1. Bipolar Depression Pharmacotherapy: Part 1
Flavio Guzmán, MD

2. 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

3. Olanzapine/Fluoxetine Combination

4. 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

5. 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),

6. 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.

7. Quetiapine

8. 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

9. 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.

10. 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.

11. 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.

12. Lurasidone

13. 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.

14. Lurasidone: efficacy in bipolar depression
FDA-approval based on two studies:
Monotherapy
20-60 mg/day
mg/day
Lurasidone superior to placebo as monotherapy
Adjunct
Lurasidone + Lithium or Valproate
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.

15. 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.

16. Lithium

17. 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),

18. 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),
Malhi, G. S.,et al (2012). The science and practice of lithium therapy. Australian and New Zealand Journal of Psychiatry,46(3),

19. 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),

20. 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),

21. Lamotrigine

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

23. 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.

24. 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),

25. Valproate

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

27. 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),

28. End of presentation