Antipsychotic medications are effective in the treatment of psychotic disorders. Monotherapy (MT) with antipsychotics is consistently recommended as the treatment of choice by several guidelines yet antipsychotic polypharmacy (APP) is widespread in clinical practice. The objectives of this study were to evaluate the incidence of APP, identify predictors of APP, and compare adherence, health resource utilization, and costs between patients on MT and APP using prescription and medication claims from Texas Medicaid (2006 to 2011). Patients newly initiated on antipsychotics were followed for 12 months and categorized into the APP (exposure to two or more antipsychotics for a defined time interval) and MT (no evidence of APP during the study period) groups. This sample of patients was used to evaluate incidence and predictors of APP and compare medication adherence and persistence between the MT and APP groups using multiple, logistic, and Cox proportional hazards regressions. Patients in the MT and APP groups were then matched based on their duration of exposure to antipsychotics and all-cause healthcare utilization and costs were compared using logistic and generalized linear models regression (negative binomial, Poisson, and gamma). Regression analyses for patients matched on duration of antipsychotic exposure accounted for the correlation between matched pairs. The incidence of APP was 5.4%. Several demographic, clinical, physician, and prior utilization characteristics were associated with APP. Medication adherence and persistence were better in the APP group. Length of hospital stay and medical, drug, and total costs were higher for the APP group. Sensitivity analyses were conducted for psychiatric-related costs and varied overlap and gap periods. The results for most of the sensitivity analyses were similar to the base case. Patients prescribed APP had higher medical, drug and total costs and also higher healthcare utilization i.e. increased drug costs were not offset by decreased medical costs. Long-term APP raises concern as state Medicaid agencies are allocating their limited resources to this expensive treatment which has very scarce data supporting its use. More effectiveness research on APP is needed to help provide prescription guidance to clinicians for patients who do not respond well to treatment with a single antipsychotic. / text

Not available / text

published_or_final_version / Pharmacology / Master / Master of Philosophy

A growing body of literature has linked atypical antipsychotics (AAPs) to an increased propensity for weight gain and metabolic disturbances, including type 2 diabetes. While weight gain is a leading risk factor for diabetes, evidence suggests that AAPs may influence glucose homeostasis independently of changes in adiposity. These ‘direct’ drug effects have been consistently supported by animal models, where following even a single dose of certain AAPs immediate effects are observed with noted perturbations on insulin sensitivity, and insulin secretion. However, the mechanisms underlying these effects remain poorly understood. Also, the translational value of the acute dosing rodent model has not been established in humans. As such, we set out to first elucidate mechanisms of these ‘direct’ effects by deconstructing antipsychotic receptor binding profiles using selective antagonists and gold standard clamping techniques to examine effects on glucose metabolism. We also investigated antipsychotic administration directly into the brain in rodents to tease out central vs. peripheral effects on glucose metabolism. Finally, we examined whether the effects of a single dose of olanzapine on glucose metabolism could be replicated in healthy humans, independently of adiposity or the confounding effects of the illness of schizophrenia. Our findings suggest that cholinergic, serotonergic, and dopaminergic pathways may be involved in antipsychotic-induced glucose dysregulation. We also suggest that such effects may be mediated in part through the central nervous system. Our results in humans suggest that acute drug effects may be less pronounced than in rodents, failing to note an effect on insulin sensitivity or secretion, but observing other early perturbations in lipid and glucose metabolism. Taken together, the work here begins to elucidate mechanisms underlying the diabetogenic risk associated with AAPs, findings which have important implications given the widespread use of these drugs, as well as the increased mortality attributable to cardiovascular disease that defines those with schizophrenia.

A growing body of literature has linked atypical antipsychotics (AAPs) to an increased propensity for weight gain and metabolic disturbances, including type 2 diabetes. While weight gain is a leading risk factor for diabetes, evidence suggests that AAPs may influence glucose homeostasis independently of changes in adiposity. These ‘direct’ drug effects have been consistently supported by animal models, where following even a single dose of certain AAPs immediate effects are observed with noted perturbations on insulin sensitivity, and insulin secretion. However, the mechanisms underlying these effects remain poorly understood. Also, the translational value of the acute dosing rodent model has not been established in humans. As such, we set out to first elucidate mechanisms of these ‘direct’ effects by deconstructing antipsychotic receptor binding profiles using selective antagonists and gold standard clamping techniques to examine effects on glucose metabolism. We also investigated antipsychotic administration directly into the brain in rodents to tease out central vs. peripheral effects on glucose metabolism. Finally, we examined whether the effects of a single dose of olanzapine on glucose metabolism could be replicated in healthy humans, independently of adiposity or the confounding effects of the illness of schizophrenia. Our findings suggest that cholinergic, serotonergic, and dopaminergic pathways may be involved in antipsychotic-induced glucose dysregulation. We also suggest that such effects may be mediated in part through the central nervous system. Our results in humans suggest that acute drug effects may be less pronounced than in rodents, failing to note an effect on insulin sensitivity or secretion, but observing other early perturbations in lipid and glucose metabolism. Taken together, the work here begins to elucidate mechanisms underlying the diabetogenic risk associated with AAPs, findings which have important implications given the widespread use of these drugs, as well as the increased mortality attributable to cardiovascular disease that defines those with schizophrenia.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 7 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Thesis (M. Phil.)--University of Hong Kong, 1994. / Includes bibliographical references (leaves 133-154).

Thesis (doctoral)--University of Tartu, 2006. / This dissertation is based on 7 papers.

Thesis (Ph. D.)--Virginia Commonwealth University, 2006. / Prepared for: Dept. of Psychology. Bibliography: leaves 100-127. Also available online.