Antipsychotic Metabolic Effects Research Articles

Effect of polygenic risk for schizophrenia on cardiac structure and function: a UK Biobank observational study

Cardiovascular disease is a major cause of excess mortality in people with schizophrenia. Several factors are responsible, including lifestyle and metabolic effects of antipsychotics. However, variations in cardiac structure and function are seen in people with schizophrenia in the absence of cardiovascular disease risk factors and after accounting for lifestyle and medication. Therefore, we aimed to explore whether shared genetic causes contribute to these cardiac variations. For this observational study, we used data from the UK Biobank and included White British or Irish individuals without diagnosed schizophrenia with variable polygenic risk scores for the condition. To test the association between polygenic risk score for schizophrenia and cardiac phenotype, we used principal component analysis and regression. Robust regression was then used to explore the association between the polygenic risk score for schizophrenia and individual cardiac phenotypes. We repeated analyses with fibro-inflammatory pathway-specific polygenic risk scores for schizophrenia. Last, we investigated genome-wide sharing of common variants between schizophrenia and cardiac phenotypes using linkage disequilibrium score regression. The primary outcome was principal component regression. Of 33 353 individuals recruited, 32 279 participants had complete cardiac MRI data and were included in the analysis, of whom 16 625 (51·5%) were female and 15 654 (48·5%) were male. 1074 participants were excluded on the basis of incomplete cardiac MRI data (for all phenotypes). A model regressing polygenic risk scores for schizophrenia onto the first five cardiac principal components of the principal components analysis was significant (F=5·09; p=0·00012). Principal component 1 captured a pattern of increased cardiac volumes, increased absolute peak diastolic strain rates, and reduced ejection fractions; polygenic risk scores for schizophrenia and principal component 1 were negatively associated (β=-0·01 [SE 0·003]; p=0·017). Similar to the principal component analysis results, for individual cardiac phenotypes, we observed negative associations between polygenic risk scores for schizophrenia and indexed right ventricular end-systolic volume (β=-0·14 [0·04]; p=0·0013, pFDR=0·015), indexed right ventricular end-diastolic volume (β=-0·17 [0·08]); p=0·025; pFDR=0·082), and absolute longitudinal peak diastolic strain rates (β=-0·01 [0·003]; p=0·0024, pFDR=0·015), and a positive association between polygenic risk scores for schizophrenia and right ventricular ejection fraction (β=0·09 [0·03]; p=0·0041, pFDR=0·015). Models examining the transforming growth factor-β (TGF-β)-specific and acute inflammation-specific polygenic risk scores for schizophrenia found significant associations with the first five principal components (F=2·62, p=0·022; F=2·54, p=0·026). Using linkage disequilibrium score regression, we observed genetic overlap with schizophrenia for right ventricular end-systolic volume and right ventricular ejection fraction (p=0·0090, p=0·0077). High polygenic risk scores for schizophrenia are associated with decreased cardiac volumes, increased ejection fractions, and decreased absolute peak diastolic strain rates. TGF-β and inflammatory pathways might be implicated, and there is evidence of genetic overlap for some cardiac phenotypes. Reduced absolute peak diastolic strain rates indicate increased myocardial stiffness and diastolic dysfunction, which increases risk of cardiac disease. Thus, genetic risk for schizophrenia is associated with cardiac structural changes that can worsen cardiac outcomes. Further work is required to determine whether these associations are specific to schizophrenia or are also seen in other psychiatric conditions. National Institute for Health Research, Maudsley Charity, Wellcome Trust, Medical Research Council, Academy of Medical Sciences, Edmond J Safra Foundation, British Heart Foundation.

Behavioral sleep medicine-The need for harmonization of clinical best practice outcome measures in children and adolescents with intellectual or developmental disabilities and restless sleep.

In behavioral medicine, sleep disorders, insomnia in particular, may be considered comorbidities and precipitating factors to intellectual or developmental disabilities (IDD). Nevertheless, sleep alterations have often been neglected in favor of daytime features and symptoms, albeit simple behavioral nighttime observations may disclose hypermotor features that characterize restless sleep. The root of most hypermotor restlessness is linked to central iron deficiency. The latter is often exacerbated by vitamin D deficiency (VDD), which interferes with both dopaminergic and serotonergic mechanisms. In this way, an imbalance affecting daytime behavior and mood is created. Several sleep-related motor disorders such as bruxism, periodic and aperiodic leg movements, Restless Legs Syndrome (RLS), and Restless Sleep Disorder (RSD) are commonly seen in Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD). However, they are rarely diagnosed and often overlooked in affected children and adolescents. As a result, not only are these disorders not adequately addressed therapeutically, but their symptoms may be worsened by the side-effects of drugs used to contain disruptive daytime behavior, such as antipsychotics and antidepressants. In children with IDDs, obesity, inactivity and metabolic effects of antipsychotics often lead to Sleep Disordered Breathing (SDB), which is currently understood as an inflammatory state leading to “hyperactive” lethargy and further alterations of the hypoxic chain and vitamin D levels. Endorsing simple routine blood tests, including inflammatory markers such as C-reactive protein, ferritin, transferrin, and vitamin D levels, may favorably complement caregiver observations and ambulatory sleep recordings, leading to a sleep disorder diagnosis and consequent therapy. In fact, the treatment of SDB, RLS, and RSD has been copiously demonstrated to favorably impact vigilance, behavior, social competence, and academic skills in healthy and, to a greater extent, in IDD children. Thus, consulting and deliberating the root causes of functional and categorical diagnoses within a clinical framework may engender a more precise diagnosis and further benefit pediatric daytime and nighttime management of hyperactive behaviors.

The metabolic adverse effects of antipsychotic use in individuals with intellectual and/or developmental disability: A systematic review and meta-analysis.

Individuals with intellectual and/or developmental disability (IDD) are often prescribed antipsychotics (APs). However, despite their known propensity to cause metabolic adverse effects, including weight gain, diabetes, and increased risk of cardiovascular events, there is currently a limited body of literature describing the metabolic consequences of AP use in this population. We searched MEDLINE, EMBASE, PsychINFO, CENTRAL, and CINAHL databases to identify all randomized trials that reported on the metabolic effects of APs in individuals with IDD. Random effects meta-analyses were used to examine weight gain as both a continuous and dichotomous outcome. Eighteen randomized trials met our inclusion criteria with a total of 1376 patients across a variety of IDDs. AP use was associated with significantly greater weight gain compared with placebo (Continuous: mean difference= 1.10kg, [0.79, 1.40], p < 0.00001, I2 = 54%; Dichotomous: odds ratio=3.94, [2.15, 7.23], p < 0.00001, I2 = 0). Sub-group analysis revealed no significant effect of AP type. Data regarding the effects of APs on other metabolic outcomes were limited. This review (PROSPERO # CRD42021255558) demonstrates that AP use is associated with significant weight gain among patients with IDD. Concerningly, most reported studies were in children and adolescents, which sets up an already vulnerable population for adverse medical sequalae at an early age. There was also a lack of long-term studies in adults with IDD. Further studies are required to better understand how AP use affects metabolic parameters in this group of individuals.

Metformin reduces 12-month change in body weight among people newly commenced on clozapine: a retrospective naturalistic cohort study.

Background:People with schizophrenia have a 15–20-year reduction in life expectancy, driven in part by the metabolic effects of antipsychotics. Clozapine is associated with the highest rates of weight gain. As clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), identifying treatments to ameliorate clozapine-induced weight gain (CIWG) is urgently needed to reduce this morality gap.Methods:We retrospectively analysed digital health records of patients with TRS aged 18–65 newly initiated on clozapine at four tertiary hospitals in south-east Queensland from 1 March 2017 to 30 June 2019. Our primary outcome was the effect of metformin on change in percentage bodyweight at 12 months after clozapine initiation, with secondary outcome being proportion with >5% or >7% bodyweight change. We also explored impact on bodyweight change of other variables including sex, tobacco smoking, type 2 diabetes (T2DM), age, clozapine level and dose and clozapine/norclozapine ratio.Results:Among 90 patients initiated on clozapine, metformin use (n = 48) was associated with a smaller increase in percentage bodyweight (1.32% versus 5.95%, p = 0.031), lower rates of >7% gain in bodyweight (37.8% versus 63.0%, p = 0.025) but not >5% gain in bodyweight. Age below the median (32.0 years) was associated with greater bodyweight gain (5.55% versus 1.22%, p = 0.046). Sex, tobacco smoking, T2DM, clozapine dose and level and clozapine/norclozapine ratio were not associated with differences in change in bodyweight.Conclusion:In this small retrospective cohort study, use of metformin within 12-months of clozapine initiation was associated with a statistically and clinically significant reduction in CIWG. Although there is increasing evidence for the role of metformin to ameliorate bodyweight gain at time of clozapine initiation, our findings need replication and testing in a randomised controlled trial before recommending metformin co-commencement with clozapine as standard clinical practice.

Excessive use of antipsychotics as a global problem of clinical medicine

In recent decades in many regions of the world there has been an increase in prescribing antipsychotics, including for children and adolescents, and in many cases the drugs are used off label, in patients without diagnosis of schizophrenia and other psychoses and bipolar disorder or — in child and adolescent practice — without severe behavioral disorders. In addition, antipsychotics are often prescribed at excessive doses, and antipsychotic therapy is not accompanied by proper monitoring of physiological functions and laboratory parameters. The metabolic effects of antipsychotics contribute to weight gain, obesity and metabolic syndrome, increase the risk of type 2 diabetes, as well as cardiovascular diseases development. Children and adolescents, as well as young adults, are particularly vulnerable to the undesirable metabolic effects of antipsychotic drugs. The deterioration of physical health due to side effects of antipsychotics is one of the reasons for reducing life expectancy in patients with mental disorders.

Use of HepG2 cell line for evaluation of toxic and metabolic antipsychotic action

The toxic and metabolic effects of antipsychotics on cells of hepatic origin have been studied in vitro using human hepatoblastoma cell line HepG2. The cells were cultured in the presence of two first- and second-generation antipsychotics, haloperidol and olanzapine, respectively, at concentrations that can exist in the blood, liver and other tissues with high lipid content when the drugs are used for therapeutic purposes. During cultivation in several periods, the products of carbohydrate and lipid metabolism were quantified, the activities of several enzymes in the culture medium were measured, and viability (proliferation) of cells was assessed with MTS assay. Both drugs were toxic to HepG2 cells, which was manifested in inhibition of proliferation and an increased alkaline phosphatase activity in the culture medium. The toxic action of olanzapine in the doses used was less significant than that of haloperidol. According to literature data, antipsychotics increase the expression of lipogenesis genes in cells of the central nervous system, adipose tissue and liver, which can lead to hyperlipidemia. However, we have not observed increased levels of total cholesterol, cholesterol of low and high density lipoproteins, and triglycerides in the culture medium of HepG2 cells in the presence of haloperidol and olanzapine. This may be associated with the fact that both drugs, which are cationic amphiphiles, are able to inhibit intracellular lipid trafficking. Moreover, both drugs had no effect on the activity of aspartate aminotransferase and gamma-glutamyltransferase in the culture medium, but contributed to a decrease in the activity of alanine aminotransferase. Overall, our work has confirmed that HepG2 cells may serve as a useful model to obtain new data on drug effects on the metabolism of cells of hepatic origin and to assess the risk of hepatotoxicity in preclinical studies.

Effect of melatonin in reducing second-generation antipsychotic metabolic effects: A double blind controlled clinical trial

IntroductionThe use of second-generation atypical antipsychotics has an increasing role in the development of metabolic syndrome. However, these medications due to metabolic disorders can lead to an increased risk of cardiovascular disease and subsequently mortality as well as reduced adherence to treatment. The main objective of current study was to determine the ability of melatonin to reduce the metabolic effects of second-generation antipsychotics. MethodsThis double blind controlled clinical trial was conducted on 100 patients aged 18–64 years old were treated with the second-generation antipsychotics for the first time. The patients were divided randomly into two groups of 50. The case group received slow-release melatonin at a dose of 3mg and the control group was given oral placebo at 8 p.m. ResultsThe findings in melatonin group indicated significantly increase of HDL and decreased fasting blood sugar and systolic blood pressure, as well as had statistically significant increase in waist circumference, weight and BMI compared with placebo group. ConclusionAccording to the findings, it can be claimed that the addition of melatonin to atypical antipsychotics has led to a reduction in some of the metabolic effects of these drugs. In this study, HDL level was increased, and the mean systolic blood pressure and FBS were decreased in the melatonin group. Considering that these factors are contributing to cardiovascular disease as a leading cause of mortality in psychiatric patients, so the use of melatonin can reduce some of the medical effects of long-term treatment of atypical antipsychotics.

Reduced all-cause mortality with antipsychotics and antidepressants compared to increased all-cause mortality with benzodiazepines in patients with schizophrenia observed in naturalistic treatment settings

ABSTRACT FROM: Tiihonen J, Mittendorfer-Rutz E, Torniainen M et al. Mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines in patients with schizophrenia: an observational follow-up study. Am J Psychiatry...

Melatonin attenuates antipsychotic metabolic effects: an eight‐week randomized, double‐blind, parallel‐group, placebo‐controlled clinical trial

Second-generation antipsychotics (SGAs) are among the first-line treatments for bipolar disorder and schizophrenia, but have a tendency to generate metabolic disturbances. These features resemble a metabolic syndrome for which a central autonomic imbalance has been proposed that may originate from the hypothalamic suprachiasmatic nuclei. In a clinical trial, we hypothesized that melatonin, a hormone that regulates the suprachiasmatic nucleus, could attenuate SGA-induced adverse metabolic effects. In an eight-week, double-blind, randomized, placebo-controlled, parallel-group clinical trial, we evaluated the metabolic effect of melatonin in SGA-treated patients in terms of weight, blood pressure, lipid, glucose, body composition, and anthropometric measures. A total of 44 patients treated with SGAs, 20 with bipolar disorder and 24 with schizophrenia, randomly received placebo (n = 24) or melatonin 5 mg (n = 20). The melatonin group showed a decrease in diastolic blood pressure (5.1 versus 1.1 mmHg for placebo, p = 0.003) and attenuated weight gain (1.5 versus 2.2 kg for placebo, F = 4.512, p = 0.040) compared to the placebo group. The strong beneficial metabolic effects of melatonin in comparison to placebo on fat mass (0.2 versus 2.7 kg, respectively, p = 0.032) and diastolic blood pressure (5.7 versus 5.5 mmHg, respectively, p = 0.001) were observed in the bipolar disorder and not in the schizophrenia group. No adverse events were reported. Our results show that melatonin is effective in attenuating SGAs' adverse metabolic effects, particularly in bipolar disorder. The clinical findings allow us to propose that SGAs may disturb a centrally mediated metabolic balance that causes adverse metabolic effects and that nightly administration of melatonin helps to restore. Melatonin could become a safe and cost-effective therapeutic option to attenuate or prevent SGA metabolic effects.

Management of metabolic effects of antipsychotics during pregnancy

Management of metabolic effects of antipsychotics during pregnancy

Monitoring for Antipsychotic Metabolic Effects in an Inpatient Setting

I practice at San Antonio State Hospital, a 301-bed facility for the seriously mentally ill in South Central Texas. About one out of three to one out of four of our patients have metabolic syndrome. Almost half have at least one component of metabolic syndrome. While I am describing my own inpatient practice's monitoring, most, if not all, of these suggestions would directly translate into other practice settings where antipsychotic medications are used. I would encourage any CPNP members with comments about metabolic monitoring to send an email to the CPNP list for discussion.Metabolic effects of the antipsychotics include two sets of changes: those associated with Metabolic Syndrome (Table 1) and prolactin.The standard of practice for monitoring metabolic effects was published following a meeting of experts at Mount Sinai Hospital in New York in 2004 (Table 2). These recommendations are embodied in the Texas Department of State Health Services Mental Health Formulary Audit Criteria.I have modified these criteria for my own use based upon some additional information. The main change was to monitor fasting lipid panel annually instead of every five years. That recommendation was directly from the ATP III guideline cited in Table 1. However, I believe that having schizophrenia and treatment with an antipsychotic represents a risk-factor that should be considered and therefore in compliance with ATP III, I monitor lipids annually. Other changes are to obtain vital signs for monitoring waist circumference and blood pressure quarterly instead of annually. I believe that these vital sign changes in monitoring frequency are desirable for three reasons: (1) earlier detection of problems; (2) ease of distinguishing a problematic trend from random changes with more data; and (3) reminders to patients of the need to keep track of their diet. Finally, I use the same criteria for all antipsychotics, not just the second generation agents. The first generation agents are also responsible for adverse metabolic effects; however, this was poorly recognized due to the high frequency of movement disorders.A summary of the commonly reported adverse reactions (≥5% for any dose, and twice placebo rate) is shown in Table 3. The only metabolic effect in the entire table is weight gain. One clinical pearl I would like to share based on my clinical experience is that, I will not routinely continue an antipsychotic if the patient has gained five pounds (2.3 kg) in the first month of treatment. Patients that gain weight rapidly upon starting an antipsychotic frequently gain much more over time. However, if the patient experiences dramatic response, or there are other considerations unique to that individual, I will continue the offending antipsychotic and work to reduce the weight gain.Currently, I monitor the metabolic and other effects of medications by reviewing patients' laboratory studies and vital signs. To be honest, waist circumference is almost never documented. However, for our inpatients we obtain vital signs weekly as a routine, so that is much easier to track.This works fine for the 40 or so patients on my unit. However, we do not have sufficient staff to cover every unit. Therefore, I would like to have our electronic medical record (EMR) system generate reports that could, at a minimum, show which patients are due for laboratory studies. While the only labs needed for metabolic monitoring are fasting plasma glucose and lipid panel, I will get a more comprehensive set of laboratory studies as clinically indicated. As an aside, I will not obtain a prolactin without clinical indication. This will almost always result in a false-positive elevated prolactin concentration and requires a workup for a pituitary microadenoma. I have no concern about getting a baseline prolactin, if I ever saw a patient before they received their first antipsychotic dose, or when there are clinical symptoms that could be due to elevated prolactin.I would eventually like to develop a system that would obtain most objective data from the EMR and consider the date of the last datum needed and compare to the monitoring interval. If labs have been obtained recently for some other reason, they do not need to be repeated. Avoiding excessive blood draws for labs is a clinically important goal. I would like the report to be presented on-line and allow orders to be written and documentation to be generated with just a “click” per parameter. In addition, graphs of each parameter versus time should be available to identify trends that have not yet reached the limits of normal.Merely keeping track of metabolic effects is not sufficient, rather, changes need to be made to prevent worsening of the clinical situation, reverse problems where possible, and proactively work with the rest of the treatment team to limit adverse effects.

P.7.a.005 Antipsychotic metabolic effects in bipolar youth: comparison with other psychotic and non-psychotic diagnoses

P.7.a.005 Antipsychotic metabolic effects in bipolar youth: comparison with other psychotic and non-psychotic diagnoses

A Case of Pancreatitis Associated With Aripiprazole in the Absence of Hyperglycemia

Sir: Several atypical antipsychotic medications, including clozapine, olanzapine, and risperidone, have been associated with pancreatitis.1 Cases of pancreatitis have also been associated with the use of haloperidol. An analysis of reports of pancreatitis associated with atypical antipsychotics published in 2003 utilized data from the U.S. Food and Drug Administration's MedWatch Safety Information and Adverse Event Reporting Program (January 1981–February 2002) and MEDLINE (through February 2002). Aripiprazole2 was not available until November 15, 2002, and thus was not included in this analysis. While the case has not been conclusively proven, aripiprazole is thought to have fewer metabolic effects than other atypical antipsychotics, and one report has even discussed aripiprazole's ability to “reverse” the metabolic adverse effects of other antipsychotic agents.3 The metabolic effects seen with atypical antipsychotics include hyperglycemia, new onset or exacerbations of type 2 diabetes mellitus, and diabetic ketoacidosis.4 Although pancreatitis has been reported in conjunction with atypical antipsychotic–induced hyperglycemia,5 no cases of aripiprazole-induced pancreatitis have been reported, and prescribing information for aripriprazole2 does not carry a warning concerning pancreatitis. There is only 1 case report in the literature linking aripiprazole to hyperlipasemia complicating diabetic ketoacidosis, and no cases of isolated pancreatitis related to aripiprazole use have been reported. We describe a case of aripiprazole-associated pancreatitis without hyperglycemia. Case report. Ms. A, a 44-year-old white woman with bipolar disorder, presented to the primary care clinic with a 4-day history of epigastric pain, nausea, and early satiety. The patient had initiated use of aripiprazole 2 months prior in addition to oxcarbazepine, venlafaxine, and clonazepam. At presentation, the serum lipase level was 545 U/L (reference range: 23–300 U/L), the serum amylase level was 75 U/L (reference range: 30–110 U/L), the serum sodium level was 126 mmol/L (reference range: 137–145 mmol/L), the serum chloride level was 90 mmol/L (reference range: 98–107 mmol/L), the serum glucose level was 76 mg/dL (reference range: 65–105 mg/dL); and serum levels of CO2, urea nitrogen, creatinine, and potassium were measured, and the results were normal. The results of a complete blood count were normal except for a white blood cell count of 3.8 × 103 (reference range: 3.9–11.6 × 103); the results of liver function tests and calcium levels were within normal limits, except for the serum albumin level (4.7 g/dL [reference range: 3.5–4.6 g/dL]) and serum total bilirubin level (0.1 mg/dL [reference range: 0.2–1.3 mg/dL]). A serum triglyceride level drawn 11 months prior was 61 mg/dL (reference range: 30–149 mg/dL). The results of a test to detect helicobacter pylori antibody immunoglobulin G levels were negative. Ms. A had a remote history of alcohol abuse, in remission for 6 years, and no current substance use. She had no prior history of cholelithiasis, pancreatitis, or gastrointestinal disorders. The results of an abdominal ultrasound were negative for gallstones or common bile duct dilation. Ms. A was treated as an outpatient with fluid restriction, liquid diet, and analgesics. The results of an abdominal computed tomography scan were negative for pancreatic abnormalities and hepatic pathology. The results of an endoscopic ultrasound were negative for overt pancreatic or biliary abnormalities. Due to unstable psychiatric status, the aripiprazole was not discontinued until 8 weeks after initial presentation. Approximately 10 weeks after Ms. A's initial presentation, the serum lipase level was persistently elevated (1169 U/L), and she developed vomiting that required a 2-day hospitalization, during which a repeat abdominal ultrasound was performed and the results found to be normal. Tests for antinuclear antibodies and immunoglobulin G subclass 4 levels, were conducted, to rule out autoimmune pancreatitis and results were normal. Two months after the hospitalization, a repeat measure of serum lipase level was found to be 508 U/L. At that time the patient had been restarted on an antipsychotic medication, risperidone, due to unstable moods. Her abdominal symptoms persisted, with mild epigastric pain and nausea. One month later the risperidone was discontinued, and 4 weeks later a serum lipase level was found to be normal, and her symptoms resolved. Although Ms. A's serum amylase and lipase levels were less than 3 times the upper limit of normal, the clinical presentation was consistent with acute pancreatitis.6 A thorough evaluation for another etiology of the pancreatitis was completed, and gallstone, alcoholic, tumor, and autoimmune causes were excluded, suggesting that aripiprazole may have been a contributing factor. Ms. A's recovery was protracted because of continued use of the possibly offending medication and a subsequent switch to an alternative atypical antipsychotic (risperidone) associated with pancreatitis. Once all atypical antipsychotics were discontinued, her symptoms resolved, and serum lipase normalized. A previous case report associated aripiprazole with hyperlipasemia in the presence of severe hyperglycemia.5 Throughout Ms. A's illness, results from tests for serum glucose levels were normal, suggesting that the mechanism for pancreatitis is independent of the atypical antipsychotic metabolic effects on glucose levels. Further studies are needed to evaluate the association of aripiprazole and acute pancreatitis and to clarify the pathophysiologic cause. Bernadette Kiraly, M.D. Department of Family and Preventive Medicine, University of Utah School of Medicine, Salt Lake City, Utah Karen Gunning, Pharm.D. Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, Utah

Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: Prospective data from phase 1

BackgroundThe metabolic syndrome (MS) is associated with increased risk for diabetes mellitus and coronary heart disease, and is highly prevalent among schizophrenia patients. Given concerns over antipsychotic metabolic effects, this analysis explored MS status and outcomes in phase 1 of the CATIE Schizophrenia Trial. MethodsThe change in proportion of subjects with MS and individual criteria was compared between antipsychotic treatment groups, along with mean changes for individual criteria. Primary analyses examined subjects with fasting laboratory assessments at baseline and 3 months. Other analyses examined 3-month changes in MS status, waist circumference (WC), HDL cholesterol and blood pressure in all subjects, metabolic changes at the end of phase 1 participation (EOP), and repeated measures changes in HDL, blood pressure (BP) and WC over phase 1. ResultsAt 3 months, there were no significant between-drug differences for the change in proportion of subjects meeting MS status or individual MS criteria in the smaller fasting cohort (n = 281) or for those meeting criteria for parameters not dependent on fasting status (BP, HDL, WC) among all subjects (n=660). Among all subjects whose MS status could be determined at 3 months (n=660), MS prevalence increased for olanzapine (from 34.8% to 43.9%), but decreased for ziprasidone (from 37.7% to 29.9%) (p=.001). Although effect sizes varied across subgroups, at 3 months olanzapine and quetiapine had the largest mean increase in waist circumference (0.7 in. for both) followed by risperidone (0.4 in.), compared to no change for ziprasidone (0.0 in.) and a decrease in waist circumference for perphenazine (−0.4 in.). Olanzapine also demonstrated significantly different changes in fasting triglycerides at 3 months (+21.5 mg/dl) compared to ziprasidone (−32.1 mg/dl). EOP exposure data was obtained, on average, nine months from baseline for all metabolic variables. Results from EOP and repeated measures analyses were consistent with those at 3 months for mean changes in WC and fasting triglycerides, but between group differences emerged for HDL and SBP. ConclusionsThis large non-industry sponsored study confirms the differential metabolic effects between antipsychotics. Clinicians are advised to monitor all metabolic parameters, including WC, HDL and serum triglycerides, during antipsychotic treatment.

Latest news and product developments

AbstractGlitazones: benefits outweigh the risksFollowing a review of the safety of rosiglitazone and pioglitazone, the European Medicines Agency (EMEA) has concluded that their benefits outweigh their risks in the approved indications. The review was prompted by reports of an increased risk of fractures in women and, in patients taking rosiglitazone, ischaemic heart disease. The EMEA concluded that prescribing information for rosiglitazone should now include a warning that, in patients with ischaemic heart disease, it should only be used after careful evaluation of each patient's individual risk, and the combination of rosiglitazone and insulin should only be used in exceptional cases and under close supervision.No change was considered necessary to the prescribing information for pioglitazone. Modern dressings no better?A systematic review has found only weak evidence that modern dressings are better than saline gauze or paraffin gauze for healing acute and chronic wounds (Arch Dermatol 2007;143: 1297‐304).The analysis, which included 99 studies, found that only hydrocolloids were demonstrably better than older dressings for healing chronic wounds, and alginates were superior to other modern dressings for debriding necrotic wounds. There was no evidence that modern dressings offered superior overall performance to the older alternatives.Hospital inflation twice primary care levelThe cost of drugs prescribed in secondary care but dispensed in the community increased by 6.4 per cent in 2006 ‐ twice the rate of inflation in primary care ‐ according to the latest statistics on hospital prescribing in England. The increase follows a reduction in costs in 2005 after the introduction of the new PPRS scheme. Data from The Information Centre (www.ic.nhs.uk) show that hospital medicines make up about 24 per cent of the NHS drugs budget. Secondary care has a consistently better record than primary care in prescribing lower‐cost alternatives within therapeutic categories, eg simvastatin and pravastatin among the statins, omeprazole and lansoprazole among PPIs, and ACE inhibitors among drugs acting on the renin angiotensin system. The most expensive drug prescribed by hospital specialists and dispensed in the community is interferon beta.MHRA limits the use of fibratesThe Medicines and Healthcare products Regulatory Agency (MHRA) has advised that fibrates should now be reserved for the treatment of isolated severe hypertriglyceridaemia. They should be considered for hypercholesterolaemia only when a statin or other treatment is contraindicated or not tolerated.In the latest Drug Safety Update, the MHRA says there is insufficient evidence of long‐term benefits from fibrates, and first‐line use is no longer justified because the evidence for the benefits of statins is robust. The MHRA also warns that some breastfeeding infants have increased susceptibility to the adverse effects of codeine taken by their mother, and that St John's wort may affect the hepatic metabolism of any anticonvulsant. Annual zoledronic acid infusion cuts mortality after hip fractureOnce‐yearly infusion of zoledronic acid (Aclasta) after hip fracture reduces deaths over a two‐year period by 28 per cent compared with placebo, US investigators say (N Engl J Med 2007;357:1799‐809).The HORIZON Recurrent Fracture Trial randomised 2127 men and women (mean age 75) within 90 days of surgery for hip fracture to zoledronic acid 5mg yearly or placebo. Mortality over 1.9 years of follow‐up was 9.6 per cent with zoledronic acid and 13.3 per cent with placebo.Zoledronic acid also significantly reduced the rate of any new clinical fractures (by 35 per cent) and new clinical vertebral fractures(by 45 per cent),but the lower rate of hip fracture (2.0 vs 3.5 per cent with placebo) was not statistically significant.Rivastigmine patch for mild to moderate ADRivastigmine (Exelon) is now available as a transdermal patch for the treatment of mild to moderate Alzheimer's disease. Applied once daily, the patch delivers 9.5mg per 24 hours and, says manufacturer Novartis, is associated with a lower incidence of nausea and vomiting than a comparable oral dose. The patch is available in two strengths: 4.6mg per 24hr is equivalent to oral doses of 3 or 6mg per day, and the 9.5mg per 24hr patch is equivalent to 9 or 12mg per day orally. The recommended dose of the patch is 9.5mg per day; both strengths cost £83.84 for 30 patches. Women more aspirin resistant than men?The cardioprotective effect of low‐dose aspirin may be lower in women than men, say Canadian investigators (BMC Medicine 2007;5:29 doi: 10.1186/1741‐70155‐29).Their meta‐analysis of 23 randomised trials involving a total of 113 494 participants found that aspirin significantly reduced the risk of nonfatal but not fatal myocardial infarction (MI). About one‐quarter of the variation in its effects on nonfatal MI was accounted for by the sex mix of the trial population. Separating the results by sex showed the reduction in risk with aspirin use was statistically significant in men (relative risk, RR, 0.62) but not in women (RR 0.87).Look after physical health of mentally illGPs and other primary care workers should take more responsibility for the physical health of their mentally ill patients, say advocacy groups.Mind and Body: Preventing and Improving Physical Health Problems in Patients With Schizophrenia points out that the mental health needs of patients with schizophrenia are met in secondary care, but their physical health needs should be met in primary care. In particular, the metabolic effects of antipsychotics may lead to obesity, diabetes and cardiovascular disease, and weight gain in particular is a frequent reason for nonadherence to treatment.The Mind and Body Manifesto was developed by SANE, The Mental Health Nurses Association, The National Obesity Forum and The Disability Rights Commission and sponsored by Bristol‐Myers Squibb Pharmaceuticals Limited and Otsuka Pharmaceuticals (UK) Ltd. Copies are available from elizabeth.green@ ogilvyhealthworld.com.Health eCard costsSome costs quoted in our article on the Health eCard (The Health eCard: the way ahead for medical records?,5 October issue, pages 28‐9) have been revised: the card and initial download will cost patients £39.50, and GPs will be entitled to charge patients £10 per annum for subsequent downloads.NICE appraisals of cytokine inhibitors in RANICE has endorsed the use of the anti‐TNF agents adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), normally in conjunction with methotrexate, for the treatment of active RA when methotrexate and another DMARD have failed (also see New from NICE below).NICE has provisionally concluded, subject to consultation, that abatacept (Orencia) should not be recommended for the treatment of RA.Boots and BMJ launch health advice sitewww.askbootshealth.com is a new website providing information about health and medicines for the public produced by Boots using information provided by the BMJ Publishing Group. The website covers many of the topics already available from NHSDirect, with perhaps more information about available treatments.Diabetes care shows small improvementThe third National Diabetes Audit in England and Wales has found that more people with diabetes were achieving the targets set by NICE for cholesterol levels, glycaemic control and blood pressure in 2005/06 ‐ but younger patients were doing less well. Overall, the HbA1C target of ≤7.5 per cent was achieved in 60 per cent of people with diabetes compared with 58 per cent in 2004/05. However, HbA1C was &gt;9.5 per cent in 30 per cent of children and young people, of whom 9 per cent experienced at least one episode of ketoacidosis.More topics for NICENew topics referred to NICE include clinical guidelines on ovarian cancer, coeliac disease and stable angina, public health guidance on preventing cardiovascular disease, and technology appraisals on insulin detemir (Levemir) for type 1 diabetes, several treatments for cancer and hepatic and haematological disorders, and biological therapies for juvenile arthritis.New from NICENICE appraisal on anti‐TNFs for RASince NICE published its first appraisal of agents acting against tumour necrosis factor‐alpha (anti‐TNFs) for the treatment of RA in 2002, the product licences for etanercept (Enbrel) and infliximab (Remicade) have changed and a new agent, adalimumab (Humira), has been introduced.The anti‐TNFs act in different ways. Infliximab is a chimeric monoclonal antibody that binds to TNF‐alpha, neutralising its activity. Etanercept, a recombinant human TNF‐alpha receptor fusion protein, and adalimumab, a human‐sequence antibody, both bind to TNF‐alpha and block its interaction with cell surface receptors. Adalimumab also modulates some biological responses induced or regulated by TNF‐alpha.These agents are recommended for adults with severe active RA (defined as a disease activity score ‐ DAS28 ‐ greater than 5.1) who have already tried two disease‐modifying drugs, including methotrexate (if not contraindicated). Prior treatment should have been of at least six months' duration, including two months at the standard dose (unless limited by toxicity).Anti‐TNFs should normally be prescribed with methotrexate; when this is not appropriate, etanercept and adalimumab may be prescribed as monotherapy. Treatment with an anti‐TNF should be continued beyond six months only if there is an adequate response (defined as an improvement in DAS28 of at least 1.2). Data from the British Rheumatology Society Biologics register show that, after six months, 67 per cent of patients met NICE criteria for an adequate response; this declined to 55 per cent at 18 months.The basic annual cost of treatment is £9295 for adalimumab 40mg on alternate weeks or etanercept 25mg twice weekly; infliximab costs £3777 for a loading dose, then £7553‐£8812 depending on dose. Assuming no progression of disability, the incremental costs per QALY (compared with sequential DMARDs) were £30 200 for adalimumab, £24 600 for etanercept and £39 400 for infliximab. There are no direct comparative trials of the anti‐TNFs, and their clinical trial findings are not directly comparable. Unless other factors determine treatment choice, NICE therefore recommends the least expensive. If the first anti‐TNF is withdrawn within six months due to an adverse event, a second may be tried.

Guidelines for prevention and treatment of adverse effects of antipsychotic drugs on glucose-insulin homeostasis and lipid metabolism.

With the antipsychotic drugs available today, especially with some of the newer, atypical antipsychotics, metabolic side effects, such as weight gain, diabetes mellitus and lipid abnormalities, have become a complication to the drug therapy that have to be recognized and treated. The aim of this article is to suggest guidelines for prevention and treatment of adverse effects of antipsychotics on glucose-insulin homeostasis and lipid metabolism, whereas strategies for management of antipsychotic-induced weight gain are summarized elsewhere. The guidelines are based on results of experimental and clinical studies presented in the article, as well as on a recently published review of 180 articles in the field. Both conventional and atypical antipsychotics can indirectly, by causing obesity, promote development of insulin resistance and type-2 diabetes. In addition, some atypical agents probably directly induce hyperinsulinemia, followed by weight gain, insulin resistance and drug-induced, sometimes insulin-dependent, diabetes. In this article, guidelines for the management of adverse metabolic effects of antipsychotics are described.

P.2.049 Investigation of the metabolic effects of antipsychotics in patients with schizophrenia

P.2.049 Investigation of the metabolic effects of antipsychotics in patients with schizophrenia

Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities.

To review published and nonpublished literature describing changes in weight, glucose homeostasis, and lipid milieu with antipsychotics. A Medline search was completed using the words weight gain, diabetes mellitus, cholesterol, triglycerides, risperidone, clozapine, olanzapine, quetiapine, ziprasidone, predictors, prolactin, obesity, and conventional antipsychotics. Publications, including original articles, review articles, letters to the editor, abstracts or posters presented at professional meetings in the last 4 years, and references from published articles, were collected. Manufacturers, including Eli Lilly Canada Inc, JanssenOrtho Inc, Pfizer Canada Inc, AstraZeneca Inc, and Novartis Pharmaceuticals, were contacted to retrieve additional medical information. The topic of antipsychotic-induced weight gain is understudied, and there are relatively few well-controlled studies. Weight gain as a side effect has been described with both conventional and atypical antipsychotics. Moreover, some atypical antipsychotics are associated with de novo diabetes mellitus and increased serum triglyceride levels. Predictors of weight gain may be age, baseline body mass index, appetite stimulation, previous antipsychotic exposure, and antipsychotic treatment duration. Significant weight gain is reported with the existing atypical antipsychotics. The weight gain described is highly distressing to patients, may reduce treatment adherence, and may increase the relative risk for diabetes mellitus and hypertriglyceridemia. Physicians employing these agents should routinely monitor weight, fasting blood glucose, and lipid profiles.