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Biomarkers of ketamine's antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology.

ABSTRACT: Major depressive disorder (MDD) is one of the leading causes of morbidity and all-cause mortality (including suicide) worldwide, and, unfortunately, first-line monoaminergic antidepressants and evidence-based psychotherapies are not effective for all patients. Subanesthetic doses of the N-methyl-D-aspartate receptor antagonists and glutamate modulators ketamine and S-ketamine have rapid and robust antidepressant efficacy in such treatment-resistant depressed patients (TRD). Yet, as with all antidepressant treatments including electroconvulsive therapy (ECT), not all TRD patients adequately respond, and we are presently unable to a priori predict who will respond or not respond to ketamine. Therefore, antidepressant treatment response biomarkers to ketamine have been a major focus of research for over a decade. In this article, we review the evidence in support of treatment response biomarkers, with a particular focus on genetics, functional magnetic resonance imaging, and neurophysiological studies, i.e. electroencephalography and magnetoencephalography. The studies outlined here lay the groundwork for replication and dissemination.

SUBMITTER: Alario AA

PROVIDER: S-EPMC8186113 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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Biomarkers of ketamine's antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology.

Alario Alexandra A AA Niciu Mark J MJ

Chronic stress (Thousand Oaks, Calif.) 20210101

Major depressive disorder (MDD) is one of the leading causes of morbidity and all-cause mortality (including suicide) worldwide, and, unfortunately, first-line monoaminergic antidepressants and evidence-based psychotherapies are not effective for all patients. Subanesthetic doses of the N-methyl-D-aspartate receptor antagonists and glutamate modulators ketamine and S-ketamine have rapid and robust antidepressant efficacy in such treatment-resistant depressed patients (TRD). Yet, as with all anti ...[more]

PMID: 34159281

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Project description:BackgroundMajor depressive disorder (MDD) is a prevalent psychiatric disorder characterized by substantial clinical and neurobiological heterogeneity. Conventional studies that solely focus on clinical symptoms or neuroimaging metrics often fail to capture the intricate relationship between these modalities, limiting their ability to disentangle the complexity in MDD. Moreover, patient neuroimaging data typically contains normal sources of variance shared with healthy controls, which can obscure disorder-specific variance and complicate the delineation of disease heterogeneity.MethodsWe employed contrastive principal component analysis to extract disorder-specific variations in fMRI-based resting-state functional connectivity (RSFC) by contrasting MDD patients (N=233) with age-matched healthy controls (N=285). We then applied sparse canonical correlation analysis to identify latent dimensions in the disorder variations by linking the extracted contrastive connectivity features to clinical symptoms in MDD patients.ResultsTwo significant and generalizable dimensions linking distinct brain circuits and clinical profiles were discovered. The first dimension, associated with an apparent "internalizing-externalizing" symptom dimension, was characterized by self-connections within the visual network and also associated with choice reaction times of cognitive tasks. The second dimension, associated with personality facets such as extraversion and conscientiousness typically inversely associated with depression symptoms, is primarily driven by self-connections within the dorsal attention network. This "depression-protective personality" dimension is also associated with multiple cognitive task performances related to psychomotor slowing and cognitive control.ConclusionsOur contrastive RSFC-based dimensional approach offers a new avenue to dissect clinical heterogeneity underlying MDD. By identifying two stable, neurophysiology-informed symptom dimensions in MDD patients, our findings may enhance disease mechanism insights and facilitate precision phenotyping, thus advancing the development of targeted therapeutics for precision mental health.

Project description:Ketamine, a rapid-acting antidepressant, has undesirable psychotomimetic effects, including a dissociative effect. There is currently no effective strategy to suppress these side effects while preserving its antidepressant effect. Here, we investigated the effects of a D2/D3 receptor antagonist and partial agonists on the psychotomimetic and antidepressant effects of ketamine in mice and humans. Aripiprazole, a partial agonist, attenuated the psychotomimetic effect, but maintaining and even enhancing the antidepressant-like effect of ketamine in the forced swim test, whereas raclopride, an antagonist, suppressed both effects in mice. Brain-wide Fos mapping and its network analysis suggested the ventral tegmental area (VTA) as a critical region for distinguishing the effects of aripiprazole and raclopride. In the chronic stress model, local infusion of raclopride into the VTA inhibited ketamine's antidepressant-like effect, accompanied by activation of dopaminergic neurons, suggesting the inhibitory effect of VTA activation on the antidepressant-like effect of ketamine. Consistently, systemic injections of raclopride and brexpiprazole, a partial agonist similar to aripiprazole but closer to an antagonist (lower Emax), activated dopaminergic neurons in the VTA and suppressed ketamine's antidepressant-like effect in the model when co-administered with ketamine, whereas aripiprazole didn't. In line with these results, in a single-arm, double-blinded clinical study of sequential treatments in depressed patients (N = 9), co-administration of 12 mg of aripiprazole suppressed the dissociative symptoms induced by ketamine while maintaining its antidepressant effects. Together, these findings suggest that fine-tuning dopamine receptor signaling with aripiprazole allows selective suppression of ketamine-induced dissociation preserving its antidepressant effects, and that the combined use of aripiprazole and ketamine may be a preferred therapy for treatment-resistant depression.

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Biomarkers of ketamine's antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology.

Publications

Biomarkers of ketamine's antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology.

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