Intraoperative ketamine for prevention of depressive symptoms after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial

Abstract

Background: Ketamine is a general anaesthetic with anti-depressant effects at subanaesthetic doses. We hypothesised that intraoperative administration of ketamine would prevent or mitigate postoperative depressive symptoms in surgical patients.

Methods: We conducted an international, randomised clinical trial testing the effects of intraoperative administration of ketamine [0.5 mg kg^-1 (Lo-K) or 1.0 mg kg^-1 (Hi-K)] vs control [saline placebo (P)] in patients ≥60 yr old undergoing major surgery with general anaesthesia. We administered the Patient Health Questionnaire-8 before the operation, on postoperative day (POD) 3 (primary outcome), and on POD30 to assess depressive symptoms, a secondary outcome of the original trial.

Results: There was no significant difference on POD3 in the proportion of patients with symptoms suggestive of depression between the placebo [23/156 (14.7%)] and combined ketamine (Lo-K plus Hi-K) [61/349 (17.5%)] groups [difference = -2.7%; 95% confidence interval (CI), 5.0% to -9.4%; P=0.446]. Of the total cohort, 9.6% (64/670; 95% CI, 7.6-12.0%) had symptoms suggestive of depression before operation, which increased to 16.6% (84/505; 95% CI, 13.6-20.1%) on POD3, and decreased to 11.9% (47/395; 95% CI, 9.1-15.5%) on POD30. Of the patients with depressive symptoms on POD3 and POD30, 51% and 49%, respectively, had no prior history of depression or depressive symptoms.

Conclusions: Major surgery is associated with new-onset symptoms suggestive of depression in patients ≥60 yr old. Intraoperative administration of subanaesthetic ketamine does not appear to prevent or improve depressive symptoms.

Clinical trials registration: NCT01690988.

Keywords: anti-depressant; depression; ketamine; surgery.

Fig 1

Consort flowchart of patient participants in the study. POD, postoperative day; PHQ-8, Patient Health Questionnaire-8; PODCAST, Prevention of Delirium and Complications Associated with Surgical Treatments.

Fig 2

Effects of ketamine on postoperative depressive symptoms. Lo-K, randomised group of patients who received a low dose of ketamine (0.5 mg kg⁻¹); Hi-K, randomised group of patients who received a higher dose of ketamine (1 mg kg⁻¹). Imputation method applied; last observed value carried forward. POD, postoperative day; PHQ-8, Patient Health Questionnaire-8.

Fig 3

Percent and 95% confidence intervals of PODCAST study patients with symptoms suggestive of depression before surgery, POD3 and POD30. POD, postoperative day; PODCAST, Prevention of Delirium and Complications Associated with Surgical Treatments.