Oral Ketamine for Treatment-refractory Major Depressive Disorder and the Complicating Role of Concurrent Stressors: Implications for Research and Practice

Case Report

A 33-year-old male scientist fulfilled criteria for syndromal MDD [Diagnostic and Statistical Manual of Mental Disorders (DSM)-5] ⁴ in the context of considerable family- and work-related stress. His research was behind schedule; he had exhausted his funding; he had financial difficulties; he had been asked to vacate his current residence; he was unable to find a new home within his meager budget; he could not find a good school for his child; and his marriage was breaking up. He presented with a four-month history of pervasive low mood, loss of interest in work and hobbies, lassitude, lack of concentration, ideas of decreased self-worth, and disturbed sleep and appetite. Suicidal ideation and anxiety symptoms were prominent.

He did not respond to sequential trials of sertraline (150 mg/day) and mirtazapine (22.5 mg/day), each prescribed for eight weeks; he also failed augmentation with aripiprazole, 5 mg/day. After four months of ineffective pharmacotherapy, depression remained severe; the Montgomery Åsberg Depression Rating Scale (MADRS) ⁵ score was 42 (baseline score was 44). He was under pressure to rapidly recover and regain his ability to address work and family responsibilities. He was suicidal and had a well-formulated plan to end his life. He declined psychotherapy and ECT. A trial of outpatient oral ketamine was therefore initiated after obtaining informed consent.

We followed previously documented treatment procedures.^6,7 In the first session, 150 mg of ketamine, obtained from ketamine for injection (Verket, Verve Healthcare Ltd, India), was syringed into 100 mL of water. The reconstituted solution was sipped over 15–20 minutes. He soon experienced nausea, dizziness, and depersonalization, all of which resolved within 1–1.5 hours. The antidepressant benefits of ketamine peaked at 12 hours and declined after 24 hours; however, the MADRS score did not drop by more than two points following each ketamine session. He also continued to experience suicidal thoughts.

Due to poor response, we gradually increased the dose of ketamine to 175 mg at the second and third sessions, 200 mg at the fourth session, and reached 250 mg at the fifth session. The post-session MADRS scores ranged from 36 to 40 and did not drop by more than two points following any session. The co-medications during ketamine sessions 1–3 were mirtazapine 15 mg/day, aripiprazole 5 mg/day, and clonazepam 0.5 mg/day, all dosed once a day nightly. From sessions 4–6, mirtazapine was cross-tapered with oral bupropion (105 mg) + dextromethorphan (45 mg), administered once daily for a week, followed by twice-daily dosing. Other co-medications were continued as such.

Following continued non-response to the sixth session, we suggested discontinuing the ketamine trial; however, the patient requested continuation due to subjective improvement in cognitive ability and energy levels following each session (these, however, did not reflect in the MADRS scores). Respecting the patient’s preferences, we continued the sessions. However, no durable improvement in depression ratings, suicidality, and functioning was noticed following any ketamine session. As is standard practice with ketamine, ³ the sessions were administered thrice weekly.

By the eighth session, a few of his life stressors were resolved: He found a new home and secured his child’s admission to a reputed school. These positive developments were reflected in his MADRS ratings, which dropped from 40 after the fifth dosing session to 26 after the eighth session.

After discussion with the patient, it was decided to taper off the ketamine treatment. The last four sessions were spaced five days apart, with a seven-day gap before the last one. The patient remained stable during tapering, with an endpoint MADRS score of 22. He was thereafter maintained on oral bupropion-dextromethorphan combination twice-daily, augmented with oral aripiprazole (5 mg).

Discussion

Our patient had a poor antidepressant and anti-suicidal response to 150–250 mg of oral ketamine till the eighth dosing session, and improved only after the resolution of some of his ongoing life stressors. We suggest the reasonable explanation that severe unresolved stress either prevents, masks, or moderates the timing of ketamine-mediated benefits in MDD. Meaningful clinical benefits were observed only when the patient’s life stressors had substantially abated, not when the ketamine dose was escalated or when the sessions continued, and a cumulative effect might have emerged. Natural fluctuations in symptom severity, particularly to the extent noted, were not observed either earlier (improvement) or later (worsening) during 16 weeks of follow-up. A placebo response appears unlikely, as no such response was noted in the initial sessions, and the limited improvements noted were not sustained. Thus, the temporal relationship between resolution of life stressors and subsequent improvement in depression and suicidality supports our interpretation and is in line with the principle of Occam’s razor. ⁸

We previously reported a case where the patient had a good response to oral ketamine. ⁷ The reported patient had a pre-existing depression and was offered oral ketamine to help her cope with an upcoming life event (exams). However, in the index patient, multiple, simultaneous life stressors appeared to be driving the depression, judging from the reported contents of his negative thoughts. These stressors had negatively impacted his functioning in work and family domains. This may explain the poor response to oral ketamine sessions until the life stressors had significantly resolved. A more parsimonious explanation is that the patient may have been a poor responder to oral ketamine.

As an implication for research, we suggest that current stress be included as a measured covariate in ketamine trials in MDD. As an implication for practice, we emphasize that a DSM diagnosis of severe MDD in the context of unresolved life stressors, even in the presence of suicidality, does not automatically support the use of ketamine as a resource. When other pharmacological and psychosocial options fail, are not accepted, or are not possible, then ketamine can be considered, but with reservations.

As an important note, suicidality also did not attenuate with ketamine until life stressors resolved. This goes against the suggestion that improvement in suicidality with ketamine is independent of its antidepressant effects.^9,10

Conclusion

Our report suggests that persistent, unresolved life stressors may undermine the antidepressant benefits of a course of ketamine in MDD.

Supplemental Material

Supplemental Material