Rapid psychoactive action of Rapastinel free of psychomimetic symptoms

Newsletter # 105



Animal models


A Phase 2 clinical trial reported Rapastinel as a fast-acting and effective antidepressant in Treatment-resistant depression patients (TRD). Although Rapastinel interacts with the NMDA Receptor (NMDAR positive allosteric modulator), it does not have any of the liabilities associated with noncompetitive NMDA antagonists (Phencyclidine, Ketamine or Dizocilpine), such as psychotomimetic effects and deficits in cognition. Despite the failure of Rapastinel in phase 3, the next generation of NMDAR modulators with far greater potency and longer plasma half-life than Rapastinel are under development. .

Neurofit's preclinical data indicates a rapid change in the marble burying behavior following the administration of Rapastinel in mice. It also shows that Rapastinel does not disrupt the cognitive performance of mice as assessed in the spontaneous alternation T-maze paradigm, suggesting the absence of schizophrenia-like symptoms associated with most of the NMDA antagonist class. These results confirm the rapid-acting CNS effect and the safety profile of allosteric modulation of the NMDA receptor.

  • Rapastinel modifies
    CNS behavior

    NEUROFIT website

    Left panel :
    The graph shows the number of marbles buried by mice during a 20-minute-long session. 20 glass marbles (diameter: 1.5 cm) are spaced evenly along the walls of the homecage cage which contains about a 5 cm layer of fine sawdust bedding.
    Placebo-treated mice bury about three-quarters of the marbles whereas those treated with anxiolytics or antidepressants bury significantly less. 120 minutes pre-treatment with Rapastinel induces a dose-dependent inhibition of marble burying behavior.


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  • Rapastinel does not alter
    the cognitive function

    NEUROFIT website

    Right panel :
    The graph shows the change in the spontaneous alternation of mice in the T-maze following treatment with different drugs. The spontaneous alternation paradigm represents a useful tool for cognitive evaluation (a higher rate of alternation reflects a better cognitive performance). Placebo-treated mice perform an alternation rate > 65% which is markedly reduced by treatment with NMDA antagonists such as Phencyclidine (also known under street names of peace pill, angel dust, crystal , etc...) and MK-801 (Dizocilpine). Rapastinel, with a proven CNS effect, does not significantly alter the spontaneous alternation performance of mice which suggests the absence of potential cognitive side effects.


NEUROFIT offers a range of validated in vitro and in vivo screening tests for psychiatry and neurology.

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