Bromocriptine for Patients With Schizophrenia and Impaired Glucose Tolerance
Atslēgvārdi
Abstrakts
Apraksts
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).
Datumi
| Pēdējoreiz pārbaudīts: | 04/30/2020 |
| Pirmais iesniegtais: | 06/14/2018 |
| Paredzētā reģistrācija iesniegta: | 06/27/2018 |
| Pirmais izlikts: | 07/01/2018 |
| Pēdējais atjauninājums iesniegts: | 05/13/2020 |
| Pēdējā atjaunināšana ievietota: | 05/14/2020 |
| Faktiskais studiju sākuma datums: | 04/25/2019 |
| Paredzamais primārās pabeigšanas datums: | 12/30/2020 |
| Paredzamais pētījuma pabeigšanas datums: | 08/29/2021 |
Stāvoklis vai slimība
Iejaukšanās / ārstēšana
Drug: Bromocriptine
Fāze
Roku grupas
| Roka | Iejaukšanās / ārstēšana |
|---|---|
| Experimental: Bromocriptine This is an open-label study, so there is no comparator group. As such there is only one arm. Subjects will receive bromocriptine at a starting dose of 2.5mg daily which will be increased, if tolerated, to 5mg daily after one week. Bromocriptine will be continued for a total of 6 weeks. Laboratory investigations, telephonic interviews, and face to face visits with subjects will be conducted before, during, and after the time period that bromocriptine will be used as detailed in the study design section. | Drug: Bromocriptine This is an open-label study, so there is no comparator group. As such there is only one arm. Subjects will receive bromocriptine at a starting dose of 2.5mg daily which will be increased, if tolerated, to 5mg daily after one week. Bromocriptine will be continued for a total of 6 weeks. Laboratory investigations, telephonic interviews, and face to face visits with subjects will be conducted before, during, and after the time period that bromocriptine will be used as detailed in the study design section. |
Atbilstības kritēriji
| Vecums, kas piemērots studijām | 18 Years Uz 18 Years |
| Dzimumi, kas ir piemēroti studijām | All |
| Pieņem veselīgus brīvprātīgos | Jā |
| Kritēriji | Inclusion Criteria: 1. Adult males and females, 18-65 years of age, diagnosed with schizophrenia 2. Female participants must test negative for pregnancy at the time of enrollment based on a urine pregnancy test and agree to use a reliable method of birth control (e.g., oral contraceptives, birth control diaphragms with contraceptive jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam, intrauterine devices, partner with vasectomy, or abstinence) until the study is complete. 3. Be treated with FDA-approved second generation antipsychotic medication for at least 3 months, with no change in dose in the 1 month prior to enrollment. 4. Either fasting glucose of 100 to 125 mg/dL inclusive and/or an A1C in the range between 5.7-6.4% 5. Body mass index at least 30 kg/m2 at screening visit. 6. Negative urine drug screen at screening visit and baseline (week 0) visit 7. Subject must be willing to provide contact information for a close family member or friend that will contact the study team if the participant exhibits signs of psychological deterioration 8. Subject's primary mental health provider concurs that study enrollment is acceptable 9. Screening ECG QTc check must be <500ms 10. PANSS score Exclusion Criteria: 1. History of documented APD non-adherence in prior 3 months. 2. Historical or current diagnosis of diabetes mellitus (type 1, type 2, or other) 3. Pregnant or breast feeding. Women of child-bearing potential must be surgically-sterile or using reliable methods of birth control. 4. May not have used oral or parenteral systemic corticosteroids within 3 months prior to study enrollment or have expected use during the course of the study. The use of either inhaled or topical corticosteroids are not exclusion criteria. 5. May not be taking any antidiabetic/antihyperglycemic medications (e.g., metformin, sulfonylureas, thiazolidinediones, insulin, DPP-IV inhibitors, SGLT-2 inhibitors, etc.) currently or within 4 months prior to study enrollment. 6. May not be taking any of the following cytochrome P450 3A4 (CYP3A4) inhibitors: protease inhibitors (atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir); certain antibiotics/antifungals (clarithromycin, erythromycin, telithromycin, chloramphenicol, ciprofloxacin, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole); nefazodone; aprepitant; imatinib; certain calcium channel blockers (diltiazem, verapamil); Valerian; or grapefruit/grapefruit juice. 7. May not be taking or have sensitivity to any dopamine agonist medications (e.g., bromocriptine, cabergoline, pramipexole,ropinirole, rotigotine, etc.) currently or within 3 months prior to study enrollment. 8. May not be taking or have any sensitivity to any other ergot alkaloids (e.g., dihydroergotamine, ergotamine) 9. PANSS score >90, which is equivalent to "moderately ill" 10. Any current hepatic or renal disease 11. QTc of >500ms on screening ECG 12. Any documented history of violent behavior |
Rezultāts
Primārie rezultāti
1. HOMA-IR [Measured at weeks 0, 4, 6, 8, and 10 (weeks 8 and 10 are two and four weeks after study drug discontinuation)]
Sekundārie iznākuma mērījumi
1. Weight [Measured at weeks 0, 1, 2, 4, 6, 8, and 10]
2. Hemoglobin A1c [Measured weeks 0 and 6]
3. 75g Oral Glucose Tolerance Test [Measured at weeks 0 and 6]
4. Columbia-Suicide Severity Rating Scale (C-SSRS) [Measured at weeks 0, 1, 2, 4, 6, 8, and 10 (weeks 8 and 10 are two and four weeks after study drug discontinuation)]
5. Positive and Negative Syndrome Scale (PANSS) [Measured at weeks 0, 1, 2, 4, 6, 8, and 10 (weeks 8 and 10 are two and four weeks after study drug discontinuation)]
6. Clinical Global Impression [Measured at weeks 0, 1, 2, 4, 6, 8, and 10 (weeks 8 and 10 are two and four weeks after study drug discontinuation)]
7. Brief Psychiatric Rating Scale (BPRS) [Measured at weeks 0, 1, 2, 4, 6, 8, and 10 (weeks 8 and 10 are two and four weeks after study drug discontinuation)]
8. Pittsburgh Sleep Quality Index (PSQI) [Measured at weeks 0, 1, 2, 4, 6, 8, and 10 (weeks 8 and 10 are two and four weeks after study drug discontinuation)]
9. UKU Side Effects Scale [Measured at weeks 0, 1, 2, 4, 6, 8, and 10 (weeks 8 and 10 are two and four weeks after study drug discontinuation)]
10. Simpson-Angus Scale [Measured at weeks 0, 1, 2, 4, 6, 8, and 10 (weeks 8 and 10 are two and four weeks after study drug discontinuation)]
11. Abnormal Involuntary Movement Scale (AIMS) [Measured at weeks 0, 1, 2, 4, 6, 8, and 10 (weeks 8 and 10 are two and four weeks after study drug discontinuation)]
