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 & Objectives
Based on evidence presented here we posit that prior treatment of patients with D2 antagonist antipsychotic drugs, by inducing D2 supersensitivity, obscured the potential therapeutic actions of these novel compounds. We then examined if there was a way in which we can circumvent the confound of prior drug administration when testing the actions of novel target compounds.
Method
Pregnant Sprague Dawley rats were administered with MAM (20mg/kg) at gestational day 17 and the male offspring were tested as adults. We tested the effects of acute and repeated (3 weeks) treatment with standard and novel target antipsychotic drugs on DA and hippocampal neuron activity. DA neuron population activity was assessed by making 9 electrode tracks through the ventral tegmentum and assessing number of DA neurons active, firing rate and pattern.
Results
MAM-treated offspring showed increased activity in the limbic ventral hippocampus and an increase in the number of DA neurons spontaneously active, consistent with studies in schizophrenia patients. Acute administration of the GABA A alpha 5 PAM consistently reversed hippocampal hyperactivity and normalized DA neuron firing in the MAM model. However, after pretreatment of MAM rats with haloperidol for 3 weeks and 1 week withdrawal, this compound was no longer effective at reversing DA dysfunction, which we propose is due to D2 supersensitivity. Pomaglumetad was also effective in normalizing DA neuron function and hippocampal hyperactivity via a direct action within the hippocampus. In contrast, when we administered aripiprazole, a D2 partial agonist, either acutely or for 3-4 weeks, there was an inhibition of DA neuron firing in the MAM model; 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.