israel journal of psychiatry and related sciences

israel journal of

psychiatry

‫ח‬ ‫ד‬ ‫ש‬ !

,‫סירקדין‬ ‫ה‬ ‫ת‬ ‫ר‬ ‫ו‬ ‫פ‬ ‫ה הי‬ ‫המאושרת לש חידה ל‬ ‫ה‬ ‫פ‬ ‫ר‬ ‫ע‬ ‫ו‬ ‫ימוש לפרק ז ת שינה‬ ‫עד‬ ‫מן של‬

Pediatric Bipolar Disorder Part I I: Treatment

,‫סירקדין‬ !‫לישון כמו שצריך‬ :‫סירקדין מספק למטופלים שלך בדיוק מה שהם צריכים‬ .‫ לשחזור מבנה השינה התקין במהלך כל שעות הלילה‬,‫מלטונין בשחרור מושהה‬ :‫סירקדין מכוון לענות על צרכי המטופלים שלך‬ ‫הירדמות קלה ומהירה‬ ‫שינה רצופה ומרעננת‬ ‫שיפור משמעותי באיכות החיים‬ ,‫כשאתה רושם לו סירקדין‬ !‫אתה מאפשר לו לישון כמו שצריך‬ .‫ שבועות בלבד‬4 ‫ מאושרות לשימוש עד‬, ‫) להן אינדיקציה לטיפול בנדודי שינה בישראל‬Z-‫* כל התרופות ההיפנוטיות (בנזודיאזפינים ותרופות ה‬ References: 1). Fourtillan J. B. Role of melatonin in the induction and maintenance of sleep. Dialogues Clin Neurosci 2002;4:395-401. 2). Wade A. G. et al. Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin 2007;23(10):2597-2605. 3). Otmani S. et al. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol Clin Exp 2008; Published online in Wiley InterScience. 4). Luthinger R. et al. The effect of prolonged release Melatonin on sleep measures and psychomotor performance in elderly patients with insomnia. Int Clin Psychopharmacol 2009. 5). Paul M. A. et al. Sleep-Inducing Pharmaceuticals: A Comparison of Melatonin, Zaleplon, Zopiclone, and Temazepam. Aviation Space Environmental Med 2004;75(6):512-519. 6). Lemoine P. et al. Prolonged release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res 2007;16:372-380.

Volume 49, Number 2, 2012 Israel Journal of Psychiatry and Related Sciences

3 1 ‫ש‬ ‫ב‬ * ‫ועות‬

Vol. 49 - Number 2 2012

ISSN: 0333-7308

75 Mechanistic Comparisons of Functional Domains across Pediatric and Adult Bipolar Disorder Highlight Similarities, As Well As Differences, Influenced by the Developing Brain Ezra Wegbreit, PhD, and Mani Pavuluri, MD, PhD

86 A Family-Based Psychosocial Treatment Model Amy E. West, PhD, and Sally M. Weinstein, PhD

95 Family-Focused Treatment for Children and Adolescents with Bipolar Disorder David J. Miklowitz, PhD

104 Stress and Support for Parents of Youth with Bipolar Disorder Radha B. Nadkarni, PhD, and Mary A. Fristad, PhD

112 The Effects of Ziprasidone on Prefrontal and Amygdalar Activation in Manic Youth with Bipolar Disorder Marguerite Reid Schneider, BA,Caleb M. Adler, MD, Rachel Whitsel, BA, Wade Weber, BS, MS, Neil P. Mills, BS, Samantha M. Bitter,2 James Eliassen, PhD, Stephen M. Strakowski, MD, and Melissa P. DelBello, MD

122 Efficacy and Safety of AntiManic Agents in Children and Adults

Arif Khan, MD, James Faucett, MA, MS, Graham J. Emslie, MD, and Walter A. Brown, MD

Indications: ABILIFY is indicated for the treatment of schizophrenia from 15 years of age. ABILIFY is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder and for the prevention of a new manic episode in patients who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions: During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period. The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic therapy. Aripiprazole should be used with caution in patients with known cardiovascular disease. There were uncommon reports of treatment emergent dyskinesia. Rare cases of NMS were reported during treatment. Aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures. Elderly patients with dementia-related psychosis are reported to have increased mortality. Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. Weight gain has been reported post-marketing among patients prescribed ABILIFY. Oesophageal dysmotility and aspiration have been associated with antipsychotic treatment, including ABILIFY. ABILIFY tablets contain lactose.

References: 1. Aripiprazole (Abilify®) Physician Prescribing Information Leaet approved by Israeli Ministry of Health. 2. Kane JM et al. Efcacy and Safety of Aripiprazole and haloperidol vs placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002; 63(9):763-771. 3. Kasper S et al. Efcacy and safety of aripiprazole vs haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int. J Neuropsychopharmacol 2003; 6 (4):325-337. 4. Volavka J et al; Efcacy of aripiprazole against hostility in schizophrenia and schizoaffective disorder: data from 5 double blind studies. J Clin Psychiatry 2005; 66(11):1362-1366. 5. Lieberman JA. Dopamine partial agonist: A new class of antipsychotic. CNS Drugs 2004; 18(4):251-267.

ABI-01-11

Biotis is an exclusive representative of selected brands of BMS Biotis Ltd. 22 Hamelacha St. P.O.Box 11372 Rosh Ha’Ayin, 48091 Israel. Tel: 03-9002005. Fax: 03-9002029 www.biotis.co.il Please refer to Abilify approved Physician Prescribing Information

74

NEW TREATMENT FOR Schizophrenia and Bipolar I Disorder1 Proven Efficacy in all Symptom Clusters2,3,4,5

75

RIT-08-12 APR 2012

‫חנוך‬-‫בן‬

‫ההצלחה שלהם‬ ‫מתחילה אצלך‬

Important note: Before prescribing, consult full prescribing information. • Presentation: Immediate-release (Ritalin®) tablets containing 10 mg methylphenidate hydrochloride. Sustained-release (Ritalin® SR) tablets containing 20 mg methylphenidate hydrochloride. Modified-release capsules (Ritalin® LA) containing 10 mg, 20 mg, 30 mg, or 40 mg methylphenidate hydrochloride. • Indications: Attention-deficit/hyperactivity disorder (ADHD); narcolepsy (Ritalin tablets and Ritalin SR tablets only). • Dosage: The dosage of Ritalin should be individualised according to the patient’s clinical needs and responses. Daily doses above 60 mg are not recommended. For children, start with 5 mg once or twice daily and increase in increments of 5 to 10 mg weekly. For Ritalin LA and SR, starting dose is 20 mg once daily. Patients may begin treatment with Ritalin LA 10 mg if necessary. For adults, the average daily dose is 20 to 30 mg. Ritalin LA is for once daily administration. • Contraindications: Hypersensitivity to methylphenidate or to any of the excipients, anxiety, tension, agitation, hyperthyroidism, pre-existing cardiovascular disorders including severe hypertension, angina, arterial occlusive disease, heart failure, haemodynamically significant congenital heart disease, cardiomyopathies, myocardial infarction, potentially life-threatening arrhythmias and channelopathies, during treatment with nonselective, irreversible monoamine oxidase (MAO) inhibitors, or within a minimum of 2 weeks of discontinuing those drugs, glaucoma, phaeochromocytoma, diagnosis or family history of Tourette’s syndrome. • Warnings/Precautions: Generally should not be used in adults, children or adolescents with structural cardiac abnormalities or other serious cardiac disorders that may increase the risk of sudden death. Pre-existing cardiovascular disorders, a family history of sudden death and ventricular arrhythmia should be assessed before initiating treatment. Caution in patients with pre-existing hypertension. Blood pressure should be monitored during treatment. Patients who develop symptoms suggestive of cardiac disease should undergo prompt cardiac evaluation. Misuse may be associated with sudden death and other serious cardiovascular adverse events. Patients with pre-existing cerebrovascular abnormalities should not be treated. Patients with additional risk factors (history of cardiovascular disease, concomitant medications that elevate blood pressure) should be assessed regularly for neurological/psychiatric signs and symptoms. Pre-existing psychiatric disorders and a family history of psychiatric disorders should be assessed before initiating treatment. Should not be initiated in patients with acute psychosis, acute mania or acute suicidality. In case of emergent psychiatric symptoms (e.g. hallucinations or mania, aggressive behaviour and suicidal tendency) or exacerbation of pre-existing psychiatric symptoms, Ritalin should not be given to patients unless the benefit outweighs the potential risk. Family history should be assessed and clinical evaluation for tics or Tourette’s syndrome in children should precede ADHD treatment. Patients should be regularly monitored for the emergence or worsening of tics during initiating treatment.

Growth should be monitored during treatment as clinically necessary, treatment interruption may be considered. Caution in patients with epilepsy. Chronic abuse can lead to marked tolerance and psychological dependence. Caution in emotionally unstable patients. Careful supervision during withdrawal. Blood count monitoring during long-term treatment. Consider appropriate medical intervention in the event of haematological disorders. Not recommended for children under 6 years of age. Refrain from driving and using machinery if dizziness, drowsiness, blurred vision, hallucination or other CNS side effects occur. Not recommended during pregnancy unless benefits outweigh risks. Breast76 should not take Ritalin. • Interactions: Concomitant use contraindicated: non-selective, irreversible MAO inhibitors (currently or within the preceding 2 weeks). Caution when used concomitantly with drugs that elevate feeding women blood pressure, coumarin anticoagulants, anticonvulsants, centrally acting alpha-2 agonists (e.g. clonidine), direct and indirect dopamine agonists and antagonists (e.g. tricyclic antidepressants, DOPA, antipsychotics), phenylbutazone.

‫ להתחלת טיפול‬Ritalin® LA 10mg 1

‫ פעמיים ביום‬Ritalin® 5mg ‫או כטיפול פעם ביום לילדים המקבלים‬ :‫ מראה באופן מובהק‬Ritalin® LA

‫(י‬p<0.001)

‫ספיגה מהירה יותר מקונצרטה של החומר הפעיל‬ 2 ‫(י‬p<0.001) ‫רמות שיא בדם גבוהות יותר מקונצרטה‬ P<0.001

Ritalin® LA 20 mg Concerta® 18 mg

10

Concerta® 20 mg (dose-adjusted)

8 Concentration (μg/L)

2

‫מינון‬ ‫חדש‬

‫ מאושר בישראל‬Ritalin® LA 10mg (ADHD) ‫לטיפול בהפרעות קשב וריכוז‬ ‫ הכוללת בדרך‬,‫כחלק מתוכנית טיפולית‬ ‫ חינוכי וסוציאלי‬,‫כלל טיפול פסיכולוגי‬ ,Ritalin® LA 20mg :‫ומתווסף ל‬ 1 Ritalin® LA 40mg, Ritalin® LA 30mg

6

‫ כיסוי מלא לכל‬,‫מתן פעם ביום‬ 1,2,3 ‫שעות הלימודים‬

4

2

‫פרופיל פרמקוקנטי הדומה‬ ‫ הניתן פעמיים‬IR ‫לריטלין‬ 1 (‫ שעות‬4 ‫ביום )בהפרש של‬

0 0

5

10

15

20

25

Time (h)

1

‫טבלת החלפה‬ Ritalin SR 20 mg-‫ ו‬Ritalin 10 mg-‫מ‬ Previous Methylphnidate Dose

5 mg methylphenidate twice daily 10mg twice daily or 20mg SR once daily 15mg twice daily 20mg twice daily or 40mg SR once daily

1,2

Recommended Ritalin® LA Dose

10 mg once daily 20 mg once daily 30 mg once daily 40 mg once daily

1

‫ספיגה מהירה‬

‫ניתן לפתוח את הכמוסה ולפזר את‬ ‫תוכנה בשלמותה על מזון רך ולא חם‬ ‫מגוון רחב של מינונים המאפשר‬ 1 ‫התאמה מלאה לצרכי המטופל‬ ‫ אינו מכיל גלוטן‬Ritalin® LA

1

Alcohol: patients should abstain from alcohol during treatment. Ritalin should not be taken on the day of a planned surgery due to risk of sudden blood pressure increase during surgery. May induce false positive laboratory tests for amphetamine. • Adverse reactions: Very common: nervousness, insomnia. Common: decreased appetite, headache, drowsiness, dizziness, dyskinesia, tachycardia, palpitation, arrhythmias, changes in blood pressure and heart rate (usually an increase), abdominal pain, nausea, vomiting, dry mouth, rash, pruritus, urticaria, fever, scalp hair loss, arthralgia. Rare: difficulties in visual accommodation, blurred vision, angina pectoris, moderately reduced weight gain and slight growth retardation during prolonged use in children. Very rare: leucopenia, thrombocytopenia, anaemia, hypersensitivity reactions, hyperactivity, psychosis (sometimes with visual and tactile hallucinations), transient depressed mood, convulsions, choreoathetoid movements, tics or exacerbation of existing tics and Tourette’s syndrome, cerebrovascular disorders including vasculitis, cerebral haemorrhages and cerebrovascular accidents, neuroleptic malignant syndrome, abnormal liver function, thrombocytopenic purpura, exfoliative dermatitis, erythema multiforme, muscle cramps. Reported with other methylphenidate-containing products: nasopharyngitis, pancytopenia, auricular swelling, anxiety, irritability, aggression, affect lability, agitation, abnormal behaviour or thinking, anger, suicidal ideation or attempt (including completed suicide), mood altered, mood swings, hypervigilance, mania, disorientation, libido disorder, apathy, repetitive behaviours, over-focussing, confusional state, dependence (cases of abuse and dependence have been described, more often with immediate release formulations), tremor, reversible ischaemic neurological deficit, migraine, diplopia, mydriasis, visual disturbance, cardiac arrest, myocardial infarction, peripheral coldness, Raynaud’s phenomenon, cough, pharyngolaryngeal pain, dyspnoea, diarrhoea, constipation, angioneurotic oedema, hyperhidrosis, erythema, fixed drug eruption, myalgia, muscle twitching, haematuria, gynaecomastia, chest pain, fatigue, sudden cardiac death, weight decrease, cardiac murmur. • RIT NSS 10 2011 base on RIT API AUG 11CL V6

03-9229230 .‫ פקס‬,03-9201111 .‫ פ"ת טל‬,36 ‫ שחם‬Novartis Pharma Services AG

‫ למידע נוסף יש לעיין בעלון לרופא כפי שאושר על ידי משרד הבריאות הישראלי‬,‫ה‬/‫ה נכבד‬/‫רופא‬

References: 1. Ritalin® Prescribing Information, approved by the Israeli Ministry of Health. 2. Markowitz JS, Straughn AB, Patrick KS, et al.

Pharmacokinetics of methylphenidate after oral administration of two modified-release formulations in healthy adults . Clin Pharmacokinet 2003; 42 (4): 393-401. 3. Lopez F, Silva R, et al. Comparative efficacy of two once daily methylphenidate formulations (Ritalin® LA and Concerta) and placebo in children with attention deficit hyperactivity disorder across the school day. Pediatr Drugs. 2003:5(8):545-555.

77

Once Daily

XR

TM

Seroquel XR 150 mg

06-14-SER-12-IL-024

)add-on(

‫חדש‬ ‫בישראל‬

78

israel journal of

psychiatry and related sciences EDitor

David Greenberg DEPUTY EDITORS

David Roe Rael Strous Gil Zalsman

Book reviews editor

Yoram Barak

128 > Procedural Immunity of the

Ezra Wegbreit, and Mani Pavuluri

Jacob Margolin,Oren Asman, Roberto Mester, and Moshe Kalian

Functional Domains across Pediatric and Adult Bipolar Disorder Highlight Similarities, As Well As Differences, Influenced by the Developing Brain

86 > A Family-Based Psychosocial Treatment Model Amy E. West, and Sally M. Weinstein

Founding Editor

95 > Family-Focused Treatment for Children and Adolescents with Bipolar Disorder

Heinz Z. Winnik

David J. Miklowitz

Editorial Board

Alean Al-Krenawi Alan Apter Elliot Gershon Talma Hendler Ehud Klein Ilana Kremer ltzhak Levav Yuval Melamed Shlomo Mendlovic Ronnen Segman Eliezer Witztum Zvi Zemishlany International Advisory Board

Yoram Bilu Aaron Bodenheimer Carl Eisdorfer Julian Leff Margarete Mitscherlich-Nielsen Peter Neubauer Phyllis Palgi Leo Rangell Melvin Sabshin Robert Wallerstein Myrna Weissman

104 > Stress and Support for Parents

District Psychiatrists and Members of the District Psychiatric Committees against Civil Wrongs Claims in Israel

137 > Evidence for an Association between Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism and General Intellectual Ability in EarlyOnset Schizophrenia Nora S. Vyas, and Basant K. Puri

145 > Book reviews Yoram Barak

of Youth with Bipolar Disorder

Radha B. Nadkarni, and Mary A. Fristad

112 > The Effects of Ziprasidone on

Prefrontal and Amygdalar Activation in Manic Youth with Bipolar Disorder

Marguerite Reid Schneider, Caleb M. Adler, Rachel Whitsel, Wade Weber, Neil P. Mills,, Samantha M. Bitter, James Eliassen, Stephen M. Strakowski, and Melissa P. DelBello

122 > Efficacy and Safety of AntiManic Agents in Children and Adults Arif Khan, James Faucett, Graham J. Emslie, and Walter A. Brown

Hebrew Section

146 > News and Notes 150 > Abstracts

Assistant Editor

Joan Hooper

Marketing: MediaFarm Group

+972-77-3219970 23 Zamenhoff st.

Tel-Aviv 64373, Israel

amir@mediafarm.co.il www.mediafarm.co.il

Vol. 49 - Number 2 2012

75 > Mechanistic Comparisons of

PAst Editor

Eli L. Edelstein

The Official Publication of the Israel Psychiatric Association

Hanna Portrait of Hadas

This picture is from the exhibition "non-Stigma", an art project in which thirteen active artists worked with thirteen people who have schizophrenia, and together created artworks for the project.

Isr J Psychiatry Relat Sci - Vol. 49 - No 2 (2012)

Mechanistic Comparisons of Functional Domains across Pediatric and Adult Bipolar Disorder Highlight Similarities, As Well As Differences, Influenced by the Developing Brain Ezra Wegbreit, PhD, and Mani Pavuluri, MD, PhD Pediatric Brain Research and Intervention Center, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, U.S.A.

ABSTRACT Recent neuroimaging studies have uncovered much about the specific neural deficits in adult bipolar disorder (ABD), but despite promising results, neuroimaging research for pediatric bipolar disorder (PBD) is still developing. The neuroimaging literature is highly heterogeneous, varying in the paradigms used and in participantsâ&#x20AC;&#x2122; mood states and medication status.

Despite this variability, several dominant patterns emerge. In response to emotional stimuli, both ABD and PBD show limbic hyperactivity coupled with hypoactivity in ventral prefrontal emotion regulation systems. This pattern occurred most robustly in response to negative incidental stimuli and was especially apparent in manic PBD. ABD showed more variability in ventral prefrontal activity, possibly due to maturational and medication factors. On numerous cognitive paradigms, PBD showed dorsal prefrontal hypoactivity linked to ventral dysfunction, whereas ABD showed compensatory frontal, parietal, and temporal activity with paradigm-specific variations.

In emotion-cognition interaction paradigms, patients show dysregulation in regions interfacing between cognitive and emotional brain systems (e.g., ventral prefrontal and cingulate cortices), which expend extra effort to process emotional stimuli effectively and recruit additional posterior attention systems to cope with affective instability. In addition, novel functional connectivity techniques have uncovered connectivity deficits between frontal and limbic regions in ABD and

PBD at rest and during active emotional and cognitive tasks. Finally, the neuroimaging literature currently lacks cross-sectional studies comparing PBD with ABD and longitudinal studies following children and adolescents with BD into adulthood. Such studies would provide important insights into patientsâ&#x20AC;&#x2122; prognosis and would determine targets for early interventions in the evolving illness diathesis.

Introduction Neuroimaging studies of adult bipolar disorder (ABD) have uncovered much about the functional brain impairments involved in emotional and cognitive responding and the effects of medications to treat these deficits.

Parents and professionals alike wonder whether pediatric bipolar disorder (PBD) will continue and/or manifest as ABD, but no mechanistically-informative neuroimaging studies following PBD into adulthood or comparing PBD to ABD currently exist. Prognostic forecasts and neurobiologically-informed early interventions are only possible with improved understanding of the trajectory of bipolar disorder (BD) across the lifespan. Furthermore, such understanding will elucidate whether PBD and ABD are pathophysiologically continuous phenomena, whether PBD will morph into the adult form, or whether they are entirely different entities.

In our integrative review, we directly compare the paradigms and corresponding findings of neuroimaging studies in PBD and ABD to uncover qualitative similari-

Address for Correspondence: Ezra Wegbreit, PhD, Pediatric Brain Research and Intervention Center, 1747 West Roosevelt Road, Department of Psychiatry, Chicago, IL 60608, U.S.A. â&#x20AC;&#x2020; ewegbreit@psych.uic.edu

75

Ezra Wegbreit and Mani Pavuluri

(10), often with disastrous consequences (11).

Neuroimaging studies of BD frequently contain medicated samples (3, 12), so it is often difficult to assess the contribution of medications to participantsâ&#x20AC;&#x2122; neural activity. However, some unmedicated PBD (6, 13-18) and ABD (19, 20) have been investigated with neuroimaging.

Additionally, some studies have possessed enough medicated and unmedicated participants to assess medication effects (21-23), although low statistical power limits these resultsâ&#x20AC;&#x2122; interpretation (12). More powerful withinsubject studies have scanned patients before and after medication treatment, finding that medication blunts the extreme overactivity found during mania and increases prefrontal function (23-29). Medication effects on neural function should be explored further because patients are often medicated (3, 12) and unable to withdraw from medications to complete the study (12).

For further reading, two recent meta-analyses (1, 3) have provided general summaries of numerous ABD neuroimaging studies, mostly involving middle-aged to older adults. However, these meta-analyses specifically excluded PBD neuroimaging studies. Other recent quantitative meta-analyses and qualitative reviews of neuroimaging (9), neurocognitive (30), and neuroanatomical (31) studies have included pediatric patients.

Through literature searches and the meta-analyses (1, 3), we identified 84 studies to date (January 2012) conducting fMRI on ABD, including 11 employing connectivity methods. In contrast, we identified only 29 studies for PBD, including four using functional connectivity methods. The trends for the adult and pediatric studies are similar, however, with a steady increase in the cumulative number of studies for both populations (Figure 1).

Figure 1. Trend in Adult and Pediatric fMRI Studies of BD 90 80 cumulative number of studies

ties and differences between the neural dysfunction in each group. Of note, the focus of investigation in one age group did not always align with that of the other, thereby identifying gaps in our understanding to be addressed by future studies. This review is limited to empirical research using functional magnetic resonance imaging (fMRI) methods. Although Positron Emission Imaging and Single Photon Emission Computed Tomography studies have been conducted in ABD (1), these techniques have not been used in PBD, given the radiation risks in children. As few electroencephalographic or magnetoencephalographic studies exist in PBD (2), these studies will also not be discussed in this review.

Given the plethora of fMRI tasks run in BD, comparing findings, where possible, across studies using analogous versions of the same task is critical. Thus, paradigms used in both pediatric and adult populations are grouped under a common subheading and paradigms used solely in one group will only be mentioned briefly. Furthermore, not all fMRI studies of ABD will be included because they have been summarized elsewhere (1, 3). Instead, this review highlights the most relevant comparisons between neuroimaging findings in ABD and PBD, relative to healthy controls (HC).

Furthermore, comparisons of BD with other disorders, such as unipolar depression (4), schizophrenia (5), or attention deficit/hyperactivity disorder (ADHD) (6), are beyond the scope of this review and not included.

Furthermore, comparing ABD and PBD in similar mood states is preferable because neural activity varies among depressed, euthymic and manic states (1, 3), even for basic processing tasks (7). However, PBD neuroimaging studies have mostly involved euthymic, manic or heterogeneous samples. Therefore, neuroimaging studies of depressed ABD are less comparable to PBD and will only be included if directly relevant. Given that in general depressed ABD show less (although still abnormal) limbic overactivity and frontal underactivity than in mania (1), further neuroimaging studies of depressed PBD would elucidate whether this pattern exists in younger samples. Furthermore, no neuroimaging study has compared PBD to children with unipolar depression, but neuroimaging studies comparing ABD to adults with unipolar depression have discovered neuroimaging biomarkers (e.g., amygdala-prefrontal connectivity) potentially distinguishing bipolar and unipolar depression (4, 8). Such biomarkers, if proven to be reliable, would greatly improve the diagnosis of PBD (9), which is often misdiagnosed as unipolar depression

Adult

70 60 50 40 30

Pediatric

20 10 0

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 to date

76

Mechanistic Comparisons of Functional Domains across Pediatric and Adult Bipolar Disorder

The average (±SEM) sample size of the 29 PBD neuroimaging studies was 39.5±4.0 participants, on average consisting of 20.7±1.6 PBD and 17.0±1.3 HC. (Two studies had no HC, and four studies included 14.5±.6 non-PBD participants with ADHD on average.) These average sample sizes compare favorably with ABD studies (15.6±7.8 ABD and 15.9±7.7 HC) (3), suggesting that the pediatric and adult studies had similar power, despite the large difference in the number conducted.

This review is organized around the broad categories of neuroimaging tasks used in BD. Passive tasks require little or no overt response, whereas active tasks require a response for each trial. Some paradigms involve primarily affective processing or purely cognitive processing, and others involve interactions between cognitive and affective processing. Furthermore, some affective tasks require participants to explicitly attend to the emotional aspects of stimuli, whereas others require participants to focus on non-emotional aspects of emotional stimuli (e.g., the gender of an angry face) where emotional information is implicit. Finally, in addition to conventional fMRI analyses, functional connectivity techniques can measure temporally coherent patterns of spatially-distributed neural activity. Although studies investigating connectivity during task performance will be discussed with the relevant task, studies examining resting-state functional connectivity will be treated separately (4, 32-34).

Emotional Paradigms Passive emotion perception

Passive emotional perception tasks commonly employ emotional faces or scenes. Euthymic, unmedicated PDB passively observing angry faces exhibited hyperactivity in limbic regions such as the amygdala and the pregenual anterior cingulate cortex (ACC) (13). PBD showed a similar but less hyperactive pattern in response to happy faces, possibly because of happy faces’ decreased salience. Furthermore, these participants showed greater medial prefrontal cortex (MPFC) activity and decreased activity in dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), and inferior frontal gyrus (IFG), likely indicating increased affective processing and decreased regulatory function, respectively (13). Furthermore, portions of the emotional face processing circuit (35) were hyperactive, indicating a fundamental dysfunction in emotional processing (13).

Similarly, euthymic ABD passively viewing faces showed reduced OFC (36) and rostral ACC (23) activity.

77

Adults showed mixed evidence for heightened amygdala activity, with one study finding increases in depressed, but not manic or euthymic patients (36). In contrast, a small sample of unmedicated adults in various mood states showed increased amygdala activity, but medicated participants exhibited decreased amygdala activity (23).

Finally, upon repeated exposure to emotional faces, HC showed increased activation in regulatory areas such as the OFC and striatum, whereas ABD showed increasing activation in the emotional face processing network (37).

Overall, during passive viewing of emotional faces, both ABD and PBD show a decreased ability to recruit frontal and striatal regulatory systems and increased emotional face processing activity, but evidence for heightened amygdala activity is stronger in PBD. In response to negative scenes, euthymic PBD exhibited greater activity than HC in frontal, temporal, and insular regions in response to negative scenes, and showed decreased activity in the right posterior cingulate cortex (PCC) (38). These results suggest that PBD were hypersensitive to negative valence, as strong emotions activate the insula (39), and frontal regions regulate cognitive and affective responses to emotional material (35). In response to positive scenes, PBD activated fronto-striatal and posterior attention areas more than HC, suggesting increased attention to these pictures. Euthymic PBD viewing emotional scenes did not show amygdala hyperactivity, possibly because the scenes were not as intense as faces (38). Manic ABD, in contrast, did exhibit left amygdala hyperactivity in response to positive pictures, which correlated with their euphoric symptoms (40). However, these discrepancies may stem from mood state differences between the PBD and ABD participants. Overall, while passively viewing emotional stimuli, both PBD and ABD show increased limbic activation coupled with decreased ventral frontal activity, especially in response to negative stimuli and in manic mood states.

Overt emotion processing

Making judgments about emotional faces is a common task in neuroimaging studies of BD. However, the results differ depending on whether participants make an overt judgment of the emotion expressed by each face (e.g., fearful vs. neutral) or judge some other quality (e.g., gender) of emotional faces (7, 15, 41). In overt paradigms, participants often indicate the emotional valence of a face (15, 39) and sometimes its intensity (8, 41, 42). Other studies involve matching faces with

Ezra Wegbreit and Mani Pavuluri

the same emotional expression (43) but no study has required PBD to match emotional faces. Explicit face recognition directly engages affective systems, whereas incidental emotional processing tests the interaction between affective and cognitive systems (15). In implicit studies, emotional information interferes with the cognitive processing involved in completing the task, revealing the neural substrates of participants’ ability to filter out emotional information. Explicit and implicit facial affect recognition paradigms are similar, and many studies include both conditions so these paradigms will be discussed together.

Most emotional recognition neuroimaging studies in PBD compared explicit and implicit paradigms, but the results vary depending on participants’ mood states, their medication status, and the emotion(s) tested. For example, PBD exhibited left amygdala and ventral prefrontal overactivity only when explicitly rating the hostility of neutral faces or their own subjective fear, but not when judging a non-emotional aspect of the faces (nose width) (41). Furthermore, PBD showed reduced connectivity between left amygdala and right PCC/precuneus and right fusiform/parahippocampal gyrus (44). However, in another study, medicated PBD did not show elevated left amygdala activity in the explicit emotion condition, but unmedicated ADHD did (45). However, PBD showed no limbic activity increases while explicitly rating positive and negative scenes, likely due to their decreased emotional salience relative to faces, but did exhibit hyperactivity in insular and prefrontal regulatory areas (38). In contrast, euthymic, unmedicated PBD showed increased activity in the amygdala insula, middle frontal gyrus (MFG), and PCC during an implicit condition (age judgments), but not during explicit emotion judgments (15). Furthermore, increased amygdala activity in PBD during implicit judgments about emotional faces was associated with reduced amygdala volume (46). However, differences between these implicit paradigms in the stimuli (i.e., neutral vs. hostile faces) and judgments required (e.g., nose width [41] vs. age [15]) may explain these results.

More emotional processing paradigms have been run on ABD, so this section will focus on analogous paradigms. When adult participants explicitly labeled emotional facial expressions, activation varied depending on participants’ mood states and medication status as well as the valence of the stimuli. For example, euthymic ABD showed hyperactivity in the amygdala, hippocampus and parahippocampal gyrus and hypoactivity in prefrontal

regions such as the DLPFC in response to fearful and sad faces (26, 39, 47), but not to faces depicting disgust (39).

In contrast, manic adults showed decreased subcortical activity and increased frontostriatal activity on explicit recognition paradigms (24, 29, 42), perhaps due to medication (23) or maturational factors (43). This activity pattern persisted even after medication treatment normalized these patients’ mood states (24), suggesting ventral prefrontal and striatal hyperactivation is a trait in ABD. On tasks of implicit affect recognition, euthymic ABD showed a distinctive brain activity pattern with increased subcortical and ventral prefrontal activation coupled with decreased DLPFC activity (48, 49).

Furthermore, they showed decreased connectivity between the ventral ACC and the amygdala during the implicit task, indicating dysfunctional communication between emotionally-reactive limbic regions and prefrontal regulatory regions (50). Thus, ABD and PBD present similar patterns of neural activity during implicit affective recognition, underscoring the power and consistency of implicit designs in eliciting deficits in emotional regulation. Implicit paradigms may be more consistent because they minimize participants’ use of explicit regulation strategies, which may differ between ABD and PBD. Furthermore, implicit designs possess more ecological validity because people often must judge others’ emotional states while engaging in concurrent cognitive processing.

Even though an explicit vs. implicit processing contrast is commonly used in facial emotion processing neuroimaging studies in PBD (15, 41), only one ABD study compared processing emotional faces explicitly and implicitly (7). Although ABD showed increased amygdala activity in response to fearful faces in both explicit and implicit conditions, manic participants showed differential frontal and limbic responses to sad faces between the explicit and implicit conditions. In the explicit condition, the manic ABD showed increased frontolimbic activity (7), similar to that found in PBD (38). In the implicit rating condition, manic ABD showed decreases in limbic activity (7), but manic PBD showed increased limbic activity while implicitly rating affective faces (15). However, the implicit condition in the ABD study involved indicating the face’s color (7), whereas the PBD study required a difficult age judgment (15), so these studies divergent findings could be caused by differences in the non-emotional information being attended. Thus, age or gender discriminations might probe implicit emotional processing better than color or nose-width judgments because they require 78

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more attention to facial features and the facial expression is harder to ignore.

In summary, the “emotional recognition” fMRI literature in both ABD and PBD is highly heterogeneous, with many variants of emotion recognition tasks and wide variability in participants’ mood states and medication status. Furthermore, a plethora of emotional expressions have been employed, with few studies focusing on specific emotions (e.g., 39) and many studies employing a variety of facial expressions within the same paradigm, further complicating the picture.

Across ages, neuroimaging studies of emotional processing consistently demonstrate decreases in VLPFC activity and limbic hyperactivation during mania, with additional persistent limbic overactivity in mania (13, 15) suggesting trait limbic reactivity in BD. The traitlike amygdala overactivity seen in PBD is not always apparent in ABD (39) possibly due to the development of prefrontal cortex-amygdala connections, reduced amygdala activity with age and disease progression, and/or chronic medication use.

Cognitive Paradigms In addition to the hallmark symptoms of mood dysregulation, patients with BD and their unaffected relatives also show cognitive impairments, even in the absence of affective symptoms, suggesting that impaired cognitive function is an extended phenotype of the disorder (30, 51). Many cognitive domains have been probed with fMRI in both ABD and PBD, including attentional interference, sustained attention, response inhibition, cognitive flexibility, and working memory. However, language and social cognition have been investigated with fMRI in ABD but not PBD. Attentional interference

In the cognitive (color-word) version of the Stroop task, participants see words for colors and name the color they are written in rather than reading the word. These color names are either written in the same or different color (e.g., the word “red” written in red or blue ink, respectively). The prepotent linguistic content of the words interferes with their less prepotent color, providing a cognitive measure of focused attention and attentional screening (52). In the only fMRI study using the cognitive color-word Stroop task in PBD, a small preliminary study, patients showed increased activity in the putamen and thalamus, and did not show nor79

mal age-related signal increases in the ventral PFC and striatum, suggesting impaired development. In addition, increased ventral striatum activity correlated with these patients' depressive symptoms (53).

ABD exhibited some mood-state specific activity deficits on the color-word Stroop, but other deficits are common across mood states, indicating a potential trait dysfunction (54). Manic participants showed decreased right VLPFC activity (54), whereas depressed participants showed increased left VLPFC activity and reduced OFC/MPFC activity (54, 55), suggesting that emotional dysregulation and VLPFC abnormality are central to mania, while MPFC abnormality and rumination are at the forefront in depression. In line with this pattern, both patients and their unaffected first degree relatives showed reduced connectivity between ventral prefrontal regions and the striatum, ACC, and insula, indicating trait deficits in inhibitory control circuits (56). Across mood states, patients show decreased VLPFC, OFC, and dorsal ACC activity (52, 54, 55, 57) and increased activity in DLPFC and posterior attention regions (52, 57), underscoring a persistent pattern of DLPFC interlinking with the emotional modulatory network.

The patterns found in ABD on the cognitive Stroop tasks differ from the one cognitive Stroop study in PBD (53), but are similar to those found in euthymic (14) and manic (6) PBD on an emotional Stroop variant (discussed below). The fact that PBD require emotional material to exhibit the level of prefrontal dysregulation observed in ABD completing a cognitive task suggests a more prevalent cognitive dysfunction in adults than in children.

However, further studies should be conducted with cognitive color-word Stroop tasks in PBD to test this hypothesis.

Although numerous other tasks measure attentional interference (58) and fMRI studies of patients with unipolar depression have employed emotional and nonemotional versions of these tasks (59, 60), none thus far have been employed in an fMRI study of BD. Further paradigms measuring attentional interference, with or without concurrent emotional stimuli, could further refine our understanding of the attentional dysfunction exhibited in BD as well as the interactions between attentional control and emotional processing.

Sustained attention

Two studies in ABD (19, 61) and one in PBD (62) have investigated sustained attention using a continuous performance task (CPT). The pediatric study included patients with and without ADHD comorbidity, but no

Ezra Wegbreit and Mani Pavuluri

control group, and thus is difficult to compare to the adult studies, which included adult HC and no adults with ADHD. Nevertheless, both ABD and PBD activated the VLPFC, an area not typically activated by this simple attention task (19, 61, 62), suggesting they needed extra executive resources to complete this task. Moreover, manic ABD showed reduced responses in limbic regions and increased activity in posterior attention systems (e.g., fusiform gyrus) on an emotional CPT (61), indicating that patients need to expend extra effort when confronted with irrelevant emotional information, as observed on other cognitive tasks containing emotional stimuli (6, 17).

Additional neuroimaging studies of sustained attention in both ABD and PBD, including those with comorbid ADHD, are needed to explore these deficits further.

Response inhibition tasks

Response inhibition tasks measure participants’ ability to withhold a behavioral response and have been utilized in neuroimaging studies of BD. In the Go/NoGo and Stop Signal paradigms, participants respond to each trial unless they see an infrequent signal, creating a prepotent response tendency that must be overcome on NoGo trials and active inhibition of responses already in progress on Stop trials. Both tasks measure impulsivity, as responding on NoGo or Stop trials represents a failure of behavioral inhibition.

On the Go/NoGo task, euthymic and mildly depressed PBD showed impaired behavioral performance and increased right DLPFC activity during blocks with NoGo trials, suggesting that PBD needed to recruit extra brain regions to inhibit responding (63). Euthymic and depressed ABD completing Go/NoGo tasks either showed deactivations in frontopolar cortex (Brodmann’s Area 10) and amygdala (64) or showed no significant activation differences (65). However, the former ABD study used a cued version of the Go/NoGo task (64), and the latter study examined BD-II patients, who exhibit less dysfunction on this task (65). Thus, the apparent discrepancy between ABD and PBD may simply be due to differences in the task and the clinical states of the participants.

Manic adults, in contrast, showed decreased VLPFC activity (66) on cognitive Go/NoGo tasks and increased VLPFC activity (67, 68) on emotional Go/NoGo tasks, indicating that frontolimbic dysregulation contributes to their performance deficits. Furthermore, patients whose mood symptoms were normalized with medication showed decreased amygdala activity, suggesting that limbic dysregulation led to patients’ disinhibition

on the task (69). These Go/NoGo paradigms have not been conducted in children, but PBD have been tested on the closely related Stop Signal paradigm (16, 21, 27).

Manic and euthymic PBD completing the Stop Signal task showed reduced prefrontal (16, 27) and increased striatal activity (21), particularly during failed Stop trials. Additionally, mood-stabilizing medications improved both frontal underactivity and striatal overactivity without interfering with PBD participants’ ability to perform the task (27), with neural circuit-level specificity in the functional improvements caused by each medication (70). In contrast, manic adults completing the Stop Signal task showed increased frontal activity and reduced activity in the PCC and left middle temporal gyrus (71).

However, these adult patients may have exhibited altered neural activity because they were employing a conservative response-withholding strategy. Thus, on response inhibition tasks, matching participants’ performance (21) and inquiring about their cognitive strategies (71) are critical. Future studies including PBD and ABD completing the same task and matching for performance differences would help clarify these differences.

Response flexibility tasks

In response flexibility tasks, participants need to modify the rule they use to make a response, which tests their ability to break mental set. Two response flexibility studies have been conducted in pediatric samples (22, 72) but only one has been conducted in an adult sample (20) and each task measures “response flexibility” in different ways. The “change task” (22) required participants to respond to a target like the response inhibition task, but instead switch responses if a change signal appeared.

Manic and euthymic PBD showed a reduced ability to deactivate the DLPFC and precuneus on change trials, indicating greater difficulty with inhibiting wrong responses and switching to correct ones (22). In a more complex reversal learning task, PBD had to shift response tendencies and received negative feedback for making errors (72). On this task, PBD showed increased activity in dorsal frontal and parietal regions and less deactivation of the PCC and precuneus indicating the recruitment of additional brain regions to perform the task, especially in response to punishment.

In a similar reversal learning task using rigged feedback, depressed ABD also showed greater activation in dorsomedial frontal areas in response to perseverative errors and negative feedback (20). These adult patients did not show differences in DLPFC activation, unlike 80

Mechanistic Comparisons of Functional Domains across Pediatric and Adult Bipolar Disorder

PBD, possibly because of differences in the participants’ mood states and the rigged feedback in the adults’ task.

Further neuroimaging studies in both populations using carefully controlled tasks of similar difficulty level (e.g., 22) are needed to further explore patients’ deficits in cognitive and behavioral flexibility.

Working memory and declarative memory tasks

Both ABD and PBD exhibited persistent working memory impairments even when euthymic (30, 73), but only one PBD neuroimaging study has employed a purely cognitive working memory task (38), utilizing a visuospatial working memory task similar to one used in an adult study (18). In both studies, participants indicated whether stimuli appeared in the same location as they were two trials previously (i.e., a visuospatial 2-back), but ABD needed to recall the prior location and PBD simply needed to recognize the prior location among a set of possible locations. On the visuospatial memory task, euthymic PBD exhibited left DLPFC greater activity and decreased midline cerebellar activity (38). In comparison, euthymic ABD exhibited increased activation in frontopolar, temporal, thalamic and posterior parietal regions, and either showed decreases (74) or no significant differences (18) in the DLPFC. However, both ABD and HC activated the DLPFC while performing the task, so the patients’ additional activations suggested that they utilized a different strategy than HC, requiring brain regions outside the typical working memory network (73).

Euthymic ABD also exhibit activations outside the typical working memory network while completing verbal N-back tasks (75-77). Attenuated activity in working memory regions is possibly a trait deficit, having been observed across manic, depressed, and euthymic mood states (73), in metabolic studies (74), and in unaffected first-degree relatives (77). However, after lamotrigine treatment, euthymic ABD showed improvements in working memory areas, suggesting some malleability in this trait (25).

Additionally, delayed-matching paradigms (78, 79), face-name paired associations (80, 81), and emotional and non-emotional Sternberg memory tasks (39, 76, 82) have been employed in ABD, but not in PBD. In these tasks, ABD patients showed reduced DLPFC engagement when encoding and retrieving information (80-82) and altered limbic and medial temporal lobe activity (78, 79, 81), with some variation based on the task employed (e.g., semantic vs. phonological) and the task phase (encoding vs. retrieval) (76). Overall, ABD employed various compensatory frontal, medial tempo81

ral/limbic, and parietal brain regions on these memory tasks. Discrepant findings from PBD memory studies (17, 38, 83, 84) suggest that PBD have not developed these compensatory mechanisms, but this hypothesis should be tested with neuroimaging studies involving ABD and PBD completing identical memory tasks.

Cognitive-Emotional Interactions As detailed previously, much is known about how ABD and PBD process emotional material and complete purely cognitive paradigms. However, the interactions between emotional processing and more complex cognitive processes, such as executive control and working memory, have been probed directly in PBD but remain less explored in adults.

Emotional Stroop

Emotional Stroop tasks probe the interaction between affective processes and executive function. In the emotional color-matching Stroop task, participants match the color of positive, negative or emotionally neutral words (e.g., “victory,” “poor” or “table” respectively).

Although emotional information is entirely irrelevant to the task, even HC respond slower to emotional words, indicating that the implicit emotional content has captured their attention to some extent (14).

PBD completing the emotional color-matching task showed generally increased limbic activity and moodstate dependent frontal activity. Euthymic PBD exhibited amygdala overactivity and decreased VLPFC activity in response to the negatively valenced words (14), but manic/mixed PBD showed increases in DLPFC, dorsal ACC, and VLPFC (6, 29), suggesting these patients needed extra effort to perform the task. In response to positive words, participants showed either no differences (14) or prefrontal activity increases (28, 29), indicating that positive stimuli elicit dysfunction less effectively than negative stimuli. The limbic overactivation and prefrontal dysfunction found in PBD were reduced with treatment with lamotrigine, divalproex, or risperidone (28, 29), and elevated amygdala-frontolimbic connectivity, in this case indicating improved frontal control over the amygdala, predicted improved response to medication and lowered mania scores after treatment (85). In comparison, euthymic ABD showed activity increases in the right amygdala and left hippocampus and decreased VLPFC activity in response to negative words (86). Thus, euthymic ABD and PBD show similar neural impairments on emotional

Ezra Wegbreit and Mani Pavuluri

interference tasks, suggesting that decreased emotional filtering ability is a neurodevelopmental trait in BD. Unfortunately, manic adults have not been studied using an emotional Stroop task, so whether this is also true for adult mania is unknown.

Emotional memory paradigms

Memory paradigms containing emotional components have also been used to investigate cognitive-affective interactions in BD. PBD have been scanned with emotional face encoding (84) and N-back (17, 83) paradigms, but ABD have only been scanned with an emotional scene encoding task (5). However, no ABD study has employed an emotional N-back task, even though cognitive N-back tasks are used frequently (18, 73, 75, 77).

In the emotional face encoding paradigm, PBD showed reduced implicit memory for emotional faces, especially for fearful ones, and exhibited activity increases in the striatum and ACC for happy faces and OFC for angry faces (84). In comparison, ABD completing the analogous emotional scene encoding task (5) showed increased hippocampal activity, as well as increased activity in posterior attention areas. However, ABD showed a positive correlation between mania symptoms and ACC activity (5), similar to the pattern of increased ACC activity in manic PBD (84), with the differences in activation potentially due to the paradigm used, rather than age.

In the emotional N-back, PBD exhibited increased activation in ventral frontal and cingulate emotional areas and reduced activity in dorsal cognitive working memory areas (17). In addition, decreased ventral frontal functioning in PBD partially normalized with lamotrigine monotherapy and correlated with improvements in mania symptoms. Nevertheless, elevated amygdala activity was still observed post-treatment, suggesting that amygdala hyperactivity is a treatmentresistant trait deficit in PBD (83).

Overall, ABD and PBD completing emotion-cognition interaction paradigms exhibit similar impairments, with hypoactivity in cognitive prefrontal regions in euthymia and hyperactivity in these regions in mania, as well as persistent limbic hyperactivity across mood states and medication treatment. However, despite progress in researching interactions between emotion and executive function and working memory in BD, differences between the adult and pediatric literatures make direct comparisons difficult. Future studies of emotion-cognition interactions in both literatures could benefit from using similar paradigms.

Resting State Connectivity Finally, neuroimaging studies have examined the intrinsic connectivity of participants not performing an active cognitive task. These so-called â&#x20AC;&#x153;resting stateâ&#x20AC;? connectivity studies measure tonic states of functional integration between spatially distant brain regions using temporal correlations. However, observed connectivity patterns depend critically on the type of analysis used, as some techniques examine correlations between a priori brain regions (87), whereas other connectivity techniques, such as independent component analysis (ICA), uncover spatiotemporally coherent activity patterns across the whole brain (88). Furthermore, effective connectivity techniques, which can model the causal connections between regions, have been employed in one ABD neuroimaging study (8).

These connectivity techniques represent novel approaches to answering questions about network-level deficits in BD. While in the resting state, PBD showed reduced connectivity between a left DLPFC seed and the right superior temporal gyrus (STG), and the right STG showed increased connectivity with parahippocampal regions and decreased connectivity with PFC and striatal regions, areas implicated in working memory and learning (87). In comparison, ABD showed decreased connectivity between pregenual ACC and bilateral amygdala and thalamus (4) and between the ventral PFC and amygdala (33) during the resting state, and increased connectivity between the VLPFC, medial PFC, and anterior insula (34). In addition, whole brain ICA has detected deficient connectivity in ABD in regions of the default mode network, such as the ACC (32) and hippocampus (88), and increased recruitment of posterior visual attention areas into the network (32, 88). Although adult and pediatric resting state patterns differ somewhat, only one PBD study has been conducted, using a seed voxel not tested in ABD. Thus, further resting-state connectivity studies need to be conducted to ascertain whether there are developmental differences in tonic connectivity in BD. Finally, resting state default mode network and temporal lobe network activity successfully distinguished ABD from adults with schizophrenia and HC (32), underscoring the potential diagnostic utility of connectivity techniques and their practical implications for improving misdiagnoses in PBD. Conclusion Despite much heterogeneity in neuroimaging paradigms, patientsâ&#x20AC;&#x2122; mood states, and medication status between 82

Mechanistic Comparisons of Functional Domains across Pediatric and Adult Bipolar Disorder

studies, PBD and ABD show many similarities in the brain regions that are affected. In response to emotional stimuli, both groups show limbic hyperactivity during mania that persists into euthymia and appears to be treatment resistant. This pattern is most reliably found when the task does not explicitly focus on emotion, and these deficits are more consistently found for negative stimuli than positive stimuli. The inability to modulate amygdala activity appears to be greater in mania, when compared to depressive episodes or euthymia, though direct comparisons across states are limited. In addition, both ABD and PBD groups consistently show dysfunction in ventral prefrontal and cingulate regions, indicating difficulty with regulating limbic overactivity. Both task-related and resting state connectivity studies have detected disrupted functional integration of ventral prefrontal and limbic regions across ages. Limbic hyperactivity is somewhat more prevalent in PBD, perhaps reflecting the immature state of the prefrontal cortex.

However, BD patients in general, and PBD in particular, also over-activate limbic regions when completing cognitive tasks, especially those with irrelevant emotional information. Even on purely cognitive tasks, PBD showed distinct deactivations in dorsal cognitive regions, whereas ABD did not show these deactivations as consistently. In contrast, ABD recruited additional brain areas relative to HC, but whether this represents compensatory neural activity reflecting cognitive strategy use, maturation effects, medication effects, or some combination thereof remains unknown.

Future neuroimaging studies in both ABD and PBD should utilize paradigms run in the other age group and should utilize novel connectivity techniques to probe the distributed integration of neural regions. Cross-sectional studies including both age groups should be conducted to directly investigate the developmental underpinnings of this disorder. Each study comparing ABD and PBD could also include adult and child HC to contrast with each other, in addition to the individual ABD and PBD populations, to measure role of maturational factors in BD. Finally, longitudinal neuroimaging studies following PBD into adulthood would provide valuable prognostic information and guide the development of interventions.

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50. Wang F, Kalmar JH, He Y, Jackowski M, Chepenik LG, Edmiston EE, et al. Functional and structural connectivity between the perigenual anterior cingulate and amygdala in bipolar disorder. Biol Psychiatry 2009;66:516-521.

51. Glahn DC, Bearden CE, Niendam TA, Escamilla MA. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord 2004;6:171-182.

52. Pompei F, Jogia J, Tatarelli R, Girardi P, Rubia K, Kumari V, et al. Familial and disease specific abnormalities in the neural correlates of the Stroop Task in Bipolar Disorder. Neuroimage 2011;56:1677-1684.

53. Blumberg HP, Martin A, Kaufman J, Leung H-C, Skudlarski P, Lacadie C, et al. Frontostriatal abnormalities in adolescents with bipolar disorder: Preliminary observations from functional MRI. Am J Psychiatry 2003;160:1345-1347.

54. Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC, et al. A functional magnetic resonance imaging study of bipolar disorder - State- and trait-related dysfunction in ventral prefrontal cortices. Arch Gen Psychiatry 2003;60:601-609.

55. Kronhaus DM, Lawrence NS, Williams AM, Frangou S, Brammer MJ, Williams SCR, et al. Stroop performance in bipolar disorder: Further evidence for abnormalities in the ventral prefrontal cortex. Bipolar Disord 2006;8:28-39.

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59. Halari R, Simic M, Pariante CM, Papadopoulos A, Cleare A, Brammer M, et al. Reduced activation in lateral prefrontal cortex and anterior cingulate during attention and cognitive control functions in medication-naïve adolescents with depression compared to controls. J Child Psychol Psychiatry 2009;50:307-316.

60. Beevers CG, Clasen P, Stice E, Schnyer D. Depression symptoms and cognitive control of emotion cues: A functional magnetic resonance imaging study. Neuroscience 2010;167:97-103.

61. Strakowski SM, Eliassen JC, Lamy M, Cerullo MA, Allendorfer JB, Madore M, et al. Functional magnetic resonance imaging brain activation in bipolar mania: Evidence for disruption of the ventrolateral prefrontalamygdala emotional pathway. Biol Psychiatry 2011;69:381-388.

62. Adler CM, DelBello MP, Mills NP, Schmithorst V, Holland SK, Strakowski SM. Comorbid ADHD is associated with altered patterns of neuronal activation in adolescents with bipolar disorder performing a simple attention task. Bipolar Disord 2005;7:577-588.

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64. Kaladjian A, Jeanningros R, Azorin J-M, Nazarian B, Roth M, MazzolaPomietto P. Reduced brain activation in euthymic bipolar patients during response inhibition: An event-related fMRI study. Psychiatry Res 2009;173:45-51.

65. Welander-Vatn AS, Jensen J, Lycke C, Agartz I, Server A, Gadmar OB, et al. No altered dorsal anterior cingulate activation in bipolar II disorder patients during a Go/No-go task: An fMRI study. Bipolar Disord 2009;11:270-279.

66. Mazzola-Pomietto P, Kaladjian A, Azorin J-M, Anton J-L, Jeanningros R. Bilateral decrease in ventrolateral prefrontal cortex activation during motor response inhibition in mania. J Psychiatr Res 2009;43:432-441.

67. Elliott R, Ogilvie A, Rubinsztein JS, Calderon G, Dolan RJ, Sahakian BJ. Abnormal ventral frontal response during performance of an affective go/no go task in patients with mania. Biol Psychiatry 2004;55:1163-1170.

68. Wessa M, Houenou J, Paillere-Martinot M-L, Berthoz S, Artiges E, Leboyer M, et al. Fronto-striatal overactivation in euthymic bipolar patients during an emotional Go/NoGo task. Am J Psychiatry 2007;164:638-646.

69. Kaladjian A, Jeanningros R, Azorin J-M, Nazarian B, Roth M, Anton J-L, et al. Remission from mania is associated with a decrease in amygdala activation during motor response inhibition. Bipolar Disord 2009;11:530-538.

70. Pavuluri MN, Ellis JA, Wegbreit E, Passarotti AM, Stevens MC. Pharmacotherapy impacts functional connectivity among affective circuits during response inhibition in pediatric mania. Behav Brain Res 2012;226:493-503.

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72. Dickstein DP, Finger EC, Skup M, Pine DS, Blair JR, Leibenluft E. Altered neural function in pediatric bipolar disorder during reversal learning. Bipolar Disord 2010;12:707-719.

73. Townsend J, Bookheimer SY, Foland-Ross LC, Sugar CA, Altshuler LL. fMRI abnormalities in dorsolateral prefrontal cortex during a working memory task in manic, euthymic and depressed bipolar subjects.

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76. Monks PJ, Thompson JM, Bullmore ET, Suckling J, Brammer MJ, Williams SCR, et al. A functional MRI study of working memory task in euthymic bipolar disorder: Evidence for task-specific dysfunction.

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78. Gruber O, Tost H, Henseler I, Schmael C, Scherk H, Ende G, et al. Pathological amygdala activation during working memory performance: Evidence for a pathophysiological trait marker in bipolar affective disorder. Hum Brain Mapp 2010;31:115-125.

79. Robinson JL, Bearden CE, Monkul ES, Tordesillas-Gutierrez D, Velligan DI, Frangou S, et al. Fronto-temporal dysregulation in remitted bipolar patients: An fMRI delayed-non-match-to-sample (DNMS) study.

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Dickstein DP, Roberson-Nay R, Berghorst L, Vinton D, Pine DS, Leibenluft E. Neural activation during encoding of emotional faces in pediatric bipolar disorder. Bipolar Disord 2007;9:679-692.

85. Wegbreit E, Ellis JA, Nandam A, Fitzgerald JM, Passarotti AM, Pavuluri MN, et al. Amygdala functional connectivity predicts pharmacotherapy outcome in pediatric bipolar disorder. Brain Connect 2011;1:411-422.

86. Lagopoulos J, Malhi GS. A functional magnetic resonance imaging study of emotional Stroop in euthymic bipolar disorder. Neuroreport 2007;18:1583-1587.

87. Dickstein DP, Gorrostieta C, Ombao H, Goldberg LD, Brazel AC, Gable CJ, et al. Fronto-temporal spontaneous resting state functional connectivity in pediatric bipolar disorder. Biol Psychiatry 2010;68:839-846.

88. Öngür D, Lundy M, Greenhouse I, Shinn AK, Menon V, Cohen BM, et al. Default mode network abnormalities in bipolar disorder and schizophrenia. Psychiatry Res 2010;183:59-68.

Appendix: Alphabetical List of Abbreviations (all except SEM defined upon first use): ABD = adult bipolar disorder ACC = anterior cingulate cortex ADHD = attention deficit/hyperactivity disorder BD = bipolar disorder CPT = continuous performance task DLPFC = dorsolateral prefrontal cortex fMRI = functional magnetic resonance imaging HC = healthy control ICA = independent component analysis IFG = inferior frontal gyrus MFG = middle frontal gyrus MPFC = medial prefrontal cortex OFC = orbitofrontal cortex PBD = pediatric bipolar disorder PCC = posterior cingulate cortex SEM = standard error of the mean STG = superior temporal gyrus VLPFC = ventrolateral prefrontal cortex

Isr J Psychiatry Relat Sci - Vol. 49 - No 2 (2012)

A Family-Based Psychosocial Treatment Model Amy E. West, PhD, and Sally M. Weinstein, PhD Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, U.S.A.

ABSTRACT Background: Pediatric bipolar disorder (PBD) is a chronic and severe disorder that is associated with significant impairments in psychosocial functioning.

Psychosocial intervention is an important component of comprehensive treatment for PBD. Method: Child- and family-focused cognitive-behavioral therapy (CFF-CBT), also called RAINBOW therapy, is a manual-based, 12 session psychosocial intervention developed for youth 7-13 with PBD and their families.

It combines cognitive-behavioral therapy with psychoeducation and other therapeutic interventions from interpersonal psychotherapy, mindfulness, and positive psychology in an intensive family-based treatment model. Specifically, CFF-CBT therapy aims to improve functioning in seven core areas: routines, affect regulation, self-efficacy, negative thoughts and behaviors, social skills, interpersonal and family problem-solving, and social support. Results and Conclusion: Preliminary open trial results, detailed in this manuscript, have demonstrated promise for CFFCBTâ&#x20AC;&#x2122;s efficacy in reducing symptoms and improving psychosocial functioning and it is now being tested in a randomized clinical trial.

Introduction The chronic and severe symptoms of pediatric bipolar disorder (PBD), which may include chronic mood dysregulation, irritability, rage episodes, distractibility, hypersexuality, and poor judgment, contribute to significant psychosocial impairment (1). Specifically, children with PBD have demonstrated academic underperformance and behavioral problems in school, social impairment, including few or no friends, frequent teas-

ing, and poor social skills, and poor family functioning, including poor sibling relationships, and parental conflict (2, 3). The psychosocial impairments associated with PBD contribute to accumulated risk for disruptions in social, emotional, and academic functioning throughout development. By adolescence, youth with BD exhibit low self-esteem, hopelessness, external locus of control, and maladaptive coping strategies (4), high expressed emotion in family relationships, more negative life events and chronic stress, especially in the context of family relationships and school (4, 5), and poorer social skills performance (6).

The accumulation of psychosocial risk throughout childhood and adolescence makes PBD a significant public health concern, and places an enormous burden on educational and health care systems and on the families of affected children. Children with PBD evidence high rates of repeated hospitalizations and suicide attempts (7). As adults, they are likely to demonstrate impaired functioning, greater mental health care utilization, and lower rates of school graduation (7). The significant psychosocial risk and poor long-term prognosis for children with PBD makes psychosocial intervention an essential component of a comprehensive treatment approach. Specifically, cognitive behavioral therapy (CBT) and other evidence-based psychotherapies can be employed as an adjunct to pharmacotherapy to address the complex constellation of symptoms and associated social, academic, and family difficulties.

A few psychosocial treatments for PBD have been developed and tested. We developed child- and familyfocused cognitive-behavioral therapy (CFF-CBT) for PBD (described below). Two other interventions for youth with bipolar disorder have supportive evidence from randomized trials: multi-family psychoeducation groups for school aged bipolar and depressed youth (MFPG), a group treatment that focuses on psychoeducation, problem-solving, and coping skills (8) and a family-focused treatment for adolescents (FFT-A),

Address for Correspondence: Amy West, PhD, Department of Psychiatry, University of Illinois at Chicago, 1747 W. Roosevelt Rd. MC 747, Room 155, Chicago, IL 60608, U.S.A. â&#x20AC;&#x2020; awest@psych.uic.edu

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which includes psychoeducation, communication training, and problem-solving training (9). Several other treatment models have been adapted from the adult literature and have supportive data in open trials: dialectical behavioral therapy (DBT) and interpersonal social rhythm therapy (IPSRT), both meant for adolescents with bipolar disorder (10, 11).

Theoretical Foundation for Cognitive-Behavioral Treatment in PBD

PBD involves a combination of neurological underpinnings and both innate and learned patterns of emotional responses, thoughts, and behaviors. Research suggests that youths with PBD experience disturbances in the neural systems responsible for processing and modulating emotions (12). As a result, these youths may demonstrate difficulty regulating their emotions related to the experience of a shutdown of emotional and cognitive control systems. Cognitive-behavioral treatment (CBT) thus aims to address these impairments in affective circuitry, as well as impairments in social and family functioning. CBT for PBD has several core components.

Among them are psychoeducation to build the family’s understanding of the symptoms, etiology, and chronicity of PBD and affect regulatory strategies to address impaired emotion regulation (e.g., self-monitoring of mood states, recognizing and labeling feelings, and coping skills to manage expansive, negative, and irritable moods). In addition, youth and parents learn cognitive restructuring techniques to reduce negative thought patterns (e.g., thought stopping, reframing situations positively, modifying thoughts, and use of positive self-talk/ mantras during difficult situations). Parents also receive training in behavioral management strategies specific to the rage episodes common in PBD to help cope with these affective “storms.” For example, many parents coming to CBT commonly use behavioral management systems developed for children with disruptive behavior disorders, which emphasize immediate contingency enforcement, re-direction, and the implementation of consequences. Unfortunately, in the case of PBD, this method can backfire. Children whose rage is rooted in a loss of control over emotional responses (rather than a purposeful, manipulative behavior) will not respond to limit-setting in the moment; in fact, this may serve to exacerbate their negative emotions. Rather, parents are instructed to use calming tones, modulate their own emotion, and focus on defusing the situation, keeping everyone safe, and using an empathic, collaborative 87

problem-solving approach. Consequences and limits, if necessary, can be implemented after the child is calm.

This approach is far more effective than more traditional behavior management approaches in addressing affective outbursts typical of PBD. Other strategies for regulating mood include establishing simple and predictable routines, minimizing transitions, emphasizing the timing and tone of interactions during mood episodes, and using positive reinforcement. Youth and parents are also instructed in problem-solving skills training to target interpersonal and family communication, as well as to enhance self-efficacy related to coping with the disorder. Similarly, social skills training in CBT focuses on role-play, listening and communication skills, and empathy to improve the interpersonal difficulties associated with PBD. Finally, parents are encouraged to engage in pleasant, relaxing activities and to utilize their support networks to help cope with the demands of parenting a child with PBD. Together, these CBT interventions help address the range of cognitive, social, and interpersonal impairments that are typical of PBD and supply families with a set of tools and skills to bolster them against the negative impact of symptoms and improve their quality of life.

Child- and Family-focused Cognitive-Behavioral Therapy (CFF-CBT) Based on the recognition of these core components of CBT for PBD, our clinical research group developed CFF-CBT (13-16). We believe that CFF-CBT comprises four innovative aspects in the treatment of PBD in that: (1) it is designed to be developmentally specific to preadolescent children; (2) it is driven by the distinct needs (e.g., psychoeducation about bipolar symptoms, behavioral management for rage episodes, affect regulation strategies to decrease cycling) of these children with PBD and their families; (3) it involves intensive work with parents parallel to the work with children in order to directly address parents’ own therapeutic needs, as well as helping them develop an effective parenting style for their child with PBD, and (4) it integrates psychoeducation and cognitive-behavioral therapy with complementary techniques from mindfulness, positive psychology, and interpersonal therapy to augment the effects of pharmacotherapy. These diverse therapeutic techniques are employed across multiple domains, including individual, peer, family, and school to address the impact of PBD in the child’s broader psychosocial context.

Amy E. West and Sally M. Weinstein

The psychotherapeutic methods used in CFF-CBT are driven by three areas of research: (1) affective circuitry brain dysfunction in PBD (e.g., poor problem-solving during affective stimulation because of under activity in dorso-lateral pre-frontal cortex); (2) developmentallyspecific symptoms of PBD (e.g., rapid cycling, mixed mood states, comorbid disorders); and (3) the impact of PBD on psychosocial and interpersonal functioning (e.g., poor social functioning, family stress). The CFF-CBT core curriculum was developed based on the scientific understanding of affective circuitry, developmentallyspecific symptoms, and psychosocial and interpersonal functioning in PBD. CFF-CBT is a 12-session protocoldriven treatment program meant to be delivered weekly over the course of three months (see Table 1) as an adjunct to pharmacotherapy. Sessions range in length from 60-90 minutes. The majority of sessions are for the parent and child together, but some are for the parent only, and some the child only. Recently, CFF-CBT has also been adapted to a group format, which consists of parallel parent and child groups that run for 1½ hours each week for 12 weeks. There is established content

for each session and an ideal sequence to the delivery of this content; however, the treatment protocol can be implemented in a flexible manner as long as the essential ingredients are included. Specific treatment guidelines regarding the implementation of CFF-CBT in an individual/family versus group format are pending the outcome of our ongoing randomized controlled trial examining the efficacy of the individual format, as discussed below. Based on clinical experience, however, the following considerations may guide treatment planning. For youths who present with moderate to severe symptoms and no history of effective psychosocial treatment, the individual/family format of CFF-CBT may be indicated as the more intensive treatment option. Group treatment may nevertheless be indicated as an adjunct to individual treatment for youth with significant social difficulties that lend themselves to a group setting for in vivo skills practice. Group treatment may also be considered for youths with milder clinical presentations and/or history of effective individual/family psychosocial intervention.

The acronym “RAINBOW” was formed to help parents and children remember the key components of CFF-CBT.

Table 1. Outline of Child- and Family-Focused RAINBOW Session Content and Format* Session

Participants

Topics Covered

1

Child and parents together

• Orientation to treatment/goal-setting • Engagement and relationship-building with child and parents

2

Child and parents together

• Psychoeducation about PBD • Mood charting via Daily Mood Calendar

3

Parents only

• Affect regulation skills: establishing routines and anger management • Identifying and acknowledging parents’ difficult feelings

4

Child only; Parent check-in

• Affect regulation skills • Labeling emotions; recognizing difficult feelings; triggers of anger and sadness

5

Child only; Parent check-in

• Cognitive and behavioral (“think” and “do”) coping skills • Problem-solving and positive thinking

6

Parents only

• Identifying and promoting positive qualities in child • Positive thinking and mantras; reframing negative thoughts; mindfulness strategies

7

Child only; Parent check-in

• Communication skills and interpersonal problem-solving

8

Parents only

• Promoting child’s social competence • Behavior management strategies • Balanced lifestyle for parents and enhancing self-care

9

Parents, child, siblings

• Psychoeducation about PBD providing to siblings • Family coping and problem-solving

10

Child and parents together

• Identifying and enhancing access of social support networks

11

Child and parents together

• Reflection on RAINBOW experience • Review of RAINBOW skills, creation of RAINBOW binder to internalize and consolidate therapy tools

12

Child and parents together

• Celebration; follow-up/maintenance plan

* The format of the RAINBOW Group Program is identical in length and very similar in content. Child and Caregiver groups run concurrently, and the topics of each session parallel those outlined above although extend across several sessions to allow for practice and role-play (child group) and parent group discussion. Additional Child Group content areas not listed above include group rapport building through games and team-building activities (Sessions 1, 2, and 3). Psychoeducation is primarily provided in the Parent Group.

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The essential components of CFF-CBT “RAINBOW” covered throughout the treatment sessions are as follows: R: Routine. The goal of this component is to increase affect regulation and decrease symptom exacerbation by establishing a predictable, simplified routine that will reduce excessive reactivity and tense negotiations in response to changes in the patient’s schedule. Parents are encouraged to establish routines around sleep, diet, medication, and making transitions. Parents are also urged to integrate soothing and pleasurable activities into their own and their child’s routine.

A: Affect regulation. The goal of this component is to provide psychoeducation about symptoms of PBD and neurochemical underpinnings, teach behavioral management and coping strategies, and provide affective education to the children. Parents are educated about the biological basis of their child’s illness and the nature of bipolar symptoms. Parents are instructed in various behavioral management techniques to establish appropriate systems for negotiation and creating consistent consequences. Children are educated about recognizing and responding to affective states and consistently selfmonitoring moods. They are given a system to monitor their moods several times throughout each day.

I: I can do it! The goal of this component is to increase parents’ and children’s beliefs in their ability to cope with the disorder and to problem-solve issues that arise. CFFCBT employs techniques designed to increase a sense of self-efficacy in children and parents, including having children and parents generate a list of positive self-statements, encouraging parents to focus on the child’s positive qualities, and helping parents to give consistent positive reinforcement for good behavior. Parents are encouraged to approach interactions with their children using a mixture of quiet confidence, firm limit setting, calming tones, empathy, and a focus on positive reframing, which we believe to be an effective combination for children who are highly sensitive to criticism and whose negative mood states are easily triggered. This style of interaction is likely to be more effective than shouting, threatening, and/or swift punishment in regulating the child’s response, and instilling a sense of confidence in both the child and parent that the particular situation will resolve positively.

N: No negative thoughts and live in the Now! The goals of this component are two-fold. The first goal is to decrease negativistic thinking and thought distortions associated with depression. Children and families are taught how to differentiate between helpful and unhelpful thoughts and to reframe unhelpful thoughts into 89

helpful ones that increase their sense of hope, beliefs in efficacy around coping, and ability to solve problems. The second goal of this component is to encourage children and parents to focus on the present moment and to avoid becoming overwhelmed by thoughts of what might happen in the future. Based on evidence from the emerging literature on the use of mindfulness techniques in cognitive-behavioral therapy for depression (17), children and parents are encouraged to focus on coping in the present moment, rather than dwelling on past failures or anticipating future failures. Mindfulness techniques, such as the use of positive mantras, are incorporated.

B: Be a good friend and Balanced lifestyle for parents. The goals of this component are, again, two-fold.

The first is to improve social functioning in children.

Children with PBD often have significant difficulties in peer relationships. Thus, a major goal of this component is to help children establish and maintain friendships. Children are taught the skills necessary to be a good friend and are provided opportunities within the therapy session to practice the skills. Parents are also encouraged to seek opportunities for children to practice newly developed skills and develop friendships (such as sleepovers, play dates, and supervised group activities). The second goal of this component is to increase parents’ sense of well-being and ability to cope through achieving a balanced lifestyle. Parents of children with BD often suffer from physical and emotional exhaustion, frustration, guilt, and feelings of isolation (18). Therefore, we encourage parents to develop a more balanced lifestyle that involves findings ways to rest, replenish their energy, and enjoy life. As an initial strategy related to this goal, parents draw a pie diagram that depicts the amount of time they invest in “recharging their own batteries” versus being a spouse, worker, or parent. Then, the therapist and the parent together discuss how to “carve the pie” so that parents strike a healthier balance between the demands of caring for a child with PBD and taking care of themselves.

O: Oh, how can we solve the problem? The goal of this component is to engage parents and children in a collaborative and effective problem-solving process. As part of this treatment component, parents are encouraged to view their children as partners in the problem-solving process and to explain the pros and cons of potential solutions in an empathic way. Parents and children are encouraged to try creative ways to approach problem-solving in order to minimize reactivity and the exacerbation of negative emotion.

Amy E. West and Sally M. Weinstein

W: Ways to Get Support. The goal of this component is to increase social support. Isolation, shame, and lack of access may prevent parents of children with BD from finding friends or family members that can provide respite and support. Therefore, the techniques used in this component emphasize the identification and active seeking out of people who can help the child and the parents through difficult situations. School advocacy is also a part of this component. Teachers are provided with a portfolio of CFF-CBT materials, information about the diagnosis, and information about ways in which the disorder may interfere with a child’s performance in school. Parents will be encouraged to engage the child’s individual therapist or school counselor in further advocating for the child’s needs at school.

Over the past 10 years, our group has conducted multiple studies to test the feasibility and efficacy of CFF-CBT. The preliminary open trial of CFF-CBT (13) assessed its feasibility, patient adherence to the treatment, therapist adherence to the treatment protocol, and parent satisfaction with their treatment experience.

Outcome measures explored the effect of the treatment on symptom severity and overall functioning. Thirtyfour children and young adolescents (mean age 11.33 years, SD = 3.06) with bipolar disorder (82% BP I, 9% BP II, 9% BP NOS) were assessed for bipolar symptoms and global functioning pre- and post-treatment.

Results indicated that the CFF-CBT intervention was feasible to deliver and that patients reported high levels of satisfaction with their treatment experience. Data analyses indicated a reduction in symptoms of attention problems, aggression, mania, psychosis, depression, and sleep disturbance on the Clinical Global Impressions Scale (CGI-BP [19]; t = 14.65, p < .0001), and increased global functioning after the intervention on the Children’s Global Assessment Scale (CGAS [20, 21]; t = 5.7, p < .0005).

These initial data were encouraging; however, our clinical experience with the long-term treatment of these patients suggests that improvements may not be sustained without ongoing maintenance treatment.

Therefore, we developed a maintenance model of CFFCBT, comprised of psychosocial booster sessions and pharmacotherapy (14). We followed the 34 patients who participated in the preliminary open trial for a threeyear period and assessed their symptoms and global functioning at years 1, 2, and 3 during the maintenance phase. All participants in the initial 12-session treatment were transitioned into the maintenance phase of

treatment, which consisted of medication management with a study psychiatrist and psychosocial booster sessions with study clinicians. During the maintenance phase of the study, there were no dropouts, although two patients transferred clinicians within the clinic and one patient aged out and moved into adult care after 27 months. Maintenance sessions were administered from once per week to once every three months as determined by patient and family need and access to the clinic. Each booster session comprised a standard 50-minute psychotherapy session in which the CFF-CBT therapist readdressed elements of the initial seven core ingredients of CFF-CBT as well as common themes that arise with patients during follow-up treatment (e.g., behavioral difficulties, helplessness and low self-esteem, social impairment, and family functioning; for details, see 14). Results indicated that patients were able to maintain initial positive effects of the treatment over the three-year follow-up period with continued booster treatment. These findings suggest that maintenance treatment models may help facilitate the longterm management of symptoms.

Next, we adapted CFF-CBT into a group format, comprised of 12 weeks of parallel parent and child groups.

This treatment is also manual-based and delivers the same content as is delivered in the individual treatment format. However, parent support and skills development is enhanced through the interchange occurring in multiple parent group sessions. A preliminary open trial of the CFF-CBT group treatment was completed to test feasibility. Twenty-six children (mean age = 9.45, SD = 1.93) with bipolar disorder (39% BP I, 4 % BP II, 46% BP NOS) and their parents were recruited through our pediatric mood disorders clinic to participate in the 12-week study protocol. Results from pre- to post-test indicated that the group adaptation is feasible to deliver and resulted in a significant increase in the parents’ report of their child’s coping skills as measured by the Strengths and Difficulties Questionnaire (SDQ [22]; t = 3.13, p = .01) and a decrease in parent-reported symptoms of mania after treatment as measured by the Child Mania Rating Scale (CMRS [23]; t = 3.30, p = .01) (16).

Although early trials suggest very promising findings regarding the feasibility and efficacy of CFF-CBT, the limitations of uncontrolled open trial studies must be considered. Across studies, participants were treated concurrently with medication, and the study design did not allow us to discern the variance accounted for by medication versus psychotherapy in improvements.

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Improvement could be the result of the natural history of the disorder, stabilization over time on medication, or the impact of attention and structure via treatment rather than the specific CFF-CBT intervention under examination. Thus, a randomized controlled clinical trial of CFF-CBT is currently underway to address many of these limitations. The trial is examining the efficacy of this treatment in the individual/family format compared to psychosocial treatment as usual in children 7-13 with bipolar spectrum disorders. Patients are randomly assigned to either CFF-CBT or treatment as usual (TAU) and assessed on a variety of symptom, global functioning, psychosocial, parent, and family functioning measures. Fifty participants have been enrolled in the past 22 months (n = 24 in TAU, n= 24 in CFF-CBT; n = 2 dropouts before random assignment). Preliminary analyses on the sample to date (n = 27 that have completed the 12-week acute treatment protocol) support the efficacy of CFF-CBT as compared to TAU on key symptom outcomes. Youth in CFF-CBT evidenced significant improvement in mania and depression symptoms, while those in TAU did not. Further, mixed subjects ANOVAs on PBD symptom outcomes revealed significant treatment by time interactions for mania and depressive symptoms, indicating that symptom response trajectories significantly differed for those in CFF-CBT versus TAU. Detailed results on the full sample are forthcoming after the completion of the RCT. CFF-CBT/RAINBOW Therapy: A Case Example Alice P. was an 8-year-old Caucasian female who lived at home with her biological parents and 12-year-old sister. She was referred to the RAINBOW therapy program by her child psychiatrist at the Pediatric Mood Disorders Clinic at the University of Illinois-Chicago.

At the start of therapy, Alice had recently initiated treatment with a mood stabilizer and the family had attended bi-monthly medication management sessions with the child psychiatrist for two months.

Initial assessment via structured interview and mood symptom rating scales (parent-, child-, and clinicianreport) indicated that Alice met diagnostic criteria for Bipolar I Disorder and Generalized Anxiety Disorder.

Alice was experiencing frequent irritability, mood lability, and intense periods of anger or “rage episodes.”

During these episodes Alice would engage in verbal and physical aggression and exhibit impaired judgment (e.g., trying to run away). Alice also had a history 91

of periods of elated and giddy moods with increased energy, increased activity in several areas, motor hyperactivity, reduced sleep, and mild flight of ideas. Periods of elated moods were typically followed by an increase in irritability and depressed mood, rage, tearfulness, and feelings of worthlessness. At times, Alice would cycle between euphoric and depressed/angry states within the same day.

Course of Treatment

Alice attended treatment sessions with her mother, and her father and older sister participated in the family session and intermittent maintenance sessions. Table 1 provides an outline of the content and format of the acute 12-session treatment phase. Treatment initially focused on engaging the family in the treatment process and identifying key treatment goals. In addition, Alice and Mrs. P. were provided with psychoeducation regarding pediatric bipolar disorder. Bipolar disorder was described as a “brain disorder,” and Alice’s core symptoms were discussed in the context of documented differences in brain functioning during periods of excessive emotions to reduce blame and negative attributions surrounding Alice’s rage episodes. Alice and her mother also developed a common language for her symptoms (e.g., rage episodes were named “volcanoes” and Alice’s anger was described as “lava”). This process allowed Alice to distance herself from her symptoms, thereby increasing her comfort and ability to discuss these difficulties at home and in treatment. Last, Mrs. P. and Alice each began monitoring Alice’s daily mood fluctuations, as well as triggers of mood shifts, on a “mood calendar.”

The second phase of treatment focused on Alice’s affect dysregulation and the prevention and management of rage episodes. Parent sessions dealt with the implementation of consistent routines to improve two identified areas of difficulty: bedtime and abrupt transitions. Specific methods for improving Alice’s bedtime routine (e.g., incorporating soothing activities prior to bedtime; use of a picture chart for necessary bedtime activities, with rewards for consistent activity completion) and minimizing abrupt transitions (ample warnings prior to transitions; posted reminders of the day’s schedule) were implemented at home. Parent sessions also concentrated on helping Alice manage her anger outbursts as a family. The analogy of “putting out a fire” was used to facilitate Mr. and Mrs. P.’s ability to remain neutral and calm while defusing the situation, versus engaging in the episode and exacerbating Alice’s dis-

Amy E. West and Sally M. Weinstein

tress. Coping plans for the prevention and acute management of rage episodes were developed with Mrs. P., including using mantras to remain calm and empathic (e.g., “She is not in control and needs my help”), enlisting support from Alice’s father, and implementing soothing activities to help Alice de-escalate her anger.

Coping plans also involved how and when to enforce appropriate consequences for target negative behaviors (e.g., physical or verbal aggression), such that consequences would be enforced only after Alice and others’ emotions had stabilized.

Additionally, parent sessions during this phase focused on Mrs. P.’s range of emotions regarding parenting a child with bipolar disorder, and identifying ways to both accept and cope with the inevitable feelings of anger, helplessness, and guilt. Mrs. P. learned cognitive techniques to use during difficult situations (e.g., reframing Alice’s behavior in the context of her neurocircuitry to foster greater empathy) as well as mindfulness techniques to focus on the present moment and avoid feeling overwhelmed. Mrs. P. expressed relief after disclosing her difficult emotions, and began to recognize how her own negative emotions may contribute to Alice’s escalation during rage episodes.

Child sessions with Alice focused on recognizing and expressing her feelings and increasing Alice’s insight into the triggers of her negative moods, which we called her “bugs.” Games, worksheets, drawings, songs, and role-play were used to help Alice identify and practice cognitive and behavioral skills for coping with future “bugs” and difficult emotions. However, Alice often resisted using her identified coping skills when triggered at home or school. Thus, it was important to normalize the experience of anger and sadness as acceptable emotions as well as the difficulty of learning new skills to combat her resistance to attempting new skills.

As Alice’s family improved in their ability to prevent and manage Alice’s affect dysregulation, our focus widened to the management of family and environmental stressors during the third phase of treatment. Child sessions centered on improving Alice’s social skills and self-esteem. Alice practiced various ways to engage in appropriate conversations with peers and to communicate respectfully with her parents. Additionally, Alice’s bipolar diagnosis was discussed as one small part of her identity, and sessions focused on the recognition of Alice’s positive qualities that comprise the core of her identity. Parent sessions focused on building Alice’s social competence through supervised one-on-one play activities with peers, and advocating for Alice’s needs

in the classroom. An essential component of this phase was also the emphasis on Mrs. P.’s well-being and balance between self-care and parenting responsibilities to avoid “burn out.” Last, a family session was held with Alice, her sister and her parents. This session was used to provide education on Alice’s diagnosis and course of therapy, and to improve family interactions via family problem-solving. To prevent a negative focus on Alice, it was important to maintain an atmosphere of acceptance and teamwork to manage the difficulties that all family members experience. With assistance from the therapist, family members identified their strengths as well as family-wide “bugs” and developed coping plans for managing their bugs as a team. Alice’s family also agreed on ways to increase positive family interactions (e.g., planned family outings).

The final sessions of the acute treatment phase focused on preparing for the shift from weekly therapy to monthly maintenance sessions. Alice created a book of therapy exercises to help her remember and use these therapy tools. Mrs. P. and Alice also discussed ways to continually use therapy strategies at home, such as weekly meetings to discuss family “bugs” and plan family outings. Positive changes in the family across treatment were reviewed and celebrated, including Alice’s increased awareness of her moods and triggers and a reduction in Alice’s rage episodes from near-daily outbursts to milder episodes occurring less frequently.

During the maintenance phase, sessions included child, parent, and family components and focused on continued practice of skills and problem-solving difficulties. In addition, school consultation was provided to Alice’s education team regarding bipolar disorder and recommended accommodations to enhance Alice’s classroom functioning. An Individualized Education Program (IEP) was developed by the school personnel to provide accommodations for her bipolar diagnosis, including a sanctioned cool-down area outside of the classroom and use of a private cue system between Alice and her teacher to prompt Alice’s use of her coping strategies.

Outcomes

Across treatment, Alice demonstrated greater insight into her symptoms, self-esteem, and ability to cognitively reframe her angry thoughts (e.g., “Mom doesn’t love me”). Alice was also increasingly able to use her coping skills independently at less intense levels of anger.

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was the presentation of therapy material in a non-threatening, creative, and engaging manner, as well as helping her recognize her many positive qualities. Alice’s parents became increasingly proficient in their ability to recognize warning signs of distress and help soothe Alice to prevent further escalation. As a result of these changes at the individual and family level, Alice’s anger episodes had decreased in intensity, frequency and duration. Mrs. P. also reported great improvement in her self-efficacy as a parent and improved family relationships. Objective measures at the conclusion of the acute phase indicated significant improvement in Alice’s mania and depression symptoms, family cohesion, and overall global functioning, and these treatment gains were maintained on objective measures at the final treatment session.

Conclusion Children and families who suffer from PBD experience numerous impairments in social, emotional, and academic functioning and psychosocial treatment is clearly indicated as part of a comprehensive treatment approach.

Although the evidence base for effective psychosocial treatments for PBD is growing, future treatment development and research will add important information to enhance our treatment approaches. Future research should include randomized clinical trials to clarify whether psychosocial treatment enhances long-term outcomes and quality of life, the efficacy of combined pharmacologic and psychosocial approaches, the mechanisms through which psychosocial treatments work, and the capacity to disseminate evidence-based psychosocial treatment approaches into community practice settings.

Treatment outcome research in PBD is complicated by many factors, including disagreement about the diagnosis of bipolar disorder in children and adolescents, the lack of specific, clear, and agreed-upon diagnostic criteria for PBD, and the episodic nature of PBD, which makes it difficult to discern results of an intervention from the natural course of the disorder. These challenges suggest the need for rigorously designed longitudinal studies that utilize large samples, ideally across multiple locations.

Indeed, the few evidence-based psychosocial treatments for PBD (including CFF-CBT) are delivered in academic tertiary care settings and do not reach the majority of children and families who would benefit. The next phase of research on CFF-CBT will involve dissemination into a community treatment context to answer important questions such as: what level of training is needed to ensure 93

competency in the delivery of CFF-CBT in regular practice settings, can fidelity be maintained in non-academic settings, and how might the treatment need to be adapted to facilitate uptake in everyday practice settings? Future large multi-setting randomized treatment outcome studies for PBD will hopefully address these and other important research questions regarding moderators and mediators of treatment outcome (i.e., which treatments work for which people under which conditions) in order to improve our ability to increase the quality of life and reduce disability and morbidity associated with PBD. References 1. Goldstein TR, Birmaher B, Axelson D, Goldstein BI, Gill MK, EspositoSmythers C, et al. Psychosocial functioning among bipolar youth. J Affect Disord 2009;114:174-183.

2. Geller B, Craney JL, Bolhofner K, Nickelsburg MJ, Williams M, Zimerman B. Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2002;159:927-933.

3. Wilens TE, Biederman J, Forkner P, Ditterline J, Morris M, Moore H, et al. Patterns of comorbidity and dysfunction in clinically referred preschool and school-age children with bipolar disorder. J Child Adolesc Psychopharmacol 2003;13:495-505.

4. Rucklidge J. Psychosocial functioning of adolescents with and without pediatric bipolar disorder. J Affect Disord 2006;91:181-188.

5. Kim EY, Miklowitz DJ, Biuckians A, Mullen K. Life stress and the course of early-onset bipolar disorder. J Affect Disord 2007;99:37-44.

6. Goldstein TR, Miklowitz DJ, Mullen KL. Social skills knowledge and performance among adolescents with bipolar disorder. Bipolar Disord 2006;8:350-361.

7. Lewinsohn PM, Olino TM, Klein DN. Psychosocial impairment in offspring of depressed parents. Psychol Med 2005;35:1493-1503.

8. Fristad MA. Psychoeducational treatment for school-aged children with bipolar disorder. Dev Psychopathol 2006;18:1289-1306.

9. Miklowitz DJ, George EL, Axelson DA, Kim EY, Birmaher B, Schneck C, et al. Family-focused treatment for adolescents with bipolar disorder.

J Affect Disord 2004;82:S113-S128.

10. Goldstein TR, Axelson DA, Birmaher B, Brent DA. Dialectical behavior therapy for adolescents with bipolar disorder: A 1-year open trial. J Am Acad Child Adolesc Psychiatry 2007;46:820-830.

11. Hlastala SA, Kotler JS, McClellan JM, McCauley EA. Interpersonal and social rhythm therapy for adolescents with bipolar disorder: Treatment development and results from an open trial. Depress Anxiety 2010;27:457-464.

12. Pavuluri MN, O’Connor MM, Harral E, Sweeney JA. Affective neural circuitry during facial emotion processing in pediatric bipolar disorder.

Biol Psychiatry 2007;62:158-167.

13. Pavuluri MN, Graczyk PA, Henry DB, Carbray JA, Heidenreich J, Miklowitz DJ. Child- and family-focused cognitive-behavioral therapy for pediatric bipolar disorder: Development and preliminary results. J Am Acad Child Adolesc Psychiatry 2004;43:528-537.

14. West AE, Henry DB, Pavuluri MN. Maintenance model of integrated psychosocial treatment in pediatric bipolar disorder: A pilot feasibility study. J Am Acad Child Adolesc Psychiatry 2007;46:205-212.

15. West AE, Pavuluri MN. Psychosocial treatments for childhood and adolescent bipolar disorder. Child Adolesc Psychiatr Clin N Am 2009;18:471-482.

16. West AE, Jacobs RH, Westerholm R, Lee A, Carbray J, Heidenreich J, et al. Child and family-focused cognitive-behavioral therapy for

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pediatric bipolar disorder: Pilot study of group treatment format. J Can Acad Child Adolesc Psychiatry 2009;18:239-246.

17. Segal ZV, Williams JMG, Teasdale JD. Mindfulness-based cognitive therapy for depression: A new approach to preventing relapse. New York, N.Y.: Guilford, 2002.

18. Fristad MA, Goldberg-Arnold JS. Family interventions for earlyonset bipolar disorder. In: Geller B, DelBello MP, editors. Bipolar disorder in childhood and early adolescence. New York, N.Y.: Guilford, 2003: pp. 295-313.

19. Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W. Modification of the Clinical Global Impressions (CGI) scale for use in bipolar illness (BP): The CGI-BP. Psychiatry Res 1997;73:159-171.

20. Bird HR, Canino GJ, Rubio-Stipec M, Ribera JC. Further measures of the psychometric properties of the Childrenâ&#x20AC;&#x2122;s Global Assessment Scale. Arch Gen Psychiatry 1987;44:821-824.

21. Shaffer D, Gould MS, Brasic J, Ambrosini P, Fisher P, Bird H, et al.

A childrenâ&#x20AC;&#x2122;s global assessment scale (CGAS). Arch Gen Psychiatry 1983;40:1228.

22. Goodman R. The strengths and difficulties questionnaire: A research note. J Child Psychol Psychiatry 1997;38:581-586.

23. Pavuluri MN, Henry DB, Devineni B, Carbray JA, Birmaher B. Child mania rating scale: Development, reliability, and validity. J Am Acad Child Adolesc Psychiatry 2006;45:550-560.

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Isr J Psychiatry Relat Sci - Vol. 49 - No 2 (2012)

Family-Focused Treatment for Children and Adolescents with Bipolar Disorder David J. Miklowitz, PhD Division of Child and Adolescent Psychiatry, University of California, Los Angeles Semel Institute for Neuroscience and Behavior, California, U.S.A.

ABSTRACT The course of bipolar disorder in children and adolescents is highly recurrent and impairing. This article describes the adaptation of family-focused treatment (FFT) for children and adolescents with bipolar disorder. FFT is given in 21 sessions over 9 months, and is usually initiated during the recovery period following an acute episode of depression or (hypo)mania. The treatment consists of an engagement phase followed by psychoeducation, communication enhancement training, and problem-solving skills training. Results of randomized trials in adults and adolescents find that patients with bipolar disorder who receive FFT and pharmacotherapy recover from episodes more quickly and have longer periods of sustained remission than patients who receive briefer forms of therapy and pharmacotherapy. The application of FFT to youth who are genetically at risk for bipolar disorder is described. Problems in disseminating empirically supported family interventions in community settings are discussed.

Introduction Between 50%–66% of adults with bipolar disorder (BD) report disease onset prior to age 18, and 15%–28% before age 13 (1). BD I and II appear to affect about 2% of youth under age 18, although there is variability across cultures (2). Among offspring of parents with BD I or II, subthreshold or “high-risk” forms of the disorder, which affect between 3%-9% of clinically referred youth, can be detected as much as 10 years prior to the onset of full BD (3-5).

Significant controversies exist about the definition, ascertainment, and boundaries of early-onset BD (4, 6-8). Nonetheless, agreement is substantial that BD spectrum disorders and their high risk antecedents have a significant impact on functionality and quality of life (6, 9). Youth who meet DSM-IV definitions of BD I or II or BD, not otherwise specified (BD-NOS), the latter characterized by brief, recurrent subthreshold (hypo) manic and depressive periods, have high rates of affective morbidity, impairment, suicidal ideation, comorbidity and service use (10, 11).

Without early intervention, the social, intellectual, and emotional development of youth with BD may be seriously compromised. Delays to first treatment of BD spectrum disorders in childhood are associated with greater depressive morbidity and less time euthymic in adulthood (12). Accordingly, well-tolerated interventions early in the course of the illness that reduce affective morbidity, enhance functioning, and teach emotion regulation skills could have a dramatically favorable impact on individual suffering. Early interventions in a developing population may allow for the normative acquisition of skills such as personal autonomy, academics, and peer relationships before the more debilitating cycles of patterns of relapses and remissions begin. Currently, youth with BD spectrum disorders are treated with a wide variety of medications and therapies, with little evidence-based practice (10).

Increasingly, family psychoeducational interventions are being used as adjuncts to somatic therapies in the treatment of major psychiatric disorders and medical conditions (13). Substantial progress has been made in the development and application of family interventions to BD. The purpose of this article is to review the current state of knowledge regarding one form of family intervention – family-focused treatment (FFT) – for youth with BD or at risk for BD (see the accompanying articles

Address for Correspondence: Dr. David J. Miklowitz, Division of Child and Adolescent Psychiatry, UCLA Semel Institute for Neuroscience and Behavior, David Geffen School of Medicine at UCLA, 760 Westwood Plaza Rm 58-217, Los Angeles, CA 90024-1759, U.S.A. dmiklowitz@mednet.ucla.edu

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by Nadkarni and Fristad, and west and Weinstein for other approches. for other approaches to treating families). The article begins by explaining the basis of the FFT approach in expressed emotion (EE) research. The second section describes the clinical methods of FFT for youth with BD. A brief case study is offered. Third, evidence for the effectiveness of FFT in clinical trials of adults and adolescents is reviewed, including recent work in youths at high genetic risk for bipolar disorder. Finally, recommendations for future research and community dissemination efforts are offered.

Research on Expressed Emotion EE, a construct well-known in the schizophrenia literature, refers to the expression of certain emotional stances or attitudes among caregivers of patients with a psychiatric disorder: criticism, hostility, or emotional over-involvement (over-protectiveness, inordinate self-sacrifice) (14).

Families are classified as “high-EE” if one or more caregivers (i.e., parent, spouse, sibling) expresses 6 or more critical comments or shows high levels of hostility or over-involvement during a 1-hour interview regarding the patient’s illness history. The significance of EE is a prognostic one: patients who are discharged from the hospital to families rated high in EE are at 2-3 times greater risk of relapse in the next year than patients who recover in lowEE (less critical or protective) households. This longitudinal association has been observed in numerous studies of patients with schizophrenia, major depression, and other psychiatric and medical disorders (15).

Several studies of EE have been conducted in families of patients with BD, and all indicate that patients whose relatives express high EE attitudes have higher rates of relapse and more severe mood symptoms over 9 month – 2 year periods than patients whose relatives express lowEE attitudes (16-20). One small-scale study found that adolescents with BD with high-EE parents had higher levels of depressive and manic symptoms over 2 years than BD adolescents with low-EE parents, despite ongoing psychosocial and pharmacological treatment (21).

The dynamics of families with high and low-EE relatives offer clues as to why the EE construct – a simple behavioral measure of critical or hostile comments – has such strong prognostic validity. High-EE parents or spouses of patients with schizophrenia or mood disorders are more likely to attribute the negative behaviors of patients to internal, controllable, and personal factors, whereas low-EE parents/spouses are more prone to attri-

bute negative patient behaviors to external, uncontrollable, or universal factors (15, 22). High-EE caregivers of patients with schizophrenia are more likely than low-EE caregivers to use “avoidance coping” (i.e., escapism) when dealing with their offspring’s symptoms (23). Families with high-EE are often locked into negatively escalating cycles of communication, in which criticism from one family member reliably elicits counter-criticism from another, such that conflicts become lengthy and difficult to resolve (24). One study found a link between criticism from parents, odd or grandiose thinking in patients, and later relapse of BD among adult patients (25).

For patients with BD, the implications of EE research are several-fold: 1) modifying the emotionally-charged environment of the family during a post-episode period may hasten the patient’s recovery and delay recurrences; 2) caregivers may benefit from psychoeducation oriented toward distinguishing what behaviors of the patient are controllable (i.e., purposeful) and not controllable (i.e., illness-driven); and 3) families of patients with BD may benefit from learning communication and problem-solving skills to resolve stressful conflicts during the post-episode period. These implications are addressed in one model of integrated treatment for BD: family-focused treatment (FFT).

Family-Focused Treatment Based in large part on our findings regarding EE in bipolar adults, we developed FFT in simultaneous trials at the University of California, Los Angeles (UCLA; 26, 27) and the University of Colorado, Boulder (17, 28). Our most recent work has concerned FFT in adolescents with BD, the focus of this article. FFT involves the patient and his or her parent(s) (or, in the case of some adults, a spouse) or extended relatives, depending on who the patient lives with and who has caregiving responsibilities. It is initiated after a patient has had an acute episode of mania, hypomania, depression, or mixed disorder from which he or she is in the process of recovering. Typically, patients are still symptomatic during this period and at high risk for relapse.

FFT is conducted by a clinical psychologist, social worker or family therapist who works in tandem with a psychiatrist responsible for pharmacotherapy. It consists of four stages: an engagement phase, where the therapeutic goal is to connect with the patient and relatives and relay information about the treatment’s structure and expectations; a psychoeducational phase, in which thera96

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pists lead the family in discussions of the nature, causes, and management of BD; communication enhancement training, in which patients and parents rehearse effective speaking and listening skills (e.g., how to give praise and constructive criticism; how to listen actively); and problem-solving skills training, in which patients and parents define specific problems, generate and evaluate solutions, and implement solutions to problems in the family’s or the individual patient’s life. The treatment is ordinarily given in 21 sessions (12 weekly, 6 biweekly, 3 monthly) over 9 months. When practiced in the community, clinicians and families sometimes opt for shorter versions or longer intervals between sessions.

The techniques of FFT for adults with BD can be found in the clinician’s manual (29). In the sections that follow, we describe the FFT in relation to the treatment of adolescents with BD. The treatment objectives are listed in Table 1.

Table 1. Objectives of Family-Focused Treatment (FFT) for Bipolar Disorder To assist the patient and parents to: • make sense of their experiences with manic and depressive episodes • develop plans to arrest future mood escalations or deteriorations • accept the need for mood-stabilizing medications for ongoing symptom control • distinguish between personality or temperament and bipolar disorder • cope with stressful life events that trigger mood swings • establish a family context that facilitates long-term recovery

Psychoeducation Psychoeducation, conducted in the first 7-8 sessions of FFT, offers teens and parents didactic information about the symptoms, differential diagnosis, comorbidity, prognosis, treatment, and self-management of BD. Handouts and self-guided homework (e.g., keeping a daily mood and sleep chart) accompany these topics. First, the clinician asks the teen and family to discuss the youth’s recent symptoms of BD and helps them distinguish mood symptoms from symptoms of anxiety disorder, substance abuse, schizophrenia, or disruptive behavior disorders. The clinician explains the interactive roles of genetic and biological vulnerability, stress, and coping in the disorder’s onset; the role of risk factors (e.g., disruptions in sleep/wake rhythms, substance misuse, escalating family conflicts) and protective factors (e.g., appropriate medication management, consistency with treatment visits, stable sleep/wake patterns, structured family routines). The impact of the disorder on day-to-day fam97

ily functioning is discussed. Care is taken to avoid any implication of blame of parents or the teen. Clinicians explain that many of the patient’s behaviors are driven by a biologically- and genetically-based mood illness (rather than willful intention), and that negative reactions of parents often reflect frustration in their attempts to cope with highly stressful family circumstances.

A key component of psychoeducation is the mood management plan, or the planning during periods of mood stability for emergency intervention when the adolescent’s moods start to change or when he/she becomes suicidal. With the aid of a flip chart, clinicians pose three questions: What makes your mood worse (or, more elevated/irritable/depressed)? How would we know if your mood had changed? What strategies improve your mood? Families recall previous periods of the teen’s mood instability and identify sequences consisting of triggers, early warning signs of mood exacerbation, and preventative measures. A management plan is developed which for mania symptoms usually includes clarifying the conditions under which the treating psychiatrist should be notified, strategies for reducing stress at home and at school, and working towards greater regulation in sleep/wake rhythms.

Special emphasis is placed on regulating family routines (e.g., mealtimes, bed times); often, the teen’s chaotic sleep/wake schedules may be traced to the lack of structure in the family’s life. Plans for managing depressive symptoms may include no suicide/no harm contracts, behavioral activation exercises (i.e., scheduling pleasant events), mindfulness meditation, or constructive selftalk. For some teens, the plan may include management of psychotic symptoms (for example, relaxation or distraction techniques).

Communication Enhancement Training CET (sessions 10-15) is designed to reduce aversive interactions among family members and teens and to improve the quality of exchanges. During role-play/ skills training exercises and between-session practice, participants learn to (a) down-regulate impulsive expressions of negative affect through pausing and putting difficult feelings into words, (b) communicate in a manner that does not trigger emotional dysregulation in others, and (c) shift attention from destructive emotions to more conciliatory states. Adolescents and family members learn four skills: expressing positive feelings, active listening, making positive requests for

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changes in each others’ behaviors, and constructive negative feedback. The clinician offers handouts listing the components of each skill (e.g., for active listening: making eye contact, paraphrasing each others’ statements), and demonstrates each for the family. Then, participants practice the skills with each other, with coaching and shaping by the clinician. Communication training is done less formally with adolescents than adults, capitalizing on the family’s spontaneous interactions. Homework assignments, in which the participants record their efforts to use each skill, enhance generalization to other settings.

Problem Solving In the problem solving module (sessions 16-21), families are taught to identify areas of disagreement, break down large problems (e.g., “we don’t get along”) into smaller ones (“we need to use lower tones of voice”), generate and evaluate pros/cons of solutions, and choose solutions to implement (e.g., alert each other to aggressive voice tones). Because it requires enhanced executive planning, problem-solving may augment functional capacity.

Participants list their most pressing problems and define each one (e.g., an adolescent does not get homework done, his mother becomes highly anxious, and conflict ensues). Then, family members generate 2–3 solution choices and evaluate the pros and cons of each.

Next, the teen and family members conjointly choose a best option or set of options and develop an implementation plan. Families practice problem solving between sessions using a self-guided homework sheet and report on their attempts in the next session. As treatment sessions are tapered in frequency to once per month, more emphasis is placed on between-session practice.

Case Example Marissa was a 17-year-old with bipolar I disorder and comorbid attention deficit hyperactivity disorder, who lived with her mother, father, grandmother, and two brothers, one 19 and one 16. She was being treated with lithium 1200 mg and quetiapine 200 mg. She had had several instances of self-injurious behaviors (e.g., cutting). Her parents described the household as a “war zone” due to her frequent outbursts of rage. All family members agreed that Marissa’s rages created huge problems for the family, but they disagreed on the causes

of these episodes. Her mother described them as being “manic-like,” with rapid speech, excessive movements, and flight of ideas. She was particularly worried about how Marissa would cope when she went off to college the following year; would she curse at her professors and alienate her roommates? Marissa claimed that her “attacks” were largely triggered by the highly critical, hostile, and insulting interactions she had with her brothers, who, she said, regularly called her “fat and stupid.” When asked, her brothers used more colorful words to describe her behavior.

In the early sessions of FFT, the clinician encouraged Marissa, her parents, and her brothers to identify the triggers, early warning signs, and potential preventative strategies for her rage reactions. Her reactions were often precipitated by family arguments (e.g., certain looks from her brothers) or multiple requests from her parents that confused her. The clinician assisted her in developing a stress thermometer, which clarified the stages of her angry escalations. Marissa and her family members were then encouraged to use a set of emotional self-regulation techniques when her mood escalations began, including: disclosing to one another that “something isn’t feeling right”; using calming self-talk “when we feel the heat rising”; mindful breathing; exiting the situation (e.g., going outside to cool down), or attempting to separate the warring members of the family.

With repeated practice, Marissa found that she could better control her outbursts with her parents, but was still repeatedly provoked by her brothers. When their interactions degenerated into back and forth yelling matches, she was especially likely to start self-cutting.

The communication enhancement module focused on her relationships with her brothers and encouraging each of them to practice active listening (paraphrasing, asking clarifying questions, nodding one’s head to show acknowledgment). The use of these skills was helpful to Marissa and her brothers in slowing down their volatile interactions. Being able to limit negative interchanges to a maximum of three “volleys” also helped to reverse these predictable sequences.

In the final segment of FFT, Marissa and her parents worked on problem solving to maximize her chances of making a successful adjustment to college. The sessions included how to manage her medications (i.e., filling her medication prescriptions and taking her pills without reminders), getting herself out of bed in the morning without continual intervention by her parents, and completing household tasks. They also involved emo98

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tional self-regulation techniques to use when she felt herself becoming angry with others (e.g., deep breathing, distraction).

By the end of treatment, Marissa still had impulsive, angry reactions brought on by negative interactions with her brothers. However, both Marissa and her parents reported that these episodes were becoming fewer and further between, did not last as long, and were not as destructive. She reported fewer suicidal thoughts and better overall mood states. Her brothers, although still angry with her, acknowledged that they had not understood the nature of her mood disorder, had on many occasions deliberately provoked her. She acknowledged, in turn, that they were becoming more patient with her. At termination, she continued with her ongoing pharmacotherapy appointments but did not seek additional therapy.

Empirical Studies of FFT

The results of 11 trials of FFT in BD are described in Table 2. There have been five published randomized controlled trials (RCTs), one of which concerned bipolar adolescents, and four open trials, two involving children or adolescents. Two other RCTs, one of adolescent BD patients (N = 144) and one of youth at risk for BD (N = 40) are nearing completion (Table 2).

In an RCT at the University of Colorado, 101 adult BD I patients, 82 of whom had been newly discharged from the hospital were randomly assigned to FFT and pharmacotherapy or to crisis management (CM) and pharmacotherapy (28). FFT was given in 21 sessions over 9 months. Patients in CM received 2 sessions of psychoeducation, and crisis intervention sessions over 9 months. The overall 2-year study completion rate was

Table 2. Results of Trials of Family - Focused Treatment and Pharmacotherapy in Bipolar Disorder Study

Sample

Type of Trial

Clinical State

Comparison Group

Key Findings

Miklowitz & Goldstein (26)

32 adults

Open with historical controls (9 mos)

Manic episode in prior 3 mos

Treatment as usual

FFT, 11% relapse rate Comparison, 61%

Miklowitz et al. (28)

101 adults

RCT (2 yrs.)

Depressed or manic episode in prior 3 mos

Crisis management (2 family psychoeducation sessions)

54% survival rate in FFT versus 17% in crisis management

Rea et al.

(27)

53 adults

RCT (2-3 yrs.)

Manic episode in prior 3 mos

Individual therapy

36% rehospitalization rate in FFT, 60% in individual therapy

Miklowitz et al. (50)

100 adults

Open with historical controls (1 yr)

Depressed or manic episode in prior 3 mos

Crisis management

FFTplus interpersonal therapy associated with longer delays to relapse and less severe depression than crisis mgmt.

Miklowitz et al. (30, 31)

293 adults

RCT

Acute episode of bipolar depression

Collaborative care (3 education sesions) (RCT)

77% recovered in FFT in 1 year; 65% in IPT; 60% in CBT; 52% in Collaborative care; better social functioning in FFT and IPT

Miklowitz et al. (21)

20 adolescents

Open

Various states

None

Adolescents showed significant improvement over 2 years in depression, mania, and problem behaviors

Miklowitz et al. (33)

58 adolescents

RCT (2 yrs)

Acutely or subsyndromally ill

3 education sessions

Adolescents in FFT recovered from depression 7 weeks faster than adolescents in brief psychoeducation

Miklowitz et al. (44)

13 children (ages 9-17)

Open (1 yr)

Depression or subthreshold manic or hypomanic symptoms

None

Youth in FFT showed significant improvements in depression, mania, and global functioning scores

Perlick et al. (51)

Caregivers of 46 BD I adults, 1 yr

RCT (4.7 months)

Various states

8-12 session health program

Caregivers and patients in FFT had decreases in depressive symptoms

Miklowitz et al. (52)

144 teens w/BD I or II

RCT

Acutely or subsyndromally ill

3 sessions of psychoeducation

In progress; treatment completion and follow-up rates 78%-91%

Miklowitz & Chang (53)

40 children (ages 9-17)

RCT (1 year)

Depression or subthreshold manic or hypomanic symptoms

Enhanced care (1 session of family education)

In progress; completion rates 78%-85%

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David J. Miklowitz

71% in FFT and 61% in CM, a nonsignificant difference. In a 2-year follow-up, patients in FFT were three times more likely to survive without relapsing (52% versus 17%) and had longer periods of remission without relapse (73.5 weeks versus 53.2 weeks) than patients in CM. FFT was also associated with greater remission of depression and mania symptoms over 2 years.

An RCT at UCLA examined FFT and pharmacotherapy when compared to an equally intensive individual therapy and pharmacotherapy (27) in 53 patients who had just been discharged following a manic episode.

Patients in the individual therapy received 21 sessions of psychoeducation, medication adherence monitoring, and relapse prevention planning over 9 months.

Patients in the two groups did not differ in rates of relapse or rehospitalization during the first year of treatment. However, in a 1-2 year post-treatment follow-up, patients in FFT showed lower rates of rehospitalization (12%) and symptomatic relapse (28%) than patients in individual therapy (60% and 60%, respectively).

A large-scale comparative effectiveness trial examined FFT in comparison with similarly intensive forms of therapy for adult bipolar patients recovering from a depressive episode (30, 31). In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), conducted across 15 U.S. sites, 293 acutely depressed BD I and II patients were assigned randomly to a medication algorithm and one of four psychosocial treatments: up to 30 sessions of FFT, interpersonal and social rhythm therapy (IPSRT), cognitive-behavioral therapy (CBT), or a 3-session individual treatment called collaborative care (CC). All three of the intensive therapies were associated with higher 1-year recovery rates (105/163, or 64.4%) than CC (67/130, or 51.5%).

Adding intensive psychotherapy to medication management speeded recovery by an average of 110 days during the study year. The rate of recovery for FFT was 77% over 1 year; for IPSRT, 65%; CBT, 60%; and CC, 51.5%.

Patients in intensive therapy also had greater improvements in relationship functioning and life satisfaction than patients in CC (31).

The STEP-BD study suggests that patients with BD who enter treatment in states of depression benefit from intensive psychotherapy in combination with optimal medication management. There was no clear evidence that one of these treatments was more effective than the other, although the study was not statistically powered to address this question. Possibly, the common ingredients of intensive therapies for BD – teaching strategies

to monitor and stabilize mood and sleep, intervening early with prodromal symptoms, enhancing consistency with mood stabilizing medications, and working toward resolution of key interpersonal or family problems – contributed to patients’ more rapid recoveries.

Application of FFT to Adolescents with BD

In the trials of FFT for BD adolescents (Table 2), we have recruited patients from both inpatient settings and outpatient referrals. We have included patients recovering from both depressive and manic or hypomanic episodes, as well as patients with or without psychotic symptoms.

We have excluded patients with active substance or alcohol abuse, although an adaptation of FFT for adolescents with BD and substance abuse has been developed (32).

In an open trial (21), 20 adolescents (mean age 15 yrs) received 21 sessions of FFT and pharmacotherapy over 9 months. At 2-year follow-up, adolescents showed significant improvements in depression, mania, and total problem behavior scores. In a 2-site RCT, 58 adolescents with BD (75% with BD I or II) were allocated to FFT and pharmacotherapy or 3 sessions of family education and pharmacotherapy (33). Of the 58, 48 (83%) completed 1 year of treatment and follow-up. Over 2 years, patients in FFT had shorter times to recovery from their initial depressive episodes, less time in states of depression, and more time in remission than patients in the briefer treatment. They also had less severe depressive symptoms over time. FFT was particularly effective in stabilizing mania and depressive symptoms among adolescents in high-EE families, even though adolescents in high- and low-EE families did not differ in pretreatment symptom severity (34).

Application of FFT to Children at Risk for BD

The effectiveness of FFT in studies of teens and adults with BD raised the question of whether a modified version of FFT could prove effective as an early intervention for youth at risk for BD. Prior research has identified at least three behavioral phenotypes that, when present in a child with a parent with BD I or II, may signal an increased risk for developing the disease over time. The Course and Outcome in Bipolar Youth study, a 4-5 year naturalistic follow-up of children with BD I, II, or NOS (defined as one DSM-IV symptom less than full criteria for a (hypo)manic episode, a clear change in functioning, and a minimum of 4 lifetime episodes each lasting > 1 day), were at substantial risk for converting to BD I or II in 4 years (35). In the most recent (5 year) 100

Family-Focused Treatment for Children and Adolescents with Bipolar Disorder

report from this study, the risk of conversion was 58% among BD NOS youth with familial BD I or II, and 36% in BD NOS youth without familial BD (36).

Apart from early manic symptoms, the most reliable symptom complexes pre-dating mania are major depressive episodes or cyclothymic disorder. Rates of conversion from these states to BD I/II are highest in the first 4-5 years after initial onset, ranging from 15%44% in 2 years to 20%-49% in 4 years (37-42).

A brief version of FFT for youth at high-risk for BD has been developed. This version consists of 12 sessions in 4 months after the high-risk youth has had a period of mood exacerbation (i.e., major depression or subthreshold (hypo)mania). The focus is on skills relevant to managing the prodromal stages of BD – mood monitoring, reducing family conflict, improving problemsolving, and working toward stabilization of daily routines and sleep/wake cycles (43). The Colorado/Stanford High-Risk Trial is examining a cohort of 53 children and adolescents who meet criteria for BD-NOS, MDD, or cyclothymia (with active symptoms in the previous month) and have at least one parent with BD I or II. Results of a treatment development study (44), in which 13 youth (age 9-17, mean 13.4 yrs) were treated openly with FFT-HR over 4 months, indicated significant improvements over 1 year in (hypo)mania, depression, and psychosocial functioning, with Cohen’s d effect size estimates ranging from .51 – 1.76. The results could not be attributed to participants’ medication regimens at entry into the trial. Results of a recently completed RCT with high-risk youth (N = 40) will determine whether there are specific effects of FFT in bringing about symptom stabilization.

Conclusions and Future Directions When combined with pharmacotherapy, FFT is an effective means of stabilizing youth and adults with BD. Recent research has examined the applicability of the approach to non-bipolar populations. A version of FFT for youth at risk for psychosis has recently been developed and is now being tested in an RCT (45). There is also an ongoing randomized trial of FFT for children (aged 6-14) with major depressive disorder, and promising open trial results (46).

There are significant gaps in the literature on FFT and other family interventions, notably the extension of these interventions into community settings. The difficulty with uptake of family interventions in community 101

settings may stem from several issues: the mistrust of family therapy approaches because of their association in many clinicians’ minds with blaming parents for causing mental illness; a belief that family therapy is not cost-effective because too many people are involved; lack of training of clinicians in how to approach family members or conduct conjoint sessions; lack of reimbursement by insurance companies; and other issues which may not be related to treatment effectiveness.

The primary responsibility for dissemination is on researchers, who need to 1) familiarize clinicians and administrators with the ways in which new forms of family psychoeducational treatment differ from traditional family system approaches; 2) conduct comparative cost-effectiveness studies; and 3) develop and test forms of family intervention that are economical and easily learned. Secondarily, the responsibility lies with clinicians and administrators to familiarize themselves with treatment research relevant to family interventions and seek training when it is offered.

Most studies of family intervention consider only the behavioral pathways to change; future studies need to consider changes at the neural level as well. Bipolar adults and youth show increased amygdala activation and decreased prefrontal cortical activation (notably, the dorsolateral prefrontal cortex and the ventrolateral prefrontal cortex) on functional magnetic resonance imaging during affective challenge tasks (47-49). Studies that examine pre/post-treatment changes in neural markers may yield clues as to why family treatment, or more broadly, intensive psychosocial treatments have a positive impact on the course of BD. Our RCT of youth at high-risk for BD is examining neural activation during emotion challenge tasks that mirror the skills being taught in FFT, such as the ability to self-regulate one’s emotions when in conflict with family members.

Long-term follow-up of high-risk samples will help determine whether the provision of brief, targeted interventions like FFT can prevent or delay the onset of BD I or II. More generally, psychosocial interventions designed to reduce stress, conflict, and affective arousal by enhancing communication, problem-solving, and emotion regulation skills may decrease the functional disabilities associated with this life-long disorder.

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7. Chang KD. Diagnosing bipolar disorder in children and adolescents. J Clin Psychiatry 2009;70:e41.

8. Kim EY, Miklowitz DJ. Childhood mania, attention deficit hyperactivity disorder, and conduct disorder: A critical review of diagnostic dilemmas. Bipolar Disord 2002;4:215-225.

9. Luby JL, Navsaria N. Pediatric bipolar disorder: Evidence for prodromal states and early markers. J Child Psychol Psychiatry 2010;51:459-471.

10. Axelson DA, Birmaher B, Strober M, Gill MK, Valeri S, Chiappetta L, et al. Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006;63:1139-1148.

11. Findling RL, Youngstrom EA, McNamara NK, Stansbrey RJ, Demeter C, Bedoya D, et al. Early symptoms of mania and the role of parental risk. Bipolar Disord 2005;7:623-634.

12. Post RM, Leverich GS. Early recognition and treatment of schizophrenia and bipolar disorder in children and adolescents. Bipolar Network News 1999;5:3-11.

13. Heru AM. Family psychiatry: From research to practice. Am J Psychiatry 2006;163:962-968.

14. Vaughn CE, Leff JP. The influence of family and social factors on the course of psychiatric illness: A comparison of schizophrenia and depressed neurotic patients. Brit J Psychiatry 1976;129:125-137.

15. Hooley JM. Expressed emotion and relapse of psychopathology. Ann Rev Clin Psychology 2007;3:329-352.

16. Miklowitz DJ, Goldstein MJ, Nuechterlein KH, Snyder KS, Mintz J. Family factors and the course of bipolar affective disorder. Arch Gen Psychiatry 1988;45:225-231.

17. Miklowitz DJ, Simoneau TL, George EL, Richards JA, Kalbag A, Sachs-Ericsson N, et al. Family-focused treatment of bipolar disorder: 1-year effects of a psychoeducational program in conjunction with pharmacotherapy. Biol Psychiatry 2000;48:582-592.

18. Yan LJ, Hammen C, Cohen AN, Daley SE, Henry RM. Expressed emotion versus relationship quality variables in the prediction of recurrence in bipolar patients. J Affect Disorders 2004;83:199-206.

19. Oâ&#x20AC;&#x2122;Connell RA, Mayo JA, Flatow L, Cuthbertson B, Oâ&#x20AC;&#x2122;Brien BE. Outcome of bipolar disorder on long-term treatment with lithium. Brit J Psychiatry 1991;159:132-129.

20. Priebe S, Wildgrube C, Muller-Oerlinghausen B. Lithium prophylaxis and expressed emotion. Brit J Psychiatry 1989;154:396-399.

21. Miklowitz DJ, Biuckians A, Richards JA. Early-onset bipolar disorder: A family treatment perspective. Dev Psychopathol 2006;18:1247-1265.

22. Wendel JS, Miklowitz DJ, Richards JA, George EL. Expressed emotion and attributions in the relatives of bipolar patients: An analysis of problem-solving interactions. J Abnorm Psychol 2000;109:792-796.

23. Scazufca M, Kuipers E. Coping strategies in relatives of people with schizophrenia before and after psychiatric admission. Brit J Psychiatry 1999;174:154-158.

24. Simoneau TL, Miklowitz DJ, Saleem R. Expressed emotion and interactional patterns in the families of bipolar patients. J Abnorm

Psychol 1998;107:497-507.

25. Rosenfarb IS, Miklowitz DJ, Goldstein MJ, Harmon L, Nuechterlein KH, Rea MM. Family transactions and relapse in bipolar disorder. Fam Process 2001;40:5-14.

26. Miklowitz DJ, Goldstein MJ. Behavioral family treatment for patients with bipolar affective disorder. Behav Modif 1990;14:457-489.

27. Rea MM, Tompson M, Miklowitz DJ, Goldstein MJ, Hwang S, Mintz J. Family focused treatment vs. individual treatment for bipolar disorder: Results of a randomized clinical trial. J Consult Clin Psychology 2003;71:482-492.

28. Miklowitz DJ, George EL, Richards JA, Simoneau TL, Suddath RL. A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder.

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29. Miklowitz DJ. Bipolar disorder: A family-focused treatment approach.

2nd ed. New York, N.Y.: Guilford, 2008.

30. Miklowitz DJ, Otto MW, Frank E, Reilly-Harrington NA, Wisniewski SR, Kogan JN, et al. Psychosocial treatments for bipolar depression: A 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry 2007;64:419-427.

31. Miklowitz DJ, Otto MW, Frank E, Reilly-Harrington NA, Kogan JN, Sachs GS, et al. Intensive psychosocial intervention enhances functioning in patients with bipolar depression: Results from a 9-month randomized controlled trial. Am J Psychiatry 2007;164:1-8.

32. Goldstein BI, Goldstein T, Miklowitz DJ, Collinger KA, Bukstein O, Axelson D, Birmaher B. Family-focused treatment of adolescents with comorbid bipolar disorder and substance use disorders. Oral symposium presentation. American Academy of Child and Adolescent Psychiatry Annual Meeting; October 2009, Honolulu.

33. Miklowitz DJ, Axelson DA, Birmaher B, George EL, Taylor DO, Schneck CD, et al. Family-focused treatment for adolescents with bipolar disorder: Results of a 2-year randomized trial. Arch Gen Psychiatry 2008;65:1053-1061.

34. Miklowitz DJ, Axelson DA, George EL, Taylor DO, Schneck CD, Sullivan AE, et al. Expressed emotion moderates the effects of familyfocused treatment for bipolar adolescents. J Am Acad Child Adolesc Psychiatry 2009;48:643-651.

35. Birmaher B, Axelson D, Goldstein B, Strober M, Gill MK, Hunt J, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry 2009;166:795-804.

36. Axelson DA, Birmaher B, Strober MA, Goldstein BI, Ha W, Gill MK, et al. Course of subthreshold bipolar disorder in youth: Diagnostic progression from bipolar disorder not otherwise specified. J Am Acad Child Adolesc Psychiatry 2011;50:1001-1016.

37. Angst J, Sellaro R, Stassen HH, Gamma A. Diagnostic conversion from depression to bipolar disorders: Results of a long-term prospective study of hospital admissions. J Affective Disorders 2005;84:149-157.

38. Duffy A, Alda M, Crawford L, Milin R, Grof P. The early manifestations of bipolar disorder: A longitudinal prospective study of the offspring of bipolar parents. Bipolar Disord 2007;9:828-838.

39. Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL. Bipolar disorder at prospective follow-up of adults who had prepubertal major depressive disorder. Am J Psychiatry 2001;158:125-127.

40. Kochman FJ, Hantouche EG, Ferrari P, Lancrenon S, Bayart D, Akiskal HS. Cyclothymic temperament as a prospective predictor of bipolarity and suicidality in children and adolescents with major depressive disorder. J Affective Disord 2005;85:181-189.

41. Nadkarni RB, Fristad MA. Clinical course of children with a depressive spectrum disorder and transient manic symptoms. Bipolar Dis 2010;12:494-503.

42. Strober M, Carlson G. Bipolar illness in adolescents with major depression: Clinical, genetic, and psychopharmacologic predictors in a 3-4 year prospective follow-up investigation. Arch Gen Psychiatry

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43. Miklowitz DJ, Chang KD. Prevention of bipolar disorder in at-risk children: theoretical assumptions and empirical foundations. Dev Psychopathol 2008;20:881-897.

48. Yurgelun-Todd DA, Gruber SA, Kanayama G, Killgore WD, Baird AA, Young AD. fMRI during affect discrimination in bipolar affective disorder. Bipolar Disord 2000;2:237-248.

44. Miklowitz DJ, Chang KD, Taylor DO, George EL, Singh MK, Schneck CD, et al. Early psychosocial intervention for youth at risk for bipolar disorder: A 1-year treatment development trial. Bipolar Disord 2011;13:67-75.

49. Pavuluri M. Effects of early intervention on the course of bipolar disorder: theories and realities. Curr Psychiatry Rep 2010;12:490-498.

45. Schlosser DA, Miklowitz DJ, Oâ&#x20AC;&#x2122;Brien MP, De Silva S, Zinberg JL, Cannon TD. A randomized trial of family-focused treatment for adolescents and young adults at risk for psychosis: Study rationale, design, and methods.

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47. Rich BA, Vinton DT, Roberson-Nay R, Hommer RE, Berghorst LH, McClure EB, et al. Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder. Proc Nat Acad

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52. Miklowitz DJ, Axelson DA, Kowatch R. Effectiveness of family-focused treatment plus pharmacotherapy for bipolar disorder in adolescents. wwwClinicalTrialsGov. 2009;NIMH Grant MH073871, ClinTrials ID: NCT00332098.

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Isr J Psychiatry Relat Sci - Vol. 49 - No 2 (2012)

Stress and Support for Parents of Youth with Bipolar Disorder Radha B. Nadkarni, PhD,1 and Mary A. Fristad, PhD2 1

Behavioral Health Services, Nationwide Children’s Hospital, Columbus, Ohio, U.S.A. Departments of Psychiatry, Psychology & Human Nutrition, the Ohio State University, Columbus, Ohio, U.S.A.

2

ABSTRACT Background: This article reviews stress related to parenting a youth with bipolar disorder (BD), maladaptive coping, immunologic and physical functioning related to chronic stress; presents preliminary findings about the association between immune parameters and health conditions, mental health indices and interpersonal functioning in parents of children with mood disorders; and provides recommendations for stress management based on clinical trials of family-based psychoeducational psychotherapy (PEP).

Data: Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), Epstein Barr Virus (EBV), nutritional markers and measures of physical health, mental health and interpersonal functioning were collected from 26 parents of mood disordered children.

Higher CRP was associated with more perceived stress, more depression, increased incidence of illness/ physical conditions, and lower albumin levels. Elevated IL-6 was associated with higher nicotine use.

Limitations: Sample size and demographics were restricted, limiting generalizability.

Conclusion: Pilot data are consistent with literature from adult caregivers, and suggest caregivers who are more stressed also evidence some signs of immune abnormality. Evidence-based strategies to support parents are discussed.

Financial support for this project obtained through a grant awarded to Dr. Mary A. Fristad from National Institute of Mental Health grant # R01MH061512 and the Ohio Department of Mental Health (IRB# 2004H0052). Dr. Fristad receives royalties from Guilford Press, Inc. for a treatment manual and from CFPSI for corresponding MF-PEP and IF-PEP workbooks (www.moodychildtherapy.com).

Introduction Raising a child with bipolar disorder (BD) is a daunting task. In addition to the struggles one can experience simply obtaining an appropriate diagnosis, developing a functional treatment plan, and dealing with the myriad of difficult symptoms at home and at school, stigma and blame can further challenge parents, who often battle mood disorders themselves, or in their immediate family members (1).

In this article, we review the literature on parenting stress related to raising a child with BD. Next, we focus on stress associated with parental BD, as children with BD often have parents with a mood disorder, adding to the parenting challenge. Then, we discuss maladaptive coping related to chronic stress. Subsequently, we provide findings from a pilot study that assessed immunologic functioning in caregivers of children with mood disorder. Finally, we suggest strategies to support parents in managing the stress associated with parenting a child with BD based on clinical trials of family-based psychoeducational psychotherapy (PEP).

Caregiver Stress Childhood onset BD is likely to be lifelong, with waxing and waning symptoms that require ongoing, active management (2). As a result, caring for a child with BD can be quite stressful and can adversely impact multiple areas of parents’ lives. Parents cope with a wide range of difficulties that may include: diminished relationships with friends and relatives; financial strain due to limited insurance coverage for behavioral health care; and strains on the caregiver’s emotional and physical health (3-5).

Even factors that might typically serve as protective factors from stress, such as higher income and educa-

Address for Correspondence: Mary A. Fristad, PhD, ABPP, Department of Psychiatry, The Ohio State University, 1670 Upham Drive, Suite 460G, Columbus, OH 43210, U.S.A. Mary.Fristad@osumc.edu

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tion levels, may not be sufficient to relieve the parental burden associated with caring for a child with BD. Hellander and colleagues (5) surveyed 732 caregivers of children with BD via the Child and Adolescent Bipolar Foundation (CABF) website. Most respondents were female (97%), White (97%), married (75%), and financially middle-class or above (two-thirds of respondents reported income over $50,000). Many were professionals including doctors, teachers and social workers.

Presumably, this sample had greater access to adequate professional care for their children with BD than the overall population of parents raising children with BD. Despite this, significant levels of stress were reported.

The three most stressful aspects of caregiving were: “walking on the eggshells around child to avoid rages”; “trying to get child to do chores or self-care”; and “having less time to take care of self.” The authors speculated that caregivers from non-affluent and less educated families would likely experience even more stress. This stress can be caused by many aspects of raising a child with BD, one common and particularly difficult phenomenon being blame for the child’s symptoms.

Historically parents of children with mood disorders have been blamed rather than supported in their parenting (4). Caregivers report condemnation and social isolation from family gatherings, church and community events, and extended social networks due to their child’s difficult behavior and stigma associated with mental disorder (3, 5). Blame often includes the presumed etiology for their child’s mental illness and associated behavioral problems (6). Caregivers focus attention and devote time to caregiving, leading to neglect of self and others in the family (5). Often parents develop anxiety and depressive symptomatology associated with chronic stressors comparable to those described for caregivers of dementia (6).

Attempting to obtain appropriate services or accommodations can also be a challenging experience. Barriers to receiving adequate care include: professionals not believing parental report of behavior; professionals insinuating that poor parenting strategies have caused the child’s symptoms; and professionals who lack training and knowledge that results in inappropriate questioning, erroneous diagnosis, and unsuitable treatment (1). In addition to not being helpful in the moment, encounters such as this can prevent families from seeking professional assistance later in the course of the child’s development if they have learned through experience that interventions costs them time, money and hope without the benefit of symptomatic relief.

105

Bidirectional causes of stress are common in families of children with BD. In addition to the stress of raising a child with BD, parents often have a mood disorder themselves, further complicating family life.

Parents with a Mood Disorder Genetic risk. Mood disorders are highly heritable.

Having a first degree relative with BD increases the risk of this illness 10-fold (7). Individuals with BD have an increased likelihood of marrying a person with a mood disorder, a phenomenon referred to as “assortative mating” (7), which places the children of such couplings at an even higher risk for developing a mood disorder. A child who has one parent with a mood disorder has a 27% lifetime risk of a mood disorder whereas a child who has two parents with a mood disorder carries a 74% lifetime risk (7). Thus, children with BD not infrequently have parents with a mood disorder.

Psychosocial risk. In addition to the genetic risk, parental mood disorders may expose children to maladaptive child rearing practices, which can contribute to an earlier onset of disorder for the child and/or make recovery from an episode more prolonged (7-9) Even if parents of children with BD do not have a mood disorder themselves, they often have experienced the effects of BD within their family of origin. Having grown up with a parent or sibling who has BD colors what adults bring to their parenting.

Several predictors of poorer outcome for adults with BD are also factors that increase familial stress. These include less social support and lower social adjustment (10), familial negative expressed emotion and negative interaction (11), impaired social and leisure activities, poor quality of relationship with extended family (12), more stressful life events (13), and poorer marital adjustment (14). Targum and colleagues (15) found that the social problems that resulted from BD included marital problems, unemployment, financial difficulties, social withdrawal due to depression, and relapse leading to re-hospitalization.

Impact on parenting. Children benefit by consistency in parenting behavior. When parents have BD, consistency in parenting practices may be challenging.

Parenting behavior may be influenced by the parent’s depression, mania/hypomania, or mixed state, chronicity of episodes, suicidality/suicide attempts, risky behavior associated with mania, difficulty with treatment adherence, withdrawn/irritable behavior during

Radha B. Nadkarni and Mary A. Fristad

depressed mood, relapse in spite of treatment adherence, and recovery time between episodes. In sum, parents with a mood disorder experience life stressors due to their own diagnosis. Raising a child with BD amidst these stressors can be challenging.

Psychological and Physical Consequences of Caregiving Clearly, parents of children with BD experience ongoing stress. Prior research indicates that caregiving has long-term impact on psychological well-being even after caregiving ceases. For example, in a study conducted

by Robinson-Whelen and colleagues (16), even though perceived stress and negative affect decreased in former caregivers of a relative with a progressive dementing illness, scores on measures of psychological well-being (depression, positive affect and loneliness) did not return to non-caregiver levels within three years after caregiving demands ceased. The stress of caregiving for children with mental health problems, due to the physical and emotional challenges involved in early years of caregiving, lack of service coordination among service providers, and inadequate time and energy for self care, might similarly negatively influence caregivers’ psychological well being and physical health in later years (17, 18).

Numerous studies have linked chronic psychological stress and adverse health outcomes (19-22). For example, chronic psychological stress has been associated with increased risk for developing mild hypertension (19), hastening the progression of coronary artery disease (20), aggravating the course of rheumatoid arthritis (21), and increasing susceptibility to colds (22). Research further indicates that individuals with chronic stress are more likely to abuse substances, including alcohol, nicotine and caffeine, as a method of coping (23, 24). They are also likely to eat “comfort foods” instead of nutritionally healthy foods (25) and may have sleep-related problems such as difficulty falling asleep, awakening in the middle of the night or waking in the early morning (26).

Moreover, individuals with chronic stress may lack the time to devote to physical exercise and other healthy habits due to caregiving demands (27). This combination of stress and maladaptive coping can also negatively influence physical health in later years (16).

Chronic stress and poor health behaviors have also been linked to adverse immune and neuroendocrine consequences. Studies have shown that chronic stress and depression can provoke immune dysregulation,

including elevations in inflammatory markers (interleukin-6 [IL-6], tumor necrosis factor - alpha [TNFα], C-reactive protein [CRP] and Epstein Barr Virus [EBV]) (26-30). Elevations of proinflammatory cytokines (IL-6 and TNF -α), CRP and EBV have serious health consequences, including increased morbidity and mortality (28-30). Studies of the effects of poor health behaviors have found that alcohol abuse is associated with decreased natural killer cell activity and/ or daytime increase of IL-6 (31); cigarette smoking is associated with elevated levels of cortisol (32); caffeine is associated with increase in plasma ephinephrine and cortisol (24); and depressive mood in individuals with obesity is associated with elevated levels of CRP (33).

Individuals who experience partial night sleep deprivation are prone to over-secrete IL-6 during the daytime and under-secrete IL-6 during nighttime (34). This is a problem, as good quality night sleep is associated with decreased secretion of daytime IL-6 levels (35). Sleep deprivation elevates daytime IL-6 levels, resulting in drowsiness and fatigue during the next day (35). Not surprisingly, physical activity and exercise are associated with improved immune functioning, with regular exercise producing anti-inflammatory effects (36).

Immune Functioning in Parents of Children with Mood Disorder Immune dysregulation associated with caregiving stress has been studied in older adults (37, 38), but no studies have assessed IL-6, TNF-α, CRP and EBV in parents of children with mood disorders. To document the relationship between stress and immune functioning in caregivers of children with mood disorder, IL-6, TNF-α, CRP, EBV and health conditions, mental health indices and interpersonal functioning were measured in 26 caregivers of children participating in a family-based psychosocial intervention for children with mood disorders.

Pilot Study Participants. Twenty-six caregivers (M = 41.0 years, SD = 6.2) from the Multi-Family Psychoeducational Psychotherapy (MF-PEP) treatment study participated in this study after providing informed consent. Both this research study and the MF-PEP parent study, results of which have been published elsewhere (39, 40), were approved by the university medical center Institutional Review Board. Participants were primarily female 106

Stress and Support for Parents of Youth with Bipolar Disorder

(62%), White/Non-Hispanic (96%), had more than a high school education (92%), a family income between $40,000-$80,000 (58%), and lived with a spouse who was the child’s other biological parent (58%).

Measures. Levels of IL-6, TNF-α, CRP, EBV, and nutritional markers (total iron binding protein, plasma transferrin and albumin) were assessed. Information regarding physical health (health-related behavior questions [26], physical activity (frequency of exercise [41]; general health (questions from the Older Adults Resources Survey [42]); sleep (Pittsburgh Sleep Quality Index [43], parenting stress (Parent Stress Survey Sisson [44]); depression (Center for Epidemiological Studies Depression Scale [45], anxiety (Beck Anxiety Inventory [46]), stress (Perceived Stress Scale [47]); interpersonal functioning (social functioning subscale, Older Americans Resources and Services Multidimensional Functional Assessment Questionnaire [42]); and parentchild relations (Expressed Emotion Adjective Checklist [48]) were also collected.

Data Analysis. Q-Q Plots were used to verify normality of the distribution for IL-6, TNF-α, and CRP. Distributions for IL-6 and CRP were normal; however, the distribution for TNF-α was not. TNF-α values were transformed by taking the reciprocal of the data, Q-Q plots were used to verify normality of the distribution of transformed data. To explore the relationship between immune parameters, nutritional markers, physical health conditions, health-related behaviors, mental health indices, and interpersonal functioning, Pearson Product Moment correlations were calculated. As this was an exploratory study, analyses were not corrected for the 68 multiple comparisons made; therefore, some significant findings could be expected by chance.

Results and Discussion. Higher CRP levels were associated with lower levels of albumin, more illnesses/ physical conditions, higher perceived stress and higher reported depression levels (Table 1). Higher usage of nicotine was associated with higher levels of IL-6. No significant relationships between TNF-α, EBV and other variables were detected.

Findings indicated that parents with higher CRP levels had increased illnesses/physical conditions, consistent with past research indicating that elevations of proinflammatory cytokines have significant health consequences (29, 30). Also consistent with past research, higher CRP levels were associated with higher perceived stress and depression (38, 49, 50). Parents who used nicotine had higher levels of IL-6 than those 107

Table 1. Pearson Product Moment Correlations between IL-6, TNF-α, CRP, EBV and Physical Health Behaviors and Indices, Mental Health Indices, and Measures of Interpersonal Functioning Variables

IL-6

TNF-α

CRP

EBV

r

r

R

R

Physical Health Behaviors and Indices Alcohol Caffeine Nicotine Physical activity Weight changes Medications Illnesses PSQI

-0.14 0.34* 0.67** 0.03 -0.14 -0.18 0.21 0.13

0.33 -0.32 -0.11 0.18 0.28 0.22 -0.27 0.16

-0.1 -0.16 -0.06 -0.15 -0.03 -0.11 0.58*** 0.1

-0.17 0.28 -0.12 -0.06 -0.01 -0.12 0.004 -0.15

0.21 0.02 0.01

-0.27 0.25 0.25

-0.54*** 0.14 0.14

-0.23 0.16 0.16

-0.09 -0.21 -0.24 -0.21

-0.24 0.23 -0.009 0.17

-0.10 0.50*** 0.37 0.58***

-0.70 0.05 0.08 0.22

0.05 -0.22

-0.09 0.27

-0.19 -0.24

-0.02 0.07

Nutritional Measures Albumin Transferrin TIB Mental Health Indices BAI CES-D PrSSa PSS Interpersonal Functioning EEAC OARS

Note: IL-6 = Interleukin-6; TNF-α = tumor necrosis-alpha; CRP = C-reactive protein; EBV = Epstein Barr Virus; PSQI = Pittsburgh Sleep Quality Index; TIB = Total Iron Binding; BAI = Beck Anxiety Inventory; CES-D= Center for Epidemiological Studies Depression Scale; PrSS = Parent Stress Survey; PSS = Perceived Stress Scale; EEAC = Expressed Emotion Adjective Checklist; OARS = Social support functioning from the Older Americans Resources and Services Multidimensional Functional Assessment Questionnaire. a n = 19 and for all remaining variables N = 26; * p = 0.09; ** p = 0.000; ***p ≤0.009

who did not. Parents with higher CRP levels had lower albumin levels. Higher serum albumin has a protective effect in older individuals without cytokine-mediated inflammation (51). In short, preliminary results suggest that parents of children with mood disorders who are more stressed are also showing some signs of immune abnormality. As these parents continue to age while caring for their children, it will be important to provide psychological interventions that target caregiving stress.

Limitations. This pilot study was limited by the small and homogenous sample, thereby limiting the generalizability of results to other groups.

Conclusions. Parents of youth with BP may experience chronic stress due to the demands of caregiving and stigma associated with the disorder (52). Due to the genetic aspect of BD, parents themselves may have

Radha B. Nadkarni and Mary A. Fristad

a mood disorder, which can further exacerbate the situation. Instead of receiving support and understanding from friends and/or family, community, social network, and church groups, parents may experience isolation, guilt and blame due to child’s difficult behavior. Chronic stress has been associated with decreased utilization of healthy habits, immune dysregulation and poor physical health outcomes. Long-term caregiving has clearly documented consequences on emotional and physical health, including immunologic functioning. Our pilot data suggest that parents of children with mood disorders who are more stressed also show some signs of immune abnormality. Thus, interventions supportive of parents may be particularly important, both for parents’ mental and physical well-being. Psychoeducational interventions are designed to provide social support, enhance coping, encourage healthy behaviors (e.g., regarding sleep hygiene, less nictone/smoking usage, diet and exercise) and improve family climate; they may positively impact these immune parameters in caregivers of children with mood disorders. Below we discuss components of familybased psychoeducational psychotherapy, which can support parents as they care for children with BD. Clinical Implications Utilizing Psychoeducational Psychotherapy (PEP)

Parents are ultimately responsible for the care of their child with BD; thus, it is imperative that mental health providers make available interventions that provide the information, support and skill building so that parents can dismiss guilt and move forward productively with their child to more effectively manage symptoms. This includes learning about various mood diagnoses, monitoring mood states, recognizing prodromal symptoms and patterns, developing strategies to enhance treatment adherence, understanding medication — how to monitor its effectiveness and manage side effects, safety planning for risky behaviors, building school and mental health treatment teams, and learning to differentiate the child from the disorder (2). This psychoeducational approach has been demonstrated in three randomized controlled trials to improve outcomes for children and families (39, 53, 54), in part by helping parents become better consumers of care (40).

Pre-Planning For Crises

Crisis pre-planning can decrease the emotional intensity that surrounds crisis points. In many families,

simply having a crisis plan defined and in place can avert the frequency with which it actually needs to be implemented. Pre-planning strategies might include: 1) preemptive visits to the local police precinct to determine the most appropriate steps for calling the police, if needed to deescalate a violent situation; 2) preparing and maintaining a binder that includes: the child’s list of medications and side effects, treatment providers’ names and emergency contact information; insurance information; 3) determining the route to the most appropriate emergency department if hospitalization is being considered; 4) developing “safe places” for siblings to go to during periods of escalation at home.

Improving Family Climate

Learning to manage symptoms of BD in a matter of fact, problem solving manner using clear, direct communication is highly beneficial in improving the emotional climate in the home. Reducing critical, hostile, and overinvolved family interactions, a trio of family interaction behaviors referred to as “expressed emotion, or EE,” provides a more stable environment in which the child can recover. Asarnow and colleagues (55) have demonstrated that depressed children who return post-hospitalization to a low EE environment are less likely to relapse over the course of a year than those who return to a high EE home. High EE is associated with increased relapse rates in children and adults with BD (56, 57).

Moreover, higher maternal warmth is associated with lower relapse rates post-recovery in youth with BD (58, 59). This highlights the importance of treatments that focus on family adaptability, cohesion and conflict (60).

Mediators of effective family interventions may include enhancing medication adherence, family communication, problem solving and ability to recognize prodromal symptoms (61). In addition to improved symptom management, overt attention to all relationships within the family can improve family climate. This includes making time for and valuing the marital/couple relationship and addressing sibling needs.

Maintaining Physical Health

As evidenced by the immunologic data previously presented, the importance of maintaining physical health is important. This includes engaging in health behaviors such as regular check-ups, regular exercise, healthy eating habits and sufficient sleep. In addition to promoting “healthy habits” in children, parents can, and 108

Stress and Support for Parents of Youth with Bipolar Disorder

should, role model reliance on these SEE (Sleep, Eating, Exercise) behaviors themselves.

Improving quality of sleep can make a critical difference for family functioning. Insufficient sleep can trigger a manic episode or intensify depressive symptoms.

Thus, sleep hygiene is important for all family members.

When a parent’s lack of sleep is secondary to worrying about a child’s risky behavior at night while manic, use of a motion detector on the door can provide some assurance of the child’s whereabouts.

Eating habits are largely set by parents within a family. Thus, if children are to engage in eating nutritious food that does not lead to excessive weight gain (a problem for many children on weight-gaining medications), parents typically need to be involved to plan, purchase and prepare the food. Including children in this process is desirable, whenever possible.

Parents may choose to interact with their child around exercise, such as going to the park together or playing together on a video/TV interactive game console, for example, or they may use exercise as their chance either for solitude or adult interactions, perhaps going for a long run, or attending an exercise class or game of basketball with friends. Regardless, engaging in exercise both helps to promote health in the parent as well as to model healthy behavior for the child.

Maintaining Mental Health

In addition to pursuing the previously described strategies, attention to parental mental health is of obvious critical importance. This can include seeking professional assistance, be it psychotherapy and/or medication management, as well as utilization of relaxation techniques such as mindfulness meditation. A growing scientific literature supports the use of stress reduction via mindfulness practice. Studies have demonstrated that regular practice of various relaxation techniques can lower blood pressure, slow breathing rate, increase blood flow to major muscles, reduce muscle tension, reduce chronic pain, improve concentration, and reduce anger and frustration (62-64). No-cost relaxation techniques such as self massage, guided imagery, yoga, progressive muscle relaxation, Tai Chi and deep breathing can be useful for stress reduction. Again, utilization of these techniques can not only be beneficial to the parent, but also provide good role modeling for the child, as some therapy manuals (e.g., MF-PEP) incorporate breathing exercises for children and their parents as part of the overall intervention.

109

Reducing Caregiving Burden

Accessing formal or informal respite care can allow for parents to take a break as well as to meet other family obligations. While some formal respite is available in many communities, most families do not have as much access to this formalized assistance as would be desired. Thus, helping parents to problem-solve how to arrange for additional informal respite can be a useful step in therapy. Informal respite might be available via extended family, supportive friends, church youth groups, through a bartering arrangement (e.g., the parent might exchange gardening for a friend for that friend taking the child with BD on a weekly outing), or a paid provider such as a baby sitter. There are various ways of using respite time. Caregivers might use this time to spend quality time with their significant other, with the child’s siblings, to run errands alone, or to simply do something relaxing alone or with friends. It is vital that parents not feel guilty about this “me” time.

Increasing Social Support

Maintaining social networks via family, friends, neighbors, religious communities and social networking all are options for parents. One specialized form of social support comes from internationally accessible Internet support networks such as The Balanced Mind Foundation (formerly known as Child and Adolescent Bipolar Foundation, CABF). The Balanced Mind Foundation has been found beneficial to parents for support and guidance as the website offers informative resources, chat rooms, message boards and email support group (5). Other advocacy and support organizations include in the United States, Depression and Bipolar Support Alliance (DBSA) and the National Alliance on Mental Illness (NAMI) and in Israel, the Israel Mental Health Association (ENOSH). These organizations work with patients and their families by offering educational programs, self-help support groups, telephone hotlines for emergencies, referrals to mental health professionals and newsletters. Moreover, through advocacy parents may feel empowered as they may be able to influence services and supports, and fight stigma associated with the disorder, in turn giving them a sense of strength and control. Finally, face-toface and Internet support groups provide a means to make new friends while learning tips from others with similar concerns. Information on these resources may be made available to parents at their first appointment through offices of mental health professionals.

Radha B. Nadkarni and Mary A. Fristad

Summary Raising a youth with BD can be stressful. Our pilot data suggest that parents of children with mood disorders who are more stressed are also showing some signs of immune abnormality. Interventions may help caregivers avoid premature aging of the immune system due to chronic stress, which makes caregivers vulnerable to a range of diseases (37, 38, 50). Our previous RCTs of family-based psychoeducational psychotherapy indicate that children and parents benefit from psychoeducational interventions designed to provide information, support and stress management skill building. Reducing caregiving stress may positively impact immune parameters in caregivers of children with mood disorder. Additional study of familybased psychosocial interventions to aid the child and family in recovery from BD is recommended.

Acknowledgements We wish to acknowledge Ms. Katherine Mount, research assistant, for her effort and time in compiling the references for this article.

Author Contributions: Dr. Nadkarni was involved in analysis and interpretation of data, drafting and final approval of this manuscript. Dr. Fristad was involved in conception and design, collection, analysis and interpretation of data, critical revision and final approval of the manuscript.

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Isr J Psychiatry Relat Sci - Vol. 49 - No 2 (2012)

The Effects of Ziprasidone on Prefrontal and Amygdalar Activation in Manic Youth with Bipolar Disorder Marguerite Reid Schneider, BA,1 Caleb M. Adler, MD,2,3 Rachel Whitsel, BA,2 Wade Weber, BS, MS,2 Neil P. Mills, BS,2 Samantha M. Bitter,2 James Eliassen, PhD,3 Stephen M. Strakowski, MD,2,3 and Melissa P. DelBello, MD2 1

Physician Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, Neuroscience Graduate Program, University of Cincinnati, Cincinnati, Ohio, U.S.A. 2 Division of Bipolar Disorders Research, Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A. 3 Department of Psychiatry & Behavioral Neuroscience, Center for Imaging Research, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.

ABSTRACT Background: Prior research has found that manic adolescents with bipolar disorder exhibit neurofunctional changes in the amygdala and prefrontal cortex following treatment with some pharmacological agents. We examined the neurofunctional effects of ziprasidone in manic adolescents.

Method: Manic adolescents with bipolar disorder (n=23) participated in a placebo-controlled study of ziprasidone and underwent a functional magnetic resonance imaging scanning session while performing a task of sustained attention at baseline, prior to treatment as well as on days 7 and 28 (or early termination) of treatment.

A comparison group of healthy adolescents (n=10) participated in a single scanning session. Region of interest analyses were performed to assess activation changes associated with treatment in Brodmann Areas (BA) 10, 11 and 47 and in the amygdala.

Results: Compared with placebo, treatment with ziprasidone was associated with greater increases over time in right BA 11 and 47 activation. These effects were not associated with differences in symptom improvement between the treatment groups. Patients who subsequently responded to ziprasidone showed significantly greater deactivation in the right Brodmann area 47 at baseline than those who did not respond to

ziprasidone. Similarly, among the bipolar adolescents who were treated with ziprasidone, baseline activation in right BA 47 was negatively correlated with improvement in Young Mania Rating Scale (YMRS) score.

Limitations: The small sample size limits the ability to detect significant group differences in other regions of interest. Healthy comparison subjects were scanned only at a single timepoint, which limits the interpretation of the results. Ziprasidone is not currently approved by the United States Food and Drug Administration for the treatment of adolescents with mania, and, therefore, the clinical relevance of these results is limited.

Conclusions: The increases in right BA 11 and 47 activation observed during sustained attention tasks following ziprasidone treatment and the association identified between lower baseline BA 47 activation and ziprasidone treatment response suggests that ziprasidone may correct prefrontal dysfunction in manic adolescents with bipolar disorder.

Support for this project was provided by Pfizer Data from this manuscript was presented in part at the 58th Annual Meeting of the American Academy of Child and Adolescent Psychiatry, 2011, October 18-23, 2011, Toronto, Canada

Address for Correspondence: Melissa DelBello, MD, Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, 260 Stetson St., Suite 3200, Cincinnati, OH 45219, U.S.A. â&#x20AC;&#x2020; melissa.delbello@uc.edu

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Effects of Ziprasidone in Adolescents

Introduction Bipolar disorder is a serious psychiatric disorder that often presents during adolescence (1). Several investigators hypothesize that alterations in ventral prefrontal and amygdala structure and function underlie the symptoms of bipolar disorder (2, 3). Indeed, structural imaging studies of youth with bipolar disorder consistently report decreased amygdala volumes relative to healthy subjects (4-8). Moreover, findings from functional imaging studies identify increased amygdala activation in children and adolescents with bipolar disorder during cognitive and emotional tasks (9-13). In addition to amygdala abnormalities, several studies identify decreased orbitofrontal cortex gray matter (Brodmann areas 11/47) in children and adolescents with bipolar disorder (14, 15).

Furthermore, findings from functional MRI studies of adolescents with bipolar disorder indicate ventral prefrontal dysfunction during performance of both emotional and cognitive tasks. Together, these studies suggest that prefrontal and amygdala abnormalities are involved in the neuropathology of bipolar disorder.

Pharmacological intervention is the primary treatment for children and adolescents with bipolar disorder.

In recent years, second generation antipsychotics (SGAs) have increasingly been used as first-line treatments for mania in adolescents (16). However, the specific mechanisms of action of SGAs that lead to the reduction of manic symptoms remain unknown. Neuroimaging studies examining functional changes associated with pharmacological treatment and response may help to identify these mechanisms. However, to date, there have been few reports prospectively examining neurofunctional changes associated with pharmacological interventions in youth with bipolar disorder (13, 17-20). A majority of these studies focus on the neurofunctional effects of the mood stabilizer lamotrigine (10, 13, 18, 20), although in some of these reports manic patients were initially stabilized with SGAs. Several studies report decreases in amygdala activation following treatment with lamotrigine (14, 20), which is correlated with symptom reduction (14). However, even after treatment, youth with bipolar disorder continue to demonstrate amygdala overactivation relative to healthy subjects (20). In contrast, these studies reported baseline underactivation and treatment related increases in ventral prefrontal activation of manic bipolar youth who were treated with lamotrigine (18, 20). To our knowledge, there is only one report examining the neurofunctional effects of monotherapy with an SGA in children and adolescents 113

(19). In this study, bipolar youth were randomized to monotherapy with either risperidone or divalproex. In contrast to the results seen with lamotrigine, as well as those observed in the divalproex treated group, risperidone was associated with decreased activation in several areas of prefrontal cortex, including dorsolateral, ventrolateral and medial regions. Taken together, these results suggest that specific pharmacological treatments may be associated with distinct patterns of prefrontal activation changes. However, prior studies have not included a placebo control group, making it difficult to distinguish between medication effects and mood state changes.

Ziprasidone is a SGA that is approved by the United States Food and Drug Administration (FDA) for the treatment of manic or mixed episodes in adults with bipolar disorder. Preliminary research supports its safety and efficacy in children and adolescents with bipolar disorder (21, 22). When compared to other SGAs, ziprasidone may have a more benign metabolic side-effect profile (21-23) and, therefore, may represent an important treatment option for youth with manic or mixed episodes associated with bipolar disorder.

With these considerations in mind, we used functional magnetic resonance imaging (fMRI) during a task of sustained attention to examine the neurofunctional correlates of treatment and response in a placebocontrolled study of ziprasidone for mania in adolescents with bipolar disorder. Prior research has shown that patients with bipolar disorder exhibit deficits in sustained attention (24, 25) as well as abnormal activation in emotional networks during the performance of purely attentional tasks (12, 26). This abnormal functional pattern and the observed deficits in attention may be due to a primary abnormality of limbic networks, which are normally inhibited in the face of attentional demands. Therefore, tasks of sustained attention serve as effective probes for dysfunction in limbic brain networks. Based on prior studies, we hypothesized that treatment with ziprasidone would be associated with increases in ventral prefrontal activation which would lead to greater inhibition of amygdala overactivation. As an exploratory aim, we also examined baseline patterns of neuronal activity that are associated with subsequent clinical improvement to identify potential predictors of ziprasidone response. To our knowledge, this is the first study to explore the neurofunctional effects of ziprasidone and the first placebo-controlled study to examine the neurofunctional correlates of pharmacological treatment for youth with bipolar disorder.

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Methods Study Participants

This study was conducted in conjunction with a multisite placebo-controlled registration clinical trial of ziprasidone for the treatment of adolescent mania. Patients from 10 and 17 years old with bipolar I disorder, current episode manic or mixed, according to the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR) criteria, were recruited (n=23). Diagnoses were confirmed using the Kiddie Schedule of Affective Disorders and Schizophrenia for School Aged Children – Present and Lifetime Version (K-SADS-PL). Patients were included if they had a Young Mania Rating Scale (YMRS) total score ≥ 16 at both screening and baseline visits. Patients were excluded for a diagnosis of substance abuse or dependence in the previous month for any substances other than nicotine or caffeine, being clinically stable on a well-tolerated treatment regimen, prior treatment with ziprasidone, a known allergy to ziprasidone, or a serious suicidal risk. Patients were also excluded if they had any history of head injury resulting in loss of consciousness for > 10 minutes, or any unstable medical or neurological disorder.

Healthy adolescents (n=10), who were demographically matched to the study participants, were recruited from the community. The healthy adolescents were included in order to interpret the changes in the patient group (i.e., whether activation normalized with treatment). All healthy adolescents were free of DSM-IV-TR Axis I disorders, as confirmed by a K-SADS-PL interview. Both healthy adolescents and adolescents with bipolar disorder were included only if they had an estimated IQ > 80 and were free of any contraindications to undergoing an MRI scan (e.g., braces or claustrophobia). A negative urine pregnancy test was required prior to each scan for girls.

Written informed consent from the participant’s legal guardian and written informed assent from the child were obtained prior to study procedures. This protocol was approved by the University of Cincinnati and Cincinnati Children’s Hospital Medical Center Institutional Review Boards.

Ziprasidone Treatment

Study participants with mania entered a washout period of exclusionary medications, including antipsychotics, mood stabilizers, stimulants, and antidepressants.

None of the patients were taken off medications for the

purpose of the study. Patients were only eligible to participate if their non-study related treatment team had determined that their symptoms warranted discontinuation of their current medication regimen prior to enrollment. Eleven of the participants had been treated with medication in the month prior to study participation. Seven patients had no history of prior treatment with any psychotropic agent.

Patients were randomized to receive either ziprasidone (n=14) or placebo (n=9) twice daily for four weeks as part of a large multi-center study. The dose was titrated over a 1-2 week period from an initial dose of 20mg/day to a target dose of 120-160 mg/day for subjects weighing ≥45 kg and 60-80 mg/day for subjects weighing < 45 kg.

Participants who had an insufficient clinical response at 1 week following titration and had reached a maximum tolerated dose were discontinued from participation in the double-blind phase of the study, and were eligible to enroll in a 6-month open-label extension trial. Healthy adolescents received no medication.

Ratings and Assessments

Patients with bipolar disorder were assessed at baseline, and then weekly during the 4 weeks of ziprasidone treatment. At each visit, study participants were evaluated using the YMRS, the Children’s Depression Ration Scale – Revised (CDRS-R), and the Clinical Global Impression Scale-Severity (CGI-S). Additionally, the Clinical Global Impression Scale-Improvement (CGI-I) score was administered at each visit beginning at week one. All ratings were performed by trained raters with established reliability (ICC > 0.8 for each rating scale), and when possible, the same rater performed all ratings for an individual patient. IQ score estimates were obtained at baseline for all study participants using the Wechsler Abbreviated Scale of Intelligence (WASI)(27) or the Kaufman Brief Intelligence Test, 2nd edition (K-BIT) (28). Handedness was assessed for all study participants using the Crovitz Handedness Questionnaire (29).

Behavioral Task

During each scanning session, all study participants completed a single-digit version of the Continuous Performance Task – Identical Pairs Version (CPT-IP), a sustained attention task. The task was administered using E-Prime (Psychology Software Tools, Inc.) on a dedicated PC. In this task, study participants were presented with series of single-digit numbers, and were asked to respond via button press using the thumb 114

Effects of Ziprasidone in Adolescents

of their dominant hand each time the same number was presented twice in a row. During each 30 second epoch, numbers were presented for 700ms at 750ms intervals, for a total of 40 stimuli/epoch. There were 5 target stimuli in each active task epoch. This active task was presented in an alternating block design with a control task that consisted of the number “1” presented repeatedly with the same rate and intervals used in the active task. To control for activation associated with the motor response, subjects were asked to press the button 5 times at the onset of each control epoch, and then to simply view the remaining numbers without responding. Responses were recorded electronically, and response parameters, including discriminability and mean reaction time for target responses were calculated for all subjects. Discriminability is the ability to discriminate signal and noise, and incorporates both target and false positive responses; it is calculated as A’=0.5+(y-x)(1+y-x)/4y(1-x), where x is the probability of a false alarm and y is the probability of a hit.

Functional MRI scanning protocol

Study participants with bipolar disorder were scanned at baseline, prior to the initiation of treatment, as well as on days 7 and 28 (or at early termination for those who did not complete all four weeks of the trial). Healthy adolescents underwent a single scan, which served a basis for the interpretation of treatment-associated changes seen in the bipolar youth. All scans were performed at the University of Cincinnati Center for Imaging Research (CIR) using a 4.0 Tesla (4T) Varian Unity INOVA MRI. A radio-frequency coil was placed over the subject's head and padding was placed between the head and the coil to minimize movement during the scanning session. Following a scout scan for alignment and brain localization, a shimming procedure was used to generate a homogeneous magnetic field. A high resolution T1-weighted, 3D scan of the brain was obtained to provide anatomic localization for functional imaging data using a modified driven equilibrium Fourier transform (MDEFT) sequence [TMD=1.1s, TR=13ms, TE=6ms, FOV=25.6 x19.2x19.2 cm, matrix = 256x192x96 pixels, flip angle = 20o). A midsagittal localized scan was used to place 30 contiguous 5mm coronal slices, covering the entire brain. Subjects then completed the fMRI session by performing the CPT-IP task. Functional images were acquired using a T2*-weighted gradient echo EPI pulse sequence (TR/TE = 3000/30ms, FOV = 4 X 4 X 5mm, matrix = 256 X 256 pixels, slice thickness =5mm, flip 115

angle = 75o). Data from the first acquisition of each run were discarded in post-processing to avoid non-equilibrium intensity modulation effects.

Functional MRI Processing

MRI images were reconstructed using in-house software to convert the raw data into AFNI format, and all subsequent analysis was performed using AFNI (30) (Analysis of Functional NeuroImages: http://afni.nimh.nih.gov/ afni). Specifically, MDEFT (structural) and EPI (functional) images were co-registered using scanner coordinates, and EPI data were then corrected for motion.

Data was normalized to Talairach space, and binary masking was applied to remove voxels outside the brain.

Individual activation maps were created using a deconvolution algorithm that compares the actual hemodynamic response to a canononical hemodynamic response function. AFNI was then used to generate an estimate of the “fit coefficient” describing the magnitude of the hemodynamic response during the active task relative to the control task. Final activation maps consisted of these fit coefficients divided by the average signal intensity, to create a percentage change score associated with task performance. For our primary analysis, the following regions of interest (ROIs) were defined using AFNI; left and right Brodmann Areas 10, 11, and 47 in the ventral prefrontal cortex, and left and right amygdala. The location of these regions of interest is illustrated in Figure 1. The average percent change in activation during performance of the active CPT-IP task for these regions was extracted using the 3dROI program in AFNI and a mask created using AFNI Talairach coordinates. These numerical percent change results were used for all subsequent analysis.

Statistics and Imaging Analyses

All statistical analyses were performed using SAS Version 9.2 (SAS Institute, Inc.). Comparisons for baseline demographic, clinical and task performance variables were performed using Wilcoxon Signed Rank tests for continuous variables and Fisher Exact tests for categorical variables. Analysis of the task performance variables over time for the treatment groups was performed using a repeated measures mixed effects model, with treatment group as a between subject factor and time-point as a within subject factor.

Primary analysis focused on treatment related changes in activation patterns in the eight pre-selected ROIs. Therefore, Bonferroni correction for multiple comparisons was applied for all primary analyses, yielding a cor-

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rected threshold for significance of p<0.006. Although the groups did not differ on task performance, discriminability was initially considered as a potential covariate because prior work using a similar task demonstrated Figure 1. Locations of the regions of interest (ROIs) used. (Left =Left)

Brodmann Area 10

Brodmann Area 47

Brodmann Area 11

Amygdala

activation changes are associated with task performance in individuals with bipolar disorder (12, 26). However, when analyses were repeated including this variable, results did not differ from those reported here.

Activation in a priori selected ROIs was compared between treatment (ziprasidone vs. placebo) groups using a repeated-measures mixed effects model, controlling for sex and days of treatment. Significant main effects were further explored using pair-wise t-tests on least squares means and the Tukey-Kramer adjustment for multiple comparisons. This mixed model analysis was then repeated also controlling for change in YMRS score (endpoint-baseline) to determine if differences between the groups were due to differences in symptom improvement or medication effects.

We also explored whether baseline activation patterns were associated with subsequent treatment response.

For this purpose, patients were classified as treatment responders if at study endpoint (day 28 assessment or early termination visit) they demonstrated ≥50% reduction in YMRS from baseline and a CGI-I score ≤ 2.

Baseline activation in each ROI was compared between responders and non-responders within the ziprasidonetreated group using a general linear model. The placebo group was too small to allow for a separate responder analysis. We also performed correlation analyses to assess whether baseline activation or activation change in any of the ROIs was correlated with reduction in symptom severity as measured by change in YMRS scores.

Secondary exploratory analyses were conducted comparing the activation between healthy and bipolar

Table 1. Baseline demographic and clinical characteristics of study participants with bipolar disorder (n=23) who were treated with either ziprasidone (n=14) or placebo (n=9) and healthy comparison adolescents (n=10) Healthy adolescents (n=10)

Adolescents with bipolar disorder (n=23)

Ziprasidone (n=14)

Placebo (n=9)

Age, mean (SD)

15.0 (1.8)

14.6 (2.2)

14.7(2.3)

14.5 (2.2)

Sex, N (%), boys

6 (60)

11 (48)

9 (64)

2 (22)a

Race, N (%), White

7 (70)

20 (87)

IQ, mean (SD)

111 (9)

104 (12)

106 (14)

103 (10)

Attention Deficit Hyperactivity Disorder, N(%)

0(0)

10(43)

3(33)

7(50)

YMRS

n/a

27 (6)

27(6)

27(7)

CDRS-R

n/a

37(10)

37 (9)

39(10)

Age of Onset, mean (SD)

n/a

12.1 (3.0)

11.6 (3.6)

12.6 (1.8)

Current Episode, N(%), Mixed

n/a

18 (78)

9 (64)

9(100)

a

12 (86) b

8 (89) b

p <0.1 IQ data was not available for three study participants with bipolar disorder who were in the ziprasidone group.

YMRS = Young Mania Rating Scale CDRS-R = Children’s Depression Rating Scale- Revised a

b

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adolescents. The goal of these analyses was to provide a basis for the interpretation of the results of the primary analyses of treatment effects.

Table 3. Ziprasidone and placebo response breakdown and mean YMRS change by response classification Ziprasidone

Results Demographic and Clinical Characteristics

Table 1 illustrates the demographic information and baseline clinical characteristics for all study participants.

There were no significant differences in demographic characteristics between healthy youth (n= 10) and youth with bipolar disorder (n=23), nor between bipolar youth randomized to placebo (n=9) and those randomized to ziprasidone (n=14), with the exception that more boys were assigned to ziprasidone than placebo (using a liberal criteria of p< 0.1 for consideration of potential covariates).

There were also no significant differences between the treatment groups in baseline symptom rating scale scores, age of onset of bipolar disorder, percentage of patients with co-morbid ADHD, or current episode type.

Table 2 provides a summary of the scans completed for participants with bipolar disorder. At baseline, a participant from the ziprasidone group was too ill to complete the scan, and a participant from the placebo group had unusable scan data. At day 7, scan data was not available for 4 patients treated with ziprasidone for the following reasons: termination from the study (n=1), refusal to participate in the scan (n=1), unusable data (n=1), and not receiving medication during the 48 hours prior to day 7 scan (n=1). A participant in the placebo group had unusable day 7 scan data. Four participants in the ziprasidone group and a participant in the placebo group terminated participation prior to

Placebo

Responders

NonResponders

Responders

NonResponders

Number (%)

7 (50)

7 (50)

4 (44)

5 (56)

YMRS Change, Mean (SD)

-18 (6)

-7 (5)

-14 (3)

-2 (2)

their final scanning session. A participant in the placebo group had unusable endpoint scan data.

Table 3 provides a summary of the number of responders and non-responders in each treatment group, and the mean change in YMRS score for each subgroup. There was no significant difference in the dose of ziprasidone at day 7 between responders (mean = 74 mg) and nonresponders (mean = 80mg). There was also no significant difference in the dose of ziprasidone received at study endpoint between responders (mean = 90 mg) and nonreponders (mean = 120 mg).

There was a significant difference between the treatment groups in the number of days between their baseline and endpoint scans (p=0.03). Participants randomized to placebo remained in the study for fewer days (mean= 20) than those treated with ziprasidone (mean = 28), likely due to the fact that participants were allowed to discontinue for non-efficacy. Therefore, number of days of treatment was included as a covariate in analyses comparing the treatment groups.

CPT-IP Performance

Table 4 illustrates the mean CPT-IP performance measures at each time-point for study participants with bipolar disorder by treatment group. Healthy adolescents Table 2. Summary of study participation for study participants with bipolar disorder and adolescents with bipolar disorder performed similarly on the CPT-IP, and there were no signifiTotal Baseline Day 7 Endpoint cant differences on task performance measures at Participants Scan Scan Scan baseline. There were also no statistically significant Ziprasidone 14 13 10 10 treatment group by time differences in performance Early Study Termination Completion measures, nor were there differences in performance 1 9 measures between treatment groups at each time Placebo 9 8 8 7 point or within each treatment group over time.

Early Termination 5

Total

23

21

18

17 Early Termination 6

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Study Completion 2

Study Completion 11

Activation Changes Associated with Treatment

Mixed model analyses revealed a treatment (ziprasidone vs. placebo) by time interaction for right BA 11 and right BA 47 (F2,20=27.1, p<0.0001 and F2,20=16.2, p<0.0001, respectively) indicating that the change

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seven were classified as responders and six were classified as non-responders.

To examine whether baseline activation Baseline Day 7 Endpoint in each of the ROIs is associated with subseHCs BP Plc BP Zip BP Plc BP Zip BP Plc BP Zip quent treatment response to ziprasidone, we (n=10) (n=8) (n=13) (n=8) (n=10) (n=7) (n=10) compared baseline activation in each of the Discriminability, .96 .96 .95 .98 .95 .94 .93 mean (SD) (.04) (.04) (.05) (.03) (.06) (.06) (.08) ROIs between ziprasidone responders and non-responders. Baseline activation in right Reaction time, 634 622 623 640 615 637 615 mean (SD), msec (59) (68) (57) (64) (70) (58) (41) BA 47 was significantly different between HC=healthy comparison adolescents, BP=adolescents with bipolar disorder, subsequent responders and non-respondZip=ziprasidone, Plc=placebo ers to ziprasidone (F=11.6, p= 0.006). over time in these regions differed between treatment Specifically, responders exhibited decreased activation groups. Specifically, the ziprasidone group exhibited in right BA 47 (mean= -0.40), while non- responders greater increases in activation over time compared with showed little task related activation change in this ROI the placebo group in both right BA 11 and 47. (mean = 0.04).

Furthermore, there was a significant main effect for Similarly, among the patients treated with ziprasitime (i.e., change over time among the entire patient done, baseline activation in right BA 47 (Figure 2) was group) for both right BA 11 and 47 (F2,20=15.3, p<0.0001 negatively correlated with improvement in YMRS score and F2,20=8.4, p=0.002, respectively). Pair-wise compari(r=-0.78, p=0.002), i.e., larger decreases in activation of sons revealed that independent of treatment group, study right BA 47 at baseline were associated with greater participants had deactivation in right BA 11 at baseline symptom reduction within the ziprasidone group. and increased activation over time such that by study Since there were too few responders in the placebo endpoint, participants activated this region during task group, we did not examine baseline predictors of sympperformance. At endpoint right BA 11 activation across tom improvement in this group. However, among all both treatment groups was significantly greater than at bipolar study participants there were no statistically sigbaseline (p<0.0001) and at day 7 (p=0.0002). There were nificant associations between change in activation and no significant differences between the treatment groups change in YMRS score for any of the ROIs. at any time in right BA11 activation. Similarly, pair-wise Comparisons between Bipolar Adolescents comparisons also revealed that independent of treatment and Healthy Controls group, study participants exhibited deactivation in right Exploratory analyses were conducted to compare activaBA 47 at baseline and increased activation over time such tion in the ROIs between healthy adolescents and adothat by endpoint, participants activated this region durlescents with bipolar disorder, in order to provide a basis ing task performance. Right BA 47 activation at endpoint for interpreting treatment-related activation changes. At was significantly higher than at baseline (p=0.002) and at baseline, there were significant differences in right BA day 7 (p=0.003).

10 and left amygdala between bipolar and healthy youth.

The mixed model analyses were repeated to include Specifically, bipolar youth exhibited deactivation in right change in YMRS score as a covariate in effort to distinBA 10 during task performance, whereas healthy youth guish the group differences that were related to ziprasiexhibited increased activation in this region during task done treatment vs. those related to symptom improveperformance (F=5.5, p=0.03). Both healthy study particiment. Activation patterns were similar to those described pants and those with bipolar disorder showed deactivation above adjusting for group differences in change in YMRS in the left amygdala during task performance. However, scores, indicating that the group by treatment effects are healthy youth exhibited a significantly larger decrease in likely due to ziprasidone treatment rather than group difleft amygdala activation during task performance as comferences in symptom improvement. pared to youth with bipolar disorder (F=4.6, p=0.04).

There were no statistically significant differences in Baseline Activation Patterns Associated with Subsequent Response to Ziprasidone activation of any of the ROIs between healthy adolesWithin the ziprasidone group there were 13 participants cents and adolescents with bipolar disorder at day 7, who completed a baseline scan. Of these individuals, nor at endpoint.

Table 4. Baseline task performance for healthy controls and task performance over time and by treatment group for adolescents with bipolar disorder

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Effects of Ziprasidone in Adolescents

Figure 2. Improvement in YMRS (baseline-endpoint) score over the study period vs. baseline right BA 47 activation in manic adolescents with bipolar disorder (n= 13) treated with ziprasidone

Discussion In the present study, we found that treatment with ziprasidone was associated with increased activation during a task of sustained attention in several areas of the ventral prefrontal cortex, including right BA 11 and right BA 47, but not with detectable changes in amygdala activation. These changes appear to be associated with ziprasidone treatment, rather than symptomatic improvement.

Additionally, study participants with bipolar disorder who subsequently responded to ziprasidone had less baseline BA 47 activation during CPT-IP performance than those who did not respond. Similarly, lower baseline activation in this region was also associated with greater improvement in manic symptoms following treatment with ziprasidone, suggesting that a subgroup of patients with lower activation in these regions may be more sus119

ceptible to the anti-manic effects of ziprasidone. These findings also indicate that ziprasidoneâ&#x20AC;&#x2122;s anti-manic effects may be related to increasing prefrontal modulation of emotional regulation.

These findings provide the first placebo-controlled evidence for neurofunctional effects of pharmacological treatment in manic adolescents with bipolar disorder.

Our results are consistent with a neuropathological disease model in which patients with bipolar disorder show inappropriate limbic activation in the face of non-emotional tasks due to a failure to properly engage regions of the ventral prefrontal cortex to modulate activity in limbic regions, including the amygdala. This may represent a failure of the reciprocal inhibition of emotional and attentional networks that has been demonstrated in healthy individuals. Moreover, our findings suggest that treatment with ziprasidone is associated

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with increased functional activation in regions of the ventral prefrontal cortex, and indeed that patients with the lowest levels of activation in these regions may experience the most robust response to treatment with this medication. Although we did not detect changes in amygdala activation associated with ziprasidone treatment, there was a difference in amygdala activation between healthy controls and bipolar patients at baseline, which was no longer present at endpoint. Our small sample size and short duration of treatment may have limited our ability to detect statistically significant changes in amygdala activation following treatment.

Our results are consistent, in part, with those reported

by Passarotti and colleagues (18), who found a pattern of increased amygdala activation and decreased prefrontal activation in manic youth relative to healthy youth during a combined emotion-attention task. Following treatment the increases in amygdala activation persisted, while prefrontal cortex activity increased over time, normalizing relative to healthy subjects. Consistent with this, in a study of euthymic adults with bipolar disorder, both amygdala and ventrolateral prefrontal cortex activation were found to be increased compared to healthy controls during a sustained attention task (12), indicating that such increased prefrontal modulation may be related to symptomatic improvement.

The fact that the treatment groups were not balanced with regard to gender is an important potential confound in the current study. Prior research has suggested that there may be differences between boys and girls in timing of developmental progress (31, 32) and on the performance of emotional tasks (33). However, no published studies described significant gender differences in response to ziprasidone. We included gender as a covariate in the models comparing the treatment groups. The gender term was not significant for either of the regions in which we report significant findings (p=0.89 for Right BA 11, p=0.72 for Right BA47), suggesting that the difference in gender ratio between the groups did not contribute significantly to the findings that we describe. Further research may be needed to explore gender differences in response to treatments for bipolar disorder.

There are several additional limitations to consider when interpreting the results of this study. First, despite the fact that deficits in sustained attention are well-documented in individuals with bipolar disorder, we were not able to detect performance differences between adolescents with bipolar disorder and healthy adolescents, nor were there any performance alterations associated

with the changes in activation pattern seen with ziprasidone treatment. This is likely due to ceiling effects of task performance. Nonetheless, we identified differences in activation of prefrontal and amygdala regions between patients and healthy controls. Additionally, the small sample size of this study limits our ability to explore activation patterns seen in specific subgroups of our sample, (e.g., placebo responders, manic vs. mixed patients) and also prevents us from assessing the potential influences of comorbid psychiatric disorders. Also, although we included a comparison group of healthy youth, they underwent fMRI scans at a single time point, making it difficult to control for differences in activation that are related to practice effects.

Finally, this study was conducted as an add-on to the multi-site clinical trial of ziprasidone for adolescents with mania. Ziprasidone is not currently approved by the FDA for the treatment of mania in patients younger than 18 years, and there are ethical considerations that must be addressed whenever medications are being used â&#x20AC;&#x153;off-label.â&#x20AC;? We believe that the prior research (21, 22) provided sufficient justification for a clinical trial of ziprasidone in this population, and ziprasidone has been approved for the treatment of adolescent mania in the European Union. Still, the clinical relevance of these results is limited by the fact that ziprasidone is not approved for the population described. However, several other SGAs are approved for the treatment of mania in adolescents with bipolar disorder, and these results contribute to our understanding of the mechanisms of action which may be common to other members of this frequently-used class.

Despite the limitations, the findings of this study contribute to our understanding of the neurofunctional effects of pharmacological treatment for mania in adolescents with bipolar disorder. Further research is needed to determine whether treatment related increases in ventral prefrontal activation are associated with improvements in sustained attention and other executive function domains, if there are differences in patterns of change patients experiencing manic versus mixed episodes, as well as to investigate whether functional alterations in specific regions of ventral prefrontal cortex may be useful as specific biomarkers of ziprasidone response in patients with mania.

Acknowledgements Dr. Adler has served on the speakersâ&#x20AC;&#x2122; bureau for Merck, and Janssen. He has received research support from Eli Lilly and Co., Janssen, Pfizer, Forrest,

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Effects of Ziprasidone in Adolescents

AstraZeneca, Bristol-Myers Squibb, Repligen, and Johnson and Johnson.

Dr. DelBello has served on the speakers’ bureau or as a consultant for Bristol-Myers Squibb, Pfizer, and Merck. She has received research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Co., Forrest, Amylin, GlaxoSmithKline, Pfizer, Janssen, Merck, and Johnson & Johnson. Stephen Strakowski has received research support from Eli Lilly, Janssen, Johnson and Johnson, AstraZeneca, Martek Biosciences, Nutrition 21, Repligen, Sumatomo, Pfizer, NIDA, NIAAA, NIMH and NARSAD. He has received speaker fees from American Association of Child and Adolescent Psychiatry, CME Outfitters, Adamed and John Hopkins University. He has served as a consultant for the University of Utah. He also received fees to serve as the chair of a symposium for Consensus Medical Communications (CME through U. Minnesota; unrestricted grant from Ortho McNeil/Janssen); to mentor young investigator meeting – American Psychiatric Association; and for directed discussion on Web MD. Marguerite Reid Schneider, Neil P. Mills, Wade Weber, James Eliassen, Samantha M. Bitter and Rachel Whitsel have no relevant financial disclosures.

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12. Strakowski SM, Adler CM, Holland SK, Mills N, DelBello MP. A preliminary fMRI study of sustained attention in euthymic, unmedicated bipolar disorder. Neuropsychopharmacology 2004;29:1734-1740.

13. Chang KD, Wagner C, Garrett A, Howe M, Reiss A. A preliminary functional magnetic resonance imaging study of prefrontal-amygdalar activation changes in adolescents with bipolar depression treated with lamotrigine. Bipolar Disord 2008;10:426-431.

14. Wang F, Kalmar JH, Womer FY, Edmiston EE, Chepenik LG, Chen R, et al. Olfactocentric paralimbic cortex morphology in adolescents with

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bipolar disorder. Brain 2011;134:2005-2012.

15. Najt P, Nicoletti M, Chen HH, Hatch JP, Caetano SC, Sassi RB, et al. Anatomical measurements of the orbitofrontal cortex in child and adolescent patients with bipolar disorder. Neuroscience Letters 2007;413:183-186.

16. Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: A comparative analysis of acute, randomized, placebocontrolled trials. Bipolar Disord 2010;12:116-141.

17. Pavuluri MN, Passarotti AM, Parnes SA, Fitzgerald JM, Sweeney JA. A pharmacological functional magnetic resonance imaging study probing the interface of cognitive and emotional brain systems in pediatric bipolar disorder. J Child Adolesc Psychopharmacology 2010;20:395-406.

18. Passarotti AM, Sweeney JA, Pavuluri MN. Fronto-limbic dysfunction in mania pre-treatment and persistent amygdala over-activity post-treatment in pediatric bipolar disorder. Psychopharmacology 2011;216:485-499.

19. Pavuluri MN, Passarotti AM, Lu LH, Carbray JA, Sweeney JA. Doubleblind randomized trial of risperidone versus divalproex in pediatric bipolar disorder: fMRI outcomes. Psychiat Res-Neuroim 2011;193:2837.

20. Pavuluri MN, Passarotti AM, Harral EM, Sweeney JA. Enhanced prefrontal function with pharmacotherapy on a response inhibition task in adolescent bipolar disorder. J Clin Psychiatry 2010;71:1526-1534.

21. Biederman J, Mick E, Spencer T, Dougherty M, Aleardi M, Wozniak J. A prospective open-label treatment trial of ziprasidone monotherapy in children and adolescents with bipolar disorder. Bipolar Disord 2007;9:888-894.

22. DelBello MP, Versavel M, Ice K, Keller D, Miceli J. Tolerability of oral ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. J Child Adolesc Psychopharmacology 2008;18:491-499.

23. De Hert M, Dobbelaere M, Sheridan EM, Cohen D, Correll CU. Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: A systematic review of randomized, placebo controlled trials and guidelines for clinical practice. Eur Psychiatry 2011;26:144-158.

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26. Adler CM, Delbello MP, Mills NP, Schmithorst V, Holland S, Strakowski SM. Comorbid ADHD is associated with altered patterns of neuronal activation in adolescents with bipolar disorder performing a simple attention task. Bipolar Disord 2005;7:577-588.

27. Wechsler D. Wechsler Abbreviated Scale of Intelligence. San Antonio, TX: Pearson, Inc., 1999.

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Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence. P Natl Acad Sci USA 2010;107:16988-16993.

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Isr J Psychiatry Relat Sci - Vol. 49 - No 2 (2012)

Efficacy and Safety of Anti-Manic Agents in Children and Adults Arif Khan, MD,1,2 James Faucett, MA, MS,1 Graham J. Emslie, MD, 3 and Walter A. Brown, MD4,5 1

Northwest Clinical Research Center, Bellevue, Washington, U.S.A. Department of Psychiatry and Behavioral Health, Duke University, Durham, North Carolina, U.S.A. 3 Department of Psychiatry and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A. 4 Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, U.S.A. 5 Department of Psychiatry, Tufts University, School of Medicine, Boston, Massachusetts, U.S.A. 2

ABSTRACT Objective: Pediatric trials in depression have led to major concerns about potential suicide inducing properties of antidepressants and doubts about their efficacy. Several trials of anti-manic agents in children were recently conducted and regulatory reviews of the data have become available.

Methods: We acquired pediatric and adult anti-mania agent Medical and Statistical Reports from the U.S. FDA. We used these to evaluate efficacy, mortality, severe adverse events and suicidality.

Results: The six pediatric studies enrolled 1,228 patients (828 drug/460 placebo). The seven adult drug approval programs enrolled 4,228 patients (2,356 drug/1,932 placebo). Mean mania rating scale baseline (pediatric=30.3/adult=30.3) scores were identical, and drug-placebo difference scores (pediatric=5.8/ adult=5.2) were not significantly different. There were no reported deaths during the pediatric trials. During the 23 adult trials there were 8 deaths (3 in drug group/5 in placebo group), a mortality rate of 3,290/100,000 patient exposure years. The proportion of patients that reported severe adverse events was slightly lower for the pediatric (4.2%) as compared to adult (4.7%) trials.

A higher proportion of children (5/460, 1.1%) than adult (7/2,012, 0.3%) patients assigned to placebo reported suicidality, Ď&#x2021;2(df=1)=4.2, p=0.04. We did not find evidence of increased suicidality for children assigned to drug (7/828, 0.8%) as compared to the children assigned to placebo (5/460, 1.1%).

Address for Correspondence: â&#x20AC;&#x2020; akhan@nwcrc.net

Conclusions: These data suggest remarkable similarity between the outcomes of pediatric and adult trials for bipolar mania. The therapeutic profile of these anti-manic agents in children is notably better than that for some other psychotropic drugs, for example, antidepressants.

Introduction The assumption that psychotropics such as antidepressants and anxiolytics have a similar therapeutic profile in children and adults has not been borne out. In fact, pediatric trials in depression have led to major concerns about both the efficacy and the potential suicide inducing properties of antidepressants (1-3).

In recent years several psychotropics have been approved for the treatment of acute mania in children and adolescents. Recent reports have criticized the growing use of these agents for this group of patients (4, 5).

Although the therapeutic index of these agents for adults is very good (6), it is unclear whether the data from the pediatric trials reflect a similar profile.

In this context, Correll and his colleagues have analyzed all of the published efficacy and tolerability (7) data for the adult and pediatric trials for anti-manic agents.

They reported similar efficacy profiles although children experienced higher levels of somnolence and weight gain than adults. However, their analysis lacks two factors due to use of only published papers. First, this compilation does not provide information on the frequency of failed

Arif Khan, MD, Northwest Clinical Research Center, 1951 152nd Pl NE #200, Bellevue, WA 98007, U.S.A.

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Efficacy and Safety of Anti-Manic Agents in Children and Adults

or negative trials since they often go unpublished (8).

Second, it is unclear what the extent of mortality and morbidity is among children and adolescents participating in mania trials compared to the adult population.

Such details of severe adverse events are not included uniformly in published reports (9) such as those reviewed

by Correll et al. (7). We wished to assess the frequency of completed suicides, reported suicidality and serious adverse events (SAEs) such as those resulting in hospitalization or similar. In fact, concerns about pediatric antidepressant use surfaced only after specific regulatory reviews and not from published data as the medical journal authors, reviewers, and editors do not have primary access to source data. Only regulatory agencies such as the FDA or EMEA have legal availability of source data as well as authority to conduct data integrity audits of the clinical trial sites and pharmaceutical companies.

Based on the results from the comprehensive review of Correll et al. (7), we hypothesized that the magnitude of drug-placebo differences, frequency of positive trials and frequency of mortality and morbidity risk would be similar in pediatric mania trials as compared to adult mania trials. In order to test our hypothesis, we obtained data from the U.S. FDA archives which is not subject to publication bias and also requires detailed independent review by the FDA staff.

Methods Overview

The Food and Drug Administration Amendment Act (FDAAA) of 2007 (10) requires that results from federally requested pediatric trials be reviewed for efficacy and safety and made available in the public domain. The Statistical, Medical and Clinical Pharmacology Reviews from pediatric trials are posted at the website www.fda. gov (11). During July and August of 2010 we searched the FDA website and acquired Statistical and Medical Reviews from five pediatric trials for anti-manic agents divalproex, ziprasidone, quetiapine, olanzapine, and aripiprazole. Reviews of the risperidone pediatric trial were not available online due to completion of the risperidone trial prior to the FDAAA. We therefore requested the risperidone FDA SBA via the Freedom of Information Act (FOIA). We received FDA reviews for risperidone on CDRom from the FDA and were, as a result, able to include risperidone in our analysis.

We also used data from the FDA archives to evaluate adult anti-mania trials. During the past several years we 123

obtained FDA Summary Basis of Approval (SBA) reports for seven anti-manic agents (divalproex, olanzapine, risperidone, quetiapine, carbamezapine ER, aripiprazole, ziprasidone). The SBA reports are comprised of Statistical, Medical, and Clinical Pharmacology Reviews compiled from all data submitted during New Drug Applications (NDA). We obtained these reports from the FDA website or via request through the FOIA for a nominal fee.

The Statistical Reviews are a rigorous evaluation of efficacy data from all pivotal clinical trials reviewed during the NDA or in accordance with FDAAA. Medical Reviews are oriented towards evaluating the risk/benefit ratio detailing all safety data acquired during the drug approval programs and pediatric trials. All protocols for pivotal trials registered with the FDA during drug development process and pediatric trials conducted in accordance with the FDAAA are subject to this oversight of safety data.

Efficacy Comparisons

Our efficacy evaluations consisted of comparing the rate of successful as compared to failed trials between the adult and pediatric studies. Furthermore, we evaluated the Young Mania Rating Scale (YMRS) and Mania Rating Scale (MRS) baseline and change scores in the pediatric trials and the adult drug approval programs.

For the pediatric trials, we used the mean baseline and change scores that were reported in the Statistical Reviews that we obtained from the FDA website. For the adult trials, we first calculated a cumulative baseline and change score for each drug approval program. We then used overall drug approval program baseline and change scores to calculate a mean score for the adult trials.

Safety Comparisons

In order to evaluate mortality and morbidity we compared the proportion of pediatric and adolescent patients that suffered a fatal or non-fatal SAE to the proportion of adult patients that suffered a fatal or non-fatal SAE. Non-fatal SAEs are operationally defined as events of clinical significance that result in hospitalization, permanent disfigurement, or similar. We also compiled the number of SAEs that occurred during the trials that were specifically associated with suicidality according to the FDA SBA reports.

It is important to note that there are no current guidelines for reporting SAEs in either the product labeling or sources for clinicians such as the Physicianâ&#x20AC;&#x2122;s Desk Reference (PDR) (12). Thus, obtaining data on these

Arif Khan et al.

from independent federal agencies is the only way to truly evaluate the occurrence of SAEs in patients treated with drug as compared to placebo.

We considered that resources such as the published literature, product labeling, and Physician’s Desk References (PDR) (12) are adequate for evaluation of more common adverse events (AEs) and thus did not include these in our analysis. AEs that happen in at least 5% of patients and that happen in twice as many drug treated patients than placebo treated patients are required to be reported. These types of AEs are also subject to ongoing surveillance as additional trial data and clinical reports become available. Resources such as product labeling and the PDR provide current summaries of minor AEs for both adults and children.

Analysis of Data

All efficacy analyses were conducted using SPSS version 19.0. We used independent samples t-tests to compare pediatric and adult trial efficacy measures. Cumulative results from the six pediatric studies were compared to the cumulative results from the seven adult drug approval programs.

We assessed patient mortality rates by recording the number of fatal SAEs that occurred during the trials and calculating the number of deaths per 100,000 patient exposure years. We calculated the mean exposure time as 3.4 weeks for the pediatric studies and 3 weeks for adults (0.067 years pediatric /0.0575 years adults). We then multiplied the total number of patients by patient exposure time to determine patient exposure years. The number of deaths that occurred was then divided by patient exposure years and multiplied by 100,000 to create an estimate of the mortality rates per 100,000 patient exposure years.

We used chi square tests to evaluate the proportion of patients that reported SAEs between the pediatric studies and adult drug approval programs. We used the number of pediatric and adult patients that suffered an SAE during the trials as the numerator and the number of pediatric and adult patients that did not suffer an SAE as the denominator during these analyses. Chi square tests were conducted using an online chi square calculator (13).

Results A single trial for each of the six agents was conducted and reported to the FDA in compliance with the Best Pharmaceuticals for Children Act. Based on reports from FDA staff, the divalproex, aripiprazole, and ziprasidone

trials were of 4 weeks duration, the quetiapine and olanzapine, and risperidone trials were 3 weeks. A total of 1,288 children (828 drug/460 placebo) enrolled in trials.

Pediatric patients were given the option of being inpatients during the aripiprazole and quetiapine trials. The olanzapine, risperidone, divalproex and ziprasidone trials were strictly outpatient. Each of the pediatric trials used change in YMRS score as the primary outcome variable.

The success rate of the pediatric anti-mania trial was 83% as five of the six were positive. There was no evidence of publication bias of the pediatric trials as all six were available in the published literature.

The seven adult drug approval programs consisted of 23 clinical trials involving 4,288 patients (2,356 drug/1,932 placebo). The majority of these trial were 3 weeks duration (one was 4 weeks, two were 6 weeks).

Each of the adult trials required inpatient stay during at least the first week. The majority of studies reported as a primary efficacy outcome the change in YMRS score (two ziprasidone studies reported change in MRS score). The success rate of the adult anti-mania clinical trials was 78% (18/23) based on the FDA SBA reports.

As shown in Figure 1 the mean mania rating scale baseline (pediatric=30.3/adult=30.3) scores were identical, and drug-placebo difference scores (pediatric=5.8/ adult=5.2) were not significantly different. The pediatric placebo arm change scores (M=-8.8, SD±0.7) were slightly higher than the adult placebo arm change scores (M=-7.0, SD±1.9), t(df=11)=2.2, p=0.05.

The proportion of pediatric and adult patients that experienced SAEs is shown as Table 1. There was no significant difference in the frequency of SAEs that occurred in the drug arms between the pediatric (35/828, 4.2%) and adult trials (108/2,356, 4.6%), χ2(df=1)=0.18, p=0.67.

Figure 1. Comparison of Mean Rating Scale Baseline and Change Scores Between Pediatric Anti-Mania Studies and Adult Anti-Mania New Drug Approval Programs.

35 30

Children Adults

35 20 15 10 5 0

Baseline

Change with drug

Change with placebo

Change scores with placebo were significantly higher for children as compared to adults, t (df=10)=2.2, p=0.04.

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Efficacy and Safety of Anti-Manic Agents in Children and Adults

Table 1. Serious Adverse Events (SAE) Reported During Pediatric and Adult Mania Trials Pediatric

Adult

Active Agent

Drug N*

Drug SAE (%)

Placebo N*

Placebo SAE (%)

Quetiapine

188

9 (4.8)

89

3 (3.4)

405

16 (3.9)

401

23 (5.7)

Ziprasidone

149

6 (4.0)

88

7 (8.0)

279

7 (2.5)

136

3 (2.2)

Olanzapine

107

3 (2.8)

54

0

354

18 (5.1)

244

17 (6.9)

Aripiprazole

197

7 (3.6)

97

5 (5.2)

568

33 (5.8)

409

23 (5.6)

Divalproex

76

2 (2.6)

74

1 (1.3)

89

0

97

0

Risperdone

111

8 (7.2)

58

3 (5.1)

409

25 (6.1)

395

20 (5.1)

252

9 (3.6)

250

12 (4.8)

2,356

108 (4.6)

1,932

98 (5.0)

Carbamazepine ER Column Totals

828

35 (4.2)

460

19 (4.1)

Drug N*

Drug SAE (%)

Placebo N*

Placebo SAE (%)

N* = Safety N.

There was also no significant difference in the frequency of SAEs that occurred in the placebo trial arm between the pediatric studies (16/402, 4.0%) and adult drug approval program (98/1,932 5.1%), χ2 (df=1) = 0.86, p = 0.36.

Mortality rates and reports of suicidality are shown in Table 2. There were no reported deaths during the pediatric trials compared to the 8 deaths (3 in drug group/5 in placebo group) that occurred during the 23 adult trials, an overall mortality rate of 3,290/100,000 patient exposure years.

The proportion of children that were assigned to placebo that reported suicidality was significantly higher than the proportion of adults assigned to placebo that reported suicidality, χ2(df=1)=4.2, p=0.04. The proportion of children that were assigned to drug that reported suicidality was not significantly higher than the proporTable 2. Mortality Rate and Suicidality Observed During Pediatric and Adult Mania Trials as Reported in Food and Drug Administration Medical and Statistical Reviews Mortality Rate

Completed Suicides

Reported Suicidality

Drug Arm

Placebo Arm

Drug Arm

Placebo Drug Arm Arm**

Placebo Arm*

Pediatric

0/100K/ Year

0/100K/ Year

0

0

7/828

5/460

Adult

2,214.5/ 100K/ Year

4,500/ 100K/ Year

1

0

12/2,324 7/2,012

*In the placebo treatment arms, reported suicidality was significantly higher in the pediatric as compared to adult trials, χ2(df=1)=4.2, p=0.04. **In the drug treatment arms, there was no significance differences in suicidality in the pediatric as compared to adult treatment arms, χ2(df=1)=1.1, p=0.3.

There were no significant differences in reported suicidality in drug versus placebo arms for the pediatric(χ2[df=1]=0.2, p=NS) or adult (χ2[df=1]=0.7, p=NS) trials.

125

tion of adults that were assigned to drug that reported suicidality, χ2(df=1)=1.1, p=0.3 (see Table 2).

A detailed report of the SAEs that occurred during each of the pediatric trials is shown as Table 3. The overall proportion of children and adolescents that experienced SAEs during a trial was consistent, ranging from 1.8% to 6.8%.

Discussion The aim of this study was to evaluate the therapeutic profile of anti-mania medications in the pediatric population compared to adult population. To do so we obtained data free from publication bias, the FDA Medical and Statistical reports of the pediatric studies and the FDA SBA reports from adult anti-mania New Drug Approval programs. We found that, similar to adult anti-mania drug-approval programs, the safety and efficacy profile from the pediatric studies is quite good.

Based on the FDA reports, 83% of the pediatric studies were positive and the efficacy profile was remarkably similar to the profile from adult clinical trials. The baseline symptom evaluations and overall trial drug-placebo differences were nearly identical between the pediatric studies and adult drug approval programs.

Although it didn’t result in a higher proportion of negative trials, the greater placebo response in the children and adolescents is noteworthy. Children and adolescents, as compared to adults, have been shown to benefit more from placebo in several conditions, including depression (14, 15), anxiety (16), asthma (17), epilepsy (18), and migraine headaches (19). Our data suggest that we can now add acute mania to the list. The consistently greater placebo response in children may be a possible

Arif Khan et al.

Table 3. Severe Adverse Events (SAEs) Reported during 5 Pediatric Acute Mania Trials Based on Food and Drug Administration Summary Basis of Approval Reports Agent Under Study

Placebo Arm SAEs

Drug Arm SAEs

Divaloproex

Suicidal ideation

Suicidal ideation Disorientation and hospitalization with elevated serum ammonia level

Ziprasidone

Bipolar 1 Disorder Bipolar disorder Suicidal ideation (3) Aggression, hallucination, paranoia Aggression, verbal aggression, violence

*Overdose dystonia Viral infection Suicidal ideation LFTs abnormal Aggression, physical aggression, verbal hypersexuality Mania

Quetiapine

Bipolar disorder (3)

Bipolar disorder (3) Bipolar disorder / Suicidal ideation Aggression / Mania Syncope Staphylococcal infection Drug rash with eosinophilia and systemic symptoms Aggression

Olanzapine

None Reported

Exacerbation of bipolar symptoms Relapse of bipolar disorder Decreased WBC count and decreased neutrophils

Aripiprazole

Bipolar disorder (5)

Bipolar disorder (2) Fatigue Accidental overdose Grand mal convulsion Aggression (2) Oppositional defiant

Risperidone

Psychosis manic-depressive Psychosis manic-depressive with suicide attempt Manic Reaction

Psychosis manic-depressive Psychosis manic-depressive with suicide attempt (3) Suicide attempt Allergic reaction Asthma with bronchospasm

* = Acute dystonic reaction resulting from accidental overdose of study medication.

exception to the generally accepted notion that certain types of people are not more or less likely than others to have a placebo response. Whatever the reasons for the relatively high placebo response in kids, this phenomenon has implications for the design and interpretation of treatment studies involving children.

There were no pediatric anti-mania trials reviewed by the FDA staff that did not result in publication. This suggests that the thorough review of published pediatric antimania studies conducted by Correll et al. (7) is not limited by selective publication of trials or efficacy outcomes.

In regards to the safety profile for these agents, there were no deaths during the pediatric studies as compared to the eight deaths that occurred during the adult New Drug Approval programs. It is interesting to note that three of the six pediatric studies were exclusively outpatient whereas the adult trials required an inpatient

stay for a minimum of one week at the beginning of the trial. The pediatric studies were also of a longer average duration than were the adult trials.

Additionally, incidence of severe adverse events was slightly lower in children and adolescents as compared to the adults. We did not find evidence of increased suicidality for children treated with an anti-manic agent rather than placebo. In fact, among those assigned to placebo, a higher proportion of children than adults reported suicidality. There were no significant differences in suicidality based on drug assignment for children or adults. This is in contrast to the profile for pediatric SSRI therapy (3).

Alternatively, Correll and his colleagues did report that more children and adolescents experienced somnolence and weight gain as compared to the adult patients (7).

Although the number of children that experienced SAEs was low in our study, the adverse effects of weight gain 126

Efficacy and Safety of Anti-Manic Agents in Children and Adults

and health implications from a potential link to obesity should be considered by practicing clinicians who prescribe atypical antipsychotics to children in the clinical setting. All of this suggests that the review conducted by Correll et al. is a practical guide for clinicians in evaluating treatment options for children and adolescents.

It is also worth noting that the patients who participated in these trials are not necessarily representative of bipolar patients in clinical practice. All of these trials were conducted for the indication acute mania, and the patients presented in either a mixed or manic episode.

Just as importantly, each patient was diagnosed by a clinician specifically trained to identify pediatric mania, and scientific diagnostic procedures were followed using standardized measurement tools. These data do not suggest that the medications included in our study would be appropriate for any other indications.

Study limitations include the unavailability of regulatory reviewed data for first generation antipsychotics and lithium. These agents were approved for treatment of bipolar disorder over 30 years ago. High quality efficacy and safety data that have undergone a thorough regulatory review are simply not available for these agents, for either pediatric or adult patients.

In conclusion, our review of FDA data did not produce evidence of increased mortality, morbidity, or suicidality in relation to these anti-manic agents. The results of our study suggest that the recently approved anti-manic agents for the pediatric group of patients have a very good therapeutic index. These results from the pediatric trials compare well with the results of adult mania trials.

References 1. United States Food and Drug Administration. Suicidality in children and adolescents being treated with antidepressant medications, 2004.

Available from http://www.fda.gov/Drugs/DrugSafety/Postmark etDrugSafetyInformationforPatientsandProviders/DrugSafety InformationforHeathcareProfessionals/PublicHealthAdvisories/ucm 161679.htm.

2. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: A meta-analysis of randomized controlled trials. Jama 2007; 297:1683-1696.

127

3. Tsapakis EM, Soldani F, Tondo L, Baldessarini RJ. Efficacy of antidepressants in juvenile depression: Meta-analysis. Br J Psychiatry 2008;193:10-17.

4. Curtis LH, Masselink LE, Ostbye T, et al. Prevalence of atypical antipsychotic drug use among commercially insured youths in the United States. Arch Pediatr Adolesc Med 2005;159:362-366.

5. Cooper WO, Arbogast PG, Ding H, Hickson GB, Fuchs DC, Ray WA. Trends in prescribing of antipsychotic medications for US children.

Ambul Pediatr 2006;6:79-83.

6. Tamayo JM, Zarate Jr CA, Vieta E, Vasquez G, Tohen M. Level of resopnse and safety of pharmacological monotherapy in the treatment of bipolar 1 disorder phases: A systematic review and meta-analysis. Int J Neuropsychopharmacol 2010;13:813-832.

7. Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: A comparative analysis of acute, randomized, placebocontrolled trials. Bipolar Disord 2010;12:116-141.

8. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004; 363:1341-1345.

9. Benjamin DK, Jr., Smith PB, Sun MJ, et al. Safety and transparency of pediatric drug trials. Arch Pediatr Adolesc Med 2009;163:1080-1086.

10. Food and Drug Association Amendments Act (FDAAA) of 2007. Public Law #111/18. Available from http://frwebgate.access.gpo.gov/cgi-bin/ getdoc.cgi?dbname=110_cong_public_laws&docid=f:publ085.110.

11. United States Food and Drug Administration. Medical, Statistical, and Clinical Pharmacology Reviews of Pediatric Studies conducted under Section 505A and 505B of the Federal Food, Drug, and Cosmetic Act (the Act), as ammended by the FDA Ammendments Act of 2007. Available from http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Develop mentResources/ucm049872.htm.

12. Thompson Reuters. Physicianâ&#x20AC;&#x2122;s Desk Reference, 64th Edition. Montvale: Thompson Reuters, 2010.

13. Preacher KJ. Calculation for the chi-square test: An interactive tool for chi-square tests of goodness of fit and independence. 2010. Available from http://people.ku.edu/~preacher/chisq/chisq.htm.

14. Bridge JA, Birmaher B, Iyengar S, Barbe RP, Brent DA. Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder. Am J Psychiatry 2009; 166:42-49.

15. Cheung AH, Emslie GJ, Mayes TL. The use of antidepressants to treat depression in children and adolescents. Cmaj 2006;174:193-200.

16. Cohen D, Deniau E, Maturana A, et al. Are child and adolescent responses to placebo higher in major depression than in anxiety disorders? A systematic review of placebo-controlled trials. PLoS One 2008;3:e2632.

17. Kemeny ME, Rosenwasser LJ, Panettieri RA, Rose RM, Berg-Smith SM, Kline JN. Placebo response in asthma: A robust and objective phenomenon. J Allergy Clin Immunol 2007; 119:1375-1381.

18. Rheims S, Cucherat M, Arzimanoglou A, Ryvlin P. Greater response to placebo in children than in adults: A systematic review and metaanalysis in drug-resistant partial epilepsy. PLoS Med 2008;5:e166.

19. Fernandes R, Ferreira JJ, Sampaio C. The placebo response in studies of acute migraine. J Pediatr 2008;152:527-533, e521.

Isr J Psychiatry Relat Sci - Vol. 49 - No 2 (2012)

Procedural Immunity of the District Psychiatrists and Members of the District Psychiatric Committees against Civil Wrongs Claims in Israel Jacob Margolin, MD, MHA,1 Oren Asman, LLM,2, 3 Roberto Mester, MD,3, 4 and Moshe Kalian, MD5 1

Formerly District Psychiatrist of Tel Aviv, Secretary of the Israel Society for Forensic Psychiatry, and Director of the Jerusalem Mental Health Center Eitanim-Kfar Shaul and Jaffa Community Mental Health Center, Tel Aviv, Israel 2 Zefat Academic College, School of Law, Zefat, Israel 3 Department of Mental Health, Law and Ethics, International Center of Health, Law and Ethics, Faculty of Law, Haifa University, Israel 4 Formerly Director of the Ness Ziona Mental Health Center and District Psychiatrist of Central Area, Associate Clinical Professor (Emeritus), Sackler School of Medicine, Tel Aviv University. Past Chairman of the Israel Society for Forensic Psychiatry, Israel 5 District Psychiatrist of Jerusalem and Chairman of the Israel Society for Forensic Psychiatry, Jerusalem, Israel

ABSTRACT In the public sector, psychiatrists as well as other physicians and mental health workers are subject to legal claims as a result of their clinical decisions.

Until 2006, these professionals had no procedural immunity for such claims. The paper describes the legal change that took place in Israel since February 2006 with regard to some civil servants, including District Psychiatrists and members of District Psychiatric Committees. A clinical case vignette illustrates the possible implications of this statute amendment.

Introduction This paper presents and discusses an amendment to the Israeli Civil Wrongs Ordinance that has major legal implications for the routine practice of mental health professionals in their activities as public servants.

On February 10, 2006, Amendment number 10 of the Civil Wrongs Ordinance (Liability of a Public Servant), 2005, came into effect after being passed by the Knesset (Israeli parliament) on July 25, 2005. This amendment granted procedural immunity to public servants, among them District Psychiatrists (1) and members of District Psychiatric Committees (2). This paper focuses on the Address for Correspondence:

District Psychiatrists and on the District Psychiatric Committees, since they were often sued before the implementation of the new amendment. The authors are unaware of legal claims brought against members of other statutory organs, such as Helsinki Committees, Inquiry Committees or Ethical Committees.

A clinical vignette will first be presented to clarify the legal situation which was in effect prior to the implementation of the new amendment. Then, the principles and concepts underlying this amendment will be discussed, and their implications, ramifications and limitations will be explored.

Clinical Vignette In the period prior to the implementation of the amendment, a married couple requested a meeting with the District Psychiatrist. During the meeting, the District Psychiatrist got the impression that this couple, well educated and intelligent people, were extremely anxious and frightened because of their 25-year-old daughterâ&#x20AC;&#x2122;s behavior.

According to their report, the daughter, who had been living independently in her own apartment for the past several months, had been neglecting her self-care and her house, eating irregularly, refusing to meet anyone and making frequent offensive phone calls to her parents.

The District Psychiatrist, assuming that the daughter was in a psychotic state with high risk of dangerous behavior, issued an order for a compulsory psychiatric examination. In doing this, the District Psychiatrist was

Jacob Margolin, MD, MHA, POB 262, Har Adar 90836, Israel.

â&#x20AC;&#x2020; jacob.margolin@gmail.com

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relying on the formal requirements of the 1991 Israeli Mental Health Act (3).

The daughter was brought to the emergency room of a public and university-affiliated psychiatric hospital.

There, she was examined by two psychiatrists, one of them a fully qualified senior psychiatrist, who diagnosed her condition as an acute psychosis with dangerous behavior to others and to herself. They decided that she needed immediate hospitalization in a closed, medium security psychiatric ward. The two examining psychiatrists contacted the District Psychiatrist and requested, orally and in writing, an order of compulsory hospitalization. The District Psychiatrist carefully examined the new medical information just delivered to him, and came to the conclusion that the request was acceptable. Therefore, he issued an order of compulsory hospitalization. In doing this, he again relied on the formal requirements of the 1991 Israeli Mental Health Act. Almost seven years later, shortly before the procedural barrier of the statute of limitation applied and could allow the defendant to avoid liability for damages, the daughter filed a claim against the District Psychiatrist in a Magistrate’s Court (court of the first instance), claiming that there had been no need to forcibly bring her to be examined in the emergency room. She claimed that it would have been enough to call her, asking her to come in of her own accord to be examined. She presented her case in a well articulated manner, without the assistance of a lawyer, demanding financial compensation. In court, and in front of their daughter, the parents denied having made the serious complaints the District Psychiatrist said he had heard from them seven years before. The judge granted the daughter the present day equivalent of U.S. $15,000.

The District Psychiatrist, being convinced that his professional decision was firmly based on the Mental Health Act, requested the insurance company to appeal.

However, the insurance company paid according to the court’s ruling, perhaps to avoid the litigation costs and the risk of a loss in a higher instance.

At present, according to the new amendment to the Civil Wrongs Ordinance, the District Psychiatrist would probably not be personally sued in such a case.

However, the plaintiff still has the right to put a claim against the employer of the District Psychiatrist (the Ministry of Health).

It should be emphasized that if it seems to the plaintiff that the District Psychiatrist was intentionally wrong or was indifferent in regard to the possibility of doing 129

wrong to the plaintiff, the latter still has the option to sue the District Psychiatrist on a personal level.

Background Concepts A basic principle in civil wrongs law holds that a person is personally responsible for his actions towards others, and if his wrongful act caused damage he should be held liable (“The culpability principle”). An important deviation from this personal culpability principle can be seen in the concept of vicarious liability, for instance, employers’ liability or Agent’s principals’ liability – where a claim can be made against the wrongdoer or against his employer/principal or against the two of them together or separately.

Another exception to the principle of personal culpability and liability is immunity, an issue on which this paper focuses. In essence, immunity actually means the blocking of the discussion leading up to the presentation of claim. The significance of immunity is that even though a person committed a wrong, a civil claim cannot be brought against him personally. This is considered a procedural barrier and not an essential barrier. When this type of immunity is granted, while the wrongdoer is personally immune, if he is a worker of a particular organization, or an agent of a specific company, it may be possible to file a civil wrongs claim against his employer (e.g., the Ministry of Health), based on vicarious liability.

The amendment to the law, with which we are dealing here, is made through the granting of immunity to civil servants. This amendment does not grant immunity to the civil servant for all the acts and activities of the State in private cases, but for activities of the State as a ruling (governmental) body whose activities are carried out by its public servants. It should be emphasized that the public servant legally belongs to a special category – someone who serves the public and whose work should be considered to be on behalf of the public.

The subject of the responsibility of the civil servant, up until the amendment to the act came into effect, was dealt with in the former Section 7(a) of the Civil Wrongs Ordinance, which established that “a civil servant is responsible for any civil wrong that he commits and, if he is sued for it, he will be personally sued; However, without detracting from the instruction laid down in Sections 6 and 8, the worker will have a defense for any action which is not one of negligence, provided that the action was within his jurisdiction as laid down by the law.” As

Jacob Margolin et al.

we can see, this workers’ protection does not extend to acts of negligence.

The current Section 6 of the Civil Wrongs Ordinance is of relevance to civil servants. It states that “In an action brought for a civil wrong other than negligence, it shall be a defense that the act complained against was under and in accordance with the provisions of an enactment, or that it was carried out within the bounds of a legal authorization or in the reasonable belief in good faith that legal authorization existed; in this section, ‘act’ includes an omission.”

The rationale for this proviso of negligence is the recognition that the worker makes use of his discretionary powers in accordance with what is determined in the statutes, while at the same time this recognition does not grant permission to act negligently. That is to say, the worker should not disregard his duty to act with caution, as is always incumbent on him, being a sensible and rational person.

Prior to the amendment to the Law, the State was generally liable with the exception of the provisos set down in the Law. The State was granted protection against liability that was placed upon it in acts that were carried out under legal permission or in good faith under the proposition of legal permission, with the exception of cases where there was negligence in the acts.

In contrast to the State, the civil servant had no provisos in the Law. Prior to the amendment to the Law, it had been possible to prosecute him personally. However, the civil servant did have protection in all suits which were not ones of negligence or acts carried out within the legal jurisdiction of the worker or acts carried out in good faith where the worker was convinced that he was acting within his legal jurisdiction. In the 1970s, the Supreme Court of Israel ruled that this protection is “too wide and it is no wonder that we have not come across many claims of this type in the country against civil servants” (4).

With time this legal immunity became less relevant, since many claims have been submitted against the State and against civil servants based on negligence.

The notion that such claims or threats of potential claims directed personally at public servants who are carrying out governmental tasks may frighten them and have a negative influence upon their judgment was a major catalyst for the amendment of the Civil Wrongs Ordinance (5).

Aims and Reasons for the Amendment to the Law The aim of the amendment was to protect the discretion practiced by the civil servant such as the District

Psychiatrist or members of District Psychiatric Committees while performing their work. The main reason was actually to allow them to fulfill their duties on behalf of the public without being negatively influenced by threats of legal action against them, which, in turn, could endanger their discretion in decision making and professional performance.

Other reasons for this statutory amendment were a fear that civil servants may be exposed to personal claims to a greater extent than ordinary workers, and the notion that the employing organization is the correct and more suitable defendant in such torts claim. The basis for these reasons is that civil servants act within the framework of the duties assigned to them by their employer.

Principles Governing the Arrangement Set Out in the Amendment to the Law The current Section 7a(a) of the Civil Wrongs Ordinance states that “Action shall not be brought against a public servant for an act that raises liability in tort and that he performed in the course of performing his governmental function as a public servant; this provision shall not apply to a said act that was knowingly committed with the intention to cause damage, or with indifference to the possibility that the said act will cause damage.”

Three principles are raised in this amendment: a. The immunity granted to a civil servant within the framework of the amendment to the law represents a procedural barrier and not one of substance. In other words, while the worker is immune against certain claims, it is possible to make a claim, instead, against the State or the public body which employs the worker based on his wrongdoing. This means that there is a preservation of the right of the claimant to receive the suitable compensation from the public body either based on its vicarious liability or its direct liability (for instance, based on wrongful procedures that resulted in the damage caused to the claimant). b. An exception to the principle of the immunity (proviso to immunity) exists when the act performed by the civil servant is done out of malice or complacency, that is to say out of indifference as to the outcome of his act.

The complementary instructions found in the continuation of Section 7a(a) rule as follows: Section 7a(b) – “(b) the provisions of subsection (a) shall not derogate from the liability of the State 130

Procedural Immunity of District Psychiatric Committees against Civil Wrongs Claims in Israel

or of a public authority under sections 13 and 14 and under any statute.”

Section 7a (c) – “(c) The immunity under this section shall also apply to whoever was a public servant when the act, which is the subject of the action, was committed.”

The relevant definitions of the new arrangement about civil servants are set out in the new Section 7 of the rules. Two types of workers are included in the definition of civil servant: a “State employee and a public authority employee.” “State employee” includes “an organ of the State and every person who under an enactment performs a public function in the name of the State, including persons who serve in the Israel Defense Forces, in the Israel Police, in the Israel Prison Authority, and in other security organizations of the State.”

“State employee” includes the phrase “every person who under an enactment performs a public function in the name of the State.” This is, among other things, inclusive of anyone whose profession is not necessarily governmental, but who fills a governmental job (such as the District Psychiatrist) and also members of statutory committees which also include people who are not civil servants, for example the District Psychiatric Committees, Inquiry Committees set up according to the Patient’s Rights Law, and the Supreme Helsinki Committee for research on human beings. All such committee members should be entitled to procedural immunity if they are the subject of a claim against their State function in the committee.

“Public authority employee” is defined as an “organ of the public authority and every person who under an enactment performs a public function in the name of the public authority, and exclusive of a contracting party.” It includes legal advisors employed in government ministries, since their functions involve implementing governmental discretion. This applies also to prosecutors who make assumptions in their work according to governmental discretion. On the other hand, this does not apply to a physician who is employed in a governmental hospital and who carries out functions which do not involve using governmental discretion. However, such physicians and other health professionals are routinely insured by medical insurance companies who take care of any suits against unintentionally, non-malicious professional decisions that caused harm to patients.

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Re-examining the Clinical Vignette Earlier in this paper a case was presented where a District Psychiatrist was sued for wrongfully issuing a forced examination order and was held liable. According to the amendment to the Civil Wrongs Ordinance, in order to hold the District Psychiatrist liable, one should prove that his actions were done out of intention to cause harm or with indifference to the possibility that his action will cause harm.

It seems that the first alternative, causing an intentional harm, is of a very severe nature, and if proven in court, may also lead to a criminal investigation for abuse of powers.

As for the second alternative, this is debatable. One can argue that the actions of the District Psychiatrist are performed with good intentions to protect the patient as well as his family and surroundings, and especially when there is a proven violent psychiatric record, it is more than reasonable to issue a forced psychiatric order, and even if not, it is merely potential negligence and not indifference.

In such a case, the District Psychiatrist will be procedurally immune, but the state could still be sued for damages.

Another argument is that issuing a forced examination order without being assured first that the patient is actually refusing to be examined is not just a breach of a legal duty but also an act which proves indifference on the part of the District Psychiatrist to the potential breach of the patient’s autonomy, freedom and human rights. Based on such an argument, if accepted, one can claim that even after the Civil Wrongs Ordinance amendment, such a case could still be personally filed against the District Psychiatrist.

Furthermore, if this case was viewed “only” as negligence when it was discussed in court in the past, one may expect the psychiatric system to learn from its experience and take it into future consideration. Thus, in the next similar case, such behavior on the part of the District Psychiatrist may be viewed not only as negligence but perhaps even as “indifference” – as he is already supposed to be aware of the potential harm involved. Needless to say that every health professional should function in his daily activities not only with due respect to his patients, but also with professional caution, innocence and integrity. Such behavior, combined with respect and empathy toward the patient, can favor the possibility that patients will think more than twice before suing a health professional.

Summary The purpose of the amendment discussed above is to offer protection to the discretionary powers of the pub-

Jacob Margolin et al.

lic servant by providing immunity covering negligence, but not acts carried out with malice or indifference and callousness. This goal is achieved through maintaining a balance between the defense provided to the worker and the assistance offered to the victim in a legal action against the governing body. The amendment applies to those filling a governmental post, and in the case of the medical profession, applies, among others, to District Psychiatrists, members of District Psychiatric Committees, and members of Inquiry Committees set up according to the Patient’s Rights Law, and also to members of the Supreme Helsinki Committee of the Ministry of Health. The amendment’s intention is to provide the public servant with further legal protection, by safeguarding the distinction between “minor and unintentional negligence” and “gross negligence”

(which is clearly below acceptable standards of service), a distinction that is not always so clear. However, the rational worker should not rely on legal immunity but should take his professional work seriously and perform his tasks with full empathic respect for the patient’s civil rights and human needs.

References 1. Kalian M, Witztum E. The Israeli model of the “district psychiatrist” - a fifty-year perspective. Isr J Psychiatry Relat Sci 2006; 43:181-197.

2. Offer G, Melamed Y, Elizur A. Characteristics of district psychiatric committee decisions regarding discharge from compulsory hospitalization. Med Law 2004; 23:615-624.

3. The Law for the Treatment of the Mentally Ill, 1991.

4. Supreme Court 101/74 Binui U’Pituah Banegev v. Defense Ministry.

Piskey Din; 22(2): 449, 1974 (in Hebrew).

5. Calahorra T, Bardenstein M. Amendment no. 10 of the Torts Ordinance: civil servant immunity. Hapraklit 2011; 51: 293-348 (in Hebrew).

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Isr J Psychiatry Relat Sci - Vol. 49 - No 2 (2012)

Evidence for an Association between Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism and General Intellectual Ability in Early-Onset Schizophrenia Nora S. Vyas, PhD, CSci, CPsychol, AFBPsS, 1,2 and Basant K. Puri, PhD, FRCPsych3 Child Psychiatry Branch, National Institutes of Health, Bethesda, Maryland, U.S.A. Kingâ&#x20AC;&#x2122;s College London, Institute of Psychiatry, SGDP Centre and Department of Psychosis Studies, London, U.K. 3 Department of Imaging, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, U.K. 1

2

ABSTRACT Background: Brain-derived neurotrophic factor (BDNF) plays a crucial role in the survival, development and maintenance of neuronal systems, and the Val66Met polymorphism has been implicated in memory functions.

Method: We examined the association of BDNF with general intellectual ability in 161 individuals including 53 early-onset patients with schizophrenia (EOS), 91 healthy biological relatives, and 17 relatives with major depressive disorder (MDD), using the Wechsler Intelligence Scales (WISC).

Results: Regardless of diagnosis, individuals with the Met66 allele had a significantly higher performance score than those homozygous for Val66 on vocabulary, block design and object assembly subtests of the WISC. EOS probands showed poor performance on all IQ subtests compared with relatives with and without MDD. Limitations: Relatively smaller sample size of individual genotypes.

Conclusions: BDNF genotype may play a role in specific cognitive functions and dimensions of intelligence. The Met allele appears to be associated with superior performance in IQ compared with relatives Val/Val genotype.

INTRODUCTION Brain-derived neurotrophic factor (BDNF), a glutamate neurotrophic factor, is a member of the neurotrophin family that plays a crucial role in the survival and differentiation of particular neuronal systems, and has a strong involvement in promoting brain growth and development (1-3). BDNF also appears to mediate activity-dependent synaptic plasticity and neuronal development (4-7), and is more widely distributed and expressed in the central nervous system (CNS) and has survival-promoting functions on various CNS neurons including human hippocampus and cerebral cortex (8).

Association studies have implicated BDNF as a strong candidate gene in bipolar disorder (9-11), schizophrenia (12, 13), Alzheimerâ&#x20AC;&#x2122;s disease (14, 15), eating disorders (16), neuroticism (17), and obsessivecompulsive disorder (18). BDNF has been implicated in schizophrenia based on its effects on neurotransmitter systems that are dysregulated during the illness and its involvement in the mechanism of action of antipsychotic drugs (19, 20). BDNF is involved in the development and survival of dopaminergic and serotonergic neurons (21). An increase in BDNF mRNA levels has been reported in the hippocampus in schizophrenia (22). High concentrations of BDNF in cortical areas and reductions of neurotrophins in the hippocampus have been reported in patients with schizophrenic psychosis in comparison with normal

Address for Correspondence: N.S. Vyas, PhD, Child Psychiatry Branch, National Institute of Mental Health, NIH, Building 10, Rm 3N202, Bethesda, MD, U.S.A. nora.vyas@nih.gov

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controls (23). In contrast, two further studies showed reduced BDNF levels in schizophrenia (24, 25).

However, Shimizu et al. (26) showed no significant differences in serum BDNF levels between antipsychotic-naïve and medicated patients with schizophrenia and healthy individuals. In addition, there was no correlation between BDNF levels and duration of illness, age of onset, clinical symptoms.

The BDNF gene, located on 11p13, has a nonconservative exonic single nucleotide polymorphism (SNP) at nucleotide 196 (dbSNP number rs6265, G/A), which results in a valine (Val) to methionine (Met) substitution within the 5’ proBDNF protein at codon 66 (Val66Met). This SNP may be related to hippocampus-mediated memory performance in humans.

Several studies have reported that BDNF Met66 carriers with a diagnosis of schizophrenia may be at a substantially greater risk of hippocampal dysfunction (27, 28). Pezawas et al. (29) reported 12-15% volume reductions in the hippocampus in Met66 carriers relative to Val66 homozygotes; significant reductions were observed in the dorsolateral prefrontal cortex. The association of BDNF and hippocampal function raised concerns about whether the Val66Met polymorphism influenced intelligence scores in schizophrenia.

The Val allele of the BDNF Val66Met polymorphism is expressed more frequently in patients with psychosis (13), schizophrenia (30), and schizoaffective disorder or other affective disorders (31), linking genetic variation of the BDNF polymorphism with symptoms of psychosis. In a Chinese cohort study, Tsai and colleagues (32) examined the association of BDNF gene polymorphism with general intellectual ability in a healthy female population (aged 18-21 years, n=114) using the Wechsler Adult Intelligence Scale - Revised version (WAIS-R). Individuals with the Val/Val genotype showed modest increases in performance intelligence quotient (IQ)scores in comparison with individuals with the Met/Met genotype and the heterozygous group, suggesting a relationship between BDNF and dimensions of general intellectual ability. Egan et al. (27) reported that the Met allele of the functional polymorphism was associated with poor performance on human episodic memory and abnormality in hippocampal function in patients with schizophrenia (n=106), their unaffected siblings (n=138) and healthy controls (n=59). However, the authors reported no association of BDNF Val66Met polymorphism on IQ. Whalley et al. (33) reported no

difference in a sentence completion task between Val/ Val and Met carriers in young subjects at high risk of developing schizophrenia, although the former group showed relatively increased activation of the anterior cingulate cortex. Rosa et al. (13) showed a preferential transmission of the Val allele from heterozygous parents to offspring affected with psychosis, suggesting a possible role of this gene in the vulnerability to schizophrenia spectrum disorder.

Individuals with early-onset and adult-onset schizophrenia show intellectual deficits across the lifespan (34-38). Early onset schizophrenia (EOS; onset before age 18 years) is a rare, chronic, and relatively severe variant of the adult-onset counterpart of the disorder (39, 40). Intelligence scores in patients with EOS often range between 80 and 90 (approximately 1-1.5 standard deviations below the normative mean), which is significantly lower than adult-onset cases (41-44).

Individuals with a genetic predisposition to schizophrenia show a significant difference in IQ scores in comparison to normal controls (45-51), including premorbid periods (50). One study showed an association of BDNF Val55Met polymorphism with general intellectual ability in healthy individuals (32), but no studies to date have investigated the association of this polymorphism with intelligence in schizophrenia. The lower than average IQ scores of EOS patients informed our choice of examining the association of the BDNF Val66Met polymorphism and general intellectual ability in EOS probands and their first-degree relatives.

METHODS Participants

Patients were identified by clinicians’ referrals from secondary care services within the South London and Maudsley NHS Trust and were included if they: (a) were aged between 13-18 years; (b) fulfilled Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (52) criteria for schizophrenia; and (c) had at least one first-degree relative unaffected by schizophrenia. Eligible first-degree relatives were invited to participate, with the patients’ consent, if aged 13-65 years and without a personal history of schizophrenia spectrum disorders.

Exclusion criteria for the entire sample (patients and healthy relatives) included: (a) head injury leading to a loss of consciousness for > 1 hour; (b) a per138

Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism in Early-Onset Schizophrenia

sonal history of neurological or medical disorders; (c) a family history of hereditary neurological disorders; and (d) fulfilling DSM-IV criteria for lifetime drug or alcohol dependence and drug or alcohol abuse in the preceding six months.

All participants were recruited as part of the Vulnerability Indicators in Psychosis Study (VIPS) from January 2003 to January 2007. This study examines clinical, cognitive, and genetic liability and disease expressivity in schizophrenia. The study procedures were in accordance with the Joint South London and Maudsley and the Institute of Psychiatry NHS Research Ethics Committee. Written informed consent or assent was obtained from all participants.

Clinical Evaluation and Neuropsychological Assessment

All participants underwent an interview by a trained child and adolescent psychiatrist who was initially blind to diagnosis but not family status, using the Structured Clinical Interview for DSM-IV (SCID) for Axis I disorders (patient and non-patient version) (53, 54).

General intellectual ability was measured using ageappropriate Wechsler Intelligence Scales. The Wechsler Adult Intelligence Scale–Revised edition (WAIS-R) (55) was used for individuals aged 16 years and above and the Wechsler Intelligence Scale for Children–Third edition (WISC-III) (56) was used for younger subjects. Five healthy relatives and eight EOS probands were assessed using the WISC-III, and the WAIS-R was performed on 86 healthy relatives, 45 EOS probands and 17 rela-

tives with major depressive disorder (MDD). All participants were assessed on the following IQ subtests of the Wechsler Intelligence Scales (WISC-III or WAIS-R): vocabulary, comprehension, similarities, object assembly, and block design. The age-appropriate scaled scores for each subtest were inputted for statistical analysis.

Genotyping Procedures

Buccal swab DNA was obtained from 161 participants.

The G→A SNP encoding the amino acid substitution Val66Met (dbSNP rs6265) was genotyped. Genotype for rs6265 was determined by a TaqMan SNP genotyping assay (assay ID: C_11592758_10) (Applied Biosystems, 850 Lincoln Centre Drive, Foster City, California 94404, U.S.A.). 10 ng DNA was used in a 10-μl reaction, according to the manufacturers’ instructions. Endpoint analysis was performed on an AB Prism 7900HT Sequence Detection System (SDS) and a probability > 95% was attained for the SDS package. Genotype frequencies for rs6265 were 0.22, 0.76, and 0.02 for Val66Met, Val66Val, and Met66Met, respectively. The genotype frequencies were comparable with Hap-Map population genome build dbSNP (http://www.ncbi. nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=6265). The genotype distribution of the rs6265 SNP in BDNF was in Hardy-Weinberg equilibrium. There were 21 undetermined BDNF genotypes in the full sample, owing to amplification failure. One hundred and seven subjects had the Val/Val genotype, 33 the Val/Met genotype, and three the Met/Met genotype. Owing to the low frequency of the Met66 homozygotes (~2%), the

Table 1. Group comparisons of IQ subtest scores Variable

EOS Patients (n = 53)

Relatives with MDD (n = 19)

Healthy Relatives (n = 91)

Test Statistic

P-value *

Age (yr)

17.25 (1.31)

43.27 (8.16)

34.87 (14.67)

Wald χ22=610.36

<0.01

Years of Education

10.47 (1.04)

12/0 (2.59)

12.32 (2.41)

2

Wald χ 2=40.32

<0.01

Gender (m/f)

29/24

4/13

42/29

χ2=7.73

<0.05

GAF score

56.2±1.99

65.9±1.77

81.6±0.81

2

Wald χ 2=89.34

<0.01

Vocabulary

7.2±3.07

9.6±3.51

8.6±3.57

Wald χ22=10.02

<0.01

Comprehension

7.1±3.49

10±3.21

10±2.72

Wald χ22=18.38

<0.01

Similarities

8.1±2.59

10±2.92

9.4±3.05

Wald χ 2=7.14

<0.01

Block Design

8.6±3.39

9.2±3.03

10.1±3.61

Wald χ22=3.31

0.19

Object Assembly

8.0±2.75

7.8±2.64

8.2±3.02

Wald χ 2=5.42

0.83

IQ subtests

*Uncorrected P values.

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2

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Nora S. Vyas AND BASANT K. PURI

genotypes Val/Met and Met/Met were combined for the analysis (n = 36), and known as “Met carriers.”

Statistical Analysis

Statistical analyses were carried out using the Statistical Package for the Social Science (SPSS) version 18. To study the effect of genotype and diagnosis on IQ we used generalized estimating equation (GEE) with an exchangeable within-subject working correlation structure and robust standard errors covariates (57, 58) approach to account for familial inter-correlation between the EOS probands and their first-degree relatives. The Hubert White sandwich estimator was used which provides standard errors that are robust to possible misspecification of the correlation matrix. Unlike repeated measurement ANOVA a GEE allows for several observations per case (i.e., observations of two parents) and uses a full case analysis in the presence of missing data. We used a factorial design to study genotype (Val/Val vs. Met carriers) × diagnosis (EOS vs. healthy relatives vs. MDD) interaction on IQ subtests. Following a significant main effect of genotype or genotype × diagnosis interaction, Bonferroni correction (p-value multiplied by the number of pairwise comparisons) was performed. We calculated the effect sizes using Cohen’s d for measures that survived Bonferroni correction.

RESULTS Sample Characteristics

One hundred and one families of schizophrenia patients were assessed. The age entry criterion was between 13 and 65 years for all participants. Fourteen families did not meet the inclusion criteria for the study, and 23 families refused to participate. In total, 64 patients with schizophrenia and 179 relatives were enrolled into the study. Of these, 32 relatives were excluded for not meeting the inclusion criteria (substance abuse), 39 relatives withdrew or were unavailable to participate in the study, and 11 patients with schizophrenia did not meet the criteria for remission. The total sample used in the analysis constituted 161 individuals: 53 patients with schizophrenia and 108 of their first-degree relatives. Seventeen relatives were diagnosed with MDD (two relatives had bipolar disorder), and 91 relatives had no psychiatric disorder.

The majority of schizophrenia patients were prescribed antipsychotics, most commonly atypical

agents (n=46); one was taking typical medication and six were unmedicated at the time of assessment. The mean time since onset of positive symptoms, as documented in the medical notes, to study entry was 1.77 years (SD 0.93).

Group Comparisons

Group differences across IQ subtests are presented in Table 1. As there was a significant difference between groups for age and years of education, these variables were inputted as covariates. As shown in Table 1, there was a significant main effect of diagnosis prior to Bonferroni correction (uncorrected p-values presented) on all IQ subtests, except the block design subtest. Specifically, there was a main effect of diagnosis on vocabulary, where EOS probands performed less well than healthy relatives (P=0.07, Cohen’s d=0.40) and MDD relatives (P=0.01, Cohen’s d=0.77). Similarly, EOS probands performed significantly less well on the comprehension subtest than healthy relatives (P<0.001, Cohen’s d=0.82) and MDD relatives (P<0.05, Cohen’s d=0.03). A trend was observed for a diagnosis effect on similarities in which EOS probands showed below average performance than healthy relatives (P=0.095, Cohen’s d=0.44) and MDD relatives (P=0.07, Cohen’s d=0.39). There was no difference in performance IQ across groups.

Effect of Genotype

Table 2 shows the means and standard deviations of IQ subtests in relation to BDNF genotype. There was a significant main effect of genotype on vocabulary (Wald χ2=5.66, df=1, P=0.017), with Met carriers outperforming Val/Val genotype (Cohen’s d=0.39). With regard to performance IQ measures, there was a significant main Table 2. Effect of BDNF genotype on IQ across diagnostic groups IQ subtest

BDNF (Val66Met) Val/Val (n = 109)

Met carriers (n = 36)

Vocabulary

7.8±0.3*

9.2±0.6*

Comprehension

8.8±0.3

9.8±0.6

Similarities

8.9±0.2

9.5±0.5

Block Design

9.3±0.3*

10.5±0.6*

Object Assembly

7.8±0.2*

8.9±0.4*

*p < 0.05

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Brain-Derived Neurotrophic Factor Val66Met Gene Polymorphism in Early-Onset Schizophrenia

effect of genotype on block design (Wald χ2=4.48, df=1, P=0.034, Cohen’s d=0.40) and object assembly scaled score (Wald χ2=5.42, df=1, P=0.02, Cohen’s d=0.39), revealing significantly higher scores for Met carriers compared with the Val/Val genotype. Figure 1 depicts the association of BDNF on these IQ subtests. As shown in Table 2, there was no evidence for any association between the BDNF Val66Met polymorphism and comprehension (Wald χ2=2.03, df=1, P=0.15) or similarities (Wald χ2=2.53, df=1, P=0.11).

Genotype by Diagnosis Interaction

We found no significant genotype × diagnosis interactions for vocabulary (Wald χ2=3.86, df=2, P=0.145), comprehension (Wald χ2=2.19, df=2, P=0.33), similarities (Wald χ2=2.47, df=2, P=0.29), block design (Wald χ2=0.93, df=2, P=0.62) or object assembly (Wald χ2=0.36, df=2, P=0.83).

Discussion The BDNF Val66Met gene polymorphism has been found to be associated with performance on specific IQ subtests in EOS probands and their first-degree relatives. Regardless of diagnosis, individuals with the Met/ Met or Val/Met genotype demonstrated enhanced performance on the vocabulary, block design, and object assembly subtests of the Wechsler Intelligence scale.

Our findings support previous studies showing an assoFig. 1: Association of BDNF Genotype on vocabulary, block design and object assembly subtests regardless of diagnosis 11.00

10.00

9.00

8.00

7.00 Block Design Object Assembly Vocabulary

6.00

5.00

141

Val/Val

Met carriers

ciation of the BDNF polymorphism with intelligence (32) and generalized cognitive functioning (27, 59).

Rosa and colleagues (13) recently showed that individuals with the Met/Met genotype performed better on prefrontal-cortical related tasks (as measured using the Wisconsin card sorting task and the Trail Making Test) in comparison with the Val/Met and Val/Val genotypes.

With respect to intelligence scores, our results follow a similar trend in which individuals with the Met allele are associated with better performance on specific IQ measures compared with the Val/Val genotype. Our findings harmonize with those of Harris et al. (60) who observed an association of the BDNF Met66 allele with enhanced verbal reasoning ability, which correlated with IQ, in community-dwelling elderly volunteers. In contrast, Tsai et al. (32) reported that Val66 homozygotes had significantly higher performance IQ scores than heterozygotes; a parsimonious explanation of these findings may reflect the cohort studied: the cohort involved only females, they were all ethnically Han Chinese, and they were all young healthy nursing students who were not predisposed to a lower IQ. Previous studies have shown that the Met allele of the Val66Met polymorphism is associated with poor IQ scores (27, 61, 62). Our findings are supported by previous studies that demonstrate an association of the Met allele with better performance on general intellectual ability and other cognitive functions (13, 33, 62). However, owing to the small sample size and the family-based design of this investigation, further studies with larger sample sizes are needed to confirm these associations.

Previous studies showed an association between BDNF and hippocampal function, which led to investigations into the influence of BDNF on intelligence in schizophrenia (27, 32). Semantic memory has been shown to be associated with verbal IQ in clinical and research settings (63), although some reports consider semantic memory to be hippocampally-independent (64, 65). Our findings showed that, compared with the Val/Val genotype, Met66 carriers achieved the highest score in the vocabulary subtest, which is a measure of an individual’s general mental ability articulately to describe the meaning of words. Egan and colleagues (27) reported an association of the BDNF genotype on episodic memory in patients with schizophrenia, their siblings, and normal controls. Although the hippocampal system is considered to be a common pathway between semantic memory and episodic memory (66), the expressivity of BDNF and the accumulation

Nora S. Vyas AND BASANT K. PURI

of different effects on cognitive functions in different psychotic disorders points to a general effect of the polymorphism on cognitive abilities, and more specifically to memory performance and IQ. However, further replication is warranted to confirm this result.

The lack of a genotype × diagnosis interaction may at least partly result from a lack of diagnostic specificity of BDNF genotype in relation to general intellectual ability. Indeed, it has been argued that the nosological classification of DSM-IV-TR (67) may be somewhat arbitrary (68). As noted by Owen and colleagues (68), there is an absence of a distinctive “zone of rarity” between schizophrenia and mood disorders, which may explain our findings. In addition, the additive actions of several susceptibility genes, which could either be multiple risk genes or protective gene variants, may be associated with the differential expression of general intelligence.

There are some limitations in this study. In view of the critical role of activity-dependent secretion of BDNF in hippocampus-based synaptic plasticity and learning and memory (27), antipsychotic medication could have contributed to impairments in general intellectual ability in schizophrenia. Our EOS patients and their firstdegree relatives were clearly related and the comparison sample was relatively small for a genetic association study. Age and years of education were included as covariates in the analysis, although we cannot exclude potential stratification entirely. Therefore, our findings should be taken with caution, and considered as a preliminary investigation, which may be useful for future studies incorporating larger sample sizes. We dealt with the issue of inter-correlation by using the GEE method and a within-subjects design. Indeed, our EOS sample was small however this reflects the rare and severe form of the illness in comparison with adult-onset schizophrenia (69, 70). Similar to previous studies (13, 32, 59), we lacked a control group, however our aim was to study the influence of BDNF on intelligence in EOS and investigate the possibility of genetic differentiation of the BDNF gene polymorphism in families of schizophrenia patients. Future larger studies should elucidate the critical role of BDNF on these specific cognitive measures in schizophrenia and healthy non-relatives, and fully evaluate the validity of these conclusions.

In conclusion, the BDNF Val66Met polymorphism appears to be associated with general intellectual ability.

The IQ subtests used in our study suggests an association of the BDNF polymorphism with vocabulary, block design, and object assembly, which provides support

to the hypothesis that BDNF may play a critical role in the neurodevelopment of brain circuitry involved in general cognitive abilities, and more specifically to memory and dimensions of IQ. Further investigation is warranted to provide a more validated conclusion.

Acknowledgements This work was supported by a departmental fund at King’s College London, Institute of Psychiatry, London, U.K. We are grateful to the patients and relatives who participated in the VIPS project. We thank child and adolescent consultant psychiatrists from the adolescent services who referred suitable participants for this study.

Dr. Nora S. Vyas was supported by the Fulbright Distinguished Scholar Award by the US-UK Fulbright Commission and is currently supported by the Lindemann Trust Fellowship.

Contributions NSV was involved in the design, analysis and interpretation of data, and wrote the first draft of the manuscript. BKP was involved in the interpretation of the data and critically revised the manuscript. Both authors approved the final version.

Conflicts of Interest None.

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Straub RE, Egan MF, Meyer-Lindenberg A, Weinberger DR.The brainderived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 2004;24:10099-10102.

30. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, Sinclair M, Crombie C, Walker N, St Clair DM. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 2005;10:208-212.

31. Lencz T, Lipsky RH, DeRosse P, Burdick KE, Kane JM, Malhotra AK. Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes. Br J Psychiatry 2009;194:313-318.

32. Tsai SJ, Hong CJ, Yu YW, Chen TJ. Association study of a brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and personality trait and intelligence in healthy young females. Neuropsychobiology 2004,49:13-16.

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Kurtz MM. Neurocognitive impairment across the lifespan in schizophrenia: An update. Schizophr Res 2005;74:15-26.

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144

Book Reviews

Book reviews "Six Million and One" A film by David Fisher; Fisher Features.

93 min. DCP/HD, Israel-Germany-Austria co-production, Hebrew/English/German (English and Hebrew subtitles)

J

oseph Fisher’s memoir was discovered only after his death. His children refused to confront it, except for David, the filmmaker, for whom it became a compass for a long journey. When he found it unbearable to be alone in the wake of his father’s survival story and his struggle not to lose his sanity, David convinced his brothers and sister to join him in the hope that this would also contribute to releasing tensions and making them as close as they used to be. They, for their part, couldn’t understand why anyone should want to dig into the past instead of enjoying life in the present. In the dark depths of the tunnels, part of the Austrian forced labor camp of Gusen, where their father had slaved during the Holocaust, illuminated only by flashlights, the Fishers seek meaning in their personal and family histories. As their deepest pains are exposed, they find themselves crying and laughing, in bitter-sweet scenes that give this personal film a rare sense of intimacy.

I should start this review with a disclosure: I know and love the Fishers and have been on intimate terms with this magnificent family for many years. This has not dulled my sense of criticism. The movie is not flawless. It is humane in a manner more profound then seen in the various "classics" of the Holocaust movies. The enigmatic father whose diary leads to the making of this feature remains beyond reach. Four tortured souls try to reach out to him in vain. In the parallel world of the U.S. Army veterans who freed and tried to save the survivors of the horrific Austrian forced labor camp the trauma has never ceased. The elderly veterans cry as they recall how survivors died as they gobbled the army food rations. The four Fisher children attempt a pastoral picnic where their father was served a life saving bowl of soup by a local peasant. This does not really provide nourishment for them. American or Israeli, Catholic or Jewish, veterans or middle-aged, no one can embrace the survivors and go unscathed. Josef Fisher has left a legacy of despair and the revelation of evil. The Fishers attempt to modify this legacy or turn it into one of rehabilitation. Like all the heart-to-heart conversations held among the Israeliborn Fisher siblings in the film "Six Million and One," the one inside the tunnels of Gusen is sharp and painful - and yet also full of humor.

"Six Million and One" is a journey that all mental health

care professionals must view. It teaches humility, humor, angst and the vicissitude of trauma across generations. I am grateful for the Fisher family for this lesson.

Yoram Barak, Bat Yam

Workplace –Based Assessments in Psychiatry (2nd edn).

Edited by Amit Malik, Dinesh Bhugra and Andrew Brittlebank Paperback, 236 pages. RCPsych Publications £18 . ISBN 978-1-908020-06-2

T

his book reflects the changes made to the way psychiatric residents’ training skills are assessed for the membership in the Royal College of Psychiatrists. This in and of itself should "put-off " anyone who does not feel associated with this prestigious institution. Not so!

The book is a wise guide to help teachers and mentors of psychiatry residents learn how to focus their assessments of the resident’s clinical performance in the workplace. The authors explore the theory and practice of different assessment methods such as case-based discussion, long-case evaluation and directly observed practices. Workplace-based assessments in psychotherapy and views from the residents themselves are novel issues explored in this edition.

Following a concise introductory chapter and a chapter providing a literature overview the next three chapters focus on case-based discussion, the assessed clinical encounter and the assessment of clinical expertise. The editors then provide seven chapters looking at assessing non-clinical skills and the final three chapters aid interested parties in developing assessments in their workplace. I would like to emphasize one of the book’s chapters which I found to be novel, useful and worthy of consideration for our own – Israeli – board examinations. Chapter 7 describes Direct Observation of Non-Clinical Skills: a new tool to assess higher psychiatric training. The chapter, written by Andrew Brittlebank, prompts teachers to assess their residents’ skills in the following events and situations: chairing a meeting, teaching, testifying, written communication, supervising, consulting and as participants at meeting. The Direct Observation of Non-Clinical Skills makes the assessment of day-to-day tasks of leadership and management practical and broadens our comprehensive view of our residents. The book is written in an easy, flowing language. Some of the details are relevant only for U.K. residents. It does provide a learned and methodical assessment of psychiatry residents that can – and should – be applied in every teaching hospital here in Israel.

Yoram Barak, Bat Yam

145

‫ישיבת הוועד המרכזי של האיגוד‬ ‫אפריל ‪2012‬‬

‫‪1 .1‬לוועד המרכזי צורפו‪ ,‬כמשקיפים‪ ,‬נציגי השירותים‬ ‫האמבולטוריים‪ .‬הצרכים והקשיים הוצגו‪ ,‬וסוכם כי‬ ‫הסוגיות הדורשות מעורבות של הוועד יגובשו לקראת‬ ‫המפגשים הבאים‪ .‬ייערך כנס של האיגוד בנושא איכותו‬ ‫והספקתו של הטיפול בקהילה וישתתפו בו מנהלי‬ ‫השירותים בקהילה‪.‬‬ ‫‪ 2 .2‬הוצגו העקרונות להעברת שירותי בריאות הנפש בקהילה‬ ‫‪1‬לקופות‪:‬‬ ‫‪1‬א‪ .‬כל השירותים ימשיכו להיות באחריות המדינה (לפי‬ ‫‪1‬התוספת השלישית לחוק) עד ‪ - 1.1.2015‬לתקופת ביניים‪.‬‬ ‫‪1‬ב‪ .‬אופי וסטנדרט השירות הקיים יימשך‪.‬‬ ‫‪1‬ג‪ .‬הקופות יהיו ספקיות שירות והן יפתחו את השירותים‬

‫‪ 1‬בקהילה על פי תכנית שתאושר ותתוקצב בתקופת‬ ‫‪ 1‬הביניים‪.‬‬ ‫‪1‬ד‪ .‬כל שירותי בריאות הנפש הניתנים כיום על ידי המדינה‬ ‫ימשיכו להינתן למטופלים‪.‬‬ ‫‪3 .3‬אושרה העסקת מזכירה לשם טיוב מערך ההוצאה לאור של‬ ‫‪1‬עיתון האיגוד (‪.)IJP‬‬ ‫‪4 .4‬האזוריות בהספקת שירותי האשפוז תישמר‪ ,‬למעט בקשות‬ ‫חריגות שיאושרו על ידי מנהלי המרכזים‪ ,‬עד להורדת‬ ‫התפוסות באשפוז‪.‬‬ ‫‪5 .5‬האיגוד תומך בשינוי החקיקה לאשפוז כפוי של חולי אנורקסיה‬ ‫הנמצאים בסכנת חיים על רקע גופני בתנאים הנדרשים‬ ‫וביחידות המתאימות לכך בבתי חולים כלליים‪.‬‬

‫איגוד הפסיכיאטריה בישראל‪ :‬ההסתדרות הרפואית ‪ -‬המועצה המדעית ‪Israeli Psychiatric Association -‬‬

‫יו"ר‪ :‬פרופ' משה קוטלר ‪Elected President: Prof. M. Kotler /‬‬ ‫‪Moshe.kotler@beerness.health.gov.il‬‬ ‫מזכירה‪ :‬ד"ר טל ברגמן לוי ‪President: Dr. T.Bergman–Levy /‬‬ ‫‪Tal.Bergman–Levy@beerness.health.gov.il‬‬ ‫גזבר‪ :‬ד"ר שמואל הירשמן ‪Treasurer: Dr. S.Hirschmann /‬‬ ‫‪shmuel hirschmann@yahoo.com‬‬

‫מרכז לבריאות הנפש באר יעקב‬

‫‪Beer Yaacov Mental Health Centre‬‬

‫ ת‪.‬ד‪ 1 .‬באר יעקב‬ ‫‪Beer Yaacov Mental Health Centre, P.O.B 1 ,‬‬ ‫‪Beer Yaacov, Israel, 70350‬‬

‫יו"ר נבחר‪ :‬פרופ' חיים בלמייקר ‪/‬‬

‫‪Elected President: Prof. H.Belmaker‬‬ ‫‪belmaker@bgu.ac.il‬‬

‫יו"ר יוצא ואחראי קשרי חו"ל‪ :‬פרופ' זאב קפלן ‪/‬‬ ‫‪President: Prof. Z. Kaplan‬‬ ‫‪Zeev.kaplan@pbsh.health.gov.il‬‬

‫ברכות והצלחה ליו"ר הנכנס‪ ,‬פרופ' קוטלר‪ ,‬ולוועד הנבחר החדש‪.‬‬ ‫תודה לכל החברים שתמכו ופעלו במהלך השנים המורכבות למערך הפסיכיאטריה בישראל‪.‬‬

‫על אובדנות בהשוואה למבוגרים (‪P–004, 4.2 ,)0.3% ,7/2012‬‬ ‫‪ .= (df =1)2x‬לא נמצאה עדות לאובדנות מוגברת בקרב ילדים‬

‫שקיבלו תרופה (‪ )0.8% ,7/828‬בהשוואה לילדים אשר קיבלו‬ ‫אינבו (‪.)1.1% ,5.460‬‬ ‫מסקנות‪ :‬נתונים אלו מצביעים על דמיון מרשים בין התוצאות‬ ‫מעבודות בקרב ילדים לעבודות בקרב מבוגרים במצבים של‬ ‫מאניה דו–קוטבית‪ .‬פרופיל הטיפול של תרופות אנטי–מאניות‬ ‫אלו בקרב ילדים טוב יותר בצורה בולטת בהשוואה לתרופות‬ ‫פסיכוטרופיות אחרות כדוגמת נוגדי דיכאון‪.‬‬ ‫חסינות דיונית של פסיכיאטרים מחוזיים ושל‬ ‫חברי ועדות פסיכיאטריות מחוזיות מפני‬ ‫תביעות אזרחיות בישראל‬ ‫י‪ .‬מרגולין‪ ,‬א‪ .‬אסמן‪ ,‬ר‪ .‬מסטר ומ‪ .‬קליאן‪ ,‬ירושלים‬

‫פסיכיאטרים‪ ,‬רופאים ואנשי מקצוע אחרים העובדים במערכת‬ ‫הציבורית‪ ,‬חשופים לתביעות משפטיות שמקורן בהחלטות‬ ‫קליניות אשר מתקבלות על ידם‪ .‬עד לשנת ‪ 2006‬לא הייתה‬ ‫לאנשי מקצוע אלה חסינות כלשהי מפני תביעות מסוג זה‪.‬‬ ‫במאמר מתואר תיקון חקיקה שקיים במדינת ישראל מאז‬ ‫פברואר ‪ ,2006‬ואשר מתייחס לעובדי ציבור מסוימים‪ ,‬ביניהם‬ ‫פסיכיאטרים מחוזיים וחברי ועדות פסיכיאטריות מחוזיות‪.‬‬ ‫כן מובא במאמר תיאור מקרה קליני לשם הדגמת ההשלכות‬ ‫האפשריות של שינוי חקיקה זה‪.‬‬

‫ראיות ראשוניות לקורלציה בין ‪ BDNF‬לפולימורפיזם‬ ‫גנטי ‪ Val66Met‬וליכולת אינטלקטואלית כללית בקרב‬ ‫חולי סכיזופרניה שחוו התקף מוקדם‬ ‫נ‪.‬ס‪ .‬ויאס וב‪.‬ק‪.‬פיורי‪ ,‬בת'סדה‪ ,‬ארה"ב‬

‫רקע‪ :‬ל–‪ )BDNF( Brain–derived neurotrophic‬תפקיד‬ ‫חיוני בהישרדות‪ ,‬בפיתוח ובתחזוקה של מערכות עצביות‪,‬‬ ‫והפולימורפיזם ‪ Val66Met‬מעורב בתפקוד הזיכרון‪.‬‬ ‫שיטה‪ :‬במחקר זה נבחן‪ ,‬באמצעות מבחן אינטליגנציה של ‪,WISC‬‬ ‫הקשר של ‪ BDNF‬ליכולת האינטלקטואלית הכללית בקרב ‪161‬‬ ‫אנשים‪ ,‬וביניהם ‪ 53‬חולי סכיזופרניה שסבלו מהתקף ראשון‬ ‫מוקדם‪ 91 ,‬קרובי משפחה ביולוגיים בריאים של חולים אלו ו–‪17‬‬ ‫קרובי משפחה הסובלים מהפרעת דיכאון מג'ורי (‪.)MDD‬‬ ‫תוצאות‪ :‬בלי קשר לאבחון‪ ,‬אנשים עם אלל ‪ Met66‬קיבלו‬ ‫ציונים גבוהים יותר משמעותית מאשר הומוזיגוטים לאלל‬ ‫‪ Val66‬בכל הקשור לאוצר המילים‪ BLOCK DESIGN ,‬ו–‬ ‫‪ OBJECT ASSEMBLY‬במבחן ‪ .WISC‬אצל ‪probands EOS‬‬ ‫נמצא תפקוד ירוד בכל מבחני ה–‪ IQ‬בהשוואה לקרובי משפחה‬ ‫ללא ‪.MDD‬‬ ‫מגבלות‪ :‬גודל המדגם הקטן יחסית של גנוטיפים בודדים‪.‬‬ ‫מסקנות‪ :‬לגנוטיפ ‪ BDNF‬עשוי להיות משמעותי בתפקודים‬ ‫קוגניטיביים ובממדים ספציפיים של אינטליגנציה‪ .‬נראה כי האלל ‪Met‬‬ ‫קשור לתפקוד טוב יותר במבחני ‪ IQ‬בהשוואה לגנוטיפ ‪.Val /Val‬‬

‫עקה אצל הורים למתבגרים הסובלים‬ ‫מהפרעה דו־קוטבית ודרכים לתמיכה בהם‬ ‫ר‪.‬ב‪ .‬נדקרני ומ‪.‬א‪ .‬פריסטד‪ ,‬קולומבוס‪ ,‬ארה"ב‬

‫רקע‪ :‬מאמר זה סוקר עקה הקשורה להורות לצעירים הסובלים‬ ‫מהפרעה דו–קוטבית‪ ,‬דרכי התמודדות לא יעילות וכן תפקוד‬ ‫חיסוני ומצב גופני הקשורים לעקה כרונית‪ .‬המאמר מציג‬ ‫ממצאים ראשוניים על הקשר בין מדדים חיסוניים לבין משתנים‬ ‫של בריאות גופנית ונפשית ותפקוד בין־אישי אצל הורים‬ ‫לילדים הסובלים מהפרעות במצב הרוח‪ .‬כמו כן ניתנות המלצות‬ ‫להתמודדות עם עקה‪ .‬ההמלצות מתבססות על מחקרים קליניים‬ ‫בתחום הפסיכותרפיה המשפחתית‪.‬‬ ‫ממצאים‪ :‬ערכים של ‪Interleukin–6 (IL–6), tumor necrosis‬‬ ‫‪factor–alpha (TNF–α), C–reactive protein (CRP),‬‬ ‫‪ ,(EBV) Epstein Barr virus‬סמנים תזונתיים‪ ,‬מדדים של‬ ‫בריאות גופנית ונפשית ושל תפקוד בין־אישי נאספו מ־‪ 26‬הורים‬ ‫לילדים הסובלים מהפרעות במצב הרוח‪ .‬רמות גבוהות של ‪CRP‬‬ ‫קשורות לתחושת עקה גבוהה יותר‪ ,‬וכן ליותר דיכאון‪ ,‬ליותר‬ ‫תחלואה גופנית ולרמות אלבומין נמוכות‪ .‬רמות גבוהות של ‪IL–6‬‬ ‫קשורות לשימוש מוגבר בניקוטין‪.‬‬ ‫מגבלות‪ :‬גודל המדגם והדמוגרפיה מוגבלים‪ ,‬ולפיכך גם היכולת‬ ‫לבצע הכללה של הממצאים מוגבלת‪.‬‬ ‫מסקנות‪ :‬ממצאי המחקר הראשוני מתאימים לממצאים בספרות‬ ‫על מטפלים מבוגרים‪ ,‬ומצביעים על כך שאצל מטפלים שנמצאים‬ ‫בעקה ישנם גם סימנים להפרעות חיסוניות‪ .‬כמו כן נידונו דרכים‬ ‫מבוססות מחקר לתמיכה בהורים‪.‬‬ ‫השפעת זיפרזידון על הפעלה של אזורים‬ ‫פרה־פרונטליים באמיגדלה בקרב מתבגרים‬ ‫מאניים הסובלים מהפרעה דו־קוטבית‬ ‫מ‪ .‬רייד שניידר‪ ,‬ס‪.‬מ‪ .‬אדלר‪ ,‬ר‪ .‬וויטסל‪ ,‬וו‪ .‬וובר‪ ,‬נ‪.‬פ‪ .‬מילס‪ ,‬ס‪.‬מ‪ .‬ביטר‪,‬‬ ‫ג'‪ .‬אליאסין‪ ,‬ס‪.‬מ‪ .‬סטרקובסקי ומ‪.‬פ‪ .‬דלבלו‪ ,‬סינסינטי‪ ,‬ארה"ב‬

‫רקע‪ :‬ממחקרים קודמים עלה כי אצל מתבגרים מאניים הסובלים‬ ‫מהפרעה דו–קוטבית נראים שינויים בתפקוד המוח באזור‬ ‫האמיגדלה והקורטקס בעקבות טיפולים פרמקולוגיים‪ .‬במחקר‬ ‫זה נבחנה ההשפעה של זיפרזידון על תפקוד המוח של מתבגרים‬ ‫הסובלים ממאניה‪.‬‬ ‫שיטה‪ :‬מתבגרים מאניים הלוקים בהפרעה דו–קוטבית (‪23‬‬ ‫נבדקים) השתתפו במחקר מבוקר אינבו של זיפרזידון‪ .‬הנבדקים‬ ‫עברו בדיקת תהודה מגנטית תפקודית בעודם מבצעים מטלה‬ ‫של קשב מתמשך‪ .‬הם נבדקו לפני התחלת הטיפול כערך בסיסי‪,‬‬ ‫ובימים ‪ 7‬ו–‪ 28‬לטיפול‪ .‬קבוצת ביקורת של מתבגרים בריאים (‪10‬‬ ‫נבדקים) נבדקה פעם אחת בלבד‪ .‬באזורי העניין נבדקו שינויים‬ ‫במידת ההפעלה בהקשר לטיפול באזור ברודמן (‪)BA‬נ‪11 ,10‬‬ ‫ו–‪ 47‬ובאמיגדלה‪.‬‬ ‫תוצאות‪ :‬בהשוואה לאינבו‪ ,‬הטיפול בזיפרזידון נמצא קשור‬ ‫להפעלת יתר לאורך זמן באזורי ‪ BA 11‬ו–‪ 47‬בצד ימין‪ .‬השפעות‬

‫אלו לא היו קשורות להבדלים בתסמינים בין קבוצות הטיפול‪.‬‬ ‫אצל מטופלים אשר הגיבו לטיפול בזיפרזידון נראתה יותר‬ ‫תת–הפעלה באזור ‪ BA 47‬מימין בנקודת ההתחלה בהשוואה‬ ‫לאלו שלא הגיבו לזיפרזידון‪ .‬כמו כן‪ ,‬אצל המתבגרים שטופלו‬ ‫בזיפרזידון‪ ,‬נמצא יחס הפוך בין מידת ההפעלה לפני התחלת‬ ‫הטיפול באזור ‪ BA 47‬מימין לבין השיפור בציון במבחן‬ ‫‪ YOUNG‬להערכת מאניה (‪.)YMRS‬‬ ‫מגבלות‪ :‬בשל גודל המדגם הקטן‪ ,‬היכולת להדגים הבדלים‬ ‫בין הקבוצות באזורי עניין אחרים הייתה מוגבלת‪ .‬הנבדקים‬ ‫הבריאים נבדקו רק בנקודת זמן אחת‪ ,‬דבר המגביל את יכולת‬ ‫פענוח התוצאות‪ .‬ה–‪ FDA‬לא אישר שימוש בזיפרזידון בקרב‬ ‫מתבגרים הסובלים ממאניה‪ ,‬ולכן הרלווטיות הקלינית של‬ ‫תוצאות אלו מוגבלת‪.‬‬ ‫מסקנות‪ :‬ההפעלה המוגברת באזורים ‪ BA 11‬ו–‪ 47‬מימין בזמן‬ ‫מטלת קשב מתמשך‪ ,‬והקשר שזוהה בין הפעלה ראשונית חלשה‬ ‫יותר באזור ‪ BA 47‬לתגובה לטיפול בזיפרזידון מצביעים על כך‬ ‫שזיפרזידון יכול לתקן תפקוד פרה–פרונטלי לקוי אצל מתבגרים‬ ‫מאניים הסובלים מהפרעה דו–קוטבית‪.‬‬ ‫יעילותן ובטיחותן של תרופות‬ ‫אנטי־מאניות בקרב ילדים ומבוגרים‬ ‫א‪ .‬קאן‪ ,‬ג‪ .‬פאוסט‪ ,‬ג‪.‬ג‪ .‬אמסלי‪ ,‬וו‪.‬א‪.‬בראון‪ ,‬בלביו‪ ,‬ארה"ב‬

‫מטרה‪ :‬עבודות קליניות שבחנו את יעילותן ואת בטיחותן של‬ ‫תרופות אנטי–מאניות בקרב ילדים הסובלים מדיכאון העלו חשש‬ ‫בנוגע להגברת הסיכון לאובדנות וכן עוררו ספקות לגבי יעילותן‬ ‫של התרופות‪ .‬לאחרונה נערכו כמה ניסויים קליניים של תרופות‬ ‫אנטי–מאניות בקרב ילדים‪ ,‬וסיכום הנתונים שהתקבלו הועבר‬ ‫לרשויות הפיקוח‪.‬‬ ‫שיטות‪ :‬בחינת דוחות רפואיים וסטטיסטיים מה–‪FDA‬‬ ‫האמריקאי על אודות תרופות אנטי–מאניות שניטלו על ידי‬ ‫מבוגרים וילדים‪ .‬נתונים אלו שימשו להערכת התמותה‪ ,‬תופעות‬ ‫הלוואי הקשות והאובדנות‪.‬‬ ‫תוצאות‪ :‬חמש העבודות שנעשו בקרב ילדים כללו ‪1,228‬‬ ‫מטופלים (‪ 828‬קיבלו תרופה ו–‪ 460‬קיבלו אינבו)‪ .‬שבעה מחקרים‬ ‫בקרב מבוגרים כללו ‪ 4,228‬מטופלים (‪ 2,356‬קיבלו תרופה‬ ‫ו–‪ 1,932‬קיבלו אינבו)‪ .‬ממוצע הניקוד הבסיסי ב–‪MANIA‬‬ ‫‪ RATING SCALE‬היה זהה בקרב מבוגרים וילדים = ‪ .30.3‬לא‬ ‫נמצא הבדל משמעותי בניקוד בין הקבוצה שקיבלה תרופה לזו‬ ‫שקיבלה אינבו (ילדים = ‪ ,5.8‬מבוגרים = ‪.)5.2‬‬ ‫לא אירעו מקרי מוות במחקרי הילדים‪ .‬ב–‪ 23‬עבודות בקרב‬ ‫מבוגרים נצפו שמונה מקרי מוות‪ ,‬שלושה בקבוצת הטיפול‬ ‫וחמישה בקבוצת האינבו‪ .‬שיעור התמותה עמד על ‪ 3,290‬לכל‬ ‫‪ 100,000‬שנות חשיפת חולה‪.‬‬ ‫אחוז המטופלים שדיווחו על תופעות לוואי קשות היה נמוך‬ ‫במקצת במחקרי הילדים (‪ )4.2%‬לעומת המבוגרים (‪.)4.7%‬‬ ‫אחוז גבוה יותר של ילדים שקיבלו אינבו (‪ )1.1% ,5/460‬דיווחו‬

‫כתב עת ישראלי‬ ‫לפסיכיאטריה‬ ‫תקצירים‬ ‫השוואה של אזורים תפקודיים במוח בין צעירים‬ ‫למבוגרים עם הפרעה דו קוטבית מדגישים נקודות‬ ‫דמיון ושוני המושפעות מהמוח המתפתח‪.‬‬ ‫ווגברייט‪ ,‬מ‪ .‬פבלורי‪ .‬שיקגו‪ ,‬ארה"ב‪.‬‬

‫מחקרים אחרונים בתחום ההדמיה המוחית חשפו מיידע רב‬ ‫בנוגע לחסרים נוירולוגיים בהפרעה דו קוטבית במבוגרים‪ .‬אולם‪,‬‬ ‫למרות תוצאות מבטיחות‪ ,‬המחקר בתחום ההפרעה הדו קוטבית‬ ‫בילדים עדיין בהתפתחות‪ .‬הספרות בתחום ההדמייה המוחית הינו‬ ‫מאד הטרוגני עם שונות בפרדיגמות שמשתמשים‪ ,‬במצב הרוח‬ ‫של המשתתפים ובתרופות שהם נוטלים‪ .‬למרות שונות זו עולים‬ ‫מספר דפוסים ברורים‪ .‬בתגובה לגירוי ריגשי נצפית פעילות יתר‬ ‫באזור הלימבי ביחד עם תת פעילות באזור המערכת לויסות ריגשי‬ ‫באזור הונטרלי–פרהפרונטלי‪ .‬ממצא זה קיים בהפרעה דו קוטבית‬ ‫במבוגרים וילדים‪ .‬אצל מבוגרים הלוקים בהפרעה נמצאה יותר‬ ‫שונות בפעילות באזור הונטרלי ‪ -‬פרה פרונטלי‪ ,‬יתכן בשל גורמים‬ ‫של הבשלה ותרופות‪.‬‬ ‫בפרדיגמות קוגניטיביות רבות‪ ,‬צעירים עם הפרעה דו קוטבית הראו‬ ‫תת פעילות באזורים דורסליים פרהפרונטליים הקשורים לדיספונציה‬ ‫ונטרלית בעוד שמבוגרים הראו פעילות קומפנסטורית באזורים‬ ‫פרונטליים‪ ,‬פריאטליים וטמפורליים עם שונות ספציפית לפרדיגמה‪.‬‬ ‫בפרדיגמות של אינטראקציה ריגשית ‪ -‬קוגניטיבית‪ ,‬חולים הראו‬ ‫דיסרגולציה באזורים המחברים בין מערכות מוחיות קוגניטיביות‬ ‫לריגשיות (כלומר אזורים ונטרליים פרהפרונטליים והצינגולט‬ ‫קורטקס)‪ ,‬אזורים אלו‪ ,‬בהם נעשה מאמץ מיוחד לעיבוד גירויים‬ ‫ריגשיים באופן יעיל‪ ,‬מגייסים אזורים אחוריים של מערכת קשב‬ ‫על מנת להתמודד עם חוסר היציבות האפקטיבית‪.‬‬ ‫בנוסף‪ ,‬טכניקות חדשניות הראו חסרים בחיבורים בין אזורים‬ ‫פרונטליים ללימביים במבוגרים וצעירים הלוקים בהפרעה דו‬ ‫קוטבית הן במנוחה והן בזמן פעילות ריגשית וקוגניטיבית‪.‬‬ ‫לבסוף‪ ,‬הספרות בנושא הדמיה מוחית חסרה מחקרים המשווים‬ ‫מבוגרים לצעירים עם הפרעה דו קוטבית ומחקרי אורך העוקבים‬ ‫אחרי ילדים ומתבגרים עם הפרעה דו קוטבית ההופכים‬ ‫למבוגרים‪ .‬מחקרים כאלו יספקו תובנות חשובות לפרוגנוזה‬ ‫ויקבעו מטרות להתערבות מוקדמת בשלבי התפתחות המחלה‪.‬‬ ‫מודל לטיפול משפחתי–פסיכוסוציאלי‬ ‫א‪ .‬ווסט וש‪ .‬מ‪ .‬וינשטיין‪ ,‬שיקגו‪ ,‬ארה"ב‪.‬‬

‫‪israel journal of‬‬

‫‪psychiatry‬‬ ‫רקע‪ :‬הפרעה דו–קוטבית אצל ילדים היא מחלה כרונית וקשה‪,‬‬ ‫והיא מובילה להפרעה בתפקוד הפסיכוסוציאלי‪ .‬התערבות‬ ‫פסיכוסוציאלית היא מרכיב חשוב בטיפול הכוללני בהפרעה זו‪.‬‬ ‫שיטה‪ :‬טיפול קוגניטיבי התנהגותי ממוקד ילד ומשפחה‬ ‫(‪ )CFF–CBT‬המכונה גם ‪ ,RAINBOW‬הוא טיפול מבוסס‬ ‫פרוטוקול של ‪ 12‬מפגשים של התערבות פסיכוסוציאלית‬ ‫המיועד לצעירים בני ‪ 13–7‬הלוקים בהפרעה דו–קוטבית‬ ‫ולמשפחותיהם‪ .‬הגישה במודל טיפול משפחתי משלבת טיפול‬ ‫קוגניטיבי התנהגותי עם מרכיבים פסיכו–חינוכיים וטיפולים‬ ‫נוספים מתחום הפסיכותרפיה הבין–אישית‪ ,‬מיינדפולנס‬ ‫והפסיכולוגיה החיובית‪ CFF–CBT .‬מכוון לשיפור התפקוד‬ ‫בשבעה תחומים עיקריים‪ :‬שגרה‪ ,‬ויסות אפקט‪ ,‬יעילות עצמית‪,‬‬ ‫מחשבות והתנהגות שלילית‪ ,‬מיומנויות חברתיות‪ ,‬פתרון בעיות‬ ‫בין–אישיות וחברתיות ותמיכה חברתית‪.‬‬ ‫תוצאות ומסקנות‪ :‬תוצאות ראשוניות ממחקר פתוח‪,‬‬ ‫המפורטות במאמר‪ ,‬מצביעות על יעילות מבטיחה של שיטת‬ ‫ה–‪ CFF–CBT‬בהפחתת הסימפטומים ושיפור התפקוד‬ ‫הפסיכוסוציאלי‪ .‬גישה זו נבדקת כעת במחקרים קליניים‬ ‫הכוללים רנדומיזציה‪.‬‬ ‫טיפול ממוקד משפחה לילדים ולמתבגרים‬ ‫הסובלים מהפרעה דו־קוטבית‬ ‫ד‪ .‬ג'‪ .‬מיקלוויץ'‪ ,‬לוס אנג'לס‪ ,‬ארה"ב‬

‫מהלך ההפרעה הדו–קוטבית בקרב ילדים ומתבגרים מאופיין‬ ‫בשכיחות גבוהה של התקפים ובהפרעה לתפקוד‪ .‬מאמר זה‬ ‫מתאר את ההתאמה של טיפול ממוקד משפחה (‪ )FFT‬לילדים‬ ‫ולמתבגרים הסובלים מהפרעה דו–קוטבית‪ FFT .‬ניתן ב–‪21‬‬ ‫מפגשים לאורך תשעה חודשים‪ ,‬והוא מתחיל בדרך כלל בתקופת‬ ‫החלמה אחרי התקף חריף של דיכאון או (היפו)מאניה‪ .‬הטיפול‬ ‫מורכב מכמה שלבים‪ :‬התחייבות לטיפול פסיכו–חינוכי‪ ,‬רכישת‬ ‫מיומנויות לשיפור התקשורת ורכישת מיומנויות לפתרון בעיות‪.‬‬ ‫מחקרים אקראיים שנערכו בקרב מבוגרים ומתבגרים‬ ‫מראים שחולים הסובלים מהפרעה דו–קוטבית ושקיבלו ‪FTT‬‬ ‫וטיפול פרמקולוגי‪ ,‬החלימו מההתקף מהר יותר‪ ,‬ותקופות‬ ‫הרמיסיה שלהם היו ארוכות יותר מאלו של מטופלים שקיבלו‬ ‫פסיכותרפיות קצרות וטיפול תרופתי‪.‬‬ ‫עוד מתואר במאמר היישום של ‪ FFT‬בקרב מתבגרים‬ ‫הנמצאים‪ ,‬מבחינה גנטית‪ ,‬בסיכון להפרעה דו–קוטבית‪,‬‬ ‫ומתוארים הקשיים בהרחבת ההתערבויות המשפחתיות‬ ‫במסגרת הקהילה‪.‬‬

‫‪www.doctorsonly.co.il‬‬

‫רבע מהמטופלים שינו את‬ ‫הטיפול שהרופא קבע לאחר‬ ‫שגלשו באתרים רפואיים‬ ‫מערכת דוקטורס אונלי | ‪25/4/2011‬‬

‫לעיתים מגיע המטופל לרופא לאחר שכבר גיבש לעצמו מסקנה‬ ‫ממה הוא סובל‪ .‬לרוב הוא לא יחשוף מידע זה מול הרופא‪,‬‬ ‫וזאת בין היתר כדי "לבדוק" את הרופא‪ .‬ייתכנו מצבים שבהם‬ ‫המטופל מקדים במידע את הרופא > לידיעה המלאה‬

‫אתר‬ ‫אינטרנט‬ ‫חדש מבית‬ ‫הר"י‬

‫כל מה שמעניין רופאים‬ ‫חדשות | דעות | מינויים | מחקרים | איגודים | אתיקה | משפט | כתבי עת | דרושים | סקרים | ארועים‬

israel journal of

psychiatry

‫ח‬ ‫ד‬ ‫ש‬ !

,‫סירקדין‬ ‫ה‬ ‫ת‬ ‫ר‬ ‫ו‬ ‫פ‬ ‫ה הי‬ ‫המאושרת לש חידה ל‬ ‫ה‬ ‫פ‬ ‫ר‬ ‫ע‬ ‫ו‬ ‫ימוש לפרק ז ת שינה‬ ‫עד‬ ‫מן של‬

Pediatric Bipolar Disorder Part I I: Treatment

,‫סירקדין‬ !‫לישון כמו שצריך‬ :‫סירקדין מספק למטופלים שלך בדיוק מה שהם צריכים‬ .‫ לשחזור מבנה השינה התקין במהלך כל שעות הלילה‬,‫מלטונין בשחרור מושהה‬ :‫סירקדין מכוון לענות על צרכי המטופלים שלך‬ ‫הירדמות קלה ומהירה‬ ‫שינה רצופה ומרעננת‬ ‫שיפור משמעותי באיכות החיים‬ ,‫כשאתה רושם לו סירקדין‬ !‫אתה מאפשר לו לישון כמו שצריך‬ .‫ שבועות בלבד‬4 ‫ מאושרות לשימוש עד‬, ‫) להן אינדיקציה לטיפול בנדודי שינה בישראל‬Z-‫* כל התרופות ההיפנוטיות (בנזודיאזפינים ותרופות ה‬ References: 1). Fourtillan J. B. Role of melatonin in the induction and maintenance of sleep. Dialogues Clin Neurosci 2002;4:395-401. 2). Wade A. G. et al. Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin 2007;23(10):2597-2605. 3). Otmani S. et al. Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Hum Psychopharmacol Clin Exp 2008; Published online in Wiley InterScience. 4). Luthinger R. et al. The effect of prolonged release Melatonin on sleep measures and psychomotor performance in elderly patients with insomnia. Int Clin Psychopharmacol 2009. 5). Paul M. A. et al. Sleep-Inducing Pharmaceuticals: A Comparison of Melatonin, Zaleplon, Zopiclone, and Temazepam. Aviation Space Environmental Med 2004;75(6):512-519. 6). Lemoine P. et al. Prolonged release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res 2007;16:372-380.

Volume 49, Number 2, 2012 Israel Journal of Psychiatry and Related Sciences

3 1 ‫ש‬ ‫ב‬ * ‫ועות‬

Vol. 49 - Number 2 2012

ISSN: 0333-7308

75 Mechanistic Comparisons of Functional Domains across Pediatric and Adult Bipolar Disorder Highlight Similarities, As Well As Differences, Influenced by the Developing Brain Ezra Wegbreit, PhD, and Mani Pavuluri, MD, PhD

86 A Family-Based Psychosocial Treatment Model Amy E. West, PhD, and Sally M. Weinstein, PhD

95 Family-Focused Treatment for Children and Adolescents with Bipolar Disorder David J. Miklowitz, PhD

104 Stress and Support for Parents of Youth with Bipolar Disorder Radha B. Nadkarni, PhD, and Mary A. Fristad, PhD

112 The Effects of Ziprasidone on Prefrontal and Amygdalar Activation in Manic Youth with Bipolar Disorder Marguerite Reid Schneider, BA,Caleb M. Adler, MD, Rachel Whitsel, BA, Wade Weber, BS, MS, Neil P. Mills, BS, Samantha M. Bitter,2 James Eliassen, PhD, Stephen M. Strakowski, MD, and Melissa P. DelBello, MD

122 Efficacy and Safety of AntiManic Agents in Children and Adults

Arif Khan, MD, James Faucett, MA, MS, Graham J. Emslie, MD, and Walter A. Brown, MD