Bromocriptine for Patients With Schizophrenia and Impaired Glucose Tolerance

Summary

Participation Requirements

Description

Background: APDs are among the most widely prescribed medications for psychotic, mood, and anxiety disorders including schizophrenia, bipolar disorder, and major depressive disorder. Many APDs, currently available in the United States, particularly second generation APDs, have been associated to var...

Background: APDs are among the most widely prescribed medications for psychotic, mood, and anxiety disorders including schizophrenia, bipolar disorder, and major depressive disorder. Many APDs, currently available in the United States, particularly second generation APDs, have been associated to varying degrees with significant dysmetabolic side effects including insulin resistance (IR), impaired glucose tolerance (IGT), hypertension, abdominal obesity, and dyslipidemia. Indeed, 32% of patients taking olanzapine develop IR in addition to gaining at least 15% of their baseline bodyweight. These changes substantially increase the risk of developing T2D and cardiovascular disease (CVD). In fact, the prevalence of metabolic dysfunction in APD-treated patients is more than twice that of the general population and leads to poorer long-term outcomes. Perhaps most concerning is that APD-treated individuals with schizophrenia have a 15-20-year reduction in life expectancy as compared to the general population, with APD-induced IR being a major contributor to this early mortality. Thus, preventing APD-induced metabolic dysfunction may have a significant impact on morbidity and mortality. Currently there is no consistently effective way to prevent APD-associated metabolic dysfunction and reduce the risk of T2D. Most studies attempting to elucidate the underlying cause of APD-induced metabolic dysfunction have focused on regions of the central nervous system (CNS) associated with metabolic control (i.e. hypothalamus) because these drugs are utilized primarily to treat neuropsychiatric symptoms in the CNS. Consequently, numerous neurotransmitter and neuropeptide systems in the brain, including dopamine and serotonin, have been implicated in the development of APD-induced metabolic side effects. Rationale: Bromocriptine is a dopamine D2/D3 receptor and serotonin 5-HT2C receptor agonist that the study team proposes as a potential treatment for APD-induced IR. It has received FDA approval for treatment of T2D, having been shown to significantly lower postprandial plasma glucose and hemoglobin A1c (HbA1c) without increasing insulin or C-peptide levels. To date, there are few studies using bromocriptine in schizophrenia. Although most of the studies have been small, the cumulative results have consistently shown safety and benefit in psychiatric patients. Bromocriptine, even when used at high doses, has been found to be safe in APD-treated patients despite theoretical concerns of exacerbating psychosis due to dopaminergic receptor agonism. Design: This study is a multicenter open-label, dose-escalation pilot to evaluate the safety and tolerability of bromocriptine as an adjunct to preexisting standard-of-care antipsychotic drug (APD) regimens in the management of APD-associated impaired glucose tolerance (IGT)/insulin resistance (IR). Twenty APD-treated participants aged 18 to 60 years old with schizophrenia who have been psychiatrically stable for at least 3 months and show signs of IR (obesity [BMI > 30 kg/m2] plus impaired fasting glucose (100-125mg/dL) and/or impaired glucose tolerance (A1c 5.7-6.4%) will receive bromocriptine in an open-label, flexible-dose design. The initial dose will be 2.5mg which will be increased to the 5mg target dose by week one unless limited by side effects. Bromocriptine will be given as adjunctive treatment to a participant's current APD regimen. The ultimate aim of the study team is to evaluate the efficacy of bromocriptine in treating the metabolic disturbances associated with APDs and the overarching hypothesis is that bromocriptine will be a well-tolerated, safe, and inexpensive way to ameliorate these metabolic complications and prevent or delay the onset of type 2 diabetes (T2D) in these at-risk patients. That said, this study will be a small, short-duration pilot focusing on safety and tolerability. The main purposes of the study are to demonstrate safety/tolerability, demonstrate feasibility, provide proof of concept, and provide an open-label assessment of the metabolic and psychiatric effects of bromocriptine in patients with schizophrenia treated with APDs. Psychiatric symptoms will be measured by the Columbia-Suicide Severity Rating Scale (C-SSRS), Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression (CGI), the Brief Psychiatric Rating Scale (BPRS), and the Pittsburgh Sleep Quality Index (PSQI). General side effects of bromocriptine will be assessed by the UKU Side Effects Scale. The extrapyramidal side effects of APDs will be monitored via the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale (AIMS).

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