been interpreted as visual seizures, an approach which also helped to explain the efficacy of benzodiazepines and led to the use of Phenytoin (39). Pharmacological agents like Valproic Acid (200-600 mg/day), Carbamazepine (200-600 mg/day), Oxcarbamazepine (300 mg/day), Gabapentin (300-900 mg/day), Topiramate (25-100 mg/ day) and Levetiracetam (250-500 mg/day) may be useful (13). Lamotrigine at different doses (25-200 mg/ day) also seems to have some therapeutic usefulness (13, 40). These medications may also be helpful when visual disturbances are accompanied by mood swings and mood disorders. Effective doses can vary between patients. Experience and expertise are recommended to use these medications. Serotonin selective reuptake inhibitors
There are controversial reports regarding SSRIs like Sertraline which has been reported to worsen (41) as well as improve (18) visual disturbances. Alleviation after longterm administration of SSRIs was attributed to the down regulation of 5-HT2 receptors, adding further evidence to support the serotonergic mechanisms underlying this syndrome (18). Other SSRIs which have been utilized with some success are Citalopram (10-20 mg/day) (42), Paroxetine (10-20 mg/day) and Escitalopram (10-20 mg/
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day) (13). NSRI like Duloxetine (30-60 mg/day) and Milnacipram (25-50 mg/day) have shown some improvement in symptomology (13). NRE like Reboxetine have also been tried with some success (43). These medications could help in treating visual disturbances with co-occurring anxiety and depressive disorders (22, 43). Long-acting opioid receptor antagonists
Naltrexone may assist in specific cases. The underlying mechanism of Naltrexone’s efficacy could be that visual imagery and associated features might be so distressing as to represent painful stimuli, which have been shown to provoke a greater release of endorphins (44). Naltrexone has been generally used alone or with other agents, in chronic patients with continuous unremitting visual disturbances that previously did not respond to other medications (13, 44). Calcium channel blockers
These medications have been utilized in treating recurrent perceptual disturbances in patients with co-occurring anxiety and mood disorders. Despite the weak evidence of the role of calcium in the genesis of these disorders, medications affecting calcium channels may be useful in the treatment of anxiety disorders (45-48). Verapamil (180 mg/day) and Nifedipine (30-60 mg/day) have been used with success in some patients (13). These medications may be utilized alone or with other agents in subjects who previously did not respond to different remedies. Beta blockers
There is clinical evidence for the efficacy of a β-noradrenergic receptor blockade with Propranolol in the alleviation of anxiety symptoms (49). Propanolol at low (20-60 mg/day) and high doses (240 mg/day) have been used to reduce the accompanying anxiety of visual imagery, being used alone or with other agents in chronic patients who previously did not respond to other medications remedies (13). Catechol-O-Methyl Tranferase Inhibitiors (COMT)
A combination of reversible COMT inhibitor Tolcapone, Carbidopa and Levodopa augmentation appear to be helpful in some HPPD subjects (19). Studies of HPPD patients with qEEG mapping showed that HPPD is represented by disinhibition (16, 50) in the cerebral cortex (15). The rationale behind this treatment is that improving sensory gating by dopaminergic enhancers may lead to inhibition of COMT that may reduce symptoms in HPPD.
Discussion In summary, the critical first step towards understanding HPPD syndromes is the establishment of accepted terminology and treatment targets. HPPD I is typically an independent condition without co-occurring psychiatric disorders and can be treated with one type of medication, i.e., clonidine, clonazepam or small doses of first or second generation antipsychotics. HPPD II as a condition is largely associated with co-occurring psychiatric disorder. If one medication is ineffective, a combination of medications may be needed according to preceding or subsequent psychopathology. Clinical experience and comprehensive knowledge of these phenomena is vital for a successful treatment outcomes. Some symptoms may rapidly subside whereas others like “trailing phenomenon” (51) may be resistant to treatment. Controlled studies are needed to more accurately understand these complicated substance-associated phenomena and to clinically evaluate the efficacy of different medications used in distinct subtypes for treating those affected by this syndrome (23). References 1. Abraham HD, Aldridge AM, Gogia P. The psychopharmacology of hallucinogens. Neuropsychopharmacology 1996; 14:285-298. 2. Abraham HD. Visual phenomenology of the LSD flashbacks. Arch Gen Psychiatry 1983; 40:884-889. 3. Abraham HD, Aldridge AM. Adverse consequences of lysergic acid diethylamide. Addiction 1993; 88:1327-1334. 4. Espiard ML, Lecardeur L, Abadie P, Halbecq I, Dollfus S. Hallucinogen persisting perception disorder after psilocybin consumption: A case study. Eur Psychiatry 2005; 20:458-460. 5. Halpern JH, Pope HG. Hallucinogen persisting perception disorder: What do we know after 50 years? Drug Alcohol Depend 2003; 69:109-119. 6. Lerner AG, Goodman C, Rudinski D, Bleich A. Benign and time-limited visual disturbances (flashbacks) in recent abstinent high-potency heavy smokers. Isr J Psychiatry Relat Sci 2011; 48:25-29. 7. Ikeda A, Sekiguchi K, Fujita K, Yamadera H, Koga Y. 5-methoxy-N,Ndiisopropyltryptamine-induced flashbacks. Am J Psychiatry 2005; 162: 815. 8. McGuire PK, Cope H, Fahy TA. Diversity of psychopathology associated with use of 3,4-methylenedioxymethamphetamine (“Ecstasy”). Br J Psychiatry 1994; 165:391-395. 9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington DC: American Psychiatric Association, 2000. 10. Soyka M, Krupinski G, Volgi G. Phenomenoly of ketamine-induced psychosis. Ger J Addict, Res Practice 1993; 5: 327-331. 11. Ziaae V, Akbari HE, Hosmand A, Amimi H, Kebriaeizadeh A, Saman K. Side effects of dextromethorphan abuse: a case series. Addict Behav 2005; 30: 1607-1613. 12. Vroegop MP, Dongen RT, Vantroyen B, Kramers C. Ketamine as a party drug. Ned Tijdschr Geneeskd 2007; 151:2039-2042.
301
Isr J Psychiatry Relat Sci - Vol. 51Flashbacks - No 4 (2014) and HPPD: A Clinical-oriented Concise Review
13. Lerner AG. Unpublished data. 14. Sander-Bush E, Burris KD, Knoth K. Lysergic acid diethylamide and 2,5-dimethoxy-4-mathylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. J Pharmacol Exp Ther 1988; 246:924-928. 15. Abraham HD, Duffy FH. Stable qEEG differences in post-LSD visual disorder by split half analyses: Evidence for disinhibition. Psychiat Res- Neuroim 1996; 67:173-187. 16. Abraham HD, Duffy, FH. EEG coherence in post-LSD visual hallucinations. Psychiatry Research: Neuroimaging 2001; 107:151-163. 17. Garrat J, Alreja M, Aghajanian GK. LSD has high efficacy relative to serotonin in enhancing the cationic current. In: Intracellular studies in rat facial motor neurons. Synapse 1993; 13:123-134. 18. Young CR. Sertraline treatment of hallucinogen persisting perception disorder. J Clin Psychiatry 1997; 58:85. 19. Abraham HD. Catechol-O-Methyl transferase inhibition reduces symptoms of hallucinogen persisting perception disorder. Biol Psychiatry 2012; 71: No. 8S, 945. 20. Sipes TE, Geyer MA. DOI disruption of prepulse inhibition of startle in the rat is mediated by 5-HT(2A) and not by 5-HT(2C) receptors. Behav Pharmacol 1995; 6:839-842. 21. Stahl SM. Essential psychopharmacology, neuroscientific basis and practical applications. Cambridge, U.K.: Cambridge University, 1996. 22. Lerner AG, Gelkopf M, Skalman I, Rudinski R, Nachshon H and Bleich A. Clonazepam treatment of LSD-induced hallucination persisting perception disorder with anxiety features. Int Clin Psychopharmacol 2003; 18:101-105. 23. Lerner AG, Gelkopf M, Skladman I, Oyffe I, Finkel B, Sigal M, Weizman A. Flashback and hallucinogen persisting perception disorder: Clinical aspects and pharmacological treatment approach. Isr J Psychiatry Rel Sci 2002; 39:92-99. 24. Lerner AG, Gelkopf M, Oyffe I, Finkel B, Katz S, Sigal M, Weizman A. LSD-induced hallucinogen persisting perception disorder (HPPD) treatment with clonidine: An open pilot study. Int Clin Psychopharmacol 2000; 18:35-37. 25. Lerner AG, Shufman E, Kodesh A, Rudinski D, Kretzmer G, Sigal M. Risperidone-associated, benign transient visual disturbances in schizophrenic patients with a past history of LSD abuse. Isr J Psychiatry Relat Sci 2002; 39:57-60. 26. Rich AN, Mattingley JB. Anomalous perception in synaesthesia: A cognitive neuroscience perspective. Nat Rev Neurosci 2002; 3:43-52. 27. Russ MJ, Gold JM. LSD-like flashbacks associated to ECT. Convuls Ther 1987; 3: 296-301. 28. Lerner AG, Skladman I, Kodesh A, Sigal M, Shufman E. LSD-induced hallucinogen persisting perception disorder treated with clonazepam: Two case reports. Isr J Psychiatry Relat Sci 2001; 38:133-136. 29. Miller NS. The principles and practice of addictions in psychiatry. Philadelphia, Penn.: W.B. Saunders Company, 1997. 30. Hewlett WA, Vinogradov S, Agras WS. Clomipramine, clonazepam, and clonidine treatment of obsessive compulsive disorder. J Clin Psychopharmocol 1992; 12: 420-430. 31. Kemph JP, DeVane L, Levin GM, Jarecke R, Miller R. Treatment of aggressive children with clonidine: Results of an open pilot study. J Am
302
Acad Child Adolesc Psychiatry 1993; 32:577-581. 32. Davidson J. Drug therapy for post-traumatic stress disorder. Br J Psychiatry 1992; 160:309-314. 33. Kolb L, Burris BC, Griffitshs S. Propanolol and clonidine in the treatment of post traumatic disorders of war. In van der Kolk, BA, editor. Post Traumatic Stress Disorder: Psychological and Biological Sequelae. Washington, DC: American Psychiatric Press, 1984. 34. Abraham HD, Mamen A. LSD-like panic from risperidone in post-LSD visual disorder. J Clin Psychopharmacol 1996; 16:238-241. 35. Morehead DB. Exacerbation of hallucinogen persisting perception disorder with risperidone. J Clin Psychopharmacology 1997; 17:327-328. 36. Alcantara AG. Is there a role of alpha 2 antagonism in the exacerbation of hallucinogen persisting perception disorder with risperidone? J Clin Psychopharmacology 1998; 18:487-488. 37. Moskowitz D. Use of haloperidol to reduce LSD flashbacks. Milit Med 1971; 136:754-756. 38. Anderson W, Oâ&#x20AC;&#x2122;Malley J. Trifluoperazine for the trailing phenomena. JAMA 1972; 220:1244-1245 39. Thurlow HJ, Girvin JP. Use of antiepileptic medication in treating flashbacks from hallucinogenic drugs. Can Med Assoc 1971; 105:947-948. 40. Hermle L, Simon M, Ruchsow M, Geppert M. Hallucinogen persisting perception disorder. Therapeutic advances in psychopharmacology 2012; 2: 199-205. 41. Markel H, Lee A, Holmes RD, Domino EF. LSD flashback syndrome exacerbated by selective serotonin reuptake inhibitor antidepressants in adolescents. J Pediatr 1994; 125:817-819. 42. Hanck L, Schellekens AF. Hallucinogen persisting perception disorder after ecsasty use. Ned Tidjschr Geneeskd 2013; 157: A5649 43. Lerner AG, Shufman E, Kodesh A, Kretzmer G, Sigal M. LSD-induced hallucinogen persisting perception disorder with depressive features treatment with reboxetine. Isr J Psychiatry Relat Sci 2002; 39:100-103. 44. Lerner AG, Oyffe I, Isaacs G, Sigal M. Naltrexone treatment of hallucinogen persisting perception disorder. Am J Psychiatry 1997; 154:437. 45. Balon R, Ramesh C. Calcium channel blockers for anxiety disorders? Ann Clin Psychiatry 1996; 8:215-220. 46. Klein E, Uhde TW. Controlled study of verapamil for treatment of panic disorder. Am J Psychiatry 1988; 145:431-434. 47. Giannini AJ, Houser Jr WL, Loiselle RH, Giannini MC, Price W. Antimanic effects of verapamil. Am J Psychiatry 1984; 141:1602-1603. 48. Giannini AJ, Taraszewski R, Loiselle RH. Verapamil and lithium in maintenance therapy of manic patients. J Clin Pharmacology 1987; 27: 980-982. 49. Hurlemann R, Walter H, Rehme AK, Kukolja J, Santoro SC, Schmidt C, Schnell K, Musshoff F, Keysers C, Maier W, Kendrick KM, Onur OA. Human amygdala reactivity is diminished by the β-noradrenergic antagonist propranolol. Psychol Med 2010; 40:1839-1848. 50. Abraham HD, Duffy FH. Stable quantitative EEG difference in postLSD visual disorder by split-half analysis: Evidence for disinhibition. Psychiatry Res 1996; 67:173-187. 51. Asher H. Trailing phenomena, a long lasting LSD side effect. Am J Psychiatry 1971; 127: 1233-1234.
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Stephen Malnick et al.
A Model for Treating HCV Hepatitis in Patients Receiving Methadone Maintenance Therapy Stephen Malnick, MA(Oxon) MSc MBBS(Lond),1 Victoria Sheidvasser, MD,2 Alon Basevitz, MD,1 and Shabtai Levit, PhD3 1
Kaplan Medical Center, Rehovot, Israel Methadone Treatment Center, Ashdod, Israel 3 Ex-director of Jerusalem & Ashdod MMT and adjunct Lecturer in School of Social Work and Social Welfare, The Hebrew University of Jerusalem and Ariel University Center of Samaria, Israel 2
Abstract Introduction: Although hepatitis C virus (HCV) is associated with substance abuse, treatment of addicts is problematic. We report the results of a pilot scheme for treatment of HCV –infected substance abusers in a methadone maintenance center (MMC). Methods: The treatment program was carried out at a single MMC. Patients were not using illicit drugs or alcohol and received regular treatment with methadone. The program consisted of 5 stages: 1. An explanatory lecture concerning HCV (50/114 attended). 2. 25 of the 50 presented for examination including HCV RNA, genotype and viral load. 3. HCV treatment with pegylated alfa-interferon-1b and ribavarin. 4. The MMC physician and staff aided the clients’ medical compliance. 5. A hepatologist (SM) volunteered his services on the basis of one 3 hourly session every 4-6 weeks, in addition to open access telephone consultation with the MMC staff physician. Results: 50 of 114 HCV seropositive clients attended the initial meeting , 25 (50%) were candidates for treatment, of whom 20 were treated. 10 had genotype 3 infection, 9 genotype 1 and 1 genotype 2. The sustained virological response (SVR) on an intention-to-treat basis was 8/20 (40%). Discussion: We present a model for the successful treatment of chronic HCV hepatitis in patients receiving methadone.
Address for Correspondence: Stephen@malnick.net
Introduction Chronic hepatitis C virus (HCV) infection is estimated to be present in 170 million people worldwide (1). Since the discovery of the virus and the use of ELISA testing and subsequently nucleic acid testing of blood products, the main route of new infection is via injection drug use (IDU) (2). Despite the fact that IDU is a major source of HCV infection, prior to 2002 this group of patients was not evaluated for treatment of chronic HCV hepatitis. A 1997 NIH consensus conference recommended a period of 6-12 months of abstinence from illicit drug use prior to HCV treatment (3). A subsequent NIH consensus panel in 2002 stated that patients with active injection drug use could be considered for HCV treatment (4). There is limited experience in the successful treatment of current intravenous drug users and persons receiving drug dependency treatment in both the U.S.A. and Europe. Several groups have reported outcomes with an SVR between 29% to 50%, although these studies used non-pegylated interferon and in some cases interferon monotherapy only (5-10). Despite this only a small minority of intravenous drug users receive treatment. Hepatitis C is classified into several genotypes, from type 1 to type 6. The common forms in the U.S.A., Europe and Israel are type 1, 2 and 3. The standard of care of chronic HCV hepatitis at the time of the study consisted of pegylated interferon and ribavirin. Genotype 1 causes a more severe disease, responds less to treatment and requires 48 weeks of treatment. Genotypes 2 and 3 cause a less severe disease and require only 24 weeks of treatment. Therapeutic decisions including stopping rules are based on changes in viral load at predetermined time points (11).
Dr. Stephen Malnick, Department of Internal Medicine C, Kaplan Medical Center, Rehovot 76100, Israel.
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A Model Treating Hepatitis in Patients Receiving Methadone Maintenance Therapy Isr J Psychiatry Relat for Sci - Vol. 51 - No 4HCV (2014)
In Israel all citizens are eligible for treatment of illnesses within a basket of services, at minimal cost. This basket includes treatment of HCV hepatitis. There is a 50% prevalence of HCV hepatitis in recipients of methadone maintenance treatment (12). We, therefore, decided to implement a scheme for effectively treating clients of a MMC who had chronic HCV hepatitis. We report the results of this trial. Methods The treatment program was carried out at a single methadone maintenance center in Ashdod in central Israel. Clients attending these centers are routinely tested for HBV, HCV and HIV infection. The clients are required to attend the methadone maintenance center on a weekly basis in order to receive their weekly dose of methadone. At this time they are also tested for the use of illicit drugs or alcohol. This mandatory visit was utilized as an opportunity for the client to be reviewed by the staff physician of the methadone maintenance center regarding problems with the treatment, both medical and social, and in addition on certain occasions to be examined by a hepatologist. The program consisted of 5 stages:
1. An initial explanatory lecture concerning HCV with a question-and-answer session made available to all HCV seropositive clients (50/114 attended). 2. 25 of the 50 presented for a standard HCV hepatitis work-up including routine biochemical tests, autoantibody screen, serum ferritin, ceruloplasmin, TSH, HCV RNA, genotype and viral load. 3. HCV treatment with pegylated alfa-interferon-1b and ribavarin on a standard weight-based regimen. 4. The methadone maintenance center physician and staff aided the clients’ medical compliance and advised regarding side-effects of the treatment including depression, weakness and issues related to problems with employment due to absences related to the sideeffects of the medication. 5. A hepatologist volunteered his services on a regular basis at the methadone maintenance center for 2 hourly sessions, and was available on an open access basis to the physician from the methadone maintenance center in order to advise on any problems that arose. The hepatologist worked in conjunction with all the major health funds (HMOs) in Israel which reduced bureaucratic obstacles. 304
Indications for treatment of HCV hepatitis included elevated liver enzymes, fibrosis of at least F2 grade and HCV RNA positivity in the blood. Contraindications for the program included HIV positivity, evidence for HBV infection, autoimmune disease, active angina pectoris, retinopathy of any kind, newly diagnosed thyroid disease and recent or active depression. A sustained viral response (SVR) which is equivalent to cure was defined as the absence of HCV RNA in the serum on a sensitive assay 24 weeks after the end of treatment. This study was approved by the Institutional Review Board of Kaplan Medical Center. Results Of 114 clients with HCV seropositivity by standard ELISA testing, 50 attended an initial group meeting. Of these 50, 25 were judged to be candidates for treatment and 20 of these received treatment; 5 declined treatment for social reasons. The other 25 candidates were not suitable for treatment for several reasons – lack of HCV RNA in the serum (8), normal liver transaminases (5), depression (2), employment issues (9), planning pregnancy in the near future (1). Of the 20 clients who received treatment 9 (45%) were genotype 1, 1 (5%) was genotype 2 and 10 (50%) were genotype 3. The vast majority of the clients were of male gender, 19 (95%). Treatment was stopped in 4 patients for social reasons – three had problems with performing their jobs and one was imprisoned and his treatment was discontinued, despite this not being permitted. In 2 patients the treatment was stopped due to depression. An SVR was achieved in 8 of the 20 treated patients (40% on an intention to treat basis), 1 patient was a viral relapser. The SVR in the patients who completed treatment was 8 of 13 (61.5%). Discussion In this report we describe a model for treating patients with HCV hepatitis acquired by IDU who are receiving methadone maintenance. This model is based on close cooperation between a volunteering hepatologist and the methadone maintenance center staff, especially the physician from the methadone maintenance center and the center’s director who is a registered social worker. The results obtained are similar to those achieved in real world treatment situations in patients with chronic HCV hepatitis who are not substance abusers (4).
Stephen Malnick et al.
Despite IDUs being a major risk group for past and current HCV infection, physicians often exclude IDUs from therapy of HCV hepatitis due to concerns about compliance, psychiatric comorbidity and the risk of HCV reinfection. Initial studies by Sylvestre (5) and Backmund et al. (6) showed a SVR among IDU patients similar to that observed in trials of HCV treatment. Following this the NIH issued revised guidelines in 2002 stating that HCV treatment should be linked to drug treatment programs and to consider active IDUs on a case-to-case basis (4). Despite this treatment uptake among IDUs is only about 1% annually (13). More than 80% of IDUs have reported a willingness to receive treatment (13) and also in our study 44% (50/114) of those who attended a single explanatory lecture were willing to consider therapy. This suggests that in Israel IDUs are interested in receiving treatment for HCV hepatitis. In our model of treatment, the care of the HCV-infected patient is carried out at the methadone maintenance center. The clients are required to attend the methadone maintenance center on a weekly basis as a condition for receiving their methadone therapy. The methadone maintenance center has a well developed support system including a physician and social worker. The physician from the methadone maintenance center acted as an intermediary between the medical requirements (laboratory tests for therapeutic decisions, such as stopping rules) and the sometimes burdensome medical bureaucracy. In addition, the methadone maintenance center clients found it difficult to attend clinics for blood tests to be taken and having a familiar physician on-site increased their compliance. This support system is able to identify those patients who are interested in receiving treatment for HCV hepatitis and provide a support system for dealing with the side-effects of treatment. The provision of volunteer services by a hepatologist in our model enabled the use of the existing medical services with no additional expenses. The hepatologist was also available for telephone consultations regarding issues associated with the treatment, specifically treatment-related side-effects such as anemia, neutropenia and depression, in addition to decisions regarding cessation of treatment based on stopping rules. The greater part of the cost of the treatment (both therapeutic and diagnostic) is covered by the basket of services to which Israeli citizens are entitled. Furthermore, during the treatment it became apparent that treatment-related mood changes were a problem for many of the clients and their partners and an evening meeting with all the staff, the clients and the hepatologist
was arranged in which all these issues were addressed. This may explain the 80% rate of adherence to treatment in our patients. The health system in Israel requires a maximum copayment by patients of approximately $70 per month. The copayment for methadone is an additional charge and the total cost may approach 40% of the client’s total monthly income received from National Insurance. Financial support, if available, would greatly increase the ability of clients to receive treatment. The treatment of HCV hepatitis is prolonged with many potential side-effects. In addition there is a marked similarity between the physiological symptoms induced by treatment and the withdrawal syndrome. For this reason an effective support system is very important, both prior to the start of treatment to increase the client’s awareness of this possibility and also during treatment to help them deal with such situations should they arise. The clients participate in the methadone treatment program in order to avoid the withdrawal symptoms and find themselves having such symptoms as a result of treatment. Half of our patients had genotype 3 which has a high rate of response to treatment, requires only 24 weeks of treatment and if there is a rapid viral response (HCV RNA negative after 4 weeks of treatment) may be eligible for only 12 weeks of treatment (14). This shortened period of treatment may improve compliance. Recently the protease inhibitors boceprevir and telaprevir have been approved for treatment of genotype 1 HCV hepatitis in both naïve and treatment-experienced patients (15). These treatment protocols are more complicated than the previous standard of care, have a higher rate of success for both naïve and treatment-experienced patients and also have drug interactions with methadone. Our model for treatment can be applied to these new treatment regimens. The incorporation of telemedicine may be useful, too, especially since treatment with telaprevir has a high incidence of rashes and severe cutaneous reactions including Stevens-Johnson syndrome. In summary, we present a successful model, utilizing existing infrastructure, for diagnosing and treating chronic HCV hepatitis in a methadone maintenance center. This model could be applied nationally and also adapted for use in prisons which also have a large number of inmates with HCV hepatitis. References 1. Lavanchy D. The global burden of hepatitis C. Liver Int 2009;29: 74-81. 2. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C
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A Model Treating Hepatitis in Patients Receiving Methadone Maintenance Therapy Isr J Psychiatry Relat for Sci - Vol. 51 - No 4HCV (2014)
virus infection. Lancet Infect Dis 2005;5:558-567. 3. National Institutes of Health. Management of hepatitis C. NIH Consensus Statement 1997. Available at http://consensus.nih. gov/1997/1997HepatitisC105html.htm Accessed March 5, 2012. 4. National Institutes of Health Consensus development Conference Statement: Management of hepatitis C 2002-June 10-12, 2002. Hepatology 2002;36:S3-S20. 5. Sylvestre DL. Treating hepatitis C in methadone maintenance patients: An interim analysis. Drug Alcohol Depend 2002;67:117-123. 6. Backmund M, Meyer K, Von Zielonka M, Eichenlaub D. Treatment of hepatitis C infection in injection drug users. Hepatology 2001;34:188-193. 7. Van Thiel DH, Anantharaju A, Creech S. Response to treatment of hepatitis C in individuals with a recent history of intravenous drug abuse. Am J Gastroenterol 2003;98:2281-2288. 8. Schaefer M, Schmidt F, Folwaczny C, et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups. Hepatology 2003;37:443-451. 9. Mauss S, Berger F, Goelz J, Jacob B, Schmutz G. A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on
methadone maintenance. Hepatology 2004;40:120-124. 10. Matthews G, Kronrborg IJ, Dove GJ. Treatment for hepatitis C virus among current injection drug users in Australia. Clin Infect Dis 2004;40:S325-S329. 11. Ghany MG, Strader DB, Thomas DL, Seef LB. Diagnosis, management and treatment of hepatitis C: An update. Hepatology 2009;49:1335-1374, 12. Cohen-Moreno, R., Schiff, M., Levit, S., Bar-Hamburger R, Strauss S, Neumark Y. Knowledge about hepatitis-C among methadone maintenance treatment patients in Israel. Substance Use Misuse 2010;45: 58-76. 13. Grebely J, deViaming S, Duncan F, Vijoen M, Conway B. Current approaches to HCV infection in current and former injection drug users. J Addict Dis 2008;27:25-35. 14. Mangia A, Santoro R, Minerva N, et al. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks I HCV genotype 2 or 3. N Engl J Med 2005;352:2609-2617. 15. Cooper CL, Druyts E, Thorlund K, et al. Boceprevir and telaprevir for the treatment of chronic hepatitis genotype 1 infection: An indirect comparison meta-analysis. Ther Clin Risk Manag 2012;8:105-130.
List of reviewers for Israel Journal of Psychiatry The Editors would like to thank the following for their contribution as reviewers of manuscripts during 2013 and 2014 Henry Abraham Henry Abramovitch Idan Aderka Abraham Adunsky Kelly Allison Paul Appelbaum Alan Apter Rachel Bachner-Melman Yoram Barak Yehuda Baruch Chaim Belmaker Yechayaou Beloosesky Gershon Ben Shachar Moshe Bensimon Yael Benyamini Tzachi Ben Zion Howard Beger David Blass Avi Bleich Ehud Bodner David Brent Anat Brunstein-Klomek Laura Canetti Orna Chishinski Rena Cooper-Kazaz John Coverdale Efrat Dagan Pinhas Danon Giancarlo Dimaggio Zippi Dolev Adiel Doron Adrienne Einarson Tzachi Ein Dor Smadar Even Tov Liana Fattore David Feingold Shmuel Fennig
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Sylvana Fennig Gabriele Fischer Annette Gallant Marc Gelkopf Saralee Glasser Jon Grant Michal Granot Talya Greene Alexander Grinshpoon Cornelius Grop Leon Grunhaus Sami Hamdan Ilanit Hasson-Ohayon Helen Herrman Jonathan Huppert Iulian Iancu David Israeli Yulia Kartalova-Oâ&#x20AC;&#x2122;Doherty Gregory Katz Therese A. Keary Arad Kodesh Natan Kellerman Sean Kidd Ehud Klein Robert Kohn Moshe Kotler Anatoly Kreinin Amir Krivoy Jesper Krogh Sefi Kronenberg Jonathan Kushnir Dori Laub Julian Leff Stephen Levine Hilik Levkovitz Andrea Letamendi Arturo Lerner
Vladimir Lerner Itzhak Levav Nava Levit Binnun Tomer Levy Alon Liberman Pesach Lichtenberg Rachel Liebman Mark Lukowitsky Ido Lurie Paul Lysaker David Mankuta Jacob Margolin Binyamin Maoz Gal Meiri Yuval Melamed Shlomo Mendelovic Beth Merenstein Roberto Mester Piper Myers Hanan Munitz Maayan Nagar Uri Nitzan Susan Ochoa Femi Oyebode Avi Peled Einat Peles Zvi Perry Alexander Ponizovsky Paul L. Prather Nicky Pugh Jamie Ringer Tami Ronen Hamidreza Roohafza Dan Rosen Amir Rotem Shiri Sadeh Sharvit Isaac Sakinofsky
Miriam Schiff Aya Secker-Einbinder Harold Sgan-Cohen Golan Shahar Michal Shaked Simone Shamay-Tsoory Gaby Shefler Lea Shelef Edward Shorter Anat Shoshani Gal Shoval Shaul Shreiber Emi Shufman Zahava Solomon Eli Somer Dan Stein Rael Strous Rivi Tauman Tom Trauer Martin Teufel Anne-Marie Ulman Onno Van der Hart Gary Walter Michael Weinberg Michael Weingarten Myrna Weissman Omri Weissman Laura Widman Vicky Wing Eliezer Witztum Leo Wolmer Phil Yanos Moshe Zeidner Zvi Zemishlany Nava Zisapel Shlomo Zusman
Isr J Psychiatry Relat Sci - Vol. 51 - No 4 (2014)
Arturo G. Lerner et al.
LSD Flashbacks – The Appearance of New Visual Imagery Not Experienced During Initial Intoxication: Two Case Reports Arturo G. Lerner, MD,1,2 Craig Goodman, PhD,1 Dmitri Rudinski, MD,1 and Shaul Lev-Ran, MD3 1
Lev Hasharon Mental Health Medical Center, Pardessya, Israel Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel 3 Addiction Medicine Clinic, Department of Psychiatry, Sheba Medical Center, Tel Hashomer, Israel 2
Abstract A side effect associated with the use of synthetic hallucinogens such as lysergic acid diethylamide-(LSD) is the partial or total recurrence of perceptual disturbances which previously appeared during intoxication, despite absence of recent use. These are commonly referred to as “flashbacks” or Hallucinogen Persisting Perception Disorder (HPPD). Here we present two cases of patients with a prior history of LSD use who turned to psychiatric consultation following brief episodes of HPPD. Surprisingly, in both cases new visual imagery appeared during episodes of flashbacks which was not experienced during primary LSD use. Both subjects reported the ability to discern between LSD-associated visual disturbances and new visual imagery. This phenomenon did not cause functional impairment and in both cases caused gradual concern due to its persistence. Both patients refused medical treatment and continued psychiatric follow-up. At one year follow-up both patients reported almost complete spontaneous remission. To the best of our knowledge these are the first reported cases of LSD-related benign flashbacks in which new imagery is experienced. Reasons for this reversible and apparently harmless side effect are proposed. Conclusions from case reports should be taken with caution.
Introduction Hallucinogens encompass a family of natural-occurring and synthetic substances (1) which may induce states of generally short-term reversible intoxications principally characterized by the presence of visual disturbances popularly named “trips” (2). These phenomena may be manifested as pleasant “good trips” and unpleasant “bad trips.” These “trips” may generally exhibit recurrent single-visual disturbances (i.e., the emergence of the same visual disturbance when intoxicated) or recurrent multiple-visual disturbances (i.e., the emergence of different visual disturbances when intoxicated). A poorly understood side effect mainly associated with the use of synthetic hallucinogens such as lysergic acid diethylamide (LSD) and LSD-like substances is the partial or total recurrence of visual disturbances which previously appeared during intoxication, despite absence of recent use. These are commonly described as identical to the primarily single or multiple visual disturbances that appeared during prior substance use. Single visual disturbances during intoxication implicate the continuous return of the same single-visual disturbance meaning total recapitulation of the only perceptual disturbance experienced during hallucinogen use. Multiple visual disturbances during intoxication implicate the continuous return of a single or some of the multiple visual disturbances experienced during hallucinogen use (3). As defined in DSM-5 perceptual recurrences in HPPD recapitulate the prior substance intoxication reflecting the primary perceptual experience (4), namely, visual imagery experienced under hallucinogen intoxication should be re-experienced during recurrent perceptual disturbances.
Address for Correspondence: Arturo G. Lerner, MD, Lev Hasharon Mental Health Medical Center, POB 90000, Netanya, 42100, Israel. alerner@lev-hasharon.co.il, lerneram@internet-zahav.net
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Flashbacks Isr J LSD Psychiatry Relat Sci–- The Vol. 51Appearance - No 4 (2014) of New Visual Imagery Not Experienced During Initial Intoxication
We present the cases of two patients with a prior history of LSD recreational use, who sought professional consultation for the presence of visual disturbances after totally stopping substance use. They interestingly reported that following substance discontinuation, they experienced the emergence of new visual disturbances which had not appeared during primary LSD intoxication. To the best of our knowledge this is the first report on the matter in the professional literature. Both patients gave informed consent for the publication of their cases. Case 1 Mr. R is a 24 year-old single male university student who completed compulsory military service and did not have any previous police or criminal records. He had a three years past history of occasional “social” cannabis use during weekends and holidays. He additionally reported social alcohol drinking and sporadic MDMA, cocaine and LSD use. He fulfilled DSM-5 full criteria for tobacco use disorder (4). During LSD intoxication he reported a variety of visual disturbances including halos (a circular band of slight colored light around a light source), color intensification (more intensified color), flashes of colors (a patch of bright color that is apparent only during motion) and distorted perception of distance (objects were seen closer or distant). He attributed the psychedelic experience to LSD use. One week after totally suspending substance use he noted some new returning visual imagery not previously experienced, in the form of increased brightness (static or moving source appears to be radiating or reflecting light) and illusions of movement (slow motion movement of stationary objects). These recurring visual reminiscences were experienced as benign “free trips.” Mr. R reported the ability to discern between his original LSD-associated visual disturbances and the “new” visual imagery. As the condition persisted Mr. R began expressing concerns regarding these perceptual disturbances and feelings of discomfort when they appeared. He then turned to psychiatric consultation. On examination there was no previous history of acute or chronic neurological, ophthalmological or other comorbid medical diseases or co-occurring psychiatric disorders. A complete physical, neurological (including EEG) and laboratory examination were without abnormal findings. Mr. R was not interested in “chemical” pharmacological treatment and agreed to psychiatric follow-up. After approximately one year these benign visual disturbances completely disappeared. 308
Case 2 Ms. B is a 25-year-old female student university student who finished compulsory military service and did not have any prior police or criminal records. She had a four year past history of occasional “social” cannabis use. She also drank alcohol socially and sporadically used MDMA and LSD. She fulfilled DSM-5 full criteria for tobacco use disorder (4). During LSD intoxication she reported a variety of visual disturbances including positive afterimages (an image continuing to emerge after the exposure to the original image has ceased), color intensification (more intensified color), flashes of colors (a patch of bright color that is apparent only during motion) and trailing phenomena (slight afterimage-like trail or perception of a series of slow-movement discrete positive afterimages in the wake of moving objects). She referred the psychedelic experience to LSD use. Four days after complete substance discontinuation she began to experience recurrent visual imagery she had not previously experienced, mainly in the form of visual distortions (slightly blurred forms and shapes of stationary objects). As in the previous case, these recurring visual reminiscences were experienced as benign “free trips.” Ms. B reported the capacity to differentiate between her original LSD-associated visual disturbances and the “new” visual imagery. After two months during which this condition continued Ms. B expressed concern and sought psychiatric evaluation. As in the case of R described above, all examinations revealed no abnormalities, treatment was not requested, and the phenomena had disappeared at one-year follow up. Trailing phenomena continued to appear intermittently. Discussion We report two cases in which patients reported the appearance of visual disturbances that were not originally experienced during LSD-intoxication. HPPD has been comprehensively reviewed (5). Despite extensive research, understanding of these complex multifaceted conditions remains obscure (3). The proposed biological platform which intends to explain these phenomena may encompass partial or total changes in the expression of genes implicated in synaptic plasticity in prefrontal cortical neurons; kindling, reverse tolerance or sensitization; chronic potentiation or depression of brain specific areas; and temporary or permanent impairment in areas involved in visual perception like Lateral Geniculate Nucleus (2, 6).
Arturo G. Lerner et al.
From a clinical point of view visual recurrences emerge as a result of the interaction between patients with a past history of use of hallucinogenic substances, vulnerability or predisposition (1, 2), co-occurring psychiatric disorders and recognized or unrecognized triggers (4). The cornerstone of this syndrome is the return of experienced visual imagery during hallucinogen use after cessation of hallucinogen use. But novel additional flashes, not experienced during previous hallucinogen use, may suggest the existence of a new subtype or an entirely different disorder. The suggested mechanism underlying recapitulation of visual disturbances originally experienced during LSD intoxication focuses on continued visual central processing (2). An LSD-generated intense current (7) mediated through 5-HT2 postsynaptic partial agonist activity (8) may provoke the reversible or irreversible destruction or dysfunction (3) of cortical serotonergic inhibitory interneurons with GABA-ergic outputs. This condition may lead to the persistence of the visual imagery due to pervasive progressive or benign unprogressive sustained disinhibition of visual processors (3). There is an inadequate inhibitory activity of the visual pathway allowing the visual stimulus to persist and giving place to the numerous visual disturbances which may reflect the failure of the each respective visual function (2). In the above described cases in which flashes not originally experienced during LSD intoxication appeared, we speculate that it could be an additional onward transient functional impairment of the Lateral Geniculate Nucleus (LGN). The LGN, located inside the thalamus, appears to be of cardinal importance in the development of recurrent visual disturbances (2). LGN is the primary retransmitting center for visual information received from the retina and also receives data straight from the ascending retinal ganglion cells via the optic tract and from the reticular activating system. The LGN remits its axons throughout the optic radiation, a straight pathway to the primary visual cortex. Additionally the LGN may collect solid feedback linkages from the primary visual cortex (9, 10). Without profoundly describing structure, layers and cells of the LGN which are beyond the scope of this clinical manuscript, it could be shortly mentioned the existence of magnocellular cells which are necessary and responsible for the perception of movement and brightness and the parvocellular cells which are necessary and responsible for the perception of forms and shapes (10). Previous research showed that neurons of the LGN may be afflicted by LSD toxic effects (11, 12).
So, it could be hypothesized and speculated that LSD ingestion leading to ongoing progressive short-term reversible and limited impairment of the LGN affecting magnocellular and parvocellular cells could, at least partly, explain the temporary and transient presence of illusions of movement, increased brightness and visual distortions in both described patients. Continuation of trailing phenomenon may suggest a more permanent impairment and deserves further investigation. These clinical case presentations may have some limitations. The basic premis of this presentation is that subjects are able to recall what they experienced when taking LSD and the current phenomena were not included. It remains a possibility that they occurred but were not recalled. Research on the matter may increase our understanding of the mechanism of action of LSD and related phenomena. The clinical value of the above described cases in everyday psychiatric clinical practice needs to be elucidated. Conclusions from uncontrolled case reports should be taken with appropriate caution. References 1. Abraham HD, Aldridge AM, Gogia P. The psychopharmacology of hallucinogens. Neuropsychopharmacology 1996; 14:285-298. 2. Abraham HD. Visual phenomenology of the LSD flashbacks. Arch Gen Psychiatry 1983; 40:884-889. 3. Lerner AG, Gelkopf M, Skladman I, Oyffe I, Finkel B, Sigal M, Weizman A. Flashback and hallucinogen persisting perception disorder: clinical aspects and pharmacological treatment approach Isr J Psychiatry Relat Sci 2002, 39: 92-99. 4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, DSM-5. Washington DC: American Psychiatric Association, 2013. 5. Halpern JH, Pope HG. Hallucinogen persisting perception disorder: What do we know after 50 years? Drug Alcohol Depend 2003, 69: 109-119. 6. Iaria G, Fox CJ, Scheel M, Stowe RM, Barton JJS. A case of persistent visual hallucination of faces following LSD abuse: A functional magnetic resonance imaging study. Neurocase 2010, 16: 106-118. 7. Garrat J, Alreja M, Aghajanian GK. LSD has high efficacy relative to serotonin in enhancing the cationic current Ih: Intracellular studies in rat facial motorneurons. Synapse 1993; 13:123-134. 8. Sander-Bush E, Burris KD, Knoth K. Lysergic acid diethylamide and 2,5- dimethoxy-4-mathylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. J Pharmacol Exp Ther 1988; 246:924-928. 9. Cudeiro, Javier; Sillito, Adam M. (2006). Looking back: corticothalamic feedback and early visual processing. Trends in Neurosciences 2006; 29: 298-306. 10. Collins CE, Hendrickson A, Kaas JH. Overview of the visual system of Tarsius. Anat Rec A Discov Mol Cell Evol Biol 2005; 287:1013-1025. 11. Evarts EV, Landau W, Freygang W Jr, Marshall WH. Some effects of lysergic acid diethylamide and bufotenine on electrical activity in the catâ&#x20AC;&#x2122;s visual system. Am J Physiol 1955; 182:594-598. 12. Bishop PO, Field G, Hennessy BL, Smith JR. Action of d-lysergic acid diethylamide on lateral geniculate synapses. J Neurophysiol 1958; 21:529-549.
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המטופלים -מספרם נע בין 26ב– 1994לבין 300ו– 350החל מ–)2009 נע בין 35%ל– 40%בשנים האחרונות ,השיעור המרבי היה 61%והשיעור הנמוך ביותר היה .25.4%מעקב של עד 19.5שנים הצביע על כך שמטופלים שבדיקות השתן שלהם היו שליליות לבנזודיאזפינים בחודש הראשון לטיפול נשארו בטיפול 8.5שנים בממוצע ( 95%רווח בר־סמך 7.6-9.4שנים) ,לעומת מטופלים שבדיקות השתן שלהם היו חיוביות לבנזודיאזפינים בעת קבלתם ,ונשארו בממוצע רק 6.9שנים בטיפול (95% רווח בר סמך 6.2-7.7שנים) .ההבדל נמצא מובהק ( )p=0.01באנליזת קפלן מאייר .מסקנות :שיעור ההימצאות של בנזודיאזפינים בבדיקות שתן בקרב מטופלי מתדון אחזקתי הוא גבוה .שימוש בבנזודיאזפינים בתחילת הטיפול מנבא התמדה בטיפול במשך זמן קצר יותר .אכיפת הנהלים על ידי צוות המרפאה תורמת להפחתת השימוש בבנזודיאזפינים. מומלץ שצוות המרפאה יקפיד על אכיפת כללי המרפאה ויתרום בכך להפחתת שיעור השימוש בבנזודיאזפינים והנזק הקשור בשימוש בהם. הערכת התוצאות הקליניות של מקרי קבלה לאשפוז בכפייה במחלקה ייעודית לתחלואה כפולה י .דליהו ,י .נחמה ,ע .שגיא ,י .ברוך וד.מ .בלס ,בת ים
רקע :מטרת המחקר היא לזהות את המאפיינים ואת התוצאות של קבלה לאשפוז בהסכמה ובכפייה במחלקה לתחלואה כפולה במרכז גדול לבריאות הנפש בישראל .שיטות :תיקיהם של 24חולים נסקרו בתקופה של חמש שנים .הושוו משתנים דמוגרפיים וקליניים של קבלה לאשפוז בכפייה ושל קבלה לאשפוז בהסכמה .תוצאות :לא נמצאו הבדלים משמעותיים במאפיינים הסוציודמוגרפיים ,באבחנות או במשך האשפוז בין שתי הקבוצות .אצל אחוז קטן יותר של מטופלים שהשתחררו מאשפוז בכפייה חלה הפוגה במחלה בהשוואה למטופלים ששוחררו מאשפוז בהסכמה .עם זאת ,קבלה לאשפוז בכפייה נמצאה קשורה לשהות ארוכה יותר בקהילה עד לאשפוז הבא .מגבלות המחקר :הנתונים התבססו על מספר קטן של מטופלים ממחלקה אחת .אי־לכך ,אפשרות ההכללה של התוצאות מוגבלת. מסקנות :ממצאי המחקר מצביעים על כך שקבלה לאשפוז בכפייה מובילה להישארות ממושכת יותר בקהילה ומרמזים כי ייתכן שלאשפוז בכפייה יש כמה יתרונות קליניים עבור חולים מסוימים הסובלים מתחלואה כפולה.
פרודרומליים ,תחילת ההופעה ,תוכן הדימויים הוויזואליים ,גורמים מחמירים ,תדירות ,משך ועוצמה של ההפרעות בתפישה ,חומרה ,מהלך התסמונת ,אבחנה מבדלת ,מצב רוח ואפקט נלווים ,תובנה והפוגה .טיפול בתרופות מוביל להקלה בתסמונת ,גם כאשר יש תחלואה פסיכיאטרית נלווית וגם כאשר אין תחלואה כזו .מגוון רחב של תרופות משמש להקלה במצב זה ,ותוצאות השימוש בתרופות אלה מגוונות ומצביעות על תתי־ סוגים שונים של מצבים אלו .מטרת מאמר זה היא לספק סקירה קלינית, מקיפה אך תמציתית ,לפסיכיאטרים מטפלים. מודל לטיפול בחולי הפטיטיס סי שמקבלים טיפול אחזקה במתדון ס .מלניק ,ו .שיידווסר ,א .בסביץ וש .לויט ,רחובות
רקע :נגיף ההפטיטיס סי קשור לשימוש בסמים תוך־ורידיים ,והטיפול במכורים לסמים בעייתי .אנו מדווחים כאן על תוצאות של תכנית הרצה לטיפול בחולי הפטיטיס סי המשתמשים בסמים במרכז לטיפול אחזקה במתדון .שיטות :תכנית הטיפול יושמה במרכז יחיד לטיפול אחזקה למתדון (טתא"ל) .המטופלים לא השתמשו בסמים או באלכוהול והמשיכו לקבל את הטיפול הרגיל שלהם במתדון .תכנית הטיפול כללה 5 שלבים .1 :הרצאה שבה ניתן הסבר על הפטיטיס סי (נכחו בה 50מתוך 114משתתפים בתכנית) 25 .2 .מה־ 50הגיעו לבדיקה שכללה בדיקת גנוטיפ ועומס נגיפי .3 .קבלת טיפול נגד הפטיטיס סיpegylated alfa- : interferon-1bוריבברין .4 .רופא מהמטא"ל והצוות סייעו למטופלים בכל הקשור להיענות לטיפול .5 .רופא מומחה למחלות כבד (ס.מ ).תרם את שירותיו בפגישה שנמשכה 3שעות כל 6–4שבועות ,נוסף על ייעוץ טלפוני זמין בכל שעות היממה .תוצאות 50 :מתוך 114המטופלים שנבדקו ונמצא כי הם חולים בהפטיטיס סי השתתפו בפגישה הקבוצתית הראשונה 25 .מהם ( )50%היו מועמדים לטיפול ,ו־ 20מהם טופלו .ל־10 היה גנוטיפ ,3ל־ 9גנוטיפ 1ול־ 1גנוטיפ .2התגובה הווירלית המתמשכת על בסיס כוונה לטפל הייתה .)40%( 8/20דיון :אנו מציגים מודל לטיפול מוצלח בהפטיטיס סי במטופלים שמקבלים מתדון. פלאשבקים הקשורים לשימוש ב־ :LSDהופעתם של דימויים חזותיים חדשים שלא הופיעו במהלך השימוש הראשון :דיווח על שני מקרים
א .ג .לרנר ,ק .גודמן ,ד .רודינסקי וש .לב רן ,נתניה
"פלאשבק" ו"הפרעת תפישה ממושכת אחרי שימוש בחומר הזייתי" :סקירה קלינית תמציתית
תופעת לוואי הקשורה בשימוש בחומרי הזיה סינתטיים כגון LSD
מאפיין ייחודי של השימוש ב– LSDובחומרים דמויי LSDשיש להם תכונות הזייתיות ,הוא חזרה של תסמיני הזיות שהופיעו במהלך השימוש גם לאחר שהשפעת החומר פגה .תסמונת חוזרת זו ,הקשורה בעיקר בהזיות ראייה ,אינה מוסברת עד תומה .בספרות המקצועית ,הביטויים "פלאשבק" ( )Flashbackו"הפרעת תפישה ממושכת אחרי שימוש בחומר הזייתי" (Hallucinogen Persisting Perception Disorder )- HPPDמשמשים לסירוגין לתיאור התסמונת .אובחנו לפחות שתי תסמונות חוזרות נפרדות .התסמונת הראשונה" ,פלאשבק" או ,HPPD I היא קצרת טווח ,שפירה ,הפיכה ,אינה גורמת למצוקה ומלווה בתחושה נעימה .התסמונת השנייה" ,הפרעת תפישה ממושכת אחרי שימוש בחומר הזייתי" או ,HPPD IIהיא ממושכת ,טורדנית ,אינה הפיכה או הפיכה במידה חלקית ,נמשכת לאורך זמן ,אינה שפירה ומלווה בתחושה לא נעימה HPPD I .ו– HPPD IIהן חלק מספקטרום רחב של מצבים פסיכופתולוגיים ושאינם פסיכופתולוגיים ,שעליהם מדווחים משתמשים בחומרי הזיות .אפשר לאפיין קלינית תסמונות אלה על פי תסמינים
היא חזרה חלקית או מלאה של הפרעות בתפישה שהופיעו בעבר בעת השימוש הראשון באותו חומר ,אף על פי שהמטופל אינו משתמש עוד בחומר כזה .תופעה זו מכונה "פלאשבק" או "הפרעת תפישה ממושכת אחרי שימוש בחומר הזייתי" .כאן אנו מציגים שני מקרים של מטופלים שיש להם היסטוריה של שימוש ב־ LSDשפנו לייעוץ פסיכיאטרי בעקבות הופעת אפיזודות קצרות של פלשבקים .באופן מפתיע ,בשני המקרים הופיעו גם דימויים חזותיים חדשים שהמטופלים לא חוו בשימוש הראשון .שני הנבדקים דיווחו על היכולת להבחין בין הפרעות ראייה הקשורות ל־ LSDלבין דימויים חזותיים חדשים .תופעה זו לא גרמה לפגיעה כלשהי בתפקוד ,ובשני המקרים גרמה לדאגה הדרגתית בשל התמדתה .שני החולים סירבו לקבל טיפול פסיכיאטרי אך הסכימו להמשיך מעקב .לאחר שנת מעקב שני המטופלים דיווחו על היעלמותם הספונטנית והכמעט מוחלטת של הפלאשבקים .למיטב ידיעתנו אלה המקרים המדווחים הראשונים של פלאשבקים שפירים הקשורים ל־LSD שבו דימויים חדשים חוו .סיבות לתופעת לוואי הפיכה ,שפירה ומסקרנת זו מוצעות במאמר .יש להיזהר מהסקת מסקנות מדיווחי מקרה.
א.ג .לרנר ,ד .רודינסקי ,א .בור וק .גודמן ,נתניה
310
לתחלואה ולתמותה .בהקשר זה ,יש השפעה רבה להפרעות עקב שימוש בחומרים ממכרים בקרב בני נוער ,שכן קיומן מעלה את הסבירות להתנהגות אובדנית .במאמר סקירה זה אנו דנים בנושאים עדכניים שבלטו לאחרונה במיוחד בקשר שבין השימוש בחומרים ממכרים בקרב בני נוער לבין התנהגות אובדנית .אנו מתמקדים בתיאור דפוסי שימוש שכיחים ומסוכנים בחומרים ממכרים כגון "סביאת אלכוהול" ושימוש בכמה סמים יחדיו ,וכן מתייחסים לשינויים בדפוסי ההעדפה של חומרים ממכרים מסוימים ,כמו השימוש הנרחב כיום בקנבינואידים סינטטיים .אנו מתמקדים באוכלוסיות נוער פגיעות יותר ,כגון מיעוטים מיניים ובני נוער הסובלים ממחלת נפש. לבסוף אנו מציגים את האתגרים הקיימים ואת האתגרים הצפויים העולים מסוגיות אלו ,לשם התוויית תכניות מניעה וטיפול בהתנהגות אובדנית בקרב בני נוער אשר משתמשים לרעה בחומרים ממכרים. תסמונת הגמילה מקנביס -קטגוריית אבחנה חדשה ב־5-DSM
ג .כץ ,צ .ליבל ,א .טייטלבאום וס .רסקין ,ירושלים
רקע :תסמונת הגמילה מקנביס לא סווגה באופן רשמי במסגרת ה– ,DSM-IVאבל נרשמה ללא קריטריונים לאבחנה על ידי ה–.ICD-10 האיגוד האמריקאי לפסיכיאטריה סיווג לאחרונה את תסמונת הגמילה מקנביס ב– DSM-5כחלק מ"הפרעות הקשורות בסמים ובחומרים והפרעות התמכרות" .עם זאת ,לפסיכיאטרים רבים ,כמו גם לאנשי רפואה אחרים ,יש ידע מועט למדי ,אם בכלל ,על אבחנה זו ועל מהותה. שיטות :המידע הושג מחיפוש במאגר המידע של ( Pubmedמילות חיפוש.)Cannabis, THC, Hashish, Marijuana, Withdrawal : התסמינים הקליניים השונים של התופעה וחלק מהמנגנון הפתופיזיולוגי והשיקולים בטיפול סוכמו ונדונו .תוצאות ומסקנות :ממחקרים בשנים האחרונות נרכש ידע רב על מהימנות ותקפות תסמונת הגמילה מקנביס ועל חשיבותה הקלינית .חסר עדיין ידע לגבי ההשלכות האפשריות של הגמילה מקנביס על חומרתן של הפרעות פסיכיאטריות שונות ,ודרוש מחקר נוסף בנושא .מגבלות :בין המחקרים שנסקרו הייתה שונות רבה מבחינת גודל המדגם ,מבנה המחקר ושיטות המחקר .הבדלים אלו הגבילו את היכולת להסיק מסקנות ברורות. שימוש בקנביס סינתטי ו"הפרעת תפישה ממושכת אחרי שימוש בחומר הזייתי" :דיווח על שני מקרים א.ג .לרנר ,ק .גודמן ,א .בור וש .לב רן ,נתניה
"הפרעת תפישה ממושכת אחרי שימוש בחומר הזייתי" היא חזרה חלקית או מלאה של הפרעות תפישה בעלות אופי טורדני ומציק שהופיעו בעבר בעת השימוש הראשון בחומרי הזיה ,אף על פי שהמטופל אינו משתמש עוד בחומר כזה .כאן אנו מציגים שני מקרים של מטופלים שסבלו מ"הפרעת תפישה ממושכת אחרי שימוש בחומר הזייתי" ללא היסטוריה קודמת של שימוש בחומרי הזיה טבעיים או סינתטיים .לשני המטופלים הייתה היסטוריה של התמכרות לקנביס טבעי ובעת הטיפול היו מכורים לטבק .הם דיווחו על הופעתן של הפרעות תפישה ויזואליות לאחר שימוש בקנביס סינתטי בזמן הסתכלות על אובייקטים ועל חפצים נייחים ונעים .שניהם הפסיקו את השימוש בקנביס סינתטי בצורה פתאומית לאחר הופעתם של התקפי חרדה .למרות הפסקת השימוש ,המשיכו המטופלים לסבול מ"הפרעת תפישה ממושכת אחרי שימוש בחומר הזייתי" שלוותה בחרדה .לאחר טיפול בקלונזפם שני המטופלים דיווחו על שיפור משמעותי במצבם. למרות ההטבה והפחתה משמעותית בחרדה ,ההפרעות הוויזואליות 311
לא נעלמו לחלוטין .למיטב ידיעתנו אלו הדיווחים הראשונים בספרות המקצועית על "הפרעת תפישה ממושכת אחרי שימוש בחומר הזייתי" הקשורה לשימוש בקנביס סינתטי .לאור השימוש ההולך וגדל בחומרים אלה ,פסיכיאטרים צריכים להיות מודעים לתופעות המתוארות לעיל. טיפול בהתמכרות לאופיאטים: הצגת נתונים ממרפאת בופרנופרין
ל .גורן ,ז .כרמל וס .מרצ'בסקי ,תל־אביב
התמכרות לאופיאטים מאופיינת בשימוש חוזר בחומרים שפעילותם אופיואידית על אף התפתחות של תלות גופנית ,הפרעות התנהגות וירידה בתפקוד החברתי והבין־אישי .יש שתי גישות עיקריות לטיפול בהתמכרות זו :טיפול בתרופות חלופיות או טיפול התנהגותי שמטרתו להוביל לניקיון מוחלט מחומרים פסיכואקטיביים .הטיפולים התרופתיים החלופיים המוצעים פועלים כאגוניסטים על רצפטורים אופיואידיים ,אשר העיקריים בהם הם מתדון ובופרנורפין .מתדון משפיע בדרך של אגוניסט מלא על הרצפטור האופיאטי ,ולעומתו פעילות הבופרנורפין נובעת מהיקשרות לרצפטורים באופן של אגוניזם חלקי .התכונות הפרמקולוגיות של המתדון מחייבות הקפדה יתרה על נוהלי רישום התרופה ,זאת כיוון שנטילת מנת יתר עלולה להוביל למוות .לעומת זאת ,היקשרות הבופרנורפין לרצפטורים האופיאטיים מאופיינת באפיניות גבוהה ובזמן דיסוסיאציה ארוך .בשל תכונות אלו הבופרנורפין היא תרופה בטוחה שאינה מצריכה פיקוח רפואי מיוחד. שיטות :במאמר זה מתוארת השפעת הבופרנורפין על אוכלוסיית מכורים לאופיאטים .הנתונים המוצגים נאספו רטרואקטיבית מנתוני המרפאה הפרטית הראשונה שנפתחה בישראל למתן בופרנורפין. הנתונים נאספו מרישומים ממוחשבים במרפאה משנת 2005ועד .2012כמדד להצלחת הטיפול נבדק משך הזמן שבו הקפיד המטופל להגיע למרפאה בהתאם לנהלים .תוצאות :משנת 2005ועד 2012 נרשמו במרפאה 1,399מטופלים 1224 .מהם ( )87.5%חזרו לביקור נוסף אחד לפחות; 66.5%דבקו בתכנית הטיפול במשך שנה לפחות. סיכום :אחוזי ההצלחה של הטיפול מצביעים על כך שמטופלים הסובלים מהתמכרות לאופיאטים יכולים להיעזר בבופרנורפין על מנת לעבור תהליך שיקום .המודל המוצג כאן הוא דוגמה למרפאה אמבולטורית אשר מצליחה לתת מענה לבעיית התמכרות קשה באחוזי הצלחה גבוהים יחסית ותוך התערבות טיפולית נמוכה. שיעור ההימצאות של בנזודיאזפינים בקרב מטופלי מרפאת מתדון אחזקתי במהלך 19.5שנים ,והקשר להצלחת טיפול ממושך ע .פלס ,מ .אדלסון וש .שרייבר ,תל אביב
רקע :ידוע כי לקבוצת הבנזודיאזפינים מגוון השפעות מזיקות על מטופלי מתדון אחזקתי .במחקר זה בדקנו את שיעור ההימצאות החודשי של בנזודיאזפינים בקרב מטופלי מרפאת מתדון אחזקתי במהלך 19.5 שנים ,ואת הקשר בין שימוש בבנזודיאזפינים לבין התמדה בטיפול ממושך .שיטות :במחקר נכללו כל 787המכורים לאופיאטים שהחלו טיפול במתדון אחזקתי במרפאת אדלסון שבמרכז הרפואי תל אביב, מאז הקמתה ב– 1993ועד .2012בדיקות שתן אקראיות להימצאות בנזודיאזפינים נערכות לכלל המטופלים באופן שגרתי בתדירות של כמה פעמים בחודש .נקבע כי בחודש מסוים התקבלה תוצאה חיובית, אם לפחות בדיקה אחת במהלך החודש נמצאה חיובית לבנזודיאזפינים. הישארות ממושכת בטיפול חושבה באמצעות אנליזת קפלן מאייר. תוצאות :שיעור ההימצאות של בנזודיאזפינים (בכל חודש נבדקו כלל
כתב עת ישראלי לפסיכיאטריה תקצירים דיכוי תגובה וערנות (התמשכות־קשב) בקרב מעשנים כבדים לעומת לא מעשנים
ל .דינור־קליין ,ס .קרצמן ,ע .רוזנברג ,מ .קוטלר ,א .צנגן ופ .דנון ,באר יעקב
רקע :צריכת ניקוטין מתמשכת גורמת לנוירו–אדפטציות המשויכות לפעילות דופמינרגית אבנורמלית .שינויים עצביים אלו עשויים לגרום לפגיעה ביכולת של דיכוי תגובה ובערנות .אף על פי כן ,אין עדיין תשובה חד־משמעית לשאלה אם מעשנים משיגים תוצאות גרועות יותר בהשוואה ללא מעשנים במבחנים קוגניטיביים אשר בודקים ערנות ושליטה באימפולסיביות .במחקר הנוכחי נבדקו יכולות דיכוי התגובה והערנות במדגם גדול של מעשנים ולא מעשנים .שיטות :דיכוי תגובה וערנות נבדקו באמצעות מבחנים ממוחשבים :מבחן ביצוע מתמשך ( )CPTומבחן .Go/No Go הניתוח הסטטיסטי נעשה באמצעות מבחן אנקובה תלת־כיווני למדידות חוזרות למשתנים התלויים הבאים :זמן תגובה ,שונות בזמן התגובה ,מספר שגיאות של תגובת יתר ומספר שגיאות השמטה. שלושת האפקטים העיקריים היו קבוצה (מעשנים מול לא מעשנים), תנאי המבחן ( CPTאו )Go/No Goושלב המבחן (בכל תנאי). המשתנים המפוקחים ( )Covariateהיו מין ,השכלה וגיל.תוצאות ומסקנות :בקרב מעשנים נמצאו יותר שגיאות של תגובת יתר המצביעות על פגיעה ביכולות דיכוי התגובה בהשוואה ללא מעשנים. לעומת זאת ,במדדי הערנות לא נמצא הבדל משמעותי בין הקבוצות. יכולת דיכוי תגובה לקויה נצפתה אצל מעשנים כבדים ,ועשויה אם כן להיות יעד פוטנציאלי לפיתוח תכניות גמילה יעילות יותר בעתיד. שיעור החשיפה לעישון סיגריות ,לשתיית אלכוהול ולשימוש בסמים בקרב נשים בהיריון המגיעות לביה"ח במהלך הריונן ,ומידת היענותן להתערבות ממוקדת
ע .פלס ,ע .ששון ,מ .בלוך ,ש .מסלוביץ ,ש .דולברג ,א .מני ,מ .קופרמינץ ומ. אדלסון ,תל־אביב
רקע :במחקר זה נבחנו שיעור ההיענות להתערבות ממוקדת המוגבלת לזמן קצר שמטרתה הפחתת עישון סיגריות ,שתיית אלכוהול ושימוש בסמים בקרב נשים בהיריון ששהו מסיבות שונות בבית־חולים .נבחנה גם מידת ההצלחה של התערבות כזו .שיטות: נשים בשלבי היריון מוקדמים (עד שבוע )30ששהו בביה"ח ביחידות להיריון בסיכון גבוה ,במחלקת מיון נשים ובטרום לידה ,רואיינו בנושא חשיפה לאלכוהול (שאלונים AUDITו– ,)TWEAKעישון סיגריות (מודיפיקציה של שאלון פגרסטרום) ושימוש בסמים פסיכואקטיביים (מודיפיקציה של שאלון .)ASIהנשים שענו כי הן חשופות לאחד מגורמים אלה הוזמנו לעבור התערבות ממוקדת ()BI ומעקב עד לאחר הלידה .שיעור החשיפה ומאפייני הנשים הושוו לקבוצה לא סלקטיבית "סטנדרטית" של נשים שהגיעו לביה"ח
israel journal of
psychiatry כרך ,51מס' 2014 ,4
ללידה .תוצאות 46 :מתוך 108המשתתפות ( )42.6%נחשפו לעישון ( ,)85%לאלכוהול ( )41%או לסמים פסיכואקטיביים ( ,)39%ו–41 נשים עברו התערבות ממוקדת .על פי דיווח עצמי מידת החשיפה לחומרים אלו לאחר ההתערבות הממוקדת פחתה באופן מובהק במהלך ההיריון ,אך עלתה חזרה לאחר הלידה .עוד נמצא כי הנשים מהקבוצה ה"סטנדרטית" היו משכילות יותר ,שיעור החשיפה שלהן היה נמוך יותר ,והן אף ילדו תינוקות במשקל לידה גדול יותר ( 3254.7±506.9גרם לעומת 2650.8±785.6גרם) מהנשים בקבוצה השנייה .מסקנות :שיעור ההיענות להתערבות ממוקדת המוגבלת בזמן היה גבוה ותרם להפחתת החשיפה במהלך ההיריון ,אך לא לאחר הלידה .מומלץ לערוך התערבות זו במהלך ההיריון ואחריו. מתאמים קליניים של הפרעות עקב שימוש באלכוהול בקרב בני נוער באשפוז פסיכיאטרי בישראל
ד .פיינגולד ,א .ניצן ,ג .רצוני וש .לב־רן ,הוד השרון ותל השומר
רקע :ממחקר אפידמיולוגי עולה כי בשנים האחרונות חלה עלייה בשימוש באלכוהול בקרב בני נוער .כמו כן ,במחקר חוזר נמצא קשר משמעותי בין שימוש באלכוהול לבין הפרעות פסיכיאטריות בגיל הנעורים .המחקר הנוכחי השווה בין הנתונים הדמוגרפיים והקליניים של בני נוער הסובלים מהפרעות עקב שימוש באלכוהול לבין הנתונים הדמוגרפיים והקליניים של בני נוער ללא הפרעות כאלה ברקע, בקרב קבוצת בני נוער המאושפזים במחלקה פסיכיאטרית.שיטות: סקירת התיקים הרפואיים הממוחשבים של 238מטופלים שאושפזו במחלקת נוער במרכז לבריאות הנפש על פני תקופה של ארבע שנים. תוצאות :נמצא כי הסיכוי של מטופלים שברקע שלהם הפרעה עקב שימוש באלכוהול לבצע ניסיונות אובדניים ופציעה עצמית גבוה יותר ביחס לאלו שאין להם רקע כזה .השכיחות של הפרעות קשב וריכוז והפרעות התנהגות הייתה רבה יותר בקבוצת המטופלים שברקע שלהם הפרעה עקב שימוש באלכוהול ,ובקרב מטופלים אלו השכיחות של רקע פלילי ושימוש בסמים הייתה רבה יותר .חציון משך האשפוז היה גדול יותר בקבוצת המטופלים ללא הפרעות שימוש באלכוהול ברקע .מגבלות :המחקר הוא מחקר חתך ,יש לנקוט בזהירות בהסקת מסקנות של סיבתיות מתוך הנתונים .מסקנות :שכיחות יתר של התנהגות פלילית ,פציעות עצמיות וניסיונות אובדניים בקרב מטופלים הסובלים מהפרעות עקב שימוש באלכוהול עשויים להיות קשורים לרמות גבוהות יותר של אימפולסיביות ,כפי שייתכן שמתבטא בשכיחותן המוגברת של הפרעות קשב וריכוז באוכלוסייה זו .חשוב לבחון שימוש באלכוהול בקרב בני נוער במערכות בריאות הנפש לצורך התאמת מסגרת טיפול ותכנית טיפול. דגשים עדכניים על הקשר בין השימוש בחומרים ממכרים לבין התנהגות אובדנית בקרב בני נוער ד .שלוסברג ,ג .זלצמן וג .שובל ,פתח־תקווה
התנהגות אובדנית בקרב בני נוער מציבה אתגר גדול בפני מערכות בריאות ברחבי העולם בשל שכיחותה הגבוהה ,ומאחר שהיא מובילה 312