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.

Refractory hypotension secondary to chronic treatment with high doses of quetiapine.

Quetiapine is an atypical antipsychotic used in the treatment of depressive, schizophrenic, or bipolar disorders. It acts on dopamine D1 and D2, histamine, and 5HT1A and 5HT2 receptors. However, it also acts as an antagonist for α1 receptors causing cardiovascular side effects, including hypotension. We present the case of a patient chronically medicated with Quetiapine who developed hypotension refractory to vasoconstrictors and intraoperative fluid therapy. Noradrenalin has a strong α1 effect with lower affinity for ß2 receptors unlike adrenalin. This translates into peripheral vasoconstriction and an improved clinical picture. Therefore, it should be considered the vasoactive drug of choice in patients on high doses of Quetiapine.

Post-therapy plasma concentrations of quetiapine in Taiwanese patients.

AIMS: Quetiapine is widely used to treat psychiatric disorders such as major depression, generalized anxiety disorder, dysthymic disorder, and insomnia other than schizophrenia and bipolar disorder. This study investigated the diagnostic distribution of quetiapine use in patients in a psychiatric hospital, the doses of quetiapine prescribed, and the plasma concentrations (Cps) of quetiapine and active metabolites. METHODS: We enrolled 107 patients who had been prescribed quetiapine for at least 4 weeks. Diagnoses, demographics, and concomitant medications were recorded. Blood sampling was performed in the morning, approximately 12 h after the before-bed dose of quetiapine. RESULTS: Diagnoses comprised schizophrenia (n = 25), bipolar disorder (n = 51), major depression (n = 15), dysthymic disorder (n = 9), and others (n = 7). The daily dose (DD) of quetiapine ranged from 25 to 800 (175.9 ± 184.4) mg, with the mean Cp being 105.6 ± 215.3 ng/ml, with a mean Cps/DD ratio of 0.58 ± 0.55 ng/ml/mg. There was a moderate positive linear correlation between the dose and Cps of quetiapine (r = 0.60), and the interpatient variation in Cps/DD ratio was up to 26-fold. CONCLUSION: Quetiapine is used in various doses to treat many psychiatric disorders other than psychosis, and it is usually prescribed as a secondary antipsychotic for symptoms such as insomnia or agitation. A wide interpatient variation of the Cps/DD ratio was noticed. Patients of East Asian descent may exhibit a 50% to 100% increase in the Cps/DD ratio for quetiapine compared with patients of Western descent.

Association Between Sexual Dysfunction and Dose of Atypical Antipsychotics: Essential to Learn the Basics.

There is paucity of data on sexual dysfunction associated with atypical antipsychotics in Indian population. We estimated the prevalence of sexual dysfunction and assessed dose dependency, if any, in patients on monotherapy of atypical antipsychotics. This cross-sectional study analyzed the data from patients with F20 to F29 (International Classification of Diseases 10th Revision, ICD-10) receiving monotherapy of risperidone (group 1), olanzapine (group 2), or quetiapine (group 3) for at least 4 weeks. The sexual function of participants was assessed using Arizona sexual experiences (ASEX) scale. Chlorpromazine (CPZ) equivalent dose and doses in terms of dose years were calculated. Kruskal-Wallis test, Mann-Whitney U-test, and Pearson correlation were used for analysis. Of the 154 subjects, 65.58% were males, with 44%, 48%, and 8% receiving risperidone, olanzapine, and quetiapine, respectively. The mean duration of treatment was 20.9 weeks. Lower ASEX scores were reported with quetiapine. The differences in mean ASEX scores between groups 1 and 2 were statistically significant for sex drive (P = .016), sexual arousal (P = .025), and overall score (P = .037). Sexual dysfunction was more frequent with risperidone (48.5%) than with olanzapine (28.4%) and quetiapine (0%). In group 1, the duration of therapy positively correlated with the mean scores of sexual desire (P = .003) and arousal (P = .033), but this was not the case for group 2 (receiving olanzapine). The mean CPZ equivalent doses were comparable between the groups (P = .064); those receiving <200 mg CPZ dose equivalents showed greater sexual impairment. We conclude that the occurrence of atypical antipsychotic-induced sexual dysfunction is not dose dependent. Olanzapine has a better safety profile in terms of sexual dysfunction, whereas the data reflecting the experience with quetiapine are insufficient.

Efficacy and safety/tolerability of antipsychotics in the treatment of adult patients with major depressive disorder: a systematic review and meta-analysis.

BACKGROUND: Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use as monotherapy and adjunctive therapy. METHODS: A systematic review and a meta-analysis were conducted on randomized placebo-controlled trials (RCTs) that reported on the efficacy and safety/tolerability of antipsychotics for the treatment of adults with MDD. Data of both monotherapy and adjunctive antipsychotic use were extracted, but analyzed separately using a random-effects model. Co-primary outcomes were study-defined-treatment response and intolerability-related discontinuation. We also illustrated the risk/benefit balance of antipsychotics for MDD, using two-dimensional graphs representing the primary efficacy and safety/tolerability outcome. Secondary outcomes included psychopathology, remission, all-cause-discontinuation, inefficacy-related discontinuation, and adverse events. RESULTS: Forty-five RCTs with 12 724 patients were included in the analysis. In monotherapy (studies = 13, n = 4375), amisulpride [1.99 (1.55-2.55)], sulpiride [1.50 (1.03-2.17)], and quetiapine [1.48 (1.23-1.78)] were significantly superior to placebo regarding treatment response. However, intolerability-related discontinuations were significantly higher compared to placebo with amisulpride and quetiapine. In adjunctive therapy (studies = 32, n = 8349), ziprasidone [1.80 (1.07-3.04)], risperidone [1.59 (1.19-2.14)], aripiprazole [1.54 (1.35-1.76)], brexpiprazole [1.41 (1.21-1.66)], cariprazine [1.27 (1.07-1.52)], and quetiapine [1.23 (1.08-1.41)] were significantly superior to placebo regarding treatment response. However, of these antipsychotics that were superior to placebo, only risperidone was equivalent to placebo regarding discontinuation due to intolerability, while the other antipsychotics were inferior. CONCLUSION: Results suggest that there are significant differences regarding the risk/benefit ratio among antipsychotics for MDD, which should inform clinical care.

Effect of quetiapine on inflammation and immunity: a systematic review.

INTRODUCTION: Knowledge about the neurobiology of psychiatric disorders is increasing in the last decades and evidence from literature suggests a central role for immuno-inflammatory mechanisms in these illnesses. The antipsychotic quetiapine acts on dopamine and serotonin signalling and well-established evidence demonstrates that these neurotransmitters can modulate immune functions in healthy and diseased conditions. Starting from this perspective, in the last few decades, a number of studies attempted to identify quetiapine effects on immune functions in order to highlight a possible additional effect of this drug in psychotic diseases, although no conclusive results were obtained. METHODS: We critically reviewed preclinical and clinical studies evaluating quetiapine effects on immune systems, suggesting strategies for future work in this field. RESULTS: Computerised search, in PubMed and Embase databases, was performed in March 2020: 120 studies were identified but only 29 relevant papers were selected for detailed review. CONCLUSION: Despite some interesting preliminary findings about anti-inflammatory effects of quetiapine, mainly supported by preclinical studies, it is possible to conclude further studies are needed to investigate the immunomodulatory effects of this drug and achieve a better understanding of its relevance on clinical outcomes to finally identify new therapeutic approaches in psychiatric treatment. KeypointsMounting evidence points to a role for immuno-inflammatory mechanisms in psychiatric disorders.Quetiapine (QUE) acts on catecholamine (dopamine and norepinephrine) and serotonin signalling.The immunomodulatory effects of catecholamines are well established.Treatment with QUE in psychiatric disorders could leverage immunomodulatory effects.QUE unclear role in immune function modulation suggests future work.

Relationship between serum concentration and clinical response of quetiapine in adolescents and adults with bipolar disorders in acute stage: a prospective observational study.

BACKGROUND: It is found that there are great differences in the efficacy of quetiapine at the same dose in many patients with bipolar disorders. Therefore, therapeutic drug monitoring (TDM) is a valuable tool for guiding treatment with quetiapine. The aims of this study were to assess the relationship between serum concentration and clinical response of quetiapine in adolescents and adults with bipolar disorders in acute stage. METHODS: The study design was prospective and observational. Within the naturalistic setting of a routine TDM service at the First Affiliated Hospital, Zhejiang University School of Medicine. Psychiatric symptoms were assessed using the HAMD (Hamilton Depression Scale), YRMS (Young manic rating scale) and CUDOS-M (Clinically Useful Depression Outcome Scale-Mixed Subscale). The decline of HAMD and YMRS scores was were used to assess clinical outcome of bipolar disorders respectively. RESULTS: 169 inpatients (23.7 % male, 76.3 % female) were enrolled in the study. We found that there was a strong correlation between quetiapine serum concentrations and clinical outcomes (rs = 0.702, p < 0.001). While, quetiapine daily dose was not correlated with clinical outcome. We found that when the quetiapine serum level is >146.85 ng/ml in depression episodes patients could obtain a satisfactory treatment effect after 2 weeks of hospitalization. CONCLUSIONS: We found a significant positive relationship between serum concentration and clinical outcome, and also determined the serum concentration of quetiapine for the treatment of bipolar depression.

"One-Pot" CuCl2-Mediated Condensation/C-S Bond Coupling Reactions to Synthesize Dibenzothiazepines by Bi-Functional-Reagent N, N'-Dimethylethane-1,2-Diamine.

The efficient "One-pot" CuCl2-catalyzed C-S bond coupling reactions were developed for the synthesis of dibenzo[b,f][1,4]thiazepines and 11-methy-ldibenzo[b,f][1,4]thiazepines via 2-iodobenzaldehydes/2-iodoacetophenones with 2-aminobenzenethiols/2,2'-disulfanediyldianilines by using bifunctional-reagent N, N'-dimethylethane-1,2-diamine (DMEDA), which worked as ligand and reductant. The reactions were compatible with a range of substrates to give the corresponding products in moderate to excellent yields.

[Low doses of quetiapine (Seroquel) as an impulsivity corrector in patients with bipolar affective disorder in remission]. / Nizkie dozy kvetiapina (Serokvelya) v kachestve korrektora impul'sivnosti u patsientov s bipolyarnym affektivnym rasstroistvom v remissii.

OBJECTIVE: To evaluate the effectiveness of low doses (25-75 mg/day) of quetiapine (Seroquel) in patients with bipolar affective disorders in a euthymic state with signs of impaired impulse control. MATERIAL AND METHODS: The main criteria for patients' selection were as follows: both sex, diagnoses of bipolar affective disorders, remission (euthymic state), adult age (from 18 to 60 years old), stable basic therapy. The duration of the study was 6 weeks, a dose of quetiapine (Seroquel) varied from 25 to 75 mg. The examinations were carried out with the Barratt scale, computerized Go-No-Go and Balloon tests. RESULTS: The study group included 32 patients (11 men and 21 women), mean age 31.2±9.7 years (minimum 18, maximum 60 years). The changes in Barratt total score (p=0.000014, Wilcoxon test, effect size 0.48) and Balloon total earnings (p=0.03, Wilcoxon test, effect size 0.22) were statistically significant and reflected clinically significant improvement. The changes of the indices of the Go-No-Go test were not significant. The data of fMRI showed an increase in the connectivity of the cortex of the central and parietal tegmentum of the left hemisphere with other areas of the brain, which correlated with the changes in psychometric and test parameters. CONCLUSION: The results of the study showed that add-on of the low doses of quetiapine (Seroquel) significantly decreases impaired impulse control in remitted patients with bipolar affective disorders both in self-evaluation and in risk-taking experimental test. The drop of high level of impulsivity can improve the quality and stability of remission and reduce behavioral risks due to impaired impulse control.

Dose-Dependent Biphasic Action of Quetiapine on AMPK Signalling via 5-HT7 Receptor: Exploring Pathophysiology of Clinical and Adverse Effects of Quetiapine.

Recent pharmacological studies indicated that the modulation of tripartite-synaptic transmission plays important roles in the pathophysiology of schizophrenia, mood disorders and adverse reactions. Therefore, to explore the mechanisms underlying the clinical and adverse reactions to atypical antipsychotics, the present study determined the effects of the sub-chronic administration of quetiapine (QTP: 3~30 µM) on the protein expression of 5-HT7 receptor (5-HT7R), connexin43 (Cx43), cAMP level and intracellular signalling, Akt, Erk and adenosine monophosphate-activated protein kinase (AMPK) in cultured astrocytes and the rat hypothalamus, using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. QTP biphasically increased physiological ripple-burst evoked astroglial D-serine release in a concentration-dependent manner, peaking at 10 µM. QTP enhanced the astroglial signalling of Erk concentration-dependently, whereas both Akt and AMPK signalling's were biphasically enhanced by QTP, peaking at 10 µM and 3 µM, respectively. QTP downregulated astroglial 5-HT7R in the plasma membrane concentration-dependently. Protein expression of Cx43 in astroglial cytosol and intracellular cAMP levels were decreased and increased by QTP also biphasically, peaking at 3 µM. The dose-dependent effects of QTP on the protein expression of 5-HT7R and Cx43, AMPK signalling and intracellular cAMP levels in the hypothalamus were similar to those in astrocytes. These results suggest several complicated pharmacological features of QTP. A therapeutically relevant concentration/dose of QTP activates Akt, Erk and AMPK signalling, whereas a higher concentration/dose of QTP suppresses AMPK signalling via its low-affinity 5-HT7R inverse agonistic action. Therefore, 5-HT7R inverse agonistic action probably plays important roles in the prevention of a part of adverse reactions of QTP, such as weight gain and metabolic complications.

Integrative Analyses of Transcriptomes to Explore Common Molecular Effects of Antipsychotic Drugs.

There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10, ANK2, and AKT3, suggesting further investigation on these genes as potential novel treatment targets.

Successful treatment of severe quetiapine intoxication with CytoSorb hemoadsorption.

WHAT IS KNOWN AND OBJECTIVE: While many drug poisonings are successfully treated with specific antidotes, intoxications with tricyclic antidepressants and/or atypical neuroleptics still represent a major challenge. Besides conventional approaches, a new hemoadsorption device might represent an opportunity for therapeutic detoxification. CASE SUMMARY: We report a 64-year-old female patient who attempted suicide by ingesting an unknown dose of quetiapine. Following application of all available standard diagnostic and therapeutic measures, she was admitted to the intensive care in a deeply somnolent state. Gastroscopy was performed necessitating analgo-sedation, intubation, and mechanical ventilation. Since quetiapine is in principle not dialysable, CytoSorb hemoadsorption was commenced resulting in a clear and rapid decrease in plasma levels of quetiapine and its metabolite norquetiapine over the next few hours. The next day, analgesia was stopped, the patient became alert, and cooperative so that she could be extubated without issues. CytoSorb blood purification therapy was discontinued after 2 days. One day later, the patient was transferred to a psychiatric clinic. WHAT IS NEW AND CONCLUSION: We were able to quickly and efficiently reduce quetiapine and norquetiapine to non-toxic serum levels and to stabilize a critical situation using CytoSorb. Therefore, in the absence of a proven beneficial treatment regimen, the use of CytoSorb might represent an alternative for life-threatening complications of quetiapine intoxication. In particular, intoxications caused by lipophilic agents should be further evaluated.

Randomized, Placebo-Controlled Effectiveness Study of Quetiapine XR in Comorbid Depressive and Anxiety Disorders.

Objective: Quetiapine is approved as an adjunctive treatment for major depressive disorder (MDD) and as monotherapy for bipolar depression. It is often used off-label for treating anxiety conditions and as an augmentation agent for treatment-resistant depression. However, its benefit in depression with comorbid anxiety disorders has not been systematically evaluated. The current study evaluated the benefit and tolerability of quetiapine as augmentation to first-line antidepressants for MDD comorbid with anxiety disorders.Methods: In this multicenter trial (June 2008-June 2013), 76 adults (aged 18-65 years) with a primary diagnosis of unipolar depression comorbid with at least 1 anxiety disorder (per DSM-IV-TR criteria) received flexible-dose quetiapine extended-release (XR) 50-300 mg/d or placebo as add-on for 12 weeks in a 2:1 ratio. Depression, anxiety, life satisfaction, and adverse events were assessed.Results: Depression, anxiety, and function improved significantly in both groups. On primary outcome measures, quetiapine was superior to placebo in improving depression (17-item Hamilton Depression Rating Scale score: mean difference = -3.64; 95% CI, -7.01 to -0.27) and anxiety symptoms (Hamilton Anxiety Rating Scale score: mean difference = -4.02; 95% CI, -7.41 to -0.64), as well as Clinical Global Impressions-Severity of Illness scale score (mean difference = -0.64; 95% CI, -1.13 to -0.15). On secondary measures including the Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, Penn State Worry Questionnaire, and Quality of Life Satisfaction and Enjoyment Questionnaire, quetiapine produced a greater degree of improvement compared to placebo, but group differences were not statistically significant. Quetiapine was well tolerated, with mostly minor and no serious adverse effects.Conclusions: Quetiapine augmentation may be a useful intervention for MDD with comorbid anxiety.Trial Registration: ClinicalTrials.gov Identifier: NCT00688818.

[Acute respiratory distress syndrome caused by quetiapine poisoning: a case report].

Quetiapine is a psychotropic drug. Excessive use of quetiapine may lead to drowsiness, blurred vision, respiratory depression, hypotension and extrapyramidal reactions. Acute respiratory distress syndrome (ARDS) is rare due to overdose of quetiapine. On 14 February 2020, a patients with coma, respiratory arrest and hypotension due to overdose of quetiapine were admitted to our hospital. After receiving mechanical ventilation、plasma adsorption and anti-inflammatory treatment, the patient's consciousness turned clear, the machine was successfully removed and extubated, and the patient's condition was improved and discharged from hospital. We analyzed the clinical data of the patient with quetiapine poisoning, and discussed the clinical symptoms and chest CT characteristics of ARDS caused by quetiapine poisoning, in order to improve the understanding of quetiapine poisoning and improve the success rate of rescue.

Impaired central set point of thyroid homeostasis during quetiapine treatment in the acute phase of schizophrenia.

AIM: To evaluate the impact of quetiapine treatment on central set point of thyroid homeostasis in patients with acute phase schizophrenia. METHODS: During Jan. 2016 to Dec. 2018, we conducted a retrospective cohort study in "the Second Affiliated Hospital of Xinxiang Medical University". All patients admitted for treatment of schizophrenia being euthyroid at admission and reevaluated for thyroid function during hospitalization were recruited and followed until discharge. Patients treated with mood stabilizers during hospitalization were excluded. Quetiapine use was the exposure measure. The primary outcomes were the parameters of central set point of thyroid homeostasis measured by "thyroid-stimulating hormone (TSH) index" and "thyroid feedback quantile-based index (TFQI)". Multiple regression models were used to estimate the association between quetiapine exposure and outcomes. RESULTS: A total of 1302 patients were enrolled in this study. Quetiapine exposure was associated with a more significant decline in the TSH index and TFQI, and the adjusted ß and 95% confidence interval (CI) were -0.12 (-0.22, -0.01) and -0.10 (-0.15, -0.05), respectively. A dose-response association between quetiapine exposure and decline in TSH index and TFQI was observed (P < 0.05). Sensitivity analyses restricting to patients under mono-atypical antipsychotic therapy, or selecting patients in the non-quetiapine group matched to quetiapine group yielded similar results. CONCLUSION: Quetiapine was associated with TSH index and TFQI reduction in a dose-response pattern, suggesting that impaired central set point may be involved in the mechanism by which quetiapine affects hypothalamus-pituitary-thyroid axis in acute phase schizophrenia patients.

Quetiapine Combined with Sodium Valproate in Patients with Alzheimer's Disease with Mental and Behavioral Symptoms Efficacy Observation.

Quetiapine combined with sodium valproate is an effective and more suitable drug treatment for Alzheimer's disease. At present, there are relatively few studies on the combined action mechanism of these two drugs. This study has certain practical value. Alzheimer's disease is a multifaceted, highly genetically heterogeneous neurodegenerative disease. The main clinical manifestations are memory loss, abnormal mental behavior, and loss of various cognitive functions. In order to improve the symptoms of patients with Alzheimer's disease, especially those with mental symptoms, this article combines quetiapine and sodium valproate, two commonly used drugs for the treatment of mental illnesses, and applies them to different levels of Alzheimer's and observes the results of the combination's curative effect. This article introduces Alzheimer's disease and its potential mental behaviors in the method section, and it also introduces the mechanism of action of quetiapine and sodium valproate. For the algorithm, this paper introduces a data mining algorithm to understand the effect of drug efficacy. In the experimental part, firstly, it introduces the experimental objects, the proportion of medicines, and the statistical methods. Secondly, this article covers adverse reactions, inflammatory factors and vascular endothelial indicators, Alzheimer's disease performance, MOAS score, treatment effect evaluation, and satisfaction surveys. It can be seen from the experiment that, in mental behavior, the experimental group decreased from 8.2 before treatment to 0.5, and the control group decreased from 7.1 before treatment to 2.6. It can be seen that the scores of the experimental group changed after receiving the treatment of quetiapine combined with sodium valproate.

Associations between off-label low-dose olanzapine or quetiapine and cardiometabolic mortality.

Olanzapine and quetiapine are routinely used off-label at lower doses, though it remains unclear whether treatment is associated with mortality. Here, we examined the associations between low-dose olanzapine/quetiapine, defined as 5 mg/day of olanzapine equivalents (OE) with cardiometabolic mortality in a population-based, longitudinal cohort of individuals who sought specialized psychiatric services. Through cross-linked Swedish registries, 428,525 individuals without psychotic, bipolar, or cardiometabolic disorders, or previous treatment with antipsychotics or cardiometabolic-related drugs were followed for up to 10.5 years. Extended stratified Cox proportional hazards regressions were employed to estimate the hazard ratios (HR) of cardiometabolic mortality as a function of cumulative OE exposures, adjusted for age, sex, inpatient care, and time-dependent psychiatric diagnoses and treatments. Individuals were followed for a total of 2.1 million person-years. Treatment with olanzapine/quetiapine occurred in 18,317 of the cohort. In total, 2606 cardiometabolic-related deaths occurred. Treatment status (treated vs. untreated) was not significantly associated with cardiometabolic mortality (adjusted HR 0.86, 95% CI 0.64-1.15, P = 0.307). However, compared to no treatment, treatment for <6 months was significantly associated with a reduced risk (adjusted HR 0.56, 95% CI 0.37-0.87, P = 0.010) whereas treatment for 6-12 months was significantly associated with an increased risk (adjusted HR 1.89, 95% CI 1.22-2.92, P = 0.004), but not significantly beyond 12 months. Among those treated, each year exposed to an average 5 mg/day was significantly associated with increased cardiometabolic mortality (adjusted HR 1.45, 95% CI 1.06-1.99, P = 0.019). Overall, low-dose olanzapine/quetiapine treatment was weakly associated with cardiometabolic mortality. Clinicians should consider potential cardiometabolic sequelae at lower doses.

Levetiracetam adjunct to quetiapine for the acute manic phase of bipolar disorder: a randomized, double-blind and placebo-controlled clinical trial of efficacy, safety and tolerability.

Unsatisfactory responses to bipolar disorder treatments have necessitated novel therapeutic approaches. Evidence of levetiracetam's effectiveness in mania was reported in previous studies. This study evaluated its efficacy, safety and tolerability as an adjunct to quetiapine in mania. Forty-four patients with Young Mania Rating Scale (YMRS) score ≥20 entered and were randomized to receive levetiracetam plus quetiapine or placebo plus quetiapine for 6 weeks. Patients were assessed using the YMRS and Beck Scale for Suicidal Ideations (BSSI) at baseline and weeks 2, 4 and 6. Changes in the scores, remission rates and response to treatment were compared between the groups. Forty patients completed the trial. The general linear model (GLM) repeated measures demonstrated a significant effect for time × treatment interaction on the YMRS score during the trial (P = 0.04). A greater reduction in YMRS scores was seen in the levetiracetam group compared with the placebo group from baseline to week 4 (P = 0.045). Response to treatment was significantly better in the levetiracetam group (P = 0.046). No significant effect for time × treatment interaction on BSSI score was seen in GLM repeated measures. Finally, there was no significant difference in the frequency of adverse events. Adjunctive levetiracetam is effective, safe and well-tolerated in patients with mania. Further high-quality, large-scale trials are recommended.