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. 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.
An estimated 1 million people die from suicide every year, with more than two-thirds of cases occurring during a major depressive episode. Although major depressive disorder (MDD) is amenable to pharmacotherapy, up to one-third of patients fail to respond to treatment and may remain at risk of suicide. Suicidal ideation (SI) is a common symptom in patients with MDD and its development represents a critical step in the progression from suicidal thoughts to attempts. SI often requires rapid intervention(s) but very few treatments are effective in reducing SI and none are fast-acting.
Sub-anaesthetic doses of intravenous (IV) ketamine, have been shown to elicit rapid, albeit transient reduction in depressive symptoms in patients with mood disorders. A recent meta-analysis has also provided evidence of the efficacy of ketamine to acutely decrease SI. While preliminary evidence of the effects of ketamine on SI primarily came from secondary analyses of randomized controlled trials investigating the antidepressant effects of single ketamine infusions, several recent trials have examined change in SI with ketamine as a primary outcome measure.
Despite the rapid relapse rates following a single ketamine infusion, fewer studies have examined the administration of ketamine beyond an acute treatment phase. While reduction in SI appears to last at least 7 days following a single infusion, data from open-label trials suggest that anti-suicidal effects may be sustained with repeated infusions. Few studies have examined the development of a maintenance strategy that would allow the beneficial effects of ketamine to be prolonged with reduced frequency of infusions. In a secondary analysis of data derived from a ketamine augmentation trial involving participants with treatment-resistant depression (TRD) and SI, we tested whether the anti-suicidal effects of ketamine could be augmented through a course of repeated infusions, and whether once-weekly ketamine administration was sufficient to maintain the attenuation of SI obtained with repeated infusions. We have recently shown that this administration strategy extends the duration of depressive symptom remission following repeated infusions.
The findings reported herein support the rapid and cumulative effects of single and repeated ketamine infusions on suicidal thoughts in individuals with TRD, even for those with high pre-treatment SI severity. In subjects with an antidepressant response to ketamine, the alleviation of SI obtained following single and repeated infusions was prolonged with once-weekly treatment. The effects of ketamine on SI appear to be at least partially independent of antidepressant effects and were seen even in participants who failed to meet antidepressant response criteria.
All but three participants (92% of the sample) had a decrease in SI following repeated ketamine infusions, including 14 subjects with marked SI at baseline. These results substantiate emerging evidence that ketamine is a potential therapeutic option for patients with acute SI consistent with previous reports. The three patients without an SI decrease were among those with the highest baseline SI. This finding may be consistent with other findings which found, using pooled data from five clinical trials, that individuals with more severe pre-treatment SI were less likely to achieve an SI response to a single ketamine infusion. On the other hand, according to our subgroup analysis, ketamine infusions were effective in reducing SI overall even among those with marked SI. In the present study, participants had an initial reduction in SI with the single Phase 1 infusion that persisted despite relapse of depressive symptoms and further decreased with repeated infusions administered during Phase 2. This carry-over effect suggests that the anti-suicidal effects of ketamine may last longer than its antidepressant effects, though this was not directly tested. According to clinician-administered MADRS-SI scores, SI decreased significantly after three Phase 2 infusions while with self-reported QIDS-SI scores, the full course of six infusions was required to result in a significant SI decrease. This could be due to a difference in the measures. Nevertheless, participants obtained a decrease in SI following successive Phase 2 infusions, with both measures suggesting cumulative effects. Consequently, patients may gain additional benefits from repeated infusions beyond those obtained from single infusions. Within the present sample, a doubling of antidepressant response rates was achieved with repeated infusions.
The present findings suggest that the effects of ketamine on SI and depression are partially independent. This is supported by the facts that 60% of the variance in overall change in SI was not explained by change in depressive symptoms. Participants’ change in SI with ketamine remained significant when adjusted for their change in depressive symptom scores, and several individuals who failed to meet antidepressant response criteria with ketamine still experienced an alleviation of SI with repeated infusions. These results are consistent with the findings of a meta-analysis that reported that the effects of ketamine on SI are partially independent from its effects on depressive symptoms. This partial independence hints at the potential use of ketamine as a treatment for SI outside the context of TRD.
In summary, this study showed that single and repeated ketamine infusions reduced SI in individuals with TRD, with cumulative effects observed with thrice-weekly repeated infusions, and maintenance of the effects of ketamine on SI with once-weekly infusions. Current treatment options for SI are limited and these findings add to the growing body of research suggesting the promise of ketamine as a novel treatment strategy for SI. In particular, the preliminary evidence of rapid reduction in SI with ketamine suggests its use as a possible emergency strategy for individuals at high risk of suicide as an alternative to more disruptive and costly hospitalization. How long the antisuicidal effects of repeated ketamine infusions last, and whether ketamine-induced reduction in SI can be maintained with alternate pharmacological strategies remains unknown. Moreover, further research is required to determine whether reductions in SI following ketamine treatment translate into decreased risk for suicidal behavior and suicide attempts.