Effect of lipid emulsion on neuropsychiatric drug-induced toxicity: A narrative review.

Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was to examine the effect of lipid emulsions on neuropsychiatric drug-induced toxicity using relevant case reports of human patients, with a particular focus on the Glasgow Coma Scale (GCS) score and corrected QT interval, to analyze drugs that frequently require lipid emulsion treatment. The following keywords were used to retrieve relevant case reports from PubMed: "antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone" and "lipid emulsion or Intralipid." Lipid emulsion treatment reversed the corrected QT interval prolongation and decreases in Glasgow Coma Scale scores caused by toxic doses of neuropsychiatric drugs, especially lipid-soluble drugs such as amitriptyline, trazodone, quetiapine, lamotrigine, and citalopram. The log P (octanol/water partition coefficient) of the group which required more than 3 lipid emulsion treatments was higher than that that of the group which required less than 3 lipid emulsion treatments. The main rationale to administer lipid emulsion as an adjuvant was as follows: hemodynamic depression intractable to supportive treatment (88.3%) > lipophilic drugs (8.3%) > suspected overdose or no spontaneous breathing (1.6%). Adjuvant lipid emulsion treatment contributed to the recovery of 98.30% of patients with neuropsychiatric drug-induced toxicity. However, further analyses using many case reports are needed to clarify the effects of lipid emulsion resuscitation.

Serum S100B protein and white matter changes in schizophrenia before and after medication.

Schizophrenia patients have abnormalities in white matter (WM) integrity in brain regions. S100B has been shown to be a marker protein for glial cells. The atypical antipsychotics have neuroprotective effects on the brain. It is not clear whether antipsychotics can induce S100B changes and improve symptoms by protecting oligodendrocytes. To investigate WM and S100B changes and associations and determine the effect of quetiapine on WM and S100B in schizophrenia patients, we determined serum S100B levels with solid phase immunochromatography and fractional anisotropy（FA）values of 36 patients and 40 healthy controls. Patients exhibited significantly higher serum concentrations of S100B and decreased FA values in left postcentral，right superior frontal，right thalamus, and left inferior occipital gyrus, while higher in right temporal cortex WM compared with healthy controls. Following treatment with quetiapine, patients had decreased S100B and higher FA values in right cerebellum，right superior frontal，right thalamus, and left parietal cortex，and decreased FA values in right temporal cortex WM compared with pre-treatment values. Furthermore, S100B were negatively correlated with PANSS positive scores and positively correlated with FA values in the left postcentral cortex. In addition，the percentage change in FA values in the right temporal cortex was positively correlated with the percentage change in the S100B, percentage reduction in PANSS scores, and percentage reduction in PANSS-positive scores. Our findings demonstrated abnormalities in S100B and WM microstructure in patients with schizophrenia. These abnormalities may be partly reversed by quetiapine treatment.

Molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania based on network pharmacology and molecular docking: Evidence from computational biology.

BACKGROUND: Quetiapine monotherapy is recommended as the first-line option for acute mania and acute bipolar depression. However, the mechanism of action of quetiapine is unclear. Network pharmacology and molecular docking were employed to determine the molecular mechanisms of quetiapine bidirectional regulation of bipolar depression and mania. METHODS: Putative target genes for quetiapine were collected from the GeneCard, SwissTargetPrediction, and DrugBank databases. Targets for bipolar depression and bipolar mania were identified from the DisGeNET and GeneCards databases. A protein-protein interaction (PPI) network was generated using the String database and imported into Cytoscape. DAVID and the Bioinformatics platform were employed to perform the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the top 15 core targets. The drug-pathway-target-disease network was constructed using Cytoscape. Finally, molecular docking was performed to evaluate the interactions between quetiapine and potential targets. RESULTS: Targets for quetiapine actions against bipolar depression (126 targets) and bipolar mania (81 targets) were identified. Based on PPI and KEGG pathway analyses, quetiapine may affect bipolar depression by targeting the MAPK and PI3K/AKT insulin signaling pathways via BDNF, INS, EGFR, IGF1, and NGF, and it may affect bipolar mania by targeting the neuroactive ligand-receptor interaction signaling pathway via HTR1A, HTR1B, HTR2A, DRD2, and GRIN2B. Molecular docking revealed good binding affinity between quetiapine and potential targets. LIMITATIONS: Pharmacological experiments should be conducted to verify and further explore these results. CONCLUSIONS: Our findings suggest that quetiapine affects bipolar depression and bipolar mania through distinct biological core targets, and thus through different mechanisms. Furthermore, our results provide a theoretical basis for the clinical use of quetiapine and possible directions for new drug development.

Efficacy and tolerability of FDA-approved atypical antipsychotics for the treatment of bipolar depression: a systematic review and network meta-analysis.

We employed a Bayesian network meta-analysis for comparison of the efficacy and tolerability of US Food and Drug Administration (FDA)-approved atypical antipsychotics (AAPs) for the treatment of bipolar patients with depressive episodes. Sixteen randomized controlled trials with 7234 patients treated by one of the five AAPs (cariprazine, lumateperone, lurasidone, olanzapine, and quetiapine) were included. For the response rate (defined as an improvement of ≥50% from baseline on the Montgomery-Åsberg Depression Rating Scale [MADRS]), all AAPs were more efficacious than placebo. For the remission rate (defined as the endpoint of MADRS ≤12 or ≤ 10), cariprazine, lurasidone, olanzapine, and quetiapine had higher remission rates than placebo. In terms of tolerability, olanzapine was unexpectedly associated with lower odds of all-cause discontinuation in comparison with placebo, whereas quetiapine was associated with higher odds of discontinuation due to adverse events than placebo. Compared with placebo, lumateperone, olanzapine, and quetiapine showed higher odds of somnolence. Lumateperone had a lower rate of ≥ weight gain of 7% than placebo and other treatments. Olanzapine was associated with a significant increase from baseline in total cholesterol and triglycerides than placebo. These findings inform individualized prescriptions of AAPs for treating bipolar depression in clinical practice.

The role of QRS complex prolongation in predicting severe toxicity in single-xenobiotic overdose.

OBJECTIVE: The QRS complex duration is commonly used to prognosticate severity, predict outcomes, and indicate treatment in overdose. However, literature to support this practice is mixed in tricyclic antidepressant overdoses and absent in non-tricyclic antidepressant overdoses. Our objective was to assess the validity of QRS complex duration as a prognostic marker in overdose. METHODS: This was a secondary analysis of cases reported to the Toxicology Investigators Consortium between January 1, 2010, and December 31, 2022. Cases were assessed to determine the six xenobiotics most associated with QRS complex prolongation. All cases involving these six xenobiotics, regardless of QRS complex duration, constituted the study cohort. Inclusion criteria were cases of patients older than 12 years old with single-xenobiotic exposures. Clinical outcomes evaluated were seizure, ventricular dysrhythmia, metabolic acidosis, and death. RESULTS: Of 94,939 total cases, diphenhydramine, amitriptyline, bupropion, quetiapine, nortriptyline, and cocaine were most associated with QRS complex prolongation. Inclusion criteria were met by 4,655 cases of exposure to these xenobiotics. QRS complex prolongation was associated with increased odds ratio of seizure in all included xenobiotics, of ventricular dysrhythmia in all included xenobiotics except nortriptyline, and of metabolic acidosis or death in all included xenobiotics except nortriptyline and quetiapine. A normal QRS complex duration had a negative predictive value of greater than or equal to 93.0 percent of developing metabolic acidosis and 98.0 percent of developing a ventricular dysrhythmia or death from the xenobiotics studied. DISCUSSION: This study demonstrates that patients with QRS complex prolongation from all six xenobiotics studied had an increased prevalence and odds of developing severe outcomes. Furthermore, patients who did not develop QRS complex prolongation were unlikely to develop a ventricular dysrhythmia, metabolic acidosis, or death. These findings were noted in six xenobiotics that mechanistically can cause QRS complex prolongation through sodium channel or gap junction inhibition. CONCLUSION: Identification of patients at risk for severe outcomes after overdose can be aided by measuring the QRS complex duration. If prospectively validated, these outcomes have implications on risk stratification, disposition level of care, and appropriateness of treatments.

Distribution of quetiapine between serum and whole blood in therapeutic drug-monitoring specimens.

Quetiapine use is on the rise, leading to a corresponding increase in acute intoxications, some of which have fatal outcomes. When assessing whole-blood quetiapine concentrations during forensic autopsies, interpretations are primarily based on toxicity data from studies of serum concentrations. To our knowledge, there are only two previous studies that have attempted to establish the ratio between whole blood and serum quetiapine concentrations with limited populations and high variability of results. Paired specimens of whole blood and serum from 16 quetiapine users recruited from the Psychiatric Clinic, St. Olav University Hospital were analyzed using LC-MS-MS. Quetiapine concentrations in both matrices were determined and compared. The mean blood:serum ratio of quetiapine was 0.74 (standard deviation (SD) = 0.05, 95% confidence interval (CI) 0.71-0.76, P < 0.001), range 0.66-0.85. Simple linear regression showed strong linear correlation between quetiapine concentrations in the two matrices (B = 0.774, P > 0.001, r = 0.999). Our results imply that quetiapine occurs at lower concentrations within erythrocytes than in plasma. This is most likely due to a high degree of plasma protein binding. Other factors which may influence the distribution of quetiapine between these compartments are solubility, metabolism and passive or active efflux mechanisms. We did not observe any covariation between blood:serum ratios and serum concentrations. Quetiapine was consistently present at lower concentrations in whole blood than in serum. If so inclined to, a conversion factor of ∼0.7 may be considered for extrapolation of concentrations from serum to whole blood, at least in cases with therapeutic quetiapine concentration levels.

Antipsychotic agents in anxiety disorders: An umbrella review.

BACKGROUND: Although not approved for the treatment of anxiety disorders (except trifluoperazine) there is ongoing off-label, unapproved use of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) for anxiety disorders. There have been systematic reviews and meta-analyses on the use of antipsychotics in anxiety disorders, most of which focused on SGAs. OBJECTIVE: The specific aims of this umbrella review are to: (1) Evaluate the evidence of efficacy of FGAs and SGAs in anxiety disorders as an adjunctive treatment to traditional antidepressant treatments and other nonantipsychotic medications; (2) Compare monotherapy with antipsychotics to first-line treatments for anxiety disorders in terms of effectiveness, risks, and side effects. The review protocol is registered on PROSPERO (CRD42021237436). METHODS: An initial search was undertaken to identify systematic reviews and meta-analyses from inception until 2020, with an updated search completed August 2021 and January 2023. The searches were conducted in PubMed, MEDLINE (Ovid), EMBASE (Ovid), APA PsycInfo (Ovid), CINAHL Complete (EBSCOhost), and the Cochrane Library through hand searches of references of included articles. Review quality was measured using the AMSTAR-2 (A MeaSurement Tool to Assess Systematic Reviews) scale. RESULTS: The original and updated searches yielded 1796 and 3744 articles respectively, of which 45 were eligible. After final review, 25 systematic reviews and meta-analyses were included in the analysis. Most of the systematic reviews and meta-analyses were deemed low-quality through AMSTAR-2 with only one review being deemed high-quality. In evaluating the monotherapies with antipsychotics compared with first-line treatments for anxiety disorder there was insufficient evidence due to flawed study designs (such as problems with randomization) and small sample sizes within studies. There was limited evidence suggesting efficacy of antipsychotic agents in anxiety disorders other than quetiapine in generalized anxiety disorder (GAD). CONCLUSIONS: This umbrella review indicates a lack of high-quality studies of antipsychotics in anxiety disorders outside of the use of quetiapine in GAD. Although potentially effective for anxiety disorders, FGAs and SGAs may have risks and side effects that outweigh their efficacy, although there were limited data. Further long-term and larger-scale studies of antipsychotics in anxiety disorders are needed.

Parkinson's disease psychosis management: an evidence based, experience informed, pragmatic approach.

INTRODUCTION: Psychotic symptoms in people with Parkinson's disease (PD) have attracted increasing. Recommendations on treating psychosis often fail to take into account what psychotic symptoms require treatment, which has been complicated by the increasing number of reports documenting the frequency of 'minor' hallucinations. AREAS COVERED: This article focuses both on the phenomenology of psychotic symptoms and their management. EXPERT OPINION: Understanding the nature and implications of the types of psychotic symptoms in PD is the key to proper treatment. Evidence and experience-based data on the effect of anti-psychotic medications will be reviewed and how the various clinical settings should determine the treatment approach. The evidence base consists of all reported blinded trials recorded in PubMed and the experience-based studies are those chosen by the author from PubMed as illustrative. Specific recommendations for the treatment of psychosis will be listed for specific situations. Pimavanserin is the first-line choice for mild symptoms; quetiapine for symptoms that require improvement in a short period and clozapine for urgent problems or those which fail the other approaches.

Psychotic symptoms are common in PD, affecting the majority of patients by the time of death. 'Minor hallucinations' rarely require treatment but formed hallucinations and delusions often do. The vast majority of patients requiring treatment are on medications for PD motor problems. Some patients can be treated with reduction of psychoactive medications that are unrelated to PD, and some may tolerate reductions in PD medications without intolerable worsening of motor function. The remainder require treatment with medications that reduce psychotic symptoms, which include cholinesterase inhibitors, clozapine, pimavanserin, and possibly quetiapine and electroconvulsive therapy. Only clozapine and pimavanserin have unequivocal evidence for efficacy and motor tolerance. Data will be reviewed in support of each of these medications will be reviewed and pragmatic suggestions based on a large experience on when each might be used, and in what order they may be tried if initial approaches fail.

A systematic review of the real-world effectiveness and economic and humanistic outcomes of selected oral antipsychotics among patients with schizophrenia in the United States: Updating the evidence and gaps.

BACKGROUND: Schizophrenia is a chronic, relapsing, and burdensome psychiatric disorder affecting approximately 0.25%-0.6% of the US population. Oral antipsychotic treatment (OAT) remains the cornerstone for managing schizophrenia. However, nonadherence and high treatment failure lead to increased disease burden and medical spending. Cost-effective management of schizophrenia requires understanding the value of current therapies to facilitate better planning of management policies while addressing unmet needs. OBJECTIVE: To review existing evidence and gaps regarding real-world effectiveness and economic and humanistic outcomes of OATs, including asenapine, brexpiprazole, cariprazine, iloperidone, lumateperone, lurasidone, olanzapine/samidorphan, paliperidone, and quetiapine. METHODS: We conducted a literature search using PubMed, American Psychological Association PsycINFO (EBSCOhost), and the Cumulative Index of Nursing and Allied Health Literature from January 2010 to March 2022 as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English-language articles describing adults with schizophrenia receiving at least 1 of the selected OATs and reporting real-world effectiveness, direct or indirect costs, humanistic outcomes, behavioral outcomes, adherence/persistence patterns, or product switching were identified. RESULTS: We identified 25 studies from a total of 24,190 articles. Real-world effectiveness, cost, and adherence/persistence outcomes were reported for most OATs that were selected. Humanistic outcomes and product switching were reported only for lurasidone. Behavioral outcomes (eg, interpersonal relations and suicide ideation) were not reported for any OAT. The key economic outcomes across studies were incremental cost-effectiveness ratios, cost per quality-adjusted life-years, and health care costs. In studies that compared long-acting injectables (LAIs) with OATs, LAIs had a higher pharmacy and lower medical costs, while total health care cost was similar between LAIs and OATs. Indirect costs associated with presenteeism, absenteeism, or work productivity were not reported for any of the selected OATs. Overall, patients had poor adherence to OATs, ranging between 20% and 61% across studies. Product switching did not impact the all-cause health care costs before and after treatment. CONCLUSIONS: Our findings showed considerable gaps exist for evidence on behavioral outcomes, humanistic outcomes, medication switching, and adherence/persistence across OATs. Our findings also suggest an unmet need regarding treatment nonadherence and lack of persistence among patients receiving OATs. We identified a need for research addressing OATs' behavioral and humanistic outcomes and evaluating the impact of product switching in adults with schizophrenia in the United States, which could assist clinicians in promoting patient-centered care and help payers understand the total value of new antipsychotic drugs.

Case report: Uncovering hidden glucose patterns in medicated versus unmedicated bipolar disorder and comorbid type 1 diabetes mellitus.

Introduction: Type 1 diabetes mellitus is characterized by an absolute insulin deficiency requiring the lifetime intensive insulin therapy accompanied by daily self-monitoring, self-management, ongoing education, and complex diabetes care. Regular patient-clinician shared therapeutic decisions based on age, sex, comorbidities, medications, predicted impact of meals, physical activity, stress, hormonal changes, insulin therapy, and patterns of glycemic changes are key for achieving glycemic targets. The impact of various phases of bipolar disorder and their treatment on continuous glucose levels remains unexplored and calls for future assessments. Case presentation: The present case reports a 41-year-old Caucasian female with an established diagnosis of bipolar II disorder and type 1 diabetes mellitus who discontinued long-term mood-stabilizing pharmacotherapy with quetiapine. Real-time continuous glucose monitoring performed before and 6-months following the discontinuation of quetiapine revealed hidden glucose patterns in medicated versus unmedicated bipolar disorder. Despite the known adverse metabolic effects of quetiapine, the continuous glucose monitoring captured more stable and near-normal continuous glucose values during the antipsychotic treatment compared to unmedicated stages of bipolar disorder with considerably higher glucose values and glucose variability. Conclusion: The case report highlights the importance of the ongoing psychopharmacotherapy of bipolar disorder in comorbid type 1 diabetes mellitus to reduce mood-induced reactivity, emotional urgency, and non-emotional impulsivity that may contribute to dysglycemia. If not effectively treated, the "bipolar diabetes" is likely to progress to multiple psychiatric and somatic complications. The bidirectional links between the phases of bipolar disorder and the corresponding continuous glucose patterns can help advance clinical decision-making and yield innovative1 research that can translate into efficacious clinical practice.

Second-generation antipsychotics for Parkinson's disease psychosis: A systematic review and network meta-analysis.

OBJECTIVE: This network meta-analysis assessed the efficacy, tolerability, and acceptability of second-generation antipsychotics (SGAs) for Parkinson's disease psychosis (PDP). METHODS: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials investigating SGAs for PDP up to October 26, 2023. RESULTS: We included 16 trials (N = 1252) investigating clozapine, melperone, olanzapine, pimavanserin, quetiapine, ulotaront, and placebo. In comparisons between SGAs and placebo, the findings were: i) Standardized mean differences, 95% confidence intervals (SMDs, 95%CIs), for psychotic-symptom reduction revealed the first rank of clozapine (-1.31, -1.73 to -0.89), the second rank of pimavanserin, with significant inferiority of quetiapine (SMD = 0.47, 0.02 to 0.92); ii) Mean differences (MDs, 95%CIs) for abnormal movement, as assessed by the Unified Parkinson's Disease Rating Scale - Part III, indicated that clozapine had the least motor side effects (-0.92, -2.75 to 0.91); iii) Risk ratios (RRs, 95% CIs) for adverse-effect dropout rates were lowest for melperone (1.02, 0.20 to 5.24); and iv) RRs (95% CIs) for all-cause dropout rates were lowest for clozapine (0.73, 0.42 to 1.25). CONCLUSIONS: For patients with PDP, clozapine may substantially reduce psychotic symptoms with minimal abnormal movement, high acceptability, and moderate overall tolerability. Pimavanserin, not quetiapine, could be an alternative.

Sedative drug prescription patterns in Danish adults from 2002 through 2021. A register-based cohort study.

OBJECTIVE: Pharmacological treatment strategies for insomnia seem to vary, and there is lack of knowledge about how sedative drugs are used in a real-world setting. We investigated changes in sedative drug prescription patterns in Danish adults who initiated treatment between 2002 and 2016. METHODS: All adults with a first-time purchase of a sedative drug registered in the Danish National Prescription Register from 2002 through 2016 were followed for five years between 2002 and 2021 for subsequent prescriptions of sedative drugs, death, or emigration. Sedative drugs were classified into anxiolytic benzodiazepines (N05BA), hypnotic benzodiazepines (N05CD), Z-drugs (N05CF), melatonin (N05CH01), promethazine (R06AD), and low-dose quetiapine (N05AH04). Analyses were stratified on time: 2002-2006, 2007-2011, and 2012-2016. RESULTS: A total of 842,880 individuals purchased their first sedative drug between 2002 and 2016. Most of them (40.0%) initiated treatment between 2002 and 2006, whereas 29.2% initiated treatment in 2012-2016. In 2002-2006, anxiolytic benzodiazepines (46.4%), Z-drugs (42.8%), and hypnotic benzodiazepines (5.4%) were the most common first treatment. This pattern changed over time with a gradual increase in the use of melatonin, promethazine, and low-dose quetiapine, which in 2011-2016 accounted for 27% of all first treatments. During the five years from first prescription, around 27% shifted to a different sedative drug. This percentage increased slightly over time, but over time the first shift to another drug class was most often to a Z-drug or anxiolytic benzodiazepine. Few individuals (5.8%) had more than one shift and the third choice seemed randomly distributed across all other drug classes. CONCLUSION: Sedative drug prescriptions are distributed on different drug classes, with Z-drugs and anxiolytic benzodiazepines as the most frequent first treatment, and second choice in case of shift.

Relationship between C-reactive protein and antipsychotics levels in schizophrenic patients infected with COVID-19.

In the context of the COVID-19, inflammation emerges as a prominent characteristic. C-reactive protein (CRP) serves as a commonly employed marker for the evaluation of inflammation. This study aimed to examine the correlation between CRP levels and antipsychotic drug concentrations in patients diagnosed with SCZ during the COVID-19 pandemic. A total of 186 SCZ patients were included in this study, which utilized electronic medical records. The collected data encompassed SCZ diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, respiratory symptoms, and treatments. Laboratory assessments involved the measurement of CRP levels and monitoring of blood drug concentrations. The most prevalent symptoms observed in the patient cohort were fever (59.14%), cough (52.15%), fatigue (45.7%), sore throat (46.24%), runny nose (28.49%), and stuffy nose (25.27%). The levels of CRP during the infection period were significantly higher compared to both the prophase and anaphase of infection (all p < 0.001). The serum levels of clozapine, olanzapine, aripiprazole, quetiapine, and risperidone were elevated during the infection period (all p < 0.001). During the anaphase of infection, patients exhibited higher serum levels of clozapine, olanzapine, and risperidone (all p < 0.001) compared to the infection period, but there was no significant change in serum levels of aripiprazole and quetiapine. Multiple regression analysis revealed a statistically significant positive correlation (P < 0.0001) between CRP and clozapine concentration. In light of the COVID-19 pandemic, it is crucial to adjust the dosage based on drug serum concentration to prevent intoxication or adverse drug reactions.

Incidences, risk factors, and clinical correlates of severe QT prolongation after the use of quetiapine or haloperidol.

BACKGROUND: Case reports suggest that quetiapine or haloperidol use is associated with severe QT prolongation (SQTP) and torsades de pointes. OBJECTIVE: The purpose of this study was to examine the incidences, risk factors, and outcomes of SQTP in quetiapine and haloperidol users. METHODS: This study accessed electronic medical records from a multicenter health-care hospital system in Taiwan and included patients who received quetiapine or haloperidol therapy and had both baseline and follow-up electrocardiograms. SQTP was defined as a posttreatment corrected QT (QTc) interval exceeding 500 ms or an increase in QTc interval of >60 ms compared with the baseline value. We analyzed the risk factors and outcomes of SQTP using multivariate logistic regression. RESULTS: Mean increases in QTc interval were +8.3 ± 51.8 and +8.9 ± 44.0 ms after the administration of quetiapine (n = 8832) and haloperidol (n = 2341). Among these users, 1149 (13.0%) and 333 (14.2%) developed SQTP, respectively. Common risk factors for SQTP included old age, heart failure, hypokalemia, amiodarone use, and baseline QTc interval. SQTP in quetiapine users was significantly associated with ventricular arrhythmias (odds ratio 2.84; 95% confidence interval 1.95-4.13) and sudden cardiac death (odds ratio 2.29; 95% confidence interval 1.44-3.66). CONCLUSION: More than 10% of patients receiving quetiapine or haloperidol therapy developed SQTP, and many of them were exposed to risk factors for SQTP. SQTP in quetiapine users was significantly associated with increased risks of ventricular arrhythmias and sudden cardiac death. Clinicians should be vigilant for ventricular arrhythmias in quetiapine users who have risk factors for SQTP.

A systematic review and network meta-analysis on comparative efficacy, acceptability, and safety of treatments in acute bipolar mania in youths.

BACKGROUND: The evidence of treatment options' efficacy on acute bipolar manic episodes is relatively less in youths than adults. We aimed to compare and rank the drug's efficacy, acceptability, tolerability, and safety for acute mania in children and adolescents. METHOD: We systematically reviewed the double-blinded, randomized controlled trials (RCTs) comparing drugs or placebo for acute manic episodes of bipolar disorder in children and adolescents using PRISMA guidelines. We searched PubMed/MEDLINE, EMBASE, Web of Science, EBSCO, Scopus, the Cochrane Central Register of Controlled Trials, and https://clinicaltrials.gov from inception until November 20, 2022. Response to treatment was the primary outcome, and random-effects network meta-analyses were conducted (PROSPERO 2022: CRD42022367455). RESULTS: Of 10,134 citations, we included 15 RCTs, including 2372 patients (47 % female), 15 psychotropic drugs, and the placebo. Risperidone 0.5-2.5 mg/day, aripiprazole 30 mg/day olanzapine, quetiapine 400 mg/day, quetiapine 600 mg/day, asenapine 5 mg/day, asenapine 10 mg, ziprasidone, and aripiprazole 10 mg were found to be effective (in comparison with placebo) in children and adolescents, respectively (τ2 = 0.0072, I2 = 10.2 %). The tolerability of aripiprazole 30 mg/day was lower than risperidone 0.5-2.5 mg/day and olanzapine. Oxcarbazepine had the highest discontinuation due to the adverse effects risk ratio. LIMITATIONS: Efficacy ranking of the treatments could be performed by evaluating relatively few RCT results, and only monotherapies were considered. CONCLUSIONS: Efficacy, acceptability, tolerability, and safety are changing with the doses of antipsychotics for children and adolescents with acute bipolar manic episodes. Drug selection and optimum dosage should be carefully adjusted in children and adolescents.