Assessment of anti psychotic-related risk of diabetes mellitus in a Medicaid psychosis population: Sensitivity to study design
ABSTRACT The effect of study design on findings regarding diabetes risk associated with antipsychotics was studied.
This study was a retrospective analysis of data from more than 100,000 Medicaid patients. Diabetes odds ratios (ORs) for patients treated with clozapine, olanzapine, quetiapine, risperidone, ziprasidone, or conventional antipsychotics versus untreated patients were estimated with and without the following design enhancements: screening for preexisting diabetes, selecting for antipsychotic monotherapy, and identifying diabetes with prescription claims only. Logistic regression controlled for patient sex, race and ethnicity, type of psychosis, length of observation and treatment, antipsychotic dosage, pre-existing excess weight or dyslipidemia, and use of other drugs with potential diabetogenic effects.
Under the weakest study design (none of the above enhancements), all antipsychotics were associated with significantly higher odds of diabetes relative to no treatment (p < 0.05). Estimated ORs were as follows: clozapine, 1.468; olanzapine, 1.108; quetiapine, 1.270; ziprasidone, 1.226; risperidone, 1.232; and conventional antipsychotics, 1.159. Under the strongest design (all of the above enhancements), ORs relative to no treatment were significant for clozapine (1.484) and olanzapine (1.149) and nonsignificant for quetiapine (0.998), risperidone (1.124), ziprasidone (0.717), and conventional antipsychotics (1.025). The data also strongly suggest selection bias by clinicians (i.e., selecting antipsychotics based on preexisting diabetes or risk factors for diabetes), disfavoring risperidone and favoring olanzapine. Although the evidence is weaker, quetiapine may also have been affected by unfavorable selection bias.
In large database studies, estimated risks of diabetes among patients treated with antipsychotics appeared to be influenced by study design. When a more rigorous design was used, only clozapine and olanzapine were associated with diabetes risk significantly greater than that in untreated patients.
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ABSTRACT: Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.Diabetes 07/2013; 62(9). DOI:10.2337/db13-0430 · 8.47 Impact Factor
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ABSTRACT: Objective To evaluate the relationship between initiation of atypical antipsychotic agents and the risk of hyperglycemic emergencies. Method We conducted a multicentre retrospective cohort study using administrative health data from 7 Canadian provinces and the UK Clinical Practice Research Datalink. Hospitalizations for hyperglycemic emergencies (hyperglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state) were compared between new users of risperidone (reference), and new users of olanzapine, other atypical antipsychotics, and typical antipsychotics. We used propensity scores with inverse probability of treatment weighting and proportional hazard models to estimate the site-specific hazard ratios of hyperglycemic emergencies in the year following drug initiation separately for adults under and over age 66 years. Site-level results were pooled using meta-analytic methods. Results Among 725,489 patients, 55% were aged 66 + years; 5% of younger and 19% of older patients had pre-existing diabetes. Hyperglycemic emergencies were rare (1–2 per 1000 person years), but more frequent in patients with pre-existing diabetes (6–12 per 1000 person years). We did not find a significant difference in risk of hyperglycemic emergencies with initiation of olanzapine versus risperidone; however heterogeneity existed between sites. The risk of an event was significantly lower with other atypical (99% quetiapine) compared to risperidone use in older patients [adjusted hazard ratio, 95% confidence interval (CI): 0.69, 0.53–0.90]. Conclusions Risk for hyperglycemic emergencies is low after initiation of antipsychotics, but patients with pre-existing diabetes may be at greater risk. The risk appeared lower with the use of quetiapine in older patients, but the clinical significance of the findings requires further study.Schizophrenia Research 04/2014; 154(1-3). DOI:10.1016/j.schres.2014.01.043 · 4.43 Impact Factor
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ABSTRACT: The efficacy and side effects of long-term administration of antipsychotic drugs (APDs) may be attributed to drug-induced change in protein expression in brain cells. Glial cells are non-neuronal cells that can provide nutrients and physiological support to neuronal cells. Glial cells are believed to participate in neurotransmission, neurons' early development, and guiding migration of neurons. Accumulated clinical data also indicate relationships between disturbance of glial cells' function and various psychotic diseases including schizophrenia. We used two-dimensional gel electrophoresis coupled with MALDI-TOF/TOF mass spectrometry protein identification to analyze differentially expressed proteins in haloperidol-, risperidone-, and clozapine-treated C6 glioma cells. We found that the expression of pericentrin, glial fibrillary acidic protein, Rho GDP-dissociation inhibitor 1, anionic trypsin-1, peroxiredoxin-1, and parvalbumin were regulated by each of the three APDs. Western blot analysis supported the findings. Real-time quantitative PCR detected changed transcriptions of those proteins. Protein and gene expression of N-cadherin in C6 cells were affected by haloperidol and clozapine but not risperidone. In addition, regulatory effects of clozapine on the glyceraldehyde 3-phosphate dehydrogenase gene were observed in C6 cells. This may be the first study to uncover how APD-modulated genes may cause protein expression changes and affect ARHGDIA-mediated regulation of Rho GTPase family proteins in glial cells.Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/2012; 40. DOI:10.1016/j.pnpbp.2012.08.013 · 4.03 Impact Factor