Quetiapine Dosage Across Diagnostic Categories

Objective The aim of the current study was to evaluate quetiapine doses used across diagnosis categories in a sample of psychiatric inpatients. Methods Discharge letters of all adult inpatients who had received quetiapine between 1999 and 2005 were retrospectively reviewed. Logistic regressions were carried-out to assess links between quetiapine discharge dosage (≥800 mg/day vs. <800 mg/day), diagnostic categories, substance abuse or dependence, benzodiazepine discharge doses, age and sex. Results The data of 231 patients were included. Five hundred and for discharge documents were analyzed: 113 for psychotic disorders, 190 for personality disorders, 134 for bipolar and schizoaffective bipolar disorders, 29 for unipolar depression or anxiety disorders, and 35 for mental retardation. Considering psychotic disorders as a reference group, patients with personality disorders were statistically significantly less likely to be in the high quetiapine dosage group at discharge (P = 0.007, OR = 0.1 and CI [0.03; 0.6]). Conclusions Quetiapine seems to be used in a variety of clinical situations, with a wide range of doses and a lower dosage in patients treated for personality disorders.     

Bipolar depression: a new role for atypical antipsychotics?

Bipolar depression, the most common phase of bipolar disorder, causes significant morbidity and mortality. Traditional drugs such as lithium, lamotrigine or antidepressants each offer some clinical efficacy; however, efficacy can be limited and side effects are sometimes problematic. Thus there is a major unmet need for effective, well-tolerated agents for the treatment of bipolar depression. The atypical antipsychotics, with their proven efficacy against manic symptoms, are emerging as candidates for use against the depressive phase of bipolar disorder. Several studies have shown that some atypicals improve depressive symptoms in mixed episodes in patients with bipolar disorder; however, few studies have been performed in patients specifically with bipolar depressive episodes. In a randomized, placebo-controlled trial in patients with acute bipolar I depression, olanzapine monotherapy and an olanzapine-fluoxetine combination significantly improved Montgomery-Asberg Depression Rating Scale (MADRS) total scores compared with placebo (p < 0.001) with corresponding effect sizes (improvement of active treatment over placebo divided by pooled standard deviation) of 0.32 and 0.68, respectively. Importantly, there were no significant differences in rates of switch into mania among the three groups. Recent results from an 8-week, randomized placebo-controlled trial in patients with bipolar I and II disorder who were experiencing a bipolar depressive episode showed that quetiapine (300 and 600 mg/day) had significantly greater efficacy compared with placebo in improving the core symptoms of depression, including suicidal thoughts. Quetiapine significantly improved MADRS total scores compared with placebo (p < 0.001); effect sizes (improvement of quetiapine over placebo divided by pooled standard deviation) of 0.66 and 0.80 for 300 and 600 mg/day quetiapine, respectively, were observed. Both doses of quetiapine significantly improved symptoms of anxiety, sleep quality and global quality of life (all, p < 0.001 versus placebo). These initial findings suggest that atypical antipsychotics may prove to be important future treatments for patients with bipolar depression.     

Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling disease course: a randomized, double-blind, placebo-controlled study

OBJECTIVES: To investigate the efficacy and tolerability of quetiapine monotherapy in patients with bipolar I or II disorder with a rapid-cycling disease course. METHODS: Adult patients with a DSM-IV diagnosis of bipolar disorder, most recent episode depressed, with a rapid-cycling disease course from a previously completed multicenter trial randomized to 8 weeks of treatment with quetiapine 600 mg/day (n = 31), quetiapine 300 mg/day (n = 42), or placebo (n = 35) were included in this sub-analysis. The primary efficacy variable was change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. RESULTS: Quetiapine (600 and 300 mg/day) provided significantly greater mean reductions from baseline to week 8 in the MADRS total score than placebo (-21.1, -20.7 versus -11.6, both p < 0.001) in this patient population. Effect sizes in patients with a rapid-cycling disease course were 1.2 (600 mg/day) and 1.1 (300 mg/day) and were similar for bipolar I (0.98 and 1.22) and bipolar II (1.45 and 0.97) sub-groups. Significant improvements were also noted on the Clinical Global Impression, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire scales. Quetiapine was generally well tolerated with moderate increases in weight and extrapyramidal side effects compared to placebo. The incidence of treatment-emergent mania was similar to placebo. CONCLUSIONS: Quetiapine monotherapy (600 or 300 mg/day) is clinically effective and well tolerated in the short-term treatment of depressive episodes in patients with bipolar I or II disorder who have a rapid-cycling disease course.     

Quetiapine alone and added to a mood stabilizer for serious mood disorders.

BACKGROUND: Use of antipsychotic medication intermittently or over the long term may be necessary in treating patients with bipolar disorder whose symptoms have responded suboptimally to standard mood-stabilizing agents. Quetiapine fumarate is an effective novel antipsychotic with mixed serotonergic (5-HT2) and dopaminergic (D2) activity. This is an open-label, 12-week prospective study to assess the efficacy and tolerability of quetiapine in the treatment of patients with bipolar and schizoaffective disorder who were suboptimally responsive to mood stabilizers alone. METHOD: Participants in the study were inpatients or outpatients with a DSM-IV diagnosis of bipolar or schizoaffective disorder. Baseline psychopathology was evaluated with the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMRS), and the Hamilton Rating Scale for Depression (HAM-D). Involuntary movements were rated with the Simpson-Angus Neurologic Rating Scale. Quetiapine was added on an open-label basis and increased to optimum clinical dosage. Psychopathology and Abnormal Involuntary Movement Scale ratings were repeated weekly for the first 4 weeks and then again at weeks 8 and 12. RESULTS: Ten individuals with bipolar disorder and 10 with schizoaffective disorder received quetiapine therapy. Overall, patients improved, with significant improvement in BPRS (p < .001), YMRS (p = .043), and HAM-D scores (p = .002). Simpson-Angus score also significantly decreased (p = .02). Overall. quetiapine was well tolerated by patients in this group with serious mood disorders. The mean +/- SD quetiapine dose was 202.9 +/- 124.3 mg/day (range, 50-400 mg/day). Mean weight gain was 10.9 lb (4.9 kg). CONCLUSION: Although limited by its small size, open-label design, and relative gender homogeneity, this study suggests that quetiapine therapy may be useful in the treatment of individuals with serious mood disorders who are suboptimally responsive to mood stabilizers alone. These preliminary findings should be explored in larger, controlled trials.     

Corrigendum

In Volume 10, Supplement 1, February 2008, this Abstract was omitted from the Poster Session. The correct citation for the Abstract is Bipolar Disord 2008; 10 (Suppl. 1). We apologize for this error. A DOUBLE‐BLIND, PLACEBO‐CONTROLLED STUDY WITH ACUTE AND CONTINUATION PHASE OF QUETIAPINE AND LITHIUM IN ADULTS WITH BIPOLAR DEPRESSION (EMBOLDEN I) AH Young^a, A Carlsson^b, B Olausson^b, B Paulsson^b and M Brecher^{c a}Department of Psychiatry, Institute of Mental Health, The University of British Columbia, Vancouver, Canada, ^bAstraZeneca, Södertälje, Sweden, ^cAstraZeneca Pharmaceuticals LP, Wilmington, DE, USA Background and aims: Evaluate the efficacy and tolerability of quetiapine and lithium monotherapy for major depressive episodes in bipolar disorder during an acute 8‐week period and up to 52‐week continuation phase. Methods: A total of 802 patients (499 bipolar I, 303 bipolar II) were randomized to quetiapine 300 mg/day (n = 265), quetiapine 600 mg/day (n = 268), lithium 600 mg/day (n = 136), or placebo (n = 133) for 8 weeks. Primary endpoint was change from baseline to 8 weeks in MADRS total score. After 8 weeks, patients with MADRS ≤ 12 and YMRS ≤ 12 entered a 26–52‐week continuation phase of quetiapine (300 mg/day or 600 mg/day) or placebo. Patients on lithium received 300 mg/day of quetiapine (results of continuation phase not included here and to be presented separately). Results: LSM MADRS score change at 8 weeks was ?15.36 (quetiapine 300 mg/day), ?16.10 (quetiapine 600 mg/day), ?13.60 (lithium), and ?11.81 (placebo; p < 0.001 for both quetiapine doses, p = 0.123 for lithium, versus placebo; LOCF ANCOVA). Quetiapine (both doses)‐treated, but not lithium‐treated, patients showed significantly greater improvements (p ≤ 0.05) in MADRS response and remission rates, HAM‐D, CGI‐BP‐S, CGI‐BP‐change, and HAM‐A at Week 8 versus placebo; MADRS item 10 (suicidal thoughts) improved with quetiapine 600 mg/day versus placebo (p = 0.013). Most common adverse events considered drug‐related included somnolence, dry mouth, and dizziness with quetiapine (both doses) and nausea with lithium. Conclusions: Quetiapine (300 mg/day or 600 mg/day) was more effective than placebo for the treatment of acute depressive episodes in bipolar I and bipolar II disorder. Quetiapine treatment was generally well tolerated.     

An open multicentre pilot study examining the safety,efficacy and tolerability of fast titrated (800 mg/day by day 4) quetiapine in the treatment of schizophrenia/schizoaffective disorder

Objective. Rapid dose escalation of quetiapine could offer prompt and effective therapy to patients requiring hospitalization for schizophrenia or schizoaffective disorder. This study evaluated the safety, tolerability, and efficacy of a rapid dose escalation of quetiapine to 800 mg/day over 4 days in patients with severe psychotic symptoms diagnosed as schizophrenia or schizoaffective disorder. Methods. In this open-label, multicenter, pilot study, 14 patients aged 18 years or older, requiring hospitalization for schizophrenia or schizoaffective disorder, received quetiapine orally twice daily for 14 days. Quetiapine was administered according to the schedule: 200, 400, 600, and 800 mg/day on the first four treatment days, followed by flexible dosing within the range 400–800 mg/day during the next 10 days. The primary endpoint was to evaluate the safety and tolerability of a fast titration of quetiapine (200, 400, 600, 800 mg/day on the first four treatment days). Effectiveness of a fast titration of quetiapine was the secondary objective of this investigation. Efficacy assessments in the intent-to-treat (ITT) population included changes in the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Severity of Illness (CGI-S) scores from Day 1 (baseline) to Day 14. Results. In 4 days 14 patients were titrated up to a dose of 800 mg/day. Ten patients were diagnosed with schizophrenia, one subject was suffering from schizoaffective disorder of the depressive type and three patients were diagnosed with schizoaffective disorder of the bipolar type. Eleven patients (79%) completed the study. Two patients discontinued the trial because of non-compliance and one patient because of a prolonged QTcB interval. Overall, 29 AEs were reported during this trial, all were considered mild or moderate in severity. During the first 7 days of the trial, 25 AEs were reported in 11 patients. The majority of AEs were considered as possibly related to the study medication. No deaths or serious adverse events were reported. Physical examination at the last trial visit revealed no clinically relevant changes versus baseline and there were no consistent changes over time in vital signs. The BARS and SAS scores indicated an improvement of EPS during the study. After 4 days of fast titration, the mean total PANSS score decreased from 92.8 at baseline to a value of 87.4, there was a further decrease to 78.2 at endpoint. This corresponds to a statistically significant decrease by 14.6 versus baseline (P<0.01). After 4 days of fast titration, the mean CGI-S score was improved from 4.7 at baseline to a value of 4.3 and improved further to 3.8 at endpoint, corresponding to a statistically significant decrease of 0.9 points versus baseline (P<0.01). Conclusion. In this study, fast titration of quetiapine to 800 mg/day over 4 days was generally well tolerated and effective in reducing psychotic symptoms in patients requiring hospitalization for schizophrenia/schizoaffective disorder.     

Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials

OBJECTIVES: The efficacy of lamotrigine as maintenance treatment for bipolar disorder (BD), particularly for delaying depressive episodes, is well established, but its efficacy in the acute treatment of bipolar depression is less clear. This paper reports the results of five randomized, double-blind, placebo-controlled trials of lamotrigine monotherapy for the acute treatment of bipolar depression. METHODS: Adult subjects with bipolar I or II disorder experiencing a depressive episode were randomized to placebo or lamotrigine monotherapy (after titration, at a fixed dose of 50 mg or 200 mg daily in Study 1; a flexible dose of 100-400 mg daily in Study 2; or a fixed dose of 200 mg daily in Studies 3, 4 and 5) for 7-10 weeks. RESULTS: Lamotrigine did not differ significantly from placebo on primary efficacy endpoints [17-item Hamilton Depression Rating Scale in Studies 1 and 2; Montgomery-Asberg Depression Rating Scale (MADRS) in Studies 3, 4 and 5]. In Study 1, lamotrigine significantly separated from placebo on some secondary measures of efficacy, including the MADRS, the Clinical Global Impressions-Severity (CGI-S) and the CGI-Improvement (CGI-I), but seldom differed on secondary efficacy endpoints for the other studies. CONCLUSIONS: Lamotrigine monotherapy did not demonstrate efficacy in the acute treatment of bipolar depression in four out of five placebo-controlled clinical studies. Lamotrigine was well tolerated in the acute treatment of bipolar depression.     

双相情感障碍混合相临床特征对照研究

目的:了解双相情感障碍混合相的临床特征。方法:收集42例双相情感障碍混合相患者(混合组)与93例无混合发作的双相情感障碍躁狂相的患者(躁狂组)住院治疗的临床资料进行对比。结果:混合组年龄稍低,多见于女性和独身者,性格多为外向型或中间型,首次发作多为抑郁,多伴有精神病性症状及自杀意念和企图。多元逐步回归分析提示,混合发作与自杀意念和企图、性格、性别、首次发作形式有显著的相关性。混合组具有易被误诊、住院时间长、疗效较差的特点。结论:双相情感障碍混合相临床表现具有特殊性、严重性及相应的难治性,应加强重视。     

Use of High Doses of Quetiapine in Bipolar Disorder Episodes are not Linked to High Activity of Cytochrome P4503A4 and/or Cytochrome P4502D6

The use of quetiapine for treatment of bipolar disorders at a higher dosage than the licensed range is not unusual in clinical practice. Quetiapine is predominantly metabolised by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP2D6. The large interindividual variability of those isozyme activities could contribute to the variability observed in quetiapine dosage. The aim of the present study is to evaluate if the use of high dosages of quetiapine in some patients, as compared to patients treated with a dosage in the licensed range (up to 800 mg/day), could be explained by a high activity of CYP3A4 and/or of CYP2D6. CYP3A4 activities were determined using the midazolam metabolic ratio in 21 bipolar and schizoaffective bipolar patients genotyped for CYP2D6. 9 patients were treated with a high quetiapine dosage (mean ± SD, median; range: 1467 ± 625, 1200; 1000–3000 mg/day) and 11 with a normal quetiapine dosage (433 ± 274, 350; 100–800 mg/day). One patient in the high dose and one patient in the normal dose groups were genotyped as CYP2D6 ultrarapid metabolizers. CYP3A4 activities were not significantly different between the two groups (midazolam metabolic ratio: 9.4 ± 8.2; 6.2; 1.7–26.8 vs 3.9 ± 2.3; 3.8; 1.5–7.6, in the normal dose group as compared to the high dose group, respectively, NS). The use of high quetiapine dosage for the patients included in the present study cannot be explained by variations in pharmacokinetics parameters such as a high activity of CYP3A4 and/or of CYP2D6.     

Oxcarbazepine: clinical experience with hospitalized psychiatric patients

Background: Oxcarbazepine (10-keto-carbamazepine) appears to be better tolerated and simpler to use than carbamazepine. It has antimanic effects but, as its potential clinical usefulness and tolerability in broad samples of psychiatric patients remain to be tested, we reviewed both the pharmacology of oxcarbazepine and our early experience with this new agent among psychiatric inpatients.
Methods: We reviewed medical records of all inpatients given oxcarbazepine in the first 15 months of its use at McLean Hospital. Data analyzed included dosing, presenting illnesses, other medications, clinical changes, and adverse effects.
Results: Oxcarbazepine was given to 56 inpatients (1.3% of admissions; 31 women, 25 men) presenting with depression (n = 23), mania (n = 19), or psychosis (n = 14). The discharge daily dose for the 43 patients (76%) taking oxcarbazepine was 831 mg/day, 34% higher in men than women, and fell by 9 mg/year-of-age. Oxcarbazepine was the only putative mood-stabilizing agent given at discharge in 19 of 43 cases (44%). It was discontinued in 20% of patients for apparent inefficacy, and 4% for adverse effects. Changes in CGI and GAF scores were similarly high across illnesses, and unrelated to days of use of oxcarbazepine or its dose.
Conclusions: Oxcarbazepine was well tolerated and simpler to use clinically than its precursor carbamazepine. This agent should be studied in controlled trials to test its efficacy in specific types of major psychiatric disorders, and particularly for long-term maintenance treatment in bipolar disorder.