The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis

Wilkinson, Samuel T.; Ballard, Elizabeth D.; Bloch, Michael H.; Mathew, Sanjay J.; Murrough, James W.; Feder, Adriana; Šóš, P.; Wang, Gang; Zarate, Carlos A.; Sanacora, Gerard

doi:10.1176/appi.ajp.2017.17040472

Cited by 479 publications

(313 citation statements)

References 33 publications

Supporting

Mentioning

283

Contrasting

Unclassified

Order By: Relevance

“…Meta-analyses have confirmed and further supported the significance of both ketamine’s antidepressant [25–28] and anti-suicidal [29] actions compared to placebo controls. This finding revolutionized and established the concept of rapid-acting antidepressant medications.…”

Section: Introductionmentioning

confidence: 89%

“…Relapse to depression following ketamine treatment might be related to the reversal of the synaptic effects of ketamine [39]; also see Sections 4 and 5. In addition to its antidepressant actions, a single infusion of ketamine induces anti-anhedonic effects [40] and reduces suicidal ideation [29] in depressed patients with an effect commencing within a few hours of administration and lasting for up to 1 week, similar to its antidepressant time course. Importantly, the anti-suicidal actions of ketamine are partially independent of its antidepressant effects [29, 41], although further studies are required to confirm this conclusion.…”

Section: Ketamine: the Prototype Rapid-acting Antidepressantmentioning

confidence: 99%

“…In addition to its antidepressant actions, a single infusion of ketamine induces anti-anhedonic effects [40] and reduces suicidal ideation [29] in depressed patients with an effect commencing within a few hours of administration and lasting for up to 1 week, similar to its antidepressant time course. Importantly, the anti-suicidal actions of ketamine are partially independent of its antidepressant effects [29, 41], although further studies are required to confirm this conclusion. The clinical findings regarding ketamine’s antidepressant actions are also supported by animal tests that predict rapid-onset antidepressant action, including the 24-h forced-swim test [42–44], learned helplessness [42, 43, 45–51], novelty-suppressed feeding [49, 52–55], and novelty-induced hypophagia [56, 57].…”

Section: Ketamine: the Prototype Rapid-acting Antidepressantmentioning

confidence: 99%

See 2 more Smart Citations

Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

Self Cite

View full text Add to dashboard Cite

Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal and anti-anhedonic actions following a single administration to depressed patients. Proposed mechanisms of ketamine’s antidepressant action include N-methyl-D-aspartate receptor (NMDAR) modulation, GABAergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergoing pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine - pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists (i.e. GLYX-13 (rapastinel)), metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

show abstract

Section: Introductionmentioning

confidence: 89%

Section: Ketamine: the Prototype Rapid-acting Antidepressantmentioning

confidence: 99%

Section: Ketamine: the Prototype Rapid-acting Antidepressantmentioning

confidence: 99%

See 1 more Smart Citation

Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Included patients did not differ significantly in ketamine (pooled N = 93) vs control (pooled N = 74) groups on sociodemographic and important clinical parameters such as baseline severity of depression. The findings of this meta-analysis 15 are summarized in Table 1. In short, on almost all outcomes at almost all time points between posttreatment days 1 and 7, ketamine was superior to control intervention.…”

Section: Ketamine Reduces Suicidality Inmentioning

confidence: 99%

“…At least 2 RCTs, 18,19 not included in the meta-analyses discussed, 13,15 have recently been published. Both RCTs recruited patients with clinically significant suicidal ideation, operationalized as a Scale for Suicidal Ideation (SSI) score of at least 4.…”

Section: Recent Randomized Controlled Trials Of Ketamine In Patientsmentioning

confidence: 99%

Ketamine for Depression, 6: Effects on Suicidal Ideation and Possible Use as Crisis Intervention in Patients at Suicide Risk

Andrade

2018

J. Clin. Psychiatry

View full text Add to dashboard Cite

A growing body of literature suggests that ketamine, administered in subanesthetic doses, has early-onset antidepressant action in patients with severe and even treatment-refractory depression. Many case reports, open-label studies, and randomized controlled trials (RCTs) suggest that ketamine may have dramatic antisuicidal effects, as well. This article examines the benefits of ketamine in patients with suicidal ideation with particular focus on the findings of recent RCTs and meta-analyses. Important findings are that a single dose of ketamine is associated with antisuicidal benefits that emerge within an hour of administration and persist for up to a week. The benefits are seen in patients with mild as well as clinically significant suicidal ideation. The benefits are observed in midazolam- as well as saline-controlled trials. Effect sizes are medium to large. The improvement in suicidal ideation is only partly explained by improvement in depression severity. It is concluded that there is consistent evidence that a single dose of ketamine has dramatic antisuicidal action that emerges almost immediately after dosing and persists for at least a week. The short- and intermediate-term safety and efficacy of ketamine as a crisis intervention treatment for suicidal patients merit study. Areas that need research are outlined.

show abstract

Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression

et al. 2020

View full text Add to dashboard Cite

IMPORTANCE There is an unmet need for effective treatments for suicidality in mental disorders. Magnetic seizure therapy (MST) has been investigated as an alternative to electroconvulsive therapy, a known effective treatment for suicidality, in the management of treatment-resistant major depressive disorder, with promising findings. Yet, there are very limited data on the association of MST with suicidality directly. It is important to explore the potential of MST as a viable treatment alternative to electroconvulsive therapy for suicidality. OBJECTIVE To determine the association of MST with suicidality in patients with treatmentresistant major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS This nonrandomized controlled trial took place at a single tertiary care psychiatric facility in Canada. It followed an open-label study design with consecutive treatment cohorts. Consecutive groupings of 67 patients with treatment-resistant major depressive disorder and with baseline suicidality present were treated for up to 24 treatments. The study was run from February 2012 through June 2019. Patients were followed up for 6 months at the end of the treatment period. This post hoc secondary analysis of the trial was performed from January to November 2019. INTERVENTIONS MST was delivered at 100% stimulator output over the prefrontal cortex with low (25 Hz), moderate (50 or 60 Hz), or high (100 Hz) frequency, for a maximum of 24 sessions. MAIN OUTCOMES AND MEASURES Remission from suicidality was measured as an end point score of 0 on the Beck Scale for Suicidal Ideation. A linear mixed model was used to assess the trajectory of Beck Scale for Suicidal Ideation scores. RESULTS A total of 67 patients (mean [SD] age, 46.3 [13.6] years; 40 women [60.0%]) received a mean (SD) of 19.5 (5.1) MST treatments. The overall number of patients achieving remission was 32 (47.8%). Sixteen patients (55.2%) receiving low-frequency MST achieved remission, as well as 12 patients (54.5%) in the moderate-frequency group, and 4 patients (25.0%) in the high-frequency group. The linear mixed model revealed an association of time with Beck Scale for Suicidal Ideation scores (F 8,293.95 = 5.73; P < .001). CONCLUSIONS AND RELEVANCE These findings suggest that MST may be an effective treatment for suicidality, and sensitivity analysis shows this may be particularly so at low and moderate frequencies. Future studies should directly compare MST with electroconvulsive therapy for treating suicidality and should evaluate MST as a treatment for suicidality across mental disorders.

show abstract

The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis

Cited by 479 publications

References 33 publications

Convergent Mechanisms Underlying Rapid Antidepressant Action

Convergent Mechanisms Underlying Rapid Antidepressant Action

Ketamine for Depression, 6: Effects on Suicidal Ideation and Possible Use as Crisis Intervention in Patients at Suicide Risk

Magnetic Seizure Therapy for Suicidality in Treatment-Resistant Depression

Contact Info

Product

Resources

About