Opioid antagonism mitigates antipsychotic-associated weight gain: focus on olanzapine.

BACKGROUND: The endogenous opioid system affects metabolism, including weight regulation. Evidence from preclinical and clinical studies provides a rationale for targeting this system to mitigate weight-related side effects of antipsychotics. This review describes the role of the opioid system in regulating weight and metabolism, examines the effects of opioid receptor antagonism on those functions, and explores the use of opioid antagonists to mitigate antipsychotic-associated weight gain and/or metabolic effects. METHODS: A PubMed literature search was conducted to identify representative opioid antagonists and associated preclinical and clinical studies examining their potential for the regulation of weight and metabolism. RESULTS: The mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) types have overlapping but distinct patterns of central and peripheral expression, and each contributes to the regulation of body weight and metabolism. Three representative opioid antagonists (eg, naltrexone, samidorphan, and LY255582) were identified for illustration. These opioid antagonists differed in their receptor binding and pharmacokinetic profiles, including oral bioavailability, systemic clearance, and half-life, and were associated with varying effects on food intake, energy utilization, and metabolic dysregulation. CONCLUSIONS: Preclinical and clinical data suggest that antagonism of the endogenous opioid system is a mechanism to address antipsychotic-associated weight gain and metabolic dysregulation. However, evidence suggests that the differing roles of MOR, DOR, and KOR in metabolism, together with the differences in receptor binding, pharmacokinetic, and functional activity profiles of the opioid receptor antagonists discussed in this review, likely contribute to their differential pharmacodynamic effects and clinical outcomes observed regarding antipsychotic-associated weight gain.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 = 1.10 kg, [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. CONCLUSION: 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.

Previous exposure to antipsychotic drug treatment is an effective predictor of metabolic disturbances experienced with current antipsychotic drug treatments.

BACKGROUND: Antipsychotic drugs are associated with adverse events, but serious side effects are not frequent. This study aimed to ascertain whether previous exposure to antipsychotic treatment was associated with metabolic disturbances induced by current antipsychotic medication. METHODS: A total of 115 antipsychotic-naïve patients, 65 patients with previous exposure to low-metabolic-risk antipsychotics, and 88 patients with previous exposure to high-metabolic-risk antipsychotics were enrolled in our case-control study. All patients were administered olanzapine. Body weight, body mass index (BMI), biochemical indicators of blood glucose and lipids, the proportion of patients who gained more than 7% of their body weight at baseline, and the percentage of dyslipidemia were evaluated. All assessments were conducted at baseline and at 4 and 6 weeks after treatment. RESULTS: Olanzapine treatment resulted in a significant increase in body weight and BMI in antipsychotic-naïve patients compared with the other two groups (both p < 0.05). However, increases in lipid levels in the high-metabolic-risk antipsychotics group were significantly higher than that in the other two groups (both p < 0.05). A history of antipsychotics use was not associated with weight gain (all p > 0.05). Higher low-density lipoprotein cholesterol ≥3.37 mmol/L-1 was observed in antipsychotics exposure group compared with no history of antipsychotics exposure (aOR, 1.75; 95% CI, 1.07-3.52). Particularly, a history of high-metabolic-risk antipsychotics use was associated with a higher risk of LDL-C ≥3.37 mmol/L-1(aOR, 2.18; 95% CI, 1.03-3.32) compare with other two groups. CONCLUSIONS: A history of exposure to antipsychotics, particularly high-metabolic-risk antipsychotics, is associated with current antipsychotic-induced metabolic disturbances.

Patient, Treatment, and Health Care Utilization Variables Associated with Adherence to Metabolic Monitoring Practices in Children and Adolescents Taking Second-Generation Antipsychotics.

OBJECTIVE: Children and adolescents with a range of psychiatric disorders are increasingly being prescribed atypical or second-generation antipsychotics (SGAs). While SGAs are effective at treating conduct and behavioural symptoms, they infer significant cardiometabolic risk. This study aims to explore what patient, treatment, and health care utilization variables are associated with adherence to Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) metabolic monitoring guidelines. METHOD: A retrospective chart review of 294 children and adolescents accessing a large outpatient psychiatry setting within a 2-year study period (2014-2016) was conducted. Baseline and follow-up metabolic monitoring, demographic, treatment, and health care utilization variables were then assessed over a 1-year period of interest. RESULTS: Metabolic monitoring practices did not adhere to CAMESA guidelines and were very poor over the 1-year observation period. There were significant differences between children (ages 4-12 years, n = 99) and adolescents (ages 13-18 years, n = 195). In adolescents, factors associated with any baseline metabolic monitoring were a higher number of psychiatry visits (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.10 to 1.41), longer duration of contact (OR, 14; 95% CI, 2.31 to 82.4), and use of other non-SGA medications (OR, 3.2; 95% CI, 1.17 to 8.94). Among children, having an emergency room visit (OR, 3.4; 95% CI, 1.01 to 11.71) and taking aripiprazole (OR, 7.4; 95% CI, 2.02 to 27.45) increased the odds of receiving baseline metabolic monitoring. CONCLUSION: Findings from this study highlight the need for better metabolic monitoring for children and adolescents taking SGAs. Enhanced focus on opportunities for multidisciplinary collaboration is needed to improve the quality of care offered to this population.

A Randomized Controlled Trial of a Patient-Centered Approach to Improve Screening for the Metabolic Side Effects of Antipsychotic Medications.

Adherence to recommendations for monitoring of metabolic side effects of antipsychotic medications has been historically low. This randomized controlled trial tested whether a computerized, patient-centered intervention that educated Veterans with serious mental illness about these side effects and encouraged them to advocate for receipt of monitoring would increase rates of monitoring compared to enhanced treatment as usual. The mean proportion of days adherent to monitoring guidelines over the 1-year study was similarly high and did not differ between the intervention (range 0.81-0.98) and comparison (range 0.76-0.96) groups. Many individuals in both groups had persistent abnormal metabolic parameter values despite high rates of monitoring, contact with medical providers, and receipt of cardiometabolic medications. Participants exposed to the intervention were interested in receiving personalized information about their cardiometabolic status, demonstrating the preliminary feasibility of brief interventions for enhancing involvement of individuals with serious mental illness in health care decision making.

Effects of the Dietary Approaches to Stop Hypertension (DASH) Eating Plan on the Metabolic Side Effects of Corticosteroid Medications.

OBJECTIVE: We aimed to determine the effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the metabolic side effects of corticosteroid medication use. DESIGN: A randomized clinical trial was undertaken in 60 patients on corticosteroid therapy for 10 weeks. Patients were randomly assigned to a DASH or control diet. Carbohydrate, protein, and fat in both groups were 50-60%, 15-20%, 30%, respectively. DASH diet was a diet rich in fruits, vegetables, whole grains, low-fat dairy products, and low in total and saturated fat and cholesterol, refined grains, and also sweets. Fasting blood samples were collected to determine blood glucose and lipid profile. Blood pressure and anthropometric measurements were measured based on the standard guidelines. RESULTS: The mean age and body mass index (BMI) were 31.1 ± 3.6 year and 26.9 ± 2.6 kg/m(2), respectively. There were no significant differences between age and BMI in two groups at baseline. No significant difference was observed in body weight and waist circumference following the DASH diet compared to control diet. Systolic and diastolic blood pressures were significantly different following the DASH eating pattern (P = 0.04). Serum total cholesterol and fasting blood glucose significantly decreased in those following the DASH diet after adjustment for potential confounders. CONCLUSION: The DASH diet had beneficial effects on several metabolic side effects among patients using corticosteroid medications.

Medication-induced diabetes mellitus.

Epidemiological studies and case reports have demonstrated an increased rate of development of diabetes mellitus consequent to taking diverse types of medication. This review explores this evidence linking these medications and development of diabetes and presents postulated mechanisms by which the medications might cause diabetes. Some medications are associated with a reduction in insulin production, some with reduction in insulin sensitivity, and some appear to be associated with both reduction in insulin production and insulin sensitivity.

Metabolic Side Effects of Risperidone in Pediatric Patients with Neurological Disorders: A Prospective Cohort Study.

Background/Objectives: Risperidone-related metabolic side effects in children have been primarily linked to variations between guideline-recommended and clinical treatment procedures. We explored the metabolic effects of risperidone administration in pediatric patients diagnosed with neurological disorders, thus evaluating its influence on metabolic indicators. Methods: This prospective cohort study gathered data from electronic health records, medical databases, and clinical reports. These data included patient demographics (e.g., age, sex, and body mass index) and information on risperidone use, including dosage, dosing frequency, and treatment duration. Additionally, laboratory tests were conducted at baseline and during treatment, along with other pertinent clinical variables. Result: A total of 52 eligible children (male; 73.1%) with neurological disorders treated with risperidone were included. The mean age was 13.4 ± 2.2 years. Risperidone was administered to 32.7% of patients for <2 years, 40.4% for 2-5 years, and 26.9% for 6-9 years, with a mean duration of 3.6 years. Most (53.8%) of the children experienced at least one metabolic side effect, with hyperlipidemia being the most common (34.6%). The median prolactin level increased slightly from 448.5 ng/mL at baseline to 479 ng/mL after 6-8 weeks. No significant associations were found between age, sex, duration of treatment, dosage form, dosing frequency, and hemoglobin A1c levels. Conclusion: Monitoring metabolic and anthropometric parameters in children receiving risperidone for neurological disorders is cardinal. Clinicians should consider individualized treatment plans, closely monitor metabolic markers, and address potential risks associated with long-term risperidone use in this vulnerable population.

DNA methylation may partly explain psychotropic drug-induced metabolic side effects: results from a prospective 1-month observational study.

BACKGROUND: Metabolic side effects of psychotropic medications are a major drawback to patients' successful treatment. Using an epigenome-wide approach, we aimed to investigate DNA methylation changes occurring secondary to psychotropic treatment and evaluate associations between 1-month metabolic changes and both baseline and 1-month changes in DNA methylation levels. Seventy-nine patients starting a weight gain inducing psychotropic treatment were selected from the PsyMetab study cohort. Epigenome-wide DNA methylation was measured at baseline and after 1 month of treatment, using the Illumina Methylation EPIC BeadChip. RESULTS: A global methylation increase was noted after the first month of treatment, which was more pronounced (p < 2.2 × 10-16) in patients whose weight remained stable (< 2.5% weight increase). Epigenome-wide significant methylation changes (p < 9 × 10-8) were observed at 52 loci in the whole cohort. When restricting the analysis to patients who underwent important early weight gain (≥ 5% weight increase), one locus (cg12209987) showed a significant increase in methylation levels (p = 3.8 × 10-8), which was also associated with increased weight gain in the whole cohort (p = 0.004). Epigenome-wide association analyses failed to identify a significant link between metabolic changes and methylation data. Nevertheless, among the strongest associations, a potential causal effect of the baseline methylation level of cg11622362 on glycemia was revealed by a two-sample Mendelian randomization analysis (n = 3841 for instrument-exposure association; n = 314,916 for instrument-outcome association). CONCLUSION: These findings provide new insights into the mechanisms of psychotropic drug-induced weight gain, revealing important epigenetic alterations upon treatment, some of which may play a mediatory role.

Association of Antipsychotic Polypharmacy and Two-Year All-Cause Mortality: A Population-Based Cohort Study of 33,221 Italian Continuous Users.

Background: Differences in survival between patients treated with antipsychotic monotherapy vs. polytherapy are debated. This study aimed to examine the association of antipsychotic polytherapy with 2-year all-cause mortality in a population-based cohort. Methods: Data were retrieved from healthcare databases of four local health units of Lombardy, Italy. Subjects aged 18-79 years who received continuous antipsychotic prescriptions in 2018 were identified. Overall survival among patients with antipsychotic monotherapy vs. polytherapy was compared. A multivariate Cox PH model was used to estimate the association between antipsychotic therapy, or antipsychotic use (continuous vs. non-continuous), and all-cause mortality. Adjustments were made for the presence of metabolic disturbances, total antipsychotic dosage amount (olanzapine equivalent doses), age, and sex. Results: A total of 49,875 subjects receiving at least one prescription of antipsychotics during 2018 were identified. Among the 33,221 patients receiving continuative antipsychotic prescriptions, 1958 (5.9%) experienced death from any cause at two years. Patients with continuous antipsychotic use had a 1.13-point increased mortality risk compared with non-continuous users. Patients treated with antipsychotic polytherapy showed an adjusted mortality risk increased by 17% (95% CI: 2%, 33%) compared to monotherapy. Conclusions: The study highlights the potential risks associated with antipsychotic polypharmacy, emphasizing the importance of optimizing drug prescriptions to improve patient safety and reduce mortality rates in individuals receiving antipsychotic therapy.

Long-term metabolic side effects of second-generation antipsychotics in Chinese patients with schizophrenia: A within-subject approach with modelling of dosage effects.

BACKGROUND: Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia (SCZ), but SGAs may differ in the severity of side effects. Long-term studies are lacking, and previous observational studies have limitations, such as failure to account for confounding factors and short follow-up durations. AIMS: To compare the long-term anthropometric and metabolic side effects of seven SGAs in a Chinese population, using a within-subject approach to reduce the risk of confounding. METHOD: We collected longitudinal data of SGA prescriptions, concomitant medications, fasting blood glucose (BG), lipid profiles, and BMI in a cohort of 767 patients with SCZ, with follow-up lasting up to 18.7 years (median ∼6.2 years). A total of 192,152 prescription records were retrieved, with 27,723 metabolic measures analysed. Linear mixed models were used to estimate the effects of SGA on BG, lipid profiles and BMI. Besides studying the effects of SGA medications (as binary predictors), we also investigated the effects of SGA dosage on metabolic profiles. RESULTS: Considering SGA medications as binary predictors, clozapine and olanzapine were associated with the most substantial worsening of lipid profiles and BMI. A significant increase in BG was observed with clozapine only. Amisulpride, paliperidone and quetiapine were associated with worsened lipid profiles and increased BMI. Conversely, aripiprazole was associated with significant improvement in lipid profiles but a small increase in BMI. When SGA dosage was considered, the model showed consistent results overall. At the minimum effective dose, clozapine was associated with the most severe metabolic side effects, followed by olanzapine. Risperidone and aripiprazole showed the least metabolic side effects, with aripiprazole being significantly associated with lower lipids. CONCLUSIONS: This study clarified the long-term and dose-dependent effects of different SGAs on anthropometric and metabolic parameters in Chinese SCZ patients. Our findings may inform clinicians and SCZ patients of SGA choices.

Rare case report of moxifloxacin-induced persistent hiccups.

Moxifloxacin is a broad-spectrum antimicrobial agent that is commonly used in clinical practice. Here we report an unusual case of a patient with persistent hiccups caused by moxifloxacin. A man aged in his 40s was treated with moxifloxacin for tuberculous pleurisy. Hiccups occurred 2 hours after intravenous injection of moxifloxacin and lasted into evening. On the second day after injection, hiccups occurred again and made it difficult for him to fall asleep. The clinician ruled out gastrointestinal disease, nervous system disease, electrolyte disturbance and other factors. On assessing causality of the adverse drug reaction, the Naranjo scale for moxifloxacin was six, indicating a probable relationship of hiccups with moxifloxacin. Hiccups stopped 2 min after intramuscular injection of metoclopramide. To our knowledge, this is the first case report about moxifloxacin-induced persistent hiccups. Clinicians should be aware of the rare adverse reaction.

Weight change in a national cohort of U.S. Military Veterans engaged in medication treatment for opioid use disorder.

Medication treatments for opioid use disorder (MOUD) save lives and improve outcomes for countless individuals. However, data suggest the potential for significant weight gain during methadone treatment and little is known about weight change during buprenorphine treatment. Using Veteran Health Administration administrative data from fiscal year 2017 to fiscal year 2019, two cohorts were created: 1) Veterans diagnosed with opioid use disorder (OUD) taking methadone (N = 1425); and 2) Veterans diagnosed with OUD taking buprenorphine (N = 3756). Linear mixed models were used to analyze weight change during the first MOUD treatment episode in the observation period. Random slopes and intercepts were included in the model to estimate variation in BMI across individuals and time. The data revealed a slight upward trend in BMI over the course of treatment. Specifically, a daily increase of 0.004 for Veterans in methadone treatment and 0.002 for Veterans in buprenorphine treatment was observed. This translates to a gain of about 10 pounds over the course of 1 year of methadone treatment and 5 pounds for 1 year of buprenorphine treatment for a Veteran of average height and weight. The amount of weight gain in methadone treatment is significantly less than other published findings, but nonetheless indicates that assessment and discussions between patients and providers related to weight may be warranted.

Hypothalamic JNK1-hepatic fatty acid synthase axis mediates a metabolic rewiring that prevents hepatic steatosis in male mice treated with olanzapine via intraperitoneal: Additional effects of PTP1B inhibition.

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner.

Predicting antipsychotic-induced weight gain in first episode psychosis - A field-wide systematic review and meta-analysis of non-genetic prognostic factors.

BACKGROUND: Whether non-genetic prognostic factors significantly influence the variable prognosis of antipsychotic-induced weight gain (AIWG) has not yet been systematically explored. METHODS: Searches for both randomized and non-randomized studies were undertaken using four electronic databases, two trial registers, and via supplemental searching methods. Unadjusted and adjusted estimates were extracted. Meta-analyses were undertaken using a random-effects generic inverse model. Risk of bias and quality assessments were undertaken using Quality in Prognosis Studies (QUIPS) and Grading of Recommendations Assessment, Development and Evaluation (GRADE), respectively. RESULTS: Seventy-two prognostic factors were assessed across 27 studies involving 4426 participants. Only age, baseline body mass index (BMI), and sex were suitable for meta-analysis. Age (b=-0.044, 95%CI -0.157-0.069), sex (b=0.236, 95%CI -0.086-0.558), and baseline BMI (b=-0.013 95%CI -0.225-0.200) were associated with nonsignificant effects on AIWG prognosis. The highest quality GRADE rating was moderate in support of age, trend of early BMI increase, antipsychotic treatment response, unemployment, and antipsychotic plasma concentration. Trend of early BMI increase was identified as the most clinically significant prognostic factor influencing long-term AIWG prognosis. CONCLUSIONS: The strong prognostic information provided by BMI trend change within 12 weeks of antipsychotic initiation should be included within AIWG management guidance to highlight those at highest risk of worse long-term prognosis. Antipsychotic switching and resource-intensive lifestyle interventions should be targeted toward this cohort. Our results challenge previous research that several clinical variables significantly influence AIWG prognosis. We provide the first mapping and statistical synthesis of studies examining non-genetic prognostic factors of AIWG and highlight practice, policy, and research implications.

Metabolic side effects in persons with schizophrenia during mid- to long-term treatment with antipsychotics: a network meta-analysis of randomized controlled trials.

Metabolic side effects of antipsychotic drugs can have serious health consequences and may increase mortality. Although persons with schizophrenia often take these drugs for a long time, their mid- to long-term metabolic effects have been studied little so far. This study aimed to evaluate the mid- to long-term metabolic side effects of 31 antipsychotics in persons with schizophrenia by applying a random-effects Bayesian network meta-analysis. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (up to April 27, 2020) and PubMed (up to June 14, 2021). We included published and unpublished, open and blinded randomized controlled trials with a study duration >13 weeks which compared any antipsychotic in any form of administration with another antipsychotic or with placebo in participants diagnosed with schizophrenia. The primary outcome was weight gain measured in kilograms. Secondary outcomes included "number of participants with weight gain", fasting glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. We identified 137 eligible trials (with 35,007 participants) on 31 antipsychotics, with a median follow-up of 45 weeks. Chlorpromazine produced the most weight gain (mean difference to placebo: 5.13 kg, 95% credible interval, CrI: 1.98 to 8.30), followed by clozapine (4.21 kg, 95% CrI: 3.03 to 5.42), olanzapine (3.82 kg, 95% CrI: 3.15 to 4.50), and zotepine (3.87 kg, 95% CrI: 2.14 to 5.58). The findings did not substantially change in sensitivity and network meta-regression analyses, although enriched design, drug company sponsorship, and the use of observed case instead of intention-to-treat data modified the mean difference in weight gain to some extent. Antipsychotics with more weight gain were often also among the drugs with worse outcome in fasting glucose and lipid parameters. The confidence in the evidence ranged from low to moderate. In conclusion, antipsychotic drugs differ in their propensity to induce metabolic side effects in mid- to long-term treatment. Given that schizophrenia is often a chronic disorder, these findings should be given more consideration than short-term data in drug choice.

Adverse reactions to antimicrobials in pediatric patients admitted to a tertiary hospital: a cohort study.

BACKGROUND: Antimicrobials are widely used in hospitals and are often associated with adverse drug reactions (ADRs). The objective of this study was to determine the incidence of ADRs caused by antimicrobials and classify them according to the type of reaction, the class of antimicrobials used, causality, severity and avoidability. METHODS: A prospective cohort study was carried out with paediatric patients for 6 months. Causality was verified using the Naranjo and Liverpool algorithms, the severity was verified with the adapted scale of Hartwig and the avoidability was verified with the Liverpool Avoidability Assessment Tool. RESULTS: A total of 303 patients were followed, and 18.2% (55/303) of them had one or more ADRs during the hospital stay. Just over half of the patients (28/55) had diarrhea. The most used antimicrobials were beta-lactams and second-generation cephalosporins. Suspicions were classified mainly as possible 78.6% (55/70) according to the Naranjo algorithm, and as probable 48.6% (34/70) according to the Liverpool algorithm. The antimicrobial most involved with ADRs was cefepime. The risk of manifesting ADR was greater with the use of some antimicrobials such as clindamycin (relative risk (RR) 3.0, CI 1.67 to 5.4), as well as with the increase in hospitalisation days (OR 1.022, CI 1.008 to 1.036) and in the number of antimicrobials prescribed (OR 1.649, CI 1.360 to 2.001). CONCLUSION: ADRs were observed in approximately one-fifth of patients and were mostly gastrointestinal, moderate, unavoidable and with variable causality, depending on the algorithm used.

Metabolic Side Effects of Olanzapine in Patients With Psychotic Disorders in Oman: A Retrospective Cohort Study.

We evaluated the impact of olanzapine on metabolic changes in patients with psychotic disorders. This was a retrospective cohort study involving patients prescribed olanzapine and attending Sultan Qaboos University Hospital (Muscat, Oman). Patients were followed up retrospectively from March 2006 until April 2021. Cardiovascular treatment targets were evaluated as per the 2019 European Society of Cardiology guidelines. We enrolled 253 patients (mean age: 40±17 years). Olanzapine monotherapy was associated with increased body weight (+8 kg; 95% confidence interval (CI): 6-9; P < .001), body mass index (+3 kg/m2; 95% CI: 2-4; P < .001), total cholesterol (+.4 mmol/L; 95% CI: .3-.5; P < .001), low-density lipoprotein cholesterol (LDL-C) (+.3 mmol/L; 95% CI: .1-.4; P < .001), fasting triglycerides (+.2 mmol/L; 95% CI: .1-.3; P<.001), fasting glucose (+.6 mmol/L; 95% CI: .4-.7; P< .001), HbA1c (+.3%; 95% CI: .2-.4; P < .001), systolic blood pressure (BP) (+9 mmHg; 95% CI: 6-12; P < .001) and diastolic BP (+4 mmHg; 95% CI: 2-6; P < .001) levels. Cardiovascular therapeutic goals were attained in 38% (n = 97), 61% (n = 154), 71% (n = 180), and 59% (n = 150) for LDL-C, non-high-density lipoprotein cholesterol, triglycerides, and BP, respectively. Olanzapine was associated with adverse metabolic changes. Therefore, many patients were not at their target cardiovascular treatment goals.

Antipsychotic-Induced Weight Gain: Dose-Response Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Weight gain is among the most important side-effects of antipsychotics. It is, however, unclear whether it is associated with antipsychotic doses. We aimed to fill this gap with a dose-response meta-analysis. METHODS: We searched multiple electronic databases (last update search June 2021) for all fixed-dose studies that investigated 16 second-generation antipsychotics and haloperidol in adults with acute exacerbation of schizophrenia or with negative symptoms. We estimated the dose-response curves by conducting random-effects dose-response meta-analyses. We used the restricted cubic spline to model the dose-response relationship. The primary outcome was mean weight gain in kg from baseline to endpoint, the secondary outcome was the number of patients with clinically important weight gain. FINDINGS: Ninety-seven studies with 333 dose arms (36 326 participants) provided data for meta-analyses. Most studies were short-term with median duration of 6 weeks (range 4 to 26 weeks). In patients with acute exacerbation, amisulpride, aripiprazole, brexpiprazole, cariprazine, haloperidol, lumateperone, and lurasidone produced mild weight gain in comparison to placebo (mean difference at any dose≤1 kg), while more significant weight gain was observed by all other drugs. For most drugs, dose-response curves showed an initial dose-related increase in weight which plateaued at higher doses, while for others there was no plateau and some even had bell-shaped curves, meaning less weight gain to be associated with higher doses. INTERPRETATION: Second-generation antipsychotics do not only differ in their propensity to produce weight gain, but also in the shapes of their dose-response curves. This information is important for dosing decisions in clinical practice.

Interventions to Improve Metabolic Risk Screening Among Children and Adolescents on Antipsychotic Medication: A Systematic Review.

Objective: Antipsychotic use among youth is common and is associated with metabolic side effects such as weight gain. Guidelines recommend periodic screening of metabolic measures in youth prescribed antipsychotics; however, a guideline-to-practice gap exists. We systematically reviewed the literature to synthesize the knowledge from interventions that aim to improve antipsychotic metabolic screening. We described the interventions' effect on screening rates, the strategies used for improvement, and study quality. Methods: We conducted a systematic review of studies that attempted to improve antipsychotic metabolic risk screening practices among pediatric populations published between 2004 and August 2019. We included studies with an improvement intervention that compared screening rates before and after the intervention. We extracted data about study characteristics, screening rates in pre- and postintervention groups, strategies used to influence screening practices, and assessed studies' risk of bias. This review was prospectively registered with PROSPERO #CRD42018088241. Results: We identified six studies that demonstrated modest improvements in median metabolic screening rates for waist circumference (0%-16%), glucose (9%-39%), and lipids (11%-37%). Median postintervention screening rates were higher for weight and blood pressure (84% and 72.5%) compared with glucose and lipids (39% and 37%). Interventions used a variety of improvement strategies to address patient-, provider-, and organization-level barriers for screening, including increasing patient and provider knowledge regarding antipsychotic side effects, fostering social clinical environments that promote screening, and organizational commitment for screening antipsychotic-treated youth. All interventions were deemed at high risk of bias due to uncontrolled design and lack of adjustment for confounders. Conclusions: Included studies reported partial success in improving antipsychotic screening rates but were of poor methodological quality. Common improvement strategies may affect provider behavior to conduct metabolic screening, but these need to be tailored to local resources and organization structure. Future studies need to use rigorous methodology and theory-informed improvement strategies aligned with organizational actions to prioritize safe and judicious practice of antipsychotics among pediatric populations.