Which medication is best for acute bipolar depression?:Bipolar Disorders.2012.Supplement: May


Even though  manic episode/s define bipolar disorder, depression (episodes or symptoms) dominate the long-term course of the illness.Patients suffer from this for longer periods of time and  clinicians struggle to select/provide the right medication.

Michael Bauer et al review the evidence for treatments for bipolar depression.This is based on the literature search and appraisal  done as part of the development of the German Guideline on Diagnosis and Treatment of Bipolar Disorders following NICE search strategies.

Challenges in Treatment

The goal should be full remission as residual and subsyndromal depressive symptoms predict  increased risk of relapse.Majority of suicides in bipolar disorder occur during the depressed or mixed affective phase.ie one third of bipolar patients will attempt suicide and 4-19% will succeed in that.There is no accepted standard treatment for acute bipolar depression. A comprehensive assessment of disorder, personal and social factors, physical health, treatment response,risk review and engagement patterns and depth of knowledge etc  should guide the over all management plan. Focus here is on medications.

Scenario 1: New depressive episode in the absence of prophylactic (maintenance) treatment with a mood stabilizer (de novo bipolar depression)

Which one is better here?  antidepressant, classic mood stabiliser or atypical antipsychotic?.

Evidence for antidepressants: 5 RCTs.

1. Imipramine vs Fluoxetine vs Placebo: 6 weeks study.Both medications reduced symptoms.Response rate 86% with Fluoxetine and 57% with Imipramine and  38% with Placebo.Discontinuation was  66% in Placebo,53% in Imipramine and 43% in Fluoxetine. ( discontinuation can be due to lack of efficacy or due to side effects) (Cohn et al 1989).

2.Embolden 11 study: Paroxetine vs Placebo. 8 weeks. No significant difference. Dose of Paroxetine was 20 mg only in this study (McElroy SL et al 2010).

3. MAOI Tranylcypramine vs Imipramine. 6 weeks. MAOI was better (Himmelhoch et al 1991)

4. MAOI Moclobemide vs Imipramine: No difference in efficacy. Switch rate 11% for imipramne and 4% for Moclobemnide.( note that half of all patients were on mood stabiliser as well) (Silverstone,2001)

5.Venlafaxine vs Lithium . Bipolar 2 with depression. open label trial, 12 weeks. Response rate 58% (venlafaxine), 20% Lithium. Remission Venlafaxine 44% Lithium 8%. Switch 8% in Venlafaxine and none in Lithium (Amsterdam et al 2008).

Evidence for Classic mood stabilisers:

1.Embolden Study: 42. Lithium vs Placebo. Bipolar 1 and 2.  8 weeks. No difference with placebo. Note that Lithium levels are low (average serum level was only 0.61mmol/l). Bipolar 2 is generally considered less responsive to lithium. (Young et al 2010)

2.Carbamazepine vs Placebo. 12 week. 25 patients. CBZN more effective (Zhang et al 2007).

3.Lamotrigine vs Placebo.  7 week. High dose Lamotrigine significant improvement in 2 scales but not in HAM-D. Switch observed in Lamotrigine group. (Calabrese et al 1999) . A later metaanalysis  showed efficacy for Lamotrigine, but 4/5 placebo controlled studies in that analysis did not show benefit over placebo.(Geddes et al 2009)

2. Lamotrigine vs Lithium. 16 weeks. Both equally effective (Suppes et al 2008)

Evidence for Atypical antipsychotics:

1 BOLDER 1 and 2 : 8 weeks. Quetiapine vs Placebo. Quetiapine superior in response and remission. No  difference in switch rate (Cookson et al 2007).

2. EMBOLDEN 1 , 2 : Quetiapine vs Lithium vs Placebo. &  Quetiapine Vs Paroxetine vs Placebo. 600mg/day Quetiapine was superior to Lithium. ( Lithium serum levels were low). More discontinuation in Quetiapine group. Switch rate no difference. In Embolden 2, Quetiapine was superior to Paroxetine and Placebo. (McElroy,2010)

5.Quetapine XL. 8 weeks. Superior to Placebo (Suppes, et al 2010)

6. Aripiprazole vs Placebo. 275 patients in each arm. 8 weeks. No difference with Placebo.  (Thase et al 2008).

8.Olanzapine vs Placebo. 8 weeks. Olanzapine superior to placebo. (Tohen et al 2003). ( high attrition rate in both arms).

9.Olanzapine Fluoxetine combined pill vs Olanzapine. 8 weeks. OFC superior. (Tohen et al 2003)

10. OFC vs Lamotrigine. 7 weeks. OFC better but no significant difference. (Brown et al 2006)

Recommendation for depressive episodes while not on maintenance treatment:

1. There is limited evidence as to which agents are efficacious in the treatment of acute depression.

2.Quetiapine monotherapy is supported by strong evidence. Evidence also supports use of Olanzapine .

3. Both Lamotrigine and Carbamazepine is supported by some evidence.
4.Antidepressants may be of some utility in the short-term. Switching to mania remains  a worry with anti-depressant monotherapy. 

A  combination of antidepressants and  an agent with antimanic effect is often suggested. For those with previous history of rapid cycling, avoid antidepressants and go for additional mood stabilisers.

Scenario 2:Breakthrough depressive episode while on stabilisers

When new depressive episode while on mood stabiliser treatment, usual practice is to optimise current treatment,ie increasing dose if possible, ensuring concordance,checking serum levels (lithium,anticonvulsants) and adding thyroid hormones if low. In most cases  additional mood stabiliser or antidepressant would be required.

Evidence Review:

Adding a second medication to current  classic mood stabiliser

1. Add on Bupropion or Paroxetine or Placebo to on going stabiliser (Li, Valproate, CBZN or atypical antipsychotics). 8 weeks. No difference with placebo seen (Sachs et al 2007)

2. Add on Venlafaxine, Sertraline, Bupropion to mood stabiliser. No difference between groups seen. Note that no placebo arm in this study. Switch rates: Venlafaxine  31%, Bupropion (14%) and Sertraline (16%) (Leverich et al 2006)

3.Adding Lamotrigine to Lithium. 8 weeks. Lamotrigine superior to placebo (Van der Loos et al 2009).

No studies on adding an agent to current atypical antipsychoic agent used as maintenenace therapy was eligible for inclusion this review.

Recommendation for break through depressive episodes while on  mood stabiliser.

1.Lamotrigine should be considered an option for breakthrough depressive episode while on ongoing lithium treatment.

2.There is no evidence to support the use of antidepressants  in patients already receiving a mood-stabilizing agent.Clinical experience suggests this may be a second-line option in the absence of treatment with Lithium and Lamotrigine.

Summary of the article:

Treatment options for acute depression in bipolar disorder. Bauer M, Ritter P, Grunze H, Pfennig A.Bipolar Disord. 2012,14 Suppl 2:37-50

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