Caffeine consumption and schizophrenia: A highlight on adenosine receptor-independent mechanisms.

Schizophrenia is a common psychiatric disorder which affects approximately 1% of the population worldwide. However, the complexity of etiology, treatment resistance and side effects induced by current antipsychotics, relapse prevention, and psychosocial rehabilitation are still to be uncovered. Caffeine, as the world's most widely consumed psychoactive drug, plays a crucial role in daily life. Plenty of preclinical and clinical evidence has illustrated that caffeine consumption could have a beneficial effect on schizophrenia. In this review, we firstly summarize the factors associated with the caffeine-induced beneficial effect. Then, a variety of mechanism of actions independent of adenosine receptor signaling will be discussed with an emphasis on the potential contribution of the microbiome-gut-brain axis to provide more possibilities for future therapeutic, prognosis, and social rehabilitation strategy.