Cognitive Function Mediates the Anti-suicide Effect of Repeated Intravenous Ketamine in Adult Patients With Suicidal Ideation

Abstract

ObjectivePrior research has shown that ketamine has anti-suicide effects. Additional evidence also suggests that ketamine may offer pro-cognitive effects. Herein, we propose that the anti-suicide effects of ketamine are partially mediated via pro-cognitive effects. We aimed to determine whether improvement in cognitive function mediated change in suicidal ideation was associated with ketamine treatment.MethodsUnipolar or bipolar depressive patients (n = 86) with suicidal ideation received six infusions of ketamine (0.5 mg/kg) over 2 weeks. The current severity of suicidal ideation and depression symptoms were assessed with the Beck Scale for Suicide Ideation (SSI) and the Montgomery–Asberg Depression Rating Scale (MADRS), respectively, at baseline, days 13 and 26. Cognitive domains, including processing speed, working memory, visual learning, and verbal learning were measured with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery at the same time points.ResultsMediation analysis showed a significant total effect of ketamine treatment on SSI score (coef = –1.853, 95%CI [–2.2, –1.5]). The direct and total indirect (MADRS total score and any of cognitive domains) effects of ketamine on suicidal ideation both were statistically significant (direct: coef = –1.064 to –1.352; total indirect: coef = –0.501 to –0.788). MADRS total score and processing speed (but not other cognitive domains) were significant partial mediators of the association between ketamine treatment and improvements in suicidal ideation.ConclusionDepressive symptoms severity and processing speed performance partially mediated improvements in suicidal ideation after repeated ketamine infusions in persons with unipolar or bipolar depressive disorder.

Arketamine for cognitive impairment in psychiatric disorders

“…Repeated infusion of ( R,S )-ketamine (0.5 mg/kg) caused significant improvement of working memory in MDD patients with PTSD [ 89 ]. Interestingly, depression symptom severity and processing speed performance in patients with MDD or BD partially mediated the improvements in suicidal ideation after repeated infusion of ( R,S )-ketamine [ 90 ]. A recent systematic review indicated potential procognitive effects of subanesthetic doses of ( R,S )-ketamine among patients with depression, although there is evidence for immediate altered cognitive dysfunction in healthy subjects [ 91 ].…”

Baseline cognitive function predicts full remission of suicidal symptoms among patients with treatment-resistant depression and strong suicidal ideation after low-dose ketamine infusion

“…Novak et al reported that higher baseline cognitive flexibility was associated with lower suicidal ideation 3 months after psychiatric discharge among patients treated with oral antidepressants (Novak et al, 2022). Over the nearly 10 years that low-dose ketamine infusion has been believed to rapidly exert an antisuicidal effect, evidence suggested the predictive role of baseline cognitive function on this antisuicidal effect (Chen et al, 2021; Lee et al, 2016; Price et al, 2014; Zhou et al, 2022). Price et al performed the implicit-association test (ITA) to assess the relative speed with which patients classified words when a given manual key response was required for two constructs (escape/stay and me/not me), and they discovered that higher implicit “Escape = Me” ITA scores were associated with less severe suicidal symptoms among patients who underwent ketamine infusion (Price et al, 2014).…”

“…Price et al performed the implicit-association test (ITA) to assess the relative speed with which patients classified words when a given manual key response was required for two constructs (escape/stay and me/ not me), and they discovered that higher implicit "Escape = Me" ITA scores were associated with less severe suicidal symptoms among patients who underwent ketamine infusion (Price et al, 2014). Zhou et al reported that processing speed and verbal learning, but not working memory, significantly improved after six ketamine infusions in patients with MDSI; they also identified an association between higher pretreatment processing speed and less postinfusion suicidal ideation (Zhou et al, 2022). In this study, we discovered that both working memory and response inhibition (go/no-go task) at baseline were associated with the remission of suicidal symptoms after ketamine infusion.…”

“…Studies have suggested that several cognitive functions (e.g., working memory and processing speed) are associated with the antisuicidal effect of low-dose ketamine among patients with MDSI (Chen et al, 2021; Keilp et al, 2021; Zhou et al, 2022). Keilp et al demonstrated that relative to midazolam, a single infusion of low-dose ketamine rapidly yielded greater reductions in suicidal ideation and improvements in mood and was associated with shorter reaction times and greater cognitive control (Keilp et al, 2021).…”

“…A study of 59 patients with MDSI who completed six intravenous infusions of ketamine over 12 days reported that the improvement in the working memory of the patients was associated with the antisuicidal effect of low-dose ketamine (Chen et al, 2021). In addition, Zhou et al measured the processing speed, working memory, and visual and verbal learning of 86 patients with MDSI or bipolar depression with suicidal ideation who received six infusions of 0.5 mg/kg ketamine over 2 weeks; only baseline processing speed was a significant predictor of the remission of suicidal symptoms (Zhou et al, 2022). Given the aforementioned findings, further studies are necessary to clarify the association between baseline cognitive function and the quick-acting and sustained antisuicidal effects of low-dose ketamine infusion.…”