Relationship Between Efficacy of Lumateperone and Brain Glutamate and Dopamine

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.

Significance. There are three significant specific implications for this proposal. First, data supporting the efficacy and tolerability of lumaterperone in first episode psychosis will encourage clinical use of this agent early in the course of schizophrenia and other related disorders. The single dose profile of lumateperone is clearly an advantage in these patients who often have compliance issues. Second, identifying the location of glutamatergic deficits is critical to inform probe placement for future neuromodulation studies, aimed to improve persistent psychotic symptoms. For example, if a particular cortical area (like the medial cingulate) has persistently increased Glx in partially-responsive patients, low-frequency transcranial magnetic stimulation (TMS) targeting the medial cingulate may result in symptomatic improvement for patients who fail available antipsychotic therapy. Alternatively, clinically-relevant reductions in Glx would support high-frequency TMS targeting specific locations. Finally, these studies will also inform anatomical site selection for future postmortem studies of schizophrenia and bipolar-I aimed at examining the molecular underpinnings of these illnesses. This is critical for the development of novel compounds for psychosis that go beyond DA-2 blockade.

Experimental Design and Methods. Subjects. Two groups at baseline: first episode psychosis (FEP) patients and HVs. Subsequently, FEP will be randomized to risperidone or lumateperone for 6 weeks. All FEP subjects will be scanned twice with MRI for 3D 1H-MRS and S-N neuromelanin, at baseline and following 6 weeks of assigned antipsychotic therapy. The HV group will be scanned once at baseline.

Clinical phases of the study. The study will have three clinical phases: Screening, Double Blind and Transition.

1. Screening. After informed consent, subjects will be screened for inclusion and exclusion criteria. If included, subjects will complete a SCID interview and a medical history. HV will also complete the MATRICS cognitive battery, one MRI scan and will be finished with the study. FEP will complete baseline MRI and laboratory work (CBC, UA, chemistry, TSH, liver panel, prolactin, lipids and fasting blood sugar -FBS) as well as a physical exam. ii) Double Blind. Baseline clinical measures will include psychopathology and movement disorder ratings. FEP will be randomized 1:1 at baseline to treatment with lumateperone (single dose 42 mg/day) vs. risperidone (1 mg tablet, target dose between 1 to 4 mg/day). Tablets will be blinded and a 1-week supply will be dispensed by the research pharmacy staff at each visit, following clinical assessments by the research psychiatrist. Patients will take between 1 and 4 tablets in the evening of blinded medication targeting psychotic/manic symptoms. The following un-blinded supplemental psychotropic medications will be allowed at the discretion of the treating psychiatrist: a) benztropine 1- 4 mg/day (for parkinsonism or dystonia); b) lorazepam 1-4 mg/day (for akathisia, anxiety or insomnia); c) propranolol 20-120 mg/day (for akathisia); and d) trazodone 50 to 200 mg/day for insomnia. These supplemental medicines will not be provided by the research pharmacy as part of the study. The subject will get a regular prescription to fill at his/her local pharmacy.

Patients will be seen weekly by the research psychiatrist and clinical coordinator to assess clinical response, tolerability, compliance and to adjust the blinded and any supplemental medication. The end of study (after 6 weeks of treatment) will also include the MATRICS, the second MRI and the second set of blood-work (prolactin, lipids and FBS).

If patients experience any significant persistent intolerance to the assigned treatment (e.g.: parkinsonism that does not improve with benztropine or akathisia despite treatment with propranolol or lorazepam), their initial medication will be blindly switched to the alternative anti-psychotic. If the blinded medication switch occurs at or after 3 weeks of treatment with the original drug, the end of study assessments will be advanced to be completed as close as possible to the date of switching medications. If the switching occurs before 3 weeks of treatment, the end of study assessments will take place as planned, after a total of 6 weeks of blinded treatment (the goal is to ensure the maximum length of exposure to a particular antipsychotic before end of study assessments are implemented). If the patient's psychotic/manic symptoms are not responding as expected, the blinded medication will be gradually increased (up to 4 tab per day). However, if lack of response persists, the research psychiatrist will also have the option to switch the medication blindly (because of the gradual titration, we expect the medication switch due to lack of response to be very rare). End of study assessments will be advanced as when switching due to intolerance.

iii) Transition Finally, patients will be transitioned to open-label antipsychotic treatment with lumateperone (provided by study sponsor for up to 6 months) or to any other agent as per standard of care (for which the patient will be responsible). Patients will be seen weekly for 4 weeks by the research psychiatrist for stabilization on the selected treatment before being referred back to a community-based provider of the patient's choosing. Any other therapies, pharmacological and psychosocial, that are consistent with the standard of care will also be recommended to the subject during this transition phase.

c). Magnetic Resonance. MR scans will be performed once at baseline for all subjects and once after 6 weeks of double-blind treatment for FEP. The protocol consists of structural MRI, Neuromelanin and EPSI scans.

d). Clinical Ratings. Patients will be evaluated for psychopathology with: the Positive And Negative Symptoms rating Scale (PANSS), mania with the Young Mania Rating Scale, depressive symptoms with the Calgary Depression Scale and the Columbia Suicide Severity Rating Scale. They will be assessed for movement side effects with the Simpson-Angus Scale (SAS) for parkinsonism, Barnes Akathisia Scale (BAS) and the Assessment of Involuntary Movement (AIMS) scale for tardive dyskinesia.

e). Neurocognitive and functional measures. The MATRICS, the standard in psychosis research, is an overall neurocognitive outcome and will be collected in all subjects once. The MATRICS evaluates several domains: processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning \& problem solving, and social cognition. It will be collected once at baseline in HV and once at the end of 6 weeks of treatment in FEP (so that it better reflects the underlying cognitive capacity apart from the impact of acute psychosis).

Functional outcome will be assessed at baseline with the Specific Levels of Functioning scale (SLOF). The SLOF is administered to the caregiver of a psychotic patient and examines 6 domains: personal care skills, physical functioning, interpersonal relationships, social acceptability, activities of community living and work skills. The Validation of Everyday Real-World Outcomes study found the SLOF to be most robustly related to performance-based indices of neurocognition and everyday living skills.

f). Laboratory measures. All FEP subjects will undergo baseline clinical measures to assess safety before starting double-blind treatment including hemogram (CBC), chemistry (chem7), hepatic function (hepatic panel), thyroid stimulating hormone (TSH) and urine analyses. To examine tolerability (as per Aim 2) serum prolactin, lipids and fasting blood sugar will be collected at baseline and following 6 weeks of double-blind treatment. All blood-work will be collected while fasting, in the AM. Also all subjects (FEP and HV) will have a urine drug screen done on the day of MR scanning. Finally, to prevent MRI exposure to pregnant females, a urine pregnancy test will be collected in all female participants of child-bearing age on the day of each MRI scans.