Effects of ketamine on individual symptoms and symptom networks of depression in a randomised controlled trial of ketamine for treatment-resistant depression

Background Understanding the effects of ketamine on depressive symptoms could help identify which patients might benefit and clarify its mechanism of action in both the early (<= 1 day post-infusion) and late (e.g. 2-30 days post-infusion) post-infusion periods. Symptom network analyses could provide complementary information regarding relationships between symptoms.Aims To identify the effects of ketamine on symptom-level changes in depression across both the early and late post-infusion periods and on depressive symptom network changes.Methods In this secondary analysis of 152 adults with treatment-resistant depression (with 38.8% reporting suicidal ideation at baseline), we compared symptom changes in the early and late post-infusion periods between individuals randomised to a single 40 min infusion of intravenous ketamine 0.5 mg/kg (n = 103) or saline (n = 49) and identified changes in symptom networks between pre- and post-ketamine treatment using network analyses.Results In the early post-infusion period, the greatest improvement (comparing ketamine with saline) was in depressive symptoms related to sadness. In network analyses, symptom network connectivity increased following ketamine infusion. Symptoms of sadness and lassitude showed persistent improvement in the first week post-infusion, whereas improvements in suicidal thoughts first emerged 3-4 weeks post-infusion.Conclusion Ketamine improved all symptoms but showed the greatest effect on symptoms of sadness, both immediately and in the initial week after treatment. Ketamine also rapidly altered the topology of symptom networks, strengthening interrelationships between residual symptoms. The efficacy of ketamine (compared with saline) regarding suicidal symptoms emerged later. Our findings suggest potentially divergent efficacy, time courses and mechanisms for different symptoms of depression.