Atypical Antipsychotic Medications Research Articles

Cost Effectiveness Analysis of Antipsychotic Medications in the Management of Schizophrenia in Benin City

Background: Studies on cost effectiveness analysis (CEA) of typical versus atypical antipsychotics in the management of schizophrenia are still lacking in Nigeria thus the objectives of this study are to determine which of the class of antipsychotics is more cost-effective as well as the impact of socio-demographic factors on the response rate to antipsychotics. Method: The effectiveness was measured by Brief Psychiatric rating scale (BPRS) and costs were in Nigerian naira (NGN). The impact of different socio-demographics on the mean BPRScore ± Standard deviation (SD) reduction was determined. The study was conducted from patient’s perspective with decision tree analysis model using two-way sensitivity analysis. The model was used to explore incremental cost effectiveness ratios (ICER) of oral antipsychotic medications Haloperidol /Trifluoperazine versus Olanzepine /Risperidone over a 24-week study period. Results: Cost effectiveness analysis with 1st scenario sensitivity test of medications, trifluoperazine 17.81±2.51mg is more cost effective than olanzapine 10mg, while haloperidol 10mg is more cost effective than risperidone 3.5± 0.51mg. In the second scenario of sensitivity analysis, olanzapine is more cost effective than trifluoperazine only when the savings of making one person free from schizophrenia in a month is worth more than NGN537 while risperidone is more cost effective than haloperidol only when the savings of making one person free from schizophrenia in a month is worth more than NGN2524.1. The effect on response rate to antipsychotics gave p=0.0251, P=0.009, P<0.0001 for educational status, income, stable relationship respectively. Conclusion: Atypical antipsychotic medications are not more cost effective compared to the typical antipsychotics. Higher educational level, income and stable relationship positively affected the outcome of effectiveness of antipsychotics.

The Frequency of Antipsychotic Prescribing in Older People Mental Health Services: A Southern Health OPMH CRIS Audit

Background: Antipsychotic prescription in older people with mental health problems can have severe adverse effects such as an increased risk of falls and show higher mortality rates. Moreover, this risk is elevated for the elderly with dementia. Aims: to provide an estimate of the frequency of antipsychotic use for mental health problems in older people mental health (OPMH) services and collect evidence of adherence to NICE guidelines. Methods: A retrospective clinical audit of typical and atypical antipsychotic medication use in OPMH services. A clinical Research Interactive Search (CRIS: 2007) was conducted from 1st January 2016 until 31st December 2017. This focused on patients referred to OPMH services that were being prescribed Flupentixol, Haloperidol, Prochloperazine, Amisulpride, Olanzapine, Quetiapine or Risperidone. Results: There were 1,642 (22.75%) patients prescribed one or more of the seven selected antipsychotics within the OPMH services. Of these patients without comorbid psychotic illness 1390 (84.6%) were prescribed an antipsychotic; the most common indications for such medication were agitation, psychotic symptoms, distress or aggression. This is 22.75% of the total number of people currently under OPMH services and is not limited to those of a specific disorder. The most commonly prescribed were atypicals and specifically Risperidone. The most common diagnosis prescribed antipsychotic medication was dementia 40%. Conclusions: These prescribing behaviours reveal good practice, in line with current NICE guidelines of what would be expected for the OPMH services. However, a further investigation into the rationale for the prescribing behaviour evident and the quality of alternative pharmacological and non-pharmacological approaches available to this population is essential.

The Relationship Between Pregnancy Exposure to Antidepressant and Atypical Antipsychotic Medications and Placental Weight and Birth Weight Ratio: A Retrospective Cohort Study.

Psychotropic medication use in pregnancy has been associated with altered fetal growth. The aim of this study was to investigate the relationship between placental weight and placental weight-to-birth weight (PBW) ratio, as a potential marker of placental efficiency, and medication use in a cohort of women with severe mental illness in pregnancy. A retrospective database analysis was carried out on a cohort of pregnant women with severe mental illness (242 singleton pregnancies) and grouped according to their psychotropic medication use. Demographic, obstetric, neonatal, and psychiatric variables were analyzed using t tests, χ, analysis of variance, univariate, binary, and multiple regression adjusting for potential confounders. Multiple regression analysis demonstrated a mean adjusted increase in placental weight of 114 g (95% confidence interval [CI], 60.2-165.6 g) in women taking antidepressant medication and 113 g (CI, 65.1-162.8 g) in women taking combined antidepressant and atypical antipsychotic medication in pregnancy. There was also a significantly elevated PBW ratio in these 2 medication groups (B 0.02: CI, 0.006-0.034; and B 0.025: CI, 0.012-0.038). Binary regression, adjusted for sex and gestational age, showed a significant odds ratio of 4.57 (95% CI, 2.17-9.62) for PBW ratio of greater than 90% in those taking antidepressant medication, either alone or in combination, compared with unmedicated women. The use of antidepressant medication, alone or in combination, has a significant effect on placental weight and PBW ratio after adjusting for confounding variables. Given that this may reflect adverse effects on intrauterine growth and have possible long-term implications for the fetus, further research is warranted to confirm these findings.

Continuation of atypical antipsychotic medications in critically ill patients discharged from the hospital: a single-center retrospective analysis.

Background:Atypical antipsychotics (AAP) have been associated with reduced duration of delirium in the intensive care setting. However, long-term use of these drugs is associated with significant adverse events, including increased all-cause mortality in the elderly. Inappropriate continuation of AAPs after discharge from the intensive care unit (ICU) is worrisome and needs to be addressed.The aim of this work was to assess the prevalence of continuation of AAPs after hospital discharge and evaluate the associated risk factors.Method:This was a single-center retrospective chart analysis in the setting of adult ICUs at a tertiary care academic medical center. It involved all adult patients admitted to the ICU and initiated on AAPs from January 2012 to December 2014. The measurements were: (1) prevalence of ICU-initiated AAP continuation following hospital discharge, (2) risk factors associated with continuation of AAPs following hospital discharge, and (3) risk of continuation of AAPs in patients ⩾65 years of age.Results:A total of 55% of ICU patients initiated on AAPs were discharged from the hospital with a prescription for continued AAP therapy. Male sex and discharge location were highly associated with continuation upon discharge. Older patients (⩾65 years of age) were not at a higher risk of being continued on these drugs after discharge.Conclusion:Male sex and discharge to a healthcare facility were associated with a higher rate of continuation. Research into practical methods to reduce their continuation upon discharge should be performed to mitigate the long-term risks of AAP administration.

Antipsychotics and Their Impact on Cerebral White Matter: Part of the Problem or Part of the Solution?

Antipsychotics and Their Impact on Cerebral White Matter: Part of the Problem or Part of the Solution?

A Learning Collaborative Approach to Improve Mental Health Service Delivery in Pediatric Primary Care.

Pediatric primary care practitioners (PPCPs) report inadequate training in the care of children with common mental health conditions. Although additional training is needed, system changes are also necessary to support improvements in care. We developed the Building Mental Wellness Learning Collaborative to assist PPCPs in delivering better mental health services in primary care by targeting 5 focus areas: mental health promotion; early identification and screening; practitioner skills; collaboration and community linkages; and medication management. Aims were developed for each area. Twenty-one practices and 50 practitioners completed the collaborative in 2 seven-month waves. For mental health promotion, ≥85% of charts showed documentation in 3 of 4 preselected areas. For early identification/screening, screening increased, but the ≥85% goal was not met. For practitioner skills, a ≥20% increase in the proportion of children/youth ≥1 visits for anxiety or depression was achieved, from 0.70% of children/youth in the 12 months preintervention to 1.09% children/youth in the 12 months after. For collaboration/linkages, mental health referral completion was unchanged and below the 60% goal. For medication use, a ≥15% increase in selective serotonin reuptake inhibitor prescribing by Building Mental Wellness (BMW) practitioners was achieved from 0.72% children/youth with office visits pre-BMW to 0.92% post. Prescribing did not decrease for atypical antipsychotic medication use or for psychotropic medication use in children younger than 6 years, although there was a trend toward more appropriate prescribing. The BMW Learning Collaborative was effective in helping PPCPs implement certain aspects of a comprehensive approach to the delivery of mental health services in primary care.

A Focused Review on the Treatment of Pediatric Patients with Atypical Antipsychotics.

The use of atypical antipsychotic medications in pediatric patients has become more prevalent in recent years. The purpose of this review is to provide a clinically relevant update of recent selected key publications regarding the use of atypical antipsychotics in this population. Studies reviewed included randomized, double-blind, placebo-controlled medication trials conducted within the past 5 years. A PubMed search was conducted for each of the 11 second-generation antipsychotic medications currently approved by the Food and Drug Administration for use in the United States: clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, paliperidone, asenapine, iloperidone, lurasidone, and cariprazine. Trials published in English with subjects 18 years of age and younger were included in this review. Additional studies, chosen for their significance to clinical practice, were also included at the discretion of the authors. This review demonstrates that more empiric data are available regarding both the acute efficacy and, to a lesser extent, the longer-term efficacy and tolerability for several of the considered antipsychotic medications. The clinical conditions for which these medications have been studied include schizophrenia, bipolar disorder, Tourette's disorder, and autism spectrum disorder. They have also been used as an adjunctive treatment for disruptive behavior disorders with aggression, which have not responded to treatment with stimulants. Evidence regarding the efficacy and tolerability of antipsychotic medications for mental health disorders in children and adolescents has expanded exponentially in recent years. However, more information is needed so that evidence-based comparisons between medications can be made. In the future, data enabling the selection of medications based upon individual patient characteristics could potentially lead to greater efficacy and efficiency in treating what are frequently debilitating medical conditions. Maladaptive aggression in children, often treated with antipsychotics, is one such area in which there is a dearth of actual information available to the clinician. It is to be hoped that additional, longer-term studies of these medications will further inform evidence-based practice in clinical settings.

Results of Discontinuation Rate, Remission Rate, and Improvement in Social Functioning Associated with Atypical Antipsychotic Medications in Patients with Schizophrenia: 52-Week Evaluation of JUMPs, a Randomised, Open-Label, Naturalistic Study in Japan

Background: The Japan Useful Medication Program for Schizophrenia (JUMPs) is the first large-scale, long-term (2 years) naturalistic study to assess effectiveness and safety of aripiprazole, blonanserin, and paliperidone in patients with schizophrenia. Here, we present the 52-week results. Methods: This open-label, three-arm, multicentre, randomised, parallel-group study was conducted at 75 sites in Japan. Outpatients with schizophrenia, age ≥20 years, requiring antipsychotic treatment or switching were randomised (1:1:1) to receive oral aripiprazole, blonanserin, or paliperidone as monotherapy during a 4-week titration period (start of monotherapy). The primary endpoint was treatment discontinuation rate over 52 weeks using Kaplan-Meier analysis. Secondary outcomes included social functioning score (Personal and Social Performance Scale [PSP]; Euro QOL-5 dimensions) and safety over 52 weeks. Findings: A total of 251 patients were randomised (July 2012 to December 2013) to receive aripiprazole (n=82), blonanserin (n=85), and paliperidone (n=84). The mean (SD) age was 46·5 (13·3) years and disease duration was 17·1 (12·3) years; 53% were men. Discontinuation rate over 52 weeks (68·3%, 68·2%, and 65·5%) did not differ significantly in aripiprazole, blonanserin, and paliperidone groups, respectively (log-rank test, p=0·9771). The median (95% confidence interval; interquartile range: quartile (Q)1-Q3) time to treatment discontinuation was 144·5 (91·0‒210·0; 51-not applicable), 144·0 (81·0‒238·0; 56-417), and 129·5 (84·0‒252·0; 54.5-not applicable) days in the aripiprazole, blonanserin, and paliperidone groups, respectively. In comparison to eligibility assessments, significant improvements (all p<0·05) in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favoured blonanserin. Interpretation: The treatment discontinuation rate of aripiprazole, blonanserin, and paliperidone was similar in patients with chronic schizophrenia in Japan. Clinical Trial Number: (UMIN Clinical Trials Registry 000007942) Funding Statement: Funding provided by The Waksman Foundation of Japan Inc. Declaration of Interests: J. Ishigooka reports grant from The Waksman Foundation of Japan Inc. for the work under consideration for publication, personal fees from Dainippon Sumitomo, Eisai, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Shionogi, and Takeda, outside the submitted work. K. Nakagome reports grant from The Waksman Foundation of Japan Inc. during the conduct of this study and from Meiji Seika Pharma, Otsuka pharmaceutical, Sumitomo Dainippon pharma, Mochida pharmaceutical, Janssen pharmaceutical K.K., Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim (BI), Astellas pharma, Asahi Kasei pharma and Shionogi and personal fees from Meiji Seika Pharma, MSD K.K., Otsuka pharmaceutical, Kyowa Hakko Kirin, Sumitomo Dainippon pharma, Takeda pharmaceutical, Eli Lilly Japan, K.K., Pfizer Japan, Nippon BI, Toyama Chemical, Mochida pharmaceutical, Janssen pharmaceutical, Page 16 of 30 Yoshitomiyakuhin corporation, Taisho Toyama Pharma, and Kowa, outside the submitted work. T. Ohmori reports personal fees from Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly, GlaxoSmithKline, Meiji, Mochida, MSD, Novartis, Otsuka, Pfizer, Takeda, Mitsubishi Tanabe, and Yoshitomi, and grants from Astellas, Dainippon Sumitomo, Eisai, Meiji, Otsuka, and Pfizer. N. Iwata reports personal fees from Dainippon Sumitomo, Eli Lilly, Janssen, Otsuka, Meiji, and Pfizer and grant from Otsuka, outside of submitted work. K. Inada reports personal fees from Dainippon Sumitomo, Eisai, Eli Lilly, Janssen, MeijiSeika Pharma, Mochida, MSD, Novartis, Otsuka, Shionogi, Tanabe-Mitsubishi, and Yoshitomi and grant from MSD, outside the submitted work. J. Iga reports personal fees from Dainippon Sumitomo, Eli Lilly, Janssen, Meiji-Seika Pharma, Mochida, MSD, Mylan, Novartis, and Otsuka, outside the submitted work. T. Kishi reports personal fees from Daiichi Sankyo, Dainippon Sumitomo, Eisai, Janssen, Otsuka, Meiji, MSD, Tanabe-Mitsubishi, and Yoshitomi, outside the submitted work and grants from the Health and Labor Sciences and Fujita Health University School of Medicine for the work under consideration for publication. H. Tabuse reports personal fees from Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Otsuka, Meiji, Pfizer, Tanabe-Mitsubishi, and Yoshitomi, outside the submitted work. Hiroshi Terada reports personal fees from Eli Lilly Japan K.K., Janssen pharmaceuticals K.K., Otsuka, Meiji, Dainippon Sumitomo, Tanabe-Mitsubishi, and Yoshitomiyakuhin, outside the submitted work. Y. Tsutsumi reports personal fees from Otsuka and Janssen, outside the submitted work. Y. Kanda reports personal fees from Eli Lilly Japan K.K. and Janssen pharmaceutical K.K. during the conduct of the study and from Eli Lilly Japan K.K. outside the submitted work. K. Sekiyama reports personal fees from Otsuka, outside the submitted work. K. Fujita, Y. Kikuchi, T. Shichijo, S. Koretsune, Haruko Terada, T. Kishimoto, and K. Ohi have no conflicts of interest. Ethics Approval Statement: The study was approved by the appropriate institutional review boards and was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Tripartite Guidelines for Good Clinical Practice, and the Ethics Guidelines for Clinical Research (Ministry of Health, Labour and Welfare, 2008 revision). Written informed consent was obtained from all patients.

Effect of sulfobutyl ether-β-cyclodextrin and propylene glycol alginate on the solubility of clozapine

Clozapine (CLZ) is an atypical antipsychotic medication used in the treatment of schizophrenia and is poorly soluble in water (0.05 mM). In this study, we have investigated the effect of β-cyclodextrin (CD) and its derivatives on the solubility of CLZ. The solubility of the CLZ was measured to generate a phase solubility diagram, and the interaction between CLZ and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) in aqueous solution was observed by 1H- and 2D rotating-frame Overhauser enhancement spectroscopy (ROESY)-NMR methods. Moreover, the synergistic effect of SBE-β-CD and water-soluble polymers, including polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium salt, polyvinyl alcohol, sodium alginate, and propylene glycol alginate (PGA), on the solubility of CLZ was investigated. The results show that the solubility of CLZ with 1 w/v% PGA was 7.6 mM, which was almost four times greater than that of CLZ without PGA in a 15 mM SBE-β-CD solution. In contrast, the solubility of CLZ with 1 w/v % PGA in an aqueous solution decreased by one-third relative to that of CLZ in a 15 mM SBE-β-CD solution. 2D ROESY-NMR indicated that a CLZ/SBE-β-CD/PGA ternary complex formed. It was found that the combination of PGA and SBE-β-CD enhanced the solubility of CLZ.

Comparing the effect of the subcategories of atypical antipsychotic medications on cognition in schizophrenia using a meta-analytic approach

ABSTRACTObjectives: The aim of this study was to compare the two most commonly prescribed classes of atypical antipsychotic medications (i.e., -pines and -dones) with regard to their effects on cognition in patients with schizophrenia.Data sources: Ovid Technologies web-based software was used to search the Medline and PsycINFO computerized databases to identify articles that met the inclusion criteria.Review methods: The search was limited to papers published after 1990, written in English, employing human subjects, using atypical antipsychotics, using a within-subjects design or control group of patients with schizophrenia for comparisons, using participants aged from 18–65, and employing standardized neuropsychological measures.Results: A total of 996 eligible studies were identified, and of these 19 were finally analyzed. Nine domains of cognitive functioning were assessed. The two groups of agents produced equivalent overall effects (-dones = .254 versus -pines = .202). The -pines were found to improve the domains of attention/working memory, executive functioning, fluency, nonverbal memory, processing speed, and verbal memory, each with a significant, small effect size. The -dones were found to improve attention/working memory, executive functioning, motor function, nonverbal memory, processing speed, and verbal memory, each with a significant, small effect size. Failsafe N was robust for all of the domains for the -pines, but only for the verbal memory domain for the -dones, suggesting that the significant findings for the other domains with the -dones are more tenuous.Conclusion: The results indicate that the agents were largely equivalent and that there was no clear evidence that the pattern of cognitive effects differed as a result of the agent applied. The effects themselves, while statistically significant, were small, indicating that some or all of the differences may be attributable to practice effects on the instruments employed.

Cardiovascular Events Following Treatment Initiation with Atypical Antipsychotic Medications in Publicly Insured U.S. Youth.

To assess the risk of incident cardiovascular events that led to hospitalizations or emergency department visits following atypical antipsychotic (AAP) treatment initiation in youth according to dose, duration of use, and concomitant use of leading psychotropic medication classes. We used computerized Medicaid claims to conduct a retrospective cohort study of youth (5-20 years) who initiated AAP treatment. AAP use was operationalized in a time-dependent manner according to current vs. former use, average daily dose (in risperidone dose equivalents), and duration of use. In a secondary analysis, concomitant use of (1) stimulants and (2) serotonin-reuptake inhibitors (SSRI/SNRIs) with AAPs was also assessed. To account for confounding, disease risk score methodology was used in discrete time failure models. There were 74,700 youth who initiated AAP treatment (average follow-up = 24.8 months). During follow-up, the risk of cardiovascular events was significantly greater during current than former AAP use (RR = 1.55, 95% CI = 1.09-2.21). Furthermore, for current users of AAPs, the risk of cardiovascular events intensified with average daily dose (RR = 2.04, 95% CI = 1.11-3.77 for >3.75 mg/day vs. ≤1.25 mg/day). The risk of cardiovascular events did not significantly differ according to duration of AAP use. In AAP-treated youth, concomitant SSRI/SNRI use was associated with an increased risk of cardiovascular events (RR = 1.61, 95% CI = 1.01-2.57). By contrast, stimulant use concomitant with AAPs was not significantly associated with an increased risk of cardiovascular events. In publicly insured U.S. youth, current AAP use was associated with an increased risk of incident cardiovascular events, which intensified with increasing dose and with concomitant SSRI/SNRI use. Prudent interpretation of these findings suggests that further research is needed to identify youth subpopulations with the greatest risk of developing AAP treatment-emergent cardiovascular events.

Disease modifying effects of antipsychotic drugs in schizophrenia: a clinical and neurobiological perspective.

Disease modifying effects of antipsychotic drugs in schizophrenia: a clinical and neurobiological perspective.

Continuation of Atypical Antipsychotic Medication During Early Pregnancy and the Risk of Gestational Diabetes.

Some atypical antipsychotics are associated with metabolic side effects, which are risk factors for gestational diabetes. The authors examined the risk of developing gestational diabetes associated with the continuation of treatment with aripiprazole, ziprasidone, quetiapine, risperidone, and olanzapine during pregnancy compared with discontinuation of these antipsychotic drugs. Nondiabetic pregnant women who were linked to a live-born infant and enrolled in Medicaid (2000-2010) and who received one or more prescriptions dispensed for an antipsychotic drug during the 3 months before pregnancy were included in the analyses. Among 1,543,334 pregnancies, some expectant mothers at baseline were receiving treatment with aripiprazole (N=1,924), ziprasidone (N=673), quetiapine (N=4,533), risperidone (N=1,824), or olanzapine (N=1,425). For each antipsychotic drug, women with two or more dispensings ("continuers") were compared with women with no dispensings ("discontinuers") during the first half of pregnancy. A generalized linear model and propensity-score stratification were used to obtain absolute and relative risks of developing gestational diabetes, with adjustment for confounders. Women who continued antipsychotic treatment during pregnancy generally had higher comorbidity and longer baseline antipsychotic use. The crude risk of developing gestational diabetes among continuers compared with discontinuers, respectively, was 4.8% and 4.5% for aripiprazole, 4.2% and 3.8% for ziprasidone, 7.1% and 4.1% for quetiapine, 6.4% and 4.1% for risperidone, and 12.0% and 4.7% for olanzapine. The adjusted relative risks were 0.82 (95% CI=0.50-1.33) for aripiprazole, 0.76 (95% CI=0.29-2.00) for ziprasidone, 1.28 (95% CI=1.01-1.62) for quetiapine, 1.09 (95% CI=0.70-1.70) for risperidone, and 1.61 (95% CI=1.13-2.29) for olanzapine. Compared with women who discontinued use of an atypical antipsychotic medication before the start of pregnancy, women who continued treatment with olanzapine or quetiapine had an increased risk of gestational diabetes that may be explained by the metabolic effects associated with these two drugs.

Effects of Metformin on Spatial and Verbal Memory in Children with ASD and Overweight Associated with Atypical Antipsychotic Use.

Objectives: Studies in humans and rodents suggest that metformin, a medicine typically used to treat type 2 diabetes, may have beneficial effects on memory. We sought to determine whether metformin improved spatial or verbal memory in children with autism spectrum disorder (ASD) and overweight associated with atypical antipsychotic use.Methods: We studied the effects of metformin (Riomet®) concentrate on spatial and verbal memory in 51 youth with ASD, ages 6 through 17 years, who were taking atypical antipsychotic medications, had gained significant weight, and were enrolled in a trial of metformin for weight management. Phase 1 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group comparison of metformin (500–850 mg given twice a day) versus placebo. During Phase 2, all participants took open-label metformin from week 17 through week 32. We assessed spatial and verbal memory using the Neuropsychological Assessment 2nd Edition (NEPSY–II) and a modified children's verbal learning task.Results: No measures differed between participants randomized to metformin versus placebo, at either 16 or 32 weeks, after adjustment for multiple comparisons. Sixteen-week change in memory for spatial location on the NEPSY–II was nominally better among participants randomized to placebo. However, patterns of treatment response across all measures revealed no systematic differences in performance, suggesting that metformin had no effect on spatial or verbal memory in these children.Conclusions: Although further study is needed to support these null effects, the overall impression is that metformin does not affect memory in overweight youth with ASD who were taking atypical antipsychotic medications.

PND16 - Atypical Antipsychotic Use Among Long-Term Care Residents with Parkinson's Disease and Comorbid Depression

According to the 2015 American Geriatrics Society (AGS) Beers criteria, most antipsychotics are inappropriate in Parkinson’s disease (PD) patients due to the risk of worsening Parkinsonian symptoms. This study examined the incidence and predictors of inappropriate antipsychotic use among long-term care residents with PD and comorbid depression. This retrospective cohort study utilized 2007-2009 Minimum Data Set (MDS) linked to Chronic Condition Warehouse (CCW) Medicare data files involving patients with PD and comorbid depression. Using a 12-month baseline and a 24-month follow-up, the study examined incidence of inappropriate atypical antipsychotics, namely asenapine, brexpiprazole, iloperidone, lurasidone, olanzapine, paliperidone, risperidone, or ziprasidone as specified in the 2015 AGS Beers criteria. Appropriate atypical antipsychotic included aripiprazole, clozapine, or quetiapine. Multivariable logistic regression was used to examine various sociodemographic and clinical factors associated with inappropriate antipsychotic use in PD based on the Andersen Behavioral Model. The incidence of atypical antipsychotic use was 17.50% (13,352/76,294) among PD patients over a 2-year follow-up. The percentage of inappropriate use among atypical antipsychotic users was 36.32%. The likelihood of inappropriate antipsychotic use was higher for patients who had dementia (OR=1.22, 95% CI: 1.12-1.33) or Chronic Obstructive Pulmonary Disease ((OR=1.13, 95% CI: 1.03-1.24). However, patients who were taking levodopa (OR=0.62, 95% CI: 0.57-0.67), dopamine agonists (OR=0.90, 95% CI: 0.82-0.98), Catechol-O-methyltransferase (COMT) inhibitors (OR=0.77, 95% CI: 0.68-0.86), Monoamine Oxidase (MAO) inhibitors type B (OR=0.72, 95% CI: 0.60-0.86), or amantadine (OR=0.84, 95% CI: 0.71-0.98) were less likely to receive inappropriate antipsychotics. More than one-third of PD patients used inappropriate antipsychotics among those who were treated with atypical antipsychotic medications. Various socio-demographics and clinical factors were associated with inappropriate antipsychotic use in older patients with PD. Concerted efforts are needed to reduce inappropriate atypical antipsychotic use among PD patients.

All-cause mortality in older adults with affective disorders and dementia under treatment with antipsychotic drugs: A matched-cohort study

We aimed to compare the mortality risk between patients with affective disorders and dementia under treatment with antipsychotics. To do this, a matched-cohort study based on an electronic database of a tertiary teaching hospital in Argentina was performed. Antipsychotic exposure was defined as any antipsychotic drug initiated by the patient. Primary outcome was defined as all-cause mortality during the 5-year follow-up period. To estimate the association between baseline diagnosis (affective disorders vs. dementia) and all-cause mortality, we used a multivariate generalized linear model with robust standard errors. Of 1008 eligible patients, 114 age-matched pairs were included in the present study. The primary event occurred in 23 patients (20%) and 17 patients (15%) in the dementia and affective disorder group respectively. In the adjusted model, the risk of all cause mortality for the affective disorders group was 0.92 times the risk for the dementia group (95%CI, 0.54–1.59, p = 0.77). In conclusion, older patients with affective disorders starting antipsychotic treatment presented with a similar risk of all-cause mortality during the 5-year follow-up when compared to older patients with dementia who were also initiating either typical or atypical antipsychotic medications. Closer medical attention to older patients with mental conditions under antipsychotic treatment remains warranted.

The Wnt Signaling Pathway Effector TCF7L2 Mediates Olanzapine-Induced Weight Gain and Insulin Resistance.

Olanzapine is a widely used atypical antipsychotic medication for treatment of schizophrenia and is often associated with serious metabolic abnormalities including weight gain and impaired glucose tolerance. These metabolic side effects are severe clinical problems but the underpinning mechanism remains poorly understood. Recently, growing evidence suggests that Wnt signaling pathway has a critical role in the pathogenesis of schizophrenia and molecular cascades of antipsychotics action, of which Wnt signaling pathway key effector TCF7L2 is strongly associated with glucose homeostasis. In this study, we aim to explore the characteristics of metabolic disturbance induced by olanzapine and to elucidate the role of TCF7L2 in this process. C57BL/6 mice were subject to olanzapine (4 mg/kg/day), or olanzapine plus metformin (150 mg/kg/day), or saline, respectively, for 8 weeks. Metabolic indices and TCF7L2 expression levels in liver, skeletal muscle, adipose, and pancreatic tissues were closely monitored. Olanzapine challenge induced remarkably increased body weight, fasting insulin, homeostasis model assessment-insulin resistance index, and TCF7L2 protein expression in liver, skeletal muscle, and adipose tissues. Notably, these effects could be effectively ameliorated by metformin. In addition, we found that olanzapine-induced body weight gain and insulin resistance actively influence the expression of TCF7L2 in liver and skeletal muscle, and elevated level of insulin determines the increased expression of TCF7L2 in adipose tissue. Our results demonstrate that TCF7L2 participates in olanzapine-induced metabolic disturbance, which presents a novel mechanism for olanzapine-induced metabolic disturbance and a potential therapeutic target to prevent the associated metabolic side effects.

Hypersexuality associated with paliperidone.

We report a case of unusual sexual symptoms in a 43-year-old female patient with schizophrenia (according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition), who was being treated with a depot formulation of paliperidone palmitate, an atypical antipsychotic medication. The symptoms included increased sexual desire, sexual preoccupation, constant drive for intercourse, and sexual arousal with unrelated stimuli such as urination. Potential neurochemical mechanisms have been elucidated for this symptomatology. Paliperidone palmitate has broad neuropharmacological effects, which might have contributed to the development of this rare clinical condition. (PsycINFO Database Record

T5. LURASIDONE AND RISK FOR METABOLIC SYNDROME IN PATIENTS WITH SCHIZOPHRENIA: A COMPREHENSIVE DATABASE ANALYSIS

BackgroundPatients with schizophrenia are at increased risk for developing metabolic syndrome, with an estimated prevalence of approximately 35–50% (Correll et al. Psychiatr Serv 2010;61:892–98; Vancampfort et al. World Psychiatry 2015;14:339–47). Treatment with atypical antipsychotic medications have been shown to increase rates of metabolic syndrome, with differences observed among antipsychotic agents, most notably in propensity for weight gain: higher for olanzapine, clozapine, and iloperidone; intermediate for quetiapine, risperidone, and paliperidone; and lower for amisulpride, aripiprazole, asenapine, lurasidone, and ziprasidone (Leucht et al. Lancet 2013;382:951–62). Independent of weight gain, atypical antipsychotics also appear to have direct effects on lipid metabolism and glucose regulation. The aim of this safety analysis was to assess the effects of treatment with lurasidone on metabolic syndrome risk in patients with schizophrenia.MethodsChanges in the rate of metabolic syndrome during treatment with lurasidone (40–160 mg/d) versus active comparators (olanzapine, quetiapine, risperidone) were analyzed using pooled short-term data from 3 randomized, double-blind, placebo-controlled studies; long-term data from 2 active-controlled studies; and switch data from 2 open-label extension studies. Metabolic syndrome was defined based on the National Cholesterol Education Program criteria (NCEP ATP III; 2005 revision).ResultsIn short-term studies, risk of treatment-emergent metabolic syndrome was similar for patients in the lurasidone and placebo groups (odds ratio [OR]=0.97; week 6 LOCF-endpoint); and was significantly greater for patients in the olanzapine (OR=2.68; P<0.001) and quetiapine (OR=3.70; P<0.001) groups compared to placebo. In long-term studies, risk of treatment-emergent metabolic syndrome after 12 months was significantly lower for lurasidone compared with risperidone (OR=0.374; 95% CI, 0.180–0.774; P<0.01) and non-significantly lower for lurasidone compared with quetiapine XR (OR=0.267; 95% CI, 0.040–1.806; P>0.05). In open-label switch studies, the rate of metabolic syndrome decreased in patients switched to lurasidone after 6 weeks of treatment with olanzapine or 12 months of treatment with risperidone.DiscussionIn this comprehensive analysis of the lurasidone clinical trial data base, treatment with lurasidone (40–160 mg/d) was not associated with the development of metabolic syndrome in patients with schizophrenia. Rates of metabolic syndrome increased in patients treated with olanzapine, risperidone, and quetiapine XR.

Multi‐Omic Approach to Identifying Altered Metabolic and Signaling Pathways in the Mouse Heart with Chronic Exposure to Atypical Antipsychotic Medications

Atypical (AA) antipsychotic drugs, including Risperidone (RIS) and Olanzapine (OLAN), cause cardiac arrhythmia and significant endocrine and metabolic risk factors for cardiovascular disease, including obesity, insulin resistance, hyperglycemia, and dyslipidemia. AA drugs have complex pharmacology, antagonizing G‐protein coupled receptors including: dopamine, serotonin, α‐adrenergic and muscarinic receptors. However, the underlying pharmacology linking cardiovascular morbidities to AA therapy is unknown. We hypothesize that AAs may alter cardiac energy metabolism and present early gene expression markers in the pathogenesis to cardiovascular disease. In this study we aim to investigate the mechanisms by which AAs may promote cardiometabolic dysfunction. Male B6 mice were dosed daily with either 5 mg/kg OLAN or 1 mg/kg RIS or vehicle control (V) for 4 weeks and chronic effects of AAs were assessed in whole heart ventricles by RNAseq, miRNAseq and Proteomic analysis. Results suggest changes in transcriptomic and proteomic profiles and in the mouse heart with chronic exposure to AAs relating to mitochondrial dysfunction, lipid oxidation and metabolism, contractility, cardiac hypertrophy and PPAR signaling. Further pathway analysis of these data sets using Ingenuity Pathway Analysis revealed altered canonical pathways and disease and function that are consistent between the RIS and OLAN treated groups compared to V. To further investigate the effect of AA treatment on cardiac mitochondrial function, cardiac mitochondria were isolated from female B6 mice dosed 4 weeks daily with V or 0.75 mg/kg RIS and oxygen consumption studies were performed on the XF24 extracellular flux analyzer (Agilent) to measure various respiratory states. Isolated mitochondria were well coupled and showed a RCR (OCRADP/OCROligo) of ~ 3. RIS treatment led to an increase in State II (Succinate) and State III (phosphorylating) respiration compared to V. In conclusion, our data demonstrate chronic effects of AAs on cardiac mitochondrial function and bioenergetics and indicators of cardiac function.Support or Funding InformationThis work was funded in part by NIH grant DK095413 awarded to KH and NIH grant AR067858 awarded to KJM.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.