Comparative Physicochemical and Pharmacokinetic Properties of Quetiapine and Its Active Metabolite Norquetiapine.

Quetiapine (QTP) is an atypical antipsychotic drug commonly used to treat several psychiatric disorders and is metabolized into the active metabolite norquetiapine (NQTP). This study was designed to evaluate and compare the physicochemical properties, metabolic stability, brain distribution, and pharmacokinetics of QTP and NQTP. Compared to QTP, NQTP had a higher pKa, solubility, and rat liver microsomal stability, optimal log D and similar log P values. For pharmacokinetic evaluation, QTP and NQTP were administered orally and intravenously to rats at various doses. The plasma QTP and NQTP concentrations in rats were determined by a fully-validated liquid-chromatography tandem mass spectrometry (LC-MS/MS). Over the investigated dosing range, both QTP and NQTP showed linear pharmacokinetics. Following oral administration of the same dose, the area under the concentration-time curve (AUC0-∞) and maximum serum concentration (Cmax) were larger after NQTP administration compared to QTP administration. In addition, NQTP had a greater absolute oral bioavailability compared to QTP (15.6% vs. 0.63%, respectively). The brain-to-plasma concentration ratio was greater after NQTP administration compared to the QTP and NQTP ratios after QTP administration. NQTP administration results in increased systemic exposure and brain distribution compared to QTP administration. Future studies are needed to evaluate the pharmacologic and toxicologic effects of increased NQTP exposures.

Quetiapine inhibits osteoclastogenesis and prevents human breast cancer-induced bone loss through suppression of the RANKL-mediated MAPK and NF-κB signaling pathways.

Bone loss is one of the major complications of advanced cancers such as breast cancer, prostate cancer, and lung cancer. Extensive research has revealed that the receptor activator of NF-κB ligand (RANKL), which is considered to be a key factor in osteoclast differentiation, plays an important role in cancer-associated bone resorption. Therefore, agents that can suppress this bone loss have therapeutic potential. In this study, we detected whether quetiapine (QUE), a commonly used atypical antipsychotic drug, can inhibit RANKL-induced osteoclast differentiation in vitro and prevent human breast cancer-induced bone loss in vivo. RAW 264.7 cells and bone marrow-derived macrophages (BMMs) were used to detect inhibitory effect of QUE on osteoclastogenesis in vitro. Mouse model of breast cancer metastasis to bone was used to test suppressive effect of QUE on breast cancer-induced bone loss in vivo. Our results show that QUE can inhibit RANKL-induced osteoclast differentiation from RAW 264.7 cells and BMMs without signs of cytotoxicity. Moreover, QUE reduced the occurrence of MDA-MB-231 cell-induced osteolytic bone loss by suppressing the differentiation of osteoclasts. Finally, molecular analysis revealed that it is by inhibiting RANKL-mediated MAPK and NF-κB signaling pathways that QUE suppressed the osteoclast differentiation. We demonstrate, for the first time, the novel suppressive effects of QUE on RANKL-induced osteoclast differentiation in vitro and human breast cancer-induced bone loss in vivo, suggesting that QUE may be a potential therapeutic drug for osteolysis treatment.

[The place of quetiapine extended release in the treatment of mental disorders]. / Miejsce kwetiapiny o przedluzonym uwalnianiu w terapii osób z zaburzeniami psychicznymi.

This article presents a summary of available data on the use of quetiapine extended release (QUE-XR). QUE-XR is an example of an atypical antipsychotic drug that can be used in a single dose, thereby simplifying the treatment regimen. From the therapeutic standpoint, this issue is of paramount importance, since approximately 50% of patients have adherence issues. Therefore, availability of the drug which is comfortable in administration can significantly improve treatment outcomes. Due to its antipsychotic, antidepressive, mood stabilizing and anxiolytic efficacy, QUE-XR seems to be a promising drug with potentially broad spectrum of indications (in patients with schizophrenia, bipolar disorder, major depression and some anxiety disorders - both in the acute phase of treatment, and the maintenance treatment). Notably, QUE-XR seems to ameliorate sleep disturbances, and it may also improve patients' quality of life (as suggested by some studies). Due to the simple dosing regimen of QUE-XR, conducting therapy with this drug may contribute to the improvement of compliance. Yet, the primary clinical criterion for selection of the type of formulation of quetiapine should be the individual preferences of the patient, and the knowledge and experience of the treating physician.

[Misuse and abuse of quetiapine]. / Niewlasciwe uzywanie i naduzywanie kwetiapiny.

Quetiapine is an atypical antipsychotic agent, frequently used in psychiatry, often for symptomatic treatment against a number of mental disorders differing from the registration indications. One of the use is to soothe the clinical conditions caused by the use of various psychoactive substances. The paper presents and discusses the reports of quetiapine misuse, abuse, and even mental addiction, as well as symptoms similar to the so-called discontinuation syndrome, often mixed with withdrawal syndrome occurring in the course of addiction. Most reports concern males, and especially those with a history of other psychoactive substance abuse, and personality disorders, often in conflict with the law. Therefore, clinicians should be cautious when prescribing quetiapine to such patients. The article discusses potential mechanisms responsible for quetiapine abuse. This is probably related to its sedative and anxiolytic activity which results in the frequent use with stimulants. Also, high affinity for the H1 receptor, as antihistamines agents causes rewarding action.

Short-term quetiapine treatment alters the use of reinforcement signals during risky decision-making and promotes the choice of negative expected values in healthy adult males.

Effective decision-making can involve using environmental signals about the possible good and bad outcomes, and their probabilities, to select optimal actions. Problematic decision-making in psychiatric disorders, and particularly bipolar illness, may result from disrupted use of these reinforcement cues, leading to actions that reflect or precipitate pathological changes in mood. Previous experiments indicate that the processing of reinforcement cues while selecting between risky actions can be influenced by dopamine and serotonin activity. Quetiapine is an atypical antipsychotic agent with a complex pharmacology, including antagonist actions at 5-HT2A and, to a lesser extent, D2 receptors. Here, we investigated the effects of (short-term) treatment with quetiapine on the risky decision-making of healthy human adults. Twenty participants received 150 mg of quetiapine XL for 7 d, whereas 20 age- and IQ-matched participants received a placebo. On the eighth day, all participants completed a risky decision-making task that involved making a series of choices between two simultaneously presented gambles that differed in the magnitudes of their possible gains and losses, and the probabilities with which these outcomes were delivered. Quetiapine treatment was associated with a marked tendency to choose options with negative expected values compared with placebo treatment in male but not female participants. Our results demonstrate that antagonism of serotonin and dopamine receptor activity can alter the way individuals use information about gains and losses when selecting between risky actions, possibly reflecting gender-specific differences in risk attitudes. These effects may be beneficial by correcting decision-making biases that feature in mood disorders.

Quetiapine extended release: preliminary evidence of a rapid onset of the antidepressant effect in bipolar depression.

BACKGROUND AND AIMS: Quetiapine (QTP) has been shown to be effective as an acute treatment in patients with bipolar depression. Nonetheless, the time at onset of QTP antidepressant action has not been clarified. We aimed to evaluate the onset of the antidepressant effect of QTP extended release (XR) in bipolar depression. We also compared the different efficacy and adverse effect profile of 300- and 600-mg/d dosages. METHODS: Twenty-one acutely bipolar depressed patients were recruited; 13 were treated with QTP XR 300 and 8 with 600 mg/d. Assessment was performed with Hamilton Depression Rating Scale (also considering clusters "core," "somatic anxiety," "psychic anxiety," "activity," and "delusion"), Hamilton Anxiety Rating Scale, Dosage Record and Treatment Emergent Symptom Scale. RESULTS: Quetiapine XR was effective since the first 3 days of treatment in reducing all the efficacy measures except for somatic anxiety. The comparison of 300- and 600-mg dosages was limited by the small sample size. However, the analysis did not show any significant difference in terms of efficacy, although with a trend in favor of 600 mg. The incidence of hypotension was significantly higher in patients taking QTP 600 mg (P = 0.004). DISCUSSION AND CONCLUSION: Quetiapine seems to be effective in bipolar depression within the first days of treatment. There may be not a significant advantage for the 600-mg dose in comparison with the 300-mg one. The clinical effect seems to be not associated with sedation, suggesting that it may be due to the molecular drug effect. Further studies focusing on the first days of treatment are needed to confirm our findings.

The effects of quetiapine on sleep in recovering alcohol-dependent subjects: a pilot study.

OBJECTIVE: The aim of this hypothesis-generating pilot study was to assess prospectively the objective and subjective effects of treatment with quetiapine XR on sleep during early recovery from alcohol dependence (AD). METHODS: Recovering subjects with AD and sleep disturbance complaints were treated with quetiapine XR (n = 10) or matching placebo pills (n = 10) for 8 weeks. Polysomnography was used to assess sleep objectively, and the Insomnia Severity Index and Pittsburgh Sleep Quality Index were used to measure subjective insomnia. Other assessment measures included the 10-minute psychomotor vigilance task (for neurobehavioral functioning), the time-line follow-back measure (for alcohol consumption), the Penn Alcohol Craving Scale (for alcohol craving), the Patient Health Questionnaire-9 item scale (for depressive symptoms), and the Beck Anxiety Inventory (for anxiety symptoms). RESULTS: Although there was no effect of quetiapine XR on sleep efficiency (time spent asleep/total recording time), there was a pre-to-post reduction in wake after sleep onset time (P = 0.03) and nonsignificant trends for increases in sleep onset latency (SOL) and stage 2 sleep time. A time × drug interaction was seen for the subjective insomnia, such that quetiapine XR-treated subjects reported greater initial improvement in their subjective insomnia, but the difference was not sustained. There were no differences between treatment groups on other measures or medication compliance. CONCLUSION: Quetiapine XR improves objective sleep continuity and transiently improves subjective insomnia early in recovery from AD.

A randomized, double-blind, placebo-controlled trial of quetiapine in patients with bipolar disorder, mixed or depressed phase, and alcohol dependence.

BACKGROUND: Alcohol dependence is common in bipolar disorder (BPD) and associated with treatment nonadherence, violence, and hospitalization. Quetiapine is a standard treatment for BPD. We previously reported improvement in depressive symptoms, but not alcohol use, with quetiapine in BPD and alcohol dependence. However, mean alcohol use was low and a larger effect size on alcohol-related measures was observed in those with higher levels of alcohol consumption. In this study, efficacy of quetiapine in patients with BPD and alcohol dependence was examined in patients with higher mean baseline alcohol use than in the prior study. METHODS: Ninety outpatients with bipolar I or II disorders, depressed or mixed mood state, and current alcohol dependence were randomized to 12 weeks of sustained release quetiapine (to 600 mg/d) add-on therapy or placebo. Drinking was quantified using the Timeline Follow Back method. Additional assessment tools included the Hamilton Rating Scale for Depression, Inventory of Depressive Symptomatology-Self-Report, Young Mania Rating Scale, Penn Alcohol Craving Scale, liver enzymes, and side effects. Alcohol use and mood were analyzed using a declining-effects random-regression model. RESULTS: Baseline and demographic characteristics in the 2 groups were similar. No significant between-group differences were observed on the primary outcome measure of drinks per day or other alcohol-related or mood measures (p > 0.05). Overall side effect burden, glucose, and cholesterol were similar in the 2 groups. However, a significant weight increase was observed with quetiapine at week 6 (+2.9 lbs [SE 1.4] quetiapine vs. -2.0 lbs [SE 1.4], p = 0.03), but not at week 12. Scores on the Barnes Akathisia Scale increased significantly more (p = 0.04) with quetiapine (+0.40 [SE 0.3]) than placebo (-0.52 [SE 0.3]) at week 6 but not week 12. Retention (survival) in the study was similar in the groups. CONCLUSIONS: Findings suggest that quetiapine does not reduce alcohol consumption in patients with BPD and alcohol dependence.

Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with generalized anxiety disorder and a history of inadequate treatment response: a randomized, double-blind study.

BACKGROUND: For many patients with generalized anxiety disorder (GAD), first-line treatment does not lead to remission. This study investigated the efficacy and tolerability of adjunctive extended-release quetiapine fumarate (quetiapine XR) in patients with GAD and an inadequate response to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: Patients were randomized to quetiapine XR or placebo adjunctive to SSRI/SNRIs in an 11-week study. The primary endpoint was change from randomization to week 8 in Hamilton Anxiety Rating Scale (HAM-A) total score. Secondary variables were HAM-A psychic/somatic clusters, response, and remission, and Clinical Global Impression­Severity of Illness (CGI-S) score. RESULTS: A total of 409 patients received quetiapine XR (n=209) or placebo (n=200). The week 8 mean change in HAM-A total score was not statistically significant for quetiapine XR (­10.74; P=.079) vs placebo (­9.61). Secondary variables were generally consistent with the primary analysis, except for a significant reduction in HAM-A total score (week 1) and significant improvements in HAM-A psychic cluster and CGI-S total scores (week 8). Adverse events included dry mouth, somnolence, sedation, headache, and dizziness. CONCLUSIONS: In patients with GAD and an inadequate response to SSRI/SNRIs, adjunctive quetiapine XR did not show a statistically significant effect for the primary endpoint at week 8, although some secondary endpoints were statistically significant vs placebo. Quetiapine XR was generally well tolerated.

Characteristics and trends of low-dose quetiapine use in two western state Medicaid programs.

PURPOSE: Medicaid programs are concerned about inappropriate, potentially hazardous, and costly off-label use of second-generation antipsychotics (SGAs). Several states are exploring policies aimed at managing low-dose quetiapine, commonly prescribed for off-label conditions. This study aimed to characterize longitudinal trends and patient characteristics associated with low-dose quetiapine in two state Medicaid programs. We further aimed to quantify changes in the use of quetiapine associated with a legal settlement that curtailed off-label promotion of this product. METHODS: Using administrative data from two state Medicaid programs, Oregon and Colorado, we identified SGA initiators and determined patient level factors associated with receipt of low-dose SGAs. We evaluated changes in low-dose quetiapine initiation during and after a period in which quetiapine was being promoted illegally for off-label purposes. RESULTS: We identified 14,763 new SGA starts during the study period. Low-dose (versus therapeutic dose) SGA use was common in both states, representing 53% to 56% of initiators. Quetiapine was the most commonly used SGA in both states and both dose ranges. Diagnoses of schizophrenia, bipolar disorder, posttraumatic stress disorder, anxiety disorder, and use of newer sedative hypnotics were associated with lower likelihood of initiating low-dose quetiapine. Initiation of low-dose quetiapine as a proportion of all SGA initiation and of all quetiapine initiation significantly declined in Oregon following suspension of off-label promotional activities. CONCLUSIONS: Low-dose SGA and specifically low-dose quetiapine use remains common. Medicaid programs must set policies carefully to maximize the net safety of prescription use while optimizing disease management considering the potential for substitution effects.

Hospital stay in patients admitted for acute bipolar manic episodes prescribed quetiapine immediate or extended release: a retrospective non-interventional cohort study (HOME).

BACKGROUND: Bipolar manic episodes often require hospital admission to ensure patient safety. The antipsychotic quetiapine is a common treatment for bipolar mania and is available in immediate release (IR) and extended release (XR) formulations; however, outcomes in patients receiving these different formulations have not been directly compared in an acute hospital setting. METHODS: We conducted a multinational, observational, retrospective cohort study to describe and compare hospital stay in patients admitted for an acute bipolar manic episode treated with quetiapine IR or XR from 1 October 2009-1 October 2010. The primary outcome measure was comparison of length of stay (LOS) using zero-truncated negative binomial regression. RESULTS: In total, 1230 patients were included (659 in the IR cohort; 571 in the XR cohort). The median LOS (interquartile range) was 18.0 days (12.0, 28.0) in the IR cohort and 20.0 days (12.0, 34.0) in the XR cohort, respectively. LOS was not significantly associated with quetiapine formulation irrespective of whether or not clinical characteristics were taken into account (p = 0.820 and p = 0.386, respectively). Overall, 84.2% and 84.4% of patients in the IR and XR cohorts, respectively, had not previously used quetiapine; of these patients, 78.7% and 68.9% received one total daily dose, and 14.4% and 23.9% received dose titration. Over half of patients received antipsychotic monotherapy (53.1% and 58.3% in the IR and XR cohorts, respectively) and most received a daily quetiapine dose ≥ 400 mg (64.9% and 71.8%, respectively, for quetiapine monotherapy and 59.9% and 80.3%, respectively, for combination treatment). As a secondary outcome, multivariate analysis was used to identify other factors that affect LOS. Factors associated with a longer hospital stay included public funding versus private, maximum number of new medications administered, did not receive lithium and did not receive anxiolytics, sedatives/hypnotics (all p < 0.0001). Factors associated with a shorter hospital stay included presence of drug/alcohol abuse, living accompanied and having a psychiatric medical history (all p < 0.05). CONCLUSIONS: LOS was not found to be associated with quetiapine formulation. However, most patients received only one total daily dose of quetiapine without dose titration, which was unexpected and contrary to current recommendations. TRIAL REGISTRATION: NCT01239589.

Antipsychotic polypharmacy and high-dose prescription in schizophrenia: a 5-year comparison.

OBJECTIVE: The co-prescription of multiple antipsychotic drugs continues to increase despite a lack of evidence supporting this practice. The purpose of this study was to quantify and describe recent trends of antipsychotic polypharmacy in Korean schizophrenic inpatients by comparing prescribed medications between the years of 2005 and 2010. METHODS: We reviewed comprehensive medication profiles of schizophrenic patients discharged from a university psychiatric hospital in 2005 (n=194) or 2010 (n=201). Antipsychotic polypharmacy was defined as the concurrent receipt of two or more chemically distinct antipsychotics for at least 14 days. High antipsychotic dose was defined as a prescribed daily dose to defined daily dose ratio of greater than 1.5. RESULTS: Antipsychotic polypharmacy increased between 2005 (37.1%) and 2010 (48.3%, p=0.025). The most frequently used drug within combinations of antipsychotics was haloperidol in 2005 (51.4%) and quetiapine in 2010 (48.5%). Overall, no changes were observed between 2005 and 2010 in the rate of prescribing high-dose antipsychotics. High-dose antipsychotic monotherapy decreased across years (from 30.4 to 18.4%), but high-dose antipsychotic polypharmacy increased (from 34.0 to 45.3%). Regression analysis revealed that antipsychotic polypharmacy was strongly associated with high doses of prescribed antipsychotics (odds ratio=18.60, p<0.001). CONCLUSIONS: The practice of prescribing multiple antipsychotics to patients with schizophrenia is increasing, and high-dose antipsychotic drugs are more likely to be prescribed in combination than in isolation. The reasons for this pattern of prescription and its impact warrants further study.

Cognitive effects of acute restraint stress in male albino rats and the impact of pretreatment with quetiapine versus ghrelin.

Stress is any condition that seriously affects the balance of the organism physiologically and psychologically. Stress activates the hypothalamic-pituitary-adrenal (HPA) releasing glucocorticoid hormones that produce generalized effects on different body systems including the nervous system. This study aimed to investigate the effect of acute restraint stress (ARS) on cognitive performance by measuring spatial working memory in Y-maze, behavior (anxiety and exploratory behavior) in open field test, expression of synaptophysin and glial fibrillary acidic protein (GFAP) in the hippocampus by immunohistochemistry, dopaminergic receptors (D2) in the basal ganglia by gene expression and comparing the effect of ghrelin and quetiapine on the previous parameters. 36 adult male albino rats constituted the animal model of this work and have been divided into six groups: control group, control group exposed to ARS, quetiapine group, quetiapine group exposed to ARS, ghrelin group and ghrelin group exposed to ARS. We demonstrated more neuroprotective effect for quetiapine compared to ghrelin on stress response, anxiety behavior and working spatial memory impairment due to ARS.

Development of physiologically based pharmacokinetic model to evaluate the relative systemic exposure to quetiapine after administration of IR and XR formulations to adults, children and adolescents.

Quetiapine is an atypical antipsychotic drug with a high permeability, moderate solubility and defined as a Biopharmaceutics Classification System class ll compound. The pharmacokinetics (PK) of the quetiapine immediate-release (IR) formulation has been studied in both adults and children, but the quetiapine extended-release (XR) formulation has only been conducted in adults. The purpose of the current study was to use physiologically based pharmacokinetic modeling (PBPK) quantitatively to predict the PK of the XR formulation in children and adolescents. Using a 'learn and confirm' approach, PBPK models were developed employing in vitro ADME and physicochemical data, clinical PK data of quetiapine IR/XR in adults and clinical PK data of quetiapine IR in children. These models can predict well the effects of CYP3A4 inhibition and induction on the PK of quetiapine, the PK profile of quetiapine IR in children and adults, and the PK profile of quetiapine XR in adults. The AUC and Cmax ratios (children vs adults) for the different age groups were in reasonable agreement with the observed ratios. In addition, the PBPK model predicted that children and adolescents are likely to achieve a similar exposure following administration of either the XR formulation once daily or the IR formulation twice daily at similar total daily doses. The results from the study can help inform dosing regimens in pediatrics using the quetiapine XR formulation.

Open-label pilot study of quetiapine treatment for cannabis dependence.

BACKGROUND: There are no efficacious pharmacotherapies for cannabis dependence. The effects of quetiapine are well matched to the symptoms of cannabis withdrawal and could be useful in the treatment of cannabis dependence. OBJECTIVES: To evaluate quetiapine for the treatment of cannabis dependence and determine the optimal dosing. METHODS: In an eight-week open-label outpatient pilot trial, we evaluated the feasibility of quetiapine treatment for cannabis dependence in 15 outpatients. Quetiapine was gradually titrated to 600 mg or the maximum tolerated dose. RESULTS: The mean study retention was 6.5 weeks (±2.3), with 67% of participants completing all eight weeks of the trial. The mean maximum dose achieved was 197 mg/day (range: 25-600 mg/day). Only two of the 15 participants were able to achieve the target dose of 600 mg daily. There were no serious adverse events and no participants were discontinued from the trial due to adverse effects. The most common reported adverse effects were fatigue (80% of participants) and somnolence (47%). From baseline to week 8, the modeled overall decrease in daily dollar value of marijuana was 76.3% (CI: 63.4%, 84.7%). Over the eight weeks of the study, there was a 46.9% (CI: 11%, 68.3%) decrease in urine tetrahydrocannabinol-9-carboxylic acid (THCOOH) levels. CONCLUSIONS: These preliminary results are promising in that quetiapine treatment was tolerated by cannabis-dependent patients and associated with decreased cannabis use. The recommended maximum target dose for cannabis-dependent patients is 300 mg daily. These preliminary data support further evaluation of quetiapine as a treatment for cannabis dependence.

Despite expert recommendations, second-generation antipsychotics are not often prescribed in the emergency department.

BACKGROUND: Recent expert guidelines recommend oral second-generation antipsychotics (SGAs) as first-line therapy for acute agitation in the emergency department (ED), with intramuscular (IM) SGAs as an alternative. However, little is known about how these meds are used in the ED or how often SGAs are prescribed. OBJECTIVES: 1) The measurement of patient characteristics, concomitant benzodiazepine use, and use of SGAs compared to haloperidol or droperidol; 2) the prescribing rates of SGAs over time in ED patients. METHODS: This is a structured analysis of a historical patient cohort from 2004-2011 in two university EDs. The cohort consisted of all patients receiving aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone. Descriptive analysis compared age, gender, use of first-generation antipsychotics (FGAs) such as haloperidol/droperidol, and rates of concomitant benzodiazepine use. Linear regression was used to test whether SGA prescribing increased over time. RESULTS: There were 1680 unique patients accounting for 1779 ED visits who received SGAs over the study period, which is a minority of patients receiving any antipsychotic. Of patients receiving any SGA in the ED, most were given orally (93%). Adjunctive benzodiazepines were administered on 21% of visits, and were also administered on 21% of the visits involving alcohol + patients. The rate of SGA use in the ED is not increasing over time. CONCLUSION: Despite expert recommendations, SGAs are administered a minority of the time to ED patients. The rate is not increasing over time. When used, SGAs are most commonly given orally, are often administered with benzodiazepines, and are frequently administered to alcohol-intoxicated patients.

[Antipsychotics-induced acute necrotizing enterocolitis: a case report]. / À propos d'un cas d'entérocolite nécrosante aiguë sous antipsychotiques.

The acute necrotizing enterocolitis (ANE) is a partial or total necrosis of the small and large intestine. This is a case report of an antipsychotic induced ANE.

Quetiapine-induced urinary retention.

A 22-year-old woman, known to have a BMI of 12 kg/m2 and a personality disorder, developed urinary retention on a normal dose of quetiapine. She had earlier tolerated a dose of 800 mg quetiapine without complications. The daily dose was 600 mg in combination with oxazepam and zolpidem. Reduction had no effect. The patient intervened with intermittent urinary catheterization the next 19 months. Normal urinary function returned three days after the last dose of quetiapine 25 mg. This case report shows that patients with a low BMI may be more receptive of the anticholinergic effects of quetiapine.

Evaluation of adjunct extended-release quetiapine fumarate on sleep disturbance and quality in patients with major depressive disorder and an inadequate response to on-going antidepressant therapy.

Sleep disturbance is common in depression and is a risk factor for recurrence and suicide. This analysis evaluated the effects of adjunct extended-release quetiapine fumarate (quetiapine XR) on sleep disturbance and quality in patients with major depressive disorder (MDD) and an inadequate response to on-going antidepressant therapy. Pooled data from two 6-wk, randomized, double-blind, placebo-controlled trials were analysed post hoc. Patients received once-daily quetiapine XR [(150 mg/d), n = 309; (300 mg/d), n = 307] or placebo (n = 303) adjunct to on-going antidepressant therapy. Analyses included: change from randomization in Montgomery-Åsberg Depression Rating Scale (MADRS) Item 4 (reduced sleep) score; Hamilton Rating Scale for Depression (HAMD) Items 4 (insomnia-early), 5 (insomnia-middle) and 6 (insomnia-late) scores; HAMD sleep disturbance factor (Items 4+5+6); Pittsburgh Sleep Quality Index (PSQI) global score. Change in MADRS total score was also evaluated in patients stratified by HAMD sleep disturbance factor score (high ≥ 4 and low < 4) at randomization. At week 6, adjunct quetiapine XR (150 and 300 mg/d) reduced MADRS Item 4, HAMD Items 4, 5 and 6, HAMD sleep disturbance factor and PSQI global scores from randomization vs. placebo (all p < 0.001). In patients with high sleep disturbance, quetiapine XR (both doses) improved depressive symptoms (MADRS total score) vs. placebo from week 1 onwards (p < 0.01). Adjunct quetiapine XR improved sleep disturbance and quality vs. placebo in patients with MDD and an inadequate response to on-going antidepressant treatment, and was effective against depressive symptoms in patients experiencing high sleep disturbance.

Evaluation of the effects of extended release quetiapine fumarate monotherapy on sleep disturbance in patients with major depressive disorder: a pooled analysis of four randomized acute studies.

Effects of once-daily extended-release quetiapine fumarate (quetiapine XR) monotherapy on sleep quality and disturbance in patients with major depressive disorder (MDD) were evaluated. Pooled data from four 6- or 8-wk placebo-controlled quetiapine XR (50-300 mg/d) monotherapy studies (D1448C00001; D1448C00002; D1448C00003; D1448C00004) were analysed. Primary efficacy end-point was change from randomization in Montgomery Åsberg Depression Rating Scale (MADRS) score. Post hoc analyses of secondary end-points were conducted for change from randomization in: MADRS item 4 (reduced sleep); Hamilton Rating Scale for Depression (HAMD) items 4 (insomnia-early), 5 (insomnia-middle), 6 (insomnia-late) and sleep disturbance factor (items 4 + 5+6) scores; Pittsburgh Sleep Quality Index (PSQI) global scores. MADRS total score change was also evaluated in patients experiencing high and low baseline sleep disturbance (HAMD sleep disturbance factor scores ⩾4 and < 4, respectively). In total, 1808 patients were randomized to quetiapine XR or placebo across four studies. At last assessment, quetiapine XR reduced MADRS item 4, HAMD items 4, 5 and 6, HAMD sleep disturbance factor score and PSQI global scores from baseline vs. placebo (p < 0.001). For those experiencing high sleep disturbance (n = 865, quetiapine XR; n = 514, placebo), quetiapine XR improved MADRS total score vs. placebo at all visits (p < 0.001). For those with low sleep disturbance (n = 252, quetiapine XR; n = 121, placebo), quetiapine XR improved MADRS total score vs. placebo at weeks 2 (p < 0.001), 4 and 6 (both p < 0.05). In conclusion, quetiapine XR (50-300 mg/d) monotherapy improved symptoms of sleep disturbance vs. placebo in patients with MDD, including those with either high or low baseline sleep disturbance levels.