The effectiveness of multi-target agents in schizophrenia and mood disorders: Relevance of receptor signature to clinical action

Schizophrenia, bipolar disorder and unipolar depression are multi-dimensional and severely disabling psychiatric diseases with a strong need for improved pharmacotherapies with better adherence, long-term outcome and patient functionality. Progress has been achieved with the emergence of tailored multi-target agents (MTAs), such as second-generation antipsychotics for schizophrenia, with expanding clinical utility in bipolar disorder and depression. Better understanding of how these MTAs exert their beneficial and undesirable clinical effects in terms of receptor interaction remains an area for further elucidation, which may provide insight towards a new generation of individualized, and optimized therapies. This review explores to what extent the receptor signature of MTAs informs about their clinical action and therapeutic utility. Compelling clinical validation exists only for a limited number of molecular targets (e.g. D2 receptor blockade, serotonin transport inhibition), indicating overall high attrition and poor translation of predictive preclinical pharmacology. Nevertheless, recent advances have identified promising novel approaches for schizophrenia, bipolar disorder and depression that require further clinical validation. It is hoped that the expanding clinical and mechanistic knowledge garnered from the use of existing MTAs will provide additional opportunities for “reverse translation” and towards target validation. There is considerable scope for further developing and applying the knowledge linking receptor signature to clinical activity to drive stronger target validation, and ultimately support rational development of the next generation of MTAs for the improved treatment of schizophrenia and mood disorders.