The effects of ketamine on suicidality across various formulations and study settings

Self-injurious behavior (SIB), including both nonsuicidal self-harm and suicidal behavior, affects millions of patients annually.¹  An estimated 800 000 people die by suicide each year, and nonfatal self-harm occurs 20 times more frequently.²  Each episode of self-harm increases the likelihood of a future suicide or SIB.³  Although these behaviors are commonly associated with major depressive disorder (MDD), patients with schizophrenia, personality disorders, autism, bipolar disorder, and substance use disorders may also exhibit these characteristics.⁴ 

In addition to the detriment to the patient and those close to the patient, SIB contributes to numerous hospitalizations each year, which, in turn, result in significant cost to patients, communities, and health systems.⁵ 

Despite the prevalence of SIB across several psychiatric conditions, advances in the treatment options for these behaviors have been limited. Currently, the management options for patients with depression are limited by pharmacologic modality and inability to treat acute suicidal behaviors in a targeted manner. Additionally, first-line antidepressants may take several weeks for therapeutic effect and about two thirds of patients will require either augmentation or a trial of an alternate pharmacotherapy for their depressive symptoms.⁶  The black box warning of antidepressants for suicidality among children and adolescents may also present as barriers for using these agents. Furthermore, most clinical trials of antidepressants exclude suicidal patients, which limits generalizability of the results of efficacy trials for patients who display behaviors of self-harm.⁷  Nonantidepressants, such as lithium or clozapine, have demonstrated benefit in reducing suicidal behaviors; however, these outcomes were not demonstrated in the emergent setting.⁸  Electroconvulsive therapy may provide the most rapid response for reducing acute suicidality, but access to this treatment modality may be limited and may not be considered a favorable option for patients. Additionally, several sessions of treatment are usually necessary for full remission.⁸ 

Ketamine is an NMDA (N-methyl-D-aspartate) antagonist that has received attention as a novel pharmacologic option for major depression and, more importantly, for reducing acute suicidality.⁹  Since development, ketamine has predominantly been viewed as an anesthetic as well as an illicit drug of abuse; however, ketamine (as well as the s-enantiomer esketamine) has demonstrated benefit in rapidly reducing symptoms of depression in refractory patients at subanesthetic doses.¹⁰  Numerous investigations have been reported; albeit sample sizes remain relatively low and vary in formulation and treatment settings. The reports are flawed with other study design issues, such as inclusion of comorbid conditions, number of administrations, and duration of treatment, just to name a few.¹⁰  Despite these limitations, the discussion of how ketamine may be used to treat the consequences of so many psychiatric illnesses remains important. Most of these studies have demonstrated a benefit in improving symptoms of depression using validated measures, such as the Montgomery-Asberg Depression Rating Scale (MADRS)¹¹  or Hamilton Depression Rating Scale for Depression (HAM-D)¹² ; however, several studies have also shown ketamine's benefit in specifically reducing suicidal symptoms acutely.¹³  In this review, we summarize published reports describing the use of ketamine (intravenous [IV], intramuscular [IM], intranasal [IN], sublingual) and esketamine (IN) for SIB.

We conducted a search of the MEDLINE database for studies published between January 1, 1960, and May 31, 2018, using the following keywords: ketamine, suicid*, self-injur*, esketamine, and self-harm. We included studies published in the English language that were conducted with human subjects. From this initial search, the primary author (D.D.) gathered additional literature from cross-references. Studies that were already included in meta-analyses, studies that did not assess suicidality or SIB, or those that were post hoc analyses of included studies were excluded from this manuscript. We have summarized the studies by the formulation of ketamine studied and by strength of study design (systematic review/meta-analyses, individual randomized controlled trials, open-label trials, case series, and case reports) using the Center for Evidence-Based Medicine Levels of Evidence for Therapeutic Studies.¹⁴ 

We identified 24 studies that included 2 meta-analyses, 9 clinical trials, 12 case series/reports, and 1 retrospective chart review. We excluded trials that were included in the included meta-analyses as well as those that were post hoc analyses of previously published data.

A recent meta-analysis conducted by Wilkinson and colleagues¹³  described ketamine trials for patients with major depression, bipolar depression, or post-traumatic stress disorder for suicidal ideation (SI; Table). The authors identified 10 ketamine trials for psychiatric disorders that met the study inclusion criteria of single-dose trials, had a comparator group (placebo or midazolam), and utilized the IV route. The study authors assessed the effect of ketamine to resolve SI as compared with a control using a general linear mixed model with covariates including age, sex, race, treatment setting, diagnosis, and concomitant psychotropic medications.

In total, data were obtained for 298 patients from the selected trials. Of those, 167 were included due to baseline SI. Patients included in the analysis had more severe depressive symptoms at baseline as measured by the MADRS (33.4 vs 25.9, P < .001), HAM-D (20.5 vs 16.3, P < .001), Quick Inventory of Depressive Symptomatology – Self-Report¹⁵  (17.7 vs 14. 2, P < .001), and Beck Depression Inventory¹⁶  scales (29.2 vs 21.1, P < .001). Of the included patients, those who received ketamine did not differ significantly from control groups with regard to age, sex, diagnoses, inpatient status, or proportion receiving concomitant psychotropic medications. The two groups did not differ in their baseline MADRS scores either (33.8 vs 32.9, P = .388).

Patients who received ketamine had lower scores on clinician-rated scores of suicidality on days 1 and 7 using HAM-D or MADRS (group-by-time interaction, chi-square = 50.6, P < .001). The number needed to treat for ketamine for being free of SI ranged from 3.1 to 4.0 for time points between days 1 and 7 after ketamine infusion. Changes associated with the individual SI item on these scales was significantly correlated with overall depressive symptoms (r² = .411, t = 10.73, P < .001). When controlling for change in depressive symptoms, the effect on SI remained significant (time-by-treatment interaction, chi-square = 10.84, P = .028).

This meta-analysis should be considered in the setting in which there were relatively few patients in the final analysis. In addition, the measurement of suicidal ideation in this patient population often involved a single item on either the MADRS or HAM-D. These measures are not as sensitive specific suicidal ideation assessments and were not originally validated to be used for this purpose. Other considerations include the relatively short follow-up of 7 days and the patients not being deemed as “imminent suicide risk.”

Another meta-analysis was conducted in 2017 by Bartoli and colleagues.¹⁷  This meta-analysis assessed 5 single-arm trials of IV ketamine at reducing SI acutely (within 4 hours of infusion). This study utilized a different set of studies than the Wilkinson group¹³  as they utilized single-arm studies. Bartoli et al¹⁷  included 99 patients, 63 of which received IV bolus of ketamine 0.2 mg/kg (over 1 minute), and the remaining 36 received a ketamine 0.5 mg/kg infusion (over 40-45 minutes). A decrease in SI was noted by a standard mean difference of –0.92 (95% confidence interval [CI] –1.4 to –0.44, P < .001). The study found a nonsignificant reduction in SI in the ketamine bolus group as compared with the ketamine infusion group (standard mean difference: -2.11 vs -0.86, P = .27).

The results of this study should be considered with several limitations. There was no comparator group in any of the 5 included ketamine trials, making it difficult to discern the absolute effect of ketamine on SI. In addition, the authors primarily considered the end point of 4 hours postinfusion. Although the acute management of SI is important, the degree of durability of this effect is also important to consider. Although the inclusion criteria for the meta-analysis were trials with specific and valid measurements of suicidality, outcomes for specific scales were not reported, nor were the differences in scales used among the trials. Finally, since publication, 1 of the trials¹⁸  in the included analysis was retracted from publication due to inaccuracy in the reported data.

A randomized, midazolam-controlled trial¹⁹  to assess SI in depressed patients was published recently. This study assessed suicidality using the Scale for Suicidal Ideation (SSI) 24 hours after infusion of ketamine or midazolam. They included patients with a score of 4 or greater on the SSI, which is considered a significant cutoff for SI. The scale consists of 19 items rated 0 to 2 for a maximum score of 38. Depression was also assessed utilizing HAM-D and Beck Depression Inventory.

The study¹⁹  included 82 participants who were randomized to 1 of the treatment arms although 1 participant in each group dropped out prior to day 1 assessment; thus, 40 patients were analyzed in each group. The groups were similar at baseline with the exception of percentage of patients with borderline personality disorder (8% in midazolam group vs 28% in ketamine group, P = .03). The baseline scores for the SSI in ketamine and midazolam groups were 14.3 and 15.7, respectively. The primary outcome was SSI score, which was reduced by 4.96 points in the ketamine group compared with the midazolam group (95% CI 2.33-7.59, P < .001). Including borderline personality disorder as a covariate did not significantly alter the results (estimate = 4.76, 95% CI 1.89-7.63, P = .002). Responders were defined as those with a 50% or greater reduction in the SSI score. Fifty-five percent of ketamine patients responded at day 1 postinfusion as compared with 30% of the midazolam group (odds ratio: 2.85, 95% CI 1.14-7.15, P = .024). Although ketamine demonstrated a significantly greater response rate, it should be noted that the midazolam group, serving as an active placebo, demonstrated a stronger response than would be expected.

This trial was limited by the patient population, who were not necessarily treatment-resistant as in other ketamine trials, which may have contributed to the high response to midazolam treatment. In addition, there was a higher proportion of patients with borderline personality disorder in the ketamine group; however, subsequent analysis did not reveal a significant interaction with the results.

Several other randomized controlled trials of ketamine's antisuicidal properties have been conducted^20-23  and have demonstrated reduction in SI. One of these studies,²⁰  interestingly, occurred in patients with a recent cancer diagnosis but no past psychiatric history. The study demonstrated a significant reduction in SI as measured by both the Beck Scale for Suicidal Ideation as well as the MADRS-SI question as compared with a midazolam-controlled group. Kudoh and colleagues²¹  assessed patients with MDD who were undergoing orthopedic surgery. This study utilized ketamine as part of an anesthetic regimen and, thus, utilized higher initial doses of ketamine, 1 mg/kg. The study compared patients with MDD who did not receive ketamine as part of their general anesthesia to those who did receive ketamine. The study found that depressed patients who received ketamine had a significantly improved HAM-D score overall and a significantly reduced score on the individual SI item of the HAM-D than patients who did not receive ketamine in their general anesthesia. In a cohort of treatment-resistant MDD patients,²²  53% scored 0 on 3 explicit suicide measures after treatment with IV ketamine at a dose of 0.5 mg/kg over 40 minutes. A proof-of-concept study²³  also demonstrated a greater reduction in SSI score in patients with bipolar disorder treated with 0.5 mg/kg of ketamine over 40 minutes as compared with those treated with a midazolam control.

Intravenous ketamine has also been studied and demonstrated benefit in patients with treatment-resistant depression and SI in 3 open-label, single-arm studies.^24-26  Two of these studies^24,26  demonstrated that depressed patients scored significantly lower on the MADRS-SI item (averaging a 1- to 2-point reduction) after receiving a parenteral infusion of ketamine. Thakurta and colleagues²⁵  showed a reduction in SI utilizing a validated scale for SI; however, the demonstrated benefit seemed shorter than in other studies with benefit lasting approximately 1 day.

Finally, 8 publications^27-34  of case reports/series report both subjective and objective improvements in SI following IV infusion of ketamine (typically at 0.5 mg/kg over 40 minutes) although 1 study²⁷  utilized esketamine at a dose of 0.6 to 0.8 mg/kg. Even though the generalizability of these cases is low and warrants caution with application of the results, it is important to note that some of these cases represent patients who have presented to the hospital immediately following a highly lethal suicide attempt.^27,29,31  In another case series, Niciu et al³²  describes an initial improvement in depressive symptoms in 2 patients with comorbid obsessive-compulsive disorder several hours after ketamine infusion. However, after approximately 1 day, these patients had worsening of depressive symptoms, including subjective reports of SI without plan or intent despite negative suicidality upon hospitalization.

One case report³⁵  of IM ketamine has been reported to have subjective benefit in a patient with bipolar disorder and SI in the emergency department setting (Table). This patient received a ketamine 0.5 mg/kg IM injection with subjective improvement in SI. Of note, this patient also had a co-occurring pain disorder that the authors hypothesized would also improve with IM ketamine. The patient was discharged from the hospital in 3 days and had no SI at the follow-up appointment 30 days later.

A recent multicenter, double-blind, randomized, placebo-controlled trial³⁶  of IN esketamine found a reduction in SI as measured by the MADRS-SI item, 4 hours after the dose (Table). This effect was not significant at 24 hours postdose. Besides the formulation, this trial differs from other trials in that it utilized a fixed dose of esketamine for each patient. In addition, the patients included had a baseline suicidality that warranted inpatient admission. Although the MADRS-SI item demonstrated benefit at 4 hours, the clinician global judgment of suicide risk rating never differentiated from placebo at any time point.

Another study³⁷  that assessed the utility of IN ketamine reported results of a retrospective review of survey data. This study documented the experience from an outpatient provider in treating primarily pediatric and adolescent patients (mean age = 15 years) with bipolar disorder with the fear of harm phenotype. The fear of harm phenotype is characterized by treatment-resistant bipolar disorder that often presents with physical aggression and separation anxiety. Patients in this study were treated with IN ketamine for an average of 1.71 ± 1.36 years. During dose titration, patients were assessed clinically twice weekly. A principal component analysis of the survey data showed that SI improvement was among the most impactful measures assessed in patients who were treated with IN ketamine with a mean dosage of 165 mg every 2 to 5 days.

Finally, a case report³⁸  of a patient who was previously enrolled in an IV ketamine study but continued treatment with IN ketamine was published in 2016. This case report documents a patient with a significant past history of substance abuse and multiple suicide attempts. The prescribed dose of IN ketamine in this case is much higher than other reported IN ketamine doses. The patient did not significantly improve on ketamine or other treatment modalities and eventually died due to presumed suicide involving a motor vehicle accident.

Several case reports^39,40  have been published documenting the use of oral ketamine in patients with bipolar depression or depressive symptoms (Table). These reports use weight-based dosing of ketamine ranging from 1.5 to 3 mg/kg as well as fixed doses ranging from 16 to 128 mg/d. Although these reports have documented improvement in the MADRS-SI item and subjective improvement in SI, these cases should be carefully considered in the setting of great variability of dosing.

This review summarizes the available evidence on the effects of ketamine on SIB regardless of dosage formulation or study design. The available studies provide supporting evidence for the use of ketamine, primarily administered intravenously, to treat suicidality in patients with bipolar disorder or major depression. To date, few pharmacologic options exist for the treatment of suicidality. Clozapine is Food and Drug Administration-approved for recurrent suicidal behaviors in schizophrenia patients,⁴¹  and lithium has demonstrated antisuicidal effects in patients with mood disorders.⁸  However, few patients with MDD receive these agents due to Food and Drug Administration indication, declining use, adverse effects, and frequent monitoring.^42,43  In addition, traditional antidepressant medications were not commonly studied in patients with suicidal behaviors or those deemed to be at high risk for suicide; therefore, conclusions about their antisuicidal effects are limited and likely related to overall mood improvement.⁷ 

The evidence for the various formulations of ketamine should be carefully considered. The majority of studies report IV ketamine used at a dose of 0.5 mg/kg infused over 40 minutes. The antisuicidal effects have been demonstrated in meta-analyses, controlled trials, and case reports. Their antisuicidal effects have been measured by a variety of reliable and valid tools. In comparison, IM, IN, and PO/sublingual formulations have less data for use in SI or self-harming behaviors.

Although the antisuicidal response of ketamine in depressed patients occurs rapidly and profoundly in many of the patients reported, this effect can be short-lived. Typical duration of effects appears to be 1 week although several cases of effects lasting just a day have been reported. This also suggests that single-dose ketamine will not be sufficient in most patients because the suicidality can be persistent and recurrent.

At this time, there are limited data on repeated doses of ketamine for both safety and efficacy for SI. In this review, cases have been evaluated in which repeated dosing of ketamine did not provide additional benefit^32,37  as well as studies in which patients required multiple doses to achieve antisuicidal benefit.³³  Ketamine also demonstrated transient relief of suicidality in patients who have been admitted to the hospital following a suicide attempt or patients who have experienced chronic and severe suicidality. Although this data are limited to case reports, it represents a very high-risk population that has not been studied in other settings.

This is the first review article to report on the antisuicidal effects of multiple formulations of ketamine among patients with various diagnoses and study designs. Although this analysis is a comprehensive review of the use of ketamine in this setting, there are several limitations that should be considered. First, the majority of reported studies utilized a single question item from a validated depression rating scale. Because the sensitivity and specificity of these single items were not specifically designed or validated for this purpose, it is difficult to make definitive conclusions. To that, several studies^20,22  did use specific scales that have been studied in patients with suicidality, such as the Beck Scale for Suicidal Ideation.

Several studies^13,19  presented herein described the antisuicidal effects of ketamine occurring distinctly from the overall antidepressant response. These findings appear to be unique to ketamine and may suggest the potential for future investigation in suicidal behavior or SIB in nondepression patient populations. In addition, long-term effects of ketamine are not well described in the literature despite an increasing number of providers of various formulations of ketamine.⁴⁴  Finally, the majority of these studies include parenteral ketamine and a smaller portion of patients who received PO or IN ketamine. Enteral formulations of ketamine are available; however, assumptions about its equivalent efficacy or safety cannot be made.

It is important to note that the exact mechanism of ketamine's antisuicidal effect is not currently known. Several hypotheses have been suggested related to AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, NMDA receptors, and enhanced neuroplasticity in certain brain regions.⁴⁵  This may have implications on different ketamine formulations as enteral ketamine has been shown to produce different proportions of ketamine and the active metabolite hydroxynorketamine (thought to be related to some antidepressant properties).⁴⁶  In addition, there have been published data⁴⁷  with regard to intolerability to certain forms of ketamine, making unsupervised use potentially dangerous.

Although ketamine has seen an increase in clinical usage and research, caution is still warranted with using ketamine in certain scenarios. For instance, certain side effects, such as affective switch,⁴⁸  have been reported as well as decompensation in mood symptoms and an increase in suicidality in patients with obsessive-compulsive disorder and no current depressive symptoms.³²  Access to providers who are experienced in evaluation of patients with SIB and administration of ketamine in a controlled environment may also be challenging for patients seeking care. Future studies in elucidating the mechanism of antisuicidal effect would help identify other uses for ketamine. Currently, it is uncertain whether other disorders with SIB, such as borderline personality disorder, autism, or substance use disorders, may benefit from this type of therapy.

Overall, ketamine appears to be well-tolerated in patients. Immediately after dosing, patients are likely to experience altered sensorium, dissociative experiences, or hallucinations; however, these effects remit and are no different from midazolam controls at 240 minutes postdose.¹⁸  In addition to these psychiatric symptoms, providers should note that ketamine has demonstrated an ability to cause increases in heart rate and blood pressure; however, these effects also appear to be transient and return to baseline states within 30 to 120 minutes from dosing.⁴⁹ 

Ketamine appears to be a promising option for self-harm and suicidal behaviors with good efficacy data and relatively low risk of safety concerns. Unanswered questions remain, such as the persistence of the antidepressant effects. Future studies are warranted to investigate whether the antisuicidal actions of ketamine are related to its antidepressant effects and whether there are other pharmacological targets involved in SIB.