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.

Fig. 1

Change in estimated marginal mean Montgomery-Åsberg Depression Rating Scale suicide item (MADRS-SI) scores over time in patients with treatment-resistant depression treated with single infusions of ketamine and midazolam using a randomized, double-blind, crossover design (N = 37). Error bars represent SEM. Significant difference between ketamine and midazolam, ***P < 0.001, **P < 0.01, *P < 0.05.

Fig. 2

a Estimated marginal mean preinfusion Montgomery-Åsberg Depression Rating Scale suicide item (MADRS-SI) scores over six open-label repeated ketamine infusions in Phase 2 (N = 36). Error bars represent SEM. Significant difference relative to Phase 2 baseline, ***P < 0.001, **P < 0.01. b Estimated marginal mean preinfusion Montgomery-Åsberg Depression Rating Scale suicide item (MADRS-SI) scores over four open-label maintenance ketamine infusions in Phase 3 (N = 21). Error bars represent SEM.

Fig. 3

Distribution of participants’ Montgomery-Åsberg Depression Rating Scale suicide item (MADRS-SI) scores at study baseline and over six repeated ketamine infusions in Phase 2 (N = 37).

Fig. 4

Correlation between participants’ overall change in depressive symptoms (Montgomery-Åsberg Depression Rating Scale, MADRS items 1–9) and their change in suicidal ideation (MADRS suicide item, MADRS-SI) between baseline and post-Phase 2 follow-up (N = 36).