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 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-threshold 1 bipolar 2.4% 1.4% • Totals 4.5% 2.8% 1 Sub-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 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: • Entry with 1 st 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.
Bipolar Disorder: Later Course Two Years after STEP-BD Study Entry Among 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 studies Lifelong illness with no change in frequency of mood episodes
Bipolar Disorder: Later Course • 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 Anticonvulsants Antipsychotics 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: ValproicAcid • 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
Mood Stabilizers: Lamotrigine 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
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, 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
Quetiapine in Bipolar Depression 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, 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 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
Recommend
More recommend
