Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals

Abstract

Ketamine improves motivation-related symptoms in depression but simultaneously elicits similar symptoms in healthy individuals, suggesting that it might have different effects in health and disease. This study examined whether ketamine affects the brain’s fronto-striatal system, which is known to drive motivational behavior. The study also assessed whether inflammatory mechanisms—which are known to influence neural and behavioral motivational processes—might underlie some of these changes. These questions were explored in the context of a double-blind, placebo-controlled, crossover trial of ketamine in 33 individuals with treatment-resistant major depressive disorder (TRD) and 25 healthy volunteers (HVs). Resting-state functional magnetic resonance imaging (rsfMRI) was acquired 2 days post-ketamine (final sample: TRD n = 27, HV n = 19) and post-placebo (final sample: TRD n = 25, HV n = 18) infusions and was used to probe fronto-striatal circuitry with striatal seed-based functional connectivity. Ketamine increased fronto-striatal functional connectivity in TRD participants toward levels observed in HVs while shifting the connectivity profile in HVs toward a state similar to TRD participants under placebo. Preliminary findings suggest that these effects were largely observed in the absence of inflammatory (C-reactive protein) changes and were associated with both acute and sustained improvements in symptoms in the TRD group. Ketamine thus normalized fronto-striatal connectivity in TRD participants but disrupted it in HVs independently of inflammatory processes. These findings highlight the potential importance of reward circuitry in ketamine’s mechanism of action, which may be particularly relevant for understanding ketamine-induced shifts in motivational symptoms.

Resting-state connectivity studies as a marker of the acute and delayed effects of subanaesthetic ketamine administration in healthy and depressed individuals: A systematic review

“…Decreased connectivity was identified, after ketamine in healthy volunteers. Increased connectivity between the dorsal caudate and the ventromedial prefrontal cortex, 2 days and 10 days after ketamine, also correlated with a reduction in anhedonia in the MDD group ( Mkrtchian et al, 2020 ).…”

“…The drug effects on brain connectivity seem to persist even longer than 24 h since the decrease in the connectivity between the DMN and the insula that was identified for MDD patients compared to HCs was smaller 48 h after ketamine administration but returned to baseline 10 days past the ketamine infusion ( Evans et al, 2018 ). Ketamine produced increases in the connectivity of striatal regions ( Mkrtchian et al, 2020 ) with the dorsolateral and ventrolateral PFC, the pregenual ACC and the OFC in depressed individuals, while decreases were observed for the same set of brain regions in healthy volunteers. Moreover, the increases and decreases in the connectivity of the amygdala and the hippocampus also lasted for more than 24 h and were detectable after multiple ketamine infusion ( Vasavada et al, 2021 ).…”

A translational perspective on the anti-anhedonic effect of ketamine and its neural underpinnings

“…Human neuroimaging studies also demonstrated ketamine related changes in functional connectivity across the frontostriatal circuitry. For example, a recent study showed increased functional connectivity between the caudate and PFC regions (dlPFC and vlPFC), and between the putamen and PFC regions (more specifically perigenual ACC and the orbitofrontal cortex) in treatment-resistant depression (TRD) patients [74]. However, in healthy volunteers, ketamine reversed these functional connectivity effects.…”

N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential

“…The observed lack of difference in the action of 15 and 18 in the MK-801 impaired NORT may look bizarre. However, there have been reports of paradoxical actions of glutamatergic drugs such as different outcomes in healthy individuals and patients [ 33 , 34 ]. The observed similar effects of compounds 15 and 18 in NORT could possibly be related to the restored BDNF levels described by Rychtyk et al [ 20 ].…”