Fine-tuning of dopamine receptor signaling with aripiprazole counteracts ketamine's dissociative action, but not its antidepressant effect

  • Transl Psychiatry. 2025 Mar 8;15(1):77. doi: 10.1038/s41398-025-03284-9.
Daiki Nakatsuka  #  1  2  3 ,  Taro Suwa  #  4 ,  Yuichi Deguchi  1  2 ,  Yoshihisa Fujita  1  4 ,  Ryoichi Tashima  2 ,  Soichiro Ohnami  1  2 ,  Hirotsugu Kawashima  4 ,  Naoya Oishi  1  4  5 ,  Koichi Ogawa  1  2 ,  Hidekuni Yamakawa  6  7  8 ,  Toshiya Murai  9  10
Affiliations
  • 1. SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 2. Laboratory for Drug Discovery and Disease Research, SHIONOGI & CO., LTD, Osaka, Japan.
  • 3. Ping An-Shionogi Co., Ltd, Shanghai, China.
  • 4. Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 5. Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 6. SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. [email protected].
  • 7. Laboratory for Drug Discovery and Disease Research, SHIONOGI & CO., LTD, Osaka, Japan. [email protected].
  • 8. Ping An-Shionogi Co., Ltd, Shanghai, China. [email protected].
  • 9. SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan. [email protected].
  • 10. Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [email protected].
  • # Contributed equally.
PMID: 40057507 DOI: 10.1038/s41398-025-03284-9
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.

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