QbTest for Monitoring Medication Treatment Response in ADHD: A Systematic Review.

Introduction: Attention deficit hyperactivity disorder (ADHD) is considered one of the most common neurodevelopmental disorders in childhood and adolescence. Pharmacological treatment plays an important part in the therapy of the disorder and verifying the effectiveness of ADHD medication is essential throughout the course of treatment. QbTest is a computerized test, for which intended use is to provide healthcare professionals with objective measurements of hyperactivity, impulsivity, and inattention to aid in the clinical assessment of ADHD and the evaluation of treatment interventions. Methods: A systematic review of relevant articles was conducted for which QbTest was used for monitoring medication treatment response in ADHD. Literature published between 2004 and 2023 was appraised. Results: A total of 15 studies were included in the review. Thirteen articles involved subjects diagnosed with ADHD and two studies that were related to the disorder, which evaluated QbTest in medication treatment response. Changes in QbTest data such as Q-scores, effect size, or improvement/deterioration of QbTest variables were evaluated. A clinically relevant decrease in QbTest Q-scores was found in the majority of the studies when treated with any type of ADHD medication in therapeutic doses, both in comparison to placebo and when compared from baseline to endpoint treatment. Conclusion: QbTest can distinguish pharmacological treatment effects within hours of pharmacological titration and can be used for monitoring of long-term treatment of ADHD. A need for optimization and individualization of medication treatment response could be addressed with access to objective measures in ADHD management.

Impact of extended-release quetiapine fumarate on hospitalization length and cost in schizophrenia and bipolar disorder patients: a retrospective, hospital-based, US-cohort analysis.

AIM: The aim was to evaluate the impact of quetiapine extended release (XR) on hospitalization length and cost in schizophrenia or bipolar disorder, versus quetiapine immediate release (IR), using Premier Perspective™ inpatient hospital database data. METHODS: Inpatient discharges classified within diagnosis-related group 430 (psychoses), prescribed quetiapine XR or IR, were identified. Patients had International Classification of Disease-9 diagnosis of schizophrenia or bipolar disorder. The impact of the XR formulation on hospitalization length and costs was assessed using generalized linear model analyses. RESULTS: A total of 30,429 discharges between 1 January 2008 and 30 June 2009 were analyzed. Patients who received quetiapine XR had significantly reduced hospitalization length (10.73% estimated reduction; p = 0.001) and cost (9.52% estimated reduction; p < 0.001), versus IR. This corresponds to a 1.0-day reduction in hospitalization (10.73% of 9.2 days) and US$532 reduction in hospitalization cost (9.52% of US$5588) per patient, based on least squares mean estimations. Evaluation of patient subpopulations suggested the reduction in length of hospitalization for quetiapine XR versus IR was driven mainly by patients with bipolar disorder, whereas cost reduction was driven mainly by patients with schizophrenia. CONCLUSION: Inpatient use of quetiapine XR in schizophrenia or bipolar disorder is associated with reduced hospitalization length and cost, possibly due to the faster titration schedule versus quetiapine IR.

Extended release quetiapine fumarate as adjunct to antidepressant therapy in patients with major depressive disorder: pooled analyses of data in patients with anxious depression versus low levels of anxiety at baseline.

OBJECTIVES: To evaluate quetiapine XR in patients with anxious depression, as defined by HAM-A total and HAM-D anxiety/somatisation factor scores. METHODS: Post hoc analyses of pooled data from two 6-week, double-blind, randomised, placebo-controlled studies of adjunctive quetiapine XR (150 or 300 mg/day) in patients with MDD and inadequate response to antidepressants. Patients were stratified in a primary analysis using HAM-A (HAM-A total score at baseline ≥ 20 ["high"] or < 20 ["low"]) and a secondary analysis using HAM-D (anxious depression defined as HAM-D anxiety/somatisation factor score ≥ 7). Outcomes included change in MADRS total score. RESULTS: In patients with high anxiety levels (HAM-A total score ≥ 20), reductions in MADRS total score were -15.20 (P = 0.122) and -15.92 (P < 0.05) for quetiapine XR 150 and 300 mg/day, respectively, vs. placebo (-13.49). In patients with low levels of anxiety (HAM-A total score < 20), both quetiapine XR doses (P < 0.001) improved MADRS total scores vs. placebo. In the secondary analysis, quetiapine XR 150 (P < 0.01) and 300 mg/day (P < 0.001) improved MADRS total score vs. placebo in patients with HAM-D anxiety/somatisation factor score ≥ 7. CONCLUSIONS: Adjunct quetiapine XR demonstrates efficacy in patients with anxious and non-anxious depression, assessed using HAM-A total score, and anxious depression assessed using HAM-D anxiety/somatisation factor score.

Maintenance treatment with quetiapine when combined with either lithium or divalproex in bipolar I disorder: analysis of two large randomized, placebo-controlled trials.

BACKGROUND: To determine the efficacy and safety of quetiapine combined with lithium or divalproex for preventing mood events in patients with bipolar I disorder. In this pooled analysis of two similar long-term studies (D1447C00126 [NCT00107731] and D1447C00127 [NCT00081380]), lithium and divalproex treatment groups were analyzed separately. METHODS: Patients received open-label quetiapine (400-800 mg/d) plus lithium or divalproex to achieve ≥12 weeks of clinical stability before being randomized to double-blind combination treatment with quetiapine (400-800 mg/d) or placebo plus lithium or divalproex for up to 104 weeks. The primary endpoint was time to first mood event postrandomization following open stabilization. RESULTS: Of 3,414 patients in the stabilization phase, 1,326 were randomized. There were no differences in the risk of recurrence of mood, mania, or depression between quetiapine plus lithium or quetiapine plus divalproex. Among patients co-treated with placebo and lithium, the risk of recurrence of a mania event was significantly higher than among patients co-treated with placebo and divalproex. In patients with an index episode of mania, placebo plus lithium was associated with a significantly higher risk of recurrence of a mania event than placebo plus divalproex. Safety data were generally consistent with recognized safety profiles. CONCLUSIONS: In patients with bipolar I disorder previously stabilized on quetiapine and lithium or divalproex, maintenance therapy with quetiapine significantly increased the time to recurrence of a mood event (mania or depression) versus placebo, regardless of whether it was combined with lithium or divalproex.

Quetiapine XR monotherapy in major depressive disorder: a pooled analysis to assess the influence of baseline severity on efficacy.

The efficacy of quetiapine XR was investigated in patients with major depressive disorder and differing levels of baseline severity. Pooled data from four placebo-controlled monotherapy studies of quetiapine XR (50-300 mg/day) were analyzed. Post-hoc analyses were carried out to assess change from baseline in the Montgomery Åsberg Depression Rating Scale (MADRS) total score at endpoint (week 6 or 8) to week 1, and response (≥50% reduction in MADRS total score) and remission (MADRS total score≤10) rates at endpoint for all patients and six baseline severity cohorts (MADRS total score ≥24, ≥26, ≥28, ≥30, ≥32, and ≥34). In total, 1752 patients (all patients) were evaluated (MADRS score at baseline: ≥24, n=1601; ≥26, n=1467; ≥28, n=1269; ≥30, n=1038; ≥32, n=745; and ≥34, n=500). At endpoint, quetiapine XR reduced MADRS total score in all patients (P<0.001) and each severity cohort (≥24, ≥26, ≥28, ≥30, and ≥32, P<0.001; ≥34, P<0.01) versus placebo. Quetiapine XR also improved MADRS total score at week 1, response rates for each severity cohort, and remission rates in five out of six severity cohorts, versus placebo. Quetiapine XR monotherapy showed antidepressant effects in patients with major depressive disorder across different levels of baseline severity.

Quetiapine monotherapy in bipolar II depression: combined data from four large, randomized studies.

BACKGROUND: Despite being present in up to 1% of the population, few controlled trials have examined the efficacy of treatments for bipolar II depression. Pooled data are presented from four placebo-controlled studies (BOLDER I [5077US/0049] and II [D1447C00135]; EMBOLDEN I [D1447C00001] and II [D1447C00134]) that evaluated the efficacy of quetiapine monotherapy for depressive episodes in patients with bipolar II disorder. METHODS: All studies included an 8-week, double-blind treatment phase in which patients were randomly assigned to treatment with quetiapine 300 mg/day, quetiapine 600 mg/day, or placebo. Outcome measures included the change from baseline in MADRS total score at week 8, effect sizes, and MADRS response and remission rates. RESULTS AND DISCUSSION: Improvements in mean MADRS total scores from baseline to week 8 were significantly greater with quetiapine 300 and 600 mg/day (-15.58 [n = 283] and -14.88 [n = 289]; p < 0.001) compared with placebo (-11.61 [n = 204]). The MADRS effect sizes were 0.44 for quetiapine 300 mg/day and 0.47 for 600 mg/day (p < 0.001 vs placebo). Significantly higher proportions of patients receiving quetiapine, at both doses, than placebo-treated patients achieved response and remission at week 8 (p < 0.01). Common adverse events associated with quetiapine (both doses) included dry mouth, somnolence, sedation, dizziness, and headache. Rates of mania and hypomania were similar for quetiapine and placebo. Quetiapine monotherapy demonstrated significant efficacy compared with placebo and was generally well tolerated in the treatment of bipolar II depression.

Long-term efficacy of quetiapine in combination with lithium or divalproex on mixed symptoms in bipolar I disorder.

BACKGROUND: To evaluate quetiapine in patients with bipolar I disorder with mixed symptoms. METHODS: Data from 2 studies (D1447C00126, D1447C00127) were pooled and mixed events analyzed separately. Patients received quetiapine (400-800mg/day) plus lithium/divalproex to achieve ≥12 weeks of clinical stability, followed by double-blind quetiapine (400-800mg/day) or placebo, plus lithium/divalproex, for up to 104 weeks. Primary endpoint was time to first mood event post-randomization. RESULTS: The ITT population included 1326 patients, of whom 445 had a mixed episode at study entry, 219 received quetiapine plus lithium/divalproex, and 226 received placebo plus lithium/divalproex. Mood events were reported by fewer quetiapine-plus-lithium/divalproex than placebo-plus-lithium/divalproex-treated patients (21.0% vs 54.0%), and included mixed (6.4% vs 22.1%), pure manic (5.0% vs 13.3%), and pure depressed events (9.6% vs 18.6%). Hazard ratios (HR) for time to recurrence were longer for quetiapine plus lithium/divalproex than placebo plus lithium/divalproex for mixed (HR=0.23; 95% CI: 0.13-0.42; p<0.0001), pure manic (HR=0.30; 95% CI: 0.15-0.60; p=0.0007), and pure depressed events (HR=0.38; 95% CI: 0.22-0.64; p=0.0003). No new safety concerns were noted. LIMITATIONS: The post hoc nature of the analyses as patients were not randomized according to index symptom status. CONCLUSIONS: In stable patients with bipolar I disorder, quetiapine plus lithium/divalproex significantly increased time to recurrence of mood events versus placebo in patients with mixed symptoms at study entry and time to occurrence of mixed-mood events in patients with any mood episode at study entry.

Extended release quetiapine fumarate in major depressive disorder: analysis in patients with anxious depression.

BACKGROUND: A pooled analysis was performed on data from two studies evaluating the efficacy of once-daily extended-release quetiapine fumarate (quetiapine XR) monotherapy for patients with major depressive disorder. Through these analyses (based on Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) measures), we aim to further evaluate the efficacy of quetiapine XR in depressed patients with high levels of anxiety symptoms. METHODS: Secondary analyses were conducted of pooled individual patient data from two 8-week (6-week randomized phase, 2-week drug discontinuation phase), double-blind, placebo-controlled studies of quetiapine XR (50-300 mg/day). Outcomes included change from randomization at Week 6 in Montgomery Åsberg Depression Rating Scale (MADRS) total score for patients with anxious and nonanxious depression. RESULTS: Of 968 patients included in the analysis, 788 (81.4%) were classified as anxious depressed (defined as HAM-D anxiety/somatization factor score ≥ 7) and 180 (18.6%) were nonanxious. For patients with anxious depression and nonanxious depression, statistically significant differences versus placebo in MADRS total score were recorded for quetiapine XR 150 mg/day (-3.24, P < .001 and -4.82, P < .01, respectively) and 300 mg/day (-3.57, P < .001 and -3.39, P < .05, respectively) at Week 6. In the second analysis using an alternate definition of anxious depression (baseline HAM-A total score ≥ 20), quetiapine XR 150 and 300 mg/day resulted in significant differences versus placebo in MADRS total score reduction in patients with high and lower levels of anxiety. The adverse event (AE) profile was similar irrespective of baseline anxiety levels, although patients with anxious depression reported a somewhat greater incidence of AEs. CONCLUSION: Quetiapine XR monotherapy improved symptoms of depression in patients with higher and lower levels of anxiety.

Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies.

OBJECTIVE: To evaluate the efficacy and tolerability of quetiapine monotherapy for anxiety symptoms in patients with bipolar disorder experiencing depression in the BipOLar DEpRession (BOLDER I and II) studies. METHOD: A post hoc analysis of anxiety symptoms in 1,051 acutely depressed patients with bipolar I or II disorder (DSM-IV) from 2 double-blind, randomized, placebo-controlled 8-week studies of quetiapine (300 or 600 mg once daily) was conducted. Anxiety symptoms were assessed using Hamilton Anxiety Rating Scale (HARS) total and psychic (items 1-6, 14) and somatic (items 7-13) anxiety subscale scores (mixed-model repeated measure and last-observation-carried-forward analysis of change from baseline at each assessment). The BOLDER I study was conducted between September 2002 and October 2003, and the BOLDER II study was conducted between June 2004 and August 2005. RESULTS: Mean baseline HARS total scores were similar across the treatment groups (300 mg/d: 18.9, 600 mg/d and placebo: both 18.6). There was a significantly greater improvement from baseline in mean HARS total scores at the first evaluation (week 1) in both quetiapine groups compared with placebo (300 mg/d: -4.6, P < .001 and 600 mg/d: -4.1, P = .003 vs placebo: -2.8). These improvements were sustained through week 8 with both quetiapine doses (300 mg/d: -10.1, P < .001 and 600 mg/d: -10.5, P < .001 vs placebo: -6.9). At week 8, there was also significant improvement from baseline in HARS psychic and somatic anxiety subscale scores compared with placebo (P < .001). The baseline severity of anxiety did not impact the improvement in depressive symptoms. Common adverse events included dry mouth, sedation, somnolence, and dizziness. CONCLUSIONS: In this pooled analysis, quetiapine monotherapy was more effective than placebo and generally well tolerated for the treatment of both depressive and anxiety symptoms in patients with bipolar disorder. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00060489 (BOLDER I) and NCT00083954 (BOLDER II).

Quetiapine monotherapy in the treatment of depressive episodes of bipolar I and II disorder: Improvements in quality of life and quality of sleep.

INTRODUCTION: The depressive symptoms of bipolar disorder impact health-related quality of life, quality of sleep and functioning. The BOLDER I and II trials demonstrated that quetiapine significantly improves depressive symptoms in patients with acute bipolar depression. Post-hoc analysis of the BOLDER I and II data permits a detailed investigation of the effects of quetiapine on these other measures in this patient population. METHODS: Secondary analysis was performed on data from BOLDER I and II, which were two 8-week, double-blind, randomized, placebo-controlled studies of quetiapine at fixed doses (300 or 600 mg/day) in a total of 1051 patients with acute depressive episodes of bipolar I or II disorder. Measures included the Short-Form Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q SF) in BOLDER I and II, the Pittsburgh Sleep Quality Index (PSQI) in BOLDER I, and the Sheehan Disability Scale (SDS) in BOLDER II. Analyses of Q-LES-Q SF score changes were based on data from the combined BOLDER I and II populations, and analyses of PSQI and SDS score changes were based on BOLDER I and BOLDER II populations, respectively. RESULTS: Assessments at day 57 by mixed-model repeated measures analysis demonstrated that quetiapine relative to placebo provided significant or numerical improvements in rating scale score on the Q-LES-Q SF (10.89 with 300 mg/day and 12.14 with 600 mg/day vs. 7.79 with placebo; p<0.001 for each quetiapine dose), PSQI (-5.34 and -6.00 vs. -3.35; p<0.001, each dose), and SDS (-7.78 and -8.25 vs. -6.49; p=0.156 and 0.054, respectively). Effect sizes at day 57 with quetiapine 300 and 600 mg/day, respectively, were 0.34 and 0.46 for Q-LES-Q SF, 0.59 and 0.79 for PSQI, and 0.17 and 0.23 for SDS. Improvements were evident at first post-baseline assessment on day 29 and were consistent over the majority of rating scale domains. Quetiapine was generally well tolerated and most adverse events were of mild to moderate intensity. CONCLUSIONS: Quetiapine monotherapy is effective in improving impairment in important aspects of life that accompany improvements in depressive symptoms in patients with acute bipolar depression.

Ropivacaine may have advantages compared to bupivacaine in porcine endotoxemic shock.

Patients that undergo major abdominal surgery often receive epidural postoperative analgesia. Septic complications are frequently seen in this cohort. In a porcine model of endotoxemic shock, resembling human gram-negative septic shock, we evaluated the effects of two widely used local anaesthetics, bupivacaine and ropivacaine given intravenously. In the endotoxin-ropivacaine group mixed venous saturation and platelet count were higher as compared to endotoxemic controls. Mean arterial blood pressure and platelet count were higher in ropivacaine-endotoxin pigs than in bupivacaine-endotoxin ones. Bupivacaine augmented endotoxin-mediated decrease in left ventricular stroke work index. Ropivacaine displays pathophysiological advantages compared to bupivacaine in septic shock, which may be explained by improved tissue perfusion by ropivacaine.

Pharmacokinetics and efficacy of ropivacaine for continuous epidural infusion in neonates and infants.

INTRODUCTION: The primary objective of this noncomparative study was to evaluate the pharmacokinetics of ropivacaine during a 48-72-h continuous epidural infusion of ropivacaine in children under 1 year. The secondary objectives were to assess efficacy and safety. METHODS: Neonates and infants (ASA I-III, gestational age > or =37 weeks, > or =2.5 kg, scheduled for major abdominal or thoracic surgery) were included and separated into age groups: 0-30 (neonate), 31-90, 91-180, and 181-365 days. Ethics committee approval and informed parental consent were obtained before inclusion. An epidural catheter was introduced under general anesthesia at the appropriate dermatomal level. An initial bolus dose (0.9-2.0 mg.kg(-1) of ropivacaine 0.2%) was followed by an epidural infusion (0.2 mg.kg(-1).h(-1) for infants <180 days or 0.4 mg.kg(-1).h(-1) for infants >180 days). Plasma samples were collected every 12 h from 24 h, and on termination of the epidural infusion. Postoperative pain was evaluated using both the Objective Pain Scale and a four-graded descriptive scale. RESULTS: Forty-five infants, median age 116 (0-362) days, were included. Forty-three and 19 patients received an infusion for at least 48 and 72 h, respectively. Satisfactory analgesia was provided in the majority, only 20 patients were given supplementary medication during the infusion. In all age groups, plasma concentrations of unbound ropivacaine leveled at 24 h, without any further increase at 48 and 72 h. Because of lower clearance of unbound ropivacaine in neonates (mean 33 ml.min(-1).kg(-1)) than in infants above the age of 30 days (80, 124, and 163 ml.min(-1).kg(-1), respectively, in the age groups 31-90, 91-180, and 180-365 days), unbound ropivacaine concentrations at the end of infusion were higher in neonates [median 0.10 mg.l(-1) (0.04-0.21 mg.l(-1))] than in infants >30 days [median 0.03 mg.l(-1) (0.003-0.10 mg.l(-1))]. CONCLUSION: Epidural infusions (0.2-0.4 mg.kg(-1).h(-1) ropivacaine) provided satisfactory pain relief in neonates and infants under 1 year. As plasma concentrations of unbound ropivacaine were not influenced by the duration of the infusion, ropivacaine can be safely used for postoperative epidural infusion for 48-72 h. Levels of unbound ropivacaine were higher in the neonates than in the infants, but were below threshold concentrations for CNS toxicity in adults (> or =0.35 mg.l(-1)). This should not preclude the use of ropivacaine infusions in neonates but suggests a need for caution during the first weeks of life.

Ropivacaine in neonates and infants: a population pharmacokinetic evaluation following single caudal block.

BACKGROUND: The aims of this study were to evaluate pharmacokinetics, efficacy and safety of ropivacaine in infants aged 0-12 months following a single caudal injection. METHODS: Term ASA I-III patients, scheduled for surgery, with a body weight of > or = 2500 g received a caudal block with ropivacaine 2 mg x ml(-1), 1.0 ml x kg(-1). Plasma samples were collected at different time intervals up to 30 h, for analysis of total and unbound ropivacaine and alpha-1-acid glycoprotein (AAG). Pharmacokinetic data were characterized by population analysis. Unbound and total concentrations from 35 patients, median (min-max) postnatal age of 66 (4-351) days, were included in the nonlinear mixed effects modeling to provide estimates of pharmacokinetic parameters and the exploration of covariate relationships. Simulations were made to test the predictive performance of the final model and to describe the effect of significant covariates on systemic exposure. RESULTS: The mean (min-max) peak plasma concentration of total ropivacaine was 0.83 (0.05-1.57) mg x l(-1) at 0.5-5.7 h (median: 1.0 h) and the plasma concentration of unbound ropivacaine was 0.042 (0.012-0.081) mg x l(-1) within 0.5-1 h. The observed unbound fraction in plasma was 6% (1%-14%). A one-compartment open model with first-order absorption and elimination, incorporating a linear-binding model of ropivacaine to AAG best described the data. The only significant covariate relationship was that of age on Clu/F according to the following relationship Clu/F = 3.01 x e0.00474 x Age. This predicts a Clu/F of 3.5 l x h(-1) x kg(-1) at 30 days and 10.8 l x h(-1) x kg(-1) at 270 days with corresponding terminal half-lives of 6.7 and 2.2 h. The interindividual variability (coefficient of variation, CV) in Clu/F was 39%. The population estimate (CV) of ka was 1.65 h(-1) (30%), Vu/F was 33.6 (l x kg(-1)) (45%) and Ka was 1.78 l x mg(-1) (14%). Thirty-five infants received supplementary analgesics (mostly paracetamol). The median time to first supplementary analgesic (based on all 37 patients) was 3.9 h. No safety concerns or signs of systemic toxicity were observed. CONCLUSIONS: Following a caudal block with ropivacaine 2 mg x kg(-1) plasma concentrations of unbound ropivacaine were well below threshold levels for toxicity in adults. Apparent volume of distribution is unchanged, apparent unbound clearance increases and the terminal half-life decreases with age in 0-12-month-old neonates and infants. The postoperative pain management provided adequate analgesia and was well tolerated.