Bipolar Disorder · 2019-08-22 · Mood Stabilizers: Lamotrigine ... Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis

Bipolar DisorderRoscoe Brady M.D., Ph.D.Matcheri Keshavan M.D.

Bipolar Psychopharmacology Consultation LineAugust 22, 2019

Conflicts of Interest

• None. • Salary supported by BIDMC department funds, NIMH grants K23

MH100623 and R01 MH116170

Talk Organization

• Childhood and Development• The Onset of Symptoms• Early Treatment / Mis-Diagnosis / Co-Morbidity• A First Manic episode • Recovery after the episode / remission?• Early Treatment for Bipolar Disorder• Ten Years into a Bipolar Diagnosis• Specific Psychopharmacology Interventions

How many people have “Bipolar Related” Disorders?

• Diagnosis Lifetime 12 month

• Bipolar I 1.0% 0.6%• Bipolar II 1.1% 0.8%• Sub-threshold1 bipolar 2.4% 1.4%• Totals 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 Psychiatry. 2007;64:543-52.

Early Development

• Normal milestone achievement and social / cognitive development• Pre-morbid IQ typically normal• (note the differences from schizophrenia)

Early Illness / Treatment

• On average, onset of symptoms is ~age 17• Typically characterized by depressive symptoms and depressive

episodes with either mild or undiagnosed manic symptoms• These symptoms continue for an average of ten years before

bipolar disorder is diagnosed.

• Why is diagnosis so difficult? In part because of attenuated / non-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 CurrentAnxiety disorder 51.2 30.5 Alcohol use disorder 32.2 11.8 Drug use disorder 21.7 7.3ADHD 9.5 5.9Eating disorder 7.9 2.0

Bipolar Disorder: After the First Episode

McLean-Harvard First-Episode Project:• Entry with 1st Episode mania (hospitalization)

• Syndromal Recovery• Symptomatic Recovery• Functional Recovery

Two years after initial hospitalization

• 98% no longer met criteria for DSMIV mood episode at some point• 40% met criteria for another episode within 2 years• 30% experienced significant mood symptoms for the entire two years• Only 40% described occupational level and residential status

returning to or exceeding highest levels in year before hospitalization• 65% taking medication

Bipolar Disorder: Later Course

STEP-BD trial:Previously diagnosed (bipolar disorder I or II, outpatient at start, and in treatment. Most a full decade into current diagnosis.


Two Years after STEP-BD Study EntryAmong symptomatic participants:

• 60% experienced a period of recovery by 2 years (i.e. only one or two symptoms from DSM criteria)

• 50% of those that experienced recovery experienced a new mood episode over those 2 years

• Mean longest period in remission ~3 months

From other studiesLifelong illness with no change in frequency of mood episodes


• Why did we just talk about that?

• Everyone describes this as a episodic illness. That’s probably not the 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 AnticonvulsantsAntipsychotics and Antidepressants- Update on the Literature.Questions & Discussion

Mood Stabilizers: Lithium

• Prophylaxis versus: Mania & Depression (more equivocal)• Anti-Manic agent• Antidepressant (probably- but actually very little data that would be

considered a randomized, blinded, placebo controlled trial)• Anti-Suicide Effect?

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.

Mood Stabilizers: Lithium

• Why is Lithium less effective in modern (e.g. 2011) RCTs now than it was decades ago?

Mood Stabilizers: Valproic Acid

• Anti-Manic Agent and equivocal evidence for prophylaxis• Anti-Depressant Agent in the small RCTs that have analyzed bipolar

depression• Use in treating aggression / violence in other disorders

Mood Stabilizers: Lamotrigine

• Prophylaxis versus Mania and Depression• Anti-Depressant? Unclear• GSK and unpublished trials

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• Anti-Depressant in Combination with other medications:• LamLit trial: Addition of lamotrigine to patients who are depressed

during current lithium treatment.• CEQUEL trial: Addition of lamotrigine to patients who are depressed

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

Mood Stabilizers: Lamotrigine

Discontinuing Mood Stabilizers

• Why? • (Lack of efficacy, side effects, drug-drug interactions)• How?

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 antidepressants. Am J Psychiatry. 2010 Aug;167(8):934-41.

Antipsychotics in Bipolar Disorder

• Mania • Depression• Prophylaxis

Antipsychotics in Mania

A Well-Established Role

Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, GoodwinGM, 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

Quetiapine in Bipolar Depression

FDA approved in BPD depressionFive randomized, blinded, placebo-controlled trials in bipolar disorder.Dosing: 300mg- 600mg dailyAll mixed populations of BPI and BPIIAll significantly more likely to cause remission than treatment with placebo.

(10-25% increase in remission compared to placebo)All AstraZeneca fundedTwo Studies compared quetiapine to non-placebo treatment ( one vs SSRI,

one vs lithium)

Quetiapine in Bipolar Depression

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.

Antipsychotics in Bipolar Depression

Olanzapine (monotherapy or in combination with fluoxetine)

Olanzapine + fluoxetine is FDA approvedTwo Randomized, blinded, placebo-controlled trials:One compared olanzapine to olanzapine/fluoxetine combination and to

placebo.The other compared olanzapine monotherapy to placeboAll subjects with BPD type I, all depressedEli Lilly funded


Olanzapine monotherapy vs combination with fluoxetine:

Olanzapine 5 to 20mgOlanzapine/Fluoxetine 6/25 to 12/50mgFor 8 weeks

Both superior to placebo. Combination superior to placebo or olanzapine alone and not associated with increased risk for 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 olanzapine in patients with bipolar I depression. Br J Psychiatry. 2012


Aripiprazole monotherapy

Two randomized, blinded, placebo controlled trialsFunded by Bristol-Myers Squibb and OtsukaAll subjects with BPI depression.Aripiprazole dosed 5-30mg daily x 8 weeksNo 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 trialsFunded by PfizerAll subjects with BPI depression.Ziprasidone dosed 40-160mg daily x 6 weeksNo 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 other of a mood stabilizer plus lurasidone vs mood 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.

Antipsychotics in Bipolar Depression: Summary

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 depression. (Caveat that lurasidone monotherapy may be 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.

Antipsychotics For Prophylaxis

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 depression. (Interestingly, this is the first time this has been 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 remission. Then started on risperidone long-acting injectable formulation (typically 25mg q2 weeks). Then subjects randomized to either continue risperidone injection or placebo injection.

Risperidone injectable protective against manic episodes but notprotective 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 open label olanzapine to remission, then randomized to 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 olanzapine. Am J Psychiatry 2006; 163: 247–256.


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 treatedto remission with open label quetiapine 400-800mg (target dose 600mg) in combination with either lithium of valproic acid. Thenpatients randomized to either Li/VPA plus quetiapine or Li/VPA plus placebo. Combination treatment was more effective than moodstabilizer alone in preventing both manic and depressive episodes.


Vieta E, Suppes T, Eggens I, Persson I, Paulsson B, Brecher M. Efficacy and safety of quetiapine in combinationwith lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord2008; 109: 251–263.

Suppes T, Vieta E, Liu S, Brecher M, Paulsson B; Trial 127 Investigators.Maintenance treatment for patients withbipolar 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.


Suppes T, Vieta E, Gustafsson U, Ekholm B. Maintenance treatment with quetiapine when combined with either lithium or divalproex in bipolar I disorder: analysis of two large randomized, placebo-controlled trials. Depress Anxiety. 2013 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 olanzapine. Combination treatment had a small (non-significant) 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 of olanzapine plus mood stabilizer v. mood stabilizer alone. Br J Psychiatry 2004; 184: 337–345


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 risperidoneLAI 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 frequently. Bipolar Disord 2009; 11: 827–839.

Antipsychotics For Prophylaxis: Summary

MonotherapyIn 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 olanzapine or ~600mg daily quetiapine monotherapy, continuing this medication was also more effective than placebo at preventing depression

In CombinationFor 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.

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Bipolar Disorder · 2019-08-22 · Mood Stabilizers: Lamotrigine ... Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis