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In contrast to the dose‐occupancy relationship in the treatment of schizophrenia, the minimal effective level of dopamine receptor 2 (D2R) blockade for antipsychotics in the treatment of bipolar depression is unknown. Lower doses aimed at reducing extrapyramidal side effects must be balanced against the need to retain the therapeutic benefit of D2R blockade on emergent cycling, mixed, manic, anxiety, and/or psychotic symptoms. Dose‐reductions intended to lower D2R blockade, however, could also decrease concomitant serotonin receptor antagonism and its potential benefit on depressive symptoms. Here, we uncoupled the potential antidepressant activity in amisulpride, driven by 5‐HT7 receptor (5‐HT7R) antagonism, from the D2R‐mediated antipsychotic activity by discovering that each enantiomer favors a different receptor. Aramisulpride was more potent at 5‐HT7R relative to esamisulpride (K i  47 vs. 1,900 nM, respectively), whereas esamisulpride was more potent at D2R (4.0 vs. 140 nM). We hypothesized that a nonracemic ratio might achieve greater 5‐HT7R‐mediated antidepressant effects at a lower level of D2R blockade. The dose‐occupancy relationship of esamisulpride at D2R was determined by positron emission tomography (PET) imaging in human volunteers. Separately the dose‐relationship of aramisulpride was established in humans using suppression of rapid eye movement (REM) sleep as a marker of 5‐HT7R antagonism. These results led to the discovery of an 85:15 ratio of aramisulpride to esamisulpride (SEP‐4199) that maximizes the potential for antidepressant benefit of aramisulpride via 5‐HT7R and reduces esamisulpride to minimize D2R‐related extrapyramidal side effects while still retaining D2R‐mediated effects predicted to provide benefit in bipolar depression. The antidepressant efficacy of SEP‐4199 was recently confirmed in a proof‐of‐concept trial for the treatment of bipolar depression (NCT03543410).

Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5‐HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders