Medical therapies causing iatrogenic male infertility.

Primum non nocere. As physicians, our goal is to treat illnesses and alleviate suffering; however, in doing so, we can generate new problems in a game of medical whack-a-mole. For some patients, certain consequences or side effects are tolerable, while others may believe they have no alternative. For a male patient with infertility, a thorough history is imperative to elucidate whether the patient has been or is currently being exposed to medications that will harm libido, spermatogenesis, ejaculation, or the hypothalamic-pituitary-testosterone axis. This article will review the most common medications causing iatrogenic male infertility as well as options to minimize or even reverse their impact.

Effectiveness of Metformin for Weight Reduction in Children and Adolescents Treated with Mixed Dopamine and Serotonin Receptor Antagonists: A Naturalistic Cohort Study.

Objectives: Mixed dopamine and serotonin receptor antagonists (DSRAs) are associated with significant weight gain and its complications. Our aim was to evaluate the effectiveness of metformin in reducing body mass index (BMI) and metabolic parameters in children treated with DSRAs. Methods: We report a naturalistic study of 49 children and adolescents (mean age 14.9 ± 3.7 years), with BMI >85 percentile for age, treated with DSRAs during 2018-2020 in a child psychiatry clinic. Clinical data, anthropometric measurements, and laboratory tests were compared between those who were (study group, n = 31) and were not (control group, n = 18) treated with metformin. Results: The mean study duration was 9.7 ± 5.9 months. The BMI standard deviation scores (BMI-SDS) of the study group declined significantly (from 2.08 ± 0.40 to 1.81 ± 0.54, p < 0.001), while the BMI-SDS of the control group did not change (from 2.03 ± 0.45 to 2.04 ± 0.47, p = 0.838). In the study group, the decline in the delta BMI-SDS/month was more robust among those with good than poor adherence to metformin (-0.047 ± 0.039 vs. -0.004 ± 0.017, p = 0.003). The decrease in BMI-SDS was greater for patients treated with risperidone and clothiapine than with other DSRAs. Fasting insulin and insulin resistance index (homeostasis model assessment of insulin resistance [HOMA-IR]) declined in the study group (from 25.4 ± 13.8 to 19.9 ± 10.7, p = 0.033 and from 5.4 ± 2.7 to 4.2 ± 2.1, p = 0.028, respectively). Conclusions: Metformin treatment was associated with significant decreases in BMI, fasting insulin, and HOMA-IR. The effect of metformin seems to be dependent on adherence and type of DSRAs.

Potential drug-drug Interactions in hospitalized cancer patients: A report from the Middle-East.

INTRODUCTION: Patients suffering from solid tumors use a wide range of cytotoxic drugs. In this study, we aimed to detect, document, and descriptively analyze the potential drug-drug interactions in hospitalized solid tumor's patients in a Middle Eastern referral oncology-hematology University-affiliated hospital. MATERIALS AND METHODS: In this cross-sectional study, the medical record of solid tumor's patients who were admitted to the referral oncological center in Isfahan, Iran, during the six months period (2018) were considered. We included all patients who had received at least two chemotherapy or nonchemotherapy drugs simultaneously. The potential drug-drug interactions between chemotherapy and nonchemotherapy drugs were evaluated with Lexi-Interact ver.1.1 online software. RESULTS: During the study period, a total of 141 cancer patients were recruited, and their drug therapy regiment was thoroughly analyzed. We detected 227 drug-drug interactions with moderate or major severity out of included patients in which 96, 71, 32, and 28 interactions were in the category of C, D, B, and X, respectively. One hundred and fourteen patients (80.8%) encountered at least one potential drug-drug interactions during their hospitalization. Mechanistically, most of drug-drug interactions (56.4%) were pharmacodynamics. Interaction between granisetron and metoclopramide were the top 10 detected interaction (11.4%). The interaction between docetaxel and carboplatin was the most frequent drug-drug interactions between oncology drugs (2.6% of total drug-drug interactions). CONCLUSION: Potentially moderate or major drug-drug interactions frequently occur among solid tumor's cancer patients necessitate the establishment of a clinical pharmacy service for providing relevant pharmacotherapy consultations to prevent this potentially serious concern.

Serotonin receptor inhibitor is associated with falls independent of frailty in older adults.

OBJECTIVES: To evaluate whether fall risk in older adults is associated with the use of selective serotonin receptor inhibitor (SSRI) monotherapy among geriatric outpatients, and whether this association is moderated by the presence of depressive disorder and/or frailty. METHODS: Prospective cohort study with a 12-month follow-up and including 811 community-dwelling adults aged 60 or older from a university-based Geriatric Outpatient Unit. Major depressive disorder (MDD) was diagnosed according to DSM-5 criteria; subsyndromal depression as not meeting MDD criteria, but a Geriatric Depression Scale 15-item score ≥ 6 points. Frailty was evaluated with the FRAIL questionnaire. The association between SSRI use, depression, or both as well as the association between SSRI use, frailty, or both with falls were estimated through a generalized estimating equation (GEE) adjusted for relevant confounders. RESULTS: At baseline, 297 patients (36.6%) used a SSRI (82 without remitted depression) and 306 (37.7%) were classified as physically frail. Frailty was more prevalent among SSRI users (44.8% versus 33.7%, p =.004). After 12 months, 179 participants had at least one fall (22.1%). SSRI use, depression as well as frailty were all independently associated with falls during follow-up. Nonetheless, patients with concurrent of SSRI usage and non-remitted depression had no higher risk compared to either remitted SSRI users or depressed patients without SSRIs. In contrast, concurrence of SSRI use and frailty increases the risk of falling substantially above those by SSRI usage or frailty alone. CONCLUSION: SSRI usage was independently associated with falls. Especially in frail-depressed patients, treatment strategies for depression other than SSRIs should be considered.

MRGPRX2 is critical for clozapine induced pseudo-allergic reactions.

BACKGROUND: Clozapine is one of the most widely used second-generation antipsychotics in clinic. However, allergy-like symptoms such as rash and angioedema have been reported frequently, and the mechanism is still not clear. Mas-related G protein-coupled receptor X2 (MRGPRX2) expressed on mast cells is a crucial receptor for drug induced pseudo-allergic reactions. Therefore, we explored whether the symptoms induced by clozapine were associated with allergic reaction through MRGPRX2. METHODS: The effects of clozapine on pseudo-allergic reactions were evaluated by mast cells degranulation and calcium mobilization assay in vitro, and mice hindpaw swelling, serum histamine detection, avidin and H&E staining assay in vivo. The overexpressed MRGPRX2 cells membrane chromatography (MRGPRX2-HEK293/CMC), MRGPRX2-HEK293 cells calcium mobilization assay and molecular docking were applied to research the correlation between clozapine and MRGPRX2. RESULTS: The study showed that clozapine induced the release of ß-hexosaminidase, histamine and monocyte chemoattractant protein-1 (MCP-1), and trigged calcium mobilization in mast cells. In vivo, clozapine induced paw swelling, degranulation and vasodilation. Furthermore, clozapine could activate the calcium mobilization obviously in MRGPRX2-HEK293 cells, not in NC-HEK293 cells. Clozapine also had a good retention characteristic on MRGPRX2-HEK293/CMC column and the K D value is (2.33 ± 0.21)×10-01M. CONCLUSIONS: Our findings demonstrated that clozapine could induce pseudo-allergic reactions and MRGPRX2 might be the critical receptor for it.

Targeting the 5-HT system: Potential side effects.

Targeting the serotonin (5-HT) system is no simple task: there are at least 15 5-HT receptors, in addition to a number of transporters and metabolizing enzymes. Multiple 5-HT receptor variants exist due to genetic variations and/or post translational modifications, splice variants or editing variants. Some receptors may form homo and heteromers. The 5-HT system is targeted by multiple drugs to treat a variety of diseases. Given the homology amongst the 5-HT and neighbouring receptor classes, only few drugs are actually selective for a single target. In fact, many 5-HT drugs act on a combination of targets, i.e. several receptors and/or transporters or enzymes. For instance, a number of antidepressants or antipsychotics act on 5-HT and other transmitter systems. Recently developed drugs may show target selectivity by design, based on the current state of knowledge, whereas many older compounds hit multiple targets since they were developed using phenotypic screens, as was done well into the 1980's. Ergot analogues, antipsychotics or antidepressants, fall into this category. As our knowledge developed over the last 25-30 years, some targets have very well-defined liabilities: for instance, 5HT2B or 5-HT2A receptor agonists, will produce valvulopathies or hallucinations, respectively, whereas 5-HT3 receptor antagonists, may lead to constipation. This short review will be limited in scope as there are multiple targets and even more compounds to discuss. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Antipsychotics-associated obsessive-compulsive symptoms: individualized treatments and clinical benefits of memantine: a case report.

Antipsychotics with a prominent anti-serotoninergic profile have risks of obsessive-compulsive symptoms (OCS). These types of OCS are remain mostly intractable to existing treatments because of the dilemma between the antipsychotic effects and the OCS adverse effects, both of which brought by serotoninergic-blocking profile. This state forced us to seek non-serotonergic system pharmaceuticals. Memantine, as a glutamatergic drug, is the adjunctive agent most consistently showing an effective impact in primary OCD, however its benefit in antipsychotics-associated OCS has not been reported. Herein, we presented a case of a 34-year-old male schizophrenia patient who experienced antipsychotics-associated OCS which could not be relieved by routine managements. He had fallen into dilemma of either aggravated OCS or poorly controlled schizophrenia. Eventually his condition got significant relief by individualized utilization of antipsychotics to control psychosis and by memantine to deal with his OCS. This is the first case to report the benefit of memantine in SGAs-associated OCS. It suggests that memantine is a worth considering approach, especially when the OCS are resistant to routine managements. Moreover, this case would be helpful for clinicians to know the etiology of SGAs-associated OCS, as indicated by the interesting changes after every adjustment of antipsychotics in the whole therapeutic course.

A 5-year single-centre retrospective study of potential drug interactions in burns inpatients with psychiatric comorbidities.

INTRODUCTION: Burns patients with psychiatric comorbidities may be at increased risk of harm from drug interactions. We aimed to identify the most common classes of drug involved, the potential clinical effects and any clinical evidence for their occurrence. METHODS: The International Burn Injury Database was used to identify all admission episodes for patients with a psychiatric comorbidity over a 5-year period at an adult regional burns unit. For this group, all drugs administered were categorised as either a new or continuing medication. Following this, an established online tool was used to screen for potential interactions between drugs. Where one was identified, a retrospective notes review was used to investigate whether it had occurred clinically. RESULTS: Ninety-one admission episodes were identified and records were available for 60 of these. In total, 145 incidences of severe potential interactions were identified (89 between a new drug and a continuing drug and 56 between two new drugs). The most frequently involved continuing drugs with the potential for interaction were neurotransmitter reuptake-inhibiting antidepressants and mirtazapine, while the most common new drugs identified were ondansetron, fentanyl and tramadol. The most frequently identified potential consequence of interactions were serotonin syndrome, arrhythmias and hypokalaemia. Clinically, there was minimal evidence for any interaction. CONCLUSION: We have found many potential severe interactions in this patient group and psychotropic drugs were more commonly implicated than other drug classes. However, there was little evidence of the clinical manifestations of interaction. Serious drug interactions in burns patients are likely rare, but clinicians should be aware of the most likely drugs involved and the possible sequelae.

Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights Into Potential Mechanisms.

INTRODUCTION: Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A post hoc analysis of HSDD clinical trial data found that flibanserin treatment was associated with statistically significant weight loss relative to placebo, even though study patients were not selected for being overweight/obese and were provided no expectation for weight reduction or interventions intended to promote weight loss. AIM: To understand possible mechanisms by which flibanserin may produce weight loss. METHODS: A literature review was performed using Medline database for relevant publications on the mechanisms of action by which flibanserin may provide weight loss and the links between sexual function and weight management. MAIN OUTCOME MEASURES: Examination of (i) biopsychosocial factors regulating sexual desire, food intake, and weight regulation; (ii) clinical pharmacology of flibanserin; (iii) neurobiology of brain reward circuitry; and (iv) identification of possible mechanisms common to flibanserin and weight loss. RESULTS: Based on flibanserin clinical trial data, there was no consistent correlation between weight loss and improvement in sexual function, as assessed by HSDD outcome measures. Nausea, a common adverse event associated with flibanserin use, also did not appear to be a contributing factor to weight loss. Hypothetical links between flibanserin treatment and weight loss include modulation of peripheral 5-HT2A receptors and factors such as improved mood and improved sleep. CONCLUSION: Mechanisms of flibanserin-induced weight loss have not been well characterized but may involve indirect beneficial effects on peripheral 5-HT2A receptors and central regulation of mood and sleep. Future research may better elucidate the links between sexual function and weight management and the mechanism(s) by which flibanserin use may result in weight loss. Simon JA, Kingsberg SA, Goldstein I, et al. Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights into Potential Mechanisms. Sex Med Rev 2019;7:575-586.

Comparison of weight-adjusted dose versus fixed dose ondansetron in preventing shivering following spinal anaesthesia for caesarean deliveries.

BACKGROUND: Spinal anaesthesia is an effective regional anaesthesia technique, which is preferred in almost 86% of caesarean sections in the United States and United Kingdom. Eighty percent of caesarean sections done at the Aga Khan University hospital are under spinal anaesthesia. Shivering is a common complication of spinal anaesthesia, it occurs in 40%-64% of patients after neuraxial anaesthesia. Shivering may cause maternal and fetal hypoxemia, maternal discomfort and a problem to the anaesthesiologists when it comes to monitoring the patient during caesarean sections. Ondansetron a 5-HT3 receptor antagonist is effective in treatment and prevention of post-spinal anesthesia shivering. In published studies, use of a fixed dose in patients with different weights, masked the dose effect ondansetron in preventing shivering, such that not adjusting the dose according to the weight of patients' resulted in a higher occurrence of shivering. No study has compared different doses of ondansetron in preventing shivering in parturient women who have had spinal anaesthesia for caesarean section. OBJECTIVES: To determine if a weight-adjusted dose is better than a fixed dose of ondansetron in preventing shivering following spinal anesthesia for caesarean delivery. METHOD: This was a randomized, double-blinded controlled trial of 124 women scheduled for elective caesarean surgery. The women were randomized into two equal groups. The intervention group received intravenous ondansetron weight adjusted dosing at 0.1mg/kg and the control group received a fixed dose of 4mg before spinal anesthesia. The occurrence and severity of shivering and other outcomes, such as headache, pruritus were assessed and recorded during the surgery and post-operative period. RESULTS: A total of 124 patients were included in the study. Social demographic data and baseline vital signs did not differ significantly between the groups. Shivering was observed in 14 patients (22.6%) in the control group that received 4mg ondansetron and 7 patients (11.3%) in the intervention group that had 0.1mg/kg of ondansetron, but there was no statistical difference between the groups (p- value 0.090). The severity of shivering was greater in the control group compared to intervention group where patients who developed grade two shivering were 8.1% to 0% respectively. (P value 0.047). There was no difference in the occurrence of pruritus between the two groups. No patient required treatment for very severe shivering. CONCLUSION: This study, found that ondansetron weight adjusted dose at 0.1mg/kg, reduced the severity of shivering when compared to a fixed dose ondansetron at 4mg.

What is new in the battle against postoperative nausea and vomiting?

The issue of postoperative nausea and vomiting (PONV) still poses a significant burden on our patients. Although rarely associated with a life-threatening condition, it is consistently considered as one of the most undesirable side effects of surgery and anesthesia. There are well-established risk factors for the development of PONV that include patient-related factors, anesthetic technique, use of volatile anesthetics, use of nitrous oxide, duration of anesthesia, opioid administration, and type of surgery. Because pharmacologic interventions for PONV are not without risks, practitioners must assess patient's risk status from low to high and consider the benefits of treatment. This review summarizes the current state of knowledge related to PONV and provides a practical approach toward risk assessment, prevention, and numerous treatment strategies.

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

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

One-Year Prospective Study of Liver Function Tests in Children and Adolescents on Second-Generation Antipsychotics: Is There a Link with Metabolic Syndrome?

OBJECTIVE: To analyze liver function tests (LFT), weight, metabolic syndrome (MetS) and at risk of meeting MetS criteria (AR-MetS) in children and adolescents on antipsychotics (AP) during a year-long follow-up. METHODS: Two hundred sixteen patients, AP naïve or quasi-naïve (<30 days on AP), were included. Total bilirubin, the enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), weight and other parameters of MetS were measured at baseline, and at 3, 6 and 12 months, while patients remained on the same AP. RESULTS: At baseline, patients (mean age: 14.1 ± 3.1 years; 60.2% male) were on risperidone (N = 143), olanzapine (N = 37), or quetiapine (N = 36), although the sample decreased over time to 67 patients at 12 months (risperidone N = 46, olanzapine N = 10, and quetiapine N = 11). Around 3% of patients had ALT/AST levels that were at least twice the upper limit of normal (ULN) at 3 and 6 months; whereas roughly 19% of patients had ALP levels that were at least twice the ULN in at least one assessment after baseline, but had no clinical symptoms. From baseline to 6 months, significant increases were observed in ALT levels in the whole sample (p = 0.005), whereas ALP increased only in patients on risperidone. Patients showed significant weight gain, and more individuals met criteria for MetS and AR-MetS over time (from baseline: 2.8% and 8.3%, to 1 year: 10.5% and 23.9%, respectively). There was a trend-level group effect in global ALT across time (p = 0.076). Patients with MetS showed higher ALT concentrations (28.9 [18.4-39.4] U/L) than AR-MetS (20.4 [8.5-32.2] U/L), and no-AR-MetS (19.2 [8.4-29.9] U/L). CONCLUSIONS: Less than 3% of children and adolescents on AP during 1-year follow-up showed an increase in ALT or AST levels in one or more of the assessments, and none of these increases was of clinical significance. Patients with MetS and AR-MetS increased during this period, and the possible role of ALT levels to monitor these patients deserves further study.

A phase 2 study of fosaprepitant combined with high-dose dexamethasone for Japanese cancer patients receiving highly emetogenic chemotherapy.

PURPOSE: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug. METHODS: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course. RESULTS: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30-75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%-83%) in the overall phase and 91% (95% CI: 78%-97%) in the acute phase and 70% (95% CI: 55%-83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed. CONCLUSIONS: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

The role of 5 HT6-receptor antagonists in Alzheimer's disease: an update.

INTRODUCTION: Despite recent advances in Alzheimer's disease (AD) research, no breakthrough treatments have been discovered. Cholinesterase inhibitors and the NMDA-receptor antagonist memantine are currently the two approved symptomatic treatments for AD. 5-HT6 receptor antagonism has recently emerged as a promising treatment strategy to improve cognition in AD, with a modest side-effect profile. AREAS COVERED: 5-HT6 receptors, exclusively found in the central nervous system, modulate primarily GABA and glutamate levels, facilitating the secondary release of other neurotransmitters including dopamine, noradrenaline, and acetylcholine, all of which are compromised in AD. This review discusses findings of preclinical and phase I-III clinical trials conducted with three major 5-HT6 receptor antagonists: idalopirdine, intepirdine, and SUVN-502, in the field of AD. EXPERT OPINION: Despite early positive findings, larger phase-III trials have failed to demonstrate any statistically significant impact on cognition for both idalopirdine and intepirdine, as adjunct to cholinesterase inhibitors. Paradoxically, 5-HT6 receptor agonists have also been shown to have cognitive enhancing properties. Thus, a better understanding of the mechanism of action of the 5-HT6 receptor and its ligands is warranted. Investigating 5-HT6 receptor partial or inverse agonists may be promising in future AD trials.

Delayed Serotonin Syndrome in the Setting of a Mixed Fluoxetine and Serotonin Antagonist Overdose.

BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists. CASE REPORT A 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay. CONCLUSIONS In this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.

Classics in Chemical Neuroscience: Risperidone.

After the identification of the influence of serotonergic receptors in ameliorating the negative symptoms associated with schizophrenia, atypical antipsychotics were developed by incorporating dopamine and serotonin antagonism. Risperidone, sold under the trade name Risperdal, was the second atypical antipsychotic developed following clozapine but quickly became a first-line treatment for acute and chronic schizophrenia because of its preferential side effect profile. Despite initial Food and Drug Administration approval 25 years ago, risperidone continues to be a fundamental treatment for schizophrenia, bipolar I disorder, and autism-related irritability. It is on the World Health Organization's List of Essential Medicines for its balance of efficacy, safety, tolerability, and cost-effectiveness. In this review, we highlight the history and importance of risperidone as an atypical antipsychotic, in addition to its chemical synthesis, manufacturing, drug metabolism and pharmacokinetics, pharmacology, structure-activity relationship, indications, and adverse effects.

Genetic Polymorphisms Associated With Constipation and Anticholinergic Symptoms in Patients Receiving Clozapine.

BACKGROUND: Clozapine impairs gastrointestinal motility owing to its anticholinergic and antiserotonergic properties. This commonly leads to constipation and potentially to more severe complications such as bowel obstruction and ischemia. The aim of this study was to determine whether genetic variations in the genes encoding muscarinic and serotonergic receptors (CHRM2, CHRM3, HTR2, HTR3, HTR4, and HTR7) explain the variations in incidence of constipation and anticholinergic symptoms during clozapine treatment. Genes associated with opiate-induced constipation were also included in this analysis (TPH1, OPRM1, ABCB1, and COMT). PROCEDURES: Blood samples from 176 clozapine-treated, Finnish, white patients with schizophrenia were genotyped. Constipation and anticholinergic symptoms were rated using the Liverpool University Neuroleptic Side Effect Rating Scale self-report questionnaire. In total, 192 single-nucleotide polymorphisms (SNPs) were detected and grouped to formulate a weighted genetic-risk score (GRS). RESULTS: No significant associations between individual SNPs or GRSs and constipation or laxative use were observed. A GRS of 19 SNPs in CHRM2, CHRM3, HTR3C, HTR7, ABCB1, OPRM1, and TPH1 was associated with anticholinergic symptoms in a generalized linear univariate model, with body mass index, clozapine monotherapy, and GRS as explaining variables (permuted P = 0.014). Generalized linear univariate model analysis performed on the opiate-induced constipation-associated SNPs and a single CHRM3 SNP revealed an association between anticholinergic symptoms and a score of 8 SNPs (adjusted P = 0.038, permuted P = 0.002). CONCLUSIONS: Two GRSs are able to predict the risk of anticholinergic symptoms in patients receiving clozapine and possibly an increased risk of gastrointestinal hypomotility.