Does Ketamine Hold Promise in Mitigating Suicide Risk?

[[{"type":"media","view_mode":"media_crop","fid":"33182","attributes":{"alt":"Detail from Old Man in Sorrow (On the Threshold of Eternity) by Vincent Van Gogh, Wikimedia Commons","class":"media-image media-image-right","height":"172","id":"media_crop_2757529637621","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3493","media_crop_rotate":"0","media_crop_scale_h":"200","media_crop_scale_w":"158","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image","width":"136"}}]]Suicide is a major public health problem worldwide, and every year more than 800,000 people kill themselves. To put the problem in perspective, a World Health Organization report indicates that the number of individuals who died by suicide in 2001 exceeded the number of individuals who died by homicide and those who died in war.¹ Alarmingly, a 28.4% increase in suicide rate was observed between 1999 and 2010 in individuals aged 35 to 64 years, during the most productive years of their lives.²

Epidemiological studies show that suicide rates vary according to demographic and clinical factors. For example, women make more suicide attempts, but the rate of completed suicide is higher in men.³ In the US, elderly white men (older than 85 years) have the highest rate of completed suicide, with a risk up to 6 times higher than the national average.^4,5

The presence of a mental illness is a major risk factor for suicide, as evidenced by psychological autopsy studies that report a diagnosable psychiatric disorder at the time of the suicide in 90% to 95% of cases.⁶ MDD is the most common psychiatric illness in those who attempt suicide.⁷ Other mood disorders, anxiety disorders, and substance use disorders also play a role in suicide attempts. One-third of suicide victims are known to have had contact with a mental health professional within a year of the suicide, which underscores the importance of clinical screening and management of suicide risk.⁸

The public health burden of suicide compels the development of innovative and novel treatment strategies. In this article, we briefly review our understanding of the mechanisms of suicide and the effectiveness of current treatments. We also look at the literature pertaining to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, as a potential novel and rapidly acting treatment for suicidality.

Understanding the causes of suicide

Despite our knowledge regarding clinical and demographic risk factors for suicide, suicidal behavior is difficult to predict at the level of the individual, and a firm understanding of the biological and psychological factors that lead to suicide remains elusive. The influential “stress-diathesis” model of suicidal behavior proposes that a trait-like diathesis (or vulnerability) toward suicide exists in certain individuals and suicidal behavior results when this diathesis interacts with psychosocial stressors or a psychiatric illness, such as major depression.⁹ The diathesis may increase the sensitivity of an individual to social stressors or increase the tendency toward impulsivity, hopelessness, or a failure to successfully regulate one’s emotions.

Suicide is known to run in families. Studies have shown higher rates of suicide in the biological parents of adoptees who commit suicide and among monozygotic versus dizygotic twins, even after controlling for psychiatric comorbidities.^10,11 Despite this knowledge, the specific genetic and epigenetic causes of suicide are still unknown. Biological alterations that have been linked to suicide include disturbances within the serotonin and glutamate neurotransmitter systems; abnormalities within the hypothalamic-pituitary-adrenal axis; and changes in specific brain regions, including medial and lateral aspects of the prefrontal cortex.¹² Future research is critical to unpack the specific contribution of these systems to suicide risk.

Prevention and treatment of suicidal behavior

Given the prevalence of psychiatric illness among individuals who make a suicide attempt, adequate treatment of the co-occurring psychiatric disorder is important. For patients with schizophrenia, this includes providing symptom control with antipsychotic medication and using medical and social programs to help ensure adequate symptom monitoring, medication adherence, and case management. For patients with mood disorders, treatment with antidepressant or mood-stabilizing medication along with psychotherapy and appropriate symptom monitoring remains a cornerstone of treatment.

Making the environment safe,-eg, by removing firearms from the home or otherwise limiting access to the means to cause self-harm-is a critical component of the management of suicide risk. Current treatment recommendations for acute worsening of suicidal ideation are primarily environmental and include inpatient hospital admission and close observation.

Despite these core clinical principles, there is a concerning lack of available medical interventions with evidence to support a specific therapeutic effect on suicidal ideation or behavior. Some of the scarcity of the literature is due to the complexity of the phenomenon of suicide and to the ethical dilemmas inherent in clinical study design that impose limitations on the feasibility of suicide research.

There is only limited evidence from randomized controlled trials to support the efficacy of antidepressant medication for reducing suicide risk in mood disorders. Since most clinical trials of antidepressant agents exclude patients with elevated levels of suicidality, the existing data do not allow for a thorough evaluation of the effects of antidepressants on suicidal behavior.

A black box warning issued by the FDA in 2004 warned of an increase in suicidal ideation or behavior linked to antidepressant medication in adolescents and young adults. The results of this black box warning were a decrease in antidepressant use and a simultaneous increase in suicide attempts among young people.¹³ This finding emphasizes the importance of weighing the potential risk of antidepressant use against the risk of untreated depression.

Lithium is unique in that several studies support a specific protective effect of the medication on suicidal behavior.¹⁴ A recent meta-analysis of patients with MDD, bipolar disorder, or schizoaffective disorder compared lithium with placebo or other active treatments on outcomes that included completed suicide and all-cause mortality.¹⁵ Lithium was significantly more effective than placebo in decreasing the number of suicides (odds ratio = 0.13) and deaths from any cause (odds ratio = 0.38).

The only other psychotropic drug that has shown clear antisuicidal effects is the atypical antipsychotic clozapine. The International Suicide Prevention Trial (InterSePT), a 2-year multicenter study, included 980 high-risk patients with schizophrenia or schizoaffective disorder. The effects of clozapine were compared with those of olanzapine on suicidal behavior. The main outcomes of the study included suicide attempts, completed suicide, hospitalization, and worsening of suicidality. Fewer patients in the clozapine group made a suicide attempt (hazard ratio = 0.76).¹⁶

In the absence of response to pharmacotherapy, electroconvulsive therapy (ECT) may be considered for treatment of patients with acute suicidal ideation at risk for self-harm. Kellner and colleagues¹⁷ studied suicidal intent in patients with MDD who received bilateral ECT. The results showed that among 131 patients with high suicide intent, 80% eventually experienced full resolution of their suicidal intent. In a more recent study, of the 102 highly suicidal patients who completed the acute course of ECT, 63.7% reached resolution after 6 ECT sessions and 87.3% by the end of the treatment course.¹⁸

The role of ketamine in suicidality

Ketamine is approved in the US as an anesthetic. More recently, a growing body of literature has shown the rapid antidepressant effect of ketamine in patients with MDD and bipolar disorder. The onset of antidepressant effects of ketamine has been reported as early as 40 minutes following a single intravenous infusion¹⁹; peak antidepressant effects between 4 and 72 hours following infusion have been reported.^20,21

Several early studies have reported a rapid anti–suicidal ideation effect after administration of ketamine in patients with mood disorders. The rapidity of ketamine’s onset of action and the relatively large effect sizes reported to date make ketamine a potentially promising candidate for antisuicidality pharmacotherapy.

Significant alleviation of depression was observed in 65% of patients with treatment-resistant depression (TRD) treated with a single open- label intravenous infusion of ketamine (0.5 mg/kg).²² In a follow-up study of 6 ketamine infusions over a 2-week period, 9 of 10 patients with TRD had a clinical response. All 9 patients retained the response throughout treatment, with an average Montgomery-Asberg Depression Rating Scale (MADRS) score of 5.0 (SD = 3.7) at the end of the sixth infusion.²³

A post-hoc analysis of the effects of ketamine that combined the results of these two studies showed a large effect on suicidal ideation (as measured by the MADRS-SI) after a single infusion (P < .001; d = 1.37). This anti–suicidal ideation effect of ketamine was sustained for 2 weeks for the 9 patients who received repeated infusion (P = .001; d = 2.4).²⁴ Two other studies of repeated ketamine treatments also showed a decrease in suicidal ideation parallel to the decrease in depressive symptoms that remained significant throughout the course of treatment.^25,26

Zarate and colleagues¹⁹ reported that a single ketamine infusion decreased suicide scores as early as 40 minutes postinfusion, as measured by the Scale for Suicidal Ideation. The results of a post-hoc analysis of pooled data from 4 ketamine clinical trials in TRD and bipolar depression (single-dose, double-blind as well as open-label) by this group confirmed a decrease in suicidal ideation 230 minutes postinfusion.²⁷

Recently, in a larger, 2-site, randomized, controlled trial, our group compared the effect of a single intravenous infusion of ketamine with that of midazolam (used as an anesthetic “active placebo”) in 72 patients with TRD.²¹ Antidepressant response rates were 64% and 28% in the ketamine and control condition, respectively. In a follow-up analysis that focused on the effects of ketamine on suicidality, 53% of patients who received ketamine exhibited a rapid decrease in explicit measures of suicidal thinking compared with 24% of patients who received midazolam (P = .03).²⁸

The clinical application of the rapid antidepressant and antisuicidal effect of ketamine has also been tested in the emergency department, where suicidal ideation constitutes a major indication for referral. In a prospective open-label study, 14 patients who presented with suicidal ideation received a single low-dose infusion of ketamine (0.2 mg/kg) and were monitored for 4 hours and then discharged and re-contacted daily for 10 days. Treatment response and time to remission were measured by the MADRS-SI. Decreases from 3.9 at baseline to 0.6 were seen at 40 minutes postinfusion, and the effect remained significant for over the 10-day observation period.²⁹ Given the open-label nature of this study and other methodological limitations, these results must be considered preliminary until the results are replicated in larger, controlled studies.

It is unknown whether these antisuicidal findings can be attributed to amelioration of the depressive symptoms exclusively or whether ketamine in fact exerts a specific antisuicidal effect, independent of its effects on depression. Price and colleagues²⁴ suggested that the observed effect of ketamine on suicide was mediated by depression reduction, since there was no longer a significant effect of time on MADRS-SI score when total depression score was included as a covariate. Similarly, findings from a larger study by Price and colleagues²⁸ suggest that the effect of treatment on suicidal ideation was mediated by the change in non–suicidal ideation components of depression both at 4 and 24 hours.

In the pooled analysis by Ballard and colleagues,²⁷ the observed decrease in suicidal ideation following ketamine infusion was associated with a change in depression and anxiety, although the variance explained by these factors was only 19% and 26%, respectively. Furthermore, the authors found a significant reduction in suicidal ideation following ketamine infusion compared with placebo, even after controlling for the effect of ketamine on depression. These data suggest that ketamine may exert a direct effect on suicidality, at least in part.

Ketamine’s mechanism of action

Glutamate, the major excitatory neurotransmitter system in the brain, acts via inotropic (including NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kainate) and metabotropic (including mGluR1/5) receptors in the brain to regulate both rapid changes in postsynaptic electrical potentials and slow-acting changes in intracellular signaling cascades and neuroplasticity.

After release from the synapse, glutamate is tightly controlled and recycled to glial cells through amino acid transporters and deactivated to glutamine by glutamate-ammonia ligase (GLUL; ie, glutamine synthetase). There is some evidence to suggest that glutamate signaling pathways are dysregulated in suicide victims. For example, gene expression studies show alteration in different components of the glutamate pathway associated with suicide, including subunits within the AMPA and NMDA receptors, as well as alterations in amino acid transporter protein family genes and in GLUL.^30,31

Data from postmortem studies suggest abnormalities in aspects of neuroplasticity among suicide victims, including reduction in levels of brain-derived neurotrophic factor and its receptor, tyrosine kinase B.³² Deficits in neuroplasticity may be driven in part by abnormal glutamate signaling and result in the failure of the brain to make appropriate adaptive responses to environmental stimuli. Since ketamine is known to rapidly reverse stress-related deficits in synaptic structure and function, ketamine may alleviate suicidality in part by normalizing neuroplasticity via modulation of glutamate signaling.

Finally, there are several lines of studies that link inflammatory processes to suicide, including increased level of microglial activity in the brains of suicide victims and increased interleukin-6 levels in the cerebrospinal fluid of suicide attempters.^33,34 Intriguingly, a study that compared 64 suicide attempters with 36 control persons demonstrated an increase in cerebrospinal fluid levels of quinolinic acid, which functions as an NMDA receptor agonist.³⁵ Quinolinic acid, synthesized from l-tryptophan via the kynurenine pathway, is a marker of inflammation, and high levels of the acid may contribute to neuronal damage.³⁶ On the basis of these findings, the authors speculated that ketamine’s antagonistic action at the NMDA receptor may serve to block the functional consequences of high levels of quinolinic acid, thereby ameliorating suicide risk.

Conclusions and future directions

Suicidality is a psychiatric emergency, and the development of effective, evidence-based treatments that can treat suicidal ideation and lower suicide risk is a major area of unmet need. Vigilance to the emergence of suicidality in at-risk patient populations and treatment of any co-occurring psychiatric disorder are the mainstays of treatment. Clozapine, lithium, and ECT are among a short list of medical interventions that have evidence for a therapeutic effect on suicidality.

The limited efficacy of currently available treatments for suicidality calls for innovation in treatment discovery. Given its rapid onset of action and large magnitude of effect, ketamine appears to be a promising candidate for treatment of acute suicidality. Much more research is required, however, before ketamine can be recommended for treatment in the clinical setting. In particular, very little data exist to support the safety and efficacy of ketamine administered for longer than 2 weeks.

Because patients usually experience a relapse of depressive symptoms after discontinuing ketamine, the identification of robust maintenance strategies to prevent the return of depressive symptoms or suicidal ideation is a critical area of future research. It is important to determine the potential effects of ketamine on suicidal thinking in patients with a range of psychiatric disorders, including PTSD and anxiety disorders.

Finally, much more research is needed to elucidate the therapeutic mechanism of action of ketamine in patients with depression and suicidality. In addition to being a potential future therapeutic agent, ketamine used as a research tool may provide valuable insights into the fundamental neurobiology of depression and suicidality.

Disclosures:

Dr Soleimani is Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai, New York; Dr Murrough is Assistant Professor of Psychiatry and Neuroscience and Associate Director of the Mood and Anxiety Disorders Program at the Icahn School of Medicine at Mount Sinai.

Dr Soleimani reports no conflicts of interest concerning the subject matter of this article. In the past 3 years, Dr Murrough has served on advisory boards for Janssen Research and Development and Genentech; has provided consultation services for ProPhase, LLC, and Impel Neuropharma; and has received research support from Janssen and Avanir Pharmaceuticals. He is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders. Dr Dennis Charney (Dean of Icahn School of Medicine at Mount Sinai) and Icahn School of Medicine at Mount Sinai have been named on a use patent on ketamine for the treatment of depression. The Icahn School of Medicine has entered into a licensing agreement for the use of ketamine as therapy for treatment-resistant depression. Dr Charney and Icahn School of Medicine at Mount Sinai could potentially benefit if ketamine were to gain approval for the treatment of depression. Drs Murrough and Charney are named on a pending patent for lithium as a method for preventing depression relapse following ketamine.

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