04. Ketamine for Adolescent Depression

Text version

Hi! David Rosenberg here for the Psychopharmacology Institute. In this CAP—or Child and Adolescent Psychiatry—Smart Take, we will look at the potential role of ketamine, an NMDA receptor antagonist, in adolescent depression. Ketamine therapy has recently garnered much attention as a new, innovative, exciting intervention for treatment-resistant adults with depression and suicidality. Fueling the attraction of ketamine’s use in suicidal depression is its reported rapid antidepressant and antisuicidality effects, which compare favorably to antidepressants and their often delayed effect.

Given that as many as 40% of adolescents with major depressive disorder are treatment resistant, there is an urgent need to examine and evaluate new treatment options. In the United States, ketamine is available in IV, intramuscular, oral, sublingual, and intranasal preparations. Ketamine is not FDA approved for treatment for depression, but intranasal esketamine was FDA approved in 2019 for treatment-resistant depression with suicidality in adults 18 years and older. Its use requires providers and patients to be registered in a risk evaluation and mitigation strategy database to ensure a favorable risk–benefit ratio for its use. On the other hand, ketamine is being prescribed and offered off-label to treat depression and various psychiatric symptoms with reported effectiveness. One concern to remember is that ketamine clinics are sprouting up everywhere, as this can be a major moneymaker, although not all clinics administering ketamine are the same. It is essential to inform patients and families of this and that they do the appropriate due diligence as some providers take considerable liberty in its use.

I am biased, but I do think that, at present, academic centers are probably the safest and best option when ketamine intervention is considered. Also, remember that whereas most antidepressants are safe when used with ketamine, benzodiazepines and opiate antagonists, such as naltrexone, decrease the antidepressant effect of ketamine. There is minimal investigation on the use of ketamine in adolescents with treatment-resistant depression. There are a couple of case reports of adolescents with treatment-resistant depression and suicidality, with 1 report demonstrating rapid and sustained improvement and another showing more gradual improvement over 3 weeks. In both cases, nausea and dissociation were present during infusion, and in 1, it self-resolved, whereas in another, chlorpromazine was needed. Remember also that dissociation is not considered a side effect of ketamine but is postulated as part of its therapeutic effect. There was also an open-label study of 13 adolescents with treatment-resistant depression who received 6 ketamine infusions over 2 weeks, dosed at 0.5 mg/kg. And that particular study found that 5 patients, or 38%, responded to ketamine.

Three maintained remission at 6 weeks, and 2 relapsed within 2 weeks. The side effects included transient dissociative symptoms, infusion-related nausea treated with ondansetron, and dysphoria. In the randomized, double-blind trial of 17 adolescents with severe major depression but without active suicidal ideation or comorbid substance disorders, the patients were randomized to receive a single IV infusion of ketamine or midazolam. Ketamine was dosed at 0.5 mg/kg over 40 minutes, and midazolam—which served as a placebo control—was dosed at 0.045 mg/kg over 40 minutes. A single infusion of ketamine significantly reduced depressive symptoms 24 hours after infusion compared with midazolam, which was a very strong effect size. Over 75% of adolescents with severe major depression responded to ketamine vs 35% of those treated with midazolam. So, what is the bottom line? This is an up-and-coming area to pursue, but ketamine is not ready for routine prime-time use in adolescents with treatment-resistant depression. Interestingly, the aforementioned published studies of ketamine used IV preparations. However, in adults, the FDA has approved an intranasal preparation for ketamine—intranasal esketamine.

When asked, many parents, not surprisingly, prefer the intranasal option. The studies to date are preliminary, with very small sample sizes. More placebo-controlled studies are needed in adolescents with treatment-resistant depression with and without severe suicidality, examination of optimal dosing and titration, and way of delivery, among others. Of note, this report was written by 2 child psychiatry fellows at Stanford. They are to be commended for an outstanding and thoughtful review and roadmap for further study. Exciting times are ahead!

Abstract

Ketamine for Adolescent Depression: An Overview and Considerations for Future Directions

Janet J. Baek and Earth Hasassri

Abstract not available.

Reference

Baek, J. J., & Hasassri, E. (2022). Ketamine for adolescent depression: An overview and considerations for future directions. American Journal of Psychiatry Residents’ Journal, 17(4), 2-4.