Side Effects Of Atypical Antipsychotics Research Articles

Magnetic resonance imaging detects white adipose tissue beiging in mice following PDE10A inhibitor treatment

Weight gain is a common harmful side effect of atypical antipsychotics used for schizophrenia treatment. Conversely, treatment with the novel phosphodiesterase-10A (PDE10A) inhibitor MK-8189 in clinical trials led to significant weight reduction, especially in patients with obesity. This study aimed to understand and describe the mechanism underlying this observation, which is essential to guide clinical decisions. We hypothesized that PDE10A inhibition causes beiging of white adipose tissue (WAT), leading to weight loss. Magnetic resonance imaging (MRI) methods were developed, validated, and applied in a diet-induced obesity mouse model treated with a PDE10A inhibitor THPP-6 or vehicle for measurement of fat content and vascularization of adipose tissue. Treated mice showed significantly lower fat fraction in white and brown adipose tissue, and increased perfusion and vascular density in WAT versus vehicle, confirming the hypothesis, and matching the effect of CL-316,243, a compound known to cause adipose tissue beiging. The in vivo findings were validated by qPCR revealing upregulation of Ucp1 and Pcg1-α genes, known markers of WAT beiging, and angiogenesis marker VegfA in the THPP-6 group. This work provides a detailed understanding of the mechanism of action of PDE10A inhibitor treatment on adipose tissue and body weight and will be valuable to guide both the use of MK-8189 in schizophrenia and the potential application of the target for weight loss indication.

Evaluation of the Effect of Barberry Root (Berberis Vulgaris) on the Prevention of Metabolic Syndrome Caused by Atypical Antipsychotic Drugs in Patients with Schizophrenia: A Three-Blind Placebo-Controlled Clinical Trial.

Objective: Metabolic syndrome is a potential side effect of atypical antipsychotics which are the current standard treatment for schizophrenia. Therefore, we aimed to examine the effect of barberry root (Berberis vulgaris) on the prevention of metabolic syndrome caused by atypical antipsychotic drugs in patients with schizophrenia. Method : Our research was a three-blind randomized clinical trial. The participants included all patients who were diagnosed with schizophrenia through the SCID-5 questionnaire and based on the DSM-5-TR criteria by two psychiatric experts. These patients were randomly divided into intervention and placebo groups. During a three-month treatment period, the intervention group received three 500 mg capsules of barberry root extract daily, whereas the placebo group received the same capsules containing 500 mg of starch powder. Metabolic syndrome variables including fasting blood glucose, serum lipids (triglyceride and cholesterol), blood pressure, weight and waist circumference were measured before and after the treatment as outcome measure. Chi-square and t-tests were used for data analysis using SPSS-22 software. Results: At the beginning of the study, there was no significant difference between the intervention group (n = 41) and the placebo group (n = 47) in terms of demographic factors, and pre-treatment assessments including weight, waist size, fasting blood HDL, fasting blood triglycerides and systolic and diastolic blood pressure and fasting blood glucose (P > 0.05). Within group analysis showed that some metabolic factors significantly increased in both groups after the treatment (P < 0.05). Indeed, in both groups, metabolic syndrome measures worsened after the three-month treatment period. The parameters of weight and waist size were significantly higher in the intervention group than the placebo group after treatment (P < 0.05). Conclusion: Barberry root extract was not able to control the Effects of antipsychotic drugs on metabolic syndrome in schizophrenia.

Co-prescription of aripiprazole on prolactin levels in long-term hospitalized chronic schizophrenic patients with co-morbid type 2 diabetes: A retrospective clinical study.

One of the most frequent side effects of atypical antipsychotics is hyperprolactinemia (HPRL), and metformin or aripiprazole co-prescription is regarded as an effective therapy option for reducing prolactin (PRL) levels. However, whether either of the two drugs can reduce PRL levels in patients with long-term hospitalized chronic schizophrenia with co-morbid type 2 diabetes (T2DM) has not been adequately reported. In our study, long-term hospitalized chronic schizophrenia patients with co-T2DM who were prescribed olanzapine or risperidone as the primary antipsychotic medication were enrolled. A total of 197 of these cases with co-prescribed aripiprazole were set up as the study group (co-Ari group), and the other 204 cases without co-prescribed aripiprazole were set up as the control group (non-Ari group). The two groups' variations in each target parameter were compared, and the variables affecting PRL levels were examined. Compared to the non-Ari group, fasting blood glucose (FBG), blood uric acid (UA), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels were significantly higher in the co-Ari group, but there was no difference in PRL levels. Co-prescribing aripiprazole had no impact on PRL levels in all patients with co-T2DM, and aripiprazole dose had no impact on PRL levels in the clinical subgroup of the co-Ari group. Aripiprazole not only worsened the severity of index disturbances associated to metabolism in long-term hospitalized chronic schizophrenia patients with co-T2DM on metformin-based hypoglycemic medications but also failed to lower PRL levels.

Seborrheic Dermatitis: A Case of an Atypical Side Effect of Atypical Antipsychotics.

Seborrheic Dermatitis: A Case of an Atypical Side Effect of Atypical Antipsychotics.

Hepatoprotective effect of trypsin/chymotrypsin against olanzapine-induced non-alcoholic steatohepatitis in rats.

Metabolic side effects of atypical antipsychotics are an important cause of deterioration of cognitive function and failure of drug adherence. The antifatty effect trypsin/chymotrypsin (T/C) and their mechanisms of action remain unclear. To investigate possible therapeutic effect of T/C in rat model of chronic olanzapine (OLZ) - induced hepatic steatosis. Twenty rats were divided into two groups: control (C), given distilled water, and O, given 1mg/kg of OLZ orally daily for 7 weeks. Then, both groups were given T/C 3 enzyme activity unit (EAU)/kg orally as an add-on treatment daily for the next 5 weeks and were named T/C or T/C+O groups. Rat performance in radial arm water maze was tested twice before and after T/C treatment. We measured liver enzymes, alpha-1 antitrypsin, albumin, total protein, direct and total bilirubin, inflammatory cytokines, and lipoprotein serum levels. Liver samples were collected for histopathology and Ki67 expression. The T/C add-on caused significant reduction in OLZ-induced elevation of alanine transaminase (ALT; P< 0.01), aspartate transaminase (AST; P< 0.001), alkaline phosphatase (ALP; P< 0.05), total cholesterol (Tc; P< 0.01), low-density lipoproteins (LDL-c; P< 0.05), steatosis score (P< 0.001), hepatocyte necrosis (P< 0.01), and significantly increased Ki67 expression (P< 0.01). The T/C add-on to OLZ provided protection against hepatic steatosis, elevated enzymes, and disturbed lipid profile and increased Ki67 without disturbing memory function.

Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects.

BackgroundStroke/thromboembolic events, infections, and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events.MethodsWhole transcriptome signatures were generated for SH‐SY5Y cells treated with amisulpride, risperidone, and volinanserin using RNA sequencing. Bioinformatic analysis was performed that scored the association between antipsychotic signatures and expression data from 415,252 samples in the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) repository.ResultsAtherosclerosis, venous thromboembolism, and influenza NCBI GEO‐derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (eg, brain derived neurotrophic factor [BDNF], platelet derived growth factor receptor [PDGFR]‐beta, tumor necrosis factor [TNF], transforming growth factor [TGF]‐beta, selenoamino acid metabolism, and influenza infection).ConclusionsThese findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.

Impact of the CYP2D6 phenotype on hyperprolactinemia development as an adverse event of treatment with atypical antipsychotic agents in pediatric patients.

Treatment with atypical antipsychotics is today the election therapy for different types of psychosis, but there is a high incidence of endocrine and metabolic disturbances. One of the major enzymes involved in the metabolism of antipsychotics is CYP2D6. Depending on the existing CYP2D6 alleles, the metabolic capacity of the enzyme may vary from very low to very high, so that patients can be grouped into four phenotypic groups: slow, intermediate, extensive (normal), and fast metabolizers. The aim of the study is to find a relationship between the individual intervariability of CYP2D6 and the incidence of hyperprolactinemia as side effect of atypical antipsychotics. A total of 81 patients with schizophrenia or bipolar disorders, median age 15.74 ± 4years, were enrolled in the study and prescribed the following atypical antipsychotics: risperidone, aripiprazole, and olanzapine. They were evaluated at 6, 12, and 18months after the initiation of treatment. Using the TaqMan Genotyping Assay, it has been identified the presence of the CYP2D6*4 allele in 28 patients, representing 34.56% of the total of 81 patients in the study, and CYP2D6*3 allele was identified in 15 patients and the presence of CYP2D6*41 to 11 patients. The allele CYP2D6*5 has not been present to the study patients. The study group has 44 patients which are extensive metabolizers (54%), 34 intermediate metabolizers (42%), and 3 poor (slow) metabolizers (4%). For the slow and intermediate metabolizers, atypical antipsychotics determined a significant increase of prolactinemia with high risk of adverse events.

Does Melatonin and Melatonin Agonists Improve the Metabolic Side Effects of Atypical Antipsychotics?: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Atypical antipsychotics (AAPs) are increasingly used for the treatment of psychotic disorders but are known to be associated with metabolic abnormalities. This study is a systematic review and meta-analysis of randomized controlled trials (RCTs) studying the effectiveness of melatonin for the amelioration of AAP-induced metabolic syndrome. The MEDLINE (accessed via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials, PsycINFO, LILACS, CINAHL, and OpenGrey databases were searched for RCTs without language restrictions. Inclusion criteria were randomized, double-blind clinical trials comparing melatonin or melatonin agonists with placebo for the amelioration of AAP-induced effects at any age with selected components of metabolic syndrome as outcome measures. Two reviewers independently selected articles and assessed quality using Cochrane risk of bias and concealment tools. Of 53 records, five RCTs were eligible for the systematic review and three for the meta-analysis. The meta-analyses showed no statistically significant difference in any anthropometric or metabolic variable considered. Analysis according to psychiatric diagnosis from one RCT showed significant decreases in diastolic blood pressure (5.5 vs. −5.7 mmHg for the placebo and melatonin groups, respectively; p=0.001), fat mass (2.7 vs. 0.2 kg, respectively; p=0.032), and triglycerides (D) (50.1 vs. −20 mg/dl, respectively; p=0.08) in the bipolar group but not the schizophrenia group. Although limited to five RCTs with small sample sizes, evidence from RCT indicates that melatonin improves AAP-induced metabolic syndrome. This beneficial effect seems more significant in patients with bipolar disorder than those with schizophrenia. Further RCTs are needed to definitively establish the potential ameliorative effect of melatonin and to justify its efficacy as an add-on therapy to curtail AAP-induced metabolic syndrome.

Metabolic side effects of atypical antipsychotics in older adults.

Design: A case-control study. Psychogeriatric service in Auckland, New Zealand. Elderly patients either receiving AAP treatment (cases) or not (controls) between 1 Jan 2008 and 1 Jan 2014. metabolic data of glucose, HbA1c, lipids, and cardiovascular events and death. The data were analyzed using t-tests and linear regression models for each metabolic outcome. There were 330 eligible cases and 301 controls from a total study population of 5,307. There was a statistically significant change in the HbA1c over time, within the cases group of -1.14 mmol/mol (p = 0.018, 95% CI -0.19 to -2.09). Also statistically significant was the reduction in total cholesterol of -0.13 mmol/L (p = 0.036, 95% CI -0.008 to -0.245). The only significant difference found between cases and controls was in the change in cholesterol ratio of 0.16 mmol/L between groups (95%CI 0.01-0.31, p = 0.036). AAP use was not associated with any clinically significant change in metabolic outcomes in this study population.

English

INTRODUCTION: Prevalence of sexual and reproductive function side effects of atypical antipsychotics is 18 to 96%contributingto non-compliance in 50% of treated patients.1 The abnormal ejaculation of semen is a typical and infrequent side effect of some α1-adrenoceptor antagonists. Iloperidone, a new dopamine type 2/serotonin type 2A antagonist provides better efficacy with less extra-pyramidal symptoms than D2 receptor antagonist antipsychotics. Iloperidone additionally has high affinity for alpha1 receptors and moderate affinity for alpha-2C receptors.2,3 Despite this knowledge, there is limited data regarding retrograde ejaculation caused due to use of Iloperidone. This article features three clinical cases of schizophrenia experiencing retrograde ejaculation after therapy with Iloperidone, treated successfully with Imipramine.

Randomized controlled trial comparing changes in serum prolactin and weight among female patients with first-episode schizophrenia over 12 months of treatment with risperidone or quetiapine.

BackgroundIncreased serum prolactin and weight gain are common side effects of atypical antipsychotics but few studies have assessed the long-term pattern of these adverse effects.AimCompare the effects of risperidone and quetiapine on serum prolactin and weight over 12 months of treatment among female patients with first-episode schizophrenia.MethodsEighty female inpatients with first-episode schizophrenia were randomly assigned to receive risperidone (n=40) or quetiapine (n=40) for 12 months. Prolactin concentration, weight and height were measured one day before starting treatment and 1, 3, 6, 9 and 12 months after initiating treatment. Severity of symptoms was assessed at the same time periods using the Positive and Negative Syndrome Scale (PANSS).ResultsThirty-one patients in the risperidone group and 33 patients in the quetiapine group completed the 12 months of treatment. PANSS scores decreased at each follow-up assessment for both groups; the improvement was significantly greater in the risperidone group after 3 months and 6 months of treatment but by the 9th month of treatment the level of improvement in the two groups was similar. In the quetiapine group serum prolactin remained stable throughout the 12 months but in the risperidone group the serum prolactin level increased 3.5- to 5.2-fold over the one-year follow-up. Weight gain was seen in both groups, particularly during the first 3 months of treatment: 62% of the increase in BMI in both groups had occurred by the end of the 3rd month of treatment. No between-group differences in weight changes were observed. The correlation between changes in weight and changes in prolactin levels were weakly positive: rs=0.17(p=0.104) in the risperidone group and r=0.07 (p=0.862) in the quetiapine group.ConclusionsRisperidone and quetiapine had similar efficacy in the first year of treatment of first-episode schizophrenia though risperidone was more rapidly effective. Use of risperidone was associated with chronic hyperprolactinemia but this did not occur with quetiapine. Long-term use of both drugs was associated with sustained weight gain; the timing and magnitude of the weight gain is similar for the two drugs. Weight gain was not strongly related to changes in prolactin levels.

Atypical Antipsychotic-Induced Metabolic Disturbances in the Elderly

The metabolic side effects of atypical antipsychotics (AAPs) have been widely studied in younger populations, but research investigating these sequelae in the elderly is lacking. This article reviews the available literature examining the use of AAPs in the elderly, evaluating their association with weight gain and changes in blood glucose and lipid parameters. We find a relative paucity of studies in this area; while some data highlight significant, collective changes in metabolic parameters, the majority suggests an apparent low vulnerability to these side effects. We conclude that the risk and clinical implications of unfavorable metabolic changes in the elderly being treated with AAP medications remain largely undetermined, and we caution against drawing firm conclusions based on the available data. The conflicting evidence leaves us recommending that metabolic monitoring be implemented, with regular follow-up as advocated in other populations.

Recent evidence and potential mechanisms underlying weight gain and insulin resistance due to atypical antipsychotics

Atypical antipsychotics (AAPs) promote obesity and insulin resistance. In this regard, the main objective of this study was to present potential mechanisms and evidence concerning side effects of atypical antipsychotics in humans and rodents. A systematic review of the literature was performed using the MEDLINE database. We checked the references of selected articles, review articles, and books on the subject. This review provides consistent results concerning the side effects of olanzapine (OL) and clozapine (CLZ), whereas we found conflicting results related to other AAPs. Most studies involving humans describe the effects on body weight, adiposity, lipid profile, and blood glucose levels. However, it seems difficult to identify an animal model replicating the wide range of changes observed in humans. Animal lineage, route of administration, dose, and duration of treatment should be carefully chosen for the replication of the findings in humans. Patients undergoing treatment with AAPs are at higher risk of developing adverse metabolic changes. This increased risk must be taken into account when making decisions about treatment. The influence of AAPs on multiple systems is certainly the cause of such effects. Specifically, muscarinic and histaminergic pathways seem to play important roles.

Monitoring metabolic side effects of atypical antipsychotics in people with an intellectual disability

This audit was undertaken prospectively to examine the compliance of a group of psychiatrists against guidelines they developed for monitoring the onset of metabolic syndrome, a potential side effect of antipsychotic medication, especially second generation or atypical ones. Phase 1 of the audit was to set standards by a questionnaire survey of participating psychiatrists against Consensus Guidelines on monitoring (American Diabetic Association, 2004), which they favoured. The results led to modifying these guidelines to develop minimum acceptable standards against which their practice was audited in Phase 2. Although in Phase 1, 77% of the psychiatrists felt that they did some baseline recording, Phase 2 finding did not corroborate this--only 53.8% of the notes recorded the assessment of risk factors in personal history; 37.5% risk factors in family history; 31.7% baseline weight and 26.4% baseline blood sugar/lipid levels. In Phase 1, 85% of the psychiatrists thought that they carried out some of the recommended monitoring; our audit found the records of weight monitoring in 69.7% of the notes and blood sugar and lipids monitoring in 44.2%. People with intellectual disability have a shorter life expectancy and increased risk of early death when compared with the general population. Obesity is already a health issue for people with intellectual disability. We discuss the challenges faced by psychiatrists in implementing their own minimum acceptable standards and suggest measures to reduce the metabolic risk associated with antipsychotic medication through increasing awareness--use of information leaflets in accessible format, health promotion and use of side effect checklists and improving access--by working collaboratively with general practitioners utilising the forum of annual health checks.

Weight gain and metabolic side effects with antipsychotic drugs in children

BackgroundWeight gain and metabolic side effects are some of the most troublesome side effects of atypical antipsychotics, especially when used in children and adolescents. There have been few studies on these side effects in children in Arab countries.ObjectivesTo determine weight gain and metaboli

A Novel Insulin Sensitizer Drug Candidate—BGP-15—Can Prevent Metabolic Side Effects of Atypical Antipsychotics

Atypical antipsychotic drugs (AAPD) are widely used to treat severe psychiatric disorders, have well documented metabolic side effects such as disturbances in glucose metabolism, insulin resistance and weight gain. It has been shown that BGP-15, a hydroxylamine derivative with insulin sensitizing activity can prevent AAPD provoked fat accumulation in adipocyte cultures, and insulin resistance in animal experiments and in healthy volunteers. The aim of this study was to compare the preventive effect of BGP-15 with conventional oral antidiabetics on metabolic side effects of AAPDs. We found that BGP-15 that does not belong to either conventional insulin sensitizers or oral antidiabetics, is able to counteract insulin resistance and weight gain provoked by antipsychotic agents in rats while rosiglitazone and metformin were not effective in the applied doses. Our results confirm that BGP-15 is a promising new drug candidate to control the metabolic side effects of atypical antipsychotics. Data indicate that this rat model is suitable to analyze the metabolic side effects of AAPDs and the protective mechanism of BGP-15.

The HSP co-inducer BGP-15 can prevent the metabolic side effects of the atypical antipsychotics

Weight gain and dysfunction of glucose and lipid metabolism are well-known side effects of atypical antipsychotic drugs (AAPD). Here, we address the question whether a heat-shock protein (HSP) co-inducer, insulin sensitizer drug candidate, BGP-15, can prevent AAPD-induced glucose, lipid, and weight changes. We also examined how an AAPD alters HSP expression and whether BGP-15 alters that expression. Four different experiments are reported on the AAPD BGP-15 interventions in a human trial of healthy men, a rodent animal model, and an in vitro adipocyte cell culture system. Olanzapine caused rapid insulin resistance in healthy volunteers and was associated with decreased level of HSP72 in peripheral mononuclear blood cells. Both changes were restored by the administration of BGP-15. In Wistar rats, weight gain and insulin resistance induced by clozapine were abolished by BGP-15. In 3T3L1 adipocytes, clozapine increased intracellular fat accumulation, and BGP-15 inhibited this process. Taken together, our results indicate that BGP-15 inhibits multiple metabolic side effects of atypical antipsychotics, and this effect is likely to be related to its HSP co-inducing ability.

Managing the Metabolic Side Effects of Atypical Antipsychotics

Managing the Metabolic Side Effects of Atypical Antipsychotics

Why Research On the Pharmacogenetics of Atypical Antipsychotic-Induced Weight Gain in Individuals With Intellectual Disabilities Is Warranted

Weight gain is an often-observed side effect of atypical antipsychotics (AAPs) and is particularly significant in individuals with intellectual disabilities (ID). The majority of individuals treated with AAPs will gain at least 10% of their initial body weight over the course of therapy (Umbricht & Kane, 1996). One's genetic constitution is an important factor that influences the variability of weight gain observed among patients taking AAPs. This article reviews the existing literature on psychopharmacogenetics of AAP-induced weight gain and the importance of this research for individuals with ID.

Two models for weight gain and hyperphagia as side effects of atypical antipsychotics in male rats: Validation with olanzapine and ziprasidone

Body weight gain is one of the most serious side effects associated with clinical use of antipsychotics. However, the mechanisms by which antipsychotics induce body weight gain are unknown, and no reliable animal models of antipsychotics-induced weight gain have been established. The present studies were designed to establish male rat models of weight gain induced by chronic and acute treatment with antipsychotics. Six-week chronic treatment with olanzapine (5, 7.5, and 10 mg/kg/day) in male Sprague-Dawley rats fed a daily diet resembling a human macronutrient diet, significantly increased body weight gain and weight of fatty tissues. In contrast, ziprasidone (1.25, 2.5, and 5 mg/kg/day) administration caused no observable adverse effects. We then investigated feeding behavior with acute antipsychotic treatment in male rats using an automated food measurement apparatus. Rats were allowed restricted access to normal laboratory chow (4 h/day). With acute olanzapine (0.5, 1, and 2 mg/kg, i.p.) treatment in the light phase, food intake volume and duration were significantly increased, while treatment with ziprasidone (0.3, 1, and 3 mg/kg, i.p.) did not increase food intake volume or meal time duration. Findings from the present studies showed that chronic treatment with olanzapine in male rats induced body weight gain, and acute injection induced hyperphagia, suggesting that hyperphagia may be involved in the weight gain and obesity-inducing properties of chronically administered olanzapine. These animal models may provide useful experimental platforms for analysis of the mechanism of hyperphagia and evaluating the potential risk of novel antipsychotics to induce weight gain in humans.