Antipsychotic Drug Action, Novel Treatment Targets, and the Failure of Current Clinical Trial Designs in Evaluating...

The discovery of antipsychotic drugs more than 65 years ago revolutionized the treatment of schizophrenia that was initially based on serendipitous findings with chlorpromazine. This later led to the dopamine (DA) hypothesis, linking hyperdopaminergic states to psychosis. While D₂-based antipsychotics effectively reduce positive symptoms, they fail to address cognitive and negative deficits. Preclinical studies have provided critical insights into schizophrenia pathophysiology and treatment. These studies show that hippocampal hyperactivity and loss of parvalbumin GABAergic (gamma-aminobutyric acidergic) neuron inhibition drive DA system dysregulation, which leads to pathological hyper-responsivity to stimuli. Antipsychotic drugs induce depolarization block in DA neurons that normalizes DA hyperactivity but does not correct upstream hippocampal dysfunction. Preclinical models have also identified potential novel treatments targeting the hippocampal hyperexcitability, including GABA α₅-positive allosteric modulators and evenamide. These compounds may have the ability to restore hippocampal inhibition, normalize positive symptom-related DA activity, and improve cognitive and negative symptoms without D₂-associated side effects. Clinical trial failures of novel agents, such as pomaglumetad, may be a product of prior D₂ antagonist exposure leading to postsynaptic supersensitivity rather than lack of efficacy. This evidence underscores the importance of patient treatment history and the design of trials that account for prior antipsychotic exposure when evaluating new compounds. Targeting upstream pathology in the hippocampus offers a promising approach for developing more effective, side effect-sparing treatments for schizophrenia.