What is the Effectiveness and Safety of Adjunctive Antidepressants in the Treatment of Bipolar Depression?

Although abnormal mood elevation is the cardinal diagnostic feature that distinguishes bipolar disorder from recurrent major depressive disorder, depression, more than manic episodes, is the leading cause of impairment and death among patients with bipolar disorders. Treatment of bipolar depression with standard antidepressant medication is controversial due to two main issues.  First, the data providing support for their use in treating bipolar depression are minimal and are not considered to be sufficient to guide clinical practice. Second, the widely held belief that antidepressants can induce new episodes of abnormal mood elevation (manic/hypomanic switch) or accelerate the rate of cycling has been neither confirmed nor refuted by placebo-controlled studies. There are more than one traditional clinical approach to treatment of bipolar depression with a traditional difference between academic authorities in Europe (in favor of the use of antidepressants for the treatment of bipolar depression) and the US (in favor of so-called mood stabilizers for the treatment of bipolar depression). An example for this difference in approach could be in the different treatment guidelines for the treatment of bipolar depression. While The American Psychiatric Association treatment guidelines (1)  for the treatment of non-psychotic bipolar depression recommend lithium as a first line drug (Recommended with substantial clinical confidence) or Lamotrigine (Recommended with moderate clinical confidence) without a concurrent antidepressant even in severe depression. The British Association for Psychopharmacology: Evidence-based guidelines for treating bipolar disorder (2) recommend a combination of an antidepressant (SSRIs) and an anti-manic agent (lithium, valproate, or an antipsychotic) for the treatment of bipolar depression, regardless of severity.
          In general, all guidelines seem to gradually accept the use of antidepressants for a limited period in combination with a mood stabilizer  The majority of standard randomized controlled trials indicated efficacy of antidepressants in the treatment of the acute phase of bipolar depression. This is true when given as monotherapy or as adjuncts to mood stabilizers. The position that advises caution in prescribing antidepressants in bipolar depression (as in the APA guidelines) is based on consistent, yet limited, data that indicate a higher switch rates and increased cycle acceleration. These adverse effects are lowered when adjunct mood stabilizers are added. Nevertheless, some data indicate higher rates of relapse into depression when antidepressants are discontinued early after remission.  Surprisingly, a recent large effectiveness study, the STEP-BD, found no benefit in efficacy and no risk of affective switch when antidepressants were added to a mood stabilizer (3) . As this study is better adjusted to “real life” clinical practice it has relevance when clinical decisions are taken. Future studies designed to elucidate the issues discussed are essential and may help establish better guidelines for the treatment of the complex clinical entity of bipolar disorder. Until then factors as past depression severity and length, history of severe manias and rapid cycling will play a role in the decision of clinicians in prescribing antidepressants for bipolar depression in different phases of the disorder.
 
References
1.    American Psychiatric Association, 2002. Practice guideline for the treatment of patients with bipolar disorder, revision. Am. J. Psychiatry 159, 1 –50.
2.    Goodwin, G.M., 2003. Evidence-based guidelines for treating bipolar disorder: recommendations from the British Association for Psychopharmacology. J. Psychopharmacol. 17, 149– 173.
3.    Marangell,, Stephen R. Wisniewski, Laszlo Gyulai, Edward S. Friedman, Charles L. Bowden, Mark D. Fossey, Michael J. Ostacher, M.P.H., Terence A. Ketter, Jayendra Patel, Peter Hauser, Daniel Rapport, James M. Martinez, Michael H. Allen, David J. Miklowitz, Michael W. Otto, Ellen B. Dennehy, and Michael E. Thase. Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression N Engl J Med. 2007 Apr 26;356(17):1711-22