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israel journal of

psychiatry

Vol. 52 - Number 1 2015

ISSN: 0333-7308

4 Editorial: The Future of Randomized Clinical Trials Robert h. Belmaker

High Dose Creatine Augmentation in Treatment Resistant Negative Symptoms Schizophrenia Uri Levental et al.

Sarcosine Added on to Anti-Psychotic Treatment in Schizophrenia Revital Amiaz et al.

Long-term Follow-up of MDD Patients Who Respond to Deep rTMS Oded Rosenberg et al.

Suicides Among Persons with Psychiatric Hospitalizations Nehama Goldberger et al.

Hebrew and Arabic Versions of the Outcome Questionnaire - 45 Raz Gross et al.

Social Anxiety Disorder Comorbid with Schizophrenia Katherine Moss Lowengrub et al.

Dissociative Reality and Being in Therapy for Posttraumatic Patients Jonathan Guez et al.

Cognitive Appraisal and Psychological Distress in Irritable Bowel Syndrome Menachem Ben-Ezra et al.

Nighttime Fears in the Fear Survey Schedule for Preschool Children Jonathan Kushnir et al.

LSD-associated â&#x20AC;&#x153;Alice in Wonderland Syndromeâ&#x20AC;? Arturo G. Lerner and Shaul Lev Ran

israel journal of

psychiatry

The Official Publication of the Israel Psychiatric Association Vol. 52 - Number 1 2015

and related sciences EDitor

4 > Editorial: The Future of

DEPUTY EDITORS

Robert H. Belmaker

David Greenberg Doron Gothelf Yoav Kohn Ivonne Mansbach Ora Nakash Shaul Lev-Ran David Roe Rael Strous Book reviews editor

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Heinz Z. Winnik Editorial Board

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Randomized Clinical Trials

6 > A Pilot Open Study of Long Term High Dose Creatine Augmentation in Patients with Treatment Resistant Negative Symptoms Schizophrenia

Uri Levental, Yuly Bersudsky, Tzvi Dwalatzky, Vladimir Lerner, Sophie Medina and Joseph Levine

12 > Safety, Tolerability and Pharmacokinetics of Open Label Sarcosine Added on to Anti-Psychotic Treatment in Schizophrenia – Preliminary Study Revital Amiaz, Ilan Kent, Katya Rubinstein, Ben Ami Sela, Daniel Javitt and Mark Weiser

17 > Long-term Follow-up of

MDD Patients Who Respond to Deep rTMS: A Brief Report

Oded Rosenberg, Limor Dinur Klein, Roman Gersner, Moshe Kotler, Abraham Zangen and Pinhas Dannon

25 > Suicides Among Persons with Psychiatric Hospitalizations Nehama Goldberger, Ziona Haklai, Inna Pugachova and Itzhak Levav

40 > Social Anxiety Disorder Comorbid with Schizophrenia: The Importance of Screening for This Underrecognized and Undertreated Condition Katherine Moss Lowengrub, Rafael Stryjer, Moshe Birger and Iulian Iancu

47 > Dissociative Reality and Dissociative Being in Therapy for Posttraumatic Patients

Jonathan Guez, Mali Hertzanu-Lati, Rachel Lev-Wiesel and Stanley Rabin

54 > Cognitive Appraisal and

Psychological Distress Among Patients with Irritable Bowel Syndrome

Menachem Ben-Ezra, Yaira Hamama-Raz, Sharon Palgi and Yuval Palgi

61 > Assessing Fears of Preschool

Children with Nighttime Fears by a Parent Version of the Fear Survey Schedule for Preschool Children

Jonathan Kushnir, Doron Gothelf and Avi Sadeh

67 > LSD-associated “Alice in Wonderland Syndrome” (AIWS): A Hallucinogen Persisting Perception Disorder (HPPD) Case Report Arturo G. Lerner and Shaul Lev Ran

33 > Validation of the Hebrew and

70 > Book Reviews

Arabic Versions of the Outcome Questionnaire (OQ-45)

Raz Gross, Saralee Glasser, David Elisha, Orya Tishby, Daria Madar Jacobson, Gila Levitan Michael J. Lambert and Alexander M. Ponizovsky

Hebrew Section

> Abstracts

Autumn-Winter Naomi Nadav, 2013 A house represents an area of life. The outside is exposed and the interior is not revealed to the observer. This concealment is on purpose and there are many possible explanations for it. The windows of the house only permit viewing in one direction, from the inside out. The flowing water is also uneven and represents coping with one’s emotional, economic and existential situation. In contrast, the tree represents growth, development and the desire to go far.

Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

Editorial: The Future of Randomized Clinical Trials Jeffery Drazen, the editor of the New England Journal of Medicine, spoke in early December at Ben-Gurion University about evidence-based medicine. He described the history of case reports in medicine and the misleading recommendations that resulted from early studies of dangerous treatments of tuberculosis without proper controls. After the World War II era, medicine developed the concept of the controlled trial as the only way to find unbiased evidence that could justify our treatments in medicine including psychiatry. The methodology of controlled trials has progressed since that time and the need for randomization and often stratification as well as other statistical controls was shown in numerous articles and studies. However, in psychiatry we seem to be approaching a crisis of this whole paradigm. In almost every area of psychiatry, controlled clinical trials that yielded statistically significant and promising results have with the performance of other studies been found to be non-replicable. This confusion was the stimulus for the development of meta-analysis. The concept of meta-analysis was based on the premise that contradictory results in individual randomized controlled trials could be due to random factors and that the statistical compilation of multiple controlled studies would lead to firm knowledge that could inform our treatments in a reliable way. However, we are now facing the bankruptcy of this approach in every area of psychiatry (and I presume in most areas of medicine in which I am not expert). There are contradictory meta-analyses in almost every subject: the treatment of schizophrenia, the treatment of bipolar disorder, treatment of bipolar depression, the treatment of anxiety disorder, the treatment of obsessive compulsive disorder, etc. It is hard for the clinician to decide whether one can base treatment on research evidence at all. It is confusing for NIMH and other funding agencies to decide whether psychiatry is a field worth funding for clinical research, given the non-replicability of results. It is even more difficult for pharmaceutical companies to decide whether to invest in psychiatric research if the results with compounds that they want eventually to sell and profit from are often not replicable between phase II studies and phase III studies. What could be the reasons for this crisis? First, in a somewhat paradoxical way a reason might be the increasing faith of the public in medicine including 4

psychiatry. As the publicâ&#x20AC;&#x2122;s faith and knowledge of our treatments has increased, fewer and fewer patients are willing to participate in placebo-controlled clinical trials. The patient knows, often correctly, that active treatments exist. Therefore why he should take a chance on getting a placebo? Therefore, smaller and smaller percentages of real life patient populations are included in studies and study populations include to an increasing degree patients who are very resistant and have not gotten well with past treatments and are therefore willing to participate in a placebo controlled trial; or alternatively patients who see themselves as having such a mild disorder that they donâ&#x20AC;&#x2122;t need treatment and would be happy to receive a placebo. One approach to solving this problem is to use add-on designs. In an add-on design, whether in psychiatry or in oncology, every patient receives standard treatment while half of the patients receive an additional experimental treatment or a placebo. This add-on design has not been accepted by the American FDA for many illnesses. For depression, for example, the FDA has stated that the placebo response rate varies so much that comparison to a placebo is necessary to show that the trial is truly measuring depression. Pharmaceutical companies are also hesitant to base their marketing and development strategies on add-on trials. They are afraid that their market will be limited if their drug is used only in patients who are failures at current therapy and if their new drug is considered only as an add-on drug. Pharmaceutical companies like to compare their drug to a placebo because they feel they have a better chance of success to prove efficacy. Where are we then to go in this crisis? I think the answer is the appropriate use of the bioinformatic revolution. I believe that the model for clinical research in psychiatry will be based on the model that has been pioneered for the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Unfortunate patients with ALS usually die within a few years after diagnosis. Patients have initiated a website where others with this disease register themselves and report on their symptoms and survival at regular intervals such as weekly or monthly. They also report what treatments they are taking. Clearly this is not random allocation and violates the basic principle of the randomized controlled trial. However, the internet age has made this principle no longer neces-

RH Belmaker

sary. The bioinformatics revolution allows the numbers of patients who can register at such a site from such a large number of countries in large numbers of different environments, social classes, and ethnic groups such that, in my opinion and that of others, the statistical ability to covary will not demand prospective randomization in order to obtain firm clinical knowledge. With the introduction of the electronic medical record in many countries, the same is becoming true in other areas of medicine including psychiatry. When depressed patients can register at an internet site and rate their symptoms of depression and list their treatments, and the N’s of such data banks reach the tens of thousands, appropriate statistical calculations and covariances will allow us to determine whether a new antidepressant is better than the old or not and in which types of patients. The FDA and similar regulatory agencies in the future will concentrate on safety, that is, the proof that a compound is not dangerous for public consumption based on animal studies and small studies of normal volunteers. That will be phase I. Phase II will be small, innovative clinical trials as in this issue of the Israel Journal of Psychiatry. Phase III will disappear and be replaced by what is now Phase IV, the post marketing phase which will take place on internet sites. The results of these internet sites’ efficacy judgments will not be published in a single article that will stand as “a fact” published on a specific date, rather the results on these

internet sites will be updated perhaps daily. Physicians will be able to see the statistical chances of improvement for a patient similar to the one they have in front of them at a particular time. They will be able to see those chances of improvement with the various compounds available in the market at that time within various subgroups of patients by clinical symptoms, age, sex and country as well as other variables. The data capacity of such systems will allow also comparison of specific subgroups such as patients who had a past response to a particular antidepressant or patients that might have had a particular psychosocial precipitant such as unemployment. In clinical research we must adjust to the new internet reality and abandon the expensive, time consuming and often ethically problematic large clinical trials that have characterized the last generation. References 1. Belmaker RH, Bersudsky Y, Agam G. Individual differences and evidence based psychopharmacology. BMC Medicine 2012; 10:110. 2. Grove A. Rethinking clinical trials. Science 2011; 333:1679.

Robert H. Belmaker Bipolar Disorders Clinic, Hadassah University Hospital, Jerusalem, Israel

belmaker@bgu.ac.il

Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

A Pilot Open Study of Long Term High Dose Creatine Augmentation in Patients with Treatment Resistant Negative Symptoms Schizophrenia Uri Levental, MD, Yuly Bersudsky, MD, Tzvi Dwalatzky, MD, Vladimir Lerner, MD, Sophie Medina, MA, and Joseph Levine, MD Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheva, Israel

INTRODUCTION

Abstract Background: The effects of creatine on brain metabolism and the potential cognitive enhancing properties of this compound raise the possibility of developing a new augmentation therapeutic strategy in schizophrenia especially in patients demonstrating negative and cognitive symptomatology. Methods: Seven inpatients with chronic schizophrenia presenting with treatment resistant negative symptoms were enrolled into exploratory treatment study with creatine monohydrate augmentation at a daily high-dose of 10 grams, administered for 6 months. Several clinical rating scales and a computerized cognitive assessment battery were applied. Results: Creatine treatment mildly improved the schizophrenia symptomatology but there were no significant changes in cognitive functions. Several ward behaviors were also improved. Tardive parkinsonism improved numerically by above 40% in 4 out of 6 patients. Conclusion: This small, open design study of high dose creatine add-on for 6 months in chronic inpatients with schizophrenia demonstrated only mild positive effects on the patients’ symptomatology and behavior and might have beneficial effect on tardive parkinsonism.

Sources of financial and material support: NARSAD Independent Investigator Award Grant for Joseph Levine Address for Correspondence:

Creatine is a substrate of creatine kinase and serves as a temporal and spatial buffer for cytosolic and mitochondrial pools of the cellular energy currency adenosine triphosphate. As such it plays a pivotal role in brain energy homeostasis. Creatine also demonstrates neuroprotective qualities in a variety of experimental models (1-6). Creatine enters the brain via a specialized sodium dependent transporter leading to a significant increase in concentration of creatine and phosphocreatine across brain region (7, 8). Imaging studies – not using creatine as an internal reference (9) – suggest the possible involvement of altered creatine/phosphocreatine/creatine kinase energy metabolism in the pathophysiology of schizophrenia. Thus, Burbaeva et al. (10) reported a drastic drop of creatine kinase (CK, the enzyme converting creatine to phosphocreatine) activity and CK BB immunoreactivity in all the examined brain areas in schizophrenic patients compared to controls. Jayakumar et al. (11) in examining the volumetric and metabolic correlates of the caudate nucleus in antipsychotic-naïve patients with schizophrenia compared with healthy controls, showed that phosphocreatine (PCr)/total phosphorous and PCr/ total adenosine tri-phosphate ratios of both caudate nuclei were significantly lower in patients compared with controls. A significant negative correlation was found between the left caudate volume and left PCr/ total phosphorus ratio in the patients. Chang et al. (12) studied elderly schizophrenic patients and controls for neurometabolite concentrations in several white matter regions. Interactions between age and schizophrenia on total creatine were observed and only participants with schizophrenia showed an age-related creatine decrease in the right frontal region.

Dr. Joseph Levine, Beersheva Mental Health Center, POB 4600, Beersheva, Israel

yossilevine@gmail.com

Uri Levental et al.

These findings may suggest a decreased activity of the brain creatine/phosphocreatine/creatine kinase energy metabolism system in schizophrenia. However, there are also reports of an increase of creatine/phosphocreatine concentrations in certain brain areas in this disorder, possibly suggesting abnormal local cell-energy demands. Thus, O’Neill et al. (13) using proton magnetic resonance spectroscopic imaging showed that in children and adolescents with schizophrenia, creatine was 14% higher in the superior anterior cingulate region than in controls. Lutkenhoff et al. (14) reported that in the medial prefrontal gray matter, creatine plus phosphocreatine (Cr+PCr), did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls whereas in the left hippocampus, Cr+PCr was higher in schizophrenic patients compared both to controls and to their unaffected co-twins. Wood et al. (15) in assessing patients with a first episode of psychosis reported significant elevations of creatine/phosphocreatine (Cr/PCr) in the medial temporal lobe bilaterally in the treated group compared to controls, perhaps suggesting that these are treatmentrelated changes. The authors also note that seemingly illness-related Cr/PCr elevations were also specific to the diagnosis of schizophrenia-spectrum disorder. These findings of altered creatine/phosphocreatine/ creatine kinase energy metabolism in schizophrenia are corroborated by the reports of Volz et al. (16) who demonstrated reduced ATP in the frontal and left temporal lobe of schizophrenic patients. There are also reports of alterations in metabolic rates in a variety of brain regions, including the frontal lobes (hypofrontality), temporal lobes, the thalamus and the basal ganglia, suggesting an impairment in fronto-striatal-thalamic circuitry in schizophrenia (17). These findings of either a decrease in the activity of creatine/ phosphocreatine/creatine kinase energy metabolism, or abnormal local cell-energy demands in schizophrenia raise the possibility of developing a treatment strategy by enhancing brain energy metabolism in schizophrenia. A previous double-blind cross-over treatment study from our research group (18), comparing the effects of 3 months of creatine at a dose of 5 grams daily compared to placebo in schizophrenia failed to detect efficacy in treating symptoms, including negative symptoms and cognition, but supported the need for further research. Reported side effects of creatine treatment were few, and included mild transient nausea and vomiting. An initial placebo-controlled clinical trial in patients with Huntington’s disease – another brain disorder associated with psychotic symptomatology – in which creatine was

administered in a similar dose (namely 5 grams daily) for 1 year failed to detect significant effects (19). However, later studies in this disorder using higher doses of creatine showed beneficial brain biochemical changes including the lowering of glutamate levels (20) as well as that of serum 8-hydroxy2’-deoxyguanosine levels – the latter suggested to reflect oxidative injury to DNA (21). Moreover, creatine at a high dose of 10 g daily administered for longer periods of time, such as 12 months (22) and 24 months (23) was associated with the stabilization of neuropsychiatric function. Thus, this raises the possibility that higher doses (i.e., 10 grams daily) administered for periods longer than 3 months, may show beneficial effects in augmentation strategies in schizophrenia. A dose of creatine 10 grams daily was reported to be safe and to be associated with few side effects (22-24). We thus conducted an exploratory pilot observational study to evaluate the effect of a daily high dose of 10 grams of creatine as augmentation strategy to ongoing psychotropic treatment administered for 6 months on the illnessrelated symptomatology of inpatients with schizophrenia showing treatment resistant negative symptoms. Since creatine was previously reported to exert beneficial effects on cognition (25-27) and perhaps on extrapyramidal symptomatology (24), we also assessed these parameters. METHODS This study, approved by the local Helsinki (IRB) committee, is a small open 6 months long clinical trial examining the effect of creatine monohydrate added to ongoing psychotropic treatment for inpatients with schizophrenia – demonstrating a lack of response of their negative symptoms to at least 2 antipsychotic psychotropic treatments, each administered for at least 6 weeks. We defined these as patients with “treatment resistant negative symptoms” rather than patients with “treatment resistant schizophrenia.” Creatine monohydrate was purchased from Solgar Ltd., Israel, where 1 tablet contains 1 gram. Inclusion criteria were: Sex: male or female; Age: 18-65 years old; Diagnosis: primary diagnosis of schizophrenia according to DSM-IV-TR; a history of at least 2 previous years with predominant negative symptoms and at least 3 negative items of the Positive and Negative Symptoms Scale (PANSS), with a score equal to or above 4 points each at baseline; no change in the patients’ clinical status for at least 6 months prior to study entry. We examined each one of the candidate patients as to their understanding following repeated detailed explanations in plain language of four components related to their 7

Term Relat HighSci Dose Augmentation in Treatment Resistant Negative Symptoms Schizophrenia IsrLong J Psychiatry - Vol.Creatine 52 - No 1 (2015)

ability to sign informed consent: a. general understanding of the study design, the fact that there will be questionnaires and scales to fill, the expected benefits from creatine addon, the expected possible side effects and risks involved in this treatment; b. the patient’s understanding that he or she is influenced by a mental illness; c. the patients’ ability to consider alternative modes of treatment each with its advantages and disadvantages; d. the patients’ ability to utter his decision as to his participation in the study verbally without any fear or hesitation. Only patients who fulfilled these 4 components and agreed to sign an informed consent were recruited into the study. Exclusion criteria were: pregnant or lactating female patients; patients with clinically significant or unstable medical conditions, epilepsy, or a history of alcohol or substance abuse in the last 6 months prior to study entry; a history of liver or kidney disorders or disturbances in liver or kidney function or blood count and differential as reflected by baseline blood test; creatine use 90 days prior to study entry; known sensitivity to creatine use. Criteria for removal from the study were: any request from the patient to be withdrawn from the study; the development of hypersensitivity to creatine administration; exacerbation in the patients’ clinical condition (increase in the PANSS score equal to or above 20%). Seven consenting inpatients with chronic schizophrenia demonstrating treatment-resistant negative symptoms, 6 males and 1 female, mean (S.D.) age 45.5 (8) years, range 35-55 years, mean (S.D.) years of education 10.1 (1.5), range 8-12 years. All with more than 15 years of illness with basically no change in clinical presentation in the last 6 months as judged by the patient’s psychiatrist. All were residents of a hospital psychiatric ward for at least 10 years where they had ongoing follow-up by certified psychiatrists and nursing staff. Patients were treated with creatine monohydrate (administered by the nursing staff twice daily in equal doses) for 6 months (3 g daily in the first 2 weeks, 5 g daily in the next 2 weeks, 7 g in the next 2 weeks and finally 10 g daily for up to 6 months of treatment). Patients’ neuroleptic treatment was not be affected by study participation. Real life treatment with mood stabilizers, benzodiazepines and anticholinergic medications were allowed but doses were documented throughout the study. No changes were made in the patients’ neuroleptic treatment throughout the study, and small changes in the use of benzodiazepines were recorded. One change was made in the dose of a mood stabilizer as required in order to maintain levels within the therapeutic range (carbamazepine dose was raised 8

from 600mg/d to 800mg/d after 4 months of creatine treatment ). Routine blood tests including kidney function and liver function were monitored at baseline, and at 3 and 6 months, and were all within the normal range. In practice the 7 patients were treated respectively with the following antipsychotics and mood stabilizers (the latter were administered as these patients were not responding to antipsychotic drug therapy): 1. clozapine 500mg/d along with valproic acid 800mg/d; 2. amisulpiride 700mg/d along with chlorpromazine 200mg/d; 3. olanzapine 20 mg/d along with chlorpromazine 200 mg/d and valproic acid 800mg/d; 4. perphenazine 24 mg/d along with haloperidol decanoate 100mg IM every 3 weeks and valproic acid 800 mg/d; 5. perphenazine 20 mg/d along with carbamazepine 800 mg/d; 6. risperidone 6 mg/d along with lithium 750mg/d; 7. perphenazine 12 mg/d along with haloperidol decanoate 100mg IM every 3 weeks The Positive and Negative Symptoms Scale (PANSS), Clinical Global Impressions (CGI), The Nurse Observation Scale for Inpatient Evaluation (NOSIE; a sensitive rating scale for ward behavior), the Extrapyramidal Symptom Rating Scale (ESRS; this scale is designed to rate the severity of four types of drug-induced movement disorders – both acute and delayed-onset – including parkinsonism, akathisia, dystonia and tardive dyskinesia [28-30], the Mindstreams computerized cognitive battery (see below) were administered at baseline and at 3 and 6 months, and adverse effects were recorded. The assessment scales and the cognitive battery were performed by highly trained personnel with previous experience in delivering the specific assessment scales (Cognitive battery by TD, ESRS by VL, PANSS & CGI by UL and JL, NOSIE by SM). COGNITIVE BATTERY The Mindstreams Severe Impairment Battery (MSIB) (31) was appropriate for use for these patients with chronic schizophrenia. It consists of six technician-administered tests and one patient-administered interactive test (Go-NoGo Basic test) sampling the cognitive domains of orientation (to time and place), memory, executive function, visual spatial processing, and verbal function. Following is a brief description of the tests included in this battery. Orientation to Time and Place: the participant is asked three basic questions regarding orientation to time and place. Accuracy is weighted such that partial credit is awarded for responses that are almost correct. Language Skills: the participant is asked to comply with simple verbal commands and to name pictures of

Uri Levental et al.

common objects; partial credit is awarded for responses STATISTICAL ANALYSIS that are nearly correct. Nonverbal Memory: the participant is presented with Statistical analysis: Descriptive statistics were used to pictures of common objects followed by an immediate describe all study variables at baseline, at 3 and 6 months from the beginning of the study. To evaluate change recognition test; a delayed recognition test for the same over time we used ANOVA with repeated measures objects is administered after 5 minutes. Similarities and Judgment: a multiple-choice test in (with post hoc LSD test). Throughout our calculations, which the participant is asked simple questions relating age and education were used as co-variants. Statistical to similarities and differences of common objects, as well significance was set at .05. as basic knowledge and praxis. Reality Testing: the participant is presented with a RESULTS series of pictures in which a particular aspect of the scene is either incomplete or inconsistent with context; There was a significant change in the total PANSS with following the presentation of each picture, the participant treatment, although this was of only minimal clinical value is asked to determine which aspect is aberrant; if he is mainly due to mild improvement of the general psychopathology PANSS subscale. There was no significant improveunable to identify the aberrant aspect, multiple choices ment in PANSS negative and PANSS positive subscales for the correct answer are provided and partial credit is with treatment. CGI severity and cognitive function as awarded if a correct response is made. Spatial Orientation: computer-generated scenes containassessed by the Mindstreams Severe Impairment Battery ing a red pillar are presented; the participant is asked to did not change significantly as a result of treatment. On NOSIE there was a significant improvement in the total select the view of the scene from the vantage point of the red pillar. Go-NoGo Basic: a timed, patient-administered score, and in particular in personal neatness, psychomotor test consisting of two parts; in the simple reaction time retardation and social competence (see Table 1). (SRT) portion, large green squares are preTable 1. Results for the cognitive battery, PANSS, CGI and the NOISE scales** sented at pseudo-random intervals, and the Baseline Month 3 Month 6 F participant is required to press the mouse butScale mean SD mean SD mean SD (2,12) p ton as quickly as possible whenever a square 75.2 18.9 76.3 19.3 73.1 13.6 0.4 0.7 appears; in the inhibition stage, either a red Global cognitive score Orientation score 78.6 23.0 73.9 27.0 61.9 30.2 1.3 0.3 circle or a white square is presented, and the 86.7 14.1 87.9 18.3 83.6 18.9 0.3 0.7 participant responds only to a white square Verbal Function score Memory score 75.9 30.3 76.1 30.4 72.1 21.4 0.4 0.7 but not to a red circle. For the technician-administered tests, a Executive Function score 69.6 21.9 73.0 16.3 74.9 16.2 0.6 0.5 test supervisor reads the instructions and Visual Spatial score 73.6 17.8 76.4 17.0 71.7 20.3 0.1 0.9 verbal test stimuli to the participant and PANSS Total score 92.6 9.1 89.3* 8.3 87.4* 8.4 8.8 0.004 enters the participantâ&#x20AC;&#x2122;s response according PANSS Positive subscale score 20.6 6.2 20.0 5.7 20.1 6.8 0.8 0.5 to instructions given in small italicized text PANSS Negative subscale score 25.1 4.8 24.4 5.6 23.4 6.1 3.4 0.067 at the bottom of the screen. Only accuracy PANSS General subscale score 46.9 5.9 44.9 4.8 43.9* 6.3 5.4 0.021 outcome parameters (scale: 0 to 100%) are CGI Severity score 4.9 0.9 4.7 0.8 4.7 0.8 1.0 0.4 recorded for these tests. For the patientNOSIE total score 108.6 30.5 112.6* 21.7 134.3* 11.7 4.15 0.043 administered Go-NoGo Basic test, the patientâ&#x20AC;&#x2122;s own responses are recorded, and NOSIE social competence score 12.6 9.3 13.1* 8.3 22.9* 4.3 5.27 0.023 27.1 8.6 24.9 4.5 26.6 5.5 0.49 0.626 reaction time (RT) and standard deviation NOSIE social interest score of RT outcome parameters are recorded NOSIE personal neatness score 20.6 5.4 21.1* 5.3 25.7* 1.8 4.37 0.038 22.0 11.4 19.4 8.5 17.1 8.5 3.58 0.060 in addition to accuracy. Tests are always NOSIE irritability score NOSIE manifest psychosis score 14.0 5.7 12.9 4.0 17.1 13.8 0.67 0.532 administered in the same fixed order. All assessments were made between 9:00- NOSIE psychomotor retardation 11.7 5.3 10.3 3.9 6.9* 1.6 4.15 0.043 11:00 AM in the morning in order to rule score out diurnal fluctuations that may influence **Applied by One Way Repeated Measures Analysis of Variance with time as repeated measure *Post hoc LSD test: p<0.05 symptoms. 9

Term Relat HighSci Dose Augmentation in Treatment Resistant Negative Symptoms Schizophrenia IsrLong J Psychiatry - Vol.Creatine 52 - No 1 (2015)

The patients demonstrated TD (tardive dyskinesia) and TP (tardive parkinsonism) and no other extrapyramidal syndromes. Six patients had TP, four of them showed improvement of 40-51% whereas the other two showed no improvement. Six patients had TD, one showed improvement of 50% whereas five showed no improvement. No side effects were reported except for transient nausea in one patient. DISCUSSION The current study is a small size pilot open design with its inherent shortcomings and thus its modest results should be taken with caution. Although others have suggested that creatine may benefit some cognitive functions (25), in our study the use of a computerized cognitive assessment battery appropriate for patients with schizophrenia failed to demonstrate any beneficial effect on cognitive functions. We did find an improvement, although of minimal clinical value, in the patients’ symptomatology as measured by the general psychopathology subscale of the PANSS, yet no improvement in the PANSS negative syndrome subscale. However, there was a significant improvement in the patients’ personal neatness, social competence and psychomotor retardation as measured by the NOSIE. Personal neatness and social competence may suggest that there was some improvement of negative symptomatology detected by the highly sensitive ward behavior rating scale: the NOSIE (32, 33) but not by the PANSS negative subscale. In this regard, this beneficial effect of creatine administered for 6 months on behavioral and social parameters was also reported recently in females with Rett syndrome, although this finding did not reach statistical significance (34). However, as we stated previously one should take with caution our results concerning the above NOSIE items as no change was noted in the PANSS negative subscale and such NOSIE improvement may also be attributed to non-specific factors of being enrolled in a study with multiple encounters and staff care. Recently creatine was administered in a high dose of 30 grams daily in patients with amyotrophic lateral sclerosis (ALS) with few side effects (35) and an unpublished open-label pilot study explored creatine in doses of up to 40 g daily in patients with Huntingdon’s disease (36). It may thus be of interest to administer creatine in even higher doses and for longer periods while following behavioral and social parameters. In our study tardive parkinsonism was improved in 4 out of 6 patients and the subscale of the NOSIE also 10

showed a statistically significant improvement of psychomotor retardation. Creatine was previously suggested to have beneficial effects on extrapyramidal symptomatology in animal models (37) and a large scale futility study (24) suggested that creatine could not be rejected as futile in Parkinson disease. It is thus of interest to study this effect of creatine in future studies. Interestingly, Burbaeva et al. (10) reported a substantial decrease of creatine kinase (CK) activity and CK BB immunoreactivity in all the examined brain areas in patients with schizophrenia compared with controls. The decreased activity of this key enzyme may suggest that creatine administered to schizophrenic patients may not be converted sufficiently to creatine phosphate. This may be overcome by either increasing the dose of creatine administered (as suggested above as warranting further study) or alternatively by the administration of creatine phosphate high energy derivatives thus sparing the need to phosphorylize creatine to phophocreatine. Creatine phosphate derivatives were previously administered intravenously in certain medical conditions (i.e., cardiovascular disorders) to animals and humans (38-40). Interestingly, phosphocreatine-Mg-complex acetate (PCr-Mg-CPLX), one of these phosphocreatine compounds, was able to increase in vitro neuronal creatine independently of the creatine transporter (41) and has also shown neuroprotection in animal models in vivo (42). With regard to this finding, further research in animal models of schizophrenia is warranted. References 1. Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000; 80: 1107-1213. 2. Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev 2001; 53: 161-176. 3. Adcock KH, Nedelcu J, Loenneker T, Martin E, Wallimann T, Wagner BP. Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia. Dev Neurosci 2002;24:382-388. 4. Baker SK, Tarnopolsky MA. Targeting cellular energy production in neurological disorders. Expert Opin Investig Drugs 2003;12:1655-1679. 5. Chaturvedi RK, Beal MF. Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 2008;1147:395-412. 6. Adhihetty PJ, Beal MF.Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromolecular Med 2008;10:275-290. 7. Dechent P, Pouwels PJ, Wilken B, Hanefeld F, Frahm J. Increase of total creatine in human brain after oral supplementation of creatinemonohydrate. Am J Physiol 1999; 277: R698-704. 8. Lyoo IK, Kong SW, Sung SM, Hirashima F, Parow A, Hennen J, et al. Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatinemonohydrate. Psychiatry Res 2003; 123: 87-100. 9. Ongür D, Prescot AP, Jensen JE, Cohen BM, Renshaw PF. Creatine abnormalitiesin schizophrenia and bipolar disorder. Psychiatry Res 2009;172:44-48.

Uri Levental et al.

10. Burbaeva GSh, Savushkina OK, Boksha IS. Creatine kinase BB in brain in schizophrenia. World J Biol Psychiatry 2003;4:177-183. 11. Jayakumar PN, Venkatasubramanian G, Keshavan MS, Srinivas JS, Gangadhar BN. MRI volumetric and 31P MRS metabolic correlates of caudate nucleus in antipsychotic-naïve schizophrenia. Acta Psychiatr Scand 2006;114:346-351. 12. Chang L, Friedman J, Ernst T, Zhong K, Tsopelas ND, Davis K. Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: Implication for glial dysfunction. Biol Psychiatry 2007;62:1396-1404. 13. O’Neill J, Levitt J, Caplan R, Asarnow R, McCracken JT, Toga AW, Alger JR. 1H MRSI evidence of metabolic abnormalities in childhood-onset schizophrenia. Neuroimage 2004;21:1781-1789. 14. Lutkenhoff ES, van Erp TG, Thomas MA, Therman S, Manninen M, Huttunen MO, Kaprio J, Lönnqvist J, O’Neill J, Cannon TD. Proton MRS in twin pairs discordant for schizophrenia. Molecular Psychiatry 2010;15:308-318. 15. Wood SJ, Berger GE, Wellard RM, Proffitt T, McConchie M, Velakoulis D, McGorry PD, Pantelis C. A 1H-MRS investigation of the medial temporal lobe in antipsychotic-naïve and early-treated first episode psychosis. Schizophr Res 2008;102:163-170. 16. Volz H, Gaser C, Sauer H. Supporting evidence for the model of cognitive dysmetria in schizophrenia--a structural magnetic resonance imaging study using deformation-based morphometry. Schizophr Res 2000; 46: 45-56. 17. Andreasen NC, O’Leary DS, Flaum M, Nopoulos P, Watkins GL, Boles Ponto LL, et al. Hypofrontality in schizophrenia: Distributed dysfunctional circuits in neuroleptic-naive patients. Lancet 1997; 349: 1730-1734. 18. Kaptsan A, Odessky A, Osher Y, Levine J Lack of efficacy of 5 grams daily of creatine in schizophrenia: A randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2007;68:881-884. 19. Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Van Leemputte M, Hespel P, Dom R. Creatine supplementation in Huntington’s disease: A placebo-controlled pilot trial. Neurology 2003;61:925-930. 20. Bender A, Auer DP, Merl T, Reilmann R, Saemann P, Yassouridis A, Bender J, Weindl A, Dose M, Gasser T, Klopstock T. Creatine supplementation lowers brain glutamate levels in Huntington’s disease. J Neurol 2005;252:36-41. 21. Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L, Ulug AM, Beal MF, Matson W, Bogdanov M, Ebbel E, Zaleta A, Kaneko Y, Jenkins B, Hevelone N, Zhang H, Yu H, Schoenfeld D, Ferrante R, Rosas HD. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2’dG. Neurology 2006;66:250-252. 22. Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT. Creatine therapy for Huntington’s disease: Clinical and MRS findings in a 1-year pilot study. Neurology 2003;61:141-142. 23. Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT. High-dose creatine therapy for Huntington disease: A 2-year clinical and MRS study. Neurology 2005;64:1655-1656. 24. NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 2006; 66:664-671. 25. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebocontrolled, cross-over trial. Proc R Soc Lond B Biol Sci 2003; 270: 2147-2150.

26. McMorris T, Harris RC, Swain J, Corbett J, Collard K, Dyson RJ, Dye L, Hodgson C, Draper N. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology (Berl) 2006;185:93-103. 27. McMorris T, Harris RC, Swain J, Corbett J, Collard K, Dyson RJ, Dye L, Hodgson C, Draper N. Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology (Berl) 2006;185:93-103. 28. Chouinard G, Ross-Chouinard A, Annable L, Jones B. Extrapyramidal Symptom Rating Scale. Can J Neurol Sci (abstract) 1980;7:233. 29. Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res 2005;76:247-265. 30. Hyde TM, Egan MF, Brown RJ, et al. Diurnal variation in tardive dyskinesia. Psychiatry Res 1995; 56:53-57. 31. Ritsner MS, Blumenkrantz H, Dubinsky T, Dwolatzky T. The detection of neurocognitive decline in schizophrenia using the Mindstreams Computerized Cognitive Test Battery. Schizophr Res 2006;82:39-49. 32. Honigfeld G, Gillis RD, Klett CJ. NOSIE-30: A treatment-sensitive ward behavior scale. Psychol Rep 1966; 19: 180-182. 33. Philip AE. A note on the nurses’ observation scale for inpatient evaluation. Brit J Psychiat 1973; 122: 593-596. 34. Freilinger M, Dunkler D, Lanator I, Item CB, Mühl A, Fowler B, Bodamer OA. Effects of creatine supplementation in Rett syndrome: A randomized, placebo-controlled trial. J Dev Behav Pediatr 2011;32:454-460. 35. Atassi N, Ratai EM, Greenblatt DJ, Pulley D, Zhao Y, Bombardier J, Wallace S, Eckenrode J, Cudkowicz M, Dibernardo A. A phase I, pharmacokinetic, dosage escalation study of creatine monohydrate in subjects with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2010; 11: 508-513. 36. Hersch SM. Creatine safety, tolerability, and efficacy in Huntington’s disease: CREST-E. http://www.labome.org/grant/u01/at/creatine/safety/ creatine-safety--tolerability--and-efficacy-in-huntington-s-disease-crest-e-7374072.html 37. Yang L, Calingasan NY, Wille EJ, Cormier K, Smith K, Ferrante RJ, Beal MF. Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s diseases. J Neurochem 2009;109:1427-1439. 38. Cafiero M, Strumia E, Pirone S, Pacileo S, Santoro R. [The efficacy of creatine phosphate in the treatment of patients with heart failure. Its echographic evaluation after acute and protracted treatment]. Clin Ter 1994;144:321-328. 39. Weber P, Vlasicová Y, Lábrová R, Semrád B. [Use of creatine phosphate in treatment of cardiocerebral syndrome associated with acute myocardial infarct in the aged]. Cas Lek Cesk 1995;134:53-56. 40. Prabhakar G, Vona-Davis L, Murray D, Lakhani P, Murray G. Phosphocreatine restores high-energy phosphates in ischemic myocardium: Implication for off-pump cardiac revascularization. J Am Coll Surg 2003;197:786-791. 41. Lunardi G, Parodi A, Perasso L, Pohvozcheva AV, Scarrone S, Adriano E, Florio T, Gandolfo C, Cupello A, Burov SV, Balestrino M. The creatine transporter mediates the uptake of creatine by brain tissue, but not the uptake of two creatine-derived compounds. Neuroscience 2006;142:991997. Epub 2006 Sept. 1. 42. Perasso L, Adriano E, Ruggeri P, Burov SV, Gandolfo C, Balestrino M. In vivo neuroprotection by a creatine-derived compound: phosphocreatineMg-complex acetate. Brain Res 2009;1285:158-163.

Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

Safety, Tolerability and Pharmacokinetics of Open Label Sarcosine Added on to Anti-Psychotic Treatment in Schizophrenia – Preliminary Study Revital Amiaz, MD,1,2 Ilan Kent, MD,2 Katya Rubinstein, MA,2 Ben Ami Sela, PhD,2 Daniel Javitt, MD, PhD,3 and Mark Weiser, MD1,2 1

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel 3 Nathan Klein Institute, Orangeburg, New York, U.S.A. 2

Abstract Background: Hypofunction of NMDA receptor-mediated neurotransmission might play a critical role in schizophrenia. Sarcosine, N- methylglycine and inhibitor of the glycine transporter-1 (Gly-T1), has been suggested as a novel treatment for schizophrenia. Methods: Open label sarcosine was added to 22 stabilized patients: 5 patients received 2 gm/d, and 17 received 4gm/d. Pharmacokinetics samples, clinical and cognitive parameters using PANSS, CGI and MCCB were collected for all patients. Results: Significant improvement was observed after one week of treatment on PANSS sub-scale of ’positive symptoms‘ (Z= -2.68; P=0.007) and ’general psychopathology‘ (Z= -3.02; P=0.003), an improvement in PANSS total score and CGI-S showed a trend (Z= -2.72; P=0.06; Z=-2.69; P=0.08). Speed of processing (MCCB subscale) improved significantly (Z=-2.13; P=0.03). Sarcosine exhibited linear kinetics, with a Tmax and t½ of ~1½- 2½ hr and ~1hr, respectively. Limitations: This was a short period, open label pilot study with small sample size per dosage group. Conclusions: Sarcosine is a safe compound and might be efficacious in the treatment of schizophrenia.

Address for Correspondence: mweiser@netvision.net.il

Introduction The positive and negative symptoms of schizophrenia, as well as the cognitive impairment that is common in the illness, can be mimicked by the administration of agents that block the NMDA receptor, such as the street drug PCP (“angel-dust”) (1). It has thus been proposed that the symptoms of schizophrenia might arise from a hypofunction in NMDA neurotransmission. Therefore, enhancing NMDA neurotransmission is predicted to improve symptoms and cognition in schizophrenia. Initial studies of this theory have been conducted using direct NMDA glycine-site agonists, such as glycine and D-serine. These compounds, while crucial as proof-ofprinciple treatments, are limited by poor CNS penetration and endogenous inactivation processes. Nevertheless, most clinical studies (2, 3), as well as one meta-analysis (4), have shown significant effects of these compounds, particularly on negative symptoms. An alternative approach to the stimulation of NMDA receptor-mediated neurotransmission in the brain is use of glycine transport inhibitors. Glycine (GLYT1) transporters are localized with brain NMDA receptors and regulate local glycine levels (5). Several recent smallscale studies have shown significant beneficial effects of sarcosine as adjunct to typical or atypical antipsychotics (6, 7). Improvements were observed in both positive and negative symptoms, and efficacy appears superior to that seen with the NMDA agonist D-serine (7). In addition an animal study showed that sarcosine infusion increased brain levels of glycine. This study also showed that dosage elevation of sarcosine up to an equal dose of 8gm/d in human elevated glycine levels (8).

Mark Weiser, MD, Head of Psychiatric Division, Sheba Medical Center Tel Hashomer, 52621 Israel

Revital Amiaz et al.

However, all of the published studies on sarcosine in schizophrenia have been conducted at a single site in Taiwan and there were no replications of their findings. Furthermore, although two studies reported improvements in PANSS cognitive symptoms items (6, 7), the effect of sarcosine on cognition has not been directly tested using an assessment tool designed and validated as a primary measure of cognition in schizophrenia, such as the MATRICS Consensus Cognitive Battery (MCCB) (9). The current study was originally designed as a preliminary trial in order to establish safety, tolerability and pharmacokinetics of 2, 4 and 8gm of sarcosine. Our intention was to complete six weeks of treatment with 8gm of sarcosine open label treatment in order to establish the efficacy of sarcosine in a larger randomized controlled trial. The recruitment was terminated due to the following safety issue: An article published in Nature in February 2009 reported that sarcosine, added to tissue culture of prostate cancer cells, induced invasive phenotype in prostate epithelial cells (10). This report suggested a potential role for sarcosine in prostate cancer progression. Due to this potential safety concern this study was terminated. This finding has been questioned and parts of it were not replicated (11). We hereby present the results of the first and the second stage of the study conducted prior to recruitment termination. Methods Patients

Patients were recruited from the inpatient and the outpatient wards of Sheba Medical Center in Israel between July 2009 and June 2010. The trial was approved by the local IRB and conducted according to ICH-GCP guidelines. In addition to the local IRB approval, the trial was monitored by the NIMH Data Monitoring and Safety Board. Each participant received oral and written explanations of the study, and gave written informed consent prior to inclusion. The patients who participated in the study were aged 18-64 years and met DSM-IV criteria for schizophrenia or schizoaffective disorder as confirmed by modified SCID (12). Subjects were stabilized on any antipsychotic drug for at least four weeks prior to enrollment and sarcosine add on. Patients’ antipsychotic medication was as follows: 7 risperidone, 4 quetiapine, 4 IM zuclopenthixol depo, 3 olanzapine, 2 IM fluphenazine , 2 paliperidone. Patients who were taking clozapine were not included. In order to participate in the study a total PANSS score of >60 was required, with at least 18 points on the negative symptoms

subscale (13, 14). Medical history, routine clinical blood and urine tests were collected and physical examinations were performed prior to enrollment. Patients’ conﬁdentiality was maintained during all stages of the study. Study design

The study was performed in two dose-level phases. Following enrollment, in the first stage 5 patients received 2gm/d of sarcosine for one week and in the second stage 17 patients received 4gm/d for one week. Five patients from each group underwent a 24-hour pharmacokinetics (PK/PD) session on the first day of treatment. Clinical assessments

Cognitive effects of sarcosine were evaluated using the MATRICS Consensus Cognitive Battery (MCCB) (9), which was specifically designed to assess changes in cognition in schizophrenia. Neurocognitive assessment was conducted using a Hebrew translation of 9 out of the 10 MCCB sub-tests: Category fluency (15), Brief Assessment of Cognition in Schizophrenia (BACS)- symbol coding (16), Trail making A (17), Continuous Performance Test - Identical Pairs (CPT-IP) (18), University of MarylandLetter-Number Span (19), WMS III – Spatial span (20), Rey Auditory Verbal Learning Test (RAVLT) (21), Brief Visuospatial Memory Test-Revised (BVMT-R) (22), Neuropsychological Assessment Battery (NAB)-Mazes (23). The Hopkins Verbal Learning Test (HVLT) (21) is the task for assessment of verbal learning used in the MCCB. Since this test has not been translated or validated into Hebrew, we used the Rey Auditory Verbal Learning Test (RAVLT) (21) , which has a validated Hebrew version commonly used in clinical and research settings (24). The cognitive battery was administered at baseline and at day 8. Since only 9 of the 10 MCCB subtests were administered, the subtest scores were converted into Z-scores to allow for comparison, and a mean of these scores was used as an estimated total MCCB score and served as primary neurocognitive outcome. For positive and negative symptoms, the primary rating instrument was the Positive and Negative Symptom Scale (PANSS) (13). Other assessments included: Clinical Global Impression (CGI) Scale (25); Simpson-Angus Extrapyramidal Symptom Rating Scale (SAS) (26); Abnormal Involuntary Movement Scale (AIMS) (27); Calgary Depression Scale for Schizophrenia (CDSS) (28) and side effects checklist. The PANSS, CDSS, SAS, AIMS and CGI ratings were administered at baseline and after one week of treatment with sarcosine. 13

Open Isr J Psychiatry Relat Sci -Label Vol. 52 Sarcosine - No 1 (2015) Added on to Anti-Psychotic Treatment in Schizophrenia

Plasma sarcosine level determination

Sarcosine analysis was performed using a Biochrom 20 plus amino acid analyzer (Biochrom Ltd UK). Separation was achieved by Liquid chromatography on an ion exchange column. The separation occurred by using five different buffers of lithium citrate. Each buffer that was run sequentially through the column was at different Ph and ionic strength. Some of the buffers had the addition of varying amounts of an organic solvent. The run times of the buffers and the temperature of the columns were varied to optimize the separation. After elution from the column the eluates were mixed with Ninhydrin in dimethylsulphoxide heated to 135°C and the resultant color read at 570nm and 440nm (29). Results Stage 1 – 2gm/d

Five patients were recruited for the 2gm/d stage of the study. all patients were males, mean age was 41.0 (31-48years). Due to the small sample size (N=5), statistical analysis for the patients who received 2gm/d was not performed. All patients in this group tolerated the medication very well and had CGI≥3. Table 1. Clinical and cognitive assessments at baseline and after 8 days* Test

Baseline

Day 8

Cohen’s D

PANSS Positive

16.61±7.45

13.47±4.67

-2.68

0.00**

-0.91

PANSS Negative

19.83±5.03

18.82±5.28

-1.27

0.20

-0.62

PANSS General

35.66±11.28

31.29±9.06

-3.02

0.00**

-0.78

PANSS Total

71.00±21.82

63.58±16.39

-2.72

0.06

-0.79

CGI-S

3.89±0.73

3.78±0.71

-2.69

0.08

-0.36

MCCB speed of processing

26.95±18.18

35.63±16.29

-2.13

0.03**

0.38

MCCB Attention

23.95±12.76

23.73±17.35

-0.57

0.57

-0.01

MCCB Working memory

27.65±12.84

24.21±21.05

-0.85

0.39

-0.27

MCCB Verbal learning

31.45±7.36

30.57±9.99

-0.21

0.83

-0.13

MCCB Visual learning

29.70±14.63

34.22±16.46

-1.49

0.13

0.44

MCCB Reasoning & Problem solving

33.55±7.61

34.78±9.40

-0.71

0.47

0.21

MCCB Total

28.87±9.36

30.42±9.89

-0.88 0.37

0.28

* We used Wilcoxon signed ranks test ** Statistically significant

Stage 2 – 4gm/d

On the second stage we recruited 17 patients diagnosed with schizophrenia, mean age 41.89 (26-56 years), 12 males and 5 females. Table 1 summarizes the cognitive and clinical evaluations which included PANSS, MCCB, SAS and CGI, between baseline and after one week for patients receiving 4gm/d. Wilcoxon signed ranks tests were performed to compare baseline to day 8 safety, symptom and neurocognitive assessments. Our results show significant improvement in the PANSS subscale of ‘positive’ (Z= -2.68; P=0.007) and ‘general’ (Z= -3.02; P=0.003) symptoms subscale. The PANNS total score showed tendency toward significance (Z= -2.72; P=0.06) between baseline and after 8 days of treatment. Speed of processing, a subscale of MATRICS was significantly improved from baseline to day 8 of sarcosine add on. Pharmacokinetics

For all doses, sarcosine exhibited linear kinetics, with a Tmax and t½ of ~1½- 2½hr and ~1hr, respectively (Fig. 1). Side effects

All the subjects completed the study and reported no serious side effects. Discussion This current study has evaluated the safety, tolerability and pharmacokinetics of 2 and 4gm/d of sarcosine in order to test the possible use of this compound as add-on treatment for schizophrenia. In general, sarcosine was well tolerated by the patients. Administration of sarcosine at 2 and 4gm/d for one Figure 1. Pharmacokinetic chart: Blood levels at time intervals after first dose of 2gm/d and 4gm/d of sarcosine

Blood levels in µmol/L of sarcosine over a timeframe of 7 days. Sarcosine exhibited linear kinetics, with a Tmax and t½ of ~1½- 2½ hr and ~1hr, respectively.

Revital Amiaz et al.

week appears to be safe. No significant events, abnormal laboratory results or ECG abnormalities related to the study medication were noted. As previously mentioned, early termination of this study was due to one article presenting some evidence that sarcosine can cause exacerbation of prostate cancer (10). However, later studies failed to replicate these findings and one other study has been published showing the opposite (11, 30). Furthermore, there is another ongoing NIH funded study that examines the effects of sarcosine on brain glycine concentrations (ClinicalTrials.gov identifier: NCT00538070). To the best of our knowledge, this is the first study that presents pharmacokinetic evaluations of sarcosine. The pharmacokinetic results show that sarcosine concentration in serum reaches its peak after two hours, and the half-life of sarcosine is approximately one hour. These results indicate that sarcosine should be administered at least twice a day. It light of the above, it can be concluded that sarcosine is a safe compound, without significant side effects and with a relatively short half-life. Although we are limited by the small number of patients, and open-label administration for only one week, the results are encouraging, showing improvements in the expected direction of reduction of positive symptoms and improvement in cognition, especially in the speed of processing, MCCB. The improvement in speed of processing, MCCB, is particularly interesting, as it is a core cognitive impairment in schizophrenia. We assume that due to the short period of time between the two evaluations, learning effect was relatively high. We hypothesize that a study with more participants and considerably longer period of time between the cognitive evaluations might reduce the learning effect. These results are similar in direction to the several randomized controlled trials using sarcosine, that showed that 2gm/d of sarcosine as add-on therapy to antipsychotic treatment, can improve positive and negative symptoms in patients with chronically stable or acute schizophrenia (7, 31, 32). Furthermore, Roche is now performing a phase III clinical trial on a glycine transport inhibitor and new glycine reuptake inhibitors are being developed by other pharmaceutical companies. These ongoing research projects emphasize the potential therapeutic value of sarcosine in treatment of schizophrenia (33). In summary, we believe that sarcosine is a safe compound and further research is needed in order to evaluate its therapeutic role in schizophrenia.

Acknowledgements The study was initially funded by the Brain and Behavior Research Fund NARSAD â&#x20AC;&#x201C; Independent investigators Award and by NIMH grant (P50 MH086385).

Author Contributions Dr. Amiaz recruited the subjects, performed the clinical assessments, analyzed the data and drafted this manuscript. Dr. Kent was involved in the clinical assessments and performed blood testing. Mrs. Rubinstein was the study coordinator and preformed cognitive assessments, data analysis and drafting of this manuscript. Prof. Sela was the pharmaceutical advisor to the study and was in charge of blood tests interpretation. Prof. Javitt and Prof. Weiser conceptualized the study, contributed critically to its design, and the interpretation of the data. All authors contributed to revisions and have approved the ďŹ nal manuscript.

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Open Isr J Psychiatry Relat Sci -Label Vol. 52 Sarcosine - No 1 (2015) Added on to Anti-Psychotic Treatment in Schizophrenia

14. Lindenmayer JP, Bernstein-Hyman R, Grochowski S. Five-factor model of schizophrenia. Initial validation. J Nerv Ment Dis 1994;182:631-638. 15. Blair JR, Spreen O. Predicting premorbid IQ: A revision of the national adult reading test. Clinical Neuropsychologist 1989;3:129-136. 16. Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The brief assessment of cognition in schizophrenia: Reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res 2004;68:283-297. 17. Army Individual Test Battery: Manual of Directions and Scoring. Office AGs, editor. Washington, D.C.: U.S. War Department, 1944. 18. Cornblatt BA, Risch NJ, Faris G, Friedman D, Erlenmeyer-Kimling L. The Continuous Performance Test, identical pairs version (CPT-IP): I. New findings about sustained attention in normal families. Psychiatry Res 1988;26:223-238. 19. Gold JM, Carpenter C, Randolph C, Goldberg TE, Weinberger DR. Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia. Arch Gen Psychiatry 1997;54:159-165. 20. Wechsler D. Wechsler Memory Scale. 3 ed: San Antonio: The Psychological Corporation, 1997. 21. Brandt J, Benedict RHB. The Hopkins Verbal Learning Test-Revised. Odessa, FL, USA: Psychological Assessment Resources, Inc., 2001. 22. Benedict RHB. Brief Visuospatial Memory Test - Revised. Odessa, FL, USA: Psychological Assessment Resources, Inc., 1997. 23. White T, Stern RA. Neuropsychological Assessment Battery: Psychological Assessment Resources, Inc., 2003.

24. Vakil E, Blachstein H. Rey Auditory-Verbal Learning Test: Structure analysis. J Clin Psychol 1993;49:883-890. 25. Guy W. CGI: Clinical Global Impressions. Bonato WGaRR, editor: National Institute of Mental Health, 1976. 26. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:11-19. 27. Fann WE, Stafford JR, Malone RL, Frost JD, Jr., Richman BW. Clinical research techniques in tardive dyskinesia. Am J Psychiatry 1977;134:759-762. 28. Addington D, Addington J, Schissel B. A depression rating scale for schizophrenics. Schizophr Res 1990;3:247-251. 29. Crabb JW, Atherton D, Smith A, Kutny R. A collaborative amino acid analysis study from the Association of Biomolecular Resource Facilities. Academic Press, 1990. 30. Jentzmik F, Stephan C, Lein M, Miller K, Kamlage B, Bethan B, Kristiansen G, Jung K. Sarcosine in prostate cancer tissue is not a differential metabolite for prostate cancer aggressiveness and biochemical progression. J Urol 2011;185:706-711. 31. Lane HY, Liu YC, Huang CL, Chang YC, Liau CH, Perng CH, Tsai GE. Sarcosine (N-methylglycine) treatment for acute schizophrenia: A randomized, double-blind study. Biol Psychiatry 2008 1;63:9-12. 32. Lane HY, Lin CH, Huang YJ, Liao CH, Chang YC, Tsai GE. A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia. Int J Neuropsychopharmacol 2010;13:451-460. 33. Hashimoto K. Glycine transporter-1: A new potential therapeutic target for schizophrenia. Curr Pharm Des 2011;17:112-120.

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Oded Rosenberg et al.

Long-term Follow-up of MDD Patients Who Respond to Deep rTMS: A Brief Report Oded Rosenberg, MD,1 Limor Dinur Klein, MSc,1 Roman Gersner,PhD,2 Moshe Kotler, MD,1 Abraham Zangen, PhD,3 and Pinhas Dannon,MD1 1

Beer Ya’acov Mental Health Center affiliated to Sackler School of Medicine, University of Tel Aviv, Tel Aviv, Israel Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. 3 Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel 2

Introduction

Abstract Background: Deep transcranial magnetic stimulation (dTMS) is effective in treatment of Major Depressive Disorder (MDD), and in re-treatment in case of relapse. Our study evaluates the long-term durability of dTMS in MDD. Method: Seventeen patients that responded to dTMS treatment evaluated. Follow-up period was 9.3 months. Patients were considered as relapsed if: HDRS (Hamilton Depression Rating Scale) score was 16 points or more, in case of change in antidepressants, hospitalization due to exacerbation, referral to ECT. Results: Six months after last treatment three patients relapsed (17.6%). During the follow-up of 9.3 months, nine relapsed. Relapse rate was 5.6 per 100 person-months. Patients continued to improve in HDRS following the treatment. We have found number of treatment sessions, stimulation, age, age of depressive disorder onset, length of depressive episode prior to the first treatment, as well as number of depressive episodes to have no predictive value regarding propensity to relapse in these patients. Limitations: The study’s main limitations are the relatively small sample size, patients differing in follow-up periods and the lack of a control group. Conclusion: Relapse rates after dTMS are comparable to pharmacotherapy and ECT.

Address for Correspondence: odedaruna@gmail.com

Depression is the leading cause of disability when measured by years living with the disability and is the fourth leading contributor to the global burden of disease in 2000, according to the World Health Organization. Despite pharmacological interventions, the long-term outcome of major depressive disorder (MDD) is poor, with psychiatric studies revealing high rates of relapse and extensive disability or suicide. Moreover, MDD is a recurring illness and residual symptomatology remains after the acute episode (1). Treatment resistant depression (TRD) affects as many as 30% of patients with major depression; and in addition to lower treatment response, it is associated with higher suicide risks, relapse rates, and health care utilization costs (2). Treatment methods shown to be effective in the treatment of depression are pharmacotherapy, cognitive behavioral therapy (CBT), electroconvulsive therapy (ECT), and transcranial magnetic stimulation (TMS) (1, 3-5). Yiend et al. (5) reported that 73% of patients treated with pharmacotherapy underwent at least one recurrence of depression within 23 years. Other researchers reported a variation of 21% to 95% in relapse rates in 25 years (6-9). Yiend et al. (5) also reported that the majority of the patients treated with pharmacotherapy had at least two or more episodes, and some had up to six episodes. Wilkinson et al. (4) reported one-year recurrence rates of 27.8% and 44.4% in patients randomly allocated to a combination of CBT and antidepressant medications or an antidepressant alone, respectively. Bockting et al. (10) assessed relapse/recurrence of major depression over two years’ duration in patients randomized to treatment with continuation of pharmacotherapy, or to treatment aug-

Oded Rosenberg, MD, Beer Ya’acov Mental Health Center, POB 1, Beer Ya’acov 70350, Israel

Long-term Follow-up of MDD Patients Who Respond to Deep rTMS Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

mented with brief cognitive therapy. They found that cognitive therapy reduced relapse/recurrence from 72% to 46%. ECT, which is considered one of the most effective treatments for depression (3), is widely used for the management of severe and refractory depression (11). However, ECT is associated with adverse cognitive effects and general anesthesia-associated risks, especially in patients with clinical co-morbidities. In addition, ECT induces seizures and causes significant memory and learning impairments (12). In major depression, the efficacy of ECT is well documented in the acute phase of the treatment (11). However, Wijkstra et al. (13) demonstrated that the 6-month relapse rate of depressed patients that have been treated with ECT was 50% (13). Naturalistic studies show that the relapse rate during the 6 to 12 months following ECT exceeds 50% (14). Sackeim et al. (14) concluded that without active treatment virtually all remitted patients relapse within 6 months of stopping ECT (14), while the Consortium for Research in Electroconvulsive Therapy (CORE) reported relapse rates over 6 months to be 37.1%. Repetitive TMS (rTMS) is considered a refined alternative for ECT in TRD (12). TMS is a non-invasive form of brain stimulation, which is thought to induce significant antidepressant effects with a few mild side effects and with no need for anesthesia (3). Studies comparing the antidepressant effects of electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) have reached mixed results demonstrating that rTMS is inferior to ECT or effective as ECT in the treatment of major depression. Eranti et al. randomly assigned 46 patients with major depression to either a 15-day course of rTMS of the left dorso-lateral prefrontal cortex or a standard course of ECT, and found that HAM-D scores at the end of the treatment were significantly lower for ECT, with 13 patients (59.1%) achieving remission in the ECT group and four (16.7%) in the rTMS group. However, at six months the HAM-D scores did not differ between groups. They concluded rTMS to be less effective than ECT, and ECT was substantially more effective for the short-term treatment of depression. TMS protocol included a total of 15,000 magnetic pulses for 15 days – a relatively low dose of magnetic stimulation making the comparison between the two stimulation methods questionable. Dannon et al. and Rosa et al. (1, 3) found the efficacy of ECT and rTMS to be similar in treating major depression. Dannon et al. (1) had reported that relapse rates in MDD patients treated with either rTMS or ECT are similar and close to 25% during the six months after treatment. 18

Grunhaus et al. (16) studied 40 patients with MDD randomly assigned to rTMS/ECT. Patients were treated using the following rTMS parameters: 90% power of the motor threshold, frequency of 10 Hz, 20 trains for 20 treatment days. Electroconvulsive therapy was performed according to standard protocols. Grunhaus and his colleagues found that patients with MDD and psychosis responded significantly better to ECT, whereas MDD patients without psychosis responded similarly to both treatments. Pridmore et al. (17) compared the antidepressant effects of rTMS and ECT in 32 patients suffering major depressive episode. Treatment was continued until remission occurred or response plateaued. Pridmore and his colleagues found a significant main effect for treatment type reflecting an advantage for ECT patients on measures of depression overall. Janicak et al. (18) studied 25 patients randomly assigned to rTMS (10-20 treatments, 10 Hz, 110% motor threshold applied to the left dorsolateral prefrontal cortex for a total of 10,000-20,000 stimulations) or a course of bitemporal ECT(4-12 treatment). Janicak and his colleagues found these two techniques to have comparable therapeutic effects. O’Connor et al. (19) treated 14 patients with unilateral electroconvulsive therapy three times per week for 2 to 4 weeks and 14 with repetitive transcranial magnetic stimulation (1600 stimuli at 10 Hertz and 90% of motor threshold intensity to the left dorsolateral prefrontal cortex daily) for 2 consecutive weeks. O’Connor and his colleagues found electroconvulsive therapy to have a more positive effect on mood than rTMS but to exert a transient deleterious effect on various components of memory. Schulze-Rauschenbach et al. (20) treated 30 patients with an average of ten treatments with either unilateral ECT or left prefrontal rTMS and assessed these patients for objective and subjective cognitive impairments before and about a week after treatment .Schulze-Rauschenbach and his colleagues found the two treatment methods to have comparable efficacy but different cognitive outcomes: In patients treated with rTMS, cognitive performance remained constant or improved and memory complaints alleviated, whereas in the ECT group memory recall deficits emerged and memory complaints remained. Previous research and clinical trials demonstrated that ECT seems more effective in general but cognitive impairment is a major drawback. Additional studies with larger samples are required in order to find out which of the treatments is preferable. Janicak et al. (21) studied patients who randomly received active or sham rTMS. Ten of 99 patients relapsed. The

Oded Rosenberg et al.

authors concluded that the therapeutic effects of rTMS are durable and that rTMS may be successfully used as an intermittent rescue strategy to preclude impending relapse (21). Deep (D) TMS for indication of anti-depressants resistant major depression was approved by the FDA in 2013. DTMS was previously shown to be effective in treating major depression (12, 22-25), though long-term follow-ups have not been reported yet. DTMS, as opposed to conventional rTMS, can stimulate fibers connecting the subgenual cingulate gyrus to the prefrontal cortex, thereby inducing an antidepressant action (23). DTMS efficacy in treating major depression is predictable considering the success of rTMS since in both methods the left dorso-lateral prefrontal cortex is being stimulated. Methods This study was approved by the Institutional Review Board (IRB) and conducted at Beer Yaakov Mental Health Center. Enrollment of patients took place from January 2008 through August 2009; all patients were recruited as referrals from psychiatrists from Beer Yaakov-Ness Ziona Mental Health Complex. All patients gave informed consent to participate in this study. Previously, we treated 31

patients suffering from MDD with dTMS. The treatment results of these 31 patients have been published (22-25). Prior to dTMS treatment, patients were diagnosed with major depression according to DSM-IV-TR criteria, except one, who was diagnosed with Bipolar II Disorder. Patients failed to respond to at least two antidepressant trials with adequate dosage and duration of treatment. Within the group of 31 patients that we studied, 17 patients (Table 1) responded to treatment (we considered treatment response to be an HDRS-24 improvement of >50%, and remission to be a score <10 [27]. Eight of the 17 patients were treated with antidepressant medications before and during Deep TMS treatment and at the followup period. No switching, augmentation, addition or dosage escalation took place during dTMS treatment or during the follow-up period. Three patients underwent ECT at least six months prior to dTMS treatment, while three others also underwent dTMS at least six months prior to dTMS treatment (Table 2). The participants’ ages ranged from 24 to 63 years (46+12.1). Average age of depressive disorder onset was 31.5+14 years. Average length of depressive episodes prior to the first treatment was 10.7 + 10.2 months. Kellner et al. (26) defined relapse as a patient’s HDRS-24 total score of

Table 1. Demographic Data Length of depressive episode prior to Number of the first treatment depressive Antidepressants (months) episodes during treatment

Number Number of of daily maintenance treatments treatments

Relapse

Follow-up time points : Time elapsed between last treatment and relapse/evaluation (months)

no relapse

6 11.67

Age Sex

Age of depressive disorder onset

female

many

male

many

no relapse

female

many

Trazodone

relapse 13.8 (hospitalized)

female

Citalopram, Lamotrigine

relapse 1 (hospitalized)

male

Mianserin

relapse

7.7

male

0.5

many

Paroxetine

relapse

11.8

male

relapse

10.3

female

many

Trazodone

no relapse

7.3

male

many

Escitalopram

no relapse

14.5

female

no relapse

27.4

male

no relapse

6.8

male

relapse

male

no relapse

female

many

Escitalopram

no relapse

female

many

relapse

10.8

male

Escitalopram

relapse

1.5

male

many

relapse

9.5

Long-term Follow-up of MDD Patients Who Respond to Deep rTMS Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

Statistical analysis

Table 2. Brain Stimulation History of Six Patients Patient No.1

Patient underwent ECT 3 years prior to present depressive episode with mild improvement and severe amnesia

Relapsed

Patient No.2

Patient underwent 2 ECT courses the last being one year before enrollment. Patient did not improve after the last ECT.

No relapse

Patient No.3

Patient underwent 2 ECT courses which were partially successful

No relapse

Patient No.4

Patient underwent one deep TMS course six months before enrollment, with partial response (HDRS dropped from 30 to 21)

No relapse

Patient No.5

Patient underwent one deep TMS course one year before enrollment with remission (HDRS dropped from 27 to 1)

No relapse

Patient No.6

Patient underwent one deep TMS course one year before enrollment with response (HDRS dropped from 24 to 12)

No relapse

Results are presented as means +/- SD. Significance of differences in HDRS-24, HARS, and BDI scores between relapsed and non-relapsed patients was determined by repeated-measures ANOVA, followed by Fisherâ&#x20AC;&#x2122;s least significant difference post-hoc test. The effect of the number of treatment sessions, stimulation intensity, medication, and demographics on relapse was assessed by an unpaired two-tailed t-test. All analyses were done with Statistica 8.0. A p-value of less than 0.05 was considered statistically significant.

16 or higher in two consecutive ratings. Dannon et al. (1) defined relapse as a return of depressive symptomatology meeting DSM-IV criteria for MDD with an HDRS of 16 or more points. We have chosen to define relapse as an HDRS rating of 16 or more. In this article we report the results of one month to 27 months follow-up of depressive patients treated with dTMS. This is the first study evaluating the long-term outcome of dTMS in the treatment of depression.

Results All patients were followed during six months after treatment; some patients continued follow-up for up to 27 months. Mean follow-up period was 9.3 months At six months of follow-up time point treatment, only three out of 17 patients had relapsed (17.6%). During the extended follow-up, 9.3 months on average, nine patients relapsed and eight patients did non-relapse. The relapse rate was 5.6 per 100 person-months.

Deep TMS

Non-relapsed patients

DTMS treatment was performed with Brainswayâ&#x20AC;&#x2122;s H1 coil connected to a Magstim Rapid2 stimulator. High-frequency TMS sessions consisted of 42 trains of 20 Hz for two seconds, with inter-train interval (ITI) of 20 seconds (1,680 pulses in total). Treatment included 20 rTMS sessions on consecutive days and additional four weekly sessions. Technical information regarding the dTMS method and treatment procedure is detailed in a previous study (26). Evaluation of Long-term Efficacy

Seventeen patients who responded to the dTMS treatment were followed up for up to 27 months after treatment. Patients were evaluated using the same evaluation scales as those used for the evaluation at the active treatment sessions: the Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and the Beck Depression Inventory (BDI). Patient relapse was defined as follows: 1) HDRS score was 16 or more points at the follow-up period; 2) hospitalization due to depression exacerbation; and 3) any change in antidepressant medications including switching, augmentation, addition, and dosage escalation following a psychiatric evaluation; and 4) referral to ECT or any other neuro-stimulation treatment. 20

Eight patients (four males, four females, mean age 50.37+11.39) did not relapse during the follow-up period. Moreover, they continued to improve after the last treatment session (not statistically significant, P value>0.05). Those patients completed the DTMS treatment with HDRS average score of 9.37+4.17, average HARS of 8.1+4.9, and average BDI of 10.8+6.7. At the follow-up visit the HDRS score was 5.5+3.11, HARS score was 6+3.3, and BDI average score was 8.6+4.2. Of these eight patients, three (37.5%) were treated with antidepressants. Relapsed patients

Nine patients (six males, three females, mean age 42+11.9) relapsed. One patient was admitted for hospitalization due to depressive exacerbation one month after the last dTMS session. A second patient was admitted for hospitalization due to depressive exacerbation accompanied by suicidal ideation 13 months after the last dTMS session. A third patient was followed-up in an ambulatory clinic of Beer Yaakov and needed antidepressant replacement due to depressive exacerbation six months after the last dTMS session. The remaining six patients relapsed according to the HDRS score. Even though the end of treatment

Oded Rosenberg et al.

effect was not kept, they had a better HDRS score at the follow-up compared to their pre-treatment HDRS. Those remaining six patients had an average HDRS score of 27.17+3.19 before treatment, completed the dTMS treatment with an HDRS average score of 5.7 +5.8, an average HARS of 6.3 +5.57, and an average BDI of 10.3+8. At the follow-up visit the HDRS score was 21.5 +4.3, HARS score was 18.3 +7, and BDI average score of 25.5 +6.8. Paired t-test for the HDRS score at the followup compared to HDRS score before treatment revealed a significant lower HDRS score with P value 0.019. Of the nine patients that relapsed, five (55.5%) were treated with antidepressants.

Figure 1. Effects of deep rTMS treatment and relapse on HDRS (A), BDI (B) and HARS (C) before treatment, after treatment and at follow-up. Data are presented as mean Âą SD

Comparison of the Two Groups HDRS-24

Repeated-measures ANOVA with group (relapsed versus non-relapsed) as between-subjects factor and time points (before treatment, immediately after treatment, and at follow-up) as within-subjects factor revealed a significant main effect of group (F[1,15]=10.6, p=0.005), time (F[2, 15]=124, p<0.001), and interaction (F[2,15]=35.5, p<0.001) (Figure 1A). Post-hoc analysis showed that HDRS-24 in relapsed patients differed from patients that did not relapse only at the follow-up (p<0.001), but not before and after dTMS treatment. BDI

Repeated-measures ANOVA with group as betweensubjects factor and time points as within-subjects factor revealed a significant main effect of group (F[1,15]=4.96, p=0.042), time (F[2, 15]=63.15, p<0.001), and interaction (F[2,15]=26.97, p<0.001) (Figure 1B). Post-hoc analysis showed that BDI in relapsed patients differed from patients that did not relapse only at the follow-up (p<0.001), but not before and after dTMS treatment. HARS Repeated-measures ANOVA with group as betweensubjects factor and time points as within-subjects factor revealed a significant main effect of time (F[2, 15]=45.08, p<0.001) and interaction (F[2,15]=18.63, p<0.001), but not of group (Figure 1C). Post-hoc analysis showed that HARS in relapsed patients was lower than in those that did not relapse before treatment (p=0.044) and became higher at the follow-up (p<0.001). Comparison of Other Parameters

Differences between the two groups were measured in all optional predictive values (see Table 1).

* p<0.05, *** p<0.001 as compared between relapsed and not relapsed patients at specific time points.

The number of treatment sessions (t:[15]=1.17, NS, Figure 2A) and stimulation intensity (t:[15]=0.5, NS, Figure 2B) were not different between relapsed and nonrelapsed patients. Other parameters such as age, age of depressive disorder onset, length of depressive episode prior to the first treatment (months), and number of depressive episodes were also not significantly different between relapsed and non-relapsed patients. Discussion We followed 17 patients who were treated with Deep TMS for major depression and responded. The relapse rate in our study is comparable to other studies (21). We have found that the HDRS average score 21

Long-term Follow-up of MDD Patients Who Respond to Deep rTMS Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

Figure 2. Effects of number of treatment sessions (A), stimulation intensity (B) and medication (C) on relapse. Data are presented as mean ± SD. No significant differences between the groups

of relapsed patients six months (and even more) after dTMS treatment was lower than their pre-treatment average score. This result supports our theory in what regards the durability of dTMS effect. HDRS and BDI scores of patients who retained a non-relapsed state improved compared to their last evaluation at the end of treatment. Although the aforementioned improvement was not statistically significant and may be due to the small sample size, the fact that these patients did not relapse supports the assumption that dTMS effect is durable. Triggs et al. (28) conducted a prospective, randomized, sham-controlled, double blind, parallel group study of right or left pre-frontal rTMS in 48 subjects with medication-resistant depression. In both real and sham groups rTMS Hamilton depression scores continued to improve even three months following completion of rTMS (28). Hamilton depression scores’ long-term improvement following sham rTMS makes it difficult to decide whether TMS long-term anti-depressive effect is related to brain changes. Cohen et al. (29) identified the number of sessions as an independent predictor of long-term benefits. In our study, the number of sessions had no predictive value. We also found that HDRS or BDI scores at the end of treatment did not have a predictive value regarding efficacy persistence. Janicak et al. (21) reported on 99 major depressive patients treated with rTMS to the left dorsolateral prefrontal cortex. Of these, 77.8% had achieved full response or greater benefit (i.e., at least 50% or greater reduction of HAMD-17 total score from baseline), while 22.2% achieved partial response. Patients were tapered off rTMS over three weeks, simultaneously starting maintenance antidepressant mono-therapy. Relapse was the primary outcome measure, and was defined as a recurrence of full DSM-IV 22

criteria for major depression for two consecutive weeks. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of rTMS. Ten of 99 patients (10%) relapsed while 38 patients (38.4%) met the criteria for symptom worsening. patients with a more robust acute response to active rTMS were less likely to relapse or require rTMS reintroduction than those with a partial response. This fact contrasts with our results since we discovered no statistical differences in HDRS scores after dTMS treatment between relapsed and non-relapsed groups. Data on gender differences in depression relapse/recurrence are conflicting: Data on 2,541 participants enrolled in the STAR*D study show that men reported additional previous episodes (=higher rates of relapse) of major depression (30). In contrast, higher rates of relapse and recurrence for females have been reported (31, 32). In a co-morbidity survey, rates of relapse and chronicity were not associated with gender (33). In our study, six of ten (60%) males relapsed while three of seven (43%) women relapsed. Although our results are limited by the small sample size, they are in accordance with the STAR*D study. The mean age of relapsed patients was 42 while the mean age of patients staying in remission was 50. Cohen et al. (29) identified younger age as an independent predictor of long-term benefits. The difference that was shown in our study was not statistically significant and probably was caused by chance. Five of eight patients treated with medications relapsed (62%). Among the nine drug-free patients, four patients relapsed (44%). HDRS results at follow-up between antidepressant treated and non-treated patients showed that medication has no add-on effect on outcome. Schüle et al. (34) examined whether antidepressant pharmacotherapy can stabilize clinical improvement after rTMS mono-therapy in 26 drug-free patients suf-

Oded Rosenberg et al.

fering from a major depressive episode. They concluded that antidepressant pharmacotherapy is able to further improve the clinical response to rTMS and that responders to rTMS mono-therapy should receive subsequent psychopharmacological treatment without interruption in order to avoid a deterioration of symptoms. In our study there was no statistical difference between patients treated with dTMS as an add-on therapy to medications or treated by dTMS alone. In our study patients treated with medications were under medication prior to enrollment as well as during enrollment, while in the aforementioned study, medications started after rTMS treatment. Fitzgerald et al. (35) reported 19 re-treated patients (16 diagnosed with major depression and three with Bipolar Disorder), who were previously treated with TMS. Patients were allocated either for left High Frequency rTMS, right Low Frequency rTMS, or a combination of both treatment modalities. The mean duration of time between first rTMS treatment and re-treatment was 10.5 +6.6 months. Seventeen of 19 patients were on antidepressant medication during re-treatment. In our study mean time to relapse was 8 +4.8 months ranging from one month to 13.8 months. Time to relapse is similar between both studies, although in the Fitzgerald et al. (35) study treatment was given using a figure of eight coil in different locations and frequencies while we applied 20 HZ stimulation frequency using a deep TMS H1-coil. Dannon et al. (1) reported mean time to relapse of 6.9 +4.8 months in four patients previously treated successfully with 10HZ (figure of eight coil) to the dorsolateral prefrontal cortex. Two of these patients were on antidepressant medication (1). In our study, nine patients relapsed, with mean time to relapse being 8 +4.8 months ranging from one month to 13.8 months. Demirtas-Tatlidede et al. (36) reported 16 patients who were treated repeatedly (a mean of four treatment courses) with ten sessions of 10 HZ rTMS to the left dorsolateral prefrontal cortex. Patients were treated repeatedly with rTMS when HAM-D score was equal approximately to previous pretreatment scores (often well beyond 18 points). Mean interval between treatments was 4.9 +3.8 months. Fifty percent of patients in this study were medication-free (36). Although time length to relapse cannot be compared between this study and our own because of multiple courses given in the first, a durability effect of rTMS may be concluded. Data from 172 remitted recurrently depressed patients over a 5.5-year follow-up period disclosed a number of previous episodes to be predictive of future depressive

episodes (37). Four of the nine (44%) relapsed patients and five of the eight (62%) staying in a non-relapsed state had many (10>) depressive episodes. This apparent discrepancy may be explained by the small sample size of our study. Depression is unlikely to be a disease of a single brain region or neurotransmitter system, but rather a system level disorder, affecting integrated pathways. One system in particular receiving much attention in the study of depression is the reward circuit, whose main component is the mesolimbic dopaminergic pathway. Treating depression with direct stimulation of deeper regions might be more effective than the superficial TMS treatment. In dTMS treatment effects, deeper layers of the prefrontal cortex are interconnected with reward-related brain sites such as the ventral striatum and the ventral tegmental area. The studyâ&#x20AC;&#x2122;s limitation is the relatively small sample size, patients differ in follow-up periods, the uncertainty regarding unreported depressive episodes in-between treatment termination and long-term evaluation, lack of control group (treatment as usual group) , non-blinded naturalistic design, mix of medicated and not medicated subjects, lack of direct comparative studies and the variance in number of treatment sessions. Conclusion DTMS relapse rates are at least comparable to other methods of major depression treatment. Moreover, treatment effect is durable and maintained even in relapsed patients in the sense that their level of depression is lower than prior to treatment. Medication treatment does not have an add-on effect to dTMS treatments in regard to relapse prevention. No measure or demographic data may be used to predict the propensity of dTMS treatment successes in a depressed patient. Further studies are required in order to establish dTMS as first line treatment for treatment resistant depression, either as an adjunct to pharmacotherapy or as a sole treatment. References 1. Dannon PN, Dolberg OT, Schreiber S, Grunhaus L. Three- and six-month outcomes following courses of either ECT or rTMS in a population of severely depressed individuals - preliminary report. Biol Psychiatry 2002;51:687-690. 2. Dunner DL, Rush AJ, Russell JM, Burke M, Woodard S, Wingard P, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry 2006;67:688-695. 3. Rosa MA, Gattaz WF, Pascual-Leone A, Fregni F, Rosa MO, Rumi DO, et al. Comparison of repetitive transcranial magnetic stimulation and electroconvulsive therapy in unipolar non-psychotic refractory depression: A randomized, single-blind study. Int J Neuropsychopharmacol 2006;9:667-676.

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4. Wilkinson P, Alder N, Juszczak E, Matthews H, Merritt C, Montgomery H, et al. A pilot randomized controlled trial of a brief cognitive behavioural group intervention to reduce recurrence rates in late life depression. Int J Geriatr Psychiatry 2009;24:68-75. 5. Yiend J, Paykel E, Merritt R, Lester K, Doll H, Burns T. Term outcome of primary care depression. J Affect Disord 2009;118:79-86. 6. Angst J, Preisig M. Course of a clinical cohort of unipolar bipolar and schizoaffective patients. Results of a prospective study from 1959 to 1985. Schweiz Arch Neurol Psychiatr 1995;146:5-16. 7. Kennedy N, Abbott R, Paykel ES. Remission and recurrence of depression in the maintenance era: Long-term outcome in a Cambridge cohort. Psychol Med 2003;33:827-838. 8. Kiloh LG, Andrews G, Neilson M. The long-term outcome of depressive illness. Br J Psychiatry 1988;153:752-757. 9. Lee AS, Murray RM. The long-term outcome of Maudsley depressives. Br J Psychiatry 1988;153:741-751. 10. Bockting CL, Schene AH, Spinhoven P, Koeter MW, Wouters LF, Huyser J, Kamphuis JH. Preventing relapse/recurrence in recurrent depression with cognitive therapy: A randomized controlled trial. J Consult Clin Psychol 2005;73:647-657. 11. Medda P, Perugi G, Zanello S, Ciuffa M, Cassano GB. Response to ECT in bipolar I, bipolar II and unipolar depression. J Affect Disord 2009;118:55-59. 12. Levkovitz Y, Harel EV, Roth Y, Braw Y, Most D, Katz LN, et al. Deep transcarnial magnetic stimulation over the prefrontal cortex: Evaluation of antidepressants and cognitive effects in depressive patients. Brain Stimul 2009;2:188-200. 13. Wijkstra J, Nolen WA, Algra A, van Vliet IM, Kahn RS. Relapse prevention in major depressive disorder after successful ECT: A literature review and a naturalistic case series. Acta Psychiatr Scand 2000;102:454-460. 14. Sackeim HA, Haskett RF, Mulsant BH, Thase ME, Mann JJ, Pettinati HM, et al. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: A randomized controlled trial. JAMA 2001;285:1299-1307. 15. Eranti S, Mogg A, Pluck G, Landau S, Purvis R, Brown RG, et al. A randomized, controlled trial with 6-month follow-up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression. Am J Psychiatry 2007;164:73-81. 16. Grunhaus L, Dannon PN, Schreiber S, Dolberg OH, Amiaz R, Ziv R, et al. Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: An open study. Biol Psychiatry 2000;47:314-324. 17. Pridmore S, Bruno R, Turnier-Shea Y, Reid P, Rybak M. Comparison of unlimited numbers of rapid transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major depressive episode. Int J Neuropsychopharmacol 2000;3:129-134. 18. Janicak PG, Dowd SM, Martis B, Alam D, Beedle D, Krasuski J, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: Preliminary results of a randomized trial. Biol Psychiatry 2002;51:659-667. 19. O’Connor M, Brenninkmeyer C, Morgan A, Bloomingdale K, Thall M, Vasile R, et al. Relative effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy on mood and memory: A neurocognitive risk-benefit analysis. Cogn Behav Neurol 2003;16:118-127. 20. Schulze-Rauschenbach SC, Harms U, Schlaepfer TE, Maier W, Falkai P, Wagner M, et al. Distinctive neurocognitive effects of repetitive transcranial magnetic stimulation and electroconvulsive therapy in major depression. Br J Psychiatry 2005;186:410-416. 21. Janicak PG, Nahas Z, Lisanby SH, Solvason HB, Sampson SM, McDonald WM, et al. Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: Assessment of relapse during a 6-month, multisite, openlabel study. Brain Stimul 2010; 3:187-199.

22. Isserles M, Rosenberg O, Dannon P, Levkovitz Y, Kotler M, Deutsch F, et al. Cognitive-emotional reactivation during deep transcranial magnetic stimulation over the prefrontal cortex of depressive patients affects antidepressant outcome. J Affect Disord 2011;128:235-242. 23. Rosenberg O, Shoenfeld N, Zangen A, Kotler M, Dannon PN. Deep TMS in a resistant major depressive disorder: A brief report. Depress Anxiety 2010; 27:465-469. 24. Rosenberg O, Zangen A, Stryjer R, Kotler M, Dannon PN. Response to deep TMS in depressive patients with previous electroconvulsive treatment. Brain Stimul 2010;3:211-217 25. Rosenberg O, Isserles M, Levkovitz Y, Kotler M, Zangen A, Dannon PN, et al. Effectiveness of a second deep TMS in depression: A brief report. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:1041-1044. 26. Kellner CH, Knapp RG, Petrides G, Rummans TA, Husain MM, Rasmussen K, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: A multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry 2006;63:1337-1344. 27. Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder: Remission, recovery, relapse and recurrence. Arch Gen Psychiatry 1991;48:851-865. 28. Triggs WJ, Ricciuti N, Ward HE, Cheng J, Bowers D, Goodman WK, et al. Right and left dorsolateral pre-frontal rTMS treatment of refractory depression: A randomized, sham-controlled trial. Psychiatry Res 2010; 178:467-474. 29. Cohen RB, Boggio PS, Fregni F. Risk factors for relapse after remission with repetitive transcranial magnetic stimulation for the treatment of depression. Depress Anxiety 2009;26:682-688 30. Marcus SM, Kerber KB, Rush AJ, Wisniewski SR, Nierenberg A, Balasubramani GK, et al. Gender differences in depression symptoms in treatment-seeking adults: STAR*D Confirmatory Analyses. Compr Psychiatry 2008;49:238-246. 31. Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W, et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Am J Psychiatry 1999;156:1000-1006. 32. Bracke P. Sex differences in the course of depression: Evidence from a longitudinal study of a representative sample of the Belgian population. Soc Psychiatry Psychiatr Epidemiol 1998;33:420-429. 33. Kessler RC, McGonagle KA, Swartz M ,Blazer DG,Nelson CB. Sex and depression in the national comorbidity survey I: Lifetime prevalence, chronicity and recurrence. J Affec Dis 1993;29:85-96. 34. Schüle C, Zwanzger P, Baghai T, Mikhaiel P, Thoma H, Möller HJ, et al. Effects of antidepressant pharmacotherapy after repetitive transcranial magnetic stimulation in major depression: An open follow-up study. J Psychiatr Res 2003;37:145-153. 35. Fitzgerald PB, Benitez J, de Castella AR, Brown TL, Daskalakis ZJ, Kulkarni J. Naturalistic study of the use of transcranial magnetic stimulation in the treatment of depressive relapse. Aust N Z J Psychiatry 2006;40:764-768. 36. Demirtas-Tatlidede A, Mechanic-Hamilton D, Press DZ, Pearlman C, Stern WM, Thall M, et al. An open-label, prospective study of repetitive transcranial magnetic stimulation (rTMS) in the long-term treatment of refractory depression: Reproducibility and duration of the antidepressant effect in medication-free patients. J Clin Psychiatry 2008;69:930-934. 37. Doesschate MC, Bockting CL, Koeter MW, Schene AH. Prediction of recurrence in recurrent depression: A 5.5-year prospective study. J Clin Psychiatry 2010;71:984-991.

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Suicides Among Persons with Psychiatric Hospitalizations Nehama Goldberger, MSc,1 Ziona Haklai, MA,1 Inna Pugachova, MPH,2 and Itzhak Levav, MD, MSc3 1

Health Information Division, Ministry of Health, Jerusalem, Israel Department of Information and Evaluation, Mental Health Services, Ministry of Health, Jerusalem, Israel 3 Department of Community Mental Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Israel 2

Abstract Background: Persons with severe mental disorders have higher suicide rates than the general population. Their risk profile needs to be fully explored to better guide suicide preventive efforts. Downsizing the number of beds in psychiatric hospitals and high bed turnover may also affect the suicide risk. Objectives: To investigate 1) Suicide rates among persons who were ever hospitalized in psychiatric facilities compared to the general population, 2) Associated sociodemographic and psychiatric factors, 3) Changes in rate over time, and 4) Timing of suicide deaths. Methods: We linked the National Psychiatric Case Register (NPCR) with the national database on causes of death. Suicides in the years 1981-2009 were analyzed for the study group of Israelis aged 18 and over ever hospitalized (N= 158,800). Analysis: Suicide rates were computed by age, gender, psychiatric diagnosis and year of death, as well as agestandardized rates and rate ratios (RR) for persons in the NPCR compared with those never hospitalized. The proportion of suicides committed by the ever hospitalized from all suicides in the population was calculated. Standardized mortality ratios (SMR) for suicide were computed for the ever hospitalized based on the total suicide rates of the population. A multivariate logistic model investigated risk factors associated with suicide in the ever-hospitalized population. Results: The age-standardized suicide rate of Jews and Others with a psychiatric hospitalization was 17.6

times higher than that of the non-hospitalized (95% CI 16.7â&#x20AC;&#x201C;18.6) and 29.7 times higher for Arabs (95% CI 23.437.9). The rates were higher among females and younger persons. In the years 2007-2009, 30% of all suicides of Jews and Others were committed by persons who had been hospitalized in psychiatric facilities. The SMRs of Jews and Others, which increased at the beginning of the study period, fell steadily until 1995. In recent years they have been rising since 2000 and 2005 among females and males, respectively. One fifth (19%) of suicides of Jews and Others occurred before or on the discharge day, and another 6% and 7% within a week and between a week and a month after discharge, respectively. Logistic analysis showed significantly higher suicide risk for males, those who attempted suicide before hospitalization, persons under age 65 and Ethiopian immigrants. Suicide risk increased with number of hospitalizations. Conclusion: This study highlights the importance of suicide prevention interventions for persons both during their inpatient stay and who were expected to be followed up in community-based facilities.

In Israel, suicide rates are lower than in many other countries with reliable recording systems (1). Several explanations have been raised to account for this. Firstly, there is a strict religious prohibition to take oneâ&#x20AC;&#x2122;s life among both Muslims and Jews. Secondly, in general, Israeli society tends to be supportive, with warm and extended family ties, as well as support on the community level. (However, this support may be lesser in the case

Address for Correspondence: N Goldberger, Division of Health Information, Ministry of Health, 39 Yirmiyahu Street, Jerusalem 94467, Israel â&#x20AC;&#x2020; nehama.goldberger@moh.health.gov.il

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of recent immigrants [2]). Further factors contributing to the lower risk may be easy and free of charge access to a wide network of psychiatric facilities (3) and the availability of a hotline around the clock for individuals facing severe life crises. Studies in several countries have shown suicide risk to be much higher among persons with a severe psychiatric disorder (4-12). Our first research question is in view of the above protective factors, to what extent this is the case in Israel. In addition, psychiatric care policy has changed favoring deinstitutionalization, leading to a reduction in the number of psychiatric beds and the average length of stay for psychiatric hospitalizations (13). As a result, the rate of first admissions has fallen in recent years (13, 14). At the end of 1999, 57% of persons hospitalized had stayed for over a year compared to 35% in 2009 (13). Hospitalization rates have decreased in particular among females, as can be seen from the rate ratio of males to females in hospital at the end of 2001 of 1.60 compared to 1.97 at the end of 2009 (13). This reduced psychiatric hospital inpatient care has been compensated for by advancing communitybased trearment and rehabilitation care (15). Our second research question is whether these policy measures have had an impact on the suicide risk of persons with severe psychiatric disorders, particularly females for whom the decrease in hospitalization has been greatest. Several researchers in different countries, among them, Goldacre et al. in the U.K. (5) and Ho in Hong Kong (9) have noted that the suicide risk is particularly high in the post-discharge period. Our study also looked at the timing of suicides among persons with a psychiatric hospitalization. Israel has several facilities that enable investigating these research questions. There is a nation-wide psychiatric register that is maintained by law (16), an updated register of causes of death (17), and yearly estimates of the general population (17). Objectives Our objective was to investigate the suicide rates among Jewish and Other Israelis aged 18 and over who were ever hospitalized in psychiatric facilities in Israel by age, gender, and psychiatric diagnosis, and compare them to the non-hospitalized. We also investigated the corresponding rates among the Israeli Arab population group, the timing of the suicide (before or after discharge) and changes in risk over the years 1981-2009, cover26

ing the periods before and after the implementation of deinstitutionalization policies. Methods We used the national psychiatric case register (NPCR) to identify Israeli Jews and Others (Others is a group comprising non-Jewish Israelis who are also not Arabs, many of whom are immigrants from the Former Soviet Union) and Israeli Arabs over the age of 18 who were ever admitted to psychiatric inpatient facilities from the beginning of the NPCR (in the early 1950s) and every year henceforth until the end of 2009. The NPCR cumulatively enters all admissions and discharges to psychiatric inpatient facilities using a unique identification number. It is a reasonable assumption that all or most Jews and Others with a severe psychiatric disorder were hospitalized (particularly in the early years of the study when the supply of beds was relatively high). In contrast, the Arab minority groups, particularly women, use the psychiatric inpatient facilities considerably less (6). Therefore, the latter group was not included in the detailed analysis, but we calculated their overall rates for comparison. The NPCR includes the respective dates and diagnoses made by a psychiatrist upon admission and discharge, demographics, whether there was a suicide attempt preceding admission, and other relevant information. Diagnoses are recorded according to the 10th version of the International Classification of Diseases (ICD-10), while those made according to earlier classifications have been updated. We grouped the subjects by psychiatric diagnosis at discharge from the last hospitalization, or at admission if this was not available. This gives higher diagnostic reliability following a longer period of observation. The nationwide database of causes of death, maintained by the Central Bureau of Statistics (CBS), for the years 1981-2009, was linked to our follow up group of persons who ever had a psychiatric hospitalization between the beginning of the NPCR in the early 1950s and the end of 2009 (and who were alive at the beginning of 1981 for those hospitalized earlier). Hospitalization data including dates and diagnosis for the first and last admission were added to the cause of death file. Causes of death were coded according to the 9th version of the International Classification of Diseases (ICD-9) for 1981 to 1997 and according to the 10th version since 1998. Rates were calculated using the denominators, of total population of Jews and Others and Arabs for each year by age and gender, obtained from CBS data, and the total

Nehama Goldberger et al.

cumulative number of persons ever hospitalized for each year by gender, age and psychiatric diagnosis calculated from the NPCR. Suicide was defined as ICD-9 codes E950-E959 or ICD-10 codes X60-X84, Y870. Psychiatric diagnoses were grouped as follows: all non-affective psychotic disorders (including schizophrenia) (F20-F29); affective disorders (F30-F39); drug and alcohol addiction (F10-F19); organic brain disorders (F00–F09, G40); and others (F40-F99, Z03, Z032, Z04, Z046). The risk-period of suicide was grouped as follows: before or on the day of discharge; and for those following discharge, within first week, one week to one month, two to three months, over three months to a year, and over a year. Time to suicide was calculated as the difference between the date of death and of the last discharge Analysis Gender, age-specific, and age-standardized suicide rates were calculated using the direct method based on the 1996 total population of Jews and Others aged 18 and over for persons ever hospitalized in psychiatric facilities (hospitalized) and for those never hospitalized (non-hospitalized), and corresponding age standardized rates for Arabs. Rate ratios (RR) and their respective 95% confidence intervals (CI) were calculated, Indirect standardization was also used to calculate standardized mortality ratios (SMRs) by gender and year, by dividing observed suicides by expected suicides predicted by the rates in the total population of Jews and Others in four age groups (18-24, 25-44, 45-64, 65+) used as standard population. This enabled comparison with

SMR’s published in the literature (7, 8). The proportion of the hospitalized from all suicides of Jews and Others was calculated, for total suicides and different age groups. Multivariate logistic regression analysis was used to predict risk of suicide between 1981 and 2009 among hospitalized persons by age and psychiatric diagnosis at last discharge, gender, immigrant status, number of psychiatric hospitalizations, suicide attempt prior to the last hospitalization and length of follow-up. Ethical safeguards

Confidentiality was strictly assured since the authors who analyzed the data had no access to the identity of the persons linked by the databases. RESULTS Characteristics of hospitalized population

There were 146,500 Jews and Others aged 18 and over (53% males) who were ever admitted from the 1950s until the end of 2009, and were alive at the beginning of 1981 for those hospitalized earlier, and 13,400 corresponding Arabs (70% males). The total person-years of follow-up for both groups was 2,294,932. The accumulated number of suicides for this “hospitalized” group during the years 1981-2009 was 2,650 (2,541 Jews and Others and 109 Arabs) and for the “non-hospitalized” remainder of the population was 6,867 (6,450 Jews and Others and 417 Arabs). The distribution of the study population of the hospitalized Jews and Others by age and psychiatric diagnoses at last discharge is shown in Table 1. Diagnoses of organic

Table 1. Jews and Others aged 18 and over ever hospitalized in psychiatric facilities by gender, age and psychiatric diagnosis at discharge, 1981-2009 (%) Age/Psychiatric diagnosis at discharge

Organic disorders

Drug and alcohol addiction

Non-affective psychotic disorders

Affective disorders

Other disorders

Unknown

Total

Males (n= 77,700)

All

18-44 45-64 65+ Total

57.0 28.1 14.9 100.0

2.6 7.1 34.1 8.6

7.7 8.4 2.5 7.1

48.5 45.3 28.2 44.6

8.7 19.1 25.1 14.1

30.4 18.8 9.6 24.0

2.1 1.3 0.6 1.7

100.0 100.0 100.0 100.0

43.6 30.3 26.1 100.0

2.4 4.8 28.8 10.0

2.3 1.3 0.7 1.6

46.2 48.5 28.9 42.4

17.0 29.9 33.3 25.1

29.3 13.9 7.8 19.0

2.9 1.7 0.6 1.9

100.0 100.0 100.0 100.0

50.7 29.1 20.2 100.0

2.5 5.9 30.9 9.2

5.5 5.0 1.4 4.5

47.6 46.9 28.6 43.5

12.0 24.3 30.1 19.3

29.9 16.4 8.5 21.7

2.4 1.5 0.6 1.8

100.0 100.0 100.0 100.0

Females (n= 68, 800) 18-44 45-64 65+ Total Total (N= 146,500) 18-44 45-64 65+ Total

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and affective disorders were more prevalent at age 65 and over (31% and 30%, respectively, compared to 3% and 12%, respectively, at ages 18-44), while the diagnosis of non-affective psychotic disorders was more prevalent at younger ages. The percent of women diagnosed with drug and alcohol addiction (2%) was lower than of men (7%), but higher for affective disorders (women, 25%; men, 14%). The age of women at discharge was higher than of men (44% of them were aged 18-44 compared to 57.0% for men). Females had shorter total hospital stays. Among persons admitted between 1981 and 2009, the average cumulative hospitalization days were 25% higher for males than for the females. Suicide rates by age, gender and psychiatric diagnosis, 1981-2009

The age-adjusted suicide rate of the hospitalized group of Jews and Others for the period 1981-2009 was 131.4 (95% CI 125.4-137.4) per 100,000 persons, and of the Arabs was 68.6 (95% CI 53.8-83.4). Male rates were 158.7 (95% CI 150.1-167.2) for Jews and Others and 78.8 (95% CI 61.3-99.8) for Arabs, and females rates were 98.9 (95% CI 90.5-97.2) and 39.7 (95% CI 22.2-65.5), respectively. The age-adjusted suicide rate of the hospitalized group of Jews and Others was 17.6 times that of the non-hospitalized (95% CI 16.7-18.6), with male rate ratios (RR) of 13.1 (95% CI 12.3-13.9), and for females, 30.9 (95% CI 28.0-34.1). The age-specific RR were similarly higher, ranging from 6.5 (95% CI 5.9-7.3), for those aged 65 and over, to 25.9 (95% CI 24.3-27.7), for ages 18-44 (Table 2). The RRs

were even higher among females, reaching 57.1 (95% CI 50.0-65.2) for the 18-44 age group. The corresponding rate ratio for the total Israeli Arab population was 29.7 (95% CI 23.4-37.9). For males it was 20.6 (95% CI 15.8-26.9) and for females 50.2 (95% CI 28.6-88.1). Persons with affective disorders had the highest ageadjusted rates, followed by those with drug and alcohol addictions, who also had highest rates for those aged 18-44. The SMRs for suicide for Jews and Others for the study period, which represent an age-standardized comparison of hospitalized rates to those of the total population, were 9.6 (95% CI 9.1-10.0) and 14.7 (95% CI 13.7-15.7) for males and females, and for Arabs they were15.4 (95% CI 12.2-18.6) and 36.0 (95% CI 20.2-51.8), respectively. Changes in suicides over time, 1981-2009

Figure 1 shows the SMRs for suicides of Jews and Others by gender and by year. After an initial increase at the beginning of the 1980s, the SMR decreased for both genders. For males, the decrease was steep until 1992. It remained relatively stable until 2004, and then rose steadily until 2009. The SMR for females decreased more gradually until 2000, but then increased sharply until 2003, after which it remained high and relatively stable until 2009. Similar trends to the SMR were found in the proportion of suicides of the hospitalized group as shown in Figure 2. In 2007-2009, 30% of all suicides of Jews and Others were by hospitalized persons. The proportion was higher in the early 1980s, about 40%, decreasing steadily to 23% in

Table 2. Age-adjusted suicide rates by age, gender and psychiatric diagnoses for Jews and Others aged 18 and over who ever had a psychiatric hospitalization, and for the non-hospitalized, 1981-2009. Rates per 100,000 persons Psychiatric diagnosis at discharge Age group

Organic disorders

Drug or alcohol addictions

Non-affective psychotic disorders

Affective disorders

Other disorders

All psychiatric diagnoses

Nonhospitalized

Rate ratio1

Male

18-44 45-64 65+ Total2

88.4 109.6 124.0 100.0

215.0 135.9 79.3 171.2

202.9 113.5 73.2 157.4

210.3 250.2 258.1 228.9

118.7 94.8 107.4 110.4

175.0 125.2 133.1 158.7

9.6 11.2 22.2 12.1

18.2 11.2 6.0 13.1

Female

18-44 45-64 65+ Total2

80.2 55.8 42.0 67.3

64.9 22.7 60.6 52.9

123.1 67.8 42.8 94.9

135.9 115.1 97.6 124.0

85.8 62.9 82.8 79.2

111.8 74.8 67.2 98.9

2.0 2.9 7.8 3.2

57.1 25.4 8.6 30.9

Total

18-44 45-64 65+ Total2

85.5 85.2 74.4 83.6

189.6 119.4 76.0 151.8

170.9 90.6 54.2 129.9

168.5 165.3 146.3 163.9

106.4 82.0 94.7 98.0

149.7 100.7 92.3 131.4

5.8 6.8 14.1 7.5

25.9 14.7 6.5 17.6

Gender

1 2

Rate ratio: all hospitalized: non-hospitalized. Age-adjusted rate.

Nehama Goldberger et al.

Figure 1. Standardized mortality ratios (SMR) for suicide of Jews and Others aged 18 and over ever hospitalized in psychiatric facilities by gender, 1981-2009

Figure 3. Proportion of persons ever hospitalized in psychiatric facilities from all suicides of the population group Jews and Others by age groups and year in the period 1981-2009

Figure 4. Time from inpatient discharge until suicide: Proportion of all suicides by age at death for Jews and Others aged 18 and over, 1981-2009 Figure 2. Proportion of persons ever hospitalized in psychiatric facilities from all suicides of Jews and Others by gender, 1981-2009

1994. The proportion remained relatively stable until 2004. However, between 2004 and 2009 the proportion rose. Among females, the proportion was higher, and increased between 2000 and 2007 to 37% of all female suicides. Figure 3 shows the proportion of suicides of the hospitalized group by age and year. Among those aged 25-44, the proportion reached 39% in 2007-2009, and was about 35% for those aged 45-64 since 2006. It had been much higher in the early 1980s (over 50% for ages 25-44, and about 44% for ages 45-64), decreasing to about 30% and 24%, respectively, in the early 1990s. The proportion increased afterwards. Among the youngest age group, 18-24, the proportion also decreased from a high of 33% in the early 1980s to 13% in 1991-1996, but then increased steadily reaching 20% in 2007-2009. Among those over 65 years old, the proportion decreased slightly over the total period from 20% to 15%. Time from discharge until suicide

About a fifth (19%) of all suicides occurred in hospital or on the day of discharge, while 6% took place dur-

ing the following week, and a further 7% until a month after discharge. Among the younger age group, 18-44, the proportions were still higher, 23%, 6% and 8.5%, respectively (Figure 4). Selected factors associated with suicide in the hospitalized group

The logistic regression results are shown in Table 3. Males have a higher suicide risk than females. The risk was higher for relatively younger persons at last discharge; aged 18-64 compared to those aged 65 or over, in particular for those aged 25-64. Immigrants from the Former Soviet Union (FSU) and other countries were found to have a lower risk than non-immigrants, except for Ethiopian immigrants who were at a higher risk. Psychiatric diagnosis of affective disorder was associated with highest risk, followed by nonaffective psychotic disorders and addictions. Suicide risk increased with number of hospitalizations while a suicide attempt reported within two months of last admission was also a risk factor. The risk decreased with length of time in follow-up. 29

Among Persons with Psychiatric Hospitalizations Isr J Psychiatry Relat Sci - Vol. Suicides 52 - No 1 (2015)

Table 3. Multivariate logistic regression model: Predicting suicide among Jews and Others aged 18 and over ever hospitalized in psychiatric facilities, 1981-2009 Odds ratio (95% CI)

Effect Males vs. females Immigrant status:

1.65** (1.51-1.80) Immigrants1 from FSU vs. nonimmigrants2

0.58** (0.51-0.66)

Immigrants1 from Ethiopia vs. non-immigrants2

1.36* (1.06-1.75)

Immigrants1 from other countries vs. non-immigrants2

0.47** (0.35-0.62)

Drug and alcohol addiction vs. organic disorders

2.17** (1.60-2.95)

Non-affective psychotic disorders vs. organic disorders

3.73** (2.92-4.76)

Affective disorders vs. organic disorders

4.16** (3.27-5.31)

Other disorders vs. organic disorders

2.58** (2.00-3.32)

Age at last discharge3:

18-24 vs. 65+

1.45** (1.22-1.72)

25-44 vs. 65+

1.70** (1.47-1.96)

45-64 vs. 65+

1.72** (1.49-1.98)

Number of hospitalizations:

2-3 vs. 1

1.79** (1.61-2.00)

4-6 vs. 1

2.81** (2.48-3.18)

6-9 vs. 1

3.56** (3.02-4.21)

10+ vs 1

4.84** (4.16-5.63)

Psychiatric diagnoses:

Suicide attempt4 vs. no attempt

1.84** (1.66-2.04)

Length of follow up

0.90** (0.90-0.91)

C statistic

0.80

130,712

P value: * <0.05 ** < 0.001 1 Immigrants since 1981. 2 Born in Israel or immigrated before 1981. 3 Last discharge from psychiatric hospitalization. 4 Previous suicide attempt reported within two months of last admission to psychiatric hospitalization. 5 Time in years calculated from first admission to psychiatric facilities till death or end of study (2009). 6 Persons with missing data for variables in the regression were omitted.

DISCUSSION As in other studies (7, 8), we found a much higher rate of suicides among persons with current or past psychiatric hospitalization, with higher rates for Jews and Others than Arabs, as is the case in the total population (1). However among Jews and Others the rates were 17.6 higher than those never hospitalized, while among Arabs the corresponding rates were about 30 times higher. Since, as noted, the Arabs use the psychiatric inpatient facilities considerably less than Jews and Others, it is likely that only those with more 30

severe disorders are hospitalized. This, in addition, to their considerably lower rates in the total population, may lead to their higher rate ratios and SMRs found in this study (1). The overall SMR for suicide for Jews and Others of 9.6 for males and 14.7 for females were similar to those reported in the review article by Harris and Barraclough (7) in the U.K., based on a follow up of inpatients. Even higher SMRs, 17.1, were reported in Denmark by Hoyer et al. (8) in persons diagnosed with affective disorders, and by Harris and Barraclough (7), in a review article. This risk we found is substantial. In 2007-2009, 30% of all suicides among Jews and Others were committed by persons with a previous psychiatric hospitalization, although they constitute only 2.4% of the total population. Thus, despite the factors mentioned in the introduction as contributing to the general low suicide rates in Israel, the rates among persons with current or past psychiatric hospitalization are much higher. As in other studies conducted elsewhere, such as the U.K. (5), Denmark (8), and Hong Kong (9), we found a high risk particularly during the hospital stay and shortly after discharge, with a third (32%) of all suicides occurring before or within a month after discharge. Our results showed decreasing SMR for suicide and proportion of suicides among persons ever hospitalized in the 1980s and early 1990s, which may reflect improved treatment and service options over this period. For example, in 1987, the first SSRI, Fluoxetine, was introduced in the market for major depression. And in 1989, following research that showed its effectiveness in treatment-resistant schizophrenia, the U.S. Food and Drug Administration approved the use of Clozapine, which although not widely used, may have contributed to suicide reduction. However, a steep increase followed in SMR for females, between 2000 and 2003. SMRs have remained high until 2009. The SMR has also been increasing among males, although less steeply, between 2004 and 2009. A similar trend was found in a Danish study (8), where authors also found an increase in suicide coinciding with a 50% decrease in available inpatient beds. The Danish authors suggested that as a result of reducing inpatient beds there could be competition for the remaining beds, leading to admission of more severely affected patients. It is possible that in Israel, too, only persons with more severe disorders may have been hospitalized in more recent years due to the decrease in both beds and length of stay over the period. As we noted in the introduction, the reduction in hospitalization was more marked among females, including shorter cumulative inpatient days for them. This may provide additional

Nehama Goldberger et al.

support to the above tentative hypothesis that in particular females with more severe disorders may have been admitted in later years, resulting in their markedly increased suicide risk in the corresponding years of the study period. As suggested by Rossau and Mortensen (6), the change from longer hospital stays to shorter ones may generate more frequent readmissions. This, in turn, would increase the number of transition periods between hospital to community-based care which, as others (5, 10, 11) have shown, and our data seem to support, are particularly high risk periods for suicides. Rossau and Mortensen (6) also reported a relatively large proportion of suicides during temporary leave of absence, also a transition time. The Ministry of Health has initiated preventive programs to reduce the suicide risk among vulnerable population groups. Persons whose psychiatric disorders required hospitalization should be included among these. Our analyses thus contribute to building a profile of the hospitalized persons at higher suicide risk: younger males, those with a reported previous suicide attempt and with diagnoses in this descending order affective disorders, non-affective psychotic disorders, and substance abuse. In addition, we found that the risk increases with number of hospitalizations, which could reflect a combination of factors: 1. those associated with the person such as the greater severity of the disorder, 2. the increased risk from frequent transitions and nonadherence to treatment, and 3. those associated with the psychiatric services, such as a gap in the required seamless move from the inpatient to outpatient care. The lower suicide risk for hospitalized persons who immigrated from the FSU is surprising, as in the general population they have higher suicide rates (2) and a comparatively lower hospitalization rate (18). An explanation for this finding is pending, although it may reflect hesitation in using inpatient services among these immigrants who experienced past abuse of psychiatry in the FSU (19). This study had some limitations. Only administrative data were used and not clinical data on treatments of the patients. Our data on timing of suicide were based on the date of discharge, but if the suicide was recorded as having taken place on the discharge date, it could have occurred following the discharge on the same day, while still in hospital, while the person was on leave or with the status of runaway, or in a general hospital where the person had been referred for specialized medical or surgical treatment. We could not differentiate between these possibilities with our data. This study did not analyze suicides among persons with

psychiatric disorders who were only treated in the community, and thus included among the “non-hospitalized.” It therefore cannot draw conclusions about all persons with psychiatric disorders, including hospitalized and nonhospitalized, and how the policy of deinstitutionalization has affected suicide rates among them. Further studies would be required to determine this. Conclusions Our findings indicate the continuing need for suicide prevention among persons ever admitted for psychiatric hospitalization as a very high risk group. Suicide reduction interventions are a challenge since the higher risk has been reported in countries with generally welldeveloped facilities and in addition, there is a lack of tested interventions. However, successful but limited preventive programs have been reported: The Veterans Administration in the U.S. developed a tested program that proved helpful in reducing suicides in inpatient facilities (20). Although not aimed at ever-hospitalized people but for outpatient facilities, a large health maintenance organization (HMO) succeeded to greatly reduce suicides among persons diagnosed with depression (21). A well-tailored preventive program would target first those with the highest profile risk, for example persons who had attempted suicide before admission. In this respect, our study confirms a recent one by Madsen et al. (12) who found that “recent suicide attempt before admission to the hospital was associated with the highest risk of inpatient suicide (HR = 4.99; 95% CI, 3.57-6.96).” Since suicides occurred both in hospital and after discharge, preventive programs need to be implemented both for inpatients and outpatients and, in particular, address the critical transition period between hospital and community-based facilities and between treatment and rehabilitation facilities. Meehan et al. stated “Prevention of suicide after discharge requires early community followup and closer supervision of high-risk patients” (11). Crawford, in a short but comprehensive review (10), noted that “in the absence of evidence, helping patients prepare for discharge by providing them with clear information about follow-up plans and crisis facilities, and helping them readjust to life at home through periods of leave from the ward would seem worthwhile.” In Israel, as elsewhere, the process of transfer from inpatient to outpatient care needs to be closely monitored. 31

Among Persons with Psychiatric Hospitalizations Isr J Psychiatry Relat Sci - Vol. Suicides 52 - No 1 (2015)

References 1. Goldberger N, Aburbeh M, Haklai Z. Suicidality in Israel. Ministry of Health, 2011. www.health.gov.il (Hebrew). 2. Mirsky J, Kohn R, Dolberg P, Levav I. Suicidal behaviour among immigrants. Soc Psychiatry Psychiatr Epidemiol 2011; 46: 1133-1141. 3. Levav I, Grinshpoon A. Mental health facilities in Israel. Int Psychiatry 2004; 4:10-14. 4. Appleby L. Suicide in psychiatric patients: Risk and prevention. Br J Psychiatry 1992; 161: 749-758. 5. Goldacre M, Seagroatt V, Hawton K. Suicide after discharge from psychiatric inpatient care. Lancet 1993; 342: 283-286. 6. Rossau CD, Mortensen PB. Risk factors for suicide in patients with schizophrenia: Nested case-control study. Br J Psychiatry 1997; 171: 355-359. 7. Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry 1998; 173: 11-53. 8. Hoyer EH, Mortensen PB, Olesen AV. Mortality and causes of death in a total national sample of patients with affective disorders admitted for the first time between 1973 and 1993. Br J Psychiatry 2000; 176: 76-82. 9. Ho TP. The suicide risk of discharged psychiatric patients. J Clin Psychiatry 2003;64: 702-707. 10. Crawford MJ. Suicide following discharge from in-patient psychiatric care. Adv Psych Treat 2004; 10:434-438. 11. Meehan J, Kapur N, Hunt IM, Turnbull P, Robinson J, Bickley H, Parsons R, Flynn S, Burns J, Amos T, Shaw J, Appleby L. Suicide in mental health in-patients and within 3 months of discharge. National clinical survey. Br J Psychiatry. 2006 ; 188:129-134.

12. Madsen T, Agerbo E, Mortensen PB, Nordentoft M. Predictors of psychiatric inpatient suicide: A national prospective register-based study. J Clin Psychiatry 2012; 73:144-151. 13. Ministry of Health. Inpatient institutions and day care units in Israel, Ministry of Health various years (Part 1, Mental health facilities). www. health.gov.il (Hebrew). 14. Ministry of Israel, Mental Health in Israel. Statistical annual 2008. Mental Health Facilities, Department of Information and Evaluation, Jerusalem, 2008. http://www.old.health.gov.il/pages/default.asp?PageI d=4714&catId=312&maincat=10 15. Lachman M, Hadass-Lidor N. Rehabilitation of persons with psychiatric disabilities in the community: From de-hospitalization to recovery and inclusion. Hadea Harovachat ICSW 2003; 35: 14-17 (Hebrew). 16. Lichtenberg P, Kaplan Z, Grinshpoon A, et al. The goals and limitations of Israelâ&#x20AC;&#x2122;s psychiatric case register. Psychiatr Serv 1999; 50, 1043-1048. 17. Central Bureau of Statistics, Statistical abstracts of Israel, years 19822010. Central Bureau of Statistics, Jerusalem, Israel. 18. Youngmann R, Pugachova I, Zilber N. Patterns of psychiatric hospitalization among Ethiopian and Former Soviet Union immigrants and persons born in Israel. Psych Serv 2009; 60: 1656-1663. 19. Levav I, Kohn R, Flaherty JA, Lerner Y. Mental health attitudes and practices of Soviet immigrants. Isr J Psychiatry 1990; 27:131-144. 20. Watts BV, Yinong Young-Xu Y, Mills PD, DeRosier JM, Kemp J, Shiner B, Duncan WE. Examination of the effectiveness of the mental health environment of care checklist in reducing suicide on inpatient mental health units. Arch Gen Psychiatry 2012; 69:588-592. 21. Hampton T. Depression care effort brings dramatic drop in large HMO populationâ&#x20AC;&#x2122;s suicide rate. JAMA 2010; 303: 1903-1905.

Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

Raz Gross et al.

Validation of the Hebrew and Arabic Versions of the Outcome Questionnaire (OQ-45) Raz Gross, MD, MPH,1 Saralee Glasser, MA,2 David Elisha PhD,3 Orya Tishby PhD,4 Daria Madar Jacobson, MD,2 Gila Levitan MPH,2 Michael J. Lambert, PhD, 5 and Alexander M. Ponizovsky, MD, PhD 3 1

Sheba Medical Center, Tel Hashomer, and Department of Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel 2 Gertner Institute for Epidemiology and Health Policy Research, Tel Hashomer, Israel 3 Mental Health Services, Ministry of Health, Jerusalem, Israel 4 The Hebrew University, Jerusalem, Israel 5 Brigham Young University, Provo, Utah, U.S.A.

Abstract Background: Measuring the progress of mental health treatment aids in assessment and monitoring of psychotherapeutic outcomes. The OQ-45 is a widely accepted measure of such outcomes. The aim of this study was to validate the Hebrew and Arabic versions of the OQ-45. Method: Data were collected from three samples: nonpatient university students (n=189), university mental health clinic patients (n=37), and outpatient mental health clinic patients (n=135). Subjects completed the OQ-45 as well as the BSI and PHQ-9 questionnaires. Results: Test-retest and internal reliability, and concurrent and discriminative validity of both OQ-45 versions were satisfactory. Sensitivity of the Hebrew and Arabic versions was 0.70 and 0.80, respectively, and the specificity was 0.69and 0.93, respectively. Sensitivity-to-change was noted only for the Symptom Distress (SD) subscale. Limitations: Sensitivity-to-change was not demonstrated for the total OQ-45, possibly due to a too-short follow-up period. Conclusions: Adequate psychometric properties of the Hebrew and Arabic OQ-45 suggest that they can serve as useful measures of mental health treatment in Israel. Further research is necessary to confirm norms, cut-off scores and sensitivity-to-change using a larger representative population and diverse types of treatment over a longer period of time.

Introduction Research in the field of mental health has indicated that measurement of mental health functioning during the course of treatment aids in assessment, monitoring of progress and psychotherapeutic outcomes (1). Feedback from outcome measurement provided to clinicians regarding the progress of treatment can be an adjunct to clinical decision-making and appropriate goal-setting, enabling more successful treatment outcomes (2, 3). The Outcome Questionnaire (OQ-45) is a self-report multidimensional measure designed for determining levels of psychological distress and dysfunction in interpersonal relationships and social roles, regardless of clinical diagnosis (4, 5). Its clinical usefulness can be attributed to the fact that it encompasses criteria from three psychological domains: symptom distress, interpersonal relations and social role, thus reflecting psychological functioning across both the intrapersonal and interpersonal spheres (4). Evidence supporting the use of the OQ-45 as a valid and reliable instrument for measuring level of distress/dysfunction in clinical practice and research is well documented (4, 6-13). One of the benefits of the OQ-45 is its sensitivity to change across a relatively short course of treatment. It has been considered an effective and accepted standard for measuring the progression of a patient during the course of psychological treatment, and thus is appropriate for use in practice and research (14) and is also attractive because of its brevity and ease of administration (5). The OQ-45 has Disclaimer: Dr. Ponizovsky was supported in part by the Ministry of Absorption, State of Israel. This research was not supported by any other grant for equipment and/or drugs.

Address for Correspondence: Alexander M. Ponizovsky MD, PhD, Mental Health Services, Ministry of Health, 39 Yirmiyahu St., POB 1176, Jerusalem 9446724, Israel â&#x20AC;&#x2020; alexander.ponizovsky@moh.health.gov.il

of52the Isr J PsychiatryValidation Relat Sci - Vol. - NoHebrew 1 (2015) and Arabic Versions of the Outcome Questionnaire (OQ-45)

been translated and validated in several languages, further reflecting its current acceptance for use (7, 9, 13). As part of an ongoing effort to improve quality of care and monitoring practices in the mental health field in Israel, the OQ-45 was chosen as a psychotherapy outcome measure for the mental health service system. The aim of this study was to examine initial psychometric properties of the Hebrew and Arabic versions of the OQ-45 adapted for use in Israel. Methods Subjects

The study sample included 341 subjects in three groups, as follows: • A non-patient sample of 158 Hebrew-speaking students and 31 Arabic-speaking students at the Hebrew University of Jerusalem. The study inclusion criterion for non-patient students was age 18years or older. Twenty students were excluded from the analysis because they reported undergoing current psychological treatment and/or were taking medication for depression or anxiety, resulting in 169 subjects in this study group - 138 Hebrew-speaking and 31 Arabic-speaking. • A university clinic patient sample of 37 Hebrew speakers attending the Student Psychological Service Clinic at Hebrew University who were 18 years of age or older. There were no Arabic-speaking patients in the university clinic group. No patients in this group refused to participate or were screened out. • A community outpatient clinic patient sample of 135 participants recruited at seven Ministry of Health community outpatient mental health clinics around the country operating as part of Israel’s free-of-charge universal health insurance coverage. This group included 97 Hebrew-speakers and 38 Arabic-speakers. Six additional patients who were approached refused to participate and could not be included in the data analysis. All patients were recruited prior to their first psychotherapy session. Exclusion criteria included: age under 18 years, inability to understand or sign consent form, brain damage, acute psychosis, dementia or significant cognitive disturbance, and known opiate addiction or misuse. Instruments The Outcome Questionnaire (OQ)

The OQ consists of 45 items scored on a Likert-type fivepoint scale (from 0 to 4). Scores on the whole scale are calculated, as well as scores on each of three domains, assessing 34

Symptom Distress (SD), Interpersonal Relationships (IR), and Social-Role functioning (SR). The SD, SR and IR subscales include 22 items, 9 items, and 11 items, respectively (three items are not included as irrelevant for Israeli clients). The SD subscale taps into general emotional and lifestyle stressors such as depression, anxiety, stress, substance abuse, and suicidality (scores range from 0 to 88). The IR subscale assesses clients’ satisfaction with interpersonal relationships, especially marital and family relationships and friendships (15) (range: 0 to 44). The SR subscale evaluates clients’ work relations and leisure activities (range: 0 to 36). Scores on the total OQ-45 scale, with a range of 0 to 180, have been reported as reliable and valid, distinguishing well between clinical and non-clinical subjects (16), and sensitive to change over time in therapy (4). OQ-45 questionnaires with more than six items missing were disqualified (n=12). The instrument has been translated into more than 30 languages other than English. It requires reading ability at the 6th grade level (Copyright to the measure is held by OQ Measures, LLC; 2171 Lake Street, Salt Lake City, UT 84106; www.oqmeasures.com). Both existing Hebrew and Arabic versions of the questionnaire were provided by Prof. M. Lambert to one of the authors (DE). Neither version had been previously field-validated and so underwent refinement to improve the meaning-translation for the Israeli population. Back-translation was conducted (for both languages) and agreement was achieved by consensus. All proposed changes were approved by Prof. Lambert who agreed that the new translations improved the intended meaning of the scale. This study was designed to provide initial norms as well as investigate the reliability and concurrent validity of the Hebrew and Arabic versions of the OQ-45 for use in the mental health service system in Israel. Concurrent validity was assessed by correlating scores on the OQ-45 with two measures of psychopathology already in use in Israel. Brief Symptom Inventory (BSI)

The BSI is a self-report measure for clinically relevant psychological symptoms in adolescents and adults (17). It includes 53 items that relate to nine symptom dimensions: somatization, obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation and psychoticism. The score for each BSI item ranges from 0-4, with total scores ranging from 0 to 212 and higher scores indicating more symptoms. The BSI was adapted from the Symptom Check List (SCL-R 90), a longer questionnaire that has been used in validation studies of the OQ-45 across languages and

Raz Gross et al.

cultures. Psychometric properties include internal reliability (Cronbach α = 0.85) and test re-test reliability (r= 0.9) (18). The Hebrew and Arabic translations of the BSI have been previously used in Israel (19-21). For this study, scores on the General Symptom Index (GSI) of the BSI were used as the criterion measure, as was done in other OQ-45 research (4, 7). Questionnaires with more than 13 items missing were disqualified (n=8). Patient Health Questionnaire-9 (PHQ -9)

The PHQ-9 is a self-report screening instrument used in primary care for identifying symptoms of depression, representing the model of affective disturbances from the Primary Care Evaluation of Mental Disorders (PRIME MD) (22). The PHQ-9 includes nine items based on the criteria for a major depressive episode as defined by the DSM-IV, with scores on each item ranging from 0-3 (total 0-27), higher scores indicating increasing levels of depressive symptoms. The PHQ-9 has been translated and validated in Hebrew, and internal reliability was shown to be high (Cronbach α 0.77) [23]. Questionnaires with more than one item missing were disqualified (n=13). Demographic and personal information

Appended to the study protocol was a brief form for noting participant’s gender, age, family status and years of education. For the non-patients, questions were added regarding current psychotherapy and drug use (for purposes of exclusion). Procedure

For the non-patient sample, the Hebrew questionnaires were distributed and completed in single classroom sessions. Students who were willing to complete a second OQ-45 within two weeks, for purposes of test-retest reliability, were offered payment of 50 NIS at the time of the second completion. The Arabic language questionnaires were distributed during an orientation session. There were no Arabic language retests. All non-patient protocol forms were anonymous and did not include identifying data, except for a personal code determined by the subject for the purpose of matching test and retest forms. In both clinic settings, a study coordinator (not the therapist) approached potential participants before their first therapy session. Those agreeing to participate were included, and their personal data were recorded on a registration form kept only by the local coordinator, for the purpose of matching subjects completing a second OQ-45. All study protocol forms were labeled with a

serial number only. While the OQ-45 was presented first in the protocol, the order of presentation of the BSI and PHQ-9 was alternated, in order to reduce order effect. Statistical analysis

All analyses were conducted using the 9.1.3 release of SAS PC software (SAS Institute, Inc., Cary, NC, U.S.A.). Scores of missing items (within the number allowed) were calculated as the mean score of the remaining items. Test-retest reliability was analyzed by Pearson productmoment correlation coefficient for those students who completed the OQ-45 twice with a two-week interval. Internal consistency reliability was calculated using the raw Cronbach alpha coefficient. Concurrent validity was assessed by comparing scores on the OQ-45 with Global Severity Index (GSI) derived from BSI scores using the Pearson product-moment correlation coefficient. In addition, similar comparisons were made with the PHQ-9. Discriminant validity was assessed through t-tests comparing non-patient and patient OQ-45 scores, as well as comparing the means of the three groups (non-patient, student clinic patients and community outpatient clinic patients), computed by analysis of variance with GLM procedures, using Tukey’s HSD post-hoc single comparison option. Construct validity, based on the assumption that treated individuals’ mental health functioning should be detectable after the 8th treatment session, was assessed by comparing OQ-45 scores at pre-treatment with scores obtained after eight treatment sessions, using paired t-test analysis for pooled patient groups and each patient group separately. Cut-off scores to discriminate non-patients from patients were calculated using the Cut-off C score as proposed by Jacobson–Truax (24).The exact score was calculated according to the suggested formula, and rounded to the closest whole number. This value was the lowest point below which a subject would be unlikely to belong to the patient population. Analyses were conducted for total study groups (Hebrew-speaking and Arabic-speaking) unless otherwise noted. A P-value of 0.05 was considered significant for all analyses, unless otherwise noted. This cut-off score has special importance for clinical practice because it provides one index for judging if a specific patient has returned to a state of normal function and therefore a decision to bring treatment to an end. Ethical Considerations

Institutional Review Board approval was received from the Hebrew University and each participating clinic. All subjects signed informed consent forms, and patient 35

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anonymity was maintained by the use of serial numbers on all forms and data entry. Results

significant at P<0.0001, and paired t-tests indicated no significant differences between pre- and post-test scores for individual subjects. OQ-45 scores remained fairly stable over brief time periods in untreated individuals.

Subjects

Internal Consistency

Outcome Questionnaire Scores

Concurrent Validity

In all groups there were significantly more male than female participants (P<0.0001. Subjects in both student non-patient and clinic groups were significantly younger than the community outpatients (mean ages 22.8, 25.6 and 38.6, respectively) and fewer students were married (P<0.0001). Interestingly, the non-patient students had a lower rate of >13 years of education than might be expected, possibly attributed to the questionnaires having been distributed during the first semester of a first-year course. This difference was significant for both Hebrew- and Arabic-speaking subjects. Table 1 presents OQ-45 total and domain scores by group and language. Non-patients had significantly lower total and domain scores than did patients (P <0.0001 for all comparisons, except for the Arabic SR subscale, for which P = 0.01). T-tests revealed no significant gender or age-group differences on OQ-45 meanscores in any group. As expected, individuals who are participating in psychotherapy report more disturbance than individuals who are not. Test-Retest Reliability

Only Hebrew-speaking non-patients completed the OQ-45 twice, and their test-retest correlations for the OQ-45 Total and SD, IR, and SR subscales were 0.85, 0.88, 0.78 and 0.71 respectively. All coefficients were

Good internal consistency was demonstrated for the total OQ-45 for all groups - Hebrew - and Arabic-speaking non-patients and Hebrew- and Arabic-speaking patients (α= 0.91, 95% Confidence Interval [CI] 0.89-0.93; 0.88, CI 0.81-0.93; 0.94, CI 0.92-0.96 and 0.92, CI 0.88-0.95, respectively). The values were also satisfactory for all subscales, except for the IR for Arabic-speaking nonpatients (α=0.47, CI 0.14-0.71) and the SR for Arabicspeaking patients (α= 0.44, CI 0.12-0.67). These later figures are low and suggest great caution in interpreting these subscales with these samples. Both Hebrew and Arabic versions of the total OQ-45 showed significant positive correlations with the BSIGSI scores for both non-patient and patient groups, with Pearson product correlation coefficients ranging from 0.63 to 0.85 (Table 2). These values are similar to the r = 0.72 reported by Lambert et al. (4). The corresponding domain correlations were also similar to those reported by Lambert et al., with the SD domain most highly correlated, and the IR and SR domains significantly, but with lower correlation coefficients. Likewise, significant correlations were found between PHQ-9 scores and the OQ-45 total and domain scores for all groups. The magnitudes also were similar to those reported by Lambert et al. (4), who compared the OQ-45

Table 1. OQ-45 scores by study group and language OQ-45 Subscales* Study Group

Total Score*

Symptom Distress

Interpersonal Relations

Social Role

All Subjects Non-patients Patients

169 172

48.95 (16.16) 73.79 (26.67)

26.82 (10.29) 42.05 (17.38)

10.63 (4.98) 17.47 (7.03)

10.85 (3.53) 12.15 (5.47)

Hebrew Non-patients All Patients University clinic Community outpatient Clinic

138 134 37 97

50.17 (16.28) 69.35 (24.54) 66.40 (19.24) 70.45 (26.25)

27.60 (10.25) 38.87 (15.59) 37.65 (14.33) 39.33 (16.09)

11.06 (5.00) 16.94 (6.78) 16.22 (6.04) 17.22 (7.06)

10.86 (3.49) 11.66 (5.16) 12.19 (4.90) 11.46 (5.26)

Arabic Non-patients Patients (Community outpatient clinic only)

31 38

43.55 (14.66) 92.90 (27.39)

23.39 ( 9.90) 53.26 (18.90)

8.71 (4.47) 19.31 (7.64)

10.81 (3.77) 13.87 (6.22)

*Mean (SD) All results are significant P<0.0001, except the Arabic SR subscale, P=0.01

Raz Gross et al.

Table 2. Concurrent validity of the Total OQ-45 and subscales with criteria measures by study group and language Correlation with BSI Global Severity Index Symptom Distress

Interpersonal Relations

Correlation with PHQ-9

Group

OQ-45 Total

Social Role

OQ-45 Total

Symptom Distress

Interpersonal Relations

Social Role

Non-patients Hebrew Arabic Lambert et al.+

138 31 115

0.73*** 0.63*** 0.78

0.75*** 0.64 0.61

0.47*** 0.33** NA

0.53*** 0.54* NA

0.69 0.69 0.80

0.69* 0.76 0.63

0.43* 0.42*** NA

0.54* 0.43*** NA

Clinic patients Hebrew Arabic Lambert et al.+

134 38 238

0.85 *** 0.73*** 0.72

0.85*** 0.75*** 0.70

0.60*** 0.53* 0.50

0.53*** 0.41* 0.52

0.78* 0.72* 0.62

0.75* 0.65*** 0.59

0.55* 0.40*** 0.44

0.53* 0.56*** 0.47

* p â&#x2030;¤0.05; ** p <0.01; ***p <0.001 + Lambert et al. (1996) compared with GSI of the SCD and the Beck Depression Inventory

Table 3. Discriminant validity of the OQ-45 by study group and language Study Group

OQ-45 Total Score

All Subjects Non-patients All Patients

169 172

48.95 (16.16) 73.79 (26.67)

Hebrew Non-patients University Clinic Community Outpatient Clinic

138 37 97

50.17 (16.28) 66.40 (19.24) 70.45 (26.25)

Arabic Non-patients University Clinic Community Outpatient Clinic

31 -38

43.55 (14.66) -92.90 (27.39)

F-value*

Pr>F

105.09

<0.0001

29.00

<0.0001

77.67

<0.0001

*Mean scores (SD) are shown; based on one-way ANOVA for two-group comparisons and the GLM procedure with Tukey HSD option for multiple (3-group) comparisons.

with the Beck Depression Inventory. These coefficients suggest that the Hebrew and Arabic translations of the OQ-45 measure psychological disturbance consistent with other scales that share this goal.

Discriminant Validity

Non-patients (both languages) had significantly lower OQ-45 total scores than did the patient groups (Table 3), whether analyzed either together or separately (Pr>F <0.0001 for each comparison). Further, there was a gradient of severity, with the outpatient clinic patients trending higher than did the university clinic patients (P = 0.06). Multiple post-hoc comparisons with the Tukey HSD option confirmed significant differences (P = 0.01) between the non-patients and each of the patient groups, but not between the two patient groups. These findings were confirmed for both Hebrew and Arabic translations. Sensitivity to Change (construct validity)

No significant changes over 7-8 psychotherapy sessions were found in OQ-45 total scores for all patients (Table 4). However, inspection of the individual domains revealed a significant reduction in SD domain scores for both patient groups. This is a somewhat surprising finding given that past research suggests change can be detected. It appears that statistically significant changes in the symptoms of

Table 4. Sensitivity to change: pretest and post-test OQ-45 scores for Hebrew patients in university and community outpatient clinics* Study Group** All Patients (n =70) OQ-45 Score

Pretest

University Clinic (n = 35)

Post-test

t-value (df)

Pretest

Post-test

t-value (df)

Community Outpatient Clinic (n = 35) Pretest

Post-test

t-value (df)

Total Score

67.05 (25.07)

64.85 (25.69)

0.85 (65)

65.40 (18.53)

68.59 (30.17)

1.43 (31)

68.59 (30.17)

70.50 (31.05)

-0.82 (33)

Symptom Distress

38.30 (16.26)

31.45 (14.51)

4.33 (69)***

36.73 (13.92)

26.29 (7.85)

3.97 (34) +

39.06 (18.02)

36.15 (17.75)

2.11 (34)++

Interpersonal Relationships

16.62 (7.22)

17.19 ( 6.37)

-0.94 (69)

16.41 (6.06)

18.32 (5.78)

-1.66 (34)

16.71 (8.37)

15.94 (6.84)

1.09 (0.34)

Social Role

11.94 (4.94)

10.97 (3.83)

1.92 (69)

11.94 (4.44)

10.38 (2.90)

1.82 (34)

11.94 (5.52)

11.56 (4.54)

0.72 (34)

**Mean scores (SD) *** Pr>\t\ <0.0001; + Pr>\t\ <0.0003; ++Pr>\t\=0.04

of52the Isr J PsychiatryValidation Relat Sci - Vol. - NoHebrew 1 (2015) and Arabic Versions of the Outcome Questionnaire (OQ-45)

anxietyand depression as measured by the Symptom Distress subscale (about half the OQ-45 items) were not large enough to offset the lack of change noted in items measuring interpersonal and social role dysfunction.

total OQ-45 score and for the SD domain, while results for the IR and SR domains were poorer. It appears that these domains may need further study before they can be recommended to clinicians.

Cut-off scores

Concurrent validity was confirmed for the total OQ-45 scale and the SD domain, with significant correlations found between the OQ-45 total score and the criterion measures (BSI/GSI and PHQ-9) for all subjects groups and in both languages. Lower, although significant, correlations were found for the IR and SR subscales, particularly for the Arabic version, and were similar to those of the original study (4).Other OQ-45 validity studies have indicated that there is no strong evidence for a three-domain structure in the original version (4, 7). The results of this study demonstrated that the Hebrew and Arabic translations of the OQ-45 can effectively discriminate between patient and non-patient samples, as well as within the clinical arena, with a gradient of increasing severity from non-patients to university clinic patients to community mental health settings. Although tracking patient progress with the OQ-45 was not the major focus of the current study, the results pertaining to this issue should be addressed. Sensitivity to change (change following treatment) was demonstrated for the SD subscale, but not for the total OQ-45 or the IR and SR subscales. This is in contrast to the findings of other studies (6, 12) and may be explained by several factors. Firstly, the total OQ-45 mean scores of our clinic population are substantially below those found in the original American study. Secondly, the patients participating in this study generally received psycho-dynamic treatment, still a dominant approach at the study clinics, the course of treatment of which may require a greater number of sessions to show improvement. This is in contrast to studies conducted in the USA and Europe in which sensitivity to change of the OQ-45 was investigated in the context of short-term cognitive-behavioral approaches. However, consistent with another study using the OQ-45 to examine changes in distress associated with a longer period of dynamic psychotherapy (20-week/ sessions) among persons with HIV and AIDS (11), we found a significant reduction in SD domain scores in all clinical groups over a significantly shorter period (8-week/sessions), supporting the utility of the OQ-45 as a measure of psychological distress. Further support for the above explanation of the failure to demonstrate sensitivity to change in this study can be found in preliminary results from a psychotherapy process study, reported by one

A cut-off score of 62/63 for the total OQ-45 was determined for all subjects in the study, with differences noted between the cut-offs for the Hebrew and Arab translations (57/58 and 64/65, respectively). According to these cut-off scores, the sensitivity (i.e., classifying a patient correctly) for the Hebrew translation of the total OQ-45 would be 0.70, and for the Arabic translation 0.80. Further inspecting the Hebrew-speaking groups, it was found that the sensitivity would be greater for the community outpatient clinic patients than for those of the university clinic (0.63 vs. 0.50). Specificity (i.e., classifying a nonpatient correctly) was 0.69 for the Hebrew-speakers and 0.93 for Arab-speakers. Positive predictive value for Hebrew- and Arabic-speakers was 0.68 and 0.89, respectively.This suggests that separate cut scores are needed to classify Arabic patients as recovered than the Hebrew patients (i.e., Hebrew patients need to be functioning better than Arabic patients to be considered within the normal range). In addition, a goal of future research should be to increase the ability of the Hebrew version of the OQ-45 to correctly identify patients. Discussion The results of this study indicate that the Hebrew and Arabic versions of the OQ-45 show promise as reliable and valid instruments for use in Israel for ongoing clinical monitoring and research purposes. In general, the psychometric properties obtained for both languages are comparable to the results of the original English version and other language translations of the OQ-45 (4), contributing to its cross-cultural validity. Reliability was confirmed by test-retest among nonpatients and internal consistency of the OQ-45 among patients and non-patients in both languages. The testretest reliability was comparable to that reported by Lambert et al. (4), and the internal consistency of the total OQ-45 and the SD subscale domain were best in all samples and for both language versions, also comparable to the findings of Lambert et al. (4). In this study, the lowest alpha scores were for the IR and SR domains in both Arabic-groups. Studies in other countries (4, 7, 13) also reported the most favorable results for the 38

Raz Gross et al.

of the authors (O.T.). In that study, which has recently been completed, 60 patients were assessed at several time points in the course of psychodynamic psychotherapy. Significant changes in the total OQ-45 scores were found between the scores at intake and the scores at session 5 (p<0.01), session 15 (p<0.001) and session 28 (p<0.001). There were no significant changes in the OQ-45 scores between sessions 5 and 15, only between session 5 and 28 (p<0.01) (25). In addition to the problem of a possibly too-short period of psychotherapy to demonstrate substantial patient progress with the total OQ-45 on domains other than the SD subscale, another limitation of the current study relates to the subject samples. A broader community sample of non-patients was not included due to funding restrictions. This study has demonstrated satisfactory psychometric properties of the OQ-45-Hebrew and Arabic versions, suggesting that they can serve as useful measures in diverse clinical and research settings in Israel. However, several limitations have been noted and larger sample sizes are needed in order to further establish cut-off scores for clinically significant change. As in past research on the OQ-45 the strength of the findings surrounding the measurement interpersonal and social role problems is needed. Further research is suggested to establish sensitivity to change using a larger representative population and diverse types of treatment over a longer period. Acknowledgements: We would like to dedicate this paper to the memory of David Elisha, PhD, the prime mover of this study, who unfortunately passed away before the work was published. We hope that the fruits of his labor will contribute to the improvement of Israel’s mental health services and the well-being of the patients. The authors wish to thank Mr. Razek Khawaled for adapting the Arabic version of the OQ-45 to the local dialect. The authors also thank the directors of the participating clinics for their cooperation.

References 1. Lambert M. Presidential address: What we have learned from a decade of research aimed at improving psychotherapy outcome in routine care. PsychotherRes 2007; 17:1-14. 2. Lambert MJ. Prevention of treatment failure: The use of measuring, monitoring, and feedback in clinical practice. Washington, DC American Psychological Association, 2010. 3. Whipple JL, Lambert MJ. Outcome measures for practice. Ann Rev Clin Psychol 2010; 7: 87-111. 4. Lambert MJ, Burlingame GM, Umphress V, Hansen NB, Vermeersch DA, Clouse GC, et al. The reliability and validity of the Outcome Questionnaire. Clin Psychol Psychother 1996; 3:249-258. 5. Lambert MJ, Morton J, Hatfield D, Harmon C, Hamilton S, Reid RC. Administration and scoring manual for the OQ-45.2 (Outcome

Questionnaire) (3rded.). Wilmington, Delaware: American Professional Credentialing Services LLC, 2004. 6. Anderson T, Ogles BM, Patterson CL, Lambert MJ, Vermeersch DA. Therapist effects: Facilitative interpersonal skills as a predictor of therapist success. J Clin Psychol 2009; 65: 755-768. 7. deJong K, Nugter MA, Polak MG, Wagenborg JE, Spinhoven P, Heiser WJ. The Outcome Questionnaire (OQ-45) in a Dutch population: A cross-cultural validation. Clin Psychol Psychother 2007; 14:288-301. 8. Doerfler LA, Addis ME, Moran PW. Evaluating mental health outcomes in an inpatient setting: convergent and divergent validity of the OQ-45 and BASIS-32. J Behav Health Serv Res 2002; 29: 394-403. 9. Lo Coco G, Chiappelli M, Bensi L, Gullo S, Prestano C, Lambert MJ.The factorial structure of the outcome questionnaire-45: A study with an Italian sample. Clin Psychol Psychother 2008; 15: 418-423. 10. Okiishi JC, Lambert MJ, Eggett D, Nielsen L, Dayton DD, Vermeersch DA. An analysis of therapist treatment effects: toward providing feedback to individual therapists on their clients’ psychotherapy outcome. J Clin Psychol 2006; 62: 1157-1172. 11. Pobuda T, Crothers L, Goldblum P, Dilley JW, Koopman C. Effects of time-limited dynamic psychotherapy on distress among HIV-seropositive men who have sex with men. AIDS Patient Care STDS 2008; 22:561-567. 12. Vitriol VG, Ballesteros ST, Florenzano RU, Weil KP, Benadof DF. Evaluation of an outpatient intervention for women with severe depression and a history of childhood trauma. Psychiatric Serv 2009; 60: 936-942. 13. Wennberg P, Philips B, deJong K. The Swedish version of the Outcome Questionnaire (OQ-45): Reliability and factor structure in a substance abuse sample. Clin Psychol Psychother 2010; 83:325-329. 14. Vermeesch DA, Lambert MJ, Burlingame GM. Outcome Questionnaire: Item sensitivity to change. J Personal Assess 2000; 74: 242-261. 15. Lambert MJ, Lunnen K, Umphress V, Hansen N, Burlingame GM. Administration and scoring manual for the Outcome Questionnaire (OQ45.1). Salt Lake City: IHC Center for Behavioral Healthcare Efficacy, 1994. 16. Umphress VJ, Lambert MJ, Smart DW, Barlow SH. Concurrent and construct validity of the outcome questionnaire. J Psychoed Assess 1977;15: 40-55. 17. Derogatis LR. Brief Symptom Inventory. Baltimore, Md.: Clinical Psychometric Research, 1975. 18. Derogatis LR. BSI Brief Symptom Inventory. Adminstration, Scoring and Procedures Manual (4th Ed.). Minneapolis, Minn.: National Computer Systems, 1993. 19. Canetti L, Shalev AY, DeNour AK. Israeli adolescents’ norms of the Brief Symptom Inventory (BSI). Isr J Psychiatry Relat Sci 1994; 31:13-18. 20. Gilbar O, Ben-Zur H. Adult Israeli community norms for the Brief Symptom Inventory (BSI). Int J Stress Manag 2002; 9:1-10. 21. Lev-Wiesel R, Al-Krenawi A, Sehwail MA. Psychological symptomatology among Palestinian male and female adolescents living under political violence 2004-2005. Comm Ment Health J 2007; 43:49-56. 22. Spitzer R, Kroenke K, Williams J. Validation and utility of a self-report version of PRIME-MD the PHQ Primary Care Study. JAMA1999; 282:1737-1744. 23. Geuolayov G, Jungerman T, Moses S, Friedman N, Miron R, Gross R. Assessing the psychometric properties of the mood module of the Patient Health Questionnaire in primary care in Israel. Isr J Psychiatry Relat Sci 2009; 46: 36. 24. Jacobson NS, Traux P. Clinical significance: A statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol 1991; 30: 12-19. 25. Wiseman H, Tishby O. The client-therapist “dance”: Interplay of client and therapist interpersonal patterns, working alliance and psychotherapy outcome. Final Scientific Report submitted to the Israel Science Foundation, Grant No 178/07, 2011.

Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

Social Anxiety Disorder Comorbid with Schizophrenia: The Importance of Screening for This Underrecognized and Undertreated Condition Katherine Moss Lowengrub, MD, Rafael Stryjer, MD, Moshe Birger, MD, and Iulian Iancu, MD Rehovot Mental Health Center, Rehovot and the Beer Yaakov Mental Health Center, Beer Yaakov, both affiliated with the Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel

Abstract Background: While the presence of comorbid anxiety disorders such as obsessive-compulsive disorder and panic disorder have been well described in schizophrenia, comorbid social anxiety disorder (SAD) has been less emphasized. The goal of this study was to examine the prevalence of SAD in our ambulatory population of patients with schizophrenia. Methods: A group of 50 outpatients with schizophrenia randomly selected from our public mental health outpatient population was evaluated with the Structured Clinical Interview for DSM-IV (SCID)-schizophrenia section, the Positive and Negative Syndrome Scale (PANSS), the Schizophrenia Quality of Life Scale (SQLS), the Liebowitz Social Anxiety Scale (LSAS) and the Global Assessment of Functioning Scale (GAF). After completion of assessments, a retrospective chart review was conducted on all study patients who met criteria for a diagnosis of SAD in order to determine how many of these patients had been previously given a diagnosis of SAD. Results: Based on a cutoff score of 29/30 on the total LSAS score, 38% of our sample had a comorbid diagnosis of SAD. Compared to patients who did not suffer from comorbid SAD, patients with schizophrenia and comorbid SAD had lower ratings of quality of life, but similar GAF and PANSS scores. According to the results of the chart review, none of the affected patients had been previously diagnosed with SAD. Conclusions: According to the results of our study, SAD as a comorbid condition is highly prevalent in schizophrenia

Address for Correspondence:

and may be under-detected in the outpatient mental health care setting. Furthermore, the presence of SAD may lead to a decreased quality of life for patients with schizophrenia. Further studies should evaluate whether the diagnosis and treatment of comorbid SAD would improve the treatment and quality of life of patients with schizophrenia.

INTRODUCTION While acute psychotic episodes in schizophrenia generally respond well to treatment with antipsychotic medication, the long-term course is characterized by marked impairment in social and occupational functioning (1). Our lack of success in treating negative symptoms highlights the need for aggressively treating comorbid psychiatric conditions. For example, the current standard of care during the maintenance phase of treatment in schizophrenia is to screen aggressively for concurrent alcohol and drug use, for it is known that these conditions lead to a worsening course in schizophrenia (2). The identification and treatment of comorbid medical and psychiatric conditions in schizophrenia is critically important in preventing relapse and optimizing quality of life. It has long been recognized that anxiety disorders such as obsessive-compulsive disorder, panic disorder and post-traumatic stress disorder are common in schizophrenia, and multiple studies have demonstrated that treatment of comorbid anxiety symptoms is associated

Iulian Iancu, MD, Yavne Mental Health Center, 6 Dekel Street, Yavne 81200 Israel

â&#x20AC;&#x2020; iulian1@bezeqint.net

Katherine Moss Lowengrub et al.

with an improved outcome in schizophrenia (2-4). More recently, the implications of comorbid Social Anxiety Disorder (SAD) in schizophrenia have begun to be addressed in the literature. The essential feature of SAD is a marked fear and avoidance of one or more social and/or public performance situations due to an excessive concern about being humiliated while under the scrutiny of others (5). Two subtypes of SAD are recognized: a generalized type, in which a person fears most social or performance situations and a non-generalized type in which fears are typically limited to public speaking or few â&#x20AC;&#x153;performanceâ&#x20AC;? activities (5). Based on the premise that SAD is often underdiagnosed in schizophrenia because of confusion with negative symptoms, Pallanti et al. (6) conducted the first comparison study between outpatients with schizophrenia and concluded that comorbid SAD was common and was strongly associated with increased disability. In the limited number of studies available to date, prevalence rates for comorbid SAD in outpatients with schizophrenia have ranged from 17-36.3% (6-8). Two studies with inpatients showed prevalence rates of 11-17% (9, 10). Clearly, prevalence studies are in their preliminary stages with poor correlation between studies which might be accounted for by disparate treatment settings, as well as other variables including the demographic make-up of the study (age, socio-economic class, and years of education) and the type of antipsychotic agents used (11). Schizophrenia is characterized by positive symptoms (delusions, hallucinations) and negative symptoms (flat affect and emotions, alogia and avolition). SAD shares common elements with positive and negative symptoms in schizophrenia. Neuropsychiatric studies and functional MRI studies have shown that patients with SAD tend to misinterpret neutral facial expressions as being threatening (12). This misreading of social expression may be seen on a continuum with paranoia and ideas of reference. SAD patients are known to be very sensitive to the scrutiny of others which leads to guarded and withdrawn behavior. The tendency of patients with SAD to suffer from shyness and avoidance may likewise be seen as part of a continuum with apathy and avolition that comprise negative symptom clusters (13). The symptom overlap between SAD and schizophrenia may result in missed diagnosis of comorbid SAD when positive symptoms mask SAD or SAD overdiagnosis if negative symptoms are prominent. Comorbid SAD in schizophrenia has been associated with more distress and disability, increased rates of substance abuse and a decreased quality of life (6). Consistent

with views expressed by experts in the field, it has been our impression that patients with schizophrenia in our large and demographically diverse outpatient population are not systematically screened for the presence of comorbid SAD, and the working hypothesis of this study is that SAD is under-detected in schizophrenia. We aimed to determine the prevalence of SAD in a random cohort of our outpatients with schizophrenia. METHODS: Sample: The study was approved by the local Institutional Review Board. Fifty outpatients diagnosed with chronic schizophrenia (n= 45) or schizoaffective disorder (n= 5) were recruited in a random fashion from our public mental health outpatient clinic and were invited to participate in the study after giving written informed consent. The clinic is affiliated with Tel Aviv University and serves an ethnically diverse population in a catchment area of over 120,000 residents. Inclusion criteria were a diagnosis of schizophrenia or schizoaffective disorder according to the Structured Clinical Interview for DSM-IV and age between 18 and 65. Exclusion criteria included difficulty with spoken and written Hebrew, organic brain disease (such as dementia, mental retardation or severe dyslexia), comorbid substance abuse (during the preceding year) and lack of cooperation (e.g., due to the presence of psychotic symptoms or negativism). Patients treated with selective serotonin reuptake inhibitors (SSRI) or serotonin norepinephrine reuptake inhibitors (SNRI) were not excluded from the study. The study population consisted of 26 men and 24 women. The mean age of the subjects was 45.4 years (S.D. = 13.4). The mean duration of illness was 20.3 years (S.D. =11). All patients were receiving antipsychotic treatment at the time of the evaluation. The mean daily defined dose (D.D.D.) was 1.23 (S.D. =0.7). This is a statistical measure of drug consumption, defined by the World Health Organization (http://www.whocc.no). It is the assumed average maintenance dose per day for a drug used for its main indication in adults and also serves to compare drug use among patients taking different medications. The mean number of friends was 1.42 (S.D. =1.7) with a minimum of 0 and maximum of 6 friends. Half of the patients had distinct paranoid features (significant paranoid ideation and paranoid delusions). Fourteen patients (28%) were taking adjunctive antidepressant medication at the time the study was conducted. Seven patients (14%) had made at least one suicide attempt 41

Anxiety Disorder Comorbid with Schizophrenia Isr J Psychiatry Relat Sci - Vol. 52 Social - No 1 (2015)

in the past. Four patients (8%) abused drugs in the past and two (4%) abused alcohol in the past. Research instruments: Assessment tools included the following questionnaires: 1. Structured Clinical Interview for DSM-IV (SCID), a structured tool for the diagnosis for schizophrenia (14), All SCID assessments were performed by the last author (I.I.). 2. The self-report version of the Liebowitz Social Anxiety Scale (LSAS-SR) (15), whose objective is to assess the range of social interaction and performance situations which patients with SAD may fear and/or avoid. 3. The Positive and Negative Syndrome Scale (PANSS) (16) measuring symptom severity of patients with schizophrenia with positive, negative and general subscales. 4. The Schizophrenia Quality of Life Scale (SQLS) (17) is a practical and acceptable method of measuring self reported quality of life in people with schizophrenia. 5. The Global Assessment of Functioning scale (GAF) (5). This is a numeric scale (0 through 100) used by mental health clinicians to rate subjectively the social and occupational functioning of adults. The GAF and the PANSS scores were rated by the clinicians, whereas the LSAS and SQLS were in a self-report format. Statistical analysis: The LSAS-SR questionnaire was used as a screening tool for the presence of SAD using a cutoff of 30 or more (indicating the presence of focused SAD). A secondary measure was for generalized SAD based on a score of 60 or more on the LSAS. As mentioned above, the specifier “generalized” is used in the DSM-IV to denote a subgroup of individuals who suffer from anxiety in most social and performance situations. Although the higher cutoff score might be correlated with greater specificity in screening for SAD, the lower cutoff score was also found to predict non-generalized SAD (18, 19). We compared the characteristics of those with SAD and schizophrenia versus those with schizophrenia alone. This was done as follows: the distribution of gender and of those taking antidepressants in both groups was examined by chi square analyses and we used an analysis of t-test for independent samples for continuous variables. Correlations were reviewed between the LSAS and PANSS, between the “fear” subscale of the LSAS and positive symptoms, and between the “avoidance” LSAS subscale and negative symptoms on the PANSS. 42

Within the subset of study patients who met criteria for SAD, we examined whether this diagnosis had been previously detected by the treating psychiatrist and appeared in the patients’ files. Results The scores on the various questionnaires are presented in Table 1. In the majority of cases (78%), the social fears were judged by the clinician to be neurotic (nonpsychotic). Based on a cutoff score of 29/30 on the total LSAS score, 38% of our patients had a diagnosis of SAD (12 males and 7 females). Based on a cutoff score of the total LSAS score of 59/60, 10% of our sample had generalized SAD. None of the patients with schizophrenia+ SAD were diagnosed as such by the treating psychiatrist. Table 1 also presents the characteristics of those with and without SAD (based on a cutoff score of 29/30). The two sub-samples had similar age, gender distribution, Table 1. Clinical characteristics of SAD positive (LSAS>30) and SAD negative subjects

Variable

Total sample (n=50) Mean (S.D.)

SAD Positive (n=19) Mean (S.D.)

SAD Negative (n=31) Mean (S.D.)

Statistical Significance (df= degrees of freedom)

Age (years)

45.4(13.4)

43.9(13.8)

46.3 (13.3)

p=0.539, t=0.61, df=48

Duration of Illness (years)

20.3 (11)

20.4(10.1)

20.2 (11.7)

p=0.939, t=-0.07, df=48

Number of Friends

1.42 (1.7)

1.37 (1.9)

1.45 (1.7)

p=0.872, t=0.16, df=48

PANSS total (range 35-100)

62.7(16.8)

67.7 (19)

59.6 (14.9)

p=0.099, t=-1.68, df=48

PANSS positive (range 7-23)

13.1 (4.8)

14.68(5.7)

12.09(3.9)

p=0.092, t=-1.91, df=48

PANSS negative (range 7-39)

18.9 (6.7)

20.05 (7.2)

18.19 (6.3)

p=0.345, t=-9.54, df=48

PANSS general 30.7 (9) (range 16-49)

32.94 (9.9)

29.29 (8.1)

p= 0.165, t=-1.41, df=48

LSAS total (range 0-118)

27.7 (24.9)

52.1 (23.1)

12.8 (9.3)

p<0.001, t=-8.44, df=48

SQLS (range 43-113)

78.5 (18.1)

87.1 (18.7)

73.2 (15.8)

p=0.007, t=-2.82, df=48

GAF (range 35-75)

52.8 (8.9)

51.8 (6.1)

53.4 (10.3)

p=0.553, t=0.59, df=48

D.D.D. (range 0.4-3.7)

1.23 (0.7)

1.3 (0.84)

1.2 (0.6)

p=0.527, t=-0.63, df=48

Abbreviations: Liebowitz Social Anxiety Scale (LSAS), the Positive and Negative Syndrome Scale (PANSS), the Schizophrenia Quality of Life Scale (SQLS), Global Assessment of Functioning scale (GAF) and Daily Defined Dose (DDD).

Katherine Moss Lowengrub et al.

duration of illness, number of friends and D.D.D. The group with schizophrenia and SAD included 12 males and 7 females, whereas the group with schizophrenia alone included 14 males and 17 females. This difference in gender distribution (37% females vs 55%, respectively) was not significant (chi square = 1.529, df=1, p=0.22). The subjects with schizophrenia and SAD took antidepressant medications in a similar proportion as the subjects with schizophrenia (26% vs 29%, chi square =0.043, p=1, degrees of freedom=1). Subjects with schizophrenia and SAD had a lower quality of life (the SQLS score is inversely correlated with quality of life). Correlations: We found significant Pearson correlations between LSAS Fear subscale and PANSS general psychopathology subscale (r=0.28 [p=0.046] and SQLS [r=0.45, p=0.001]), and also between LSAS avoidance subscale and PANSS general psychopathology subscale (r=0.34, p=0.016), PANSS total (r=0.29, p=0.037) and SQLS (r=0.48, p=0.001). No significant correlations were found between LSAS fear subscale and positive PANSS and between LSAS avoidance subscale and PANSS negative. The LSAS (total score) correlated significantly with the PANSS general psychopathology subscale (r=0.31, p=0.024) and with the SQLS (r=0.47, p<0.01). An additional finding was that paranoid patients had lower GAF scores (p=0.017). Discussion To date, only a handful of studies have examined the prevalence rates of comorbid SAD in ambulatory patients with schizophrenia. The results of our study show that 38% of our patients met criteria for SAD (based on a score of 30 or greater on the LSAS) and that 10% of our patients met criteria for generalized SAD (based on a score of 60 or greater on the LSAS). The distinction between focused social anxiety and generalized social anxiety disorder is important, as the generalized form is associated with greater disability [20]. Our prevalence rate of 38% for comorbid SAD is consistent with that reported by both Pallanti et al. and Tibbo et al. in their studies of chronic ambulatory patients where prevalence rates were 36.3% and 23.3%, respectively (6, 21). Likewise several studies among first-episode patients have reported rates between 25-32% (22, 23). We note that our prevalence is higher than that reported by Braga et al. (8) who found comorbid SAD in 17% of outpatients (n=53) with schizophrenia. The lower rate reported by Braga may relate to differences in study variables, such as

patient selection and choice of screening tools for SAD (SCID vs LSAS-SR). Additionally, several recent studies have examined the prevalence of SAD in acutely hospitalized schizophrenic patients with prevalence rates ranging from 5.7-25% (9, 10, 24). These different rates may be due to the difficulty of administering screening instruments to patients who are not clinically stable and are paranoid. Consistent with data presented by Pallanti et al. (6), a clear finding of our study was that relative to patients without comorbid SAD, patients with schizophrenia with SAD had a lower overall quality of life (see Table 1). According to Kumazaki et al. (25), the association between social anxiety symptoms and a lower subjective quality of life suggests that it is clinically important to recognize the presence of social anxiety. These authors maintain that anxiety symptoms are often under-diagnosed because clinicians usually pay more attention to psychotic symptoms. In addition, they point out that recent criteria for remission in schizophrenia mainly rely on psychotic symptoms (26, 27) and, therefore, the risk of underdiagnosing anxiety factors is increased. However, this issue is far from simple. Whereas some authors conclude that social anxiety may lead to a decreased quality of life (6), others maintain, for example in community-dwelling patients with remitted schizophrenia, that a lower subjective quality of life might lead to the development of social anxiety symptoms (25), due to lifeâ&#x20AC;&#x2122;s hardships and a lack of social communication skills. Contrary to our expectations, we found no significant difference between patients with and without comorbid SAD in terms of the GAF scores. One explanation for this finding is that the GAF provides a relatively rough estimate of the overall severity of psychiatric symptoms and may not be sensitive enough to detect variances in functioning within a group of patients afflicted with schizophrenia. Accordingly, we note that the mean GAF score for both cohorts (with and without SAD) was in the low end of the moderate range showing that all patients had relatively poor functioning. While the results of our study show that SAD is associated with an impaired quality of life, experts generally agree that the distinction between comorbid SAD and symptoms related to the natural course of schizophrenia is challenging. A major question in this field is that of the ability to differentiate SAD symptoms from positive symptoms (i.e., paranoia, ideas of reference) and negative symptoms (social withdrawal) which are inherent in the disease process of schizophrenia. In the case of a chronic patient who refuses to go to a vocational rehabilitation program, it is mandatory 43

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to discern whether his behavior results from fears that spies will attack him (positive symptoms), avolition (negative symptoms) or fears that in the rehabilitation center he will sweat excessively and therefore will be mocked and will feel embarrassed (possibly SAD). For example, Mazeh et al. (9) concluded that it is difficult to differentiate SAD from positive symptoms, although we note that their study examined a cohort of acutely ill patients in which prominent positive symptoms may confound the assessment of SAD. In concordance with current studies (6, 22), the results of our study show that compared to patients who did not suffer from comorbid SAD, patients with schizophrenia and comorbid SAD had similar rates of negative and positive symptoms (see Table 1). Our results, therefore, support findings by Pallanti et al. (6) and Michail and Birchwood (22) that social anxiety appears to be unrelated to the presence of clinical psychotic symptoms. In our opinion, screening for SAD in outpatients with schizophrenia may be best accomplished by asking if the patient has a fear of embarrassment or has avoidance in particular social situations (eating in public, going to job interviews or using a public restroom), for the core features of SAD are a fear of embarrassment and an intense apprehension about being negatively evaluated by others which lead to social avoidance. The patient with comorbid SAD complicating schizophrenia will experience the avoidant behavior as ego-dystonic and therefore qualitatively different from avoidant behavior due to anhedonia or lack of social interest. Furthermore, the patient with comorbid SAD is generally motivated to gain control of the anxiety symptoms, whereas avoidant behavior due to negative symptoms is typically accompanied by impaired motivation to change. We note that user-friendly selfreport instruments (such as the Mini-SPIN) are available for identifying SAD in the managed care setting and appear to distinguish between the generalized and nongeneralized subtypes (19, 28, 29). However, the validity and ease of administration of these tools in patients with schizophrenia deserves further study. We have provided a synopsis of screening techniques for SAD, for an important finding of our study was that according to the results of the retrospective chart review, the diagnosis of comorbid SAD had been missed in every affected patient. We note that this failure to detect comorbid SAD occurred in a university-affiliated clinical setting which is staffed by experienced senior psychiatrists. We propose that several clinician-related variables contributed to the failure to correctly diagnose the comorbid SAD in our study population including: 44

1) a lack of knowledge of the high prevalence rates of comorbid SAD in schizophrenia, 2) failure to appreciate the clinical relevance and additional morbidity conferred by the presence of SAD in schizophrenia, 3) lack of knowledge regarding screening procedures, and 4) the tendency (bias) among clinicians to attribute poor social functioning to negative symptoms without exploring other comorbid conditions. A limitation of our study is the small sample size. Another limitation may be the relative homogeneity of our sample which was composed primarily of patients with chronic schizophrenia, and, therefore, the results of our study may not generalize to a more diverse population including first episode patients. The inclusion of patients with schizoaffective disorder in our study population may also be considered as a limitation of our study, for the presence of affective symptoms may represent a confounding variable in the assessment of SAD. Patients with schizoaffective disorder, however, comprised only a minority of the sample. The inclusion of patients medicated with antidepressant medication may have biased the results, for the pharmacotherapy may have masked symptoms of SAD although we attempted to conduct our study under naturalistic conditions. Furthermore, the use of the LSAS-SR to screen for the presence of SAD (in contrast to the clinicianadministered LSAS and the SCID) may have possibly decreased the reliability of our results, although both LSAS scales have been shown to be equivalent in several studies (18, 19). Seedat et al. (24) observed the low agreement between the Mini International Neuropsychiatric Interview (MINI) and a diagnosis of anxiety disorders on symptom status measures. While these authors suggest that existing cutoff scores on these measures may not be appropriate for psychotic individuals, we note that the MINI also is problematic due to its brevity and the possibility that it arouses dissimulation and denial in persons with psychosis. While the comorbidity rate in our study is much higher than chance alone, its cause is unclear. Is it a result of the fear of stigma and rejection while having a mental disorder or due to a common biological underpinning, or rather a medication-induced side effect? Schizophrenia is associated with excessive dopamine activity, which is related to novelty seeking and exploratory behaviors. Introversion and social anxiety are related to decreased dopamine levels (30) and indeed Pallanti et al. (11) reported that anti-dopaminergic drugs cause SAD symptoms in a higher rate than expected. We conclude that a failure to systematically screen for comorbid SAD in schizophrenia leads to underdetec-

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tion of this potentially treatable disorder. SAD results in patients with schizophrenia in reduced quality of life and perhaps in other impairments. We note that clinicians also need to be aware that the use of atypical neuroleptic medications such as clozapine and olanzapine may lead to the emergence of SAD during treatment (11). Patients with comorbid SAD appear to be sensitive to the social stigma linked to schizophrenia and tend to feel socially marginalized (23). Whereas a range of effective cognitive behavioral therapies (such as social skills, assertiveness, and empowerment training) and pharmacological therapies now exist for the treatment of SAD (31), there is some progress also in subjects with schizophrenia-SAD comorbidity. Antidepressant agents such as SSRIs have been reported to be efficacious in a small case series (32) and based on the potential role of oxytocin in the management of schizophrenia and also in SAD, this agent may be possibly used in subjects with this specific comorbidity (33, 34). Oxytocin reverses emotional recognition deficit and might restore the sense of trust in patients with schizophrenia and has been shown to attenuate (and normalize) fear-related brain activation and reactivity to emotionally negative cues in SAD. CBT within a group format was also found to be effective in cases with schizophrenia and SAD (35). Five therapeutic techniques could be used in that setting: a psycho-educational component, exposure simulations (gradual confrontation of a feared event/situation), cognitive restructuring (disputation of unhelpful thinking styles), role-play and intra-session assignments (homework). A more specific strategy, Morita therapy is a systematic psychotherapy based on Eastern psychology, named in 1919 after Shoma Morita, a Japanese psychiatrist (36). It involves a structured behavior program to encourage an outward perspective on life, thereby increasing social functioning. A recent review on Morita therapy in patients with schizophrenia revealed that this therapy, in addition to standard treatment, significantly improved daily living, compared with the standard treatment alone (36). Indeed, Kumazaki et al. (25) proposed to examine its efficacy in cases with schizophrenia and SAD comorbidity. Finally, we suggest that the proper detection and treatment of SAD as a comorbid disorder in schizophrenia may be a prospective way to improve the overall quality of life of these individuals. Further research in this field is warranted with larger samples and sound methodology so as to assess the rate of SAD in schizophrenia and to dissect the similarities and differences of these not so divergent disorders. These studies should also evaluate

whether the diagnosis and treatment of comorbid SAD would improve the treatment and quality of life of patients with schizophrenia. References 1. Carpenter WT, Jr. The deficit syndrome. Am J Psychiatry 1994; 151: 327-329. 2. Buckley PF, Miller BJ, Lehrer DS, Castle DJ. Psychiatric comorbidities and schizophrenia. Schizophr Bull 2009; 35: 383-402. 3. Bayle FJ, Krebs MO, Epelbaum C, Levy D, Hardy P. Clinical features of panic attacks in schizophrenia. Eur Psychiatry 2001; 16: 349-353 4. Eisen JL, Beer DA, Pato MT, Venditto TA, Rasmussen SA. Obsessivecompulsive disorder in patients with schizophrenia or schizoaffective disorder. Am J Psychiatry 1997; 154: 271-273. 5. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th. Washington, DC: American Psychiatric Association, 1994. 6. Pallanti S, Quercioli L, Hollander E. Social anxiety in outpatients with schizophrenia: A relevant cause of disability. Am J Psychiatry 2004; 161: 53-58. 7. Voges M, Addington J. The association between social anxiety and social functioning in first episode psychosis. Schizophr Res 2005; 76: 287-292. 8. Braga RJ, Mendlowicz MV, Marrocos RP, Figueira IL. Anxiety disorders in outpatients with schizophrenia: Prevalence and impact on the subjective quality of life. J Psychiatr Res 2005; 39: 409-414. 9. Mazeh D, Bodner E, Weizman R, et al. Co-morbid social phobia in schizophrenia. Int J Soc Psychiatry 2009; 55: 198-202. 10. Cosoff SJ, Hafner RJ. The prevalence of comorbid anxiety in schizophrenia, schizoaffective disorder and bipolar disorder. Aust NZ J Psychiatry 1998; 32: 67-72. 11. Pallanti S, Quercioli L, Pazzagli A. Social anxiety and premorbid personality disorders in paranoid schizophrenic patients treated with clozapine. CNS Spectr 2000; 5: 29-43. 12. Stein MB, Stein DJ. Social anxiety disorder. Lancet 2008; 371: 1115-1125. 13. Blanchard JJ, Mueser KT, Bellack AS. Anhedonia, positive and negative affect, and social functioning in schizophrenia. Schizophr Bull 1998; 24: 413-424. 14. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID), Clinical Version. Washington, DC: American Psychiatric Press, 1996. 15. Liebowitz M. Social phobia. Modern Problems in Pharmacopsychiatry 1987; 22: 141-173. 16. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261-276. 17. Wilkinson G, Hedson B, Wild D, Cookson K, Farina G, Sharma V, Fitzpatrick R, Jenkinson, C. Self-report quality of life measure for people with schizophrenia: The SQLS. Br J Psychiatry 2000; 177: 42-46. 18. Mennin DS, Fresco DM, Heimberg RG, Schneier FR, Davies SO, Liebowitz MR. Screening for social anxiety disorder in the clinical setting: Using the Liebowitz Social Anxiety Scale. J Anxiety Disord 2002; 16: 661-673. 19. Rytwinski NK, Fresco DM, Heimberg RG, et al. Screening for social anxiety disorder with the self-report version of the Liebowitz Social Anxiety Scale. Depress Anxiety 2009; 26: 34-38. 20. Stein MB, Chavira DA. Subtypes of social phobia and comorbidity with depression and other anxiety disorders. J Affect Disord 1998; 50: S11-16. 21. Tibbo P, Swainson J, Chue P, LeMelledo JM. Prevalence and relationship to delusions and hallucinations of anxiety disorders in schizophrenia. Depress Anxiety 2003; 17: 65-72. 22. Michail M, Birchwood M. Social anxiety disorder in first-episode psychosis: incidence, phenomenology and relationship with paranoia.

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Br J Psychiatry 2009; 195: 234-241. 23. Birchwood M, Trower P, Brunet K, Gilbert P, Iqbal Z, Jackson C. Social anxiety and the shame of psychosis: A study in first episode psychosis. Behav Res Ther 2007; 45: 1025-1037. 24. Seedat S, Fritelli V, Oosthuizen P, Emsley RA, Stein DJ. Measuring anxiety in patients with schizophrenia. J Nerv Ment Dis 2007; 195: 320-324. 25. Kumazaki H, Kobayashi H, Niimura H, Kobayashi Y, Ito S, Nemoto T, Sakuma K, Kashima H, Mizuno M. Lower subjective quality of life and the development of social anxiety symptoms after the discharge of elderly patients with remitted schizophrenia: A 5-year longitudinal study. Compr Psychiatry 2012; 53:946-951. 26. Andreasen NC, Carpenter WT, Kane JM, Lasser RA, Marder SR, Weinberger DR. Remission in schizophrenia: Proposed criteria and rationale for consensus. Am J Psychiatry 2005;162:441-449. 27. Harvey PD, Bellack AS. Toward a terminology for functional recovery in schizophrenia: Is functional remission a viable concept? Schizophr Bull 2009;35:300-306. 28. Letamendi AM, Chavira DA Stein MB. Issues in the assessment of social phobia: A review. Isr J Psychiatry Relat Sci 2009; 46: 13-24.

29. Conner KM, Kobak KA, Churchill LE, Katznelnick D, Davidson JRT. Mini-Spin: A brief screening assessment for generalized social anxiety disorder. Depress Anxiety 2001; 14: 137-140. 30. Schneier FR, Liebowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin SH, Laruelle M. Low dopamine D(2) receptor binding potential in social phobia. Am J Psychiatry 2000; 157:457-459. 31. Iancu I, Levin J, Stein MB: Editorial: Social anxiety disorder - New understandings and new standards. Isr J Psychiatry Relat Sci 2009; 46: 2-4. 32. Pallanti S, Quercioli L, Rossi A, Pazzagli A. The emergence of social phobia during clozapine treatment and its response to fluoxetine augmentation. J Clin Psychiatry 1999; 60:819-823. 33. Macdonald K, Feifel D. Oxytocin in schizophrenia: A review of evidence for its therapeutic effects. Acta Neuropsychiatr 2012; 24:130-146. 34. Churchland PS, Winkielman P. Modulating social behavior with oxytocin: How does it work? What does it mean? Horm Behav 2012, 61:392-399. 35. Kingsep P, Nathan P, Castle D. Cognitive behavioural group treatment for social anxiety in schizophrenia. Schizophr Res 2003;63:121-129. 36. Li C, He Y. Morita therapy for schizophrenia. Schizophr Bull 2008; 34:1021-1023.

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Dissociative Reality and Dissociative Being in Therapy for Posttraumatic Patients Jonathan Guez, PhD,1,2 Mali Hertzanu-Lati, MSW,2 Rachel Lev-Wiesel, PhD,3 and Stanley Rabin, PhD4 1

Department of Psychology, Achva Academic College, Israel Beersheva Mental Health Center, Beersheva, Israel 3 Department of Art Therapy, Haifa University, Haifa, Israel 4 Department of Psychiatry, Soroka University Medical Center and Division of Psychiatry, Faculty for Health Sciences, Ben-Gurion University of the Negev, Beersheva, Israel 2

Abstract Posttraumatic patients experience a wide range of symptoms, some of them existential in nature which we term “dissociative being.” Many varied psychotherapeutic approaches are available for the treatment of posttraumatic patients. Nevertheless, in view of this disorder’s complexity, therapists face shortcomings when employing each of these therapeutic interventions. In order to understand this, we posit the principle we call “dissociative reality” for the treatment of trauma survivors. Our proposed method “speaks the patient’s own language,” harnessing dissociative elements to help individuals recall, re-enact and integrate traumatic experiences, where words are insufficient, while still upholding reality. We believe that this may be seen as an effective part of the therapeutic dialogue, and suggest that therapists may consider supplementing this approach in their treatment “toolkit” for patients with posttraumatic stress and other trauma related disorders, irrespective of their declared therapeutic approach.

“… Any mortal who gazes at Medusa’s face is immediately

petrified with fear. But if you look only at her reflection in your shield, all will be well.” Greek Mythology

Posttraumatic stress disorder (PTSD) is the quintessential mental disorder for which an environmental factor is the key instigator of its development. Though personality and

genetic factors are known to play some role in determining patients’ vulnerability to developing PTSD (i.e., the diathesis–stress model), by definition PTSD necessitates the existence of an external event or “stressor,” which constitutes a critical threat to the self. As an exogenous disorder, PTSD poses a particular challenge to psychotherapists. Indeed, a large number of highly varied treatment models and methods have been devised to treat PTSD, including pharmacological (especially used for symptom reduction, such as anti-depressants in the selective serotonin reuptake inhibitor class) (1), traditional or dynamic (2-4), behavioral or cognitive-behavioral (5, 6), and eye movement desensitization and reprocessing (EMDR) (7), and somatic experiencing (8-10). Although these treatment approaches have been effective in many cases of PTSD, effective treatment of PTSD often remains elusive (e.g., see Foa et al., for review [11]). Maybe the very development of these myriad treatments, all targeting the same disorder, could attest to therapists’ helplessness and powerlessness in overcoming the dramatic effects of an actual, clear, quite recent event on the patient’s personality and entire life. Could it be that faced with the experience of annihilation, the overwhelming certainty of death, we, the therapists ourselves, become reliant on multiple, varied protocols in order to contain our intense emotions, to regain a sense of control? Much has been said about the pendulum as akin to the posttraumatic patient’s dynamics, swinging from oblivion and dissociation to being overcome with the flood of memories and re-experiencing of the trauma. These two extremes, in our conceptualization , can coexist and refer to dissociative experience. It can be seen expressing the unsuccessful attempt by the patient’s psyche to control the traumatizing event, thereby reiterating the terrible helplessness experienced in the wake of the traumatizing

Address for Correspondence: Jonathan Guez, PhD, Department of Behavioral Sciences, Achva Academic College, Beer Tuvia Regional Council, MPO Shikmim 79800, Israel jonjon@bgu.ac.il

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event. Herman (12) showed how this dynamic also plays out in social attitudes toward those suffering from the effects of trauma, namely observers’ fluctuation between neglect and alienation on the one hand, and respect and witnessing on the other hand. In this paper, we will pinpoint how this dialectic plays out in therapy. It may be that when it comes to treating trauma, we, psychotherapists, tend to remain on the far end, overwhelmed by the multitude of available treatments and protocols, in order to gain illusory control over the insufferable helplessness we experience when touching upon the inconceivable, deathly, existential state of trauma. In this paper we propose a therapeutic position in treating posttraumatic patients that focuses on a major element that is common to most of our patients: the dissociative experience of the patient’s being. We posit that the principle we call “dissociative reality” exists implicitly in the treatment of trauma survivors and can be used for effective, multidimensional intervention across a broad range of psychotherapeutic approaches. This paper begins with a discussion of PTSD, dissociation, and the relation between trauma and dissociation. Then we describe our therapeutic position that recommends harnessing dissociative elements to help individuals recall, re-enact, and integrate traumatic experiences by “speaking the patient’s own language” where words are often insufficient. We thereafter briefly suggest how this eclectic dissociative-reality approach can be implemented into psychotherapy. Finally, we propose that all therapists consider holding these principles in mind in order to supplement their treatment “toolkit” for patients with PTSD, irrespective of their declared therapeutic approach. We believe that this will result in a more flexible space and movement in the patienttherapist interaction. Posttraumatic Stress Syndrome Trauma produces shock in people’s lives. When people’s basic beliefs are shattered regarding the invulnerability of the self, the predictability and controllability of the world, then life becomes unbearable. People with PTSD have faced some direct traumatizing event of exceptional severity – an existential threat to the self. From that moment onwards, their beliefs and their lives are no longer the same. In fact, PTSD stands in sharp contrast to the model of human equilibrium, according to which people aspire for “psychological homeostasis.” The disorder constitutes a lasting aberration from mental equilibrium; it resurfaces 48

anew each day without any objective trigger and does not tend to return to baseline, as though this repetition is no longer functioning as a stabilizer and organizer. Various periods in history have been marked by changing approaches to trauma in social-cultural discourse, ranging from attempts to raise awareness about the effects of trauma to attempts to repress its impact. These shifts in social-cultural trends may also reflect a posttraumatic dialectic in the face of the overpowering certainty of death (12). Today, wide consensus exists recognizing the considerable impact of human exposure to traumatizing events and the unique construct of PTSD, although debate continues concerning the breadth of the disorder’s definition (see Summerfield’s criticism [13]). The definition of PTSD in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5, 14) includes commensurable characteristics such as intense re-experiencing of the trauma through dissociative flashback episodes and nightmares, along with avoidance behaviors such as efforts to avoid thoughts, people or situations associated with the trauma. Interestingly, the recent version of the DSM (DSM-5,14) includes other dissociative symptoms and specification that were missing in the DSM-IV version (15). In the normative process of reacting to trauma, individuals must make an effort to re-establish continuity with their lives before the traumatic event, as both the physical and mental distress must return to some form of balance, and mental distress must be processed (or integrated) within the person’s inner world. The diagnosis of PTSD underscores a fault in that integration process, leading the person to swing like a pendulum from defensive apathy, numbing and reclusion at one extreme, to persistent distressing thoughts and vivid flashbacks at the other. Prima facie, this syndrome is fraught with simultaneous contradictions in the patient’s mind. The patient suddenly relives the event through intense hallucinations, dreams or flashbacks and is highly aroused to stand guard against potential danger (intrusive recollection and hyper-vigilance symptoms), and then paradoxically seems to be detached, numb and unaware of the event at all and barely seems to be living in the present (avoidance symptoms). His or her entire existential being is paradoxical, having encountered the threat of injury or even death (objectively or subjectively). As we elaborate below, we posit that dissociation is the common denominator of these extreme, seemingly contradictory shifts. The uncontrollable regressions to both extremes can be understood as dissociative states of disengagement.

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Dissociation and the Spectrum of Dissociative Phenomena Despite variance in defining the term “dissociation” in the pathological sense, general agreement exists that dissociation refers to the lack of integration in the psychological make-up of the self (16). Dissociation is defined as an experience or behavior in which certain information is neither integrated nor incorporated with other information, as the case would be under regular circumstances. The primary characteristic of the posttraumatic patient is some sort of failure or change in the integrative functioning of one’s identity, memory or consciousness, so that behavior and thoughts become automatic and uncontrollable, disengaged from any central control and consciousness regarding oneself, time or the circumstances at hand. The spectrum of dissociative phenomena ranges from the healthy to the pathological, from adaptive defenses to pathological defenses. At the adaptive level, dissociative phenomena appear routinely in everyday healthy life, such as when one “forgets oneself ” while driving, or when one “gets lost in the moment” while immersed in a pleasurable book or movie – any creative activity characterized by the loss of consciousness for time or place. In those instances, which are essential for human growth and development, the boundary becomes blurred between the objective and the subjective, between distance and immediacy, between “me” and “you,” allowing the possibility of contradictory truths to co-exist, without having to determine which is real and which is imaginary. A great deal has been said about the importance of “potential space” (17) in which individuals can move between fantasy and reality and can create, act and play; This space is situated also in rites that initiate entrance into other states of consciousness, such as religious rituals, prayers and dancing to electronic “trance” music. The less frequent states of consciousness such as trances or meditative reveries that various cultures implement like religious or healing rites may demonstrate the value of dissociative states as a universal human need. One could say, from an evolutionary point of view, that there is value in creating an intentional dissociative reality in response to the psychological systems sense of being overwhelmed. Moreover, dissociative processes are of vital importance to human self-preservation and to an integral, continuous experience of the self despite the fragmented, contradictory pieces of the self that may be experienced at any particular moment. This dialectic, between experiencing

a multi-faceted self who may feel and act differently in diverse situations and experiencing oneself as an integrated whole beyond the content of particular events, is reminiscent of a movie consisting of different frames, each frame seemingly independent from the other yet somehow connected by a cohesive, continuous, meaningful experience (18). The traumatized person is caught up in one particular frame or in some interrupted flow (as though in slow motion, when the viewer can recognize the various cuts), thereby losing his or her experience as a continuous, integral self who exists beyond the sum of these few frames. Instead, the traumatized person experiences some sort of existence that is detached from the past familiar experiencing self. Additionally, one may find reactive dissociative phenomena, which are defensive reactions to an external or internal menace or threatening state. Often, the latter is an adaptive form of defense that enables the return to normal mental equilibrium. Pathology occurs when the said defenses are massively applied, which undermines the individual’s functioning and precludes the return to mental equilibrium. Pathological manifestations range from temporary or permanent memory loss of unpleasant events to more severe symptoms which pose a risk and threat to the cohesive unit defining the personality. On the pathological end of the spectrum, one could say that defenses go awry (the device turning against its own maker, as it were) in the form of functional disruptions like dissociative identity disorder (DID), dissociative fugue, de-personalization and de-realization, and other pathological dissociative disorders. This understanding of dissociation paves the road for allowing implementation of these elements in the course of psychotherapy. The Relationship between Trauma and Dissociation The roots of inquiry into PTSD and dissociative mechanisms go back to the 19th century, when Pierre Janet drew the link between traumatic experiences and hysteria (19). Janet emphasized the integrative failure involved (20), and was among the first to discuss dissociation’s adaptive function in coping with acute or chronic trauma. Indeed, numerous studies demonstrated the correlation between dissociative symptoms and personal reports of traumatic experience (21, 22) and between PTSD and dissociation. Thus, for example, people diagnosed with PTSD also revealed higher scores on the Dissociative Experiences Scale (DES) designed to evaluate dissocia49

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tive characteristics, compared to people without a PTSD diagnosis (23, 24). In light of the strong correlation between trauma and dissociation, some have suggested that dissociation is an underlying cause of PTSD development. Van der Kolk and Fisler (25), highlighted that both re-experiencing and avoidant symptoms are dissociative phenomena. Accordingly, it has been suggested that the symptoms of persistent intrusive recollection be defined as “positive dissociative symptoms” and those of avoidance as “negative dissociative symptoms” (16). Indeed, it seems that the recurring re-experiencing of the trauma matches the definition of dissociation in the sense that there is no integration of elements of one’s inner world with a consciousness of the external experience. Thus, while DSM-IV (15) lists PTSD under anxiety disorders, and the recent DSM-5 present new trauma- and stressor-related disorders (14), some call listing it under the cluster of dissociative disorders, having the same etiology (26). To further underscore this argument, both PTSD and dissociative disorders are responses to extreme stress, and both disorders include changes in memory, a criterion not listed under anxiety disorders (27, 28). We posit that the common denominator of those therapeutic approaches to trauma that were pinpointed as empirically effective consist of two simultaneous elements: addressing the core of the trauma and disengaging from it. We suggest that using the dialectical characteristics of posttraumatic stress symptoms in the course of therapy serves the patient’s needs and allows the patient to return to the life that the trauma derailed. In this sense, the very technique that elicits the expression of dissociative responses (dissociation in service of the ego) can make a change. The core of the trauma is the experience of death, which can be seen as the core of the trauma, but the subjective meaning of it is unique to the patient (29), and re-experiencing it again in the course of therapy may be seen as the root of treatment. To bring this about without paralyzing the patient, direct and indirect techniques are needed. Adopting Dissociative Being and Dissociative Reality into the Service of Therapy Many therapists working with PTSD patients often find that patients not only demonstrate attempts to compulsively repeat (re-enact, re-experience and remembering) the traumatic event/s but fluctuate in feeling detached, 50

numb or lacking any feeling. These patients reveal experiences of de-personalization and de-realization, where one has a sense of being alien to oneself or to a place, a detachment from full consciousness to oneself, to time, or to the very circumstances at hand. This may manifest itself in the patient’s feelings that he or she is “somewhere else” or reacting as if in another time or place. The emphasis of the present paper is on dissociative being in the patient’s experience, rather than, as is the case with dissociative disorders, such as DID, or structural dissociation of the personality of a high order as observed by Van der Hart et al. (16). By “dissociative being” we mean the patients’ detachment from the flow of life’s activities, from themselves and others, and from their own feelings. Dissociative being includes acknowledgement of both positive dissociative symptoms (dissociative flashbacks, re-experiencing the trauma) and negative dissociative symptoms (numbness, withdrawal, detachment, numbing) and the experiencing of helplessness in the wake of these uncontrolled states. Many patients describe themselves as “no longer alive,” “a different person,” “half-living,” “living-dead,” and so on, even without having experienced instances of extreme, dramatic detachment as in dissociative disorder. We suggest that the patient’s “dissociative being” experience described here may be adopted in the service of therapy. Explicitly, we propose that the therapist intentionally initiate, in an “artificial” way, dissociative situations in the therapy room itself, and move back and forth, into and out of them along with the patient, this being a kind of exposure and recognition of these elements in the patient’s experience. We refer to these in-therapy situations as dissociative reality, referring to the place, form and technique through which the therapist, along with the patient, can together encounter the patient’s “dissociative being” for therapeutic purposes. The latter involves the patient’s experience of the trauma where “dissociative reality” is used to fit the patient’s language and to transform something pathological into something normative, controllable and communicative. As such, in the sheltered, safe and secure “current reality” of the therapeutic relationship along with the menacing reality of the trauma, the therapist and patient join together in both the here-and-there, in both the then-and-now of the patient’s “dissociative reality.” Together they jointly experience the patient’s terrified yet calm, helplessness yet in a control, coming-in and going-out dissociative being. The posttraumatic patient is often already in dissociative being (e.g., experiencing flashbacks) when entering

Jonathan Guez et al.

the therapy room; as such, the therapist’s response can unintentionally or intentionally bring the patient back to current reality (e.g., “Please look at me, you are in the clinic now”) or bring the patient to a state of detachment (e.g., by ignoring/dissociating from the patient’s state and continuing the session as if nothing happened). Here, the therapist’s enlistment of dissociative reality can mediate the above two extremes. We maintain that a great many of the intervention techniques can utilize our dissociative-reality approach in their treatment of posttraumatic patients. The main characteristic of our dissociative-reality approach then is implementing and reactivating dissociative elements in order to regain our patients’ mental balance and to integrate the trauma within the self. Thus, we suggest that therapists using other treatment options may effectively adopt the proposed therapeutic method based on the flexible movement “coming into and out” of dissociative being, in a manner matching the patient’s needs. From the psychotherapist’s perspective, they have to be able to experience and emotionally tolerate the dissociative elements and often contain their own feelings in the process. Moreover flexibility on the part of the therapist is important, to flow in and out of the dissociative elements. The idea of dissociative reality in response to the patient’s dissociative being is then aimed at restoring the patient’s inner ability to move in and out with the therapist, rather than remain in the polarity of one reality or adopting one technique, such as dwelling with the therapist on the traumatic flood of memories alone. Working in a method that shifts “one foot in and one foot out” creates the important dissociative reality in the therapist’s room, which may indeed facilitate better communication with the patient’s symptoms, thereby promoting recovery. Implementation of Dissociative Elements in Therapy A question arises: How can we implement so called “soft” dissociative elements to the dissociative being of the patient in order to create a dissociative reality space? We maintain that these elements may include fantasy and visualization, creative enhancement of body language, empty-chair work, graded experiments, psychodrama and enactment. Here the patient assumes responsibility and accountability for his or her own symptoms while acting them out. The resulting situation is taking accountability and owning up to the symptoms while at the same time detaching oneself from the symptom; that

is, movement between “being” and “watching.” Thus, in the dissociative-reality approach, the patient is inside (the dramatic act) and yet outside (not really with the symptom itself). Using these interventions promotes dissociation by inviting the patient to look at an event from the outside (e.g., like from a train or on a screen). The therapist emphasizes that “one’s foot is in, and at the same time one’s foot is out.” This involves adopting paradoxical principles, contrasts and opposites. As seen in these examples, the idea of dissociative reality in the therapy encounter can be implemented differently in diverse treatment methods. Although all the above may be found to some degree in treatment approaches such as EMDR, Gestalt and art therapy, somatic-experience it is important to point out that the common core element of dissociative reality implicitly exists in all these approaches. We feel that it is important to make it more explicit. Therefore by introducing the dissociative-reality terminology, the therapist facilitates the patient to move away from being a prisoner, to freely master and create the dissociative space necessary for change. This mastering allows the patient to move from a pathological uncontrollable framework to a more positive and controllable space. This may extend the patients understanding and experience, beyond specific techniques. Discussion In this paper, we have underscored the centrality of the dissociative elements in posttraumatic patients and in their treatment. The dialectic of intrusive memories and lost memories, of revelation and concealment, is an essential part of understanding and defining post-trauma. This dialectic also expresses intrusions and detachments that are part of the traumatic experience. Herman (12) noted that both trauma victims and those who witness their testimony (including therapists) are subject to this dialectic of trauma. Human capacity for grasping horrors and everyday traumatic events is apparently limited, as it is nearly impossible to internally retain all the elements and integrate them. An even greater difficulty lies in finding the right words for describing the experience in full. Once a new piece of memory surfaces, another disengages and vanishes. In Winnicott’s (17) terms the traumatized person has lost his or her “potential space,” which enables the capacity for creation and play-acting between in and out, where one’s “true self ” is revealed. The threat leads the traumatized person toward polarity; for example, games either become accurate re-enactments 51

Reality and Dissociative Being in Therapy for Posttraumatic Patients Isr J Psychiatry Dissociative Relat Sci - Vol. 52 - No 1 (2015)

of the traumatic external reality or else constitute a surreal, prolonged escape. Furthermore, many researchers studying trauma describe the collapse or the “freezing” of said potential space. The “traumatic self ” is a collapsed self, whose trauma and experience of death render his or her being troubled, bruised and changed. Use of the paradoxical dissociative-reality approach enables the dyadic patient-therapist relationship to move into the space that has collapsed, to move in and out of different realities, both while taking part and while merely watching. In this space, individuals can come out of their frozen state and play, and thus re-create themselves. They are therefore able to gather the posttraumatic collapsed self and the pre-trauma self, thereby creating a “cumulative self.” Part of the treatment of trauma is to return to the patient the ability to move between the various parts of the event, which enables processing the trauma on different levels. We wish to stress that in our view, a beneficial treatment for the patient does not lead to a conscious integrative product, but rather to the processing of the traumatic event at different parallel realms of the self. We may not always know what worked, but the result would be a return to mental equilibrium. Based on this realization, we suggest that in such cases when reality is unfathomable, when reality is speechless, room must be allowed for our patients to express themselves in additional realities rather than allowing for the principle of reality to rule supreme. For this and other reasons, it is our impression that more and more trauma therapies arise from play-acting and the arts. Two main principles can be drawn from this paper: one, intentional entry into the experience of death, the exit from which is essential for recovery; and two, dissociative experiencing that enables the first principle and promotes it. Dissociative being consists of mixing tenses, past and present, physical reactions, varying affect according to the narrative, varying tone, etc. All these underscore the unique reality in which patients find themselves – and where the treatment/patient-therapist interaction takes place – dissociative reality. One of our further goals is to return and re-emphasize for therapists treating post-trauma, the concept of dissociation. This is to enable them to reconsider and rediscover it as being a useful and viable term rather than looking at it only with its pathological context. Dissociation may raise intense overwhelming feelings in the counter transference relationship where the therapist may feel emotionally overwhelmed. This can lead the therapist to subsequently disengage emotionally from 52

the patient. We maintain that some therapists facing this often intolerable emotional state and compensating for it may find themselves relying rigidly on only one particular treatment technique, thereby losing their potential space to move about flexibly. The concept of dissociative reality constitutes a common ground that may allow therapists to go beyond using one approach or another. It should be emphasized that dissociative reality is not merely a therapy protocol. Such a protocol would, in fact, contradict the idea that we are advancing here, the idea of dialectic flexibility as embodied in the problem itself. Dissociative reality can be viewed as a “play toy,” a space for play and creative psychotherapeutic intervention. However, there is a reservation in using this approach indiscriminately since it is vital to remember that, as in any psychotherapy, assessing the PTSD patient’s strengths and personality is paramount. Some posttraumatic patients may, in fact, be particularly vulnerable to acute dissociative states, or prone to psychotic states. It would be unwise to initiate dissociative games concerning the painful events for these patients. Therefore, as cautioned in various therapeutic techniques, this therapy is not recommended for patients with an existing degree of dissociation of the personality or psychosis. Furthermore, it should not be applied in the acute stage of trauma where related symptoms support spontaneous recovery. It should be applied for the more persist chronic states. In short “dissociative reality” allows the patient, in a safe secure and trustworthy setting, to express, recall, re-enact and then integrate traumatic experiences with the help of the therapist. It allows for fantasy, expression and a space to play enabling the flow of anxiety to take place, and yet it is grounded in reality. It involves different steps in a dance-in and out movements which challenges the patient’s traumatic subjective experiences, allowing for space on the dance-floor, for dynamic movement and change. In conclusion, we propose that all therapists consider this approach in supplementing their treatment “toolkit” for patients with PTSD, irrespective of their declared therapeutic position. We believe that this will enable a more flexible space and movement in the patient-therapist encounter. This paper began with a quotation from Greek mythology concerning the story of Medusa, the female monster with a petrifying gaze. In this myth, anyone who looked directly into Medusa’s eyes was turned immediately into stone. This is also the case with trauma. In myth, Perseus was tasked with killing Medusa. He succeeded by not looking at her directly but rather at her reflection in his shield, and thus

Jonathan Guez et al.

he was able to cut her head off. We believe this expresses the concept of dissociative reality: looking at the terrible trauma but differently, neither here nor there. References 1. Seedat S, Stein DJ, Ziervogel C, Middleton T, Kaminer D, Emsley RA, et al. Comparison of response to a selective serotonin reuptake inhibitor in children, adolescents, and adults with posttraumatic stress disorder. J Child Adolesc Psychopharmacology 2002; 12: 37-46. 2. Freud S. Beyond the pleasure principles (Standard ed., Vol. 18). London: Hogarth Press, 1957 (Original work published 1920). 3. Laufer RS. The serial self: War trauma, identity and adult development. In: Wilson JP, Harel Z, Kahana B, editors. Human adaptation to extreme stress from the Holocaust to Vietnam. New York: Plenum, 1988. 4. Lifton RJ. Understanding the traumatized self: Imagery symbolization and transformation. In: Wilson JP, Harel Z,Kahana B, editors. Human adaptation to extreme stress from the Holocaust to Vietnam. New York: Plenum, 1988. 5. Foa EB, Kozak MJ. Emotional processing of fear: Exposure to corrective information. Psychol Bull 1986; 99: 20-35. 6. Foa EB, Rothbaum BO. Behavioral psychotherapy for posttraumatic stress disorder. Int Rev Psychiatr 1989; 1: 219-226. 7. Shapiro F. Eye movement desensitization and reprocessing: Basic principles, protocols, and procedures. New York: Guilford, 1995. 8. Van der Kolk BA. Beyond the talking cure: Somatic experience and subcortical imprints in the treatment of trauma. In: Shapiro F, editor. EMDR as an integrative psychotherapy approach: Experts of diverse orientations explore the paradigm prism. Washington, DC: American Psychological Association, 2002. 9. Levine PA. Waking the tiger: Healing trauma: The innate capacity to transform overwhelming experiences. Berkeley, Cal.: North Atlantic Books, 1997.‫‏‬ 10. Ogden P, Minton K, Pain C. Trauma and the body: A sensorimotor approach to psychotherapy. New York: W. W. Norton, 2006. 11. Foa EB, Keane TM, Friedman MJ, Cohen JA. Effective treatments for PTSD. New York: Guilford, 2009. 12. Herman LJ. Trauma and recovery. New York: Basic Books, 1992. 13. Summerfield D. The invention of post-traumatic stress disorder and

the social usefulness of a psychiatric category. BMJ 2001; 322:95-98. 14. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. DSM-5. 5th ed. Washington DC: American Psychiatric Association, 2013. 15. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Text Revision. DSM-IV-TR. 4th ed. Washington DC: American Psychiatric Association, 2000. 16. Van der Hart O, Nijenhuis E, Steele K, Brown D. Trauma-related dissociation: Conceptual clarity lost and found. Aust N Z J Psychiatry 2004; 38:906-914. 17. Winnicott DW. Playing and reality. New York: Basic Books, 1951. 18. Mitchell S. Freud and beyond. New York: Basic Books, 1995. 19. DePrince AP, Freyd JJ. Trauma induced dissociation. In: Keane TM, Resick PA, editors, Handbook of PTSD. New York, N.Y.: Guilford, 2004. 20. Putnam FW. Pierre Janet and modern views of dissociation. J Trauma Stress 1989; 2:413-428. 21. Francia-Martinez M, de Torres IR, Alvarado CS, Martinez-Toboas A, Sayers S. Dissociation, depression and trauma in psychiatric inpatients in Puerto Rico. J Trauma Dissociation 2003; 4:47-61. 22. Irwin HJ. Pathological and nonpathological dissociation: The relevance of childhood trauma. J Psychol 1999; 133:157-164. 23. Carlier IV, Lamberts RD, Fouwels AJ, Gersons BP. PTSD in relation to dissociation in traumatized police officers. Am J Psychiatry 1996; 153:1325-1328. 24. Yehuda R, Elkin A, Binder-Brynes K, Kahana B, Southwick SM, Schmeidler J, et al. Dissociation in aging Holocaust survivors. Am J Psychiatry 1996; 153:935-940. 25. Van der Kolk BA, Fisler R. Dissociation and the fragmentary nature of traumatic memories: Overview and exploratory study. J Trauma Stress 1995; 8:505-525. 26. Davidson JR, Foa EB. Posttraumatic stress disorder: DSM-IV and beyond. Washington DC: American Psychiatric, 1993. 27. Braun BG. The BASK model of dissociation. Dissociation 1988; 1: 4-21. 28. Van der Hart O, Nijenhuis ER, Steele K. Dissociation: An insufficiently recognized major feature of complex posttraumatic stress disorder. J Trauma Stress 2005; 18:413-423.16. 29. Hertzano-Lati M, Toder D. Posttraumatic stress disorder as an uncompleted death. Sihot / Dialogue: Israel JPsychotherapy 2006; 20: 314-320 (Hebrew).

Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

Cognitive Appraisal and Psychological Distress Among Patients with Irritable Bowel Syndrome Menachem Ben-Ezra, PhD,1 Yaira Hamama-Raz, PhD,1 Sharon Palgi, MA,2 and Yuval Palgi, PhD3 1

School of Social Work, Ariel University, Ariel, Israel Department of Psychology, University of Haifa, Haifa, Israel 3 Department of Gerontology, University of Haifa, Haifa, Israel 2

Abstract Background: Irritable Bowel Syndrome (IBS) is a debilitating condition that affects mainly the patient’s mental health and quality of life. There is a gap in the literature regarding the relationship between cognitive appraisals and adjustment to physical and psychological aspects resulting from IBS. The aim of the current study was to explore the psycho-social factors that are associated with psychological distress among IBS patients and the contribution of cognitive appraisal to their adjustment. Methods: One hundred and three patients diagnosed with Irritable Bowel Syndrome participated in the study. Each participant filled a battery of questionnaires targeting demographic and psycho-social factors. The study variables were analyzed via hierarchical regression along with supplementary analyses of multiple mediation tests of indirect effects. Results: The findings showed that psychological distress and depressive symptoms among IBS patients are better predicted by their global positive illness cognition appraisal, specific illness cognition appraisal of helplessness, resilience and to a lesser extent by social support, perceived optimism, illness cognitions appraisals of acceptance and perceived benefit. Global positive illness cognition appraisal gives us a sum of positive and negative appraisals into one unified appraisal. Conclusions: Our findings highlight the salience of cognitive appraisal and resilience in IBS psychological adjustment. It seems that IBS patients might benefit from psycho-educational interventions designed to assist them

Address for Correspondence:

in reducing their helplessness appraisal and increasing the appraisal of their ability to cope with the symptoms of their illness.

Introduction Irritable bowel syndrome (IBS) is considered a significant functional gastrointestinal disorder, with prevalence ranging from 10% to 15% (1). It occurs more often in women than in men, and it begins before the age of 35 in about 50% of people (2). IBS is also regarded as a chronic illness that can dramatically affect the quality of life (3). Psychiatric disorders, especially depression and anxiety, occur in up to 94% of IBS patients (2). Psycho-social factors may play an important role in the development as well as in the outcome and prognosis of the disorder (4). The aim of the present study was to explore the psycho-social factors that are associated with psychological distress among IBS patients and the contribution of cognitive appraisal to their adjustment. The study is based on the theoretical framework of Lazarus and Folkman’s model of adjustment to stress (5-8). This theory proclaims that cognitive appraisal, personal resources and social resources might alleviate or exacerbate the perceived stress experienced by an individual. Cognitive appraisal has been defined as a “process through which the person evaluates whether a particular encounter with the environment is relevant to his or her well being, and if so, in what ways” (9). This process involves both primary and secondary appraisals that occur at the same time and interact in order to determine the significance and meaning of the event

Prof. Menachem Ben-Ezra, School of Social Work, Ariel University, Ariel 40700, Israel

menbe@ariel.ac.il

Menachem Ben-Ezra et al.

in regard to well being (7). Primary appraisal considers the perceived implications of the stressor for well being through interpretation of stressful situation in one of three possible outcomes: irrelevant, challenge or threat. Secondary appraisal refers to a cognitive-evaluative process that focuses on minimizing harm or maximizing gains through coping responses. It involves purposeful evaluations of cognitive, affective and behavioral efforts to manage the perceived stress (7-9). Empirical studies show that cognitive appraisal affects adjustment to illness, including HIV (10), cardio-vascular disease (11), and cancer (12). However, there is a gap in the literature regarding the relationship between cognitive appraisal and adjustment to physical and psychological aspects among IBS patients. The main difference between IBS patients and the aforementioned medical conditions is the existence of life threatening conditions in comparison to IBS which is a debilitating condition that affects quality of life without the component of threat for one’s life. Other factors mentioned in Lazarus and Folkman’s model are personal resources which may contribute to the cognitive appraisal component and to adjustment. We chose two coping resources – optimism and resilience, which may be especially relevant in the case of IBS patients due to the association between physical condition and mental condition. Optimism is described as a relatively stable, general tendency of individuals to expect positive outcomes (13). Individuals high in optimism typically have better psychological adjustment to negative life events, report less distress across a broad range of stressful situations, have more positive social networks, and enjoy better physical health (14-16). Optimistic individuals are prone to show higher self efficacy, and adapt to stressors more effectively during time of crisis (17). Studies with various ethnicities have demonstrated that higher levels of optimism predict lower levels of depression and stress (18-20). Optimism also may serve as a protective factor that promotes resilient adaptation, as found among individuals with cancer (21), and coronary heart disease (22, 23). Resilience is defined as the ability to resist, cope with, recover from, and succeed in the face of adverse life experiences (24). Resilience represents “the ability of adults in otherwise normal circumstances who are exposed to an isolated and potential highly disruptive event to maintain relatively stable, healthy levels of psychological and physical functioning as well as the capacity for generative experiences and positive emotions” (25). Resilience also refers to important psychological skills and to the

individual’s ability to use familial, social, and external support in order to cope better with stressful events (26, 27). In light of this, we aim to explore the contribution of social support to the IBS patients’ health. The relationship between social support and health, functioning, and quality of life is well established in the literature (28-30). Two types of mechanisms have been described when studying this relationship: The direct positive path that relates to support and the buffering effect, by which social support moderates the impact of acute and chronic stressors on health (31). In the general population, social support buffers against stressful life events, increases adherence to medical treatments, and improves recovery from medical illness, among other health-promoting effects (28, 32-35). A recent study (4) has found that among IBS patients, feelings of social isolation existed regardless of the efforts of the family, friends and some physicians to be supportive. The reasons were lack of understanding relating to the complexity and severity of the disorder. Additive strain from relative and friends telling the patients to ignore or minimize their experience, telling them to ‘‘relax’’ or ‘‘do something else.” These actions have facilitated the creation of a social barrier impeding normal functioning. The goal of the current study was to further explore the psycho-social factors that are associated with psychological distress among IBS patients and to gain more information on psychiatric symptoms and cognitive attitudes, which can be further utilized in the development of psychotherapeutic treatment strategies. More specifically, we assessed the relationships between psychological distress and depressive symptoms among IBS patients and their socio-demographic and medical variables, personal resources – resilience and perceived optimism, interpersonal resource - social support and cognitive appraisal. Based on the aforementioned studies, we hypothesize that IBS patients with higher resilience, perceived optimism, and perceived social support will exhibited less psychological distress and depressive symptoms. Our second hypothesis predicted that participants with the highest combination of positive cognitions regarding their illness will have lower psychological distress and depressive symptoms in comparison to those with lower positive cognitions. Method Participants

One hundred and three patients diagnosed with Irritable Bowel Syndrome participated in the study. The sample 55

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consisted of 69 men and 34 women, aged 18-50. The average age was 24.53 (S.D. =6.243), 79.6% of the sample were unmarried (n=82). No history of previous medical conditions or psychiatric illnesses was reported by the subjects. Measures

Demographic and medical information: Digestive disease report derived from the questions: Were you diagnosed with IBS by a gastroenterologist? Did you suffer from it for at least one year? Only participants who answered “yes” to those questions were enrolled into the study. The respondents provided demographical data: age, gender coded as 0 = men, 1 = women, marital status coded as 0 = unmarried, 1 = married. The following self-report questionnaires were used in this study: • Subscales of Cognitive appraisal were measured by the Illness Cognition Questionnaire (ICQ) (36), which is an 18-item scale intended to measure the personal perception of one’s own illness and his ability to function. The ICQ has three subscales: Acceptance, perceived benefit and helplessness. High score in the acceptance scale reflects positive cognitions regarding one’s illness, while perceived benefit and helplessness reflect negative cognitions regarding one’s illness. The reliability of these scales were very good (Acceptance: Cronbach’s alpha = 0.804; Perceived benefit: Cronbach’s alpha = 0.851; Helplessness: Cronbach’s alpha = 0.892). • Global positive illness cognition was measured by the ICQ subscales using the median score of each subscale. In order to create the positive appraisal groups we selected participants who had scored the following: above the median in the acceptance sub-scale, under the median in the perceived benefit and helplessness sub-scales). This led to four groups: high global positive appraisal and low global positive appraisal groups with two intermediate groups. • Perceived optimism was measured by the single item statement: “given you current situation, do you consider yourself optimistic about the future?” This item was coded as 0 = no, 1 = yes. • Resilience was measured by the Connor-Davidson Resilience Scale (CD-RISC) (37), which is a 25-item scale intended to measure the personal resilience, tolerance for negative affect and social support. High scores reflect higher resilience. The reliability of this scale was very good (Cronbach’s alpha = 0.91). • Perceived social support was measure by a single item 56

“Do you perceived yourself as reviewing enough social support.” This item was coded as 0 = no, 1 = yes. • Depressive symptoms were measured by the Short Center for Epidemiologic Studies Depression Scale (SCES-D) which is a 10-item scale intended to measure the severity of depressive symptoms an individual experiences (38). The items are rated by frequency on a 4-point scale, where higher scores reflect higher risk for depression. The reliability of this scale was very good (Cronbach’s alpha = 0.85). • Psychological distress was measured by the General Health Questionnaire (GHQ-12) (39), which contains 12 items (e.g., “felt you couldn’t overcome your difficulties,” “been losing confidence in yourself ”) for 12 specific psychological symptoms such as anhedonia and personal competence. Each item is rated by its frequency over the past few weeks on a 4-point scale. Higher scores indicate poorer mental health. Cronbach’s alpha coefficient for this sample was 0.86. Procedure

The participants were recruited from the largest internet forum in Israel dealing with gastroenterology. The initial message stated the inclusion criteria: (a) a Gastroenterologist diagnosis of IBS, (b) 18-50 years of age. The rationale to impose age limitation was in order to prevent sample bias. Participants received the questionnaires via e-mail. Along with the questionnaires, participants received instructions and a short explanation as to the purpose of the study. After the completed questionnaires were sent back by e-mail, a verification process was begun by the research assistant (DA) who asked the participants for their permission to contact them via phone in order to verify relevant details while guaranteeing complete anonymity and to thank them personally for their contribution to the study. Only participants who were willing to participate in the verification process were enrolled in the study, in order to prevent potential biases that are known in internet studies (40). All the participants were given the opportunity to request further information. The study was approved by the Institutional Review Board committee at the Open University. Statistical methods

Four sets of hierarchical multiple regression were conducted, each one corresponding respectively to an outcome variable (psychological distress, depressive symptoms) in order to test hypotheses 1 and 2. The hierarchical regression had four steps. The first step consisted of socio-demographic variables (age, gender, marital status). The second step con-

Menachem Ben-Ezra et al.

sisted of personal variables (resilience, perceived optimism). The third step consisted of a cognitive appraisal variable (global positive illness cognition) which reflects one global illness appraisal. The fourth step consisted of an interpersonal variable (social support). A preliminary analysis was conducted for potential multicollinearity. Applying the rules used in the literature stating that tolerance of less than 0.20 and/or variance inflation factor (VIF) of 5 and above indicate a multicollinearity problem (41). The preliminary analysis of the regressions yielded tolerance ranging from 0.486-0.972 and VIF of 1.029-2.058. These results have indicated that there was no multicollinearity problem. Finally, additional supplementary analyses of multiple mediation tests of indirect effects were conducted based on the after mentioned hierarchical regressions (42). Results For basic information and correlation matrix, see Table 1. In line with hypothesis 1 and 2, as seen in Table 2 and 3, higher depressive symptoms were associated with lower level of global positive illness cognition appraisal (β = -.409; t = -4.803; p>.001) in step 3 and step 4 (β = -.394; t = -4.701; p>.001). In addition, higher psychological distress was associated with lower global positive illness cognition appraisal (β = -.509; t = -6.435; p>.001) in step 3 and step 4 (β = -.494; t = -6.375; p <.001). For more information, see Table 2 and 3. The results of the multiple mediation tests of indirect effects showed that the following mediators were significant when depressive symptoms were the dependent variable: resilience (β = -.11; t = -3.69; p <.001), perceived optimism (β = -1.708; t = -2.027; p <.05), global positive illness cogni-

tion appraisal (β = -2.039; t = -4.701; p <.001) and perceived social support (β = 1.763; t = 2.191; p <.05). This model explained about 36% of the variance (R2 = .405; adjusted R2 = .361; p < .001). For more information, see Table 2. The results of the multiple mediation tests of indirect effects showed that the following mediators were significant when psychological distress was the dependent variable: resilience (β = -.13; t = -4.000; p <.001), global positive illness cognition appraisal (β = -2.975; t = -6.375; p <.001) and perceived social support (β = 2.090; t = 2.415; p <.05). This model explained about 45% of the variance (R2 = .492; adjusted R2 = .454; p < .001). For more information, see Table 3. Discussion The results have shown that psychological distress and depressive symptoms among IBS patients are associated with global positive illness cognition, specific illness cognition of helplessness appraisal, resilience and to lesser extent by social support, perceived optimism, illness cognitions of acceptance and perceived benefit appraisals. These finding are in line with our hypotheses to some extent. While showing that resilience, illness cognition of helplessness appraisal add to the ample evidence that personal resources help persons to cope with stressful or traumatic events (7, 43) and account for at least some of the variability in individuals’ adjustment to stressors (44, 45). The results also provide further support for Lazarus and Folkman’s (7-9) claim that persons’ appraisals of stressful events are more important to their psychological adjustment than the “objective” stress of the events. Furthermore, our find-

Table 1. Baseline Characteristics of the Study Variables (n=103) Predictors Age

Mean (SD) 24.5 (6.2)

Gender (Men)

67.0

Marital status (Not Married) Resilience

-.130

.519** -.201*

-.065

79.6 93.2 (13.8)

Optimism

1.34 (.48)

Positive appraisal

1.66 (.96)

Social support

1.37 (.50)

Psychological distress

24.3 (5.8)

Depressive symptoms

19.6 (4.9)

-.115

.093

.043

-.068

-.045

-.079

-.010

-.045

-.031

.224*

.078

.063

-.007

-.047

-.084

-.091

-.171

-.130

.314**

.005

-444**

-.405**

-.045

.085

-.045

-.083

-596**

-.490**

.222*

.206* .749**

Gender was coded as 0 = men; 1 = women Marital status was coded as 0 = married/cohabitation; 1 = not married/cohabitation Psychological Distress was measured by the GHQ-12. Depressive symptoms were measured by the Short CES-D. * p< .05; ** p<.01; ***p<.001

Cognitive Appraisal Distress Among Patients with Irritable Bowel Syndrome Isr J Psychiatry Relat Sci - Vol. 52and - No 1Psychological (2015)

Table 2. Hierarchical Multiple Regression Predicting Increased Risk of Depression (CES-D) (n=103) Step 1: Model R = .181; Model R2 = .033 Predictors

Standardized β

Step 2: Model R = .474; Model R2 = .224; R2 change = .191*** Standardized β

Step 3: Model R = .612; Model R2 = .375; R2 change = .150***

Standardized β

Step 4: Model R = .636; Model R2 = .405; R2 change = .030* Standardized β

Age

.060

.523

.031

.295

.034

.353

.043

.463

Gendera

.031

.308

.033

.366

.012

.144

-.027

-.328

Marital statusb

-.196

-1.675

-.210

-1.974

-.226*

-2.360

-.224*

-2.380

Resilience

-.435***

-4.792

-.307***

-3.562

-.312***

-3.691

Optimism

-.141

-1.555

Positive appraisal

-.145

-1.769

-.164*

-2.027

-.409***

-4.803

-.394***

-4.701

.180*

2.191

Social support Gender was coded as 0 = men; 1 = women b Marital status was coded as 0 = married/cohabitation; 1 = not married/cohabitation * p< .05; ** p<.01; ***p<.001 a

Table 3. Hierarchical Multiple Regression Predicting Increased Risk of Psychological Distress (GHQ-12) (n=103) Step 1: Model R = .119; Model R2 = .014 Predictors

Step 2: Model R = .477; Model R2 = .228; R2 change = .213***

Standardized β

Age

.054

.463

.016

.154

.019

Gendera

.064

.628

.070

.766

.043

-.106

-.901

Marital status

Standardized β

Step 3: Model R = .679; Model R2 = .460; R2 change = .233***

Standardized β

Step 4: Model R = .701; Model R2 = .492; R2 change = .031* Standardized β

.219

.029

.338

.560

.003

.041

-.117

-1.101

-.137

-1.542

-.135

-1.552

Resilience

-.466***

-5.152

-.307***

-3.839

-.312***

-4.000

Optimism

-.103

-1.134

Positive appraisal Social support

-.108

-1.412

-.127

-1.695

-.509***

-6.435

-.494***

-6.375

.183*

2.415

Gender was coded as 0 = men; 1 = women b Marital status was coded as 0 = married/cohabitation; 1 = not married/cohabitation * p< .05; ** p<.01; ***p<.001 a

ings contribute to the view of coping as contextual, that is, influenced by persons’ appraisal of the actual demands in the encounter and resources for managing them. The emphasis on the context means that particular persons and situation variables shape together the coping efforts (46). More specifically, the findings highlight the importance of resilience as an interpersonal resource that contributes to one’s ability to cope, function and adapt well to the stressful situation. IBS patients who were less resilient were more distressed and exhibited higher depressive symptoms. Thus, if an individual exhibits behaviors associated with low resilience, then there is an increased likelihood that the individual will function poorly in stressful situations thus showing lesser adaptation (47). Our findings are consistent with the ample literature showing that individuals who do not display a resilient adaptation exhibit difficulties in regulating negative emotions and higher sensitivity to stressful life events (48). 58

The global positive illness appraisal was found to be discriminant predictor of psychological distress and depressive symptoms even more than resilience among IBS patients. More specifically, global perception of one’s illness gave us a sum of positive and negative appraisals into one unified construct. This is somewhat similar to other known predictors of physical and mental health in the literature such as self-rated health (49) and subjective well-being (life satisfaction) (50). This may lead to a rather bold argument favoring the unified construct of illness perception over its subscale. These subscales were less salient predictors of psychological distress and depressive symptoms. Perceived social support was another predictor of higher level of depressive symptoms among IBS patients. This finding is somewhat surprising in view of the direct positive effect of support and the buffering effect, by which social support moderates the impact of acute and chronic stressors on health (4). Another study (51) posits that social support is strongly

Menachem Ben-Ezra et al.

correlated with the stress and coping process. Specifically, social support is considered a moderator in the stress process. Moderators are “the variety of appraisals, coping strategies, resistance factors, and vulnerabilities that modify how stress is experienced and what its effects may be” (52). Moderators are believed to reduce the appraisal of stress when functioning in a positive manner. By reducing the appraisal it indirectly facilitates the coping process. A possible explanation might be that family and friends’ concerns add emotional burden to the feelings of shame and embarrassment that the IBS patients already experience. IBS patients sense that their life was interrupted while not grasping fully how their condition encompasses every domain of their lives. In this context, a study by Stansfeld (31) has found that among IBS patients, a predominant theme was perceived social stigma when others did not understand or accept their feelings (4). Limitations There are several study limitations to be noted. Firstly, we did not identify many differences in health status and illness severity, as have been showed by other studies (53). Secondly, our sample’s mean age and gender distribution are different to that of IBS subjects’ demographic characteristics found in epidemiologic studies (54). We feel that this fact limits the generalization of our findings. Another limitation relates to the sample recruitment - using an internet forum sample. One may claim this sample is different from other means of survey. However, recent studies have shown that with regard to clinical data, internet samples do not differ from other, more traditional samples (40). One possible explanation may be the fact there is a perception of anonymity which helps people disclose information about themselves. In addition, we received the completed questionnaires by personal email and our research assistant (DA) corresponded with them, thus helping to lower the level of anonymity and make it similar to phone survey. Thirdly, important medical factors were not obtained probably because of strict ethical considerations and reluctance of the participants to share medical information. This is important as severity, duration and comorbidity with other disorders may influence the results of the study. Finally, the use of single item measurement for perceived optimism and perceived social support may also impede generalization of our findings. However, it should be taken into account that we used a wide battery of scales that have merits and the use of single item measurement is a price to be paid when using a long and extensive questionnaire as in our study. Moreover, the use of single items is known in the literature (49, 50).

Clinical implication and future research

Our findings highlight the salience of cognitive appraisal and resilience in IBS psychological adjustment. It seems that IBS patients might benefit from psycho- educational interventions (CBT based) designed to assist them in reducing their helplessness appraisal and increasing the appraisal of their ability to cope with the symptoms of their illness. More specifically, a cognitive-behavioral treatment approach may help clients reconceptualize their experience with IBS from helplessness and hopelessness to resourcefulness and optimism, may help clients identify relationships among thoughts, feelings, behaviors, the environment, and IBS symptoms, and may empower clients to develop and implement increasingly more effective ways of coping with IBS in order to improve their quality of life (55). Moreover, psycho-social professionals should present resilience-based interventions to IBS patients in order to help them to adapt better to adversity inherent in their illness. Further research is suggested to examine other factors that affect adjustment to IBS. A possible direction to explore is working with families using psycho-educational techniques in order to make social support effective. Group therapy within a cognitive framing context in order to enhance positive appraisals and reduce negative appraisals thus reduces both psychological distress and depressive symptoms. References 1. Saito YA, Schoenfeld P, Locke GR. The epidemiology of irritable bowel syndrome in North America: A systematic review. Am J Gastroenterol 2002; 97: 1910-1915. 2. Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: What are the causes and implications? Gastroenterology 2002; 122: 1140-1156. 3. Mayer EA. Clinical practice-irritable bowel syndrome. NEJM 2008; 358: 1692-1699. 4. Drossman DA, Morris CB, Schneck S, et al. International survey of patients with IBS: Symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit. J Clin Gastroenterol 2009; 43: 541-550. 5. Lazarus RS. Psychological stress and coping in adaptation and illness. Int J Psychiatry Med 1974; 5: 321-333. 6. Lazarus RS. The stress and coping paradigm. In: Eisdorfer C, Cohen D, Kleinmann A, et al., editors. Models for clinical psychopathology. New York: SP Medical and Scientific Books, 1981: pp. 177-214. 7. Lazarus RS, Folkman S. Stress, appraisal and coping. New York: Springer, 1984. 8. Lazarus RS. Stress and emotion: A new synthesis. New York: Springer, 1999. 9. Folkman S, Lazarus RS, Dunkel-Schetter C, DeLongis A, Gruen R. The dynamics of a stressful encounter: Cognitive appraisal, coping, and encounter outcomes. J Per Soc Psychol 1986; 50: 992-1003. 10. Pakenham KI, Rinaldis M. The role of illness, resources, appraisal, and coping strategies in adjustment to HIV/AIDS: The direct and buffering effects. J Behav Med 2001; 24: 259-279. 11. Lash SJ, Giliespie BL, Eisler RM, Southard DR. Sex differences in cardiovascular reactivity: Effects of the gender relevance of the stressor. Health Psychol 1991; 10: 392-398.

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12. Hamama-Raz Y, Solomon Z, Shecter Y, Azizi A. Objective and subjective stressors and the psychological adjustment of melanoma survivors. Psycho-Oncology 2006; 15: 1-9. 13. Scheier MF, Carver CS. Optimism, coping, and health: Assessment and implications of generalized outcome expectancies. Health Psychol 1985; 4: 219-247. 14. Brissette I, Scheier MF, Carver CS. The role of optimism in social network development, coping, and psychological adjustment during a life transition. J Pers Soc Psychol 2002; 82: 102-111. 15. Nes LS, Segerstrom SC. Dispositional optimism and coping: A metaanalytic review. Per Soc Psychol Rev 2006; 10: 235-251. 16. Taylor SE, Stanton AL. Coping resources, coping processes, and mental health. Annu Rev Clin Psychol 2007; 3: 377-401. 17. Wrosch C, Scheier MF. Personality and quality of life: The importance of optimism and goal adjustment. Qual Life Res 2003; 12: 59-72. 18. Grote NK, Bledsoe SE. Predicting postpartum depressive symptoms in new mothers: The role of optimism and stress frequency during pregnancy. Health Soc Work 2008; 32: 107-118. 19. Grote NK, Bledsoe SE, Larkin J, Lemay EP, Brown C. Stress exposure and depression in disadvantaged women: The protective effects of optimism and perceived control. Soc Work Res 2007; 31: 19-33. 20. Kochanska G, Aksan N, Penney SJ, Boldt LJ. Parental personality as an inner resource that moderates the impact of ecological adversity on parenting. J Per Soc Psychol 2007; 92: 136-150. 21. Epping-Jordan JE, Compas BE, Osowiecki DM, Oppedisano G, Gerhardt C, Primo K, Krag DN. Psychological adjustment in breast cancer: Processes of emotional distress. Health Psychol 1999; 18: 315-326. 22. Ben-Zur H, Rappaport B, Uretzky G. Pessimism, lifestyle and survival: A follow-up study of open-heart surgery patients in Israel. Illness Crisis Loss 2004; 12: 299-306. 23. Carver CS, Scheier MF, Segerstrom SC. Optimism. Clin Psychol Rev 2010; 30: 879-889. 24. Masten AS, Powell JL. A resilience framework for research, policy, and practice. In: Haggerty RJ, Sherrod LR, Garmezy N, Rutter M, editors. Stress, risk and resilience in children and adolescents: Processes, mechanisms and intervention. New York: Cambridge University Press, 2003: pp. 1-25. 25. Bonanno GA. Loss, trauma, and human resilience: Have we underestimated the human capacity to thrive after extremely aversive events? Am Psychol 2004; 59: 20-28. 26. Campbell-Sills L, Cohan SL, Stein MB. Relationship of resilience to personality, coping, and psychiatric symptoms in young adults. Behav Res Ther 2006; 44: 585-599. 27. Friborg O, Hjemdal O, Rosenvinge JH, Martinussen M. A new rating scale for adult resilience: What are the central protective resources behind healthy adjustment? Int J Methods Psychiatr Res 2003; 12:65-76. 28. Cohen, S, Mermelstein, R, Kamarck, T, et al. Measuring the functional components of social support.In: Saranson IG, Saranson BR, editors. Social support: theory, research and application Dordrecht, The Netherlands: Martinus Nijhoff, 1985. 29. Holahan CJ, Moos RH, Bonin L. Social support, coping, and psychosocial adjustment: A resources model. In: Pierce GR, Lakey B, Sarason IG, Sarason BR, editors. Sourcebook of social support and personality. New York: Plenum, 1997: pp. 169-186. 30. Schwarzer R, Leppin A. Social support and health: A meta-analysis. Psychol Health 1989; 3: 1-15. 31. Stansfeld S. Social support and social cohesion. In: Marmot M, Wilkinson R, editors. Social determinants of health. Oxford: Oxford University, 2006: pp. 155-178. 32. Cohen S, Hoberman H. Positive events and social support as buffers of life change stress. J Appl Soc Psychol 1983; 13: 99-125. 33. DiMatteo MR. Variations in patientsâ&#x20AC;&#x2122; adherence to medical recommendations: A quantitative review of 50 years of research. Med Care 2004; 42: 200-209. 34. Heaney CA, Israel BA. Social networks and social support in health

education. In: Glanz K, Lewis FM, Rimer BK, editors. Health behavior and health education. San Francisco: Jossey-Bass, 1997: pp. 179-205. 35. Sarason BR, Sarason IG, Gurung RAR. Close personal relationships and health outcomes: A key to the role of social support. In: Duck S, editor. Handbook of personal relationships. New York: Wiley, 1997: pp. 547-573. 36. Evers AW, Kraaimaat FW, van Lankveld W, Jongen PJ, Jacobs JW, Bijlsma JW. Beyond unfavorable thinking: The illness cognition questionnaire for chronic diseases. J Consult Clin Psychol 2001; 69: 1026-1036. 37. Connor KM, Davidson JR. Development of a new resilience scale: The Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety 2003; 18: 76-82. 38. Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening for depression in well older adults: Evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). Am J Prev Med 1994; 10: 77-84. 39. Goldberg DP, Gater R, Sartorius N, Ustun TB, Piccinelli M, Gureje O, Rutter C. The validity of two versions of the GHQ in the WHO study of mental illness in general health care. Psychol Med 1997; 27: 191-197. 40. Eysenbach G, Wyatt J. Using the Internet for surveys and health research. J Med Internet Res 2002; 22: e13. doi: 10.2196/jmir.4.2.e13. 41. Oâ&#x20AC;&#x2122;Brien RM. A caution regarding rules of thumb for variance inflation factors. Qual Quant 2007; 41: 673-690. 42. Preacher KJ, Hayes AF. Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav Res Methods 2008; 40: 879-891. 43. Hobfool SE. Stress, culture and community: The psychology and philosophy of stress. New York: Plenum, 1998. 44. Antonovsky A. Unraveling the mystery of health. San Francisco: JosseyBass, 1987. 45. Maes S, Leventhal H, de Ridder DT. Coping with chronic diseases. In: Zeidner M, Endler NS, editors. Handbook of coping: Theory, research, applications. New York: Wiley, 1996: pp. 221-251. 46. Folkman S, Lazarus RS, Dunkel-Schetter C, DeLongis A, Gruen RJ. Dynamics of a stressful encounter: Cognitive appraisal, coping, and encounter outcomes. J Pers Soc Psychol 1986; 50: 992-1003. 47. White B, Driver S, Warren AM. Considering resilience in the rehabilitation of people with traumatic disabilities. Rehabil Psychol 2008; 53: 9-17. 48. Quale AJ, Schanke AC. Resilience in the face of coping with a severe physical injury: A study of trajectories of adjustment in a rehabilitation setting. Rehabil Psychol 2010; 55: 12-22. 49. Benyamini Y, Blumstein T, Lusky A. et al. Gender differences in the self-rated health-mortality association: Is it poor self-rated health that predicts mortality or excellent self-rated health that predicts survival? Gerontologist 2003; 43: 396-405. 50. Oswald AJ, Wu S. Objective confirmation of subjective measures of human well-being: Evidence from the U.S.A. Science 2010; 327: 576-579. 51. Dunkel-Schetter C, Folkman S, Lazarus RS. Correlates of social support receipt. J Pers Soc Psychol 1987; 53: 71-80. 52. Taylor SE, Aspinwall LG. Mediating and moderating processes in psychosocial stress: Appraisal, coping, resistance, and vulnerability. In Kaplan HB, editor. Psychosocial stress perspectives on structure, theory, life-course, and methods. San Diego: Academic Press, 1986: pp. 71-110. 53. Drossman DA, Chang L, Schneck S, Blackman C, Norton WF, Norton NJ. A focus group assessment of patient perspectives on irritable bowel syndrome and illness severity. Dig Dis Sci 2009; 54: 1532-1541. 54. Andrews EB, Eaton SC, Hollis KA, et al. Prevalence and demographics of irritable bowel syndrome: Results from a large web-based survey. Aliment Pharmacol Ther 2005; 22: 935-942. 55. Toner BB, Stuckless N, Ali A, Downie F, Emmott S, Akman D. The development of a cognitive scale for functional bowel disorders. Psychosom Med 1998, 60: 492-497.

Isr J Psychiatry Relat Sci - Vol. 52 - No 1 (2015)

Jonathan Kushnir et al.

Assessing Fears of Preschool Children with Nighttime Fears by a Parent Version of the Fear Survey Schedule for Preschool Children Jonathan Kushnir, PhD,1 Doron Gothelf, MD,1,2 and Avi Sadeh, DsC3 1

The Child Psychiatry Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 3 The Adler Center for Research in Child Development and Psychopathology. Department of Psychology, Tel Aviv University, Tel Aviv, Israel 2

Abstract Background: Although excessive fears are common in preschool children, validated assessment tools for this age are lacking. Our aim was to modify and provide preliminary evidence of the utility of a preschoolers’ fearscreening tool, a parent-reported Fear Survey Schedule for Preschool Children (FSS-PC). Methods: 109 Israeli preschool children (aged 4-6 years) with chronic nighttime fears (NF) and 30 healthy children (controls) participated. The FSS-PC analysis included: 1) internal reliability, 2) correlations between FSS-PC scores and Child Behavior Checklist (CBCL) measures, 3) differences between NF and a comparison sample of FSS-PC scores, and 4) FSS-PC sensitivity in detecting change in NF following an intervention for NF. Results: There were low-to-medium positive correlations between the FSS-PC scores and several internalizing scales of the CBCL measures. FSS-PC scores in the NF group were significantly higher than the control children’s score. FSS-PC scores had adequate internal reliability and were also sensitive for detecting significant changes in fear levels following behavioral interventions. Limitations: Unique cultural and environmental circumstances and specific study group. Conclusions: This new version of the FSS-PC may provide clinicians with a novel and useful screening tool for early assessment of fear- and anxiety-related phenomena of preschool children.

INTRODUCTION Fears and anxiety are very prevalent among children (1, 2) and may have negative effects on their functioning. In one study that assessed fears in school-age children, more than 60% of them had reported that their fears interfered substantially with daily activities (3). Other studies indicated that fear and anxiety symptoms were accompanied by various emotional, social and behavioral problems (4-6). Although the terms “fear” and “anxiety” are frequently employed interchangeably, an examination of the literature indicates that both concepts are quite different in terms of their manifestation, function and biological underpinning, and the distinction between these concepts was demonstrated as empirically justifiable. However, it is not easy to separate between these phenomena because of significant overlap (7, 8). It has been demonstrated that childhood fears are not merely linked to symptoms of phobias, but that they also frequently reflect other anxiety disorders (9). Previous research on normal childhood fears have relied mainly on surveys composed of lists of potentially fearprovoking stimuli and situations, such as the widely used revised versions of the Fear Survey Schedule for Children (FSSC-R) (10, 11). The majority of fear survey schedule studies were based on children’s self-reports, and most of these studies have involved school-age children (10-13). The reliability of preschool children’s self-reports on fears, however, is questionable (14, 15). In this context, while the Koala Fear Questionnaire (16) is a validated self-report scale that directly assesses fears and fearfulness in children aged between 4 and 12 years, the assistance of an adult is required for its administration in pre-schoolers. Indeed, the most practical alternative to self-reporting of preschool

Address for Correspondence: Jonathan Kushnir, PhD, The Child Psychiatry Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel yonikushnir@gmail.com

Nighttime a Parent Version of the Fear Survey Schedule for Preschool Children Isr JAssessing Psychiatry Relat Sci - Vol. Fears 52 - No 1by (2015)

children’s fears is using their parents as reporters (14), yet only a minority of studies have involved parents as sources of information. Moreover, the validity of using parental reports has been questioned because of the low level of agreement between children and parents on children’s anxiety symptoms (17-21). Additionally, most studies that relied on parents as reporters of children’s fears focused on groups of school age or on a broad age range of children (22-25). To the best of our knowledge, there is only one report on preschool children that specifically assessed parental reports of a wide spectrum of anxiety symptoms, but not of fears (26). Clearly, there is a lack of tools for adequately assessing fears in preschool children. Such tools for enabling early detection of significantly severe fears among preschool children are of vast importance in light of evidence suggesting that untreated anxiety in children is persistent, that it has adverse effects on the child’s development, and that it predicts adolescent and adult anxiety and psychopathology (4, 27-30). For example, previous studies have demonstrated that young children who had strong fears or avoidance behaviors exhibited signs of serious social anxiety manifestations in adolescence (31, 32). The issue of fears among preschool children must be addressed in spite of the complexity of obtaining reliable self-reported data and the sparse research that has been conducted on fears among them. The aim of the current study was to modify and validate the Parent Report Fear Survey Schedule for Preschool Children (FSS-PC), a commonly used parent-report questionnaire for school-age children (14, 25) that we adapted for preschool population. Testing our version of the FSS-PC scale included: assessing construct validity, comparing clinical and non-clinical groups (discriminant validity), assessing internal reliability, and evaluating the adapted scale’s sensitivity in detecting changes in fears following established intervention for nighttime fears (NF). We hypothesized that children with NF will exhibit higher FSS-PC scores compared to control children, and that these scores will decrease following intervention. In addition, we expected positive correlations between FSS-PC scores and several internalizing scales of the Child Behavior Checklist (CBCL), demonstrating converging validity for the fear scale. METHODS SUBJECTS

The study included 139 children from clinical and comparison samples. The study group had severe NF and consisted of 109 preschool children (64 boys and 45 girls). Their ages 62

ranged between 4 to 6 years (mean age = 58.91 months, SD =8.32 months). More information and a comprehensive description of the demographic data of this sample are available in an earlier publication (33). The comparison group included 30 healthy children from the same age group with no history of NF (16 boys and 14 girls, mean age = 58.93 months, SD =7.62 months). Comparisons of the demographic variables revealed no group differences for any of them (34).Taken together, these two groups yielded a sample of 139 children (80 boys and 59 girls, mean age =58.91 months, SD =8.15). MEASURES

The Fear Survey Schedule for Preschool Children (FSS-PC) We designed the FSS-PC, which is a modified version of the Israeli FSSC-R, for the assessment of fears among children in this age group (35). The Israeli version of the FSSC-R consists of 70 items, including those that are uniquely relevant for the local population, such as fear of terror attacks, fear of war, etc. (35). Because the FSSC-R was designed for elementary school children, some of its items (e.g., being next to a mentally ill person, being near a cemetery at night, getting bad grades in school, preparing for an exam) are irrelevant for preschoolers. We identified 18 such items and excluded them, thus constructing a 52-item version of the FSS-PC. Parents were asked to rate their children’s fear level on a 1–4 scale (1 = not scary at all, 4 = very scary) on items such as ghosts, snakes, getting lost from parents, etc. Adding the scores for all responses across the 52 items yields a global fear score. The Child Behavior Checklist (CBCL) The CBCL (version for 1.5- to 6-year-olds) was used to assess behavior problems as perceived by parents (36). The CBCL is a widely used tool with well-established psychometric properties for assessing behavior problems in children. The “internalizing score” represents the combined score of items concerning problems of withdrawal, emotional reactiveness, somatic complaints, and depressed/anxious symptoms. The CBCL has been translated into Hebrew and validated in Israel (37). Family Background Information Questionnaire This questionnaire includes 25 questions covering demographic and developmental subjects. The questionnaire has been established in previous studies on children (38-41). PROCEDURES

The study was approved by the Departmental Ethical Committee and the Chief Scientist of the Israeli Ministry of

Jonathan Kushnir et al.

Education. Children in the study group were recruited from the local kindergarten system by means of letters to parents offering treatment for children with NF. The control group was comprised of healthy children recruited from the same local kindergarten system by means of letters to parents offering an opportunity for their children to participate in a study on sleep. Parents of all participants signed informed consent and completed the questionnaires. They were interviewed by trained research psychologists who also reviewed the completed FSS-PC and CBCL questionnaires. The children were diagnosed as having clinically significant NF if they fulfilled all three of the following criteria: (a) NF that required parental intervention to comfort the child at least two nights per week, (b) NF duration for at least two months, and (c) NF causing clinically significant distress or impairment in functioning of the child and family. Children who did not fulfill those inclusion criteria were assigned to the control group. Exclusion criteria for both the study and control groups were the same as previously described elsewhere (34): they included having major health or neurological-developmental problems and/or concurrently receiving psychiatric treatment, psychotherapy or similar interventions. Children in the

study group received an intervention for NF and their parents completed the FSS-PC questionnaire again six months after the initial assessment and interventions (for a comprehensive description see [33]). STATISTICAL ANALYSIS

Data analysis consisted of four main components: 1) assessment of internal reliability scores of the FSS-PC, 2) evaluation of the correlations between FSS-PC scores and CBCL measures, 3) assessment of differences in FSS-PC scores between study (children with significant NF) and control samples, and 4) assessment of the FSS-PC assessment’s sensitivity in detecting change following interventions for NF. Gender and age were entered as covariates in order to control for any potential effects on FSS-PC or CBCL score. RESULTS ASSESSMENT OF INTERNAL RELIABILITY SCORES

The internal reliability of the FSS-PC was calculated for the study group, the control group, and both groups in combination. The internal reliability scores of the FSS-PC, based on Cronbach’s alpha, were 0.77, 0.86 and 0.79, respectively. Evaluation of the correlations between FSS-PC scores and CBCL measures Pearson correlations between FSS-PC scores and CBCL measures were calculated separately for the study and control

Table 1. Correlations Between CBCL Scales and FSS-PC Scores for the Study Group, the Control Group and the Entire Cohort

CBCL Scale

Study group (n=109)

Control group (n=30)

Total sample (n=139)

CBCL Cronbach’s alpha scores for the total sample