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Kappa opioid receptor plasma levels are associated with sex and diagnosis of major depressive disorder but not response to ketamine

Brandi Quintanilla, Gustavo C Medeiros, D. Greenstein, P. Yuan, J. Johnston, Lawrence T. Park, Fernando S Goes, T. Gould, Carlos A. Zarate

Journal of Clinical Psychopharmacology February 24, 2023 DOI: 10.1097/jcp.0000000000001663 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Randomized, crossover, double-blind trial Peer reviewed
Sample size 64
Population 39 unmedicated individuals with major depressive disorder (23 women) and 25 healthy volunteers (16 women)
Interventions Ketamine placebo
Dose 0.5 mg/kg
Duration Blood sampled at baseline and at 230 minutes, day 1, and day 3 postinfusion
Topics Depression Esketamine Ketamine
Registration NCT00088699
Key findings People with major depressive disorder had lower baseline plasma KOR levels than healthy volunteers, and women had higher KOR levels than men. Baseline KOR and dynorphin levels did not moderate ketamine's therapeutic or adverse effects, and ketamine produced no postinfusion changes in these levels compared with placebo.

Abstract

Abstract Background Preclinical evidence indicates that the κ-opioid receptor (KOR)/dynorphin pathway is implicated in depressive-like behaviors. Ketamine is believed to partly exert its antidepressant effects by modulating the opioid system. This post hoc study examined the following research questions: (1) at baseline, were there differences in KOR or dynorphin plasma levels between individuals with major depressive disorder (MDD) and healthy volunteers (HVs) or between men and women? (2) in individuals with MDD, did KOR or dynorphin baseline plasma levels moderate ketamine's therapeutic effects or adverse effects? and (3) in individuals with MDD, were KOR or dynorphin plasma levels affected after treatment with ketamine compared with placebo?

Methods: Thirty-nine unmedicated individuals with MDD (23 women) and 25 HVs (16 women) received intravenous ketamine (0.5 mg/kg) and placebo in a randomized, crossover, double-blind trial. Blood was obtained from all participants at baseline and at 3 postinfusion time points (230 minutes, day 1, day 3). Linear mixed model regressions were used.

Results: At baseline, participants with MDD had lower KOR plasma levels than HVs (F1,60 = 13.16, P < 0.001), and women (MDD and HVs) had higher KOR plasma levels than men (F1,60 = 4.98, P = 0.03). Diagnosis and sex had no significant effects on baseline dynorphin levels. Baseline KOR and dynorphin levels did not moderate ketamine's therapeutic or adverse effects. Compared with placebo, ketamine was not associated with postinfusion changes in KOR or dynorphin levels.

Conclusions: In humans, diagnosis of MDD and biological sex are involved with changes in components of the KOR/dynorphin pathway. Neither KOR nor dynorphin levels consistently moderated ketamine's therapeutic effects or adverse effects, nor were levels altered after ketamine infusion.

Trial Registration: NCT00088699 (ClinicalTrials.gov).

Comparable studies

Other randomized controlled trials on ketamine for depression, most cited first.

Study Year Design Participants
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68

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