Atypical Antipsychotic Olanzapine Research Articles

Atypical antipsychotic poisoning in young children: a multicentre analysis of poisons centres data

Although paediatric patients frequently suffer from intoxications with atypical antipsychotics, the number of studies in young children, which have assessed the effects of acute exposure to this class of drugs, is very limited. The aim of this study was to achieve a better characterization of the acute toxicity profile in young children of the atypical antipsychotics clozapine, olanzapine, quetiapine, and risperidone. We performed a multicentre retrospective analysis of cases with atypical antipsychotics intoxication in children younger than 6 years, reported by physicians to German, Austrian, and Swiss Poisons Centres for the 9-year period between January 1, 2001 and December 31, 2009. One hundred and six cases (31 clozapine, 29 olanzapine, 12 quetiapine, and 34 risperidone) were available for analysis. Forty-seven of the children showed minor, 28 moderate, and 2 severe symptoms. Twenty-nine cases were asymptomatic. No fatalities were recorded. Symptoms predominantly involved the central nervous and cardiovascular systems. Minor reduction in vigilance (Glasgow Coma Scale score >9) (62 %) was the most frequently reported symptom, followed by miosis (12 %) and mild tachycardia (10 %). Extrapyramidal motor symptoms were observed in one case (1 %) after ingestion of risperidone. In most cases, surveillance and supportive care were sufficient to achieve a good outcome, and all children made full recovery. Paediatric antipsychotic exposure can result in significant poisoning; however, in most cases only minor or moderate symptoms occurred and were followed by complete recovery. Symptomatic patients should be monitored for central nervous system depression and an electrocardiogram should be obtained.

Treatment of paradoxical insomnia with atypical antipsychotic drugs: a comparison of olanzapine and risperidone

Introduction To compare the efficacy of 2 atypical antipsychotic drugs, olanzapine and risperidone, in the treatment of paradoxical insomnia. Materials and methods In this cross-sectional study over a 2-year period patients with paradoxical insomnia, diagnosed in Kermanshah, Iran by both psychiatric interview and actigraphy, were randomly assigned to 2 groups. For 8 weeks, the first group ( n = 14) was treated with 10 mg olanzapine daily, and the second group ( n = 15) was treated with 4 mg risperidone daily. All participants completed the Pittsburgh Sleep Quality Inventory (PSQI) at baseline and at the end of the study. Results As expected, a baseline actigraphy analysis showed that total sleep time was not significantly different between the 2 treatment groups ( p p p Conclusion Atypical anti-psychotic drugs such as olanzapine and risperidone may be beneficial options for treatment of paradoxical insomnia. Larger clinical trials with longer periods of follow-up are needed for further investigation. Acknowledgement This work was supported by a grant from the Department of Research, Kermanshah University of Medical Sciences (KUMS).

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT1A, 5-HT2A and adrenergic a2 receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.

Diagnoses Associated With Use of Atypical Antipsychotics in a Commercial Health Plan: A Claims Database Analysis

BackgroundAtypical antipsychotics are indicated for specific psychiatric conditions; however, they are frequently used for US Food and Drug Administration–nonapproved indications. ObjectiveThis study assessed the types of medical diagnoses associated with atypical antipsychotic prescriptions in commercial health care plans. MethodsThis retrospective cohort study used the OptumInsight commercial data set from January 2008 to June 2011. The index date was defined as the earliest date of prescription for the atypical antipsychotics aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone, from January 1, 2009, through June 30, 2010. Medical claims during a 2-year period (12 months before and 12 months after the index date) were used to identify relevant diagnostic codes from the International Classification of Diseases, Ninth Edition, Clinical Modification associated with the antipsychotic prescription. A logistic regression analysis was conducted to examine the predictors of use of atypical antipsychotics without a relevant diagnosis, that is, schizophrenia, bipolar, or major depressive disorder (MDD). ResultsOf 18,352 patients included in the analysis, 3593 (19.5%) who filled a prescription for atypical antipsychotics did not have an approved diagnosis. Off-label utilization varied, with approximately a quarter of patients with prescriptions for quetiapine (24.1%), risperidone (23.1%), or olanzapine (21.8%) being without a relevant diagnostic code, whereas proportions were lower for patients prescribed aripiprazole (14.0%) or ziprasidone (13.1%). Of those with a psychiatric disorder other than schizophrenia, bipolar disorder, or MDD, approximately a third of prescriptions were for anxiety disorders, with similar proportions across all atypical antipsychotics. Patients were often prescribed quetiapine for substance abuse (22.7%), whereas patients with “other psychiatric conditions” were prescribed risperidone (26.3%) or ziprasidone (25.0%). The logistic regression analysis indicated that patients prescribed olanzapine, quetiapine, or risperidone were significantly more likely to have no diagnostic code for schizophrenia, bipolar disorder, or MDD compared with patients prescribed aripiprazole. ConclusionNearly a fifth of commercially insured patients were prescribed atypical antipsychotics, in particular, olanzapine, quetiapine, or risperidone, for diagnoses that were not aligned with US Food and Drug Administration–approved indications.

Antipsychotics and the gut microbiome: olanzapine-induced metabolic dysfunction is attenuated by antibiotic administration in the rat

The atypical antipsychotic olanzapine is often associated with serious metabolic side effects including weight gain and increased visceral fat. These adverse events are a considerable clinical problem and the mechanisms underlying them are multifactorial and poorly understood. Growing evidence suggests that the gut microbiota has a key role in energy regulation and disease states such as obesity. Moreover, we recently showed that chronic olanzapine altered the composition of the gut microbiome in the rat. It is thus possible that treatments that alter gut microbiota composition could ameliorate olanzapine-induced weight gain and associated metabolic syndrome. To this end, we investigated the impact of antibiotic-induced alteration of the gut microbiota on the metabolic effects associated with chronic olanzapine treatment in female rats. Animals received vehicle or olanzapine (2 mg kg−1 per day) for 21 days, intraperitoneal injection, two times daily. Animals were also coadministered vehicle or an antibiotic cocktail consisting of neomycin (250 mg kg−1 per day), metronidazole (50 mg kg−1 per day) and polymyxin B (9 mg kg−1 per day) by oral gavage, daily, beginning 5 days before olanzapine treatment. The antibiotic cocktail drastically altered the microbiota of olanzapine-treated rats, and olanzapine alone was also associated with an altered microbiota. Coadministration of the antibiotic cocktail in olanzapine-treated rats attenuated: body weight gain, uterine fat deposition, macrophage infiltration of adipose tissue, plasma free fatty acid levels, all of which were increased by olanzapine alone. These results suggest that the gut microbiome has a role in the cycle of metabolic dysfunction associated with olanzapine, and could represent a novel therapeutic target for preventing antipsychotic-induced metabolic disease.

P.3.d.011 Reasons for aripiprazole discontinuation – a retrospective review

The traditional antipsychotics are generally poorly effective or ineffective against the negative symptoms of schizophrenia and are also associated with extensive side effects which can themselves cause or exacerbate secondary negative symptomatology. As well as having a low propensity to cause extrapyramidal side effects (EPS), the currently available, putative, atypical antipsychotics (clozapine, risperidone, sertindole, and olanzapine), developmental antipsychotics (zotepine, quetiapine and ziprasidone) and low doses of certain traditional antipsychotics, such as amisulpride and fluphenazine, have been reported to ameliorate negative symptoms in comparison with placebo or standard antipsychotics such as fluphenazine, haloperidol or perphenazine. To date, few trials have specifically examined primary negative symptomatology and it has been suggested that the improvements observed with these drugs may be related to decreases in positive symptoms and/or reduced sedation or extrapyramidal side effects. Although atypicality has been ascribed to 5-HT2/D2 antagonism, the exact pharmacological mechanism(s) underlying the efficacy of the atypical antipsychotics have not been elucidated. Many of these drugs bind to multiple other receptors and/or inhibit neurotransmitter uptake and it seems probable that some of these other pharmacological properties may also contribute to their clinical features.

P.1.g.010 The effects of the atypical antipsychotics aripiprazole and olanzapine on learning and memory in naïve rats

First-year university students represent an important target group for health promotion and disease prevention programs. However, few studies have been carried out to evaluate the relationship between the nutritional pattern of late adolescence and health parameters related to cardiovascular risk, such as body composition and blood pressure. The purpose of this study was to compare the dietary habits of first-year university students with those of the general population and to evaluate if poor nutritional habits are associated with cardiovascular risk factors. Daily food consumption over 3 consecutive days was recorded; nutritional analysis was performed; and blood pressure, body mass index, and body composition were measured in a group of first-year university students (n = 111; mean age, 18.6 years) attending the University of the Basque Country (Leioa, Bizkaia, Spain), which is representative of a developed country. Almost a quarter of students were found to be overweight (19.3%) or obese (4.6%). The contribution of macronutrients to total energy intake was very low for carbohydrates but very high for fat and proteins. The study revealed that some nutritional behaviors have a short-term effect on the cardiovascular health of the adolescents. Thus, milk intake was negatively correlated with obesity and intake of fiber, and intake of beans was negatively correlated with BMI and blood pressure in females. We conclude that first-year university students in the University of the Basque Country have poor nutritional habits, which are associated with increased risk factors for cardiovascular disease. Greater resources should be allocated to the nutritional education of this type of youth group, not only to prevent problems in later adulthood but also to improve the current health of adolescents.

Atypical antipsychotic olanzapine reversed deficit on prepulse inhibition of the acoustic startle reflex produced by microinjection of dizocilpine (MK-801) into the inferior colliculus in rats

Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviors which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. Thus, the purpose of the present study was to elucidate the role of glutamatergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether NMDA receptor stimulation or blockade would affect this response. Unilateral microinjections of NMDA (30nmol/0.5μL) into the IC did not alter PPI while microinjections of MK-801 (30nmol/0.5μL) into this structure disrupted PPI. We also examined the ability of the atypical antipsychotic olanzapine (5.0mg/kg; i.p.) to reverse the disruption of pre-pulse inhibition produced by unilateral microinjections of MK-801 into the IC of rats. Pretreatment with olanzapine blocked MK-801-induced disruption of PPI. Altogether, these results suggest that glutamate-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic olanzapine.

Psychosis, Agitation, and Antipsychotic Treatment in Dementia

Psychosis, Agitation, and Antipsychotic Treatment in Dementia

The comparative efficacy of intramuscular antipsychotics for the management of acute agitation

To review the current role and comparative efficacy of short-acting intramuscular (IM) antipsychotics in the management of acute agitation, in current clinical practice. The efficacy and tolerability of IM antipsychotics in the management of acute agitation in current clinical practice were reviewed in the Medline, PubMed, Cinahl Plus, Scopus-v.4 and PsycInfo databases. The comparative efficacy of the rapidly-acting IM atypical antipsychotics (olanzapine, ziprasidone and aripiprazole) is similar to that of the typical antipsychotic, haloperidol. IM olanzapine and ziprasidone were associated with fewer extrapyramidal side-effects and had similar cardiac tolerability to IM haloperidol. Further studies are required in the ongoing development of contemporary, evidence-based clinical guidelines in acute agitation, including head-to-head comparisons of currently utilized IM atypical antipsychotics, sequential treatment or combinations of medications.

Routine exercise ameliorates the metabolic side-effects of treatment with the atypical antipsychotic drug olanzapine in rats

Second generation antipsychotic (SGA) drugs are effective treatments for psychosis. Common side-effects of SGAs include metabolic dysregulation and risk of cardiometabolic disorders. Metabolic side-effects, including glucose intolerance, can be accurately modelled in rodents. The benefits of interventions used for treating metabolic side-effects of SGAs are mostly unknown. In a 9wk longitudinal study, female rats were given daily olanzapine (10mg/kg s.c.) or vehicle. Animals were either sedentary or allowed 1 or 3h daily access to a running wheel, with total wheel revolutions electronically quantified to reflect exercise intensity. Glucose tolerance tests were performed once weekly to measure glycemic control. Drug levels were measured at week 4. At week 9, abdominal fat and skeletal muscle levels of Glucose Transporter 4 (GLUT4) were measured. Exercise intensity progressively increased over time in all groups given access to running wheels; however, rats treated with olanzapine consistently exercised less than those given the vehicle. Olanzapine caused acute and persistent glucose intolerance throughout the study, which was markedly, though incompletely, ameliorated by exercise. Exercise did not affect glycemic regulation in vehicle-treated rats. Olanzapine-treated rats showed greater central adiposity. Levels of GLUT4 in skeletal muscle were higher in both groups of exercising than in sedentary rats, and GLUT4 values were negatively correlated with glucose intolerance. Routine exercise reduced olanzapine-induced glucose intolerance and increased skeletal muscle levels of GLUT 4, the insulin-responsive transporter that mediates glucose uptake into cells. The current animal model is suitable for evaluating physiological pathways involved with glucose intolerance.

Repeated asenapine treatment produces a sensitization effect in two preclinical tests of antipsychotic activity

Among several commonly used atypical antipsychotic drugs, olanzapine and risperidone cause a sensitization effect in the conditioned avoidance response (CAR) and phencyclidine (PCP)-induced hyperlocomotion paradigms – two well established animal tests of antipsychotic drugs, whereas clozapine causes a tolerance effect. Asenapine is a novel antipsychotic drug recently approved for the treatment of schizophrenia and manic disorders. It shares several receptor binding sites and behavioral features with other atypical antipsychotic drugs. However, it is not clear what type of repeated effect (sensitization or tolerance) asenapine would induce, and whether such an effect is transferrable to other atypicals. In this study, male adult Sprague-Dawley rats were first repeatedly tested with asenapine (0.05, 0.10 or 0.20 mg/kg, sc) for avoidance response or PCP (3.20 mg/kg, sc)-induced hyperlocomotion daily for 5 consecutive days. After 2–3 days of retraining/drug-free recovery, they were then challenged with asenapine (0.10 mg/kg, sc), followed by olanzapine (0.50 mg/kg, sc) and clozapine (2.50 mg/kg, sc). During the 5-day drug test period (the induction phase), repeated asenapine treatment progressively increased its inhibition of avoidance response and PCP-induced hyperlocomotion in a dose-dependent fashion. On the asenapine and olanzapine challenge tests (the expression phase), rats previously treated with asenapine still showed significantly lower avoidance response and lower PCP-induced hyperlocomotion than those previously treated with vehicle. An increased reactivity to clozapine challenge in prior asenapine-treated rats was also found in the PCP-induced hyperlocomotion test. These findings suggest that asenapine is capable of inducing a sensitization effect and a cross-sensitization to olanzapine and clozapine (to a lesser extent). Because the behavioral profile of asenapine in both tests is similar to that of olanzapine, but different from that of clozapine, we suggest that asenapine resembles olanzapine to a greater extent than clozapine in its therapeutic and side effect profiles.

ANTIPSYCHOTIC PRESCRIBING PATTERN IN A TERTIARY CARE HOSPITAL OF EASTERN INDIA

Background: Psychotropic drugs are commonly prescribed in psychiatric practice. , their utilization and consequences on real life effectiveness and safety in actual clinical practice need continuous study. Materials and Methods: A prospective cross sectional study was carried out for 3 months. All the patients using antipsychotic drugs, between 18-60 years of age, irrespective of sex, were included in the study. However, patients who were pregnant, lactating, unable to comply due to mental retardation, any systemic illness ,unconsciousness or drug addiction were excluded from the study. The prescribing pattern was analyzed by Using World Health Organization basic drug indicators. Results: Average number of drugs /prescription 1.07..atypical antipsychotics are prescribed more commonly than typical antipsychotic.among the atypical antipsychotics olanzapine is most commonly prescribed.monotherapy of antipsychotic is the commonly prescribed than trihexyphenidyl is the anticholinergic that prescribed regularly with typical antipsychotic for the prevension of extrapyramidal symptoms. Conclusion: Psychotic illness patients mainly advised monotherapy of antipsychotic drugs, mainly atypical antipsychotic drugs, and olanzapine is the most prescribed antipsychotic drugs. Trihexyphenidyl is the only antichoninergic drug co-prescribed with typical antipsychotic drugs to avoid extrapyramidal side effects. Keywords: Drug utilization study , psychotic illness, psychotropic drugs

Olanzapine increases hepatic glucose production through the activation of hypothalamic adenosine 5′‐monophosphate‐activated protein kinase

To investigate the mechanism of the metabolic disturbance induced by the atypical antipsychotic olanzapine, we examined whether adenosine 5'-monophosphate-activated protein kinase (AMPK) in the hypothalamus and hepatic glucose production are involved in the effect of olanzapine. Male 6-week-old ICR mice were used. Blood glucose levels were determined by the glucose oxidase method. The mRNA levels of gluconeogenic or glycolytic enzymes were measured by reverse transcription polymerase chain reaction (RT-PCR). AMPK expression was measured by Western blotting. Systemic injection of olanzapine increased blood glucose levels in both unfasted and fasted mice. However, the increase in fasted mice was less than that in unfasted mice. Central administration of olanzapine also increased the blood glucose levels in unfasted mice, but not in fasted mice. In a pyruvate tolerance test, olanzapine significantly increased blood glucose levels. In addition, olanzapine increased the mRNA levels of glucose-6-phosphatase (G6Pase), a gluconeogenic enzyme, in the liver. Furthermore, olanzapine increased phosphorylated AMPK in the hypothalamus of unfasted mice, and olanzapine-induced hyperglycaemia was inhibited by the AMPK inhibitor compound C. Central administration of the AMPK activator AICAR significantly increased G6Pase mRNA levels in the liver and blood glucose levels. Moreover, both olanzapine- and AICAR-induced hyperglycaemia were attenuated by the β-adrenergic receptor antagonist propranolol, suggesting that olanzapine and AICAR induce hepatic glucose production through the sympathetic nervous system. Our results indicate that olanzapine activates AMPK in the hypothalamus, which increases hepatic glucose production via the sympathetic nervous system.

Cost-effectiveness of lurasidone vs aripiprazole among patients with schizophrenia who have previously failed on an atypical antipsychotic: an indirect comparison of outcomes from clinical trial data

Objective:Compare long-term costs and outcomes of lurasidone to aripiprazole among adults with schizophrenia in the US who previously failed ≥1 atypical antipsychotic (olanzapine, risperidone, quetiapine, or ziprasidone) based on an indirect comparison of outcomes data from clinical trials.Methods:A 5-year Markov cohort model was developed to compare long-term effectiveness of lurasidone to aripiprazole, including total discontinuations, relapse rates, and hospitalization rates. Cost inputs included pharmacy, mental health, and medical costs associated with cardiometabolic risks (diabetes and cardiovascular [CV] events). Effectiveness inputs were derived from an indirect comparison of aripiprazole and lurasidone using common comparators from CATIE. Cardiometabolic risks were derived from claims data analysis for diabetes, weight change and CV events, and Framingham body mass index (BMI) risk equation. Cost inputs were derived from published sources and Red Book. Costs and outcomes were discounted at 3% and tested with sensitivity analyses.Results:Over 5 years, total discounted costs for lurasidone and aripiprazole patients were $86,480 and $90,500, respectively. During this period, the number of relapses per patient, hospitalizations per patient, diabetes rates, and CV events per 1000 patients, respectively, were estimated to be lower for lurasidone (0.442, 0.245, 7.29%, and 37.3) than aripiprazole (0.478, 0.369, 7.36%, and 37.8). Results were sensitive to lurasidone and aripiprazole hospitalization rates. At a willingness-to-pay threshold of $50,000 per hospitalization avoided, lurasidone had a 100% probability of being more cost-effective than aripiprazole.Limitations:The model was based on results from various comparative clinical trials. Differences in patient population and study methods may change estimates from the model. The model does not account for patient heterogeneity.Conclusions:Based on this model, when switching from another atypical antipsychotic, lurasidone had fewer relapses and hospitalizations with a lower incidence of diabetes and CV events than aripiprazole. Additionally, lurasidone may be less costly than aripiprazole among adults with schizophrenia.

Treatment Resistant Depression: Strategies for Primary Care

Depression is commonly diagnosed and treated in primary care. Recent evidence indicates that the majority of depressed patients will not fully recover with an initial antidepressant treatment. This paper reviews commonly used options for treatment after an inadequate initial antidepressant response. The alternatives range widely, and include escalating the dose of the initial antidepressant, switching to an alternative medication, combining two antidepressants with different mechanisms of action (e.g., bupropion + SSRI or mirtazapine + venlafaxine), adding other medications such as lithium or certain atypical antipsychotics (olanzapine, aripiprazole, or quetiapine) to the antidepressant, adding a natural product such as l-methylfolate or s-adenosylmethionine (SAMe), or adding cognitive behavioral psychotherapy. What agent to be used will depend on the comfort level of the primary care practitioner and the availability of Psychiatry referral. However, it is reasonable to take one or more additional steps to attempt to achieve remission.

Effects of olanzapine and paroxetine on phospholipase D activity in the rat brain

Phospholipase D (PLD) plays a key role in a second messenger system producing phosphatidic acid, mediating, among others, serotonin 5-HT2 receptor activity. The aim of the study was to evaluate a possible effect of atypical antipsychotic drug, olanzapine (OLZ), and selective serotonin reuptake inhibitor (SSRI) antidepressant, paroxetine (PX), on oleate-activated PLD activity in plasma membranes isolated from rat brain cortex. PLD activity was determined using a fluorometric assay. Ritanserin was used to determine the 5-HT receptor mode of action. A single dose of 10 mmol/kg OLZ produced no change in rat brain cortex PLD activity, 20 mmol/kg OLZ caused a nonsignificant decrease, and long-term (21 days) administration of OLZ resulted in a 41.9% decrease in PLD activity. Single doses of PX significantly decreased PLD activity: 10 mmol/kg - by 28.6%; 20 mmol/kg - by 31.5%, and long-term (21 days) administration of PX - by 39.5%. The study indicates that the 5-HT2 receptor-mediated inhibition of oleate-activated PLD may be a common part of the mechanisms of action of OLZ and PX.

Safety and effectiveness of drug therapy for the acutely agitated patient (Part I)

Acute agitation occurs in a variety of medical and psychiatric conditions, and the management of agitated, abusive, or violent patients is a common problem in the emergency department. Rapid control of potentially dangerous behaviors by physical restraint and pharmacologic tranquillization is crucial to ensure the safety of the patient and health-care personnel and to allow diagnostic procedures and treatment of the underlying condition. The purpose of this article (the first in a 2-part series) is to review the extensive safety data published on the antipsychotic medications currently available for managing situations of this type, including older neuroleptics like haloperidol, chlorpromazine, and pimozide as well as a number of the newer atypical antipsychotics (olanzapine, risperidone, ziprasidone). Particular attention is focused on the ability of these drugs to lengthen the QT interval in surface electrocardiograms. This adverse effect is of major concern, especially in light of the reported relation between QT interval and the risk of sudden death. In patients with the congenital long-QT syndrome, a long QT interval is associated with a fatal paroxysmal ventricular arrhythmia knownas torsades de pointes. Therefore, careful evaluation of the QT-prolonging properties and arrhythmogenic potential of antipsychotic drugs is urgently needed. Clinical assessment of drug-induced QT-interval prolongation is strictly dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. Unfortunately, measurement imprecision and natural variability preclude a simple use of the actually measured QT interval as a surrogate marker of drug-induced proarrhythmia. Because the QT interval changes with heart rate, a rate-corrected QT interval (QTc) is commonly used when evaluating a drug’s effect. In clinical settings, themost widely used formulas for rate-correction are those of Bazett (QTc=QT/RR^0.5) and Fridericia (QTc=QT/RR^0.33), both of which standardize themeasuredQTinterval to an RRinterval of 1 s (heart rate of 60 bpm).However, QT variability can also be influenced by other factors that are more difficult to measure, including body fat, meals, psycho-physical distress, and circadian and seasonal fluctuations.

Simultaneous, in vivo monitoring of 10 neurotransmitters in rat prelimbic cortex (PrL) reveals that systemic and local administration of the atypical antipsychotic olanzapine (olz) differentially altered only serotonin (5HT) levels

Prefrontal cortex function is disrupted in patients with schizophrenia (J Neurosci 32:3022, 2012). 5HT receptors are known to be of key importance in the mechanism of action of atypical antipsychotics (Curr Opin Pharmacol 11:59, 2011). This study is testing the hypothesis that systemic and direct PrL administration of olz alters neurotransmitter levels in the PrL. Adult, male Sprague‐Dawley rats were anesthetized with isoflurane and received olz by IV injection (n=4, 1 mg/kg) or directly into the PrL by reverse dialysis (n=4, 100 μM). Histological analysis confirmed that transmitter measures were obtained from the PrL. IV olz significantly (P<0.05) altered only levels of dopamine (+108%), 5HT (‐39%), and adenosine (‐25%). Mean plasma level of olz during dialysis sampling of the PrL was in the therapeutic range (194 ng/mL; JPET 305:625, 2003). Direct delivery of olz to the PrL significantly altered levels of dopamine (+146%), 5HT (+31%), adenosine (‐39%), glycine (‐38%), and aspartate (‐50%). Whereas both routes of olz delivery increased dopamine, IV olz decreased 5HT but direct PrL delivery of olz increased 5HT. This differential response of 5HT suggests that IV olz decreases 5HT in the PrL by activating 5HT1A autoreceptors on brainstem 5HT neurons. Support: NIH grants MH45361 (HAB), D007268 (OSM), EB003320 (RTK), Dept Anesthesiology

Association of the Common MC4R rs17782313 Polymorphism With Antipsychotic-Related Weight Gain

Weight gain is a frequent adverse effect of many second-generation antipsychotic (SGA) drugs. Although a number of candidate gene studies have focused on SGA-related weight gain, a clinical benefit for pharmacotherapy has not been achieved as yet. Genome-wide association studies offer great potential of identifying novel candidate genes and help to complete the search for relevant polygenetic risk factors. A polymorphism near the human melanocortin 4 receptor gene (MC4R) was associated with overweight and body mass index in recent studies. Owing to the central role of the MC4R receptor in energy homeostasis, we investigated the influence of the rs17782313 polymorphism on SGA-related weight gain. Three hundred forty-five white inpatients receiving different atypical antipsychotics (clozapine, olanzapine, risperidone, paliperidone, quetiapine, or amisulpride) were included in a naturalistic design. After 4 weeks of treatment, patients homozygous for the rs17782313 C-allele had a significantly higher risk of weight gain and body mass index increase, with a dose effect of the C-allele. In a subpopulation without additional weight gain-inducing comedication, the 106 TT-allele carriers gained on average 1.09% of their baseline weight within the 4 weeks of treatment, whereas the 57 CT-allele carriers and the 9 CC-allele carriers gained 3.28% and 5.47% (P = 0.003). Our findings indicate that the rs17782313 polymorphism could increase the amount of SGA-related weight gain and may influence MC4R expression, which could result in an imbalance of energy homeostasis. Nevertheless, further studies are needed to elucidate the role and mechanism of this polymorphism.