A possible role for ketamine in suicide prevention in emergency and mainstream psychiatry.

World Suicide Prevention Day was observed on September 10, 2017. It is universally acknowledged that suicide is an important public health problem and that the problem is growing.[123] Interventions that address suicide are psychosocial and psychopharmacological in nature.[45678] Psychosocial interventions include preventative and therapeutic measures, including screening, psychoeducation, crisis intervention, nonspecific supportive therapy, and specific psychotherapies. Psychopharmacological interventions include antidepressant, antianxiety, and other treatments, usually targeting the primary psychiatric diagnosis and the general anxiety and agitation that may be present. Electroconvulsive therapy, which has a strong antisuicidal effect,[9] may be administered to severely depressed and suicidal patients.

Among the psychopharmacological interventions, antidepressant drugs, which reduce depression and thereby also the suicidal ideation, may rarely induce agitation and suicidal ideation as an adverse effect;[10] this is more likely in pediatric subjects and young adults,[1112] and in all age groups, at the time of antidepressant initiation and antidepressant dose uptitration.[10] Certain psychotropic drugs appear to have long-term protective effects against suicide risk; these include lithium and clozapine.[813]

CONVENTIONAL APPROACH TO MANAGEMENT

The presence of suicidal ideation with strong suicidal intent is considered to be a clinical emergency. Suicidal patients are usually managed as inpatients because self-harm is difficult and unlikely in a supportive, therapeutic, and controlled hospital environment. However, inpatient care requires patients to temporarily leave their ongoing domestic and professional responsibilities. In India, hospitalized patients require one or more caregiver to stay with the patient in the hospital ward, and so the caregivers will also need to temporarily leave their ongoing domestic and professional responsibilities. Furthermore, financial arrangements need to be made for the inpatient care. All of these may not be immediately possible, or may not be possible at all, in many cases.

What is the alternative? The most usual approach is to send the patients back into their stressful environment with a prescription for an antidepressant, and perhaps a benzodiazepine for immediate relief from symptoms of anxiety and agitation. A therapeutic contract may be made with the patients so that, in case of distress, the patients will contact the psychiatric team rather than attempt self-harm. Family members are asked to dispense the medicines themselves and to keep a watch on the patient lest an incident of self-harm occurs.

KETAMINE AS AN APPROACH TO THE MANAGEMENT OF SUICIDE RISK

Can anything more be done? Yes, if the recent research on the antidepressant and antisuicidal action of ketamine is considered. There is a growing body of evidence that indicates that, in subanesthetic doses, ketamine has rapid antidepressant[1415161718] and antisuicidal action. In fact, suicide risk is one context within a major depressive episode in which the use of ketamine has been specifically suggested.[15] Small studies conducted in emergency department settings have demonstrated that the antisuicidal effect of ketamine may even be apparent within 40 min of treatment.[1920]

FINDINGS FROM META-ANALYSIS

Many studies have assessed the antisuicidal effect of ketamine. These studies were examined in a systematic review and meta-analysis by Bartoli et al.[21] These authors[21] searched electronic databases and other sources and identified five clinical trials (pooled n = 99) that assessed outcomes at or within 4 h after a single session of intravenous (iv) ketamine in patients with current suicidal ideation. Two of these trials were conducted in emergency room settings. Two trials administered ketamine as an iv bolus (0.2 mg/kg; n = 63) and the other three administered ketamine as an iv infusion (0.5 mg/kg; n = 36). In summary, a single session of iv ketamine was found to be associated with a substantial reduction in suicidal ideation in patients with current suicidal ideation. The effect was seen within 4 h of treatment, and the effect size was large [Box].

Box

Antisuidical effect of ketamine: Findings from meta-analysis (Bartoli et al., 2017)

In this meta-analysis, the number of studies and the pooled sample size were both small for the main analysis in general and the subgroup and sensitivity analyses in particular. Furthermore, the meta-analysis examined single group pre- versus post-treatment outcomes rather than change scores in ketamine versus control groups (because of the study design of the included trials). The results of this meta-analysis should, therefore, be considered tentative rather than conclusive.

TREATMENT ISSUES

It is unlikely that ketamine has a specific antisuicidal effect over and above its antidepressant effect; rather, the reduction in suicidality probably occurs as a consequence of the reduction in the severity of the depression in general.[22] Therefore, ketamine may not have an antisuicidal action in patients in whom it does not have an antidepressant effect. However, no treatment in medicine comes with an assurance of efficacy in all patients.

Whereas open studies and randomized controlled trials of single and repeated doses of iv ketamine have demonstrated that ketamine attenuates measures of suicidality even in patients with treatment-refractory depression,[20222324] the benefits have been observed to wear off within days to a week, along with the wearing off of the other antidepressant benefits of ketamine.[24] In some patients, antisuicidal benefits may persist for as long as 10 days.[19] Repeated dosing with ketamine may then be necessary to maintain antisuicidal action if the risk of suicide reemerges after initial attenuation with ketamine. The brief efficacy is not necessarily a disadvantage because the time thus bought could allow the implementation of other psychopharmacological and psychosocial interventions, as appropriate.[15]

Most of the research on the use of ketamine as an antidepressant has focused on iv administration of the drug. However, the drug can be administered by oral, sublingual, transmucosal, intranasal, subcutaneous, and oral routes, as well.[17] Administration through a nebulizer is also feasible. Research is necessary to examine the antidepressant and antisuicidal efficacy of oral and subcutaneous administration because, from a clinical perspective, these could be the safest and most convenient methods of administration in routine clinical practice.[17]

Suicidal behavior does not occur only in the context of a major depressive episode. It may also occur in patients with personality disorder, those exposed to sudden, serious stress, and other conditions/situations. Research is necessary to determine whether subanesthetic dosing with ketamine has antisuicidal benefits in patients with diagnoses beyond major depressive disorder or bipolar depression.

Finally, should subanesthetic dosing with ketamine enter mainstream psychiatry as an intervention for the emergency management of depression and suicidality, and for the management of refractory depression, then psychiatrists and postgraduate students in psychiatry will need to receive training and privileging for the administration of ketamine, much as they do with regard to ECT. At the moment, although much is known, much remains to be established.[25]