2026/06/01 by Anthony A. Grace, Daniela Uliana
Medicine · Neuroscience · #Schizophrenia research and treatment #Neurotransmitter Receptor Influence on Behavior #Treatment of Major Depression
paper · doi:10.1016/j.biopsych.2026.06.010
The discovery of antipsychotic drugs over 65 years ago revolutionized the treatment of schizophrenia that was initially based on serendipitous findings with chlorpromazine. This later led to the dopamine 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 neuron inhibition drive dopamine system dysregulation which leads to pathological hyper-responsivity to stimuli. Antipsychotic drugs induce depolarization block in dopamine neurons that normalizes dopamine 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 hold the ability to restore hippocampal inhibition, normalize positive symptom-related dopamine 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.