1 Boring Old Man

Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled Randomized Trials

by J. Craig Nelson, M.D. and George I. Papakostas, M.D.

American Journal of Psychiatry. 2009 166:980-991., September 2009

Objective: The authors sought to determine by meta-analysis the efficacy and tolerability of adjunctive atypical antipsychotic agents in major depressive disorder.

Method: Searches were conducted of MEDLINE/PubMed [1966 to January 2009], the Cochrane database, abstracts of major psychiatric meetings since 2000, and online trial registries. Manufacturers of atypical antipsychotic agents without online registries were contacted. Trials selected were acute-phase, parallel-group, double-blind controlled trials with random assignment to adjunctive atypical antipsychotic or placebo. Patients had nonpsychotic unipolar major depressive disorder that was resistant to prior antidepressant treatment. Response, remission, and discontinuation rates were either reported or obtained. Data were extracted by one author and checked by the second. Data included study design, number of patients, patient characteristics, methods of establishing treatment resistance, drug doses, duration of the adjunctive trial, depression scale used, response and remission rates, and discontinuation rates for any reason or for adverse events.

Results: Sixteen trials with 3,480 patients were pooled using a fixed-effects meta-analysis. Adjunctive atypical antipsychotics were significantly more effective than placebo [response: odds ratio=1.69, 95% CI=1.46–1.95, z=7.00, N=16, p<0.00001; remission: odds ratio=2.00, 95% CI=1.69–2.37, z=8.03, N=16, p<0.00001]. Mean odds ratios did not differ among the atypical agents and were not affected by trial duration or method of establishing treatment resistance. Discontinuation rates for adverse events were higher for atypical agents than for placebo [odds ratio=3.91, 95% CI=2.68–5.72, z=7.05, N=15, p<0.00001].

Conclusions: Atypical antipsychotics are effective augmentation agents in major depressive disorder but are associated with an increased risk of discontinuation due to adverse events.

For reference, in a treatment situation like this, an NNT < 4.0 would be a respectable effect size [TCAs are in the range of 3]. An NNT > 10 would be considered no effect at all. As you can see, for the large studies [n > 100], they range from 5.0 to 15.5, average 8.9. That’s a weak effect for this situation. It means treating ~nine cases to beat placebo in one. 

While the efficacy of the atypical agents for adjunctive therapy in major depressive disorder appears fairly well established, there are other considerations. The rate of discontinuation due to adverse events was significantly higher for the atypical group [9.1%] than the placebo group [2.3%]. The risk difference by meta-analysis was 0.06, with a number needed to harm of 17. While the discontinuation rates did not differ significantly among the agents, rates of specific side effects may be quite different. In addition, during continuing treatment there may be other secondary effects that in the aggregate affect tolerability and patient acceptance. The atypical agents also are associated with a variety of relatively serious adverse effects, such as metabolic syndrome, extrapyramidal symptoms, and rare but serious symptoms such as tardive dyskinesia and neuroleptic malignant syndrome. As a consequence, the risk-benefit ratio appears to be different from that of several alternative treatments for major depressive disorder.

And in today’s world, there are always drug prices to keep in mind [this is the current cost/pill from goodRx with their discount coupon paying cash @ Walmart] [users of insurance are paying more] [the dates may be slightly off because of my patent-exclusivity-dyslexia, but they’re close]:

Let me say that again – "this is the current cost/pill" and a low-ball version at that [for the Brand® drugs, this is today’s cost as I couldn’t find their cost when introduced]. There aren’t many people around to whom this wouldn’t matter – at least not where I live. The escalation in price for the Brand drugs is well beyond inflation. The cost for the generic looks to be moving skyward. Unless you’re using one of the generics from the 1990s’ drugs, you’re quickly into sticker-shock territory.

A couple of other things. I’m not excited about adding a withdrawal-prone drug to another withdrawal-prone drug. I’ve had several cases where getting somebody off the combination is something of a nightmare. There’s another thing I don’t really understand. In the past, we saw depression as time limited. If a person responded to antidepressants, we usually continued them for 6 months to prevent relapse. But except in cases of patients with recurrent episodes of depression, we stopped the drugs after a time. These days, people stay on medications forever. At first, I thought it was what their doctors were telling them, but the patients themselves are reticent to stop. For some, it’s a misinterpretation of withdrawal. But for many, they are reluctant to stop them for no apparent reason. I presume they’ve got the idea that they are treating or protecting against some depressive disease. So I’ve taken to saying that the drugs aren’t for-ever, they’re for-a-while. up front. And these days, those responding patients who just won’t stop are in my mind every time I write a prescription.