Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group.

Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects.

The Medich giant platelet syndrome: two new cases.

Hypogranular platelet disorders in human subjects are relatively rare. They include the gray platelet syndrome, αδ storage pool deficiency, the Hermansky-Pudlak syndrome, and the white platelet syndrome. Perhaps the rarest of them all is the Medich giant platelet disorder. No additional cases of this condition have been reported since description of the first case in 2004. This study describes two children with thrombocytopenia and giant, hypogranular platelets found shortly after birth. Electron microscopic study of their platelets revealed sheets of membrane wrapped into tubes resembling scrolls. The scroll-like structures were open at both ends and often filled with glycogen particles. The abnormal structures are identical to those found in the initial case. As a result, the disorder can now be referred to as the Medich giant platelet syndrome.

Safety and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: pooled data from randomised, double-blind, placebo-controlled studies.

INTRODUCTION: Extended release quetiapine fumarate (quetiapine XR) is a new formulation that allows once-daily dosing and a titration regimen that is simpler than that of immediate release quetiapine (quetiapine IR) and may potentially increase patients' adherence to their prescribed medication. METHODS: The tolerability of quetiapine XR was examined in an analysis of pooled data from three Phase III, double-blind, placebo-controlled, randomised studies with quetiapine IR as a reference treatment. RESULTS: The overall incidence of adverse events (AEs) was similar for quetiapine XR (69.5%) and quetiapine IR (72.5%). Most AEs were mild to moderate in severity and in line with those observed with quetiapine IR. The more rapid dose titration of quetiapine XR did not produce any new safety concerns and was as well tolerated as the regimen for quetiapine IR. CONCLUSIONS: The results of this pooled analysis show that quetiapine XR administered once daily is generally as well tolerated as quetiapine IR given twice daily. These data, together with the simpler dose-titration of quetiapine XR that allowed therapeutically effective doses to be reached by Day 2, suggest that this formulation potentially may improve adherence in patients with schizophrenia.

Pharmacokinetic profiles of extended release quetiapine fumarate compared with quetiapine immediate release.

This 10-day, single-center, open-label, randomized, crossover study compared pharmacokinetic profiles and tolerability of extended release quetiapine fumarate (quetiapine XR) with quetiapine immediate release (quetiapine IR) in patients with schizophrenia, schizoaffective disorder or bipolar disorder. After a 2-day lead-in period during which patients received quetiapine XR 300 mg once daily, patients were randomized to quetiapine IR 150 mg twice daily followed by quetiapine XR 300 mg once daily, or quetiapine XR 300 mg once daily followed by quetiapine IR 150 mg twice daily. Pharmacokinetic parameters were evaluated at the end of each 4-day treatment period at steady state. Vital signs, laboratory values, and adverse events (AEs) were recorded throughout the study. The least squares means (90% confidence interval) of the ratio of the area under the plasma concentration-time curve over a 24 h dosing interval (AUC ([0-24 h])) for quetiapine XR/IR was 1.04 (0.92-1.19) and within the pre-defined range set for equivalence (0.80-1.25). Maximum plasma concentration at steady state (C(max)) was approximately 13% lower for quetiapine XR than for quetiapine IR (495.3 versus 568.1 ng/mL), time to reach C(max) (t(max)) was 5 h versus 2 h and mean concentration at the end of 24 h dosing interval (C(min)) was 95.3 versus 96.5 ng/mL, respectively. No patients withdrew from the study owing to AEs and there were no serious AEs or deaths related to study medication. No unexpected AEs, changes in vital signs or laboratory values were observed. These findings suggest that modifying the formulation does not change the overall absorption or elimination of quetiapine, and support emerging clinical evidence for the use of quetiapine XR as a once daily treatment in patients initiating therapy or those established on quetiapine IR.

The psychometric validation of the Sheehan Disability Scale (SDS) in patients with bipolar disorder.

Bipolar disorder (BD) adversely affects daily activities/functioning. The Sheehan Disability Scale (SDS) assesses disability in work/school activities, family relationships, and social functioning, and it evaluates the functional impact of psychiatric disorders. BD outpatients from 21 U.S. sites completed a battery of validated instruments (including the SDS) three times over 8-12 weeks. Instrument reliability (internal consistency, test-retest), validity (construct, convergent validity, known groups) and responsiveness were measured. There were missing data for the SDS in 2% of the 225 subjects with BD. One factor explained 82% of the variance. All SDS items had rotated factor loadings on the first factor >0.90, confirming the appropriateness of the SDS total score. Item-scale correlations surpassed 0.40. There was excellent internal consistency reliability for the SDS total score (Cronbach's alpha=0.89). Test-retest reliability was acceptable for the SDS total score (intraclass correlation coefficient=0.73). Correlations with other instruments demonstrate convergent and divergent validity. The SDS total and item scores significantly discriminated between (self-rated) overall health status, clinician-rated functional status, and clinician-rated depression, evidencing known group validity. The SDS demonstrated ability to detect change over time. The SDS is a valid, reliable measure of disability and is responsive to change over time when used in subjects with BD.

Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126).

BACKGROUND: This study examined the efficacy and safety of quetiapine in combination with lithium or divalproex compared with placebo with lithium or divalproex in the prevention of recurrent mood events in bipolar I patients, most recent episode mania, depression, or mixed. METHODS: Patients received open-label quetiapine (400-800 mg/day; flexible, divided doses) with lithium or divalproex (target serum concentrations 0.5-1.2 mEq/L and 50-125 microg/mL, respectively) for up to 36 weeks to achieve at least 12 weeks of clinical stability. Patients were subsequently randomized to double-blind treatment with quetiapine (400-800 mg/day) plus lithium/divalproex or placebo plus lithium/divalproex for up to 104 weeks. The primary endpoint was time to recurrence of any mood event. RESULTS: Treatment with quetiapine in combination with lithium/divalproex significantly increased the time to recurrence of any mood event compared with placebo plus lithium/divalproex. The proportion of patients having a mood event was markedly lower in the quetiapine than in the placebo group (18.5% versus 49.0%). The hazard ratio for time to recurrence of a mood event was 0.28 (P<0.001), a mania event 0.30 (P<0.001), and a depression event 0.26 (P<0.001) corresponding to risk reductions of 72%, 70%, and 74%, respectively. During the randomization phase, the most common adverse events occurring in > or =5% in the quetiapine group were somnolence, nasopharyngitis, and headache. Insomnia was more common in the placebo group. During the randomization phase, there was an increase in weight of 0.5 kg in the quetiapine group and a reduction of 1.9 kg in the placebo group. The incidence and incidence density of a single emergent fasting blood glucose value> or =126 mg/dL was higher with quetiapine than with placebo (9.3% versus 4.1%; 17.6 versus 9.5 patients per 100 patient-years). LIMITATIONS: This was an enriched sample of patients with bipolar I disorder responding to treatment with quetiapine plus lithium/divalproex. CONCLUSIONS: Maintenance treatment with quetiapine in combination with lithium/divalproex significantly increased time to recurrence of any event (mania, depression, or mixed) irrespective of the polarity of the index episode compared with placebo with lithium/divalproex. Long-term treatment with quetiapine was generally well-tolerated. Quetiapine with lithium/divalproex can provide an effective long-term treatment option for bipolar I disorder to prevent recurrences not only of mania but also depression.

Evaluation of the feasibility of switching from immediate release quetiapine to extended release quetiapine fumarate in stable outpatients with schizophrenia.

This double-blind, double-dummy study (D1444C00146) evaluated the efficacy and safety of switching patients with clinically stable schizophrenia from quetiapine immediate release (IR) to the same dose of once-daily extended release quetiapine fumarate (quetiapine XR). Patients received quetiapine IR 400-800 mg/day twice daily for 4 weeks, and were then randomized (2 : 1) to a once-daily equivalent dose of quetiapine XR or maintained on IR for 6 weeks. The primary variable was the proportion of patients who discontinued treatment owing to lack of efficacy or whose Positive and Negative Syndrome Scale scores increased by at least 20% from randomization to any visit. In total, 497 patients were randomized to quetiapine XR (n=331) or IR (n=166). Noninferiority (6% margin; one-sided test, 2.5% significance level) was narrowly missed for the primary efficacy variable for the modified intention-to-treat population (9.1%, quetiapine XR; 7.2%, quetiapine IR; difference 1.86%; 95% confidence interval: -3.78, 6.57; P=0.0431), but was shown for the per-protocol population (5.3%, quetiapine XR; 6.2%, quetiapine IR; difference: -0.83%; 95% confidence interval: -6.75, 3.71; P=0.0017). Serious adverse event incidence was low for quetiapine XR and IR; there were no unexpected adverse events. In conclusion, efficacy was maintained without compromising safety/tolerability when switching patients with stable schizophrenia from twice-daily quetiapine IR to once-daily quetiapine XR (400-800 mg/day).

Treatment of agitation and aggression in bipolar mania: efficacy of quetiapine.

OBJECTIVE: Agitation and aggression are potentially disruptive and dangerous features of bipolar mania. This analysis evaluated the effects of quetiapine on agitation and aggression in patients with bipolar I mania. METHODS: Four double-blind, randomized, controlled trials were conducted using similar protocols; 407 patients with bipolar I mania were randomized to quetiapine monotherapy (200-800 mg/day) or placebo for 12 weeks, and 402 patients were randomized to quetiapine (200-800 mg/day) or placebo in combination with lithium (Li) or divalproex (DVP) for 3 or 6 weeks. Measurements of agitation included the Positive and Negative Syndrome Scale (PANSS) Activation subscale, PANSS Supplemental Aggression Risk subscale scores, and Young Mania Rating Scale (YMRS) items relevant to agitation. RESULTS: Initial reductions in both the PANSS Activation and PANSS Supplemental Aggression Risk subscale scores were noted by Day 4 with quetiapine and placebo. The reduction in PANSS Activation subscale scores was significantly greater with quetiapine monotherapy than placebo first at Day 21 (-3.5 versus -1.4, P<0.001) and also at Day 84 (-4.8 versus -1.2, P<0.001). The improvement in PANSS Supplemental Aggression Risk subscale score was significantly greater with quetiapine monotherapy than placebo by Day 14 (P<0.01) and all time points thereafter including Day 21 (-4.0 versus -1.8, P<0.001) and Day 84 (-5.6 versus -1.7, P<0.001). In combination therapy, the mean improvement in PANSS Activation subscale score at Day 21 was numerically but not significantly different with QTP+Li/DVP than PBO+Li/DVP (-4.2 versus -3.2, P=0.087). The mean PANSS Supplemental Aggression Risk subscale scores were significantly improved at Day 21 with QTP+Li/DVP versus PBO+Li/DVP (-5.05 versus -3.69, P<0.05). CONCLUSIONS: Quetiapine is an effective and appropriate treatment choice in managing agitation and aggression associated with bipolar mania.

Safety and tolerability of quetiapine in the treatment of acute mania in bipolar disorder.

OBJECTIVE: To review the safety/tolerability of quetiapine in four placebo-controlled studies in patients with bipolar I disorder experiencing acute mania. METHODS: Four double-blind, placebo-controlled studies evaluated quetiapine monotherapy (12 weeks) or quetiapine in combination with lithium (mean serum concentration 0.76 mEq/L) or divalproex (mean serum concentration 68.6 microg/mL) (Li/DVP) (3 and 6 weeks) in patients with acute mania. Pooled data from the two monotherapy studies and the two combination therapy studies have been evaluated in the analysis presented here. Adverse event reporting, Simpson Angus Scale (SAS), and Barnes Akathisia Rating Scale (BARS) scores were recorded. RESULTS: Most adverse events were mild to moderate. Common adverse events (> or = 5% and at least twice the placebo rate) with quetiapine monotherapy and combination therapy were somnolence, dry mouth, weight gain, dizziness, asthenia, pharyngitis, and postural hypotension. Treatment-related discontinuations due to adverse events were not significantly different between quetiapine and placebo, nor was the incidence of extrapyramidal symptoms (including akathisia) (quetiapine monotherapy 12.9% vs placebo 13.1%; combination therapy 21.4% vs placebo 19.2%). Mean change from baseline to endpoint in SAS and BARS scores was not significantly different between groups. Mean weight change at treatment end with quetiapine compared with placebo was +1.8 vs -0.15 kg in monotherapy; and +1.97 vs +0.27 kg with combination therapy. No patients discontinued due to weight gain. The effect of quetiapine monotherapy on serum prolactin levels was no different from placebo. CONCLUSIONS: Quetiapine monotherapy and combination therapy were well tolerated in the treatment of acute mania.

DNA vaccine expressing the mimotope of GD2 ganglioside induces protective GD2 cross-reactive antibody responses.

The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly immunoglobulin (Ig)-M antibody responses in the immunized host. Here, we investigated whether interconversion of GD2 into a peptide mimetic form would induce GD2 cross-reactive IgG antibody responses in mice. Screening of the X(15) phage display peptide library with the anti-GD2 monoclonal antibody (mAb) 14G2a led to isolation of mimetic peptide 47, which inhibited the binding of 14G2a antibody to GD2-positive tumor cells. The peptide was also recognized by GD2-specific serum antibodies from a patient with neuroblastoma, suggesting that it bears an internal image of GD2 ganglioside expressed on the tumor cells. The molecular basis for antigenicity of the GD2 mimetic peptide, established by molecular modeling and mutagenesis studies, led to the generation of a 47-LDA mutant with an increased mimicry to GD2. Immunization of mice with peptide 47-LDA-encoded plasmid DNA elicited GD2 cross-reactive IgG antibody responses, which were increased on subsequent boost with GD2 ganglioside. The vaccine-induced antibodies recognized GD2-positive tumor cells, mediated complement-dependent cytotoxicity, and exhibited protection against s.c. human GD2-positive melanoma growth in the severe combined immunodeficient mouse xenograft model. The results from our studies provide insights into approaches for boosting GD2 cross-reactive IgG antibody responses by minigene vaccination with a protective epitope of GD2 ganglioside.

Improvement in social competence with short-term atypical antipsychotic treatment: a randomized, double-blind comparison of quetiapine versus risperidone for social competence, social cognition, and neuropsychological functioning.

OBJECTIVE: While neuropsychological test performance is correlated with social outcomes in patients with schizophrenia, there is little evidence to date that changes in neuropsychological performance are associated with changes in these outcomes. As part of an efficacy and tolerability study of atypical antipsychotics, the authors used a performance-based measure of social competence as a short-term outcome measure and examined the correlations between changes in social competence and improvements on neuropsychological tests. METHOD: Patients with schizophrenia were randomly assigned in a 1:1 ratio to receive treatment with either quetiapine (dose range: 200-800 mg/day) or risperidone (dose range: 2-8 mg/day) for an 8-week period. RESULTS: Of 673 patients initially randomized, 289 had baseline and endpoint neuropsychological and functional competence data. Scores on the performance-based measure of social competence significantly improved with both treatments, as did a number of aspects of neuropsychological performance. Improvements in several aspects of neuropsychological performance were correlated with the extent of improvement in social competence. There were no overall differences between the treatments in their impact on social competence and neuropsychological performance. CONCLUSIONS: Short-term treatment with both quetiapine and risperidone resulted in improvements in social competence, with these improvements associated with improvements on some of the neuropsychological measures. In addition to their clinical importance, these results support the use of performance-based competence assessments as outcome measures in clinical trials.

A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder.

OBJECTIVE: To evaluate the efficacy and tolerability of quetiapine monotherapy versus placebo for the treatment of mania associated with bipolar disorder. METHOD: In an international, multicenter, double-blind, parallel-group, 12-week study, patients with a DSM-IV diagnosis of bipolar I disorder (manic episode) were randomly assigned to treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or lithium. The primary efficacy measure was change from baseline in Young Mania Rating Scale (YMRS) score at day 21. Data were gathered from April 2001 to May 2002. RESULTS: More patients in the quetiapine (72/107) and lithium (67/98) groups completed the study compared with the placebo group (35/97). Improvement (reduction) in YMRS score was significantly greater for quetiapine than placebo at day 7 (-8.03 vs. -4.89; p < .01), and the difference between groups continued to increase over time to day 21 (-14.6 vs. -6.7; p < .001) and to endpoint at day 84 (-20.3 vs. -9.0; p < .001). Significantly more quetiapine patients compared with placebo patients fulfilled YMRS response criteria at day 21 (53.3% vs. 27.4%; p < .001) and at day 84 (72.0% vs. 41.1%; p < .001). Quetiapine was also superior to placebo in efficacy at day 21 and day 84 by all secondary measures. Lithium-treated patients improved significantly compared with placebo patients and similarly to quetiapine-treated patients on the primary efficacy measure. The most common adverse events for quetiapine were dry mouth, somnolence, and weight gain, while lithium was associated with tremor and insomnia. The quetiapine and placebo groups had similar, low levels of extrapyramidal symptom-related adverse events. CONCLUSIONS: Quetiapine demonstrated superior efficacy to placebo in patients with bipolar mania and was well tolerated.

Quetiapine or haloperidol as monotherapy for bipolar mania--a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial.

METHODS: Patients (n=302) with bipolar I disorder (manic episode) were randomised to 12 weeks' double-blind treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or haloperidol (up to 8 mg/day). The primary efficacy outcome variable was change from baseline to Day 21 in Young Mania Rating Scale (YMRS) score. RESULTS: YMRS score improved with quetiapine at Day 21 (-12.29 versus -8.32 for placebo; P<0.01). The difference in favor of quetiapine increased by Day 84 (-17.52 versus -9.48; P<0.001). Haloperidol also showed an advantage over placebo at Days 21 and 84 (P<0.001). There was no significant difference in efficacy measures between quetiapine and haloperidol groups at any assessment except Day 21. The only common adverse event with quetiapine was somnolence (12.7%). Extrapyramidal symptoms (EPS), including akathisia, occurred at 59.6% with haloperidol, 12.7% with quetiapine, 15.8% with placebo. Most quetiapine responders (84%) received a dose of 400-800 mg/day. CONCLUSIONS: Quetiapine was effective and well tolerated. The efficacy and tolerability profile of haloperidol (including its propensity for EPS) supported study validity.

Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomised, placebo-controlled studies.

OBJECTIVE: To evaluate the efficacy and safety of quetiapine monotherapy for mania in bipolar disorder by an a priori defined combined analysis of data from two placebo-controlled studies. METHOD: The intent-to-treat (ITT) populations from two studies of patients with DSM-IV bipolar I disorder, manic episode, randomised to 12 weeks of double-blind treatment with quetiapine (up to 800 mg/day) or placebo were combined. The primary efficacy endpoint was change in Young Mania Rating Scale (YMRS) score from baseline to Day 21. Secondary endpoints included change from baseline in YMRS to Day 84, YMRS response and remission rates and change from baseline to Days 21 and 84 in the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions (CGI), Clinical Global Impressions-Bipolar (CGI-BP) and the Positive and Negative Syndrome Scale (PANSS). These endpoints were analysed as continuous variables, using an analysis of covariance (ANCOVA), with the baseline as covariate. In order to account for any difference in response between studies, the analyses were stratified by study as a fixed effect, and centre as a random effect. The Cochran-Mantel-Haenszel test was used to analyse binary variables. A chi square test was used to compare the frequency of adverse events between the treatment groups. RESULTS: The combined analysis included a total of 403 patients from two quetiapine monotherapy studies in patients with bipolar I disorder. A significant improvement in YMRS score was observed from Day 4 (p = 0.021) onward in the quetiapine group compared with placebo. The treatment advantage of quetiapine over placebo continued to increase to Day 21 (p < 0.001) and Day 84 (p < 0.001). Significantly more quetiapine-treated than placebo-treated patients achieved a response (p < 0.001). The average quetiapine dose in responders was approximately 600 mg daily. Of adverse events occurring in > or = 5% of patients, quetiapine-treated patients had a significantly greater incidence versus placebo of somnolence (16.3% vs. 4.0%), dry mouth (15.8% vs. 3%), weight gain (9.1% vs. 1.5%) and dizziness (6.7% vs. 2.5%). CONCLUSIONS: The data from this combined analysis support the results from the individual studies and indicate that quetiapine monotherapy is effective across a broad range of mood symptoms, fast-acting and well tolerated in the treatment of mania.

Precursor B lymphoblastic leukemia with surface light chain immunoglobulin restriction: a report of 15 patients.

We describe 15 patients (9 children) with precursor B-cell (pB) acute lymphoblastic leukemia (ALL) with surface immunoglobulin (sIg) light chain restriction revealed by flow cytometric immunophenotyping (FCI). The same sIg+ immunophenotype was present at diagnosis and in 3 relapses in 1 patient. In 15 patients, blasts were CD19+ CD10+ (bright coexpression) in 14, CD34+ in 12, surface kappa+ in 12, surface lambda+ in 3; in 8 of 8, terminal deoxyribonucleotidyl transferase (TdT)+; and in 4, surface IgD+ in 2 and surface IgM+ in 1. The 3 CD34- cases included 1 TdT+ case, 1 with t(1;19)(q23;p13), and 1 infant with 70% marrow blasts. One adult had CD10- CD19+ CD20- CD22+ CD34+ TdT+ sIg+ blasts with t(2;11)(p21;q23). Blasts were L1 or L2 in all cases (French-American-British classification). Karyotypic analysis in 12 of 12 analyzable cases was negative for 8q24 (myc) translocation. Karyotypic abnormalities, confirmed by fluorescence in situ hybridization in 6 cases, included hyperdiploidy, t(1;19)(q23;p13), t(12;21)(p13;q22), t(9;22)(q34;q11), t(2;11)(p21;q23), and trisomy 12. The sIg light chain restriction in pB ALL might be present in neoplasms arising from the early, intermediate, and late stages of precursor B-cell maturation; sIg light chain restriction revealed by FCI does not necessarily indicate a mature B-cell phenotype, further emphasizing the importance of a multidisciplinary approach to diagnosing B-lymphoid neoplasms.

The efficacy of quetiapine vs haloperidol and placebo: a meta-analytic study of efficacy.

INTRODUCTION: Atypical antipsychotics form a new class of treatment for psychotic disorders that offers advantages over conventional antipsychotics, such as haloperidol. Among these advantages is a lower risk of side effects-in particular movement disorders. The atypical antipsychotics that are currently commercially available are clozapine, risperidone, olanzapine, quetiapine, and ziprasidone. The focus of this report is on the efficacy of quetiapine. DATA SOURCES/STUDY SELECTION: A meta-analysis was performed on three placebo- and five haloperidol-controlled clinical trials of quetiapine. Efficacy was assessed using the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression (CGI), and the Scale for the Assessment of Negative Symptoms (SANS). In addition, a responder analysis was performed assessing patients who demonstrated a 40% improvement on the BPRS total score. RESULTS: The results showed that quetiapine was significantly (p<0.05) superior to placebo in improving psychotic symptoms. In addition, quetiapine was not significantly different from haloperidol on measures of efficacy measured by BPRS change score, but was superior to haloperidol in terms of response rate using observed case analysis (but not using last observation carried forward analysis). CONCLUSION: This meta-analysis supports the use of quetiapine as a front-line treatment for schizophrenia.

Maintenance of long-term efficacy and safety of quetiapine in the open-label treatment of schizophrenia.

As schizophrenia is a chronic disorder, it is important that treatment be given over a long period of time to avoid relapse. Quetiapine, an atypical antipsychotic, has established efficacy and good tolerability in the short-term treatment of schizophrenia. This study investigated the long-term efficacy and safety of quetiapine in 674 patients with schizophrenia using combined data from the open-label extension phase of four Phase IIIa trials. The results showed that quetiapine, at a mean daily dose of 472.4 mg, provided progressive improvement and maintenance in the Brief Psychiatric Rating Scale total, positive- and negative-symptoms cluster, Clinical Global Impression Severity of Illness, and Scale for the Assessment of Negative Symptoms total scores over 208 weeks and beyond. Furthermore, quetiapine was well tolerated throughout the study period, with a low incidence of extrapyramidal symptom-related adverse events. In conclusion, quetiapine may be a suitable therapy in the long-term treatment of schizophrenia.

Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression.

OBJECTIVE: To evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression. METHODS: Blinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data. RESULTS: 1913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively). CONCLUSION: Early improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.

Long-term symptomatic remission of schizophrenia with once-daily extended release quetiapine fumarate: post-hoc analysis of data from a randomized withdrawal, placebo-controlled study.

Despite available effective medications, many patients with schizophrenia do not become completely symptom free. We report analyses of data from a randomized, double-blind, placebo-controlled relapse prevention study of extended release quetiapine fumarate (quetiapine XR) using Remission in Schizophrenia Working Group criteria for symptomatic remission. During 16-week open-label stabilization, patients with stable schizophrenia were switched from their current antipsychotic to quetiapine XR (400, 600 or 800 mg/day flexibly dosed). One hundred and ninety-seven patients were randomized to either quetiapine XR or placebo (planned for 1 year or until relapse). The study was terminated early because the planned interim analysis showed quetiapine XR to be statistically superior to placebo in the primary outcome variable (time to schizophrenia relapse). One hundred and eighty of 195 (92.3%) patients with an available Positive and Negative Syndrome Scale assessment met symptomatic remission criteria at randomization (following 16 weeks' quetiapine XR). The risk of losing symptomatic remission was statistically significantly higher with placebo versus quetiapine XR: hazard ratio 0.39 (95% confidence interval: 0.19-0.81, P=0.009), that is, 61% risk reduction for quetiapine XR-treated versus placebo-treated patients. At 6 months postrandomization, the probability that patients would be in remission was 76% for quetiapine XR and 52% for placebo. Once-daily quetiapine XR was effective in preserving symptomatic remission in the longer-term treatment of patients with schizophrenia.