Another meta-analysis has cast doubt on the effectiveness of drug therapy as a strategy for tackling depression, specifically the less severe forms of the disease.

The study published in the Journal of the American Medical Association (JAMA) found that in six trials involving treatment with paroxetine (GlaxoSmithKline’s Paxil, Seroxat), the genericised imipramine or placebo, the benefits of medication versus placebo were “non-existent to negligible” among patients with mild, moderate or even severe symptoms of depression, whereas in patients with very severe depression the effects were substantial.

“What makes our findings surprising is the high level of depression symptom severity that appears to be required for clinically meaningful drug/placebo differences to emerge, particularly given the evidence that the majority of patients receiving ADM [antidepressant medication] in clinical practice present with scores below these levels,” commented the US researchers led by Robert DeRubeis and Jay Fournier of the Department of Psychology at the University of Pennsylvania, Philadelphia.

However, Paxil manufacturer GlaxoSmithKline questioned the validity of the findings, saying the trials used for the meta-analysis “differ methodologically from studies used to support the approval of paroxetine for major depressive disorder, so it is difficult to make direct comparisons between the study results”.

One problem with the evidence base from clinical trials of antidepressants is that they exclude many of the patients whose illness reflects the forms of depression more commonly presented in clinical practice, DeRubeis et al suggested. They cited one survey in which around 70% of all patients seeking treatment for depression fell into the milder category.

Limited evidence

"Prescribers, policy makers and consumers may not be aware that the efficacy of medications largely has been established on the basis of studies that have included only those individuals with more severe forms of depression,” the authors said.

“This important feature of the evidence base is not reflected in the implicit messages present in the marketing of these medications to clinicians and the public. There is little mention of the fact that efficacy data often come from studies that exclude precisely those MDD [major depressive disorder] patients who derive little specific pharmacological benefit from taking medications.”

According to the University of Pennsylvania, the study findings suggest that doctors recommending treatment for people with mild or moderate depression should compare the expected costs and benefits of medication against alternatives such as self-help, exercise or psychological therapy.

The team led by DeRubeis and Fournier looked at randomised, placebo-controlled trials of antidepressants approved by the US Food and Drug Administration in the treatment of major or minor depressive disorder.

The selection criteria included a medication-versus-placebo comparison for at least six weeks, no exclusion of patients on the basis of a placebo wash-out period, and use of the Hamilton Depression Rating Scale. The six studies covered by the meta-analysis involved a total of 718 patients.

In February 2008, a team from Hull University in the UK published the results of a meta-analysis examining both published and unpublished data from trials of four serotonin re-uptake inhibitor antidepressants (SSRIs): Seroxat, Eli Lilly’s Prozac (fluoxetine), Wyeth’s Effexor (venlafaxine) and Bristol-Myers Squibb’s drug Serzone (nefazodone).

The Hull researchers concluded that the antidepressants did not have clinically significant effects in mildly depressed patients or in most patients with very severe depression when compared with placebo. They had used Freedom of Information legislation to access data on the SSRIs submitted as part of approval applications but not subsequently made public.