Managing Bipolar Depression and Mixed Episodes Outline Diagnosing

Managing Bipolar Depression and Mixed Episodes

Outline • Diagnosing bipolar disorder with DSM-5 • Treating mixed features of bipolar disorder • Improving health outcomes in bipolar depression • Role of psychosocial treatments in bipolar patients

Diagnosis of Bipolar Disorder Can Be Challenging Initial diagnosis can take ≥ 10 years Patients with bipolar disorder more likely to present with symptoms of depression Symptom overlap can lead to misdiagnosis as depressive symptoms are difficult to distinguish from MDD One-third of patients are misdiagnosed with MDD Comorbidities (eg anxiety disorder, alcohol and substance abuse, cognitive or attention disorders, eating disorders) are common and complicate diagnosis MDD = major depressive disorder. Pini et al 2005; Judd et al 2002; Judd et al 2003 Mitchell et al 2008; Hirschfeld et al 2003; Krishnan 2005.

Bipolar and Related Disorders Changes from DSM-IV: • Formerly listed under Mood Disorders • Abnormally and persistently increased goal-directed activity or energy added as a core symptom of manic and hypomanic episodes • Mixed Episodes removed and replaced with: “With Mixed Features, ” which can be applied to the current manic, hypomanic, or depressive episode in bipolar I or II • • • Bipolar I disorder Bipolar II disorder Cyclothymic disorder Substance/medication-induced bipolar and related disorder Bipolar and related disorder due to another medical condition American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Publishing; 2013.

Conceptualization of Pure and Mixed States in DSM-IV-TR and DSM-5 Core symptoms Manic Depressive Elevated mood >3 <5 Elevated mood + depressed mood or loss of interest >3 >5 DSM-IV-TR Manic Mixed DSM-5 Manic Core Elevated mood symptoms + energy Manic >3 Depressive <5 Hypomanic/Manic with mixed features Elevated mood + energy >3 >3 Depressed mood or loss of interest <3 >5 Depressive with mixed features Depressed mood or loss of interest >3 >5 Depressive Depressed mood or loss of interest <3 >5 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Publishing; 2013.

Bipolar Specifiers • With anxious distress: – Feeling keyed up or tense – Feeling unusually restless – Difficulty concentrating because of worry – Fear that something awful might happen – Fear that individuals might lose control of him- or herself – Moderate–severe: 4– 5 symptoms – Mild: 2 symptoms – Severe: 4– 5 symptoms + motor agitation – Moderate: 3 symptoms American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Publishing; 2013.

Jail/Prison Has Replaced State Hospitals State hospital patients Mentally ill prisoners Mandersheid RW, Sonnenschen MA, eds. Mental Health, Washington DC: US Government Printing Office; 1996. DHHS Publication SMA 99 -3285.

Mania is an Emergency • Need rapid, safe stabilization • Reduction of behavioral agitation • Sleep restoration and management of withdrawal from drugs and alcohol • Antimanic treatment based on - Manic episode (mixed vs manic) - Rapid cycling or psychotic symptoms - Patient’s medication history - Presence of comorbidities - Willingness to accept therapy

Goal of Treatment: Mood Stabilization Mood stabilizers • Acute treatment or stabilization of manic/mixed, hypomanic, and depressive episodes • Do not induce alternate mood symptoms (i. e. , switch) • Prevent future relapse or recurrence of manic/mixed, hypomanic, or depressive symptoms or episodes

What Clinicians Actually Prescribe for Treatment of Bipolar Disorder 75% of patients had at least two psychotropic drugs for bipolar disorder in the past year Percentage of patients in the WAVE-bd study who took medication prescribed for bipolar disorder in the past year Bipolar I disorder (%) Bipolar II disorder (%) Anticonvulsants 58 54 Antidepressants 39 66 Antiparkinson drugs 3 0. 3 Antipsychotic drugs 70 53 Lithium 31 17 Thyroid therapy 2 4 Other 5 4 The Wide Ambispective. VE study of the clinical management and burden of bipolar disease (WAVE-bd; NCT 01062607) study recruited patients from: Austria, Belgium, Brazil, France, Germany, Portugal, Romania, Turkey, Ukraine and Venezuela. WAVE-bd, Study of the Clinical Management of Bipolar Disease. Vieta, et al. 2011.

FDA Approved Bipolar Disorder Treatments* Agent Manic Mixed Depression Maintenance Aripiprazole + + – + Asenapine + + – – Paliperidone-ER – – Lurasidone – – + – Olanzapine + + – + Olanzapine/Fluoxetine – – + – Quetiapine/XR + + Risperidone (Oral/IM) + + – Ziprasidone + + – + Chlorpromazine + – – – Carbamazepine ER + + – – Divalproex DR/ER + + – – Lamotrigine – – – + Lithium + – – + + (IM) *Aripiprazole, asenapine, olanzapine, quetiapine, risperidone indication as monotherapy and adjunct to Li or DVPX and with/without psychosis.

Efficacy of Anti-Manic Agents Compared with Placebo Mania score changes in 55 drug/placebo comparisons, based on random effects meta-analysis Favors placebo Magnitude of the pooled effect size Favors drug Tamoxifen Risperidone Carbamazepine Haloperidol Cariprazine Olanzapine Ziprasidone Asenapine Quetiapine Lithium Paliperidone Valproate Aripiprazole Licarbazepine Verapamil Lamotrigine Topiramate Yildiz A, et al. Neuropsychopharmacology. 2011; 36: 375 -389.

Cipriani Meta Analysis Aim Evaluate comparative effects of all antimanic drugs Methods Multiple treatments meta-analysis (accounts for direct and indirect comparisons) Sample 68 RCTs Jan 1, 1980–Nov 25, 2010 16, 073 subjects All comparisons ITT population BMJ. 2011; 343: bmj. d 5616. © 2011 by British Medical Journal Publishing Group.

Variable Lithium Response Rate Based on Bipolar Subtype Rapid Mixed Substance(-) Family >3 DMI Poor Abuse History Episodes Pattern Cycling Mania Response M 30% D Eupho Few Lifetime MDI No (+) Family Good Nonrapid ric Cycling Substance History Episodes Pattern Response Mania Abuse 70% M D DMI=Depression, Mania, Interval MDI=Mania, Depression, Interval Frye MA et al. J Affect Disord. 1998; 48: 91 -104.

Atypical Antipsychotics in Acute Mania Pros • As a class, effective in acute mania • Rapid control of acute mania/mixed, rapid cycling, psychosis/no psychosis • Sustained improvement of symptoms Cons • Tardive dyskinesia, neuroleptic malignant syndrome • Weight gain TD=tardive dyskinesia; EPS=extrapyramidal symptoms.

Cariprazine in Patient With Acute Mania Associated with Bipolar I Disorder Calabrese JR, et al. J Clin Psych. Nov 2014 (epub ahead of print)

Cariprazine in Patients With Acute Mania Associated with Bipolar I Disorder Mean dose 7. 5 mg/day Not FDA approved for mania. Sachs GS et al. J Affective Dis. 2015

Typical Antipsychotics in Acute Mania Pros • Efficacious for acute mania • Haloperidol more efficacious than olanzapine, quetiapine, ziprasidone Cons/adverse effects • Acute EPS, TD, akathisia, NMS Negative impact on course of illness • ↑ post manic depressive symptom severity • ↑ frequency of major depressive episodes Vieta et al. 2010.

Anticonvulsants in Acute Mania Pros • Effective in manic and mixed episodes • Effective in alcohol withdrawal and relapse prevention • Several effective in migraine prevention Cons • Ineffective in acute mania (LTG, TPX, GBP) • P 450 3 A 4 heteroinduction • Weight gain and endocrine disturbances (VAL) • Teratogenicity (VAL, CBZ) • Rash risk CBZ=carbamazepine; VAL=valproate; LTG=lamotrigine; GBP=gabapentin; OLZ=olanzapine; DVPX=divalproex; TPX=topiramate Novick et al, 2009; Goodwin et al, 2010; Frye et al, 2006; Harden et al, 2009; Goodwin et al, 2009, Jiang et al, 2009.

ECT for Acute Mania • • Electroconvulsive therapy (ECT) is a mood stabilizer 2 controlled studies of acute mania - ECT vs lithium + haloperidol • ECT reported significant benefits for acute mania Mukherjee et al, 1988. Small et al. 1998.

Target Dose Range for Acute Mania/Mixed AGENT MONO Lithium 0. 8– 1. 2 mmol/L Divalproex 90– 125 mg/L Carbamazepine 4– 12 mcg/ml vs 800 mg Asenapine 10 mg BID sublingual Olanzapine 10– 20 mg/day Risperidone 4– 5 mg/day Quetiapine 600– 800 mg/day Ziprasidone 80– 120 mg/day Aripiprazole 15– 30 mg/day Clozapine 150– 450 mg

Mood Stabilizer Safety and Tolerability Concerns Lithium Valproate Carbamazepine Lamotrigine Gastrointestinal Weight gain Rash Neurotoxicity Tremor Neurotoxicity Headache Renal toxicity Hepatotoxicity Dizziness Thyroid toxicity Thrombocytopenia Thyroid changes Pruritis Hair Loss Blood dyscrasias Dream abnormality Cardiac toxicity Pancreatitis Cardiac toxicity Acne, Psoriasis PCOS Hyponatremia Teratogen Suicidality (? ) = boxed warning in prescribing information; (? ) = recent alert All Mood Stabilizers Have at Least One Boxed Warning In: Ketter TA (ed). Advances in the Treatment of Bipolar Disorder. 2005. Physician’s Desk Reference. 2008.

Mania/Mixed Episodes Matter • Treat the illness – Short-term high-dose benzodiazepine, sleep restoration, containment • Individualize treatment – Right medication to the right patient • Improved psychoeducation • Enhanced treatment adherence and minimize side-effect burden

Depressed State is Much More Frequent in Bipolar Patients than Hypomania NIMH Collaborative Depression Study: 13 -year follow-up of 146 bipolar patients Judd LL et al. Arch Gen Psychiatry. 2002; 59: 530 -537.

Probabilistic Approach to Bipolar Depression Bipolar I Depression more likely if ≥ 5: Symptomatology Hypersomnia Hyperphagia Psychomotor retardation Other “atypical” symptoms Psychosis and/or pathological guilt (OR=3. 3) Mood lability or manic symptoms Onset and Course Earlier onset (<25 years) (OR=1. 9) Multiple depressions (≥ 5 episodes) Family History Bipolar disorder (OR=2. 6) Confirmation of specific numbers requires further study. OR=odds ratio. From: Othmer E, et al. J Clin Psychiatry. 2007; 68(1): 47 -51. Mitchell PB, et al. Bipolar Disord. 2008; 10(1 Pt 2): 144 -152.

Progression to Bipolar Disorder from MDD with Subthreshold Hypomania Time to Hypomania or Mania Time to Hypomania Time to Mania Proportion Without Hypomania or Mania 1. 0 0. 9 0. 8 0. 7 <3 Manic symptoms ≥ 3 Symptoms 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0 260 520 780 1040 1300 1560 Weeks to Follow-up 19. 6% of patients converted to bipolar disorder during follow-up N=550 individuals followed for >1 year (mean follow-up, 17. 5 years) after a diagnosis of major depression at intake Fiedorowicz JG, et al. Am J Psychiatry. 2011; 168: 40 -48. .

Specific DSM-IV Manic Symptoms During an Index Episode of Bipolar Depression in STEP-BD 35 No mania (31. 2%) Subsyndromal mania (54. 0%) 30 Full mixed episode (14. 8%) 25 Percent of 20 Patients 15 10 5 0 0 1 2 3 4 5 6 7 Number of DSM-IV Manic Symptoms American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Publishing; 2013.

Baseline Manic Symptom Severity in Depression Prior to Antidepressant Treatment 5 2. 0 * YMRS Score 4 1. 6 3 2 CGI 1. 2 Severity Mania 0. 8 1 0. 4 0 0 TEM (n=44) ADR (n=84) ADNR (n=44) *F(2, 169)=4. 5; P<0. 01 † TEM (n=44) ADR (n=84) †F(2, 169)=3. 4; ADNR (n=494) P=0. 04 TEM=treatment-emergent mania; ADR=antidepressant responder; ADNR=antidepressant nonresponder. Frye MA, Helleman G, Mc. Elroy SL, et al. Am J Psychiatry. 2009; 166(2): 164 -172.

Increased Rates of Metabolic Syndrome in Bipolar Disorder: an International Observation NHANES III – prevalence of NCEP III-defined metabolic syndrome in general population: 23. 7% Estimates of metabolic syndrome in bipolar disorder population: 20%‒ 66% NHANES III=Third National Health and Nutrition Examination Survey. NCEP III=National Cholesterol Education Program Adult Treatment Protocol. Mc. Intyre et al. 2010.

Phenotype Obesity + MDD • Atypical features • More severe (e. g. suicide risk) • Poor cognitive performance Obesity + BD • Predominance of depressive symptoms • More severe (e. g. suicide risk) • Anxiety symptoms • Poor cognitive performance

The Needs of Patients with Bipolar Disorder Aspects of care patients would most like to see improved Better treatment of depression Lower risk of weight gain Prevention of relapse in depression Improved functionality/quality of life Lower risk of sleeping difficulties Lower risk of suicidal thoughts Lower risk of diabetes Lower risk of muscle stiffness Lower risk of sedation 0 5 10 15 20 25 30 35 40 Respondents (%) Understanding patients' Needs, Interactions, Treatment, and Expectations (UNITE) global survey of 1300 patients with bipolar disorder. Mc. Intyre 2009. 45

MADRS Response Rates Across Six Lamotrigine Acute Bipolar Depression Studies Patients (%) p=0. 005 1996– 1997 Bipolar I p=0. 8 9 1997– 1998 Bipolar I & II p=0. 21 p=0. 36 p=0. 42 2000– 2002 Bipolar I 2003– 2005 Bipolar II p=0. 03 2003– 2006 Bipolar I & II Response: ≥ 50% improvement over baseline. Pooled relative risk of response: 1. 22; confidence interval (CI) 1. 06, 1. 41; P=0. 005. MADRS=Montgomery Åsberg Depression Rating Scale. Calabrese et al 2008; Geddes et al 2009; Van der Loos et al 2009.

Bipolar I Depression: MADRS Total Score Over 8 Weeks for Olanzapine, OFC, or Placebo Time (weeks) 0 1 2 3 4 5 6 7 8 0 Placebo (n=355) Olanzapine (n=351) OFC (n=82) -5 LSM Change in MADRS Total Score -10 -15 -20 * * * * *† *† *† *p<0. 001 vs placebo for olanzapine and OFC. †p<0. 05 vs olanzapine for OFC (ITT; MMRM). Tohen et al. 2003.

Bipolar Depression: MADRS Total Score Over 8 Weeks for Quetiapine Vs Placebo BOLDER I & II and EMBOLDEN I & II Pooled Data Time (weeks) Mean Change in MADRS Total Score *** *** ***p<0. 001 vs placebo (ITT; LOCF) Pooled analysis from four randomised, double-blind, placebo-controlled studies in patients with bipolar I or II depression: BOLDER I, 5077 US/0049; BOLDER II, D 1447 C 00135; EMBOLDEN I, D 1447 C 00001; EMBOLDEN II, D 1447 C 00134. Young et al 2009.

Lurasidone Monotherapy for Bipolar Depression Change in MADRS from Baseline • 6 -week trial of lurasidone or placebo • Bipolar I depressed patients, with or without rapid cycling -10. 7 -15. 4 d =. 45 *Mean modal dose 34. 9 mg/day. †Mean modal dose = 92. 3 mg/day. Loebel A, et al. Am J Psychiatry. 2014; 171(2): 160 -168.

Add-on Lurasidone for Bipolar Depression Change in MADRS From Baseline 6 -week trial of lurasidone (20– 120 mg/day) or placebo added to lithium or divalproex in bipolar I depression MMRM: P<0. 01 -13. 5 -17. 1 Loebel A, Cucchiaro J, Silva R, et al. Am J Psychiatry. 2014; 171: 169 -177.

Lurasidone Efficacious in Bipolar Depression with Subsyndromal Hypomania Mc. Intyre RS, et al. Presented at: 166 th Annual Meeting of the APA; May 18 -22, 2013; San Francisco, CA.

Lurasidone for Mixed Depression RESOLVE Study • • 211 MDD patients with 2 or 3 manic symptoms Lurasidone 20 -60 mg/day or placebo (mean 36. 2 mg/day) MADRS primary efficacy measure CGI-S, YMRS, HAM-A secondary efficacy measures NNT was 3 and 4 for response and remission resp. Lurasidone better than placebo on all measures Nausea, insomnia, headache commonest SE Am J Psychiatry. 2015 Nov 10: appiajp 201515060770. [Epub ahead of print]

RESOLVE Study MADRS (MMRM) – Primary Endpoint LS Mean Change from Baseline Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 * Wk 6 Effect Size = 0. 80 ** *** *p<0. 05 **p<0. 01 ***p<0. 001 ITT Population BL mean = 33. 3 *** BL mean = 33. 2 Am J Psychiatry. 2015 Nov 10: appiajp 201515060770. [Epub ahead of print]

Bipolar I Depression: MADRS Total Score Over 8 Weeks for Aripiprazole or Placebo Weeks 0 1 2 3 4 5 6 7 8 -2. 0 -4. 0 -6. 0 -8. 0 -10. 0 -12. 0 -14. 0 PBO (n=177) ARI (n=162) Baseline 28. 49 29. 07 Study 1 PBO (n=176) ARI (n=175) 29. 35 29. 56 Study 2 ** * ** * P=NS at Week 8; * P ≤. 05; ** P <. 01; vs BPO. ARI=aripiprazole. ARI unapproved for acute bipolar depression. Thase ME, Jonas A, Khan A, et al. J Clin Psychopharmacol. 2008; 28: 13 -20. Improvement Mean Change in MADRS Total Score 0. 0

Ziprasidone Monotherapy Not Efficacious in Acute Bipolar Depression 0 1 2 Study 1 Study 2 Weeks 3 4 5 Mean Change in MADRS 0 0 1 2 3 4 5 0 ZIP (120– 160 mg/d) ZIP (40– 80 mg/d) PBO -2 -4 -6 -8 6 ZIP (40– 160 mg/d) -2 PBO -4 -6 * -8 -10 -12 -14 -16 -18 * * P<. 05. ZIP=ziprasidone. ZIP unapproved for acute bipolar depression. Lombardo I, Sachs G, Kolluri S, et al. J Clin Psychopharmacol. 2012; 32: 470 -478. 6

Conventional Antipsychotics Increase Severity of Depression/Dysphoria 60 Perphenazine Percentage of patients 50 Placebo 40 30 20 10 0 Discontinued from study Relapse total Relapse depression Relapse mania Side effects Zarate CA Jr, Tohen M. Am J Psychiatry. 2004; 161: 169 -171.

Antidepressant Use in Bipolar Disorder: The ISBD Task Force Consensus Report Jadad scorea Evidence levelb Antidepressant monotherapy 3 D Adjunctive antidepressants: short-term efficacy in acute depression 4 B Predictors of initial response to adjunctive antidepressants 3 D 3. 5 C Predictors of long-term responsiveness to adjunctive antidepressant treatment 3 D Antidepressant use in mania and mixed states 3 D Antidepressants and affective switch (mania, hypomania, or mixed) 4 C Are newly emerging or increasing irritability and agitation, subclinical mixed states during antidepressant treatment a form of mood switching? 3. 5 D Antidepressants and cycle acceleration 3. 5 D 3 D Topic Adjunctive antidepressants: maintenance studies Antidepressants and suicidality a. The Jadad score indicates study methodological quality from 0 to 5, with higher scores indicating higher quality b. Grades for evidence level from A (excellent) to D (poor). Pacchiarotti et al. 2013.

Adjunctive Levothyroxine in Bipolar Depression: A Randomized, Double-Blind, Placebo-Controlled Study Women (n=32) Total study group (n=62) Placebo (n=31) Levothyroxine (n=31) Placebo (n=15) Levothyroxine (n=17) 16 * 14 24 24 22 22 20 20 18 16 * 14 * 12 12 0 1 2 3 4 5 6 Placebo (n=16) Levothyroxine (n=14) HAM-D Mean 24 HAM 22 D score 20 18 Men (n=30) 0 Time (weeks) 1 2 3 4 5 Time (weeks) 6 18 16 14 12 0 1 2 3 4 5 6 Time (weeks) *p<0. 05 vs placebo (ITT; LOCF). Adjunctive levothyroxine (300 µg/day) or placebo in patients with bipolar I or II disorder. HAM-D=Hamilton rating scale for depression. Stamm et al 2013.

Novel Treatments for Bipolar Depression • • Modafinil/Armodafinil Pramipexole N-acetyl cysteine Ketamine Riluzole Insulin sensitizers Anti-inflammatory agents All agents unapproved for acute bipolar depression. Adapted from: Mc. Intyre R, et al. Psychiatric Times. April 11, 2011. http: //www. psychiatrictimes. com/bipolar-disorder/content/article/10168/1846994. Accessed March 12, 2013.

• • 8 -week randomized comparison of armodafinil 150 mg/day (n=128) vs placebo (n=129) added to lithium, olanzapine, or divalproex for bipolar depression Two negative studies Mean ± SEM IDS-C 30 Total Score Adjunctive Armodafinil in Bipolar Depression 40 Mean ± SEM Change from Baseline in Total Score on 30 -Item Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C 30) for Patients With Bipolar Depression Receiving Adjunctive Armodafinil 150 mg/d versus Placebo 35 30 25 * 20 ** ** 15 10 5 Armodafinil (n=124) Placebo (n=123) 0 Base- Week line 1 2 3 4 *P=0. 027 (ANCOVA) versus placebo; **P=0. 044 (ANOVA) and P=0. 074 (ANCOVA) versus placebo. ANCOVA, analysis of covariance, ANOVA, analysis of variance. Calabrese JR, Ketter TA, Youakim JM, et al. J Clin Psychiatry. 2010; 71(10): 1363 -1370. Visit Week 6 Week 8 Final Visit

Treatment-Resistant Bipolar Depression: ECT vs Pharmacological Treatment A Linear mixed-effects analysis showed that the mean score at 6 weeks was 6. 6 points lower in the ECT group (SE=2. 05, 95% CI=2. 5– 10. 6, p=0. 002). Schoeyen H K, et al. Am J Psych. 2015; 172(1): 41 -51.

Treatment of Acute Bipolar Depression LEVEL 1 A- Established efficacy* v. Quetiapine monotherapy (bipolar disorder I & II) v. Lurasidone monotherapy (bipolar disorder I) v. Lurasidone or quetiapine adjunctive to lithium or divalproex (biopolar disorder 1) LEVEL 1 B – Established efficacy, but with safety concerns* v. Olanzapine + fluoxetine (bipolar disorder I) *Note. Tolerability limitations include sedation and weight gain. LEVEL 2 – Established tolerability, but limited efficacy* Consult Specialist v. Lithium (bipolar disorder I) v. Lamotrigine adjunctive to lithium (bipolar disorder I) v. Lamotrigine (bipolar disorder I) v 2 drug combination of above medications *Note. Efficacy limitations include negative randomized controlled trails but positive meta-analyses. Florida Medicaid Drug Therapy Management Program for Behavioral Health. January 2014.

Treatment of Acute Bipolar - Depression LEVEL 3 – If levels 1 and 2 are ineffective or treatment not tolerated* v. Electroconvulsive therapy (ECT) *Note. Consideration merited due to clinical need, despite even greater efficacy/tolerability limitations than level 1 and 2 treatments. LEVEL 4 – If levels 1 -3 are ineffective or treatment not tolerated v. Transcranial Magnetic Stimulation (TMS) v. Antimanic therapy + (FDA approved medication for major depression)* v. Pramipexole v. Adjunctive – modafinil, thyroid, or stimulants v 3 drug combination *Note. There is inadequate information (including negative trials) to recommend adjunctive antidepressants, aripiprazole, ziprasidone, levetiracetam, armodafinil, or omega-3 fatty acids for bipolar depression. Florida Medicaid Drug Therapy Management Program for Behavioral Health. January 2014.

Numbers Needed to Treat vs Numbers Needed to Harm Olanzapine/Fluoxetine Quetiapine Lurasidone NNT NNH 4 (response) 5 (remission) 7 (weight gain) 9 (diarrhea) 6 (weight gain >7% from baseline) 6 5 (sedation) 5 17 (nausea) 15 (akathisia) 25 (sedation) -493 (weight gain) NNH, number needed to harm; NNT number needed to treat. Citrome L. Expert Opin Pharmacother. 2011; 12(17): 2751 -2758; Ketter TA, et al. Acta Psychiatr Scand. 2011; 123(3): 175 -189; Loebel A, et al. Am J Psychiatry. 2014; 171(2): 160 -168.

Antipsychotics: Adverse Events Adverse Event ARI ASE CLZ ILE LUR OLZ QTP RIS ZIP Metabolic Weight gain Dyslipidemia Glucose dysregulation +/0 0 0 ++++ ++ 0 0 +/0 0 0 +++ ++ ++ + + +/0 0 0 Neurological Somnolence/sedation EPS + + 0/+ 0 ++++ 0 0 0/+ +++ 0 ++ ++ + + Hormonal Prolactin 0 0 0 +/0 0 ++ 0 ARI=aripiprazole; ASE=asenapine; CLZ=clozapine; ILE=iloperidone; LUR=lurasidone; OLZ=olanzapine; QTP=quetiapine; RIS=risperidone; ZIP=ziprasidone. Cha DS, Mc. Intyre RS. Expert Opin Pharmacother. 2012; 13: 1587 -1598.

Variables Influencing Functional Outcomes in Bipolar Disorder Sociodemographic Variables Age, male gender, low premorbid psychosocial functioning Clinical Variables Age of onset, # of episodes, hospitalizations, Subthreshold symptomatogy, rapid cycling, medical or psychiatric comorbidity Neurocognitive Variables Neurocognitive dysfunction (attention, verbal memory, executive functions) Environmental Variables Social and family support, policies, perceived stigma Pharmacological Variables # drugs, side effects Sánchez-Moreno et al. Psychother Psychosom. 2009.

What Can Be Done to Improve Cognition and Functioning in Bipolar Disorder? • Prevention of cognitive impairment – Effective pharmacotherapy for relapse prevention – Psychoeducation • Treatment of cognitive impairment – Treating subthreshold depression – Treating comorbidities – Rational use of drugs – Cognitive enhancers – Cognitive remediation Vieta. Management of bipolar disorder in clinical practice. 3 rd Ed. CMG, London. 2013.

Functional Remediation Trial in Bipolar Disorder Double-blind, randomized design 10 centers N=239 Bipolar I and II patients in remission Functional Remediation n=77 Psychoeducation n=82 FAST >18 A score of 4 or more in the FAST cognitive domain and 2 or more in another domain Treatment as usual n=80 Primary endpoint: FAST change from baseline Randomization -3 Months Week 0 Week 21 Torrent et al. Am J Psychiatry. 2013. Week 52

Functional Remediation in Bipolar Disorder Changes in Functional Impairment Scores Before and After Intervention in Patients with Bipolar Disorder Functional Remediation Psychoeducation Treatment as Usual 34 Functioning Assessment Short Test Score, Mean (SE) 32 30 28 26 24 22 20 0 Pre-treatment Assessment Post-treatment Assessment Higher scores indicate greater impairment. Functional remediation programme consisting of 21 weekly sessions lasting 90 minutes. Change for the functional remediation group was significantly different from change for the treatment-as-usual group (Pillai’s Trace=0. 065; F=6. 51; P=. 002) SE=standard error. Torrent C, Bonnin Cdel M, Martinez-Aran A, et al. Am J Psychiatry. 2013; 170(8): 852 -859.

Conclusions • Bipolar depression and mixed episodes are the predominant presentation • Atypicals are the choice treatment in mixed features • All atypicals are not efficacious in bipolar depression • Psychosocial treatments are critical in most patients • Attention to physical health outcomes is critical to preventing and treating bipolar depression: i. e. metabolic morbidity as brain hazard

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