Solving Clinical Challenges in Bipolar Disorder

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1 Overview Bipolar Disorder Solving Clinical Challenges Solving Clinical Challenges in Bipolar Disorder Terence A. Ketter, MD Professor Emeritus Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine Stanford, California 1. Diagnostic Nosology Challenges distinguishing bipolar from unipolar 2. Pharmacologic Treatment Challenges with therapeutic vs side effects 3. Adverse Events Challenges with weight gain/sedation and akathisia 4. Non-Pharmacologic Treatment Challenges with access to evidence-based Rx Ketter TA (Ed). Advances in Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 215. Diagnostic Boundaries of Bipolar Disorder I. Diagnostic Nosology Challenges with Accurate Diagnosis Complex, variable phenomenology Different subtypes, mood states, courses, age-dependent presentations Crucial differential diagnosis MDD Confounding comorbidities Substance abuse, anxiety disorders Disruptive behavioral (ADHD, ODD, CD), cluster B disorders Measures to enhance diagnostic accuracy Collateral information DSM Screening Mood Disorders Questionnaire Beyond DSM Onset age, atypical symptoms, course, treatment effects, family history ADHD = attention-deficit/hyperactivity disorder; CD = conduct disorder; MDD = major depressive disorder; ODD = oppositional defiant disorder. Bipolar Disorders Symptoms are Chronic and Predominantly Depressive 146 BD-I Patients followed 12.8 years 8.9% 31.9% 5.9% 52.7% Percent of Weeks Asymptomatic Depressed Elevated 86 BD-II Patients followed 13.4 years 5.3% 1.3% 2.3% 46.1% Cycling / mixed Dep:Elevated/Cycling/mixed = 2.2:1 Dep:Elevated/Cycling/mixed = 14:1 Judd LL, et al. Arch Gen Psychiatry. 22;59(6): Judd LL, et al. Arch Gen Psychiatry. 23;(3): Diagnostic Challenges Question 1 Patients are famous for underestimating the number and intensity of past manic or hypomanic episodes, which can lead a clinician to inappropriately diagnosing these patients with a unipolar condition. Do you have any tips for how we can better flush out past manic type phenomena when we are first assessing a new patient?

2 Diagnostic Challenges I Patients present with depression more than mood elevation Get collateral history from significant other (more sensitive rater of mood elevation) Look for mood elevation symptoms Immediately before or after depressions Triggered by pharmacotherapy Mixed depressions In depressed patients, assess bipolar outcome risk factors Depression onset prior to age 25; lifetime history of psychosis, 1 relative with mania Presence of 1 risk factor doesn t substantively increase bipolar outcome risk (which is approximately 25% overall) In contrast, 2 or 3 risk factors substantively increase bipolar outcome risk (to approximately 5% and 67%, respectively) Substance/Medication-Induced Bipolar and Related Disorder Prominent, persistent elevated/irritable/expansive and/or depressed mood/anhedonia During/soon after substance intoxication/withdrawal or medication exposure Substance/medication capable of producing above mood symptoms Not better explained by non-substance induced bipolar disorder eg, Symptoms persist < 1 month without substance/medication Not merely delirium Distress, social/occupational impact American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 213. Elevation Depression Antidepressant Treatment-Emergent Evolution of Bipolar I Disorder from MDD Severe Moderate Mild None Mild Moderate Severe MDD, Single Episode, Moderate (296.22) 14 days Antidepressant Antidepressant discontinued 7 days or hospitalization Bipolar I Disorder, Manic (296.4) Ketter TA (Ed). Handbook of Diagnosis and Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 21. Antidepressant-Induced Mania More Common in Bipolar II Compared to Unipolar Depression Switching to Mania (%) Meta-Analysis from Clinical Trials Unipolar Depression Bipolar II Depression 11.2% 3.7% 4.2% 2.5%.7%.2% , = N Significance: TCA = SSRI > Placebo TCA > SSRI = Placebo SSRI = selective serotonin reuptake inhibitor (fluoxetine, fluvoxamine, paroxetine, or sertraline); TCA = tricyclic antidepressant. Peet M. Br J Psychiatry. 1994;164(4): Bipolar Mixed State Conceptualization in DSM-IV-TR vs DSM-5 Main Changes for Bipolar and Related Disorders in DSM-5 Compared to DSM-IV-TR with mixed features specifier added for Manic, Hypomanic, and Major Depressive Episodes Manic Episode with mixed features replaces Mixed Episode Antidepressant switching full Manic/Hypomanic Episode emerging during antidepressant treatment and persisting beyond physiological treatment effect now sufficient for Manic/Hypomanic Episode Hu J, et al. Prim Care Companion CNS Disord. 214;16(2). American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 213.

3 DSM-5 Major Depressive Episode with mixed features (AKA Mixed Depression) Predominant, full depressive episode and 3 most days: Elevated / expansive mood Inflated self-esteem / grandiosity Overtalkativeness Racing thoughts Increased goal-directed activity Impulsivity Decreased sleep need Mixed symptoms objectively evident, not usual behavior Mania trumps depression Not due to substance / medication Overlapping Symptoms Not Included in DSM-5 Mixed Specifier Symptoms characteristic of both poles: Psychomotor agitation (?) Distractibility Irritability Insomnia per se Indecisiveness American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 213. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 213. History of Bipolar I Disorder in Outpatients with History of Major Depressive Episode Percentage among Patients with History of Mania Risk Factor Odds Ratio History of psychosis 3.28 First-degree relative with mania 2.56 Depression onset < 25 years 1.93 Overall 26.9% (2/744) 14.7% (32/217) 19.3% (62/322) 48.8% (84/172) 66.7% (22/33) None One Two Three Number of Risk Factors Mean age = 37.5 years; P <.1. Data from Othmer E, et al. J Clin Psychiatry. 27;68(1): Ketter TA (Ed). Handbook of Diagnosis and Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 21. Diagnostic Challenges II Additional bipolar outcome risk factors Atypical depressive symptoms Hyperphagia, hypersomnia, anergia Episode accumulation ( 5 lifetime depressions) Postpartum mood elevation Comorbid anxiety/substance use disorder 3 consecutive generations with mood disorders Hyperthymic/cyclothymic temperament Akiskal HS, et al. J Affect Disord. 1983;5(2): Akiskal HS, et al. Arch Gen Psychiatry. 1995;52(2): Geller B, et al. Am J Psychiatry. 21;158(1): Goldberg JF, et al. Am J Psychiatry. 21;158(8): Patients (%) Most Bipolar Disorder Patients Have at Least 1 Comorbid Axis I Disorder None Number of Lifetime Comorbid Axis I Disorders McElroy SL, et al. Am J Psychiatry. 21;158(3): All BD BD-I BD-II Probabilistic Approach to Bipolar Depression Bipolar I Depression if 5: Unipolar Depression if 4: Symptomatology Hypersomnia Hyperphagia Psychomotor retardation Other atypical symptoms Psychosis and/or pathological guilt Mood lability or manic symptoms Onset and Course Earlier onset (< 25 years) Multiple depressions ( 5 episodes) Family history Bipolar disorder Insomnia Decreased appetite Psychomotor agitation Somatic complaints Confirmation of specific numbers requires further study. Adapted from Mitchell PB, et al. Bipolar Disord. 28;1(1 Pt 2): Later onset (> 25 years) Long current depression (> 6 months) No bipolar disorder

4 Summary of Clinical Features of Risk of Bipolar Diathesis in Depression Onset Early, postpartum Depressive episodes Hypersomnic-retarded, catatonic, psychotic Acute, severe, psychotic Comorbidity Substance abuse, minor antisocial acts Course Long, tempestuous course; brief well intervals Educational, marital, occupational disruption Temperament Mood lability, energy-activity, daydreaming (BD-II) Family history Bipolar / 3 consecutive generation mood disorder Treatment response Pharmacologic hypomania (counts as BD-II in DSM-5) Akiskal HS, et al. J Affect Disord. 1983;5(2): Akiskal HS, et al. Arch Gen Psychiatry. 1995;52(2): Geller B, et al. Am J Psychiatry. 21;158(1): Goldberg JF, et al. Am J Psychiatry. 21;158(8): Diagnostic Challenges Question 2 What are the strengths and limitations of DSM-5 when it comes to depressive episodes with mixed features? DSM-5 Bipolar Diagnostic Strengths and Limitations DSM-5 permits mixed depressions in both bipolar disorder and unipolar major depression This could be good, allowing unipolar major depression subtyping and avoiding a bipolar disorder over-diagnosis DSM-5 doesn t categorize concurrent threshold-level hypomania and MDD permitting diagnosis of major depressive episode with mixed features or hypomanic episode with mixed features This could be good, permitting predominant pole emphasis DSM-5 mixed depression requires 3 (rather than 2) nonoverlapping opposite pole symptoms (ie, excludes psychomotor agitation, distractibility, and irritability) This could be bad, making mixed depression too uncommon and not acknowledging importance of psychomotor agitation in depression American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 213. Kim W, et al. Acta Psychiatr Scand. 216;134(3): ; Diagnostic Challenges Question 3 What tools do you use in clinical arenas as standard measures of symptomology in bipolar disorder? Clinical Status Assessment Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) used the Clinical Monitoring Form (CMF) to establish Clinical Status at each visit STEP-BD CMF Clinical Statuses included 4 DSM-IV syndromal episodes (Depressed, Hypomanic, Manic, Mixed) 2 subsyndromal states (Continued Symptoms, Roughening) 2 euthymic states (Recovered, Recovering) Clinical Statuses indicated if new mood interventions were Practically mandated (for syndromal episodes) Elective (for subsyndromal states) Commonly avoided, unless side effects (for euthymic states) Sachs GS, et al. Bipolar Disord. 22;4(5): II. Treatment Challenges with Pharmacotherapy

5 Pharmacologic Challenges Question 1 New 17-year-old female patient with first serious depression, with profound slowing and hypersomnia, but has anorexia instead of hyperphagia. Mother and maternal grandfather had bipolar I disorder. Would you commence an antidepressant in this young lady or would you treat her from the start with bipolar medications? Balancing Therapeutic and Adverse Effects Benefit (Efficacy) - NNT Number of patients for 1 more good outcome Lower is better Preferably single-digit Risk (Tolerability) NNH Number of patients for 1 more poor outcome Higher is better Preferably at least double-digit Benefit:Risk Ratio (NNT vs NNH) Want more benefit than risk Strive for NNT lower than NNH Clinical urgency affects treatment selection Urgent prioritize efficacy Non-urgent prioritize tolerability NNT = Number Needed to Treat; NNH = Number Needed to Harm. Ketter TA (Ed). Handbook of Diagnosis and Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 21. Psychotropic Medication Adverse Effect Schematic Tolerability- First Approach Adverse effect risk over placebo (NNH) Medication Class Pharmacologic Challenges Question 2 More Adverse Effects (Go here if necessary) Medium (5 1%) (NNH = 1 2) Low (< 5%) (NNH > 2) Fewer Adverse Effects (Start here if appropriate) Ketter TA, et al. J Affect Disord. 214;169 Suppl 1:S24-S33. High (> 1%) (NNH < 1) CLZ OLZ RSP, QTP ZIP, ARI, ASN, ILO LUR, BREX, CARI Li, VPA, CBZ LTG FLX, SERT, PAR, BUP, MIRT, (ES)CIT, DLX, (DES)VEN, VTX, VIL, L-MILNA Older Newer SGAs Older Mood Stabilizers Newer Antidepressants How early in treatment should we be using lithium? Pharmacologic Challenges Answer FDA-Approved Agents for Bipolar Disorder Acute Mania Acute Depression Longer Term Year Drug Year Drug Year Drug Use lithium early in treatment (generally before antipsychotics, but commonly after psychotherapy/antidepressants/lamotrigine) especially for acute and preventive treatment of mood elevation. Ketter TA (Ed). Handbook of Diagnosis and Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; Lithium 1973 Chlorpromazine 1994 Divalproex, ER (25) 2 Olanzapine* 23 Risperidone* 24 Quetiapine, XR (28)* 24 Ziprasidone 24 Aripiprazole* 24 Carbamazepine ERC 29 Asenapine* 215 Cariprazine 23 Olanzapine+fluoxetine combination 26 Quetiapine, XR (28) 213 Lurasidone* Unmet Need 1974 Lithium 23 Lamotrigine 24 Olanzapine 25 Aripiprazole* 28 Quetiapine, XR (adjunct) 29 Risperidone LAI* 29 Ziprasidone (adjunct) Unmet Need *Adjunctive and monotherapy. ER, XR, ERC = extended release oral; LAI = long-acting injectable. Important unmet needs well-tolerated treatments for acute depression and maintenance.

6 Most Common/Problematic Side Effects III. Side Effects Management during Pharmacotherapy Ariov T (216) The Top 5 Side Effects of Psychotropics and How to Manage Them 1. Weight Gain 2. Anhedonia and Emotional Flattening 3. Sleep Disturbances 4. Sexual Dysfunction 5. Hyperprolactinemia Ketter TA (21) 1. Weight Gain (3 questions from 217 Psych Congress attendees) How to address weight gain in bipolar disorder? Specific weight gain management tips (beyond usual diet and exercise)? How to deal with weight gain and antimanic agents? 2. Akathisia (1 question from 217 Psych Congress attendees) How to address antipsychotic akathisia in bipolar depression? Ariov T. Psych Congress Network. Accessed June 6, 217. Ketter TA (Ed). Handbook of Diagnosis and Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 21. Managing Medication Side Effects Carefully assess baseline (eg, BMI, drowsiness, agitation/anxiety) Prior to intervention, warn of side/adverse effect risks Especially weight gain/sedation and akathisia Assess specific adverse effects risks (eg, weight/sedation/akathisia) Age, gender, baseline weight/sedation/akathisia, medical disorders, medications Assess both potential benefits and harms of interventions Consider current mood state Affects antidepressant/antipsychotic need/tolerability Side Effect Challenges Question 1 How to address weight gain in bipolar disorder? BMI = body mass index. Ketter TA (Ed). Handbook of Diagnosis and Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 21. Pharmacotherapy and Weight Gain in Bipolar Disorder Limited FDA-approved weight control treatments Commonly not covered by insurance Antidepressants (before Mood Stabilizers) Bupropion, non-paroxetine SSRIs, SNRIs Before mirtazapine, paroxetine, MAOIs, TCAs Mood Stabilizers (before Antipsychotics) Lamotrigine before lithium, before valproate Carbamazepine in reserve for manic symptoms (less weight gain risk vs lithium, valproate) But more treatment complexity (drug interactions and side effects) Antipsychotics (only if absolutely necessary) Cariprazine, lurasidone, aripiprazole before quetiapine before risperidone Ziprasidone (weight loss, but akathisia/unpredictable mood effects) in reserve Olanzapine/clozapine (profound weight gain risk, but superior mood efficacy) in reserve Very low dose olanzapine (1.25 mg/day) or clozapine (12.5 mg/day) may limit weight gain Olanzapine-fluoxetine combination minimal olanzapine, maximal fluoxetine 7% gain potentially significant, > 5 lb gain in 1st 3 weeks ultimate catastrophic risk Ketter TA (Ed). Handbook of Diagnosis and Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 21. Adjunctive Non-Stimulant Medications to Counter Weight Gain in Bipolar Disorder Topiramate 1 2 mg/day off-label, also 92 mg/day + 15 mg/day phentermine in Qsymia onlabel, independently off-label Zonisamide 3 4 mg/day off-label Metformin 2 mg/day off-label Bupropion 3 45 mg/day off-label, also 3 mg/day + 32 mg/day naltrexone in Contrave onlabel, independently off-label Naltrexone 5 mg/day off-label, also 32 mg/day + 3 mg/day bupropion in Contrave onlabel, independently off-label Liraglutide (daily subcutaneous injections) on-label From experienced medical provider Orlistat 3 mg/day on-label, but commonly yields diarrhea Some brand names are listed for participant clarification purposes only. No product promotion should be inferred.

7 Adjunctive Stimulant/Stimulant-like Medications to Counter Weight Gain in Bipolar Disorder Some agents have abuse potential Long half-life agents for evening appetite attenuation, less abuse risk Can yield anxiety/agitation/restlessness Lower doses, anxiolytics/dopamine blockers may address such problems Lisdexamfetamine 7 mg/day off-label Phentermine 37.5 mg/day on-label, also 15 mg/day + topiramate 92 mg/day in Qsymia onlabel, independently off-label Armodafinil 25 mg/day off-label Atomoxetine 25 mg/day off-label Levomilnacipran 12 mg/day off-label Lorcaserin (heart valve risk?) on-label From experienced medical provider Some brand names are listed for participant clarification purposes only. No product promotion should be inferred. Side Effect Challenges Question 2 How to address antipsychotic akathisia in bipolar depression? Pharmacotherapy and Akathisia in Bipolar Disorder No FDA-approved anti-akathisia treatment Reducing dose(s) of offending agent(s) commonly most helpful Anxiolytics/calming agents (before Mood Stabilizers?) Lorazepam abuse potential; pramipexole/mirtazapine mood destabilization potential Mood Stabilizers (before Antipsychotics) Lithium, valproate, carbamazepine, lamotrigine unlikely to exacerbate akathisia Antipsychotics (before Activating Agents) Quetiapine before risperidone before olanzapine before clozapine before Lurasidone before cariprazine/aripiprazole (akathisia risks) Ziprasidone (akathisia risk and unpredictable mood effects) in reserve Olanzapine/clozapine (superior efficacy, low akathisia risk, but high weight gain risk) in reserve Off-label brexpiprazole may have utility in some patients Activating Agents (only if absolutely necessary) Activating (eg, levomilnacipran) only after calming (eg, paroxetine) antidepressants Stimulants/Stimulant-like agents commonly need to be avoided IV. Treatment Challenges with Non-pharmacologic Treatments Non-Pharmacologic Treatment Challenges Question 1 Which non-pharmacologic treatments for bipolar disorder do you offer and what are their success rates? Adjunctive Non-Pharmacologic Treatments for Bipolar Disorder Adjunctive Evidence-Based Psychotherapies CBT, IPSRT, Family-Focused, Psychoeducation, Functional Remediation Single-digit NNTs Adjunctive Neuromodulation TMS, ECT, ± DBS Some have single-digit NNTs Success rates comparable to approved pharmacotherapies Single-digit NNTs CBT = cognitive-behavioral therapy; DBS = deep brain stimulation; ECT = electroconvulsive therapy; IPSRT = interpersonal and social rhythm therapy; TMS = transcranial magnetic stimulation. Ketter TA (Ed). Advances in Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 215.

8 Non-Pharmacologic Treatment Challenges Questions 2 and 3 What non-pharmacologic treatments do you recommend to a busy community-based psychiatrist? Which forms of psychotherapy have the strongest supportive evidence in treatment of bipolar disorder? Overview of Adjunctive Psychosocial Maintenance Studies NNT for Relapse/Recurrence Prevention, Rates Relapse/Recurrence (%) Contemporary Manualized Intensive Psychotherapy Studies After Sustained Recovery After Acute Episode When Euthymic / Subsyndromal NNT Psychoeducation Group vs Non-structured Group *** 25.% 66.7% 91.7% Family Focused Therapy vs Crisis Management ** 18.8% 35.5% % Cognitive Therapy vs No Psychotherapy 75.% Psychoeducation Non-structured Family Focused Crisis Cognitive No Group Group Therapy Management Therapy Psychotherapy Colom 3 Miklowitz 3 Lam 3 7 ** 31.3% 43.8% = N **P <.1, ***P <.1 vs control. Psychotherapies Ketter TA (Ed). Advances in had Treatment single-digit of Bipolar Disorders. NNTs, Arlington, comparable VA: American to approved Psychiatric Publishing, pharmacotherapies. Inc.; 215. Symptomatic Much More Than Functional Recovery in Bipolar Disorder Patients (%) Months after Hospitalization 78% (33/42) Mild or No Affective Symptoms Dion GL, et al. Hosp Community Psychiatry. 1988;39(6): % (9/42) Employed Full Time at Expected Level 21 Weekly 9-Minute Adjunctive Functional Remediation (but not Psychoeducation) Sessions Diminished Dysfunction in Recovered Bipolar Disorder Patients Functional Impairment (Functioning Assessment Short Test) Pre-Treatment ±P <.6 vs PE; **P <.1 vs TAU. Error bars are SEs of means. Completion rates: FR 71.4%, PE 75.6%, TAU 82.5% (NS). FR = Paper-and-pencil tasks/group exercises for memory, attention, problem solving, reasoning, multitasking, and organization. Torrent C, et al. Am J Psychiatry. 213;17(8): Functional Remediation (n = 77) Psychoeducation (n = 82) Treatment-As-Usual (n = 8) ±, *** Post-Treatment Improvement from Baseline Effect Size Conclusions Bipolar Disorder Solving Clinical Challenges 1. Diagnostic Nosology Challenges distinguishing bipolar from unipolar 2. Pharmacologic Treatment Challenges with therapeutic vs side effects 3. Adverse Events Challenges with weight gain/sedation and akathisia 4. Non-Pharmacologic Treatment Challenges with access to evidence-based Rx Ketter TA (Ed). Advances in Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 215. Practical Take-Aways Bipolar Disorder Solving Clinical Challenges Diagnosis Collateral significant other history crucial Pharmacologic Treatment Prioritize FDA-approved interventions Adverse Effects Balance therapeutic AND adverse effects, integrating urgency Antidepressants before mood stabilizers before antipsychotics Non-Pharmacologic Treatment Psychoeducation, Family-Focused, IPSRT, CBT Functional Remediation Ketter TA (Ed). Advances in Treatment of Bipolar Disorders. Arlington, VA: American Psychiatric Publishing, Inc.; 215.