FDA to review “missing” drug company documents

To what extent do SSRIs increase the risk of suicide or violent behaviour? A recent meta-analysis on both published and unpublished data (Whittington et al., 2004) indicates that some SSRIs lack a favourable 'risk–benefit' profile for treating childhood and adolescent depression.

This study underscored the need for improved transparency in clinical studies, and led to a statement by the International Committee of Medical Journal Editors (ICMJE) requiring open registration of such studies (Abbasi, 2004). In addition, the BMJ recently reported (Lenzer, 2005) that documents could cast doubt on conclusions that fluoxetine treatment was not associated with violence observed. This controversy raises other critical issues of SSRI use that merit our consideration.

First, it questions the external validity of clinical trials in which ‘depressed’ patients at high suicide risk are excluded, and therefore potentially different from those treated by SSRIs in primary care settings.

Second, SSRI treatment can trigger mood changes in undiagnosed bipolar patients (Henry and Demotes-Mainard, 2003) resulting in agitation and disinhibition, and such effects may lead to suicide and violence.

Finally, although all these subjects can be viewed as suffering from depression, far less is known concerning the nature of their depression.

The defining criteria for DSM-IV (APA, 1994) major depression remain in fact very similar to those employed during 19th century, where pharmacotherapy was absent and descriptions of depression phenomenology were typically restricted to profoundly depressed patients. Currently, a large number of patients are diagnosed as depressed because they complain about sadness, however it is not clear if they should be considered as depressed. They may certainly have severe depressed mood that merits attention, but do they necessarily exhibit the same illness needing the same medication? An increasing amount of data now shows that some types of depression recover under antidepressants, whereas some other forms are worsened under the same treatment (Henry et al., 2003; Benazzi et al., 2004). These studies demonstrate that patients may fulfil all DSM-IV criteria for major depressive episode, but they show highly divergent clinical patterns: responders to antidepressants appear to correspond to the former ‘endogeneous depression’ description (characterised by psychomotor retardation, affective anaesthesia, and inhibition) whereas patients worsened by antidepressants have a mixture of depressive symptoms and agitation (restlessness, racing thoughts, emotional lability and hyper -reactivity). As we now have access to efficient drug treatment, it is important to reconsider diagnostic categories in the light of patient response to treatment (as is the case for other medical fields). Perhaps differential response to antidepressants could lead practitioners to better define depression, and its subtypes.

Chantal Henry and Jacques Demotes-Mainard
chenry@perrens.aquisante.fr
Hôpital Charles Perrens, 121 rue de la Béchade, 33076 Bordeaux cedex. France

Whittington CJ., Kendall T., Fonagy P., et al. SSRIs in childhood depression: systematic review of published versus unpublished data. The Lancet, vol 363: 1341-1345

Abbasi K. Compulsory registration of clinical trials. BMJ, 2004, vol 329, 637-638

Lenzer J. FDA to review ‘missing’ drug company documents. BMJ 2005, 330:7

Henry C., Demotes-Mainard J. Avoiding drug-induced switching in patients with bipolar depression. Drug Safety 2003, 26:337-351.

American Psychiatric Association. Diagnostic and statistical Manual of Mental Disorders (DSM-IV), 1994.

Henry C., Van den Bulke, Demazeau N., Demotes-Mainard J. Why are some depressions worsened by antidepressant? Bipolar Disorders 2003: 5(1): 24.

Benazzi F., Koukopoulos A., Akiskal HS. Toward a validation of a new definition of agitated depression as a bipolar mixed state (mixed depression). Eur Psychiatry. 2004, 19(2): 85-90.

Competing interests: None declared