Alpha7 nicotinic-N-methyl-D-aspartate hypothesis in the treatment of schizophrenia and beyond

Development of novel treatments for positive, cognitive, and negative symptoms continue to be a high-priority area of schizophrenia research and a major unmet clinical need. Given that all randomized controlled trials (RCTs) conducted to date failed with one add-on medication/mechanism of action, future RCTs with the same approach are not warranted. Even if the field develops a medication for cognition, others are still needed to treat negative and positive symptoms. Therefore, fixing one domain does not completely solve the problem. Also, targeting the cholinergic system, glutamatergic system, and cholinergic plus alpha7 nicotinic and N-methyl-D-aspartate (NMDA) receptors failed independently. Hence, targeting other less important pathophysiological mechanisms/targets is unlikely to be successful. Meta-analyses of RCTs targeting major pathophysiological mechanisms have found some efficacy signal in schizophrenia; thus, combination treatments with different mechanisms of action may enhance the efficacy signal. The objective of this article is to highlight the importance of conducting RCTs with novel combination treatments in schizophrenia to develop antischizophrenia treatments. Positive RCTs with novel combination treatments that target the alpha7 nicotinic and NMDA receptors simultaneously may lead to a disease-modifying therapeutic armamentarium in schizophrenia. Novel combination treatments that concurrently improve the three domains of psychopathology and several prognostic and theranostic biomarkers may facilitate therapeutic discovery in schizophrenia.