Psychopharmacological Agents and Suicide Risk Reduction: Ketamine and Other Approaches

This review (2015) examines the neurobiology of ketamine’s potential to treat suiciadility and proposes that its working mechanism functions via the suppression of pro-inflammatory cytokines and by restoring tryptophan/serotonin production via inhibition of the kynurenine pathway. It notes that this hypothesis requires further validation via replicated randomized control research with larger samples.

Abstract

Review: Suicide is a major global public health problem and the leading cause of injury mortality in the USA. Suicide is a complex phenomenon involving several systems and neurobiological pathways, with interacting genetic and environmental mechanisms. The literature on the neurobiology and pharmacotherapy of suicide has been limited. To date, no medications have proven efficacious for treating acute suicidal crises. There is an emerging literature supporting a rapid anti-suicidal effect of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, among depressed patients with suicidal ideation. Potential ketamine’s anti-suicidal effect mechanisms are linked to interruption of the kynurenine pathway and modulating pro-inflammatory cytokines exacerbation. However, available data are not sufficient for its routine integration in clinical practice, and larger and replicated randomized control studies are needed.

Authors: Rayan K. Al Jurdi, Alan Swann & Sanjay J. Mathew

Summary

Suicide is a major global public health problem. Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, has been shown to have a rapid anti-suicidal effect among depressed patients with suicidal ideation.

Suicide is the leading cause of injury mortality in the USA, and 90 % of individuals who die by suicide have a history of mental illnesses. There are very few evidence-based approaches for prevention, and even fewer randomized clinical trials for potential treatments.

Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, may have an anti-suicidal effect in depressed patients with suicidal ideation.

Somatic Treatments for Suicide

Medication with anti-suicidal properties can be used to prevent suicide, but the evidence for this use is limited.

Clozapine

In 2002, the FDA approved clozapine for the treatment of patients with schizophrenia or schizoaffective disorder who were at risk of recurrent suicidal behavior. Patients who received clozapine had significantly fewer suicide attempts, suicide attempt hospitalization, rescue interventions, and concomitant treatment with antidepressants or anxiolytics.

Lithium

Lithium (Li) is an anti-manic drug that is FDA-approved for treating acute mania and preventing recurrent mood episodes in patients with bipolar disorder. It is also effective as an augmentation strategy in treatment-resistant depression and in relapse prevention in major depressive disorder.

Antidepressants

In a meta-analysis of 372 double-blind randomized controlled trials, comprised of 99,231 subjects, antidepressants were found to lower the risk of suicide among treated patients compared to those on placebo. Tricyclic antidepressants may have a protective effect against suicide.

The role of antidepressants in reducing suicide risk was questioned after the 2004 FDA warning that antidepressants increase suicide risk among children and adolescents. However, the same FDA data showed that antidepressants reduce the risk of suicide attempt in patients with suicidal ideation.

Electroconvulsive Therapy

A new report looked at the effect of electroconvulsive therapy (ECT) on suicide prevention. It found that ECT reduced suicidal ideation in 131 patients, but that there was no evidence that ECT maintained the reduction in suicide risk following discontinuation of treatment.

Ketamine Pharmacodynamics/Pharmacokinetics

Ketamine is an open-channel nonselective NMDA receptor antagonist that interacts with several receptors including intracellular sigma receptors, opioid -receptors, serotonin 5-HT3 receptors, muscarinic receptors, 7-nicotinic acetylcholine receptor, and the serotonin, norepinephrine, and dopamine transporters.

Ketamine Efficacy in TRD

Ketamine was the first to report on the rapid antidepressant effect of ketamine in 2000. A parallel-arm, randomized, controlled trial of 72 patients with TRD randomized to ketamine or midazolam showed that ketamine improved MADRS score at 24 h compared to midazolam, corresponding to a large effect size.

Ketamine and Suicide Risk Reduction

DiazGranados et al. reported that 33 patients with TRD received an open-label single infusion of ketamine (0.5 mg/kg over 40 min) followed by a blinded randomization toriluzoleorplacebo6hlater. The effect of ketamine on suicidal ideation was very large at 40 min and moderate at 230 min.

DiazGranados’ findings were replicated in a report by Thakurta et al., who found that 27 patients with TRD received open-label ketamine infusions over 40 min and had decreased SSI scores.

In a double-blind, randomized, two-phase cross-over study, 15 patients with bipolar depression received ketamine and their suicide ideation scores decreased by 40 min and up to 3 days post-ketamine infusion.

Ketamine decreased suicide risk in patients with treatment-resistant depression (TRD) after a single infusion and continued to reduce suicide risk after six infusions.

A triple-blind randomized control study found that patients with TRD who received ketamine scored zero on all suicide measures compared to 24 % of patients who received midazolam.

Larkin and Beautrais administered 0.2 mg/kg IV bolus to 14 patients with suicidal ideation. The MADRS-SI scores decreased from 3.9 to 0.6, 0.2, 07, and 0.1 respectively.

Ketamine and the Neurobiology of Suicide

The serotonergic system is the most studied and linked to suicide risk, and abnormal dexamethasone suppression tests, increased levels of pro-inflammatory cytokines, and brain microglia activation have all been reported in patients with increased risk of suicide.

High levels of quinolinic acid, a tryptophan metabolite, have been linked to severe depression and suicide through the activation of the tryptophan – kynurenine pathway.

Erhardt et al. found that suicide attempters had a significantly higher level of QUIN in their CSF compared to 36 healthy subjects, and that QUIN levels correlated positively with Suicide Intent Scale scores.

Dysregulated HPA axis and immune system favor tryptophan metabolism through the kynurenine pathway, which decreases serotonin production.

Ketamine is a NMDA receptor antagonist that regulates immune system homoeostasis by suppressing pro-inflammatory cytokines but not anti-inflammatory ones. It also restores normal serotonin levels.

Limitation of Suicide Treatment Literature

Suicide is a complex phenomenon involving several systems and neurological pathways, with interacting genetic and environmental mechanisms. Larger populations and standardized longitudinal measurements are required to resolve the issue of suicide, including ketamine, and to evaluate the safety of placebo-controlled studies.

Although randomized clinical trials tend to exclude subjects with comorbidities or complications of illness that might predispose to suicide, they can be ethically designed to include subjects at risk of suicide. In studies comparing patients remaining on a treatment to those discontinuing it, predictors of nonresponse to the treatment may overlap with risk for suicide. However, patients not benefitting from the effects of lithium on relapse prevention still had lower rates of suicidal behavior.

Conclusion

Ketamine may be an additional pharmacological intervention to counteract suicide risk. However, no published RCTs have examined its efficacy specifically for those at highest risk.

A search on Clinicaltrials.gov revealed 85 open, interventional suicide studies, of which 17 had suicide or suicidal behavior reduction as an outcome. Ketamine is the interventional drug in seven studies.

Future research should explore the specific anti-suicidal effects of ketamine and Bnext-generation NMDA receptor agents across diagnostic categories, the time course of anti-suicidal activity, and the biological mechanisms by which these agents confer protection against suicide.

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) inducers can shunt tryptophan through the kynurenine pathway instead of the serotonin one, which can lead to a decrease in serotonin production. Ketamine can block QUIN effects and suppress pro-inflammatory cytokines.

Study details

Compounds studied
Ketamine

Topics studied
Suicidality

Study characteristics
Literature Review Bio/Neuro