Acute Suicidal Ideation in the Context of Esketamine Maintenance Therapy

Ketamine is an N-methyl-d-aspartate receptor antagonist that is emerging as an effective, rapid-acting antidepressant for patients with treatment-resistant depression (1–3). Ketamine modulates glutamatergic transmission and increases synaptic density. It is unlike traditional antidepressant medications that predominantly affect monoamine transmission and take much longer to exert effects (2, 4).

In March 2019, the Food and Drug Administration (FDA) approved intranasal esketamine as an adjunctive treatment for patients with treatment-resistant depression, defined as failure to respond to at least two antidepressant medications (5). The approval was based on data exhibiting significant improvement in depressive symptoms in both short-term trials and a long-term trial (6). Although electroconvulsive therapy is considered the most effective intervention for treating treatment-resistant depression, ketamine and esketamine are increasingly used and continue to be investigated, with trial results confirming initial findings (1). Citing concern over sedation and dissociation, the FDA recommended administration of esketamine in a certified treatment center with 2 hours of monitoring (7, 8). Patients are given an initial trial of 56 mg of intranasal esketamine to assess tolerability. The dose is increased to 84 mg in an induction phase, with twice-weekly administration for 4 weeks, that progresses to a maintenance phase, with once-weekly administration, until remission allows for greater spacing of treatments (9).

Tolerability issues have thus far been restricted to symptoms that include nausea, dissociation, dizziness, vertigo, and headache (1, 3). Suicidal thinking is not listed as an adverse effect in studies of intranasal esketamine (1–3, 7, 9).

More recent studies have directly evaluated the effectiveness of ketamine and intranasal esketamine in patients with a high risk of suicide (10–12). Intranasal esketamine is now considered an effective treatment for reducing suicidal thinking (3, 10–14). When suicidal ideation occurs, it is considered unrelated to the drug itself (3, 6, 15). Notably, these studies are of individuals who do not use ketamine chronically. Drug use disorders in general are a risk factor for self-harm or suicide (16). Patients with ketamine use disorder are at greatly increased risk of self-harm or suicide; one study found an adjusted hazard ratio even higher than that for opioid use disorder, when the analysis controlled for other known risk factors (16).

To our knowledge, this is the first case of acute suicidality with onset during intranasal esketamine administration in a patient with depression that was responsive to esketamine treatment.

Case Presentation

A mid-30s White male with a 20-year history of major depressive disorder, concomitant anxiety, and mild sleep apnea presented for evaluation for esketamine treatment. For the treatment of many episodes of depression since adolescence, the patient reported adequate trials of nine psychotropic medications (in his words, “almost everything”): fluoxetine, sertraline, escitalopram, desvenlafaxine, duloxetine, bupropion, mirtazapine, trazodone, and quetiapine. His current medications were buspirone 30 mg twice per day, desvenlafaxine 100 mg daily, trazodone 100 mg at bedtime, and alprazolam 0.5 mg daily as needed for anxiety. Although the patient was generally dysthymic, he was in the second month of a severe depressive episode that had been triggered by family- and work-related stress. The clinic screens for a history of substance use, and the patient reported lifetime abstinence from nicotine, marijuana, cocaine, and all other illicit substances and consumption of one or two alcoholic drinks per week. The clinic also screens for violence, homicidal ideation, nonsuicidal self-injurious behavior, trauma, phobias, obsessive-compulsive disorder, posttraumatic stress disorder, attention-deficit hyperactivity disorder, manic or psychotic symptoms, and previous psychiatric hospitalizations. The patient had no history of any of these. He reported infrequent panic attacks that were treatable with alprazolam as needed; no panic attacks had occurred in recent months. Over the past couple of years, he reported gradual onset of intermittent active suicidal thoughts involving a vague plan to jump off a high building. He never had intent to carry out this plan and had made no preparations. He was medically cleared, and intranasal esketamine therapy was recommended.

Prior to the patient’s first intranasal esketamine treatment 2 weeks later, he reported persistent passive suicidal ideation, moderate anxiety, and low mood. His score on the Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR) was 16, indicating severe depression (17). The patient had a typical response to his first esketamine treatment (56 mg dose), including transient hypertension and mild dissociation.

The patient’s subjective report prior to his second session was that he was “bright, engaged, with a full-range affect” and that he felt optimistic about proceeding—consistent with observations that responses to ketamine can occur after a single dose (18). The dose was escalated to 84 mg for the second and subsequent treatments. By the third treatment (week 2), the patient’s QIDS-SR score had dropped to 8, indicating mild depression. Subjectively, his mood was greatly improved. His suicidality had completely remitted, which was a marked change from baseline.

Throughout treatment, the patient’s optimism about life grew as his mood subjectively improved. He reported minimal anxiety symptoms. His QIDS-SR scores plateaued at 6–7. Suicidal ideation remained in remission for 4 weeks. Side effects during the course of treatment included one instance of nausea and intermittent dissociation and sedation, which are commonly described in the literature (19). He was not perturbed by these effects.

During the week preceding his 10th treatment, he reported intermittent and fleeting passive suicidal ideation. One week later, at his 11th treatment session, he reported enthusiasm about the treatment, although he had a slightly lower mood. He again reported intermittent passive suicidal ideation, without intent or plan.

Within the first hour after intranasal esketamine administration during his 11th treatment, the patient reported new-onset acute suicidal ideation unlike any previous feeling of suicidality. He appeared acutely distressed, was sobbing, and reported an overwhelming hopelessness. He described a prominent focus on thoughts to “jump;” at the time, he was in a sixth-floor office and sitting next to large windows, which could not be opened. The phenomena of sudden despondency, lability, and suicidality had not occurred in any of his previous treatments, and he reported that the plan to kill himself had never felt so intense or prominent. There were no apparent triggers or new contributing factors, including dissociation. A staff member accompanied him for the remainder of his treatment. After 2 hours, the patient reported resolution of the suicidal ideation. Following assessment by the on-site psychiatrist, it was felt that he would be safe to return home, with close follow-up. In the ensuing days, the patient was in contact with his outside psychiatrist to continue to process this experience. He reported that during the esketamine session he had been feeling acutely depressed and suicidal to the point that he considered how to open the window and whether he would die on impact. This, subjectively, was “much more suicidal” than he had ever been. Despite gains in treating his depression, the patient elected to discontinue intranasal esketamine because of the acuity of the experience and anxiety about a possible recurrence.

Eight weeks after the event, the patient reported a recurrence of severe depressive symptoms, similar to his baseline symptoms prior to esketamine treatment. He continued to experience intermittent, transient suicidal thoughts without intent. His outpatient psychiatrist started a trial of pramipexole, with intent to explore treatment with a stimulant or monoamine oxidase inhibitor. The patient had no interest in future esketamine treatment.

Discussion

Recent literature on the adverse events of esketamine treatment focuses on physiological symptoms, such as elevated blood pressure, blurred vision, and sedation (10, 19). Psychiatric responses, including suicidality, are recorded less systematically (19). Increased suicidality is explicitly discussed only as a potential late-onset side effect or as a sequela of chronic use (3, 15, 16, 19). The exact mechanism of action is not fully understood, and there are no leading theories as to how esketamine might induce suicidal thinking. It is known that chronic exposure to ketamine has different neurophysiological effects than does intermittent or acute exposure (20). However, the timing of symptoms, which occurred within an hour of esketamine administration and resolved by the end of the session, implies an association between intranasal esketamine and acute suicidality during a maintenance session.

Data on suicidal ideation tracks symptom improvement, and the potential for exacerbation is rarely evaluated (10, 13). Additionally, the time frame used in most studies would miss acute exacerbations; such studies generally begin surveillance of suicidal ideation and other psychiatric symptoms at 2 to 4 hours after administration (11). This case suggests a need to assess suicidal thinking of patients throughout the course of monitoring, given the potential for this serious adverse event.

Conclusions

This case is the first to reveal the potential of intranasal esketamine therapy to induce acute suicidality. It suggests that providers should monitor for signs and symptoms of acute suicidality during esketamine treatment. Additionally, it calls into question the safety of treatment arrangements with minimal or no patient monitoring following drug administration.

Key Points/Clinical Pearls