Psychedelic treatment to improve social and cognitive function in preclinical models of schizophrenia

Background and Innovation: Cognitive and social deficits in schizophrenia are extremely debilitating and remain undertreated with current antipsychotic medications. Serotonergic psychedelics such as psilocybin and entactogens such as MDMA have shown promise as therapeutics for neuropsychiatric disorders and are being considered as adjunctive treatment for schizophrenia. Two of the proposed mechanisms for the therapeutic benefit of psychedelics and entactogens are their ability to increase social connectedness and cognitive flexibility, both of which are deficient in schizophrenia. Preclinical studies will help inform the field on the receptor and circuit mechanisms of these serotonergic compounds for the treatment of social and cognitive deficits in schizophrenia, and whether beneficial effects remain in the context of antipsychotic treatment. The goals of the proposed studies are to (1) dissect the receptor and circuit mechanisms through which psilocybin and MDMA improve cognitive flexibility and social motivation; and (2) examine their therapeutic efficacy in a neurodevelopmental model relevant to schizophrenia and in the context of antipsychotics. Significance and Impact to Veterans Healthcare: Veterans with schizophrenia are among the most ill of those treated at VA facilities, which presents a great burden on care and VA resources. The inadequacy of treatment response and myriad side effects of current medications makes long-term care and medication adherence difficult. Hence, better treatment of Veterans with psychotic disorders will greatly improve their overall quality of life and long-term care. These preclinical studies will help identify potential therapeutic targets for future studies in Veterans. Path to translation/implementation: If successful, the proposed studies will indicate whether acute administration of psychedelics and entactogens can improve behaviors associated with schizophrenia. Findings will inform clinicians on how these drugs may be working in the brain to alter behavior and whether or not the drugs produce the expected effects in the context of antipsychotic treatment. To move the research along the translational pathway, the next steps will be to use these preclinical studies to inform clinicians on the dose and timing of psychedelic administration and their interaction with antipsychotic medications. New therapeutic targets identified by these studies may lead to drug development for social and cognitive deficits in Veterans with schizophrenia.