The Relationship Between the Efficacy of Lumateperone and Central Glutamate and Dopaminergic Metabolism: A Comparison With Risperidone in First Episode Psychosis

Efficacy. To examine the differential relationships between antipsychotic efficacy and changes in central dopaminergic and glutamatergic metabolism in lumateperone and risperidone treated early psychosis patients. Hypothesis 1a). Lumateperone efficacy will be directly related to both striatal neuromelanin and medial cingulate glutamate changes. Hypothesis 1b). With risperidone, the relationship with efficacy will be restricted to striatal neuromelanin changes. Brain glutamate and dopamine measures will be collected once in healthy controls to assist in the interpretation of baseline psychosis findings.

Safety. To examine the differential extra-pyramidal and peripheral metabolic side-effects in lumateperone and risperidone-treated early psychosis patients. Hypothesis 2a). Risperidone will cause more EPS than lumateperone, and this will be related to greater increases in prolactin. Hypothesis 2b). Risperidone will cause greater weight gain than lumateperone, and this will be related to increments in plasma lipids.

Background:

Lumateperone is an effective atypical antipsychotic with dopamine, serotonin and glutamate effects, a benign safety profile in terms of EPS and metabolic syndrome and the advantage of a single dose. Efficacy and safety have been established compared to placebo in chronically-ill psychotic patients. However, lumateperone has not been tested against an active comparator or examined in first episode psychosis. With the recognition of the importance of reducing duration of untreated psychosis, establishing efficacy and safety of antipsychotics early in psychosis becomes critical. Early psychosis patients tend to respond more robustly than chronically ill patients, but may be more sensitive to side-effects. In addition, because of the absent or minimal previous antipsychotic exposure, an early psychosis sample offers a better opportunity to examine brain mechanisms underlying efficacy of novel compounds.

Glutamate abnormalities have been documented in schizophrenia mainly with single-voxel proton magnetic resonance spectroscopy (1H-MRS). Whole brain measurement of glumate (glutamate plus glutamine i.e.: Glx) with three dimentional echo planar spectroscopic imaging (3D-EPSI) and magnatic resonance scanning of neuromelanin, a sensitive proxy for dopamine concentration in the substantia nigra (S-N) has been recently implemented. The S-N is the origin of the dorsal-striatal terminal fields, where an increased dopamine release has been documented in-vivo in schizophrenia and bipolar-I subjects with positron emission tomography (PET). The lumateperone effects on brain dopamine and glutamate have been documented in rodent models of psychosis. This pilot study is proposed to examine the in-vivo effects of lumateperone on central measures of dopamine and glutamate metabolism and their relationship with efficacy, in early psychosis patients.