For decades medications used for the treatment of depression have targeted monoamine neurotransmitter systems (serotonin, norepinephrine, and dopamine); however, more recent research has focused on antidepressants with novel mechanisms of action. Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist and glutamatergic modulator which has shown promise as a rapid-acting antidepressant for patients with treatment-resistant depression (TRD). However, one of the challenges in using ketamine is its poor oral bioavailability, necessitating two to three intravenous infusions per week, a factor which has presented considerable logistical challenges.
In 2019, the US Food and Drug Administration approved an intranasal preparation of ketamine as an augmentation therapy to antidepressants for treatment-resistant depression (defined as 2 or more failed treatment trials). Marketed as Spravato, this preparation contains esketamine, the S-enantiomer of ketamine, which has a higher affinity for the NMDA receptor, and thus greater potency than the R-enantiomer of ketamine.
In a recent report, George Papakostas, MD, Associate Executive Director of the Clinical Trials Network and Institute, and colleagues in the Department of Psychiatry at MGH present a systematic review and meta-analysis of the current data on the use of intranasal esketamine to augment traditional antidepressants.
In a systematic search of PubMed/MEDLINE abstracts up to January 2019, they identified randomized, double-blind clinical trials of adjunctive treatment of standard antidepressants with intranasal esketamine for the treatment of major depressive disorder (MDD). In addition, three clinical trials were identified as recently completed, unpublished presentations at scientific meetings. The final meta-analysis included five trials with a total of 774 participants.
Adjunctive esketamine was significantly more effective than placebo in reducing levels of depressive symptoms. MADRS scores were approximately 2-5 points lower in patients treated with intranasal esketamine versus placebo. Participants receiving esketamine were more likely to respond (risk ratio [RR] = 1.40, 95% CI = 1.22–1.61) and were more likely to remit (RR = 1.45, 95% CI = 1.20–1.75) than those receiving placebo. The results remained statistically significant regardless of whether esketamine was added to a preexisting antidepressant or combined with a newly initiated antidepressant.
In order to compare the effects of augmentation with esketamine to other strategies, the authors calculated the NNT or ‘number needed to treat’ statistic, which tells us the number of patients that need to be treated in order to have one more success than in the control group. For esketamine, the NNT was 6 or 7, which is comparable to the NNT observed for standard antidepressant treatment. For augmentation with atypical antipsychotics, the NNT is around 9, thus we can infer that the treatment effect for intranasal esketamine is larger than those of standard antidepressants or atypical antipsychotics for patients with treatment-resistant depression.
While there has been much excitement about intranasal esketamine, it is still not widely used. Patients who receive esketamine must be treated at a doctor’s office or health care facility, and must be observed for 2 hours following esketamine administration. Most outpatient clinics do not have the space or resources to allow for this extended monitoring period, and insurance companies do not reimburse for this level of treatment. Given that this is one of the few rapidly acting antidepressants in our armamentarium, we hope that access to intranasal ketamine will increase as we gain familiarity with its use.
Read More:
Papakostas GI, Salloum NC, Hock RS, Jha MK, Murrough JW, Mathew SJ, Iosifescu DV, Fava M. Efficacy of Esketamine Augmentation in Major Depressive Disorder: A Meta-Analysis. J Clin Psychiatry. 2020 May 26;81(4):19r12889.
