Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety

Suicidal ideation is a common and potentially life‑threatening presentation in psychiatry, yet there are few rapid-acting pharmacological treatments specifically approved for suicidal thoughts. Earlier research has shown that ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects and can reduce suicidal ideation, anxiety and hopelessness within hours to days after a single subanesthetic infusion. However, because suicidal thinking is closely related to both depressive and anxiety symptoms, it remains uncertain whether ketamine's anti‑suicidal effects are merely a by‑product of mood and anxiety improvement or whether ketamine has a more specific effect on suicidal cognition. This study set out to evaluate whether ketamine reduces suicidal ideation independently of its effects on depression and anxiety. Using pooled patient‑level data from previous ketamine trials, the investigators tested correlations between changes in ideation, depression and anxiety at 230 minutes post‑infusion, and used linear mixed models in placebo‑controlled subsets to assess the effect of ketamine on suicidal ideation while statistically controlling for concurrent changes in depressive and anxiety symptoms. They also examined two cognitive components of ideation—the wish to live and the wish to die.

The investigators combined patient‑level data from four previously published clinical trials of ketamine in treatment‑resistant depression, including one open‑label trial and one ongoing mechanism‑of‑action trial. The pooled sample comprised adults aged 18–65 admitted to an inpatient research unit; all met DSM‑IV criteria for a major depressive episode in the context of Major Depressive Disorder or Bipolar Disorder (without psychotic features) and had moderate or greater depression severity at screening (HAMD ≥18 or MADRS thresholds reported in the original trials). Active substance use disorders were exclusionary in the preceding three months except for nicotine and caffeine, and participants were medically stable as judged by history, examination and laboratory tests. A single intravenous subanesthetic dose of ketamine hydrochloride (0.5 mg/kg over 40 minutes) was administered to all patients. Assessments were made pre‑infusion (60 minutes before) and at 40, 80, 120 and 230 minutes, and at one, two and three days post‑infusion. Key measures included the 17‑item Hamilton Rating Scale for Depression (HAMD), using the suicide item as a common index of ideation across the full sample (n = 133); the Anxiety Somatization Factor Score derived from six HAMD items to capture anxious features within depression; the Scale for Suicide Ideation (SSI), from which the first two items—"Wish to Live" and "Wish to Die"—were analysed (SSI was administered to a subset, n = 106, and a further restricted subset with baseline SSI ideation was used in some analyses, n = 39); the Beck Depression Inventory (BDI), with its suicide item excluded from total score for these analyses; and the Hamilton Anxiety Rating Scale (HAMA). For statistical analysis, Pearson correlations assessed absolute change scores at 230 minutes post‑infusion between suicidal ideation, depression and anxiety measures, with suicide items removed from depression totals to minimise redundancy. A series of linear mixed models was run in the subset of participants from double‑blind, placebo‑controlled crossover studies who had any baseline suicidal thoughts on the HAMD (n = 57); models included time and intervention as fixed within‑subject factors, a fixed intercept, and drug-by-time interaction, using a compound symmetry covariance structure. Three‑way interactions tested whether ketamine effects on ideation persisted when accounting for concurrent changes in depression or anxiety over time; non‑significant three‑way terms were omitted in favour of two‑way interactions. Separate mixed models evaluated the SSI Wish to Live and Wish to Die items in the SSI subset with baseline ideation (n = 39). Analyses were conducted in SPSS v21 with two‑tailed significance set at p < .05.

The pooled sample comprised 133 patients: 98 with Major Depressive Disorder and 35 with Bipolar Disorder (19 Bipolar I, 16 Bipolar II). The sample was 51% male (n = 68) with mean age 47.8 years (SD 12.3). At baseline, 61% (n = 81) endorsed any suicidal ideation on the HAMD suicide item and 40% (n = 53) reported a lifetime history of suicide attempts; baseline ideation was associated with prior attempt history (p = .004) but not with age, gender or age at illness onset. At 230 minutes post‑ketamine, Pearson correlations showed that changes in suicidal ideation were significantly associated with changes in depressive symptoms, with correlations ranging from r = 0.31 to r = 0.44 across measures. The strongest association (r = 0.44) was between the HAMD depression cluster and the SSI Wish to Die item, which corresponds to approximately 19% of variance in ideation change explained by depression. Changes in anxiety correlated with changes in ideation with r values from 0.27 to 0.40, explaining at most about 16% of the variance. In a combined regression using HAMD depression and HAMD anxiety factors, the depression cluster remained a significant predictor of ideation change (standardised β = 0.24, p = .03) whereas HAMD anxiety did not (β = 0.16, p = .13). Linear mixed models in the double‑blind crossover subset with baseline HAMD ideation (n = 57) found a significant overall reduction in suicidal ideation after ketamine versus placebo (F1,586 = 42.84, p < .001); the drug-by-time interaction approached but did not pass conventional significance (p = .050). When the models controlled for ketamine's effects on depression over time (three‑way interaction), ketamine retained a significant main effect on ideation (F1,587 = 10.31, p = .001) and the time-by‑intervention interaction became significant (F6,534 = 2.39, p = .03); post‑hoc testing indicated a significant difference between ketamine and placebo at the 40‑minute time point (p < .001). In analogous models controlling for anxiety over time, ketamine again had a significant main effect on ideation (F1,567 = 8.54, p = .004) though the time-by‑intervention interaction was not significant. In the placebo‑controlled SSI subset with baseline SSI ideation (n = 39), ketamine was associated with an increased wish to live (F1,393 = 53.05, p < .001) and a decreased wish to die (F1,389 = 48.53, p < .001); time-by‑intervention interactions were non‑significant. These effects on the Wish to Live and Wish to Die items persisted when statistically controlling for concurrent depressive (p < .01) and anxiety symptoms (p < .001) across time points.

Ballard and colleagues interpret these post‑hoc findings as evidence that ketamine reduces suicidal ideation in depressed patients in a manner that is related to but not fully explained by concurrent reductions in depression and anxiety. Although changes in mood and anxiety correlated with ideation change, together they accounted for only up to 19% of the variance, indicating that a substantial proportion of the anti‑suicidal response may reflect effects beyond general symptomatic improvement. The authors further highlight that ketamine specifically increased the wish to live and decreased the wish to die—cognitive components of ideation that predict future suicide—effects that remained after adjusting for depressive and anxiety symptom change. The investigators situate these clinical observations within emerging mechanistic hypotheses linking ketamine to enhanced synaptic plasticity via glutamatergic transmission, NMDA antagonism, reduced eEF2 phosphorylation, and increased BDNF translation, while noting that these mechanisms remain speculative in humans. They emphasise the importance of considering anxiety as well as depression in the assessment of suicide risk, since reductions in anxiety explained a comparable proportion of ideation change as depression in some analyses and comorbid anxiety has been associated with transition from thoughts to suicidal behaviour. Several limitations are acknowledged. This work is a secondary, post‑hoc analysis and cannot establish causality. The pooled sample was selected for current depressive episodes rather than acutely severe suicidal ideation, limiting generalisability to emergency or highly suicidal populations; the authors call for replication in samples selected for high ideation severity. Other cognitive predictors of suicide risk, such as hopelessness, were not comprehensively measured here and could be informative in future studies. Finally, the largest antisuicidal effects were observed at 40 minutes post‑infusion, the time of greatest dissociative and hemodynamic effects, which complicates interpretation of rapid benefits and suggests the need to disentangle symptomatic relief from acute psychotomimetic effects. The authors conclude that targeted investigations—including biomarker studies and trials in patients with higher baseline suicidal ideation—are warranted to clarify ketamine's specific effects on suicidal thinking.

Reductions in suicidal ideation following a single subanesthetic ketamine infusion were related to, but not wholly accounted for by, concurrent reductions in depression and anxiety in this pooled sample of patients with treatment‑resistant depressive episodes. The findings support further evaluation of ketamine as a probe to study the neurobiology of suicidal thoughts and as a potential rapid intervention for suicidal individuals, with additional trials needed in samples selected for higher ideation severity and investigations of underlying biomarkers.