Augmentation in treatment-resistant depression: meta-analyses


A number of systematic reviews have investigated the optimal approach in treatment-resistant depression (TRD), but the conclusions are somewhat inconsistent and clinical opinion appears to be evolving.

A decade ago, a survey of Canadian clinicians reported that only 10% opted for an augmentation strategy for TRD; the most commonly used augmentation agents were bupropion and lithium (Mischoulon et al. Can J Psychiatry 2000;45:476-481).

Shortly thereafter, numerous studies investigated the use of atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole) as augmentation agents in TRD. An early meta-analysis found that patients receiving adjunctive antipsychotic treatment were more likely to experience a remission (risk ratio 1.75) (Papakostas et al. J Clin Psychiatry 2007;68:826-831). The pooled remission and response rates were 47.4% and 57.2% with antipsychotic augmentation, respectively versus 22.3% and 35.4% with no augmentation.

A second meta-analysis came to the same conclusion (Nelson & Papakostas. Am J Psychiatry 2009;166:980-991). Adjunctive antipsychotics were more effective than placebo in achieving a response (odds ratio 1.69) or remission (OR 2.00). However, the rate of discontinuations due to adverse effects was significantly higher with the addition of an antipsychotic (OR 3.91).

A Cochrane review of 28 studies also found that antipsychotics were effective in augmentation but also noted the problem of adverse effects  (Komossa et al. Cochrane Database Syst Rev 2010 Dec 8;(12):CD008121). Of concern were weight gain (aripiprazole, olanzapine, risperidone), extrapyramidal symptoms (aripiprazole), increased prolactin (olanzapine, risperidone) and sedation (quetiapine).

A more recent review offered a more cautious recommendation (Wright et al. Pharmacotherapy 2013;33:344-359). The analysis concluded that atypical antipsychotics may be effective as adjunctive therapy, but noted that this approach may not be optimal in some patients because of adverse effects. The reviewers recommended switching antidepressants before trying augmentation in patients with an inadequate response to an antidepressant. They also stated that if an antipsychotic medication is used, the dosing should be individualized, and frequent reassessment of safety and efficacy was needed.

Over the past decade, the use of antipsychotics for non-psychotic depression has increased but overall use remains somewhat low, according to a recent analysis of data from the U.S. National Ambulatory Medical Care Survey (Gerhard et al. J Clin Psychiatry 2014; epublished January 7, 2014). In 1999-2000, atypical antipsychotics were used in 4.6% of all adult depression visits. This increased to 12.5% for the period 2009-2010. An antipsychotic was five-fold more likely to be prescribed by a psychiatrist compared to other health professionals. Patients with a diagnosis of major depressive disorder were more likely to receive an antipsychotic compared to those with other depressive disorders (adjusted OR 1.49). Antipsychotics were less likely to be prescribed in patients older than age 65 years (adjusted OR 0.51 vs. ages 18-44 years), and patients who were receiving psychotherapy (adjusted OR 0.68).

And what happened to lithium? Valenstein and colleagues asked this question after an analysis of the Veterans Administration database (Am J Psychiatry 2006;163:1219-1925). They found that 22% of patients with depression had received augmentation – but only 0.5% were prescribed lithium.

A recent systematic review of 12 studies compared augmentation with lithium or an atypical antipsychotic (Edwards et al. Health Technol Assess 2013;17:1-190). In the primary analysis, the SSRI was fluoxetine; the atypical antipsychotic was olanzapine. The result was a non-significant trend favouring lithium. However, there were uncertainties in the model so the group concluded that lithium and an atypical antipsychotic appear to be similarly effective in TRD.

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