A randomized placebo-controlled PET study of ketamine´s effect on serotonin1B receptor binding in patients with SSRI-resistant depression

Abstract

The glutamate N-methyl-d-aspartate receptor antagonist ketamine has a rapid antidepressant effect. Despite large research efforts, ketamine’s mechanism of action in major depressive disorder (MDD) has still not been determined. In rodents, the antidepressant properties of ketamine were found to be dependent on both the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and the serotonin (5-HT)1B receptor. Low 5-HT1B receptor binding in limbic brain regions is a replicated finding in MDD. In non-human primates, AMPA-dependent increase in 5-HT1B receptor binding in the ventral striatum (VST) has been demonstrated after ketamine infusion. Thirty selective serotonin reuptake inhibitor-resistant MDD patients were recruited via advertisement and randomized to double-blind monotherapy with 0.5 mg/kg ketamine or placebo infusion. The patients were examined with the 5-HT1B receptor selective radioligand [11C]AZ10419369 and positron emission tomography (PET) before and 24–72 h after treatment. 5-HT1B receptor binding did not significantly alter in patients treated with ketamine compared with placebo. An increase in 5-HT1B receptor binding with 16.7 % (p = 0.036) was found in the hippocampus after one ketamine treatment. 5-HT1B receptor binding in VST at baseline correlated with MDD symptom ratings (r = −0.426, p = 0.019) and with reduction of depressive symptoms with ketamine (r = −0.644, p = 0.002). In conclusion, reduction of depressive symptoms in MDD patients after ketamine treatment is correlated inversely with baseline 5-HT1B receptor binding in VST. Further studies examining the role of 5-HT1B receptors in the antidepressant mechanism of action of ketamine should be conducted, homing in on the 5-HT1B receptor as an MDD treatment response marker.

Plasma Levels of Brain-Derived Neurotrophic Factor and S100B in Relation to Antidepressant Response to Ketamine

“…The present study was conducted as part of a randomized placebo-controlled clinical trial of ketamine compared to saline in patients with SSRI-resistant MDD [see European Union Drug Regulating Authorities Clinical Trials Database (EudraCT: 2017-003405-17)]. The primary study, which investigated serotonin receptor densities using Positron Emission Tomography (PET), was previously published ( Tiger et al, 2020 ). The study was approved by the Regional Ethical Review Board in Stockholm (Dnr.…”

Identifying Potential Novel Pathways and Therapeutic Targets of Major Depressive Disorder with Functional Genomics

“…Quite nicely and without intention, ketamine is at the center of the network. Though ketamine is hypothesized to act primarily on the glutamatergic system to produce antidepressant effects, its mechanism of action may involve other systems as well, including the serotonergic system [57].…”

Potencial terapéutico de los alucinógenos en las cefaleas: una revisión teórica

“…Además de este mecanismo de acción, la ketamina muestra afinidad por los receptores opioides, de serotonina (especialmente a los receptores 5-HT 1 y 5-HT 2 ), muscarínicos (Tiger et al, 2020), así como también interactúa con la dopamina (D2) y con los bloqueadores de los canales de sodio (Peltoniemi et al, 2016). Es importante destacar que la ketamina también actúa liberando catecolaminas e inhibiendo su recaptación cuando se administra a dosis bajas (Bakhsh & Greer, 2021).…”