Preclinical Studies of Standard and Novel Target Antipsychotic Drugs in Animal Models of Schizophrenia: Why Clinical Trials May Have Failed to Recapitulate Preclinical Findings

Abstract Background Substantial research has focused on hippocampal dysregulation driving the DA dysfunction underlying psychosis and contributing to cognitive and negative symptoms. However, several agents that target normalization of the hippocampal circuit, while showing promise in preclinical studies and in early clinical trials, have failed in large multicenter studies. We posit that classic clinical trial design may not be effective at evaluating novel target agents. Aims however, this was not accompanied by depolarization block, but instead appears to be due to a direct DA agonist inhibition of DA neuron activity. Discussion & Conclusions These data support the hypothesis that prior administration of a D2 antagonist drug and a short withdrawal period interfered with the actions of novel target compounds by confounding D2 supersensitivity. While withdrawing patients from antipsychotic drugs for a sufficient period to normalize D2 receptors, which may require months, is not ethically feasible, our data suggest that transitioning patients from an effective compound that does not induce supersensitivity, such as aripiprazole, may be a more effective strategy. Alternately, while it is not ethically feasible to withdraw patients from an antipsychotic drug for extended periods, it is known that a large number of patients are not compliant with their current medication. If we can test novel compounds either on demonstrably noncompliant patients or patients early in their treatment, we may have a more effective strategy for testing the efficacy of these compounds in the treatment of schizophrenia.