Bipolar Disorder Roscoe Brady M.D., Ph.D. Matcheri Keshavan M.D. - - PowerPoint PPT Presentation
Bipolar Disorder Roscoe Brady M.D., Ph.D. Matcheri Keshavan M.D. Bipolar Psychopharmacology Consultation Line August 22, 2019 Conflicts of Interest None. Salary supported by BIDMC department funds, NIMH grants K23 MH100623 and R01
Roscoe Brady M.D., Ph.D. Matcheri Keshavan M.D. Bipolar Psychopharmacology Consultation Line August 22, 2019
MH100623 and R01 MH116170
Talk Organization
How many people have “Bipolar Related” Disorders?
Lifetime 12 month
1.0% 0.6%
1.1% 0.8%
2.4% 1.4%
4.5% 2.8%
1Sub-threshold bipolar disorder = Persons in this group experienced two or more
lifetime manic symptoms without meeting the full criteria for a hypomanic episode or manic episode
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, Kessler RCLifetime and 12- month prevalence of bipolar spectrum disorder in the national comorbidity survey replication. Arch Gen
Early Development
Early Illness / Treatment
episodes with either mild or undiagnosed manic symptoms
bipolar disorder is diagnosed.
diagnostic symptoms. In part because of the presence of many symptoms of other psychiatric diagnoses (the burden of co-morbid psychiatric illnesses).
Bipolar Disorder Psychiatric Co-morbidity
% with another psychiatric diagnosis: Lifetime Current Anxiety disorder 51.2 30.5 Alcohol use disorder 32.2 11.8 Drug use disorder 21.7 7.3 ADHD 9.5 5.9 Eating disorder 7.9 2.0
Bipolar Disorder: After the First Episode
McLean-Harvard First-Episode Project:
Two years after initial hospitalization
returning to or exceeding highest levels in year before hospitalization
Bipolar Disorder: Later Course
STEP-BD trial: Previously diagnosed (bipolar disorder I or II, outpatient at start, and in
Bipolar Disorder: Later Course
Two Years after STEP-BD Study Entry Among symptomatic participants:
symptoms from DSM criteria)
episode over those 2 years
From other studies Lifelong illness with no change in frequency of mood episodes
Bipolar Disorder: Later Course
right way to conceptualize the illness. Maybe phasic is a better description.
PHARMACOLOGY This presentation: Focus on Published Trials (Evidence-Based Practice).. Which is not meant to replace “Practice-Based Evidence” Mood Stabilizers and Anticonvulsants Antipsychotics and Antidepressants- Update on the Literature. Questions & Discussion
considered a randomized, blinded, placebo controlled trial)
Goodwin, F. K., Fireman, B., Simon, G. E., et al (2003) Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA, 290, 1467–1473. Cipriani A, Pretty H, Hawton K, Geddes JR.Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005 Oct;162(10):1805-19.
was decades ago?
depression
Calabrese JR, Huffman RF, White RL, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord. 2008;10:323-333 Geddes JR, Calabrese J, Goodwin GM. Lamotrigine for treatment of bipolar depression: an independent meta- analysis and meta-regression of individual patient data from 5 randomized trials British Journal of Psychiatry 2009 194: 4-9
Combination Treatment with Other Medications
during current lithium treatment.
during current quetiapine treatment (~300mg quetiapine target dose)
MLM Van der Loos, PGH Mulder, EGTM Hartong, et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry, 70 (2009), pp. 223-231 Geddes JR, Gardiner A, Rendell J, Voysey M, et al. Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry. 2016 Jan;3(1):31-9. doi: 10.1016/S2215-0366(15)00450-2. Epub 2015 Dec 11
When possible: Slowly.
Perlis RH, Sachs GS, Lafer B, Otto MW, Faraone SV, Kane JM, Rosenbaum JF. Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data. Am J Psychiatry. 2002 Jul;159(7):1155-9. Baldessarini RJ, Tondo L, Ghiani C, Lepri B. Illness risk following rapid versus gradual discontinuation of
A Well-Established Role
Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, Goodwin GM, Geddes JR.. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis .Lancet. 2011 Oct 8;378(9799):1306-15
FDA approved in BPD depression Five randomized, blinded, placebo-controlled trials in bipolar disorder. Dosing: 300mg- 600mg daily All mixed populations of BPI and BPII All significantly more likely to cause remission than treatment with placebo. (10-25% increase in remission compared to placebo) All AstraZeneca funded Two Studies compared quetiapine to non-placebo treatment ( one vs SSRI,
Calabrese JR, Keck PE, Macfadden W, et al. A randomized, double-blind, placebo- controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005; 162(7):1351–1360. McElroy S, Weisler R, Chang W, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010; 71(2):163–174. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression. J Clinl Psychopharmacol. 2006; 26(6):600–609. Suppes T, Datto C, Minkwitz M, et al. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord. 2010; 121:106–115. Young AH, FRCPsych, McElroy SL, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010; 71(2):150–162.
Olanzapine (monotherapy or in combination with fluoxetine) Olanzapine + fluoxetine is FDA approved Two Randomized, blinded, placebo-controlled trials: One compared olanzapine to olanzapine/fluoxetine combination and to placebo. The other compared olanzapine monotherapy to placebo All subjects with BPD type I, all depressed Eli Lilly funded
Olanzapine monotherapy vs combination with fluoxetine: Olanzapine 5 to 20mg Olanzapine/Fluoxetine 6/25 to 12/50mg For 8 weeks Both superior to placebo. Combination superior to placebo or
switch to mania
Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003; 60:1079–1088.
Olanzapine monotherapy: Olanzapine 5-20mg for 6 weeks Olanzapine superior to placebo (note that both group responded to the MADRS “Reported Sadness" question (#2) the same way at the end of trial. That answer was “sad” (score 2.01 vs 2.02.)
Tohen M, McDonnell DP, Case M, et al. Randomized, double-blind, placebo-controlled study of
Aripiprazole monotherapy Two randomized, blinded, placebo controlled trials Funded by Bristol-Myers Squibb and Otsuka All subjects with BPI depression. Aripiprazole dosed 5-30mg daily x 8 weeks No significant difference from placebo
Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in non-psychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008; 28(1):13–20.
Ziprasidone monotherapy Two randomized, blinded, placebo-controlled trials Funded by Pfizer All subjects with BPI depression. Ziprasidone dosed 40-160mg daily x 6 weeks No significant difference from placebo
Lombardo L, Sachs G, Kolluri S, Kremer C, Yang R. Two 6-week, randomized, double-blind, placebo-controlled studies of ziprasidone in outpatients with bipolar I depression. J Clin Psychopharmacol. 2012; 32(4):470–478.
Lurasidone: Two randomized, blinded, placebo-controlled trials in bipolar disorder. All BPI , currently depressed One study of lurasidone monotherapy vs placebo, the
stabilizer monotherapy Both Sunovion funded
Lurasidone monotherapy lurasidone 20mg- 60mg versus lurasidone 80-120mg daily versus placebo Both lurasidone groups superior to placebo. No difference in efficacy between luraidone dose groups. The lower dose group demonstrated a greater risk of mania (3.7% versus 1.9% in either the placebo or higher- dose group)
Loebel et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014 Feb;171(2):160-8.
Lurasidone + mood stabilizer Dosing: Li or VPA plus lurasidone 20mg- 120mg versus Li or VPA plus placebo Lurasidone superior to placebo as adjunctive therapy. (notably, lurasidone + mood stabilizer efficacy comparable to lurasidone monotherapy in other trial)
Loebel et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014 Feb;171(2):169-77.
Cariprazine Dosing: 0.75 or 1.5 or 3.0 mg versus placebo Cariprazine 1.5mg or 3.0mg superior to placebo as monotherapy Funded by Allergan
Durgam et al. An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression. Am J Psychiatry. 2016 Mar;173(3):271-81. Earley et al. Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study. Am J Psychiatry. 2019 Jun 1;176(6):439-448.
Quetiapine 300 or 600mg daily more effective than placebo at treating depression (but there’s reason to think 600mg more effective) Olanzapine 5-20mg monotherapy or in combination with fluoxetine more effective than placebo at treating depression. Lurasidone 20-120mg monotherapy or in combination with a mood stabilizer more effective than placebo in treating
more prone to manic switching at doses less than 80-120)
A Couple points about All of the trials above: Aripiprazole and Ziprasidone: failed trials or negative trials? The Difference between one trial and two trials? Example: EMBOLDEN vs BOLDER Trials: Seroquel 300mg daily versus placebo on patient's report of sadness. Significant difference in one trial, non-significant difference in the other.
Quetiapine monotherapy vs Li monotherapy: BPI patients in mood episode are treated with quetiapine until stable, then randomized to Li (dosed to level) or quetiapine (300-800mg) or placebo in double blind trial. Both medications are superior to placebo in protecting against both mania and
shown for either drug). Both similarly effective. Funded by Astra Zeneca
Weisler RH, Nolen WA, Neijber A et al. Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: A randomized controlled study). J Clin Psychiatry 2011; 72: 1452–1464.
Risperidone LAI (injectable) monotherapy BPI patients in manic or mixed episode or already stabilized on risperidone are treated with risperidone oral formulation to
formulation (typically 25mg q2 weeks). Then subjects randomized to either continue risperidone injection or placebo injection. Risperidone injectable protective against manic episodes but not protective against depressive episodes Funded by Johnson & Johnson
Quiroz JA, Yatham LN, Palumbo JM, Karcher K, Kushner S, Kusumakar V. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry 2010; 68: 156–162.
Olanzapine monotherapy BPI patients in manic or mixed episode are treated with
either placebo or continued olanzapine 5-20mg daily. Olanzapine more effective than placebo at preventing either depressive or manic episode Eli Lilly funded.
Tohen M, Calabrese JR, Sachs GS et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with
Aripiprazole monotherapy BPI subjects. All with recent manic episode, some stabilized on aripiprazole, some not are entered into open label trial of aripiprazole 15-30mg daily. Then subejcts that remain stable are randomized to placebo vs aripiprazole. Aripiprazole more effective at preventing manic episodes but not depression. Funded by Bristol-Meyers Squibb and Otsuka
Keck PE Jr, Calabrese JR, McQuade RD et al. A randomized, double-blind, placebo-controlled 26- week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry 2006; 64: 626–637.
Quetiapine plus mood stabilizer BPI subjects either depressed or manic or mixed at entry are treated to remission with open label quetiapine 400-800mg (target dose 600mg) in combination with either lithium of valproic acid. Then patients randomized to either Li/VPA plus quetiapine or Li/VPA plus
stabilizer alone in preventing both manic and depressive episodes.
Funded by Astra Zeneca
Vieta E, Suppes T, Eggens I, Persson I, Paulsson B, Brecher M. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord 2008; 109: 251–263. Suppes T, Vieta E, Liu S, Brecher M, Paulsson B; Trial 127 Investigators.Maintenance treatment for patients with bipolar I disorder: results from a north american study of quetiapine in combination with lithium or divalproex (trial 127).Am J Psychiatry. 2009 Apr;166(4):476-88
Quetiapine plus mood stabilizer BPI subjects either depressed or manic or mixed at entry are treated to remission with open label quetiapine 400-800mg (target dose 600mg) in combination with either lithium of valproic acid. Then patients randomized to either Li/VPA plus quetiapine or Li/VPA plus placebo. Lithium and Valproic acid both equally effective in combination with quetiapine at preventing both mania and depression. Interestingly, valproic acid was more effective at preventing a manic episode than lithium, contradicting other studies but this study, notably, was not a randomized trial of Li versus VPA. Funded by Astra Zeneca
Suppes T, Vieta E, Gustafsson U, Ekholm B. Maintenance treatment with quetiapine when combined with either lithium
Nov;30(11):1089-98
Olanzapine + mood stabilizer BPI subjects in manic or mixed episode who achieved remission with combination treatment of olanzapine 5-20mg in combination with Li or VPA are randomized to double blinded treatment with either Li or VPA plus placebo or Li or VPA plus
effect at preventing relapse to mania or depression. Eli Lilly funded.
Tohen M, Chengappa KNR, Suppes T et al. Relapse prevention in bipolar I disorder: 18-month comparison
Aripiprazole + mood stabilizer BPI subjects in manic or mixed episode treated with Li or VPA monotherapy x2 weeks. Significantly symptomatic subjects then received aripiprazole 10-30mg daily. Patients stabilized on this combination then randomized to Li/VPA plus placebo versus Li/VPA plus aripiprazole. Combination treatment more effective than Li/VPA alone at preventing mania but not significantly different for preventing depression.
Marcus R, Khan A, Rollin L et al. Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord 2011; 13: 133–144.
Ziprasidone + Mood Stabilizer BPI subjects with current or recent manic or mixed episode treated with Li or VPA monotherapy x2 weeks. Significantly symptomatic subjects then received ziprasidone 80-160mg daily. Patients stabilized on this combination then randomized to Li/VPA plus placebo versus Li/VPA plus ziprasidone. Combination treatment more effective than Li/VPA alone at preventing mania but not significantly different for preventing depression. Funded by Pfizer
Bowden CL, Vieta E, Ice KS, Schwartz JH, Wang PP, Versavel M. Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo controlled, double-blind trial. J Clin Psychiatry 2010; 71: 130–137.
Risperidone LAI + treatment as usual Subjects with BPI or BPII in any phase of illness with history of 4+ episodes in past year. Subjects stabilized by treatment as usual plus risperidone LAI over 16 weeks (at least 4 weeks in remission). Patients then randomized to treatment as usual + placebo versus treatment as usual + Risperidone LAI. Combination treatment more efective than treatment as usual alone in preventing relapse but mania vs depression not reported. Symptom scales (MADRS , YMRS) show significant effect on mania symptoms but not on deperessive symptoms. Funded by Janssen
Macfadden W, Alphs L, Haskins JT et al. A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse
Antipsychotics For Prophylaxis: Summary
Monotherapy In general, for patients whose mania was successfully by antipsychotic monotherapy, continuing this medication was more protective than placebo against mania but not against depression There is also evidence that for patients successfully treated with ~10mg
medication was also more effective than placebo at preventing depression In Combination For antipsychotics in general, patients whose mania was successfully treated by a combination of mood stabilizer and antipsychotic, continuing both was more effective at preventing mania than just continuing mood stabilizer alone. There is some evidence that a mood stabilizer combined with ~600mg quetiapine is also more effective at preventing depression than mood stabilizer alone.