CHALLENGES IN THE MANAGEMENT OF BIPOLAR DISORDER
Learning Objectives •Implement evidence-based treatment for patients with bipolar disorder • Address common clinical challenges in the treatment of bipolar disorder
More Specifically, When We’re Done, You Will Know… How to recognize and use moderators and mediators of treatment outcome to tailor individualized pharmacotherapy How to implement evidence-based pharmacotherapy in routine clinical practice When to use or not use antidepressants in bipolar disorder How to differentiate among antidepressant properties of second generation antipsychotics When to discontinue antipsychotics after an index episode How to recognize niche roles for specific mood stabilizers How to manage common psychiatric comorbidities in bipolar disorder How to manage common adverse effects of medications for bipolar disorder ALL IN UNDER 90 MINUTES!
Matching: Brokering the Best Fit Clinical Domains Moderators and Mediators Medications Mania Age Lithium Depression Sex Divalproex Mixed features Race Carbamazepine Psychosis Age at onset Lamotrigine Rapid cycling Familiality Topiramate Attentional problems Pharmacogenetics Gabapentin Anxiety Baseline severity Monoaminergic antidepressants Alcohol/substance use disorders Polarity proneness OFC, QUET, LURAS, CARIP Impulsive aggression Episode number Other SGAs Affective instability Chronicity Stimulants Overweight/metabolic dysregulation Past treatment response Hormones (e.g., T4) Insomnia Psychosocial stressors Calcium channel blockers Suicidality BP I vs. BP II Ketamine
Matching: Brokering the Best Fit Clinical Domains Moderators and Mediators Medications Mania Age Lithium Depression Sex Divalproex Mixed features Race Carbamazepine Psychosis Age at onset Lamotrigine Rapid cycling Familiality Topiramate Attentional problems Pharmacogenetics Gabapentin Anxiety Baseline severity Monoaminergic antidepressants Alcohol/substance use disorders Polarity proneness OFC, QUET, LURAS, CARIP Impulsive aggression Episode number Other SGAs Affective instability Chronicity Stimulants Overweight/metabolic dysregulation Past treatment response Hormones (e.g., T4) Insomnia Psychosocial stressors Calcium channel blockers Suicidality BP I vs BP II Ketamine OFC: olanzapine-fluoxetine combo; QUET: quetiapine; LURAS: lurasidone; CARIP: cariprazine
Am J Psychiatry 2016;173:672-9. Moderators : (“who should get the treatment”) Mediators : (“how to get the best treatment Baseline characteristics that influence outcome: outcomes”) • Age at onset Factors that influence treatment outcome after • Baseline severity treatment has begun • Chronicity • Treatment adherence • Episode number • Drug-drug interactions • Polarity proneness • Therapeutic alliance • Sex • Stressful life events after treatment has begun • Rapid cycling • Adverse drug effects or nocebo effects • Comorbidities • Hx of childhood trauma "Ignored moderators may be one explanation for why • Familiality so many psychiatric treatments appear to have such • Poor metabolizer genotype low effectiveness." (Kraemer, 2016)
Moderators and Mediators of Outcomes in Clinical Trials "It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has” ( Sir William Osler) Moderators : (“who should get the treatment”) Mediators : (“how to get the best treatment Baseline characteristics that influence outcome: outcomes”) • Age at onset Factors that influence treatment outcome • Baseline severity after treatment has begun • Chronicity • Treatment adherence • Episode number • Drug-drug interactions • Polarity proneness • Therapeutic alliance • Sex • Stressful life events after treatment has • Rapid cycling begun • Comorbidities • Adverse drug effects or nocebo effects • Hx of childhood trauma • Familiality • Poor metabolizer genotype Kraemer et al. Am J Psychiatry 2016;173:672-9.
Mood Stabilization: Above vs. Below Baseline Ketter, Calabrese. J Clin Psychiatry 2002;63:146-51.
Why Isn’t Lamotrigine FDA-Approved for Bipolar Depression? Or: Why Baseline Severity is a Critical Outcome Moderator Moderate High Baseline Baseline severity Severity Lamotrigine 48% 45% Response Rate Placebo 45% 30% Response Rate Geddes et al. Br J Psychiatry 2009;194:4-9. LAMLIT: Lamotrigine+Lithium
Challenge: High Placebo Response Rates and Failed Trials Pooled response rate =31% (95% CI=28-33%) 1 Bipolar Mania: Bipolar Depression: •Low baseline severity 1 • Low baseline severity 3 •Absence of psychosis 2 • Longer duration of •Women 1 treatment 3 •Older age 1 Other clinical correlates of placebo responsivity: dispositional optimism; external locus of control; novelty-seeking; neuroticism; favorable expectancy 4 1 Yildiz et al. Int J Neuropsychopharmacol 2011;14:863-75; 2 Welten et al. Eur Neuropsychopharmacol 2015;25:1018-26; 3 Nierenberg et al. Int Clin Psychopharmacol 2015;30:59-66; 4 Goldberg & Stahl. Practical Psychopharmacology. Cambridge Univ Press, in press.
The Damn Placebo Effect: N-Acetylcysteine in Bipolar Depression 20-week RCT of NAC (3 gms/day; N=80) or placebo (n=80) No significant difference in MADRS scores by mixed regression Placebo response rate= 55.6% Ellegaard et al. J Affect Disord 2019;245:1043-51.
More on Moderators: Episode Number and Antimanic Response Swann et al. Am J Psychiatry 1999;156:1264-6.
More on Outcome Moderators: Polarity Proneness NNT: Number needed to treat Popovic et al. Eur Neuropsychopharmacol 2012;22:339-46.
Antidepressants: Class Effect? All Bad? Some Good? Sachs et al. N Engl J Med 2007;356:1711-22.
Don’t Use Antidepressants in Bipolar Depression with Mixed Features Stanley Bipolar Network: antidepressants 355 STEP-BD entrants with major depression with >1 manic exacerbate mania when low-grade baseline mania symptoms symptoms are present Interaction Effect: Antidepressant use x # of mania symptoms at baseline = higher YMRS score after 3 months (p=.003) Goldberg et al. Am J Psychiatry 2007;164:1348-55. Frye et al. Am J Psychiatry 2009;166:164-72.
When to Use or Not Use Antidepressants: Sustained Improvement Only if Robust Acute Response 69% 35% 13% 27% 23% 13% OR (1-year response: 5.89, p<.001) 9% Altshuler et al., J Clin Psychiatry 2009; 70: 450-457
Antidepressants in BP II Depression Fluoxetine monotherapy for relapse prevention in bipolar II depression But: the results pertain to initial fluoxetine responders - 148 received open label fluoxetine monotherapy for 12 weeks Wow— fluoxetine looks even - 49.7% recovered and were then better than randomized to fluoxetine (mean dose lithium! 34 mg/day) vs. lithium (mean dose 1027 mg/day, mean serum [Li + ]=0.69 mEq/L vs placebo Amsterdam & Shults. Am J Psychiatry 2010;167:791-800.
Antidepressants in BP II Depression Comparable response rates over study period No difference in switch rates: Lithium=14%; Sertraline=17%; Both=10% Altshuler et al. Am J Psychiatry 2017;174:266-76.
Can Pharmacogenomics Help Gauge Risk for Antidepressant- Induced Mania? Serotonin Transporter Gene (SLC6A4) and Risk for Antidepressant-Induced Mania “s” allele: RR=1.35 (95% CI=1.04-1.76, p=.02) Daray et al. Bipolar Disord 2010;12:702-6.
When to Use or Not Use Antidepressants in Bipolar Depression Favors Antidepressant Use Discourages Antidepressant Use BP II BP I Pure depressed episodes Mixed features Absence of rapid cycling Past year rapid cycling Absence of recent Mania/hypomania in past 2–3 months mania/hypomania Absence of comorbid Alcohol or substance use comorbidity alcohol/substance use disorders Prior favorable antidepressant Suboptimal responses to prior response antidepressants No history of antidepressant- History of antidepressant-induced mania/ induced mania hypomania Goldberg & Stahl. Practical Psychopharmacology, Cambridge Univ Press 2020.
Randomized Trials of D2/D3 Partial Agonists in Bipolar Depression Agent D3 Ki RCTs in Bipolar Depression Aripiprazole 0.8-9.7 Acute: Two (-) acute RCTs; 1 Maintenance: 1 (-) RCT (oral monotherapy), 2 1 (-) RCT (LAI) 3 nM Brexpiprazole 1.1 nM Acute: One small (n=21) 8-week open label flexibly-dosed (mean=2.78 mg/day) trial; significant improvement from baseline depression scores ( d =1.4), 73.6% were “responders” 4 Maintenance: no data Cariprazine 0.085 nM Acute: 2 (+) 8-week FDA registration RCTs in acute bipolar depression: - ITT n=571: 1.5 mg/day (but not 0.75 or 3 mg/day) > placebo 5 - ITT n=480: 1.5 mg/day or 3 mg/day > placebo 6 Maintenance: no data 1 Thase et al. J Clin Psychopharmacol 2008;28:13-20; 2 Keck et al. J Clin Psychiatry 2007;68:1480-91; 3 Calabrese et al. J Clin Psychiatry 2017;78:324-31; 4 Brown et al. J Affect Disord 2019;249:315-8; 5 Durgam et al. Am J Psychiatry 2016;173:271-81; 6 Earley et al. Am J Psychiatry 2019;176:439-48.
Aripiprazole in Bipolar Depression: Failed or Negative Trial? Thase et al. J Clin Psychiatry 2008;28:13-20.
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