New Cochrane review finds weak evidence that drug combinations are more effective than monotherapy in psychotic depression


Major depression remains a serious condition that often proves refractory to pharmacological or psychotherapeutic interventions.

Because depression can have many “faces”, clinicians should be aware of the great symptom variability among depressed patients and consider subforms when prescribing medication.  In a sizeable amount of patients (up to 25%, Coryell et al., 1984), depression presents with psychotic symptoms, such as delusions or hallucinations.

As psychotic depression is usually associated with worse treatment outcome, its successful management needs stringent guidelines. In an attempt to provide these, an updated Cochrane review has looked at pharmacotherapy in psychotic depression (Wijkstra et al., 2013) more closely.


Several medical databases (Embase, Medline and PsycINFO) were searched for relevant randomised controlled trials (RCTs) and of the identified 3659 studies, 12 papers with in total 929 patients met inclusion criteria. Risk ratios (RR) and confidence intervals (CIs) are reported for all comparisons.


  • Monotherapy with either an antidepressant or antipsychotic is not supported by the evidence
  • Combinations of antidepressants and antipsychotics are significantly more efficacious than:
    • Antidepressant monotherapy (RR  1.49, CI 1.12-1.98, p = 0.006)
    • Antipsychotic monotherapy  (RR 1.83, CI 1.40-2.38, p < 0.001)
    • Placebo intervention (RR 1.86, CI 1.23-2.82, p = 0.003)

However, the authors are careful to note a considerable risk of bias because of heterogeneity across studies, including differences in treatment approaches (e.g. differences among used drugs) and outcome criteria.


The authors conclude that:

There's a dearth of high quality research to support evidence-based practice in this area

There’s a dearth of high quality research to support evidence-based practice in this area

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.


  • Research on the treatment of depression with psychotic features is hampered by the scarcity of available RCTs. Ironically, the extent to which publication bias played a role in this could not be determined precisely because of the lack of data. The authors suggest, however, that there is at least reason to suspect selective publishing.
  • Adding to this, sample sizes are usually very small, increasing the likelihood of a type 2 error that might lead to an underestimation of monotherapy efficacy.
  • The great variability among the studies regarding patient characteristics, treatment type, design and outcome measures provides a further drawback to this review.
  • Likewise, the conclusion that combinations of an antidepressant and antipsychotics are superior to monotherapy applies only to the drugs that were studied (i.e. venlafaxine, quetiapine, olanzapine, fluoxetine and sertraline). More research is needed to determine whether these findings also generalise to other, more recently developed compounds.


This review suggests that a combination of an antidepressant and antipsychotic is more efficacious than monotherapy in the treatment of psychotic depression. However, due to the limited empirical evidence, these results remain preliminary until further research is conducted.

As always, carefully considered shared decision making is the order of the day when the benefits and harms of drug treatment are not clear cut

As always, carefully considered shared decision making is the order of the day, when the benefits and harms of drug treatment are not clear cut

For practitioners, the implications of this latest review are somewhat ambiguous. While there is some evidence to recommend polypharmacy, the decision of whether or not to add an antipsychotic deserves further consideration, given the gravity of common adverse effects. In any case, depressed patients suspected of psychotic features should be carefully assessed before antipsychotic treatment is initiated.


Wijkstra, J.; Lijmer, J.; Burger, H.; Geddes, J. & Nolen, W.A. (2013). Pharmacological treatment for psychotic depression. Cochrane Database of Systematic Reviews 2013(11). Art. No.: CD004044. DOI: 10.1002/14651858.CD004044.pub3.

Coryell, W.; Pfohl, B., & Zimmerman, M. (1984). The clinical and neuroendocrine features of psychotic depression. Journal of Nervous and Mental Disease, 172(9), 521-528.

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