Bipolar Depression Pharmacotherapy: Part 1 Flavio Guzmán, MD

Bipolar depression: pharmacotherapy FDA-approved drugs SGAs Olanzapine/Fluoxetine Combination (2003) Quetiapine IR (2006) Quetiapine XR (2008) Lurasidone (2013) Non-approved treatments Lithium Lamotrigine Valproate

Olanzapine/Fluoxetine Combination

Olanzapine/Fluoxetine Combination FDA-approved indications: Manic episodes Maintenance treatment Bipolar depression Olanzapine X - Olanzapine/Fluoxetine Combination Zyprexa (Olanzapine) [Prescribing Information]Indianapolis, IN: Lilly USA, LLC Symbiax (Olanzapine/fluoxetine) [Prescribing Information]Indianapolis, IN: Lilly USA, LLC

OFC: efficacy in bipolar depression Meta-analysis 4 RCTs (1330 patients) Superior to: Olanzapine Placebo Not superior to: Lamotrigine Poor side effects profile 4 RCTs (1330 patients) Meta-analysis Silva, M. T., et al (2013). Olanzapine plus fluoxetine for bipolar disorder: a systematic review and meta-analysis. Journal of affective disorders, 146(3), 310-318.

Metabolic side effects OFC: disadvantages Metabolic side effects Significant weight gain, metabolic disturbances Limited flexibility Dosing flexibility limited Yildiz, A. (n.d.). (2015).The bipolar book: History, neurobiology, and treatment. (1st ed.). New York, N.Y.: Oxford University Press.

Quetiapine

Quetiapine in BD: FDA-approved indications Manic and mixed episodes Maintenance treatment Bipolar depression Quetiapine IR X Quetiapine XR Seroquel (Quetiapine fumarate) [Prescribing Information]  Willington, DE: AstraZeneca Pharmaceuticals LP Seroquel XR(Quetiapine fumarate) [Prescribing Information]  Willington, DE: AstraZeneca Pharmaceuticals LP

Quetiapine for bipolar depression Quetiapine 300 mg/day and 600 mg/day more efficacious than placebo BOLDER I and II Quetiapine 600 mg/day more efficacious than lithium EMBOLDEN I Quetiapine 300 mg/day more efficacious than paroxetine EMBOLDEN II Yildiz, A. (n.d.). (2015).The bipolar book: History, neurobiology, and treatment. (1st ed.). New York, N.Y.: Oxford University Press.

Quetiapine side effects Sedation / Somnolence Most common cause of premature discontinuation Frequently reported side effects Dry mouth Sedation and somnolence Yildiz, A. (n.d.). (2015).The bipolar book: History, neurobiology, and treatment. (1st ed.). New York, N.Y.: Oxford University Press.

Quetiapine side effects If after 3 weeks somnolence/sedation continues Consider prescribing a different drug Avoiding premature discontinuation Low dose Slow escalation Yildiz, A. (n.d.). (2015).The bipolar book: History, neurobiology, and treatment. (1st ed.). New York, N.Y.: Oxford University Press.

Lurasidone

Lurasidone for BD: FDA-approved indications Manic episodes No Maintenance treatment Bipolar depression: Monotherapy Adjunct to lithium or valproate Yes Latuda (Lurasidone) [Prescribing Information] Marlborough, MA: Sunovion Pharmaceuticals Inc.

Lurasidone: efficacy in bipolar depression FDA-approval based on two studies: Monotherapy 20-60 mg/day 80-120 mg/day Lurasidone superior to placebo as monotherapy Adjunct Lurasidone + Lithium or Valproate 20-120 mg/day Lurasidone superior to placebo as adjunctive therapy Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Lurasidone: side effects Minimal metabolic effects Weight Lipids Measures of glycemic control Commonly reported adverse effects Nausea Akathisia Findlay, L. J., El-Mallakh, P., & El-Mallakh, R. S. (2015). Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management, 11, 75.

Lithium

Lithium for bipolar depression Indication FDA-approved? Manic episodes Yes Maintenance treatment Bipolar depression No First-line treatment in some guidelines Monotherapy: BAP, CANMAT+ISBD Vázquez, G. H., et al (2014). Pharmacological treatment of bipolar depression.Advances in psychiatric treatment, 20(3), 193-201.

Evidence base for lithium in bipolar depression Lack of good quality RCTs Small crossover studies Meta-analysis Zornberg, G. L.,et al (1993). Treatment of depression in bipolar disorder: new directions for research. Journal of clinical psychopharmacology,13(6), 397-408. Malhi, G. S.,et al (2012). The science and practice of lithium therapy. Australian and New Zealand Journal of Psychiatry,46(3), 192-211.

Lithium for bipolar depression EMBOLDEN I trial Lithium: negative results It did not separate from placebo in MADRS scores Funded by quetiapine manufacturer Mean serum lithium concentration 0.6 mEq/L Young, A. H.,et al (2010). A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). The Journal of clinical psychiatry, 71(2), 150-162.

Lithium for bipolar depression Pros Cons May reduce suicidality Slow onset of action Up to 3 to 5 weeks Side effects profile: Weight gain, tremor, GI disturbances, lethargy Vieta, E., & Valentí, M. (2013). Pharmacological management of bipolar depression: acute treatment, maintenance, and prophylaxis. CNS drugs, 27(7),

Lamotrigine

Lamotrigine for BD: FDA-approved indications Manic episodes No Maintenance treatment Yes Bipolar depression Lamictal (Lamotrigine) [Prescribing Information] Research Triangle Park, NC: GlaxoSmithKline

Lamotrigine: efficacy in bipolar depression 5 RCTs Meta-analysis 5 RCTs Beneficial effect on bipolar depression Overall pooled effect was modest Larger advantage in more severely depressed patients Meta-analysis Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194:4–9.

Side effects Most side effects Stevens Johnson syndrome Rare and mild Rare but can be fatal Risk factor: rapid dose titration Slow escalation reduces risk Vieta, E., & Valentí, M. (2013). Pharmacological management of bipolar depression: acute treatment, maintenance, and prophylaxis. CNS drugs, 27(7),

Valproate

Valproate: FDA-approved indications Manic episodes Yes Maintenance treatment No Bipolar depression Depakote ER (divalproex sodium) [Prescribing Information] North Chicago, IL: AbbVie Inc

Valproate: efficacy for bipolar depression Meta-analysis of 4 double-blind RCTs [1] Total: 142 participants Effective for the reduction of depressive symptoms Well tolerated Could be useful combined with lithium Similar response to lithium/valproate + antidepressants [2] Meta-analysis 1 -Smith, L. A., et al (2010). Valproate for the treatment of acute bipolar depression: systematic review and meta-analysis. Journal of affective disorders, 122(1), 1-9. 2- Vieta, E., et al. (2013). Pharmacological management of bipolar depression: acute treatment, maintenance, and prophylaxis. CNS drugs, 27(7),

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