Class of 2007 Abstract / Objectives: This retrospective analysis compared the prescribing rates of typical versus atypical oral antipsychotics in the treatment of schizophrenia for 6 months before versus 6 months after the publication of the Phase 1 CATIE trial on September 22, 2005. Methods: Prescription and membership databases from COPE Behavioral Services in Tucson, AZ were utilized for determining prescribing rates of typical and atypical antipsychotics for pre- versus post-publication of the CATIE trial. Comparisons were made for gender, court order treatment, hospitalizations and length of stay, costs of services (case management, inpatient, lab, and other services), total number of prescriptions and number of tablets/capsules of typical and atypical antipsychotics, and cost of antipsychotic prescriptions. Results: There was no significant difference in prescribing rates for oral atypical and typical antipsychotics, cost of services, or hospitalization rates in the pre-publication (N=316) versus post-publication (N=336) groups. Atypical antipsychotics accounted for approximately 77% of antipsychotic prescriptions and for 98% of the total costs for antipsychotic therapy in the two time periods. During the 12-month study, the amount paid for atypical antipsychotic prescriptions was $ 1,026,004 versus $ 22,671 for typical antipsychotics. Conclusions: Prescribing patterns of oral typical and atypical antipsychotics for the treatment of schizophrenia did not change during the first six months after the publication of the phase I CATIE trail in this outpatient population. Atypical antipsychotics accounted for the majority of prescriptions and for the highest cost compared to other services provided despite similar efficacy to typical antipsychotics in the treatment of schizophrenia.

The association of extrapyramidal symptoms (EPS) with the use of antipsychotics was first discovered in the 1950s. To our knowledge, little research has been conducted with any retrospective observational database to evaluate the comparative risk of EPS between first-generation antipsychotic (FGA) and second-generation antipsychotic (SGA) users in the U.S. population. The purpose of the study was to compare EPS risk between FGA and SGA users using propensity score-matching (PSM) and instrumental variable (IV) analyses. A retrospective cohort design with an intention-to-treat (ITT) analysis (where the patients included in the cohort were assumed to take the medications without switching or dropping out) was chosen to examine the relationship between antipsychotic treatment and EPS risk. First-time antipsychotic users (as identified in the MEPS database), during the time frame 2002 to 2009, were included in the cohort. All subjects included in the cohort were followed over time to assess EPS risk. Propensity score-based logistic regression (using the Greedy 5[right arrow]1 digit match technique) was used to compare EPS risk between the SGA and FGA users after adjusting for demographic variables and risk factors (associated with EPS). In order to identify the presence of unobserved confounding, an instrumental variable analysis was attempted. Based on previous research findings, "delay in obtaining prescribed medicines" was selected as the instrument to evaluate the relationship between EPS risk and antipsychotic type. The feasibility of instrumental variable analyses was examined by evaluating the strength of the chosen instrument. The propensity score-based logistic regression analysis showed no difference in EPS risk [OR = 1.77, 95% CI = (0.49, 6.40)] between FGA and SGA users. The strength (partial r² = 0.0002) of the instrument was low. A weak instrument used in a regression model may produce biased estimates while evaluating treatment/outcome relationship; therefore, instrumental variable analysis was not conducted. EPS risk was found not to differ between the FGA and SGA users. However, clinicans may choose to evaluate other side-effects (in addition to EPS) of antipsychotics while making treatment decisions. Evaluation of economic, clinical and humanistic outcomes associated with treatment of antipsychotic-related side-effects (besides EPS) can provide clinicans the rationale for selecting one class of antipsychotics over the other. Interpretation of the study findings should be considered in light of the limitations of the MEPS database. Future research is necessary to identify a strong instrument to assess the presencec of unobserved confounding between antipsychotic exposure and EPS risk. Furthermore, additional research is warranted to assess differences in time to development of EPS between the FGA and SGA users. / text

Serious safety concerns have been raised recently about the use of second generation antipsychotics (SGAs), in young patients. In this population based study, utilization of antipsychotics use in the youth population of Manitoba between 1996 and 2011 was determined. Rates of adverse events (diabetes, hypertension, EPS) were compared among the users of SGAs. School enrolment and high school completion rates were evaluated for young users. Databases from the Population Health Research Data Repository, housed at the Manitoba Centre of Health Policy were accessed. Increased utilization (prevalence: 2.3 to 9 per 1,000 persons; incidence: 1.2 to 2.7 per 1,000 between 2001 and 2011) of SGAs was observed in the youth population of MB. The most common diagnosis recorded were Attention Deficit Hyperactivity Disorder (56.8%), Conduct Disorders (38%) and Mood Disorders (22.7%). Olanzapine therapy seemed to be associated with a higher risk of hypertension compared to risperidone users (HR: 2.52, 95% CI: 1.20 – 5.29). Risperidone users seemed to be at higher risk of EPS than quetiapine users (HR: 0.46, 95% CI: 0.26 – 0.82). School enrolment of SGAs users appeared to be comparable to those reported for the general population. High school completion rates may be lower than those of the general population.

Class of 2014 Abstract / Specific Aims: The purpose of this study is to assess whether baseline rates of metabolic monitoring of scheduled atypical antipsychotics are sustained as a result of a pharmacist intervention. Methods: This study was a retrospective chart review assessing rates of metabolic monitoring two months after a pharmacist intervention that utilized a pharmacist-physician metabolic monitoring recommendation form was discontinued. Patients ages 18 years or older with orders for a scheduled atypical antipsychotic were included. Patients with orders for first-generation antipsychotics or who have orders for as needed atypical antipsychotics were excluded. Main Results: Data from the two month post intervention period was compared to those obtained during the pharmacist intervention. For the monitoring of hemoglobin A1c and fasting lipid panels, which improved during the pharmacist intervention, there was a non-statistically significant trend towards decreased monitoring. For hemoglobin A1c, the rates of monitoring decreased from 21.59% to 12.32% (p = 0.09). For fasting lipid panels, monitoring decreased from 39.77% to 28.99% (p = 0.125). Conclusion: A pharmacist intervention utilizing a recommendation form was effective in sustaining the improvement of baseline metabolic monitoring of personal history of diabetes and cardiovascular disease and monitoring of hemoglobin A1c and lipid panels. However, a trend towards decreased monitoring was observed in both the percentage of hemoglobin A1c and lipid panels ordered. Thus, continuing pharmacist intervention may be necessary in order to ensure that baseline metabolic monitoring for atypical antipsychotics occurs.

Neben Alter, Geschlecht, Rauchen und genetischen Polymorphismen der metabolischen Enzyme können vor allem Arzneimittelinteraktionen die Pharmakokinetik und dynamik von Medikamenten beeinflussen und zu starken Unterschieden der Serumspiegelkonzentrationen führen. Eine im klinischen Alltag sehr häufig zu findende Arzneimittelkombination ist die von Antipsychotika und Antikonvulsiva. Trotz der häufigen gemeinsamen Gabe gibt es noch immer keine eindeutigen Daten über Interaktionen zwischen den beiden Klassen von Psychopharmaka und daraus resultierenden Veränderungen der jeweiligen Serumwirkspiegel. In der Arbeit werden Einflüsse von Alter und Geschlecht sowie mögliche Effekte antikonvulsiver Komedikation auf die mittels Therapeutischen Drug Monitorings gemessenen Serumwirkspiegel der Antipsychotika aufgezeigt. Genauer untersucht werden dabei die Kombinationen Clozapin und Valproat sowie Olanzapin und Valproat. Die Arbeit betont zudem die Bedeutung des Therapeutischen Drug Monitorings im klinischen Alltag. / Besides age, sex, smoking and genetic polymorphism, drug-interactions can influence pharmacokinetics and pharmacodynamics and thereby lead to major differences in serum concentrations. A commonly used drug combination is that of antipsychotic and antiepileptic drugs. In spite of the frequent use, there is a lack of conclusive data concerning interactions between these drugs and resulting changes in serum concentrations. In this paper, the influence of age, sex and possible effects of antiepileptic comedication on the serum concentration of the antipsychotic drugs, which are measured by therapeutic drug monitoring, is shown. The combinations clozapine / valproic acid and olanzapine / valproic acid are investigated in more detail. The paper also emphasizes the importance of therapeutic drug monitoring in clinical practice.

The safety of antipsychotic use in elderly persons has recently been questioned. The incidence of adverse events (AEs) (extrapyramidal syndromes (EPS), cerebrovascular and cardiac events, and all-cause mortality) in the elderly users of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) was compared. Risks of AEs in antipsychotic-exposed persons and non-exposed individuals were also assessed. A population-based retrospective cohort study was conducted in the elderly Manitoba residents who received their first antipsychotic medication between April 1, 2000 and March 31, 2007. Cox proportional hazards models were built to compare risks of AEs in FGA and SGA users, as well as in non-exposed subjects. SGAs were associated with a lower risk of all-cause mortality (adjusted HR 0.683, 95% CI 0.577–0.809) and a higher risk of myocardial infarction (1.614 [1.024–2.543]) compared to FGAs. No significant differences between FGAs and SGAs were found for cerebrovascular events, cardiac arrhythmia and congestive heart failure (CHF) but a higher incidence of EPS was observed for FGAs compared to risperidone. Both FGA and SGA users were at a higher risk of cerebrovascular events (FGAs 1.415 [1.114–1.797]; SGAs 1.611 [1.388–1.869]) and CHF (FGAs 1.228 [0.893–1.689]; SGAs 1.242 [1.003–1.536]) compared to non-exposed subjects. Only FGA-users were at a higher risk of death compared to non-exposed subjects (FGAs 1.387 [1.065–1.805]; SGAs 0.824 [0.708–0.959]). Both FGA and risperidone use were associated with a higher risk of EPS (FGAs 3.503 [2.271–5.403]; risperidone 1.733 [1.214–2.472]). Both classes of antipsychotics might lead to potentially life-threatening AEs. Neither FGAs nor SGAs seem to have a superior overall safety profile. Antipsychotic pharmacotherapy should be prescribed in elderly persons after careful consideration of all risks and benefits.

The safety of antipsychotic use in elderly persons has recently been questioned. The incidence of adverse events (AEs) (extrapyramidal syndromes (EPS), cerebrovascular and cardiac events, and all-cause mortality) in the elderly users of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) was compared. Risks of AEs in antipsychotic-exposed persons and non-exposed individuals were also assessed. A population-based retrospective cohort study was conducted in the elderly Manitoba residents who received their first antipsychotic medication between April 1, 2000 and March 31, 2007. Cox proportional hazards models were built to compare risks of AEs in FGA and SGA users, as well as in non-exposed subjects. SGAs were associated with a lower risk of all-cause mortality (adjusted HR 0.683, 95% CI 0.577–0.809) and a higher risk of myocardial infarction (1.614 [1.024–2.543]) compared to FGAs. No significant differences between FGAs and SGAs were found for cerebrovascular events, cardiac arrhythmia and congestive heart failure (CHF) but a higher incidence of EPS was observed for FGAs compared to risperidone. Both FGA and SGA users were at a higher risk of cerebrovascular events (FGAs 1.415 [1.114–1.797]; SGAs 1.611 [1.388–1.869]) and CHF (FGAs 1.228 [0.893–1.689]; SGAs 1.242 [1.003–1.536]) compared to non-exposed subjects. Only FGA-users were at a higher risk of death compared to non-exposed subjects (FGAs 1.387 [1.065–1.805]; SGAs 0.824 [0.708–0.959]). Both FGA and risperidone use were associated with a higher risk of EPS (FGAs 3.503 [2.271–5.403]; risperidone 1.733 [1.214–2.472]). Both classes of antipsychotics might lead to potentially life-threatening AEs. Neither FGAs nor SGAs seem to have a superior overall safety profile. Antipsychotic pharmacotherapy should be prescribed in elderly persons after careful consideration of all risks and benefits.

Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Schizophrenia is a debilitating disorder that occurs the world over. Although antipsychotics are largely effective in treating the positive symptoms of schizophrenia, the outcomes are non-optimal in many patients. As antipsychotic treatment response has been shown to be heritable, it is expected that the implementation of antipsychotic pharmacogenomics should aid in the optimization of antipsychotic treatments, however to date clinically applicable results are limited. Therefore this study utilized exome sequencing in a cohort of well characterized first episode schizophrenia patients to identify the genetic factors contributing to antipsychotic treatment response. The utility of exome sequencing for antipsychotic pharmacogenomic applications in the African context was assessed through examination of the literature and publically available data. Thereafter, a cohort of 104 well characterized South African first episode schizophrenia patients who were treated with flupenthixol decanoate for twelve months was collected. From this cohort, subsets of patients on extreme ends of the treatment response spectrum were identified for exome sequencing. Thereafter a bioinformatics pipeline was used to call and annotate variants. These variants and those that have previously been associated with antipsychotic response, along with a panel of ancestry informative markers, were prioritized for genotyping in the entire cohort of patients. After genotyping of the 393 variants, statistical analyses were performed to identify associations with treatment response outcomes. Examination of the literature revealed a need for exome sequencing in Africa. However, critical analyses of next generation sequencing data demonstrated that complex regions of the genome may not be well suited to these technologies. Thus, it may be necessary to combine exome sequencing with knowledge obtained from past research, as was done in this study to identify the genetic factors contributing to antipsychotic treatment response. Using this strategy, the current study highlighted the potential role that rare variants play in antipsychotic treatment response and additionally detected 11 variants that were significantly associated with antipsychotic treatment response outcomes (P=2.19x10-5). Nine of these variants were predicted to alter the function of the genes in which they occurred; of which eight were novel with regards to antipsychotic treatment response. The remaining two variants have been associated with antipsychotic treatment outcomes in previous GWAS. Examination of the function of the genes in which the variants occurred revealed that the variants associated with (i) positive symptom improvement were involved in the folate metabolism pathway and (ii) negative and general pathological symptoms improvement had potential links to neuronal development and migration. To our knowledge this study is the first to utilize exome sequencing for antipsychotic pharmacogenomic purposes. The ability of this study to identify significant associations, even after correction for multiple testing, has highlighted the importance of combining genomic technologies with well characterized cohorts. The results generated from this study have served both to replicate results from previous antipsychotic pharmacogenetic studies and to identify novel genes and pathways involved in antipsychotic response. These results should aid in improving our understanding of the biological underpinnings of antipsychotic treatment response and may ultimately aid in the optimization of these treatments. / AFRIKAANSE OPSOMMING: Skisofrenie is ‘n siekte wat wêreldwyd voorkom en lei tot erge funksionele inkorting. Alhoewel antipsigotiese medikasie redelik effektief is in die behandeling van die positiewe simptome van skisofrenie, is die funksionele uitkomste in baie pasiënte nie optimaal nie. Die reaksie op antipsigotiese behandeling blyk oorerflik te wees. Die verwagting is dus dat die implementering van antipsigotiese farmakogenomika met die optimalisering van antipsigotiese behandeling sal help. Tot dusver het die resultate van farmakogenomika studies egter beperkte kliniese toepassings opgelewer. Hierdie studie het dus eksoomvolgordebepaling in 'n groep van goed-karakteriseerde eerste-episode skisofrenie pasiënte gebruik om die genetiese faktore wat bydra tot die antipsigotiese behandelings-reaksies te identifiseer. Die gebruik van eksoom-volgordebepaling vir antipsigotiese farmakogenomika in die Afrikakonteks is deur die ondersoek van literatuur en openbaar-beskikbare data geëvalueer. Daarna is 'n groep van 104 goed-gekarakteriseerde Suid-Afrikaanse eerste-episode skisofrenie pasiënte, wat met flupenthixol dekanoaat vir twaalf maande behandel is, versamel. Uit hierdie groep is subgroepe van pasiënte op die teenoorgestelde eindpunte van die behandelings-reaksiespektrum vir eksoom-volgordebepaling geïdentifiseer. Hierna is 'n bioinformatika pyplyn gebruik om variante te identifiseer en te annoteer. Hierdie variante, asook variante wat voorheen met antipsigotiese reaksie geassosieer is, is saam met 'n paneel van afkoms-informatiewe merkers vir genotipering in die hele groep pasiënte geprioritiseer vir genotipering. Na genotipering van die 393 variante, is statistiese analises uitgevoer om assosiasies met behandelings-reaksie uitkomste te identifiseer. ‘n Ondersoek van die literatuur het getoon dat daar 'n behoefte vir eksoomvolgordebepaling in Afrika is. ‘n Kritiese analise van volgende-generasie volgordebepalings data het egter getoon dat komplekse dele van die genoom nie geskik is vir die gebruik van hierdie tegnologie nie. Om die genetiese faktore wat bydra tot suksesvolle antipsigotiese behandeling te identifiseer, mag dit nodig wees om eksoom-volgordebepaling te kombineer met bevindings verkry uit vorige navorsing, soos gedoen in hierdie studie. In die huidige studie het die gebruik van hierdie strategie die potensiële rol van skaars variante in antipsigotiese behandelings-reaksies beklemtoon en ‘n bykomende 11 variante is geïdentifiseer wat beduidend met antipsigotiese behandelingsrespons geassosieer is (P=2.19x10-5). Daar is voorspel dat nege van hierdie variante die funksie van die gene waarin hulle voorkom sal verander en agt van hierdie variante is vir die eerste keer met antipsigotiese behandelingsrespons geassosieer. Die oorblywende twee variante is met antipsigotiese behandelingsrespons in vorige GWAS geassosieer. ‘n Ondersoek na die funksie van die gene waarin die variasies voorgekom het, toon dat die variante wat geassosieer is met (i) verbetering van positiewe simptome ‘n rol speel in folaatmetabolisme, terwyl variante wat geassosieer is met (ii) die verbetering in negatiewe en algemene patologiese simptome potensiële skakels met neuron ontwikkeling en migrasie het. Na ons wete is hierdie die eerste studie wat eksoom-volgordebepaling vir antipsigotiese farmakogenomika doeleindes gebruik. Die vermoë van hierdie studie om beduidende assosiasies te identifiseer, selfs na korreksie vir veelvoudige toetse, onderstreep die belangrikheid van die kombinering van genomiese tegnologie met goed-gekarakteriseerde pasiënte. Die bevindinge van hierdie studie het nie net die resultate van vorige antipsigotiese farmakogenetiese studies bevestig nie, maar ook nuwe gene en variante wat betrokke is in antipsigotiese reaksie geïdentifiseer. Hierdie resultate sal hopelik ons begrip van die onderliggende biologiese faktore wat antipsigotiese behandelingsrespons beïnvloed verbeter en uiteindelik ook met die optimalisering van behandeling help.

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 2015 Abstract / Objectives: To determine whether disparities exist among mental health patients admitted to the emergency department in regards to the prescribing patterns of injectable benzodiazepines and antipsychotics. Methods: A retrospective chart review was performed to evaluate patients with mental health diagnoses who received an injectable antipsychotic or benzodiazepine while in the emergency department of an academic medical center. A report was generated of all injectable antipsychotics and benzodiazepines removed from the emergency department Pyxis machines from November 1, 2013 to January 31, 2014. Data from the patient medical record included the patient’s age, height, weight, gender, race/ethnicity, insurance information, mental health diagnosis, evidence of substance abuse, how they arrived in the emergency department, their length of stay in the emergency department, any signs of aggressive behavior (adapted from the Overt Aggression Scale), information about each injectable antipsychotic or benzodiazepine that was administered was recorded including the name of the medication, dose, route of administration. If the patient received multiple doses of the same medication during their stay, the total dose and the total time receiving the medication was also recorded. The prescriber’s gender and whether they were a resident or an attending physician was also recorded for each medication administered. Results: A total of 98 patient charts were reviewed and analyzed. Mental health diagnoses were broken down into categories of psychiatric disorders (39.8%), bipolar disorders (74.5%), mood disorders (40.8%), and personality disorders 54.1%). Of the 98 patients reviewed, 68% had a documented substance abuse, with 62% having a positive urinalysis for alcohol, illicit drugs, or opiates. The majority of the patients were white (64.3%). The next largest racial/ethnic categories were Hispanics (12.2%), Native Americans (8.2%), and African Americans (6.1%). There were 54 males and 44 females. Benzodiazepines comprised 74% of the medications administered with lorazepam being the most frequently administered medication overall at 63.4%. Haloperidol was the second most frequently administered medication at 22%. Initial Chi Square analysis did not yield any significant results with regards to race and prescribing patterns, gender and prescribing patterns, or insurance and prescribing patterns. Conclusions: Patients with mental health diagnoses suffer from disparities within health care, and when these patients fall under other demographic groups such as racial/ethnic minorities and low socioeconomic status, the disparate treatment they receive could be even greater. Several limitations to this study including a small sample size and lack of geographical diversity resulted in a lack of statistically significant results, and our findings may not be generalizable to other patient populations.