Fine-tuning of dopamine receptor signaling with aripiprazole counteracts ketamine's dissociative action, but not its antidepressant effect.
Daiki Nakatsuka, Taro Suwa, Yuichi Deguchi, Yoshihisa Fujita, Ryoichi Tashima, Soichiro Ohnami, Hirotsugu Kawashima, Naoya Oishi, Koichi Ogawa, Hidekuni Yamakawa, Toshiya Murai
Translational Psychiatry March 8, 2025 DOI: 10.1038/s41398-025-03284-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Single-arm, double-blinded clinical study; animal experiments Peer reviewed |
|---|---|
| Sample size | 9 |
| Population | Depressed patients |
| Interventions | Aripiprazole Ketamine Raclopride Brexpiprazole |
| Dose | 12 mg |
| Topics | Esketamine Ketamine |
| Keywords | Ketamine therapy Antidepressant medication Mental health treatment Psychiatric research Drug interactions |
| Citations | 1 |
| Key findings | Co-administration of aripiprazole suppressed ketamine-induced dissociation while preserving its antidepressant effects in both mice and humans. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 10
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial American Journal of Psychiatry December 5, 2017
- Ketamine Safety and Tolerability in Clinical Trials for Treatment-Resistant Depression The Journal of Clinical Psychiatry September 2, 2014
- Reconsidering "dissociation" as a predictor of antidepressant efficacy for esketamine. Psychopharmacology April 1, 2023
and 5 more in the library