Copyright Blackwell Munksgaard 2003 Bipolar Disorders 2003 5 421 433 BIPOLAR DISORDERS Review Article Antidepressants in bipolar disorder the case for caution Ghaemi SN Hsu DJ Soldani F Goodwin FK Antidepressants in bipolar disorder the case for caution Bipolar Disord 2003 5 421 433 Blackwell Munksgaard 2003 S Nassir Ghaemia Douglas J Hsua Federico Soldania and Frederick K Goodwinb a The 2002 American Psychiatric Association APA guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants This change in comparison with previous APA guidelines has been criticized especially from some groups in Europe The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines In this paper we re examine the argument put forward by the Munich group and we demonstrate that indeed conceptually and empirically there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder consistent with and perhaps even more strongly than the APA guidelines This rationale is based on support for the following four propositions i The risk of antidepressant induced mood cycling is high ii Antidepressants have not been shown to de nitively prevent completed suicides and reduce mortality whereas lithium has iii Antidepressants have not been shown to be more e ective than mood stabilizers in acute bipolar depression and have been shown to be less e ective than mood stabilizers in preventing depressive relapse in bipolar disorder and iv Mood stabilizers especially lithium and lamotrigine have been shown to be e ective in acute and prophylactic treatment of bipolar depressive episodes We therefore draw three conclusions from this interpretation of the evidence i There are signi cant risks of mania and long term worsening of bipolar illness with antidepressants ii Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and iii Antidepressants should be discontinued after recovery from the depressive episode and maintained only in those who repeatedly relapse after antidepressant discontinuation a minority we judge to represent only about 15 20 of bipolar depressed patients Over the last decade reports generated in the US and Canada have pointed out the paucity of evidence on the e cacy of antidepressants in bipolar disorder 1 2 Further recent North American based treatment guidelines including those of the American Psychiatric Association have been conservative recommending antidepressants only for severe bipolar depression 3 8 Moreover if antidepressants are to be used they should be withdrawn as early as possible This shift away from antidepressant use has engendered criticism from some groups in Europe particularly Germany 9 In that critical Bipolar Disorder Research Program Cambridge Hospital Cambridge MA and Harvard Medical School Boston MA USA bCenter on Neuroscience Medical Progress and Society and Department of Psychiatry and Behavioral Sciences George Washington University Washington DC USA Key words antidepressants bipolar disorder depression mood stabilizers psychopharmacology Received 29 April 2003 revised and accepted for publication 2 July 2003 Corresponding author S Nassir Ghaemi MD Cambridge Hospital 1493 Cambridge St Cambridge MA 02139 USA Fax 617 665 1623 e mail ghaemi hms harvard edu article on US and Canadian based treatment guidelines the authors assert that these guidelines are not balanced and should be rewritten to remove restrictions on the use of antidepressants in the treatment of bipolar depression The Munich group asserts that the argument for restriction of antidepressants in US guidelines is based on four premises 9 which they state as i The risk of switching into mania rapid cycling induced by antidepressants is an important clinical phenomenon in bipolar depression 421 Ghaemi et al ii The risk of suicidality suicide attempts and suicide in bipolar depressive patients is of minor clinical relevance iii The antidepressive ef cacy of antidepressants in bipolar depression is insuf ciently proven iv The antidepressive ef cacy of mood stabilizers in bipolar depression is suf ciently proven antidepressants should be used in bipolar disorder but whether or not antidepressants should be routinely used in bipolar disorder We argue for cautious selected use rather than routine use The rest of this paper will examine the evidence on which this approach is based This paper will re examine these four assertions and make the case for US based treatment guidelines that de emphasize the use of antidepressants in the treatment of bipolar disorder Methodological issues The case for caution We agree that antidepressants may be e ective in treating acute bipolar depression as there is some evidence to that e ect While all treatment guidelines recognize this the point of contention regarding North American based treatment guidelines centers on how often antidepressants should be used and for how long We believe that the evidence of antidepressant e cacy in bipolar depression is not as de nitive as many assume Given the risks of acute mania the routine use of antidepressants would appear to be more risky without much added bene t over the use of mood stabilizers alone for acute bipolar depression a point which seems even more compelling with the appearance of lamotrigine Further available studies fail to provide any rigorous evidence of antidepressant prevention of depressive relapse In contrast such evidence exists with mood stabilizers Moreover there is likely a signi cant risk of more mood episodes over time and possible rapid cycling with long term antidepressant use in bipolar disorder Seen this way the research evidence appears to support US and Canadian based treatment guidelines in which antidepressants use is restricted to cases of severe depression or when the appropriate mood stabilizer combination has failed to prevent or reverse a depression further the guidelines recommend antidepressant discontinuation after acute recovery Critics fear that if antidepressants are used less aggressively bipolar depression will go undertreated and the suicide risk will rise The evidence however is not clear that there is anti suicidal bene t with antidepressants whereas lithium among all psychotropic agents has by far the most extensive evidence of an anti suicide e ect