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Adjunctive Atypical Antipsychotics in Medication-Resistant Depression

Published online by Cambridge University Press:  07 November 2014

J. Craig Nelson
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Conventional antipsychotics have a substantial literature of >30 placebo-controlled studies supporting their use in depression. Reports describing the use of antipsychotic treatment in depression appeared as early as 1959. In the 1970s, combination products of perphenazine and amitrip-tyline were quite popular. Antipsychotic agents were effective for selected symptoms or in selected patients; yet, these agents were not viewed as “true” antidepressants, perhaps because of their lack of effects on loss of interest. The use of antipsychotics in patients with nonpsychotic depression declined rapidly in the 1980s when tardive dyskinesia (TD) surfaced as a potential adverse effect of this class of medications. Depressed patients were thought to be at increased risk. Interest in the potential utility of antipsychotics in depression resurfaced with the availability of the second-generation antipsychotics (SGAs), which possess a considerably lower risk for TD.

Most of the SGAs are inhibitors of the serotonin (5-HT)2A receptor and the dopamine (D)2 receptor. In fact, the ratio of these effects has been considered one attribute of an SGA. The SGAs have a variety of other receptor actions that might contribute to antidepressant effects but which vary substantially among the drugs. These include agonist effects at the 5-HT1A serotonin receptor, inhibition of the 5-HT2C receptor, and partial D2 agonism of aripiprazole (Slide 1). In addition, ziprasidone blocks 5-HT and norepinephrine (NE) reuptake and the metabolite of quetiapine has NE reuptake blocking effects.

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