Antipsychotics work against major depressive disorder, with caveats

Patients with major depressive disorder (MDD) generally achieve satisfactory treatment response with antipsychotic treatment, used either as monotherapy or adjunctively, a meta-analysis has shown. However, this benefit comes with an increased risk of adverse events.

“The risks for intolerability-related discontinuations were higher than with placebo and generally higher than the effect sizes for efficacy,” according to the investigators.

Looking at the use of antipsychotics as monotherapy, the pooled risk ratios (RRs) for treatment response and intolerability-related discontinuation were 1.54 (95 percent confidence interval [CI], 1.33–1.78; p<0.001, number needed to treat [NNT]=5) and 2.56 (95 percent CI, 1.86–3.54; p<0.001, number needed to harm [NNH]=21), respectively. [Psych Med 2022;doi:10.1017/S0033291722000745]

In adjunctive therapy, the corresponding RRs for treatment response and intolerability-related discontinuation were 1.35 (95 percent CI, 1.26–1.45; p<0.001, NNT=12) and 2.39 (95 percent CI, 1.69–3.38; p<0.001, NNH=37).

“Nevertheless, the risk/benefit balance of antipsychotics varied by specific [medication] and their dose,” the investigators pointed out.

Specifically, a favourable risk/benefit ratio was seen with sulpiride as monotherapy (efficacy: RR, 1.50, 95 percent CI, 1.03–2.17; p=0.032; tolerability: RR, 1.03, 95 percent CI, 0.07–16.3; p=0.981) and with low-dose risperidone as adjunctive treatment (efficacy: RR, 1.59, 95 percent CI, 1.19–2.14; p=0.002; tolerability: RR, 1.15, 95 percent CI, 0.29–4.53; p=0.840).

Differing antidepressant effects

The meta-analysis included 45 randomized controlled trials, involving a total of 12,724 patients. Pooled data of monotherapy use (13 studies, n=4,375) showed that aside from sulpiride, amisulpride (RR, 1.99, 95 percent CI, 1.55–2.55) and quetiapine (RR, 1.48, 95 percent CI, 1.23–1.78) were superior to placebo in terms of treatment response. However, both drugs were associated with higher tolerability-related discontinuations than placebo.

In adjunctive therapy use (32 studies, n=8,349), ziprasidone (RR, 1.80, 95 percent CI, 1.07–3.04), aripiprazole (RR, 1.54, 95 percent CI, 1.35–1.76), brexpiprazole (RR, 1.41, 95 percent CI, 1.21–1.66), cariprazine (RR, 1.27, 95 percent CI, 1.07–1.52), and quetiapine (RR, 1.23, 95 percent CI, 1.08–1.41) all performed better than placebo regarding treatment response. But consistent with the results of monotherapy analysis, these antipsychotics led to higher discontinuations due to intolerability.

“Notably, in our sensitivity analysis that examined the antipsychotic dose for antidepressant effect, the high-dose range did not have treatment effect when antipsychotics were used as monotherapy, whereas in low- or middle-dose range they did,” the investigators pointed out.

“When used adjunctively, this dose relationship was not prominent, indicating this mechanism of action may be more complex when antipsychotics are combined with antidepressants. Nevertheless, it is notable that the utilized mean dosages of risperidone were low (0.8–2.0 mg/day). Additionally, at higher antipsychotic doses, the intolerability-related discontinuations were also higher,” they added.

Taken together, the data indicate that the antidepressant effects of antipsychotics can differ significantly, depending on the specific second-generation antipsychotic and its doses, as well as monotherapy/adjunctive use, according to the investigators. This emphasizes the need for a better understanding of the complex role of antipsychotics in the treatment of MDD.

Despite the presence of several study limitations, including the small number of trials for individual antipsychotics, the investigators believe that their findings ought to inform the clinical use of antipsychotics in the management of MDD.