Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression

Abstract

Repeated administration of subanesthetic intravenous ketamine may prolong the rapid decrease in suicidal ideation (SI) elicited by single infusions. The purpose of this secondary analysis was to evaluate reduction in SI with a single ketamine infusion compared with an active control, and prolonged suppression of SI with repeated and maintenance infusions. Thirty-seven participants with treatment-resistant depression (TRD) and baseline SI first received a single ketamine infusion during a randomized, double-blind crossover with midazolam. Following relapse of depressive symptoms, participants received six open-label ketamine infusions administered thrice-weekly over 2 weeks. Antidepressant responders (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) received four further open-label infusions administered once-weekly. Changes in SI were assessed with the suicide items on the MADRS (item 10, MADRS-SI) and the Quick Inventory of Depressive Symptomatology-Self Report (item 12, QIDS-SI). Linear mixed models revealed that compared with midazolam, a single ketamine infusion elicited larger reduction in SI (P = 0.01), with maximal effects measured at 7 days postinfusion (P < 0.001, Cohen's d = 0.83). Participants had cumulative reductions in MADRS-SI scores with repeated infusions (P < 0.001), and no further change with maintenance infusions (P = 0.94). QIDS-SI results were consistent with MADRS-SI. Overall, 69% of participants had a complete alleviation of SI following repeated infusions. In TRD, single and repeated ketamine infusions resulted in decreases in SI which were maintained with once-weekly maintenance infusions. This study adds to the growing body of research suggesting ketamine as a possible novel treatment strategy for SI in mood disorders.

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

“…One meta-analysis found that ketamine loses its effect in bipolar depression after day 3 or 4. 58 Several RCTs have now looked at repeated infusions of six intravenous infusions over several weeks, 60–62 but to date no long-term RCTs exist.…”

Ketamine treatment for individuals with treatment-resistant depression: longitudinal qualitative interview study of patient experiences

“…13 Phillips et al found that patients with a positive response in mood ratings to a single ketamine infusion, which was maximal at 7 days post-infusion, subsequently had sustained reduction in suicidal ideation with repeated weekly infusions. 14 Review of clinical case records has indicated benefits of repeated ketamine infusions in a sizeable proportion of patients. 15 However, there is a shortage of qualitative studies of patients' experiences over time.…”

A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol

“…Second, the trial includes a novel maintenance strategy for IV ketamine administration that involves sequentially decreasing the frequency of infusions following response. This strategy was shown to effectively maintain antidepressant response and alleviation of suicidal ideation over shortterm follow-up by our group [10,49]. Further support for this approach comes from successful relapse prevention in long-term trials of maintenance administration of intranasal esketamine, an S-enantiomer of racemic ketamine [50].…”