Class of 2014 Abstract / Specific Aims: To determine the prevalence of metabolic syndrome (MetS) in patients treated in an outpatient clinic that were taking atypical antipsychotics. Methods: This retrospective chart review included 822 adults diagnosed with various personality/mood disorders. Age, gender, ethnicity, blood pressure, height, weight, lipid panels, fasting blood glucose, and second-generation antipsychotic (SGA) used and treatment length were obtained. Patients were separated into two groups: those who were not taking an SGA in/for the past three months (group 1), and those taking at least one SGA for a minimum of three months (group 2). MetS was determined using NCEP ATP III guidelines. The primary outcome measured was the difference in the prevalence of MetS between each group. Main Results: At baseline, 753 patients were in group 1 and 69 patients were in group 2, there was a higher percentage of females in group 1 (p<0.0001), and a higher percentage of males in group 2 (p<0.0001). No difference was seen with age, and weight, (p=0.294, p=0.625, respectively). There were more patients reported as Caucasian in group 2 (p=0.0001) and more reported as Caucasian/Hispanic in group 1 (p=0.0001). The rate of MetS between group 1 (54.45%) and group 2 (59.42%) was not statistically different (p = 0.427). Conclusion: No statistical difference was found in the rate of MetS between the two groups. Removing confounding drugs known to cause weight gain did not change these results.

Class of 2005 Abstract / Objectives: To describe the dosing of atypical antipsychotics among outpatients diagnosed with schizophrenia at a community mental health center in Tucson, AZ, and to contrast this to dosing recommendations set by the manufacturer during clinical trials. Methods: A prescription database from January 01, 2004 to July 31, 2004 was used to evaluate the dosing of atypical antipsychotics (Abilify®, Clozaril®, Geodon®, Seroquel®, and Zyprexa®) in patients with schizophrenia. The average daily doses were evaluated for differences from recommended dosing using the physician desk reference. Differences in dosing were also analyzed for gender and monotherapy vs. patients taking multiple atypical antipsychotics. Results: Overall differences in dosing when comparing gender and monotherapy vs. patients on multiple atypicals were not significant for all five atypical antipsychotics studied. Overall, Geodon® had the highest percentage (51.9%) of patients above recommended guidelines while Clozaril® and Seroquel® had the highest percentage (70.6% and 47.4% respectively) below recommended guidelines. Implications: This study illustrates that dosing of these atypical antipsychotics at this outpatient community mental health center differs for many patients with schizophrenia from the guidelines set by the companies during clinical trials. This information will aid in the prescribing of physicians at this community mental health center and will possibly lead to larger studies to further look at reasons for these differences in dosing.

Reports have linked atypical antipsychotics (AAPs) with weight gain. The polymorphic CYP2D6 involved in metabolism has been associated with medication morbidity. Eleven subjects receiving olanzapine were genotyped for CYP2D6 to examine the relationship between 2D6 and AAP weight gain. Using a linear regression, the dependent variable was percent change in body mass index (BMI). Genotype, dose and duration of treatment were independent. Genotype was significant (P < 0.0097) for those with a *1/*3 or *4 genotype experiencing a larger percent BMI change than those with a *1/*1 genotype. This may be due to increased olanzapine concentrations leading to increased exposure, which may trigger AAP weight gain.

Falls among older adults (age 65 years and older) residing in personal care homes (PCHs) are an important health concern. Atypical antipsychotic drugs (AADs) have been shown to be associated with fall risk among older adults. However, previous studies face some methodological limitations that affect the quality, consistency, and comparability of these studies. Therefore, a population-based study was undertaken to examine the effect of AAD use on the risk of falling among older PCH residents. A nested case-control study was conducted using the administrative healthcare records and Minimum Data Set for PCHs (MDS) housed at the Manitoba Centre for Health Policy in the Faculty of Medicine, University of Manitoba. The study period was from April 1, 2005 to March 31, 2007. Cases (n=626) were fallers as recorded in MDS. Using incidence density sampling, each case was matched to four controls on length of PCH stay, age, and sex (n=2,388). Exposure to AADs was obtained from the Drug Program Information Network database. Conditional logistic regression was used to model the effects of AAD use on the risk of falling while accounting for matching and for confounding of other covariates. While the adjusted odds of falling was statistically greater for AAD users versus nonusers (adjusted odds ratio = 1.60, 95% CI 1.10-2.32), this association was type and dose dependent. Compared to nonusers, the odds of falling was greater for quetiapine users, regardless of this drug's dose, and high dose risperidone users. On the other hand, low dose risperidone and olanzapine, irrespective of drug dose, use was not associated with the risk of falling. Furthermore, the effect of AAD use, in general, on the risk of falling was significantly greater for people with wandering problems (adjusted odds ratio = 1.84, 95% CI 1.09-3.09). Despite some methodological limitations, this research has provided some unique findings that enhance our understanding of AAD use as a fall risk factor. Study findings allow policymakers to further develop evidence-based interventions specific to AADs in order to better manage falls in the PCH setting. However, a great deal of research is still needed to address other important unanswered questions.

Falls among older adults (age 65 years and older) residing in personal care homes (PCHs) are an important health concern. Atypical antipsychotic drugs (AADs) have been shown to be associated with fall risk among older adults. However, previous studies face some methodological limitations that affect the quality, consistency, and comparability of these studies. Therefore, a population-based study was undertaken to examine the effect of AAD use on the risk of falling among older PCH residents. A nested case-control study was conducted using the administrative healthcare records and Minimum Data Set for PCHs (MDS) housed at the Manitoba Centre for Health Policy in the Faculty of Medicine, University of Manitoba. The study period was from April 1, 2005 to March 31, 2007. Cases (n=626) were fallers as recorded in MDS. Using incidence density sampling, each case was matched to four controls on length of PCH stay, age, and sex (n=2,388). Exposure to AADs was obtained from the Drug Program Information Network database. Conditional logistic regression was used to model the effects of AAD use on the risk of falling while accounting for matching and for confounding of other covariates. While the adjusted odds of falling was statistically greater for AAD users versus nonusers (adjusted odds ratio = 1.60, 95% CI 1.10-2.32), this association was type and dose dependent. Compared to nonusers, the odds of falling was greater for quetiapine users, regardless of this drug's dose, and high dose risperidone users. On the other hand, low dose risperidone and olanzapine, irrespective of drug dose, use was not associated with the risk of falling. Furthermore, the effect of AAD use, in general, on the risk of falling was significantly greater for people with wandering problems (adjusted odds ratio = 1.84, 95% CI 1.09-3.09). Despite some methodological limitations, this research has provided some unique findings that enhance our understanding of AAD use as a fall risk factor. Study findings allow policymakers to further develop evidence-based interventions specific to AADs in order to better manage falls in the PCH setting. However, a great deal of research is still needed to address other important unanswered questions.

Yes / Rationale The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. Objective The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. Methods Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for 7 days, followed by a 7-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for 7 days and were then tested in the perceptual set-shifting task. Results PCP significantly (p < 0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p < 0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). Conclusions These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCP-induced cognitive deficit.

Amisulpride, a benzamide derivative, is an atypical antipsychotic drug used to treat both schizophrenia and depression. Amisulpride is a selective antagonist at dopamine D2 and D3 receptors and at serotonin 5-HT2B and 5-HT7 receptors and displays an atypical clinical profile with reduced extrapyramidal motor effects. The drug has a chiral center and is a mixture of two optical isomers: (S)-amisulpride and (R)-amisulpride. The present study used a two-lever drug discrimination assay to allow a direct comparison between amisulpride and its two isomers. Additionally, substitution testing was conducted with the typical antipsychotics, atypical antipsychotics, antidepressants, the anxiolytic chlordiazepoxide, several benzamide derivatives, and selective ligands with receptor mechanisms relevant to amisulpride. C57BL/6 mice were trained to discriminate 10 mg/kg rac-amisulpride from vehicle in a two-lever drug discrimination task for food reinforcement in an average of 35.7 sessions (range 6-89). The amisulpride dose-response curve (0.078 – 10.0 mg/kg) yielded an ED50 = 0.64 mg/kg, 95% CI [.47, 0.84 mg/kg]. The isomers fully substituted for amisulpride with a significant left-ward shift in the dose-response curve for (S)-amisulpride as compared to rac-amisulpride and (R)-amisulpride. The benzamide derivatives sulpiride and the (S)-sulpiride isomer fully substituted for amisulpride; tiapride produced partial substitution (76.4% DLR); none of the other tested drugs substituted for rac-amisulpride’s discriminative stimulus. These results showed that the rac-amisulpride stimulus was readily acquired in C57BL/6 mice, and that it has a unique and robust discriminative stimulus that is dose-dependent, time-dependent and stereoselective and is not shared with other antipsychotic or antidepressant drugs.

Introduction: Atypical Antipsychotics (AAPs) are approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar disorder. AAPs are commonly used off-label to treat depression, post-traumatic stress disorder and neuropsychiatric symptoms in dementia due to lack of alternative treatment options and treatment resistance. Concerns for off-label use arise since AAPs increase the risk of cardiovascular events and death. The objectives were 1) describe patterns of RU and costs among off-label AAPs users in a nationally representative population 2) identify prevalence of off-label use in the Medicare population 3) compare RU and costs between off-label AAPs users and non-users with mental health conditions in Medicare. Methods: For the first objective, the Medical Expenditure Panel Survey (MEPS) datasets were used. AAPs users greater than 18 years were identified in this cross-sectional study. Generalized Linear Models (GLM) were used to estimate costs among users and non-users after controlling for age sex, gender, insurance type, marriage status, income and comorbidity index. For the second and third objective, Medicare datasets were used to identify prevalence, RU, and costs of off-label use in Medicare beneficiaries 18 years and older. RU and costs between propensity score matched AAPs user and non-user cohorts were compared in a retrospective cohort study. Results: The adjusted odds of having an office-based outpatient (OR=2.47, 95%CI: 1.55-3.92) or inpatient (OR=1.63, 95%CI: 1.26-2.10) visit were significantly higher among off-label AAPs users. Adjusted office-based visit ($1,943 vs. $1,346), prescription ($4,153 vs. $1,252) and total ($10,694 vs. $4,823) costs were significantly higher among users (p<0.0001). Among Medicare beneficiaries, approximately 37% of AAPs users had no FDA approved diagnosis. The typical off-label user was a white 70-year-old male. Common off-label uses were depression, anxiety and neurotic disorders and dementia. Off-label AAPs users had significantly higher mental health outpatient ($461 vs $297), prescription ($2,349 vs $282) and total ($3,665 vs $1,297) costs per beneficiary than non-users. About 30% of AAPs users had at least one mental health outpatient visit during the year versus 23% of non-users; no significant differences were found in inpatient visits. AAPs non-users had significantly higher all-cause inpatient costs ($6,945 vs. $4,841) per beneficiary (p Conclusion: In a nationally representative population comprising a younger age group AAPs users had higher all-cause RU and total costs than non-users. Off-label prescribing of AAPs continued to be a prevalent practice affecting 37% of Medicare AAPs users. Off-label AAPs users had higher mental health costs but no significant differences in all-cause total health care costs in a Medicare population. Off-label use of AAPs can be a cost-effective option if future research shows off-label use is associated with increased effectiveness, which offsets any additional costs.

Only one third of depressed patients experience a beneficial therapeutic effect after using a first-line medication, leaving two-thirds of patients without effective treatment. It has been shown that a combination of two drugs with different modes of action result in an increase in the number of patients responding to treatment. One of the most effective strategies is the addition of low doses of an atypical antipsychotic. In depth evaluation of the neurobiological properties of atypical antipsychotics have revealed that these agents produce antidepressant effects and enhance the therapeutic response of first-line medications through antagonism of the 5-HT2A, 5-HT2C, 5-HT1B/D, 5-HT7 receptors and NET; agonism of the 5-HT1A receptor; and/or D2/3 partial agonism. The present experiments focused on determining the mode of action of this combination of drugs to help design better antidepressant treatment in the future. A series of electrophysiological experiments were proposed to assess 5-HT and NE neurotransmission in the rat hippocampus, as well as DA transmission in the rat forebrain.

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