Pharmacological treatment for psychotic depression

Psychotic depression is a severe depression with psychotic features (i.e. delusions and/or hallucinations). Uncertainty surrounds the most effective drug treatment for psychotic depression: with an antidepressant alone, with an antipsychotic alone or with the combination of an antidepressant plus an antipsychotic.

The aim of this review is to compare the efficacy of the various forms of drug treatment that have been used to treat psychotic depression. We did this by analysing all randomised controlled trials (RCTs) that investigated drug treatments for psychotic depression. We searched for these trials in a wide-ranging way. The search identified 3659 studies, but in the end, we found only 12 RCTs that met our inclusion criteria. These trials involved a total of 929 people.

From these trials, we found evidence that the combination of an antidepressant plus an antipsychotic provides more effective treatment for psychotic depression than either treatment alone. However, our confidence in this conclusion is limited because the information came from only a small number of RCTs, which included small numbers of people. In addition, the types of people involved varied between RCTs, and the RCTs differed in design, which means that we cannot confidently generalise their findings.

Authors' conclusions: 

Psychotic depression is heavily understudied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone.

Read the full abstract...

Evidence is limited regarding the most effective pharmacological treatment for psychotic depression: combination of an antidepressant plus an antipsychotic, monotherapy with an antidepressant or monotherapy with an antipsychotic. This is an update of a review first published in 2005 and last updated in 2009.


1. To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression: antidepressant monotherapy, antipsychotic monotherapy and the combination of an antidepressant plus an antipsychotic, compared with each other and/or with placebo.

2. To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment.

Search strategy: 

A search of the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (CCDANCTR) was carried out (to 12 April 2013). These registers include reports of randomised controlled trials from the following bibliographic databases: EMBASE (1970-), MEDLINE (1950-) and PsycINFO (1960-). Reference lists of all studies and related reviews were screened and key authors contacted.

Selection criteria: 

All randomised controlled trials (RCTs) that included participants with acute major depression with psychotic features, as well as RCTs consisting of participants with acute major depression with or without psychotic features, that reported separately on the subgroup of participants with psychotic features.

Data collection and analysis: 

Two review authors independently extracted data and assessed risk of bias in the included studies, according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. Data were entered into RevMan 5.1. We used intention-to-treat data. For dichotomous efficacy outcomes, the risk ratio (RR) with 95% confidence intervals (CIs) was calculated. For continuously distributed outcomes, it was not possible to extract data from the RCTs. Regarding the primary outcome of harm, only overall dropout rates were available for all studies.

Main results: 

The search identified 3659 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction of severity (response) of depression, not of psychosis.

We found no evidence for the efficacy of monotherapy with an antidepressant or an antipsychotic.

However, evidence suggests that the combination of an antidepressant plus an antipsychotic is more effective than antidepressant monotherapy (three RCTs; RR 1.49, 95% CI 1.12 to 1.98, P = 0.006), more effective than antipsychotic monotherapy (four RCTs; RR 1.83, 95% CI 1.40 to 2.38, P = 0.00001) and more effective than placebo (two identical RCTs; RR 1.86, 95% CI 1.23 to 2.82, P = 0.003).

Risk of bias is considerable: there were differences between studies with regard to diagnosis, uncertainties around randomisation and allocation concealment, differences in treatment interventions (pharmacological differences between the various antidepressants and antipsychotics) and different outcome criteria.