(Es)ketamine as a treatment for depressive episodes with psychotic features: systematic review

Psychotic symptoms in depression are linked to worse outcomes, and treatment options are limited. Ketamine and esketamine are effective antidepressants, yet most studies have excluded patients with a history of psychotic symptoms.

To evaluate by systematic review the efficacy and safety of ketamine and esketamine in treating patients with unipolar or bipolar depressive episodes with psychotic features.

A comprehensive search of the PubMed, Ovid and Web of Science databases was conducted up to 2 November 2023. We included any study that reported the use of ketamine or esketamine in patients with depressive episodes with psychotic symptoms. The primary outcomes assessed were variations in depressive and psychotic symptoms and the incidence of adverse events. The protocol was preregistered in PROSPERO (CRD42023488524).

Ten studies were included, encompassing 60 patients with unipolar depression with psychotic symptoms and 19 patients with bipolar depression with psychotic symptoms. Treatment with (es)ketamine showed mean score changes on the Montgomery-Åsberg Depression Rating Scale ranging from -13.7 to -18.2 points in open-label studies of patients with unipolar depression with psychotic symptoms. Up to 50% of participants achieved remission. The largest study with patients with bipolar depression with psychotic symptoms reported a mean Montgomery-Åsberg Depression Rating Scale score change of -14.9 points. Adverse events were mostly mild and transient. There were no reports of switches to (hypo)mania or deterioration of psychotic symptoms, and in six studies there was substantial improvement of the latter.

The available evidence suggests that (es)ketamine shows antidepressant effects in patients with depressive episodes with psychotic features and has a reasonable safety profile. However, the heterogeneity of the studies included in this review and the high risk of bias warrant caution in interpreting the findings and underscore the need for further trials to confirm these preliminary results.