Clinical Global Impressions-Improvement Rating Research Articles

Defining a clinically meaningful within-patient change threshold for the Cohen-Mansfield Agitation Inventory in Alzheimer's dementia.

The Cohen-Mansfield Agitation Inventory (CMAI) quantifies the frequency of agitation behaviors in elderly persons. This post hoc analysis of data from the brexpiprazole clinical program aimed to determine a meaningful within-patient change (MWPC) threshold for CMAI Total score among patients with agitation associated with dementia due to Alzheimer's disease. Data were included from three 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm trials of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease (ClinicalTrials.gov identifiers: NCT01862640, NCT01922258, NCT03548584). Change in CMAI Total score (range 29-203; higher scores indicate higher frequency of agitation behaviors) from baseline to Week 12 was the primary endpoint in each trial. MWPC thresholds were estimated from anchor-based mean change analyses and receiver operating characteristic (ROC) curves. The Clinical Global Impression-Severity of illness (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales, both as related to agitation, were used as anchors. Empirical cumulative distribution functions (eCDFs) and probability density functions (PDFs) were plotted as supportive evidence. Distribution-based methods were also employed. Data from 898 patients were analyzed (mean age, 73.7 years; mean baseline CMAI Total score, 73.8). The mean CMAI Total score change corresponding to a difference of small improvement vs. stable (CGI-S one-point decrease vs. no change), or minimally improved vs. no change (CGI-I rating of 3 vs. 4), ranged from -10.6 to -13.5 points. The mean CMAI Total score change corresponding to a difference of moderate improvement vs. stable (CGI-S two-point decrease vs. no change), or much improved vs. no change (CGI-I rating of 2 vs. 4), ranged from -20.2 to -25.7 points. ROC curve analyses generally produced smaller estimates of meaningful change. eCDFs and PDFs showed good distribution and separation of CMAI Total score change between CGI-S/CGI-I categories. In distribution-based analyses, the minimal detectable change for CMAI Total score (10.5-11.8 points) was generally lower than anchor-suggested thresholds. Triangulation of evidence from anchor- and distribution-based analyses supports an MWPC threshold for CMAI Total score of -20 points, with a threshold range of -15 to -25 points, in patients with agitation associated with dementia due to Alzheimer's disease.

0579 Long-Term Safety of Once-Nightly Oxybate for Narcolepsy: RESTORE Study Interim Analysis of Data

Abstract Introduction The pivotal phase 3 REST-ON trial (NCT02720744) evaluated the efficacy and safety of once-nightly sodium oxybate (ON-SXB; FT218), an investigational extended-release formulation for treatment of adults with narcolepsy. In REST-ON, ON-SXB met its 3 coprimary endpoints: improvement in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression-Improvement rating (% much/very much improved), and number of weekly cataplexy attacks at all doses tested (P< 0.001 vs placebo). The safety profile of ON-SXB was consistent with that of immediate-release (IR) SXB. The ongoing RESTORE trial (NCT04451668) is an open-label/switch study evaluating the safety and tolerability of ON-SXB. Methods Participants aged ≥16 years with narcolepsy type 1 or 2 who completed the REST-ON trial, were on stable-dose (≥1 month) IR oxybate, or were oxybate-naive are eligible for RESTORE. Initial doses were 4.5 g/night or equivalent/closest to the previous total IR oxybate dose/night for those switching; incremental adjustments (1.5 g/week; maximum dose, 9 g/night) were allowed. Safety data for participants receiving ≥1 dose of ON-SXB as of 01 July 2022 are reported here. Results This analysis includes interim data from 180 participants (REST-ON participants, n=15 [8.3%]; oxybate-naive, n=35 [19.4%]; switch, n=130 [72.2%]). Most participants are white (n=150 [83.3%]) and female (n=122 [67.8%]); mean age is 35 years [range, 16–84]). Most participants who reported an adverse event (AE; n=105 [58.3%]) had AEs that were mild (61.9%) or moderate (32.3%) in severity. Three participants had serious AEs (abscess, deep vein thrombosis, rib fracture and pneumothorax); all were deemed unrelated to ON-SXB and all 3 participants continued in the study. Adverse drug reactions (ADRs; ie, AEs related/possibly related to study drug) were reported by 76 (42.2%) participants with 6 (3.3%) participants discontinuing ON-SXB owing to ADRs. ADRs occurring in ≥3% of participants were nausea (11.7%), somnolence (6.7%), headache (5%), enuresis (5%), somnambulism (3.9%), dizziness (3.9%), tremor (3.9%), and vomiting (3.3%). Conclusion Interim data from the RESTORE study indicate that ON-SXB is generally well tolerated with a low rate of discontinuation owing to ADRs. If granted final FDA approval, ON-SXB will offer adults with narcolepsy a once-at-bedtime oxybate treatment option. Support (if any) Avadel Pharmaceuticals

0573 Application of AASM Clinical Significance Thresholds to Once-Nightly Sodium Oxybate for Improvement in Narcolepsy Symptoms

Abstract Introduction Once-nightly sodium oxybate (ON-SXB; FT218), an investigational, extended-release treatment, was evaluated for the treatment of narcolepsy in adults in the phase 3 REST-ON clinical trial (NCT02720744). The 3 co-primary endpoints, mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement rating, and weekly number of cataplexy attacks (NCA), and the secondary endpoint of Epworth Sleepiness Scale (ESS) score were significant for ON-SXB vs placebo at weeks 3 (6-g dose), 8 (7.5-g dose), and 13 (9-g dose; all P< 0.001). These data were published after the cutoff for inclusion in the American Academy of Sleep Medicine (AASM) clinical practice guidelines for narcolepsy treatment; thus, REST-ON results were analyzed according to AASM clinical significance thresholds (CSTs). Methods Individuals with narcolepsy type 1/2 and age ≥16 years were randomized 1:1 to receive double-blind ON-SXB (4.5 g, 1 week; 6 g, 2 weeks; 7.5 g, 5 weeks; 9 g, 5 weeks) or matching placebo. For each dose (6 g, week 3; 7.5 g, week 8; and 9 g, week 13), least-squares mean (LSM) difference from placebo was calculated for change from baseline in mean sleep latency on the MWT, ESS score, and percentage reduction in NCA. As defined in the 2021 AASM guidelines, CSTs were the following changes vs placebo: MWT, ≥2-minute increase; ESS, ≥2-point decrease; and cataplexy, ≥25% decrease in NCA. Results 190 participants (ON-SXB, n=97; placebo, n=93) were in the modified intent-to-treat population. On the MWT, difference in LSM change from baseline was 5.0, 6.2, and 6.1 minutes for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Differences in LSM change from baseline ESS scores were −2.1, −3.2, and −3.9 for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Differences in LSM percentage reduction in NCA were 26.0%, 34.2%, and 36.1% for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Conclusion Clinically significant improvement in excessive daytime sleepiness and cataplexy per AASM-established criteria was met with ON-SXB 6, 7.5, and 9 g doses. If FDA approved, ON-SXB will provide a once-nightly treatment for improving EDS and cataplexy in adults with narcolepsy. Support (if any) Avadel Pharmaceuticals

Efficacy of Once-Nightly Sodium Oxybate (FT218) in Narcolepsy Type 1 and Type 2: Post Hoc Analysis From the Phase 3 REST-ON Trial.

Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2). Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5g, week 1; 6g, weeks 2-3; 7.5g, weeks 4-8; and 9g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups. The modified intent-to-treat population comprised 190 participants (NT1, n=145; NT2, n=45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, P<0.001) and NT2 (6 and 9g, P<0.05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, P<0.001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (P<0.001), nocturnal arousals (P<0.05), and ESS scores (P≤0.001) were reported for NT1 with directional improvements for NT2. Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup.

BPRS domains, items and subgroups analyses, and CGI-I ratings in pooled data from non-interventional studies of aripiprazole once-monthly in schizophrenia (REACT study)

BackgroundPatients with schizophrenia may benefit from treatment with long-acting injectable (LAI) formulations of antipsychotics. Aripiprazole once-monthly (AOM) is an LAI that was tested in two non-interventional studies in Germany and Canada.MethodsHere, we report on analyses of pooled data from the two non-interventional studies. Patients were treated with AOM under real-life conditions. Data were analyzed for a timeframe of 6 months. We analyzed data on Brief Psychiatric Rating Scale (BPRS) domains and items, BPRS total scores in various patient subgroups (male vs. female patients, patients with disease duration ≤ 5 years and > 5 years, patients with different levels of disease severity at baseline), Clinical Global Impression – Improvement (CGI-I) ratings for the total population and subgroups, and comorbidities for the total population.ResultsData from 409 patients were included. 65.5% of the patients had comorbidities. Improvements were found in all BPRS domains and items. Furthermore, improvements were similar for male and female patients, patients with disease duration ≤ 5 years and > 5 years, and across different levels of disease severity at baseline. Numerically, more favorable results were found for younger patients, female patients, and those with shorter disease duration.ConclusionsAOM can be an effective treatment in the broad range of patients, across sexes, regardless of patient age and duration of disease, independently of disease severity, and across symptoms.Trial registrationNCT02131415 (May 6, 2014), vfa non-interventional studies registry 15960N.

Toward a Definition of "No Meaningful Benefit" From Antidepressant Treatment: An Equipercentile Analysis With Cross-Trial Validation Across Multiple Rating Scales.

Background: Many patients with major depressive disorder (MDD) who experience no meaningful benefit (NMB) from antidepressive treatment go undetected. However, there is a lack of consensus on the definition of NMB from antidepressants.Methods: Equipercentile linking was used to identify a threshold for percent change in 17-item Hamilton Depression Rating Scale (HDRS-17) scores that equated with a Clinical Global Impressions-Improvement (CGI-I) score of 3 (minimally improved), a proxy for NMB, after 4 and 8 weeks of citalopram or escitalopram treatment, using data from the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS). The NMB threshold for the HDRS-17 was validated by equating a CGI-I rating of 3 with percent change values from the clinician- and patient-rated versions of the Quick Inventory of Depressive Symptomatology (QIDS-C and QIDS-SR) using data from PGRN-AMPS and phase 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. This study was conducted between June 2021 and September 2021.Results: In PGRN-AMPS, a 30% improvement in HDRS-17 score corresponded to a CGI-I rating of 3 at 4 and 8 weeks. The 30% improvement threshold was also observed for QIDS-C and QIDS-SR scores in both PGRN-AMPS and STAR*D. Similar results were observed for percent change in HDRS-17 and QIDS-based measures in lower- and higher-severity groups based on a median split of baseline total scores.Conclusions: Improvement in depressive severity of ≤ 30%, as assessed using the HDRS-17, QIDS-C, and QIDS-SR, may validly define NMB from antidepressants during short-term treatment.

A Characterization of the Clinical Global Impression Scale Thresholds in the Treatment of Adolescent Depression Across Multiple Rating Scales.

Introduction: The Clinical Global Impressions-Improvement (CGI-I) scale is widely used in clinical research to assess symptoms and functioning in the context of treatment. The correlates of the CGI-I with efficacy scales for adolescent major depressive disorder are poorly understood. This study focused on benchmarking CGI-I scores with changes in the Children's Depression Rating Scale-Revised (CDRS-R) and the Quick Inventory of Depressive Symptomatology-Adolescent (17-item) Self-Report (QIDS-A17-SR). Methods: We examined three datasets with the clinician-rated CDRS-R to ascertain equivalent percent changes in total scores and CGI-I ratings. Exploratory analyses examined corresponding percentage changes in the QIDS-A17-SR and the CGI-I ratings. The CGI-I was the reference scale for nonparametric equipercentile linking with the Equate package in R. Results: CGI-I scores of 1 mapped to ≥78%-95% change in CDRS-R scores at 4-6 weeks across three datasets. CGI-I scores of 2 mapped to 56%-94% change in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 3 mapped to 30%-68% changes in CDRS-R scores at 4-6 weeks across three studies. CGI-I scores of 4 mapped to a range of 29%-44% at 4-6 weeks across three studies. There was no significant difference (p ≥ 0.6) between treatment groups in both the Treatment of Adolescents with Depression and Treatment of Resistant Depression in Adolescents studies, for each CGI-I score ( = 1, or = 2 or = 3, or ≥4), associated mapping of total depression severity score, or associated percent change from baseline for corresponding follow-up visits. There was no significant sex difference (p > 0.2) in CGI-I linkages to CDRS-R total or percentage changes. Conclusions: These findings establish clear relationships among CGI-I scores and the CDRS-R and the QIDS-A17-SR. These benchmarks have utility for clinical trial study design, inter-rater reliability training, and clinical implementation.

Imputing the Number of Responders from the Mean and Standard Deviation of CGI-Improvement in Clinical Trials Investigating Medications for Autism Spectrum Disorder.

Introduction: Response to treatment, according to Clinical Global Impression-Improvement (CGI-I) scale, is an easily interpretable outcome in clinical trials of autism spectrum disorder (ASD). Yet, the CGI-I rating is sometimes reported as a continuous outcome, and converting it to dichotomous would allow meta-analysis to incorporate more evidence. Methods: Clinical trials investigating medications for ASD and presenting both dichotomous and continuous CGI-I data were included. The number of patients with at least much improvement (CGI-I ≤ 2) were imputed from the CGI-I scale, assuming an underlying normal distribution of a latent continuous score using a primary threshold θ = 2.5 instead of θ = 2, which is the original cut-off in the CGI-I scale. The original and imputed values were used to calculate responder rates and odds ratios. The performance of the imputation method was investigated with a concordance correlation coefficient (CCC), linear regression, Bland–Altman plots, and subgroup differences of summary estimates obtained from random-effects meta-analysis. Results: Data from 27 studies, 58 arms, and 1428 participants were used. The imputation method using the primary threshold (θ = 2.5) had good performance for the responder rates (CCC = 0.93 95% confidence intervals [0.86, 0.96]; β of linear regression = 1.04 [0.95, 1.13]; bias and limits of agreements = 4.32% [−8.1%, 16.74%]; no subgroup differences χ2 = 1.24, p-value = 0.266) and odds ratios (CCC = 0.91 [0.86, 0.96]; β = 0.96 [0.78, 1.14]; bias = 0.09 [−0.87, 1.04]; χ2 = 0.02, p-value = 0.894). The imputation method had poorer performance when the secondary threshold (θ = 2) was used. Discussion: Assuming a normal distribution of the CGI-I scale, the number of responders could be imputed from the mean and standard deviation and used in meta-analysis. Due to the wide limits of agreement of the imputation method, sensitivity analysis excluding studies with imputed values should be performed.

Transdiagnostic cognitive behavioral therapy for the treatment of emotional disorders: A preliminary open trial

Background and objectivesTo assess the efficacy of a transdiagnostic cognitive behavioral therapy (tCBT) protocol for the treatment of emotional disorders with individuals that have a principal or comorbid depressive diagnosis. MethodsTreatment-seeking adults meeting diagnostic criteria for a depressive disorder were enrolled in a 12-week tCBT open trial aimed at addressing the underlying core pathology of emotional disorders. Clinician severity ratings (CSRs) regarding principal and comorbid diagnoses, and overall severity as well as clinical global impression-severity (CGI-S) ratings were assessed at pre- and post-treatment and 4-month follow-up. Clinician's provided a clinical global impression–improvement (CGI-I) rating post-treatment and at 4-month follow-up. Depressive and anxiety symptoms were measured at pre-treatment and session-by-session using self-report measures (BDI-II and ADDQ). ResultsRepeated measure ANOVAs indicated a reduction in principal diagnosis severity, overall severity, and CGI-S with large effects observed post-treatment (Cohen's ds = 1.29–1.92) and at 4-month follow-up (Cohen's ds = 0.77–1.04). Mixed-effect regression modelling demonstrated a decrease in depressive and anxiety symptoms over the course of treatment. CGI-I ratings identified 63.64% participants as treatment responders both post-treatment and at 4-month follow-up. LimitationsThe uncontrolled nature of the trial and small sample size are the main limitations to generalizability of the findings. ConclusionsThe findings, although preliminary, provide additional evidence for the utilization of tCBT in the effective treatment of emotional disorders. Further research into the implementation of the tCBT for emotional disorders protocol through a randomized controlled trial involving groups of participants with a range of emotional disorder diagnoses is warranted.

Pharmacokinetics of venlafaxine in treatment responders and non-responders: a retrospective analysis of a large naturalistic database.

To assess in a large naturalistic sample, whether clinical response to a treatment with venlafaxine is associated with different patterns of plasma concentrations of active moiety, AM (sum of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN)). Applying a regression model, plasma concentrations and plasma concentrations corrected-by-dosage (C/D) for AM were included as independent variable with Clinical Global Impressions-Improvement (CGI-I) scale ratings as dependent variable. Moreover, AM, VEN, and ODVEN were compared between treatment responders and non-responders, defining response as much or very much improved on the CGI-I scale based on the non-parametric Mann-Whitney U (M-W-U) test with a significance level of 0.05. No correlations were found between AM and C/D AM plasma concentrations and CGI-I ratings (regression coefficient 0.0, CI 0.000, 0.001, p = 0.492 for AM and 0.047, CI - 0.065, 0.159, p = 0.408 for C/D AM). Venlafaxine daily dosage did not differ between responders and non-responders (217.7 ± 76.9 vs. 222.0 ± 72.7mg/day, p= 0.45 for M-W-U). Responders displayed lower ODVEN (p = 0.033) and AM (p = 0.031) plasma concentrations than non-responders (p = 0.033 and 0.031, respectively for M-W-U). No other differences were detected. Using a cut-off level of 400ng/mL for AM concentrations, a higher percentage of responders was reported in the group of patients with AM < 400ng/mL (13.04%) compared to patients with AM > 400ng/mL (8%) (p = 0.038). Higher ODVEN and AM concentrations in non-responders than in responders indicate that treatment escalation above upper thresholds of therapeutic reference ranges of venlafaxine is not promising. Hence, the therapeutic reference range for venlafaxine can help in improving outcomes in a measurement-based care model that takes advantage of therapeutic drug monitoring.

Therapist-Reported Features of Exposure Tasks That Predict Differential Treatment Outcomes for Youth With Anxiety

Exposure tasks are recognized widely as a key component of cognitive-behavioral therapy (CBT) for child and adolescent anxiety. However, little research has examined specific exposure characteristics that predict outcomes for youth with anxiety and that may guide its application in therapy. This study draws on a sample of 279 children and adolescents (48.4% male; 79.6% white) with a principal anxiety disorder who received 14 sessions of CBT, either alone or in combination with medication, through the Child/adolescent Anxiety Multimodal treatment Study (CAMS). The present study examines therapist-reported quantity, difficulty level, compliance, and mastery of exposure tasks as they related to CBT response (i.e., Clinical Global Impressions-Improvement ratings). Secondary treatment outcomes included reduction in anxiety symptom severity on the Pediatric Anxiety RatingScale, global impairment measured via the Children's Global Assessment Scale, and parent-report of anxiety-specific functional impairment on the Child Anxiety Impairment Scale. Regression analyses indicated a dose-response relationship between therapist-reported quantity of exposure and independent evaluations of treatment outcome, with more time devoted to exposure linked to better outcomes. Similarly, greater time spent on more difficult (rather than mild or moderate) exposure tasks predicted better outcomes, as did therapist ratings of child compliance and mastery. The present findings highlight the importance of challenging children and adolescents with difficult exposure tasks and of collaborating to ensure compliance and mastery.

A Descriptive Analysis of Factors Leading to a 1-Year Remission in Bipolar Disorder.

Bipolar spectrum disorders are associated with symptomatic and functional disability in many patients. Other studies have examined predictors of outcome with variable results. The goal of this retrospective study was to identify medications associated with a minimum of 12 consecutive months of symptomatic, functional, and syndromal remission. The charts of 121 patients with confirmed bipolar disorder were reviewed. Data on medical regimen and demographic and adherence factors were gathered using standardized data collection sheets approved by the University of Toledo Institutional Review Board. The criterion for improvement was set at 12 consecutive months of Clinical Global Impressions Improvement ratings of ≤2, which is a far higher standard of syndromal and functional remissions than the usual 8 consecutive weeks used by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. In this sample of 121 patients, 43.8% achieved a minimum of 12 consecutive months of remission, whereas 56.2% did not. When bipolar disorder was divided into its subtypes, 45.5% of our cohort were diagnosed with bipolar I disorder, 27.3% were diagnosed with bipolar II disorder, and 27.3% were diagnosed with bipolar disorder, not otherwise specified. Of the 55 patients with bipolar I disorder, 27 remitted and 28 did not. Of the 33 patients with bipolar II disorder, 12 remitted and 21 did not. Of the 33 patients with bipolar disorder, not otherwise specified, 14 remitted and 19 did not. The treatment regimen that was most closely associated with remission was a combination of atypical antipsychotics (primarily aripiprazole), mood stabilizers (primarily lamotrigine), and an antidepressant. In addition, the patients who achieved remission were more likely to be adherent to medication and with appointments. The chart review showed that 12 consecutive months of symptomatic remission was achieved in our clinic in 43.8% of patients with bipolar disorder when they were treated with tailored medication regimens. The remainder (56.2%) failed to achieve 12 consecutive months of remission based on real-time Clinical Global Impressions Improvement ratings. The combination of an atypical antipsychotic, a mood stabilizer, and an antidepressant was highly correlated with 1-year remission.

Double-blind, placebo-controlled pilot study of adjunctive quetiapine SR in the treatment of PMS/PMDD.

Premenstrual dysphoric disorder (PMDD), a more severe form of premenstrual syndrome (PMS), afflicts 5-8% of reproductive age women and results in significant functional impairment. We conducted a double-blind, placebo-controlled trial of adjunctive quetiapine in patients with PMS/PMDD who had inadequate response to selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor therapy for their symptoms. A PMS/PMDD diagnosis was confirmed by 2-month prospective diagnostic assessment of PMS/PMDD using the Prospective Record of the Impact and Severity of Premenstrual Symptoms (PRISM) calendar. Women were randomized equally to receive quetiapine sustained-release (SR) or placebo (25-mg starting dose) during the luteal phase for 3 months. Outcome variables included the Hamilton Depression and Anxiety Scales, Clinical Global Impression Scale, and PRISM. Twenty women were enrolled in the treatment phase. Although the study was underpowered, greater reductions in luteal phase mood ratings were observed in the quetiapine group on the 17-item Hamilton Depression Rating Scale, Clinical Global Impression improvement rating, and PRISM daily score. The quetiapine group showed most improvement in symptoms of mood lability, anxiety, and irritability. This small double-blind study suggests that adjunctive treatment with quetiapine SR may be a useful addition to selective serotonin reuptake inhibitor therapy in women with PMS/PMDD by reducing symptoms and improving quality of life.

Pramipexole for Chinese people with primary restless legs syndrome: a 12-week multicenter, randomized, double-blind study

BackgroundRestless legs syndrome (RLS) often responds to agents that enhance dopamine neurotransmission. The present 12-week study aimed to evaluate the efficacy and adverse events of pramipexole (PPX) for the treatment of adult, Chinese people with primary RLS. MethodsA total of 204 Chinese people with RLS were randomly assigned to receive either the placebo or PPX (flexibly titrated from 0.25 mg to 0.75 mg), 2 h to 3 h before bedtime for 12 weeks. The primary measuring outcomes were the International RLS Study Group Rating Scale (IRLS) and the Clinical Global Impressions-Improvement (CGI-I) scale. The secondary outcome was adverse events. ResultsOne hundred and ninety participants completed the study. At 12 weeks, the adjusted mean (SE) change from baseline was greater for PPX (vs placebo) for the IRLS score (−13.2 ± 0.7 vs −9.4 ± 0.6; p < 0.01), and (−12.1 ± 0.6 vs −8.3 ± 0.6; p < 0.01) at the end of one month follow-up after treatment. The CGI-I rating of “very much improved” or “much improved” in the percentage of participants (61.8% vs 34.3%; p < 0.01), and (51.0% vs 26.5%; p < 0.01) after week 12, and one month follow-up of treatment, respectively. The proportion of adverse events was 60.8% in the PPX group and 45.1% in the placebo group. No deaths related to PPX treatment were recorded. ConclusionsIn summary, the present study showed that PPX is efficacious and well tolerated in Chinese people with primary RLS.

Pilot Open Case Series of Voice over Internet Protocol-Delivered Assessment and Behavior Therapy for Chronic Tic Disorders

Comprehensive Behavioral Intervention for Tics (CBIT) is an efficacious treatment for children with chronic tic disorders (CTDs). Nevertheless, many families of children with CTDs are unable to access CBIT due to a lack of adequately trained treatment providers, time commitment, and travel distance. This study established the interrater reliability between in-person and Voice over Internet Protocol (VoIP) administrations of the Yale Global Tic Severity Scale (YGTSS), and examined the preliminary efficacy, feasibility, and acceptability of VoIP-delivered CBIT for reducing tics in children with CTDs in an open case series. Across in-person and VoIP administrations of the YGTSS, results showed mean agreement of 91%, 96%, and 95% for motor, phonic, and total tic severity subscales. In the pilot feasibility study, 4 children received 8 weekly sessions of CBIT via VoIP and were assessed at pre- and posttreatment by an independent evaluator. Results showed a 29.44% decrease in clinician-rated tic severity from pre- to posttreatment on the YGTSS. Two of the 4 patients were considered treatment responders at posttreatment, using Clinical Global Impressions–Improvement ratings. Therapeutic alliance, parent and child treatment satisfaction, and videoconferencing satisfaction ratings were high. CBIT was considered feasible to implement via VoIP, although further testing is recommended.

Efficacy of HuaDan Anshen Mistura for treating insomnia: a randomized, double-blind, placebo-controlled, multi-center clinical trial

ObjectiveTo evaluate the effect of HuaDan Anshen Mistura (mistura) in clinical treatment of Chinese patients with insomnia. MethodsIn this randomized, double-blind, placebo-controlled, multi-center study, 244 patients with insomnia were randomly assigned to a placebo group, a low-dose (10 mL/day), or a high-dose (20 mL/day) mistura group. Efficacy was assessed by using the sleep dysfunction rating scale (SDRS) and Clinical Global Impression-Improvement (CGI-I) scores. Safety and tolerability assessments included emergent adverse events, laboratory tests, and electrocardiograms. ResultsTotal SDRS scores decreased in all three groups, and there were significant differences between the placebo group and the low- and high-dose mistura groups (P=0.000). CGI-I ratings in the low- and high-dose mistura groups were significantly better than that of the placebo group (P=0.000). Incidences of rebound insomnia were similar in all three groups (placebo group: 6.94%, low-dose mistura group: 12.99%, and high-dose mistura group: 10.96%; P=0.475). The efficacy of HuaDan Anshen Mistura in the low- or high-dose group was significantly better than that of the placebo group (P=0.000), but with no significant difference found between the low- and high-dose mistura groups (P=0.887). The rates of adverse events were similar in the three groups (placebo 2.44%, low-dose mistura 0%, and high-dose mistura 5%; P=0.088). ConclusionHuaDan Anshen Mistura is an effective and generally well-tolerated hypnotic medicine for the treatment of Chinese patients with insomnia.

Clinical response and symptomatic remission in short- and long-term trials of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder

BackgroundDespite the overall high degree of response to pharmacotherapy, consensus is lacking on how to judge clinical response or define optimal treatment/remission when treating adults with attention-deficit/hyperactivity disorder (ADHD). This study examined clinical response and symptomatic remission in analyses of 2 studies of lisdexamfetamine dimesylate (LDX) in adults with ADHD.MethodsIn a 4-week, double-blind, forced-dose trial, adults with ADHD were randomized to LDX 30, 50, and 70 mg/day (mg/d) or placebo. In a second, open-label, follow-up trial, adults entering from the 4-week study were titrated to an “optimal” LDX dose (30 mg/d [n=44], 50 mg/d [n=112], and 70 mg/d [n=171]) over 4 weeks, and maintained for 11 additional months. The ADHD Rating Scale IV (ADHD-RS-IV) with adult prompts and the Clinical Global Impressions-Improvement (CGI-I) scale assessed efficacy. Clinical response was defined, post hoc, as ≥30% reduction from baseline in ADHD-RS-IV and CGI-I rating of 1 or 2; symptomatic remission was defined as ADHD-RS-IV total score ≤18. Log rank analysis examined overall significance among the treatment groups in time to response or remission.ResultsFour hundred and fourteen participants in the 4-week study and 345 in the open-label, extension study were included in the efficacy populations. All LDX groups improved by ADHD-RS-IV and CGI-I scores in both studies. In the 4-week study (n=414), 69.3% responded and 45.5% achieved remission with LDX (all doses); 37.1% responded and 16.1% achieved remission with placebo; time (95% CI) to median clinical response (all LDX doses) was 15.0 (15.0, 17.0) days and to remission was 31.0 (28.0, 37.0) days (P<.0001 overall). In the open-label study, with LDX (all doses), 313 (95.7%) and 278 (85.0%) of 327 participants with evaluable maintenance-phase data met criteria for response and remission, respectively. Of participants who completed dose optimization, 75.2% remained responders and 65.7% remained in remission in the 12-month study. Overall, 285 (82.6%) and 227 (65.8%) of 345 participants were responders and remitters, respectively, at their final visits.ConclusionIn the long-term study, with open-label, dose-optimized LDX treatment, most adults with ADHD achieved clinical response and/or symptomatic remission; almost two-thirds maintained symptomatic remission over the remaining 11 months.Trial registrationClinical Trial Numbers: NCT00334880 and NCT01070394Clinical Trial Registry: clinicaltrials.govURLshttp://www.clinicaltrials.gov/show/NCT00334880http://www.clinicaltrials.gov/ct2/show/NCT01070394?term=NCT01070394&rank=1

An open-label pilot study of aripiprazole for male and female Veterans with chronic post-traumatic stress disorder who respond suboptimally to antidepressants

Emerging data suggest that second-generation antipsychotics such as aripiprazole may be effective in the treatment of post-traumatic stress disorder (PTSD). However, few clinical trials have used aripiprazole in PTSD, and data are limited on its use in Veterans with PTSD. The objective of this pilot trial was to investigate the safety and efficacy of aripiprazole in Veterans with PTSD. Ten individuals (five men and five women) meeting the Diagnostic and statistical manual of mental disorders, 4th ed., PTSD criteria participated in this 12-week, open-label, flexibly dosed monotherapy trial. The dose range of aripiprazole was 5-30 mg/day, titrated to tolerability and clinical response. The primary outcome measure was the Clinician-Administered PTSD Scale. Additional outcomes included the Short PTSD Rating Interview, the Treatment Outcome PTSD Scale (Top-8), the Davidson Trauma Scale, the Positive and Negative Syndrome Scale, the Beck Depression Inventory-Fast Screen, and Clinical Global Impressions-Improvement. Eight participants completed the study, and aripiprazole was generally well tolerated and associated with a significant improvement in PTSD symptoms, as measured by the Clinician-Administered PTSD Scale (primary outcome measure) and by the Short PTSD Rating Interview, the Treatment Outcome PTSD Scale, and the Davidson Trauma Scale. An improvement was also observed on all three Positive and Negative Syndrome Scale subscales and the Beck Depression Inventory-Fast Screen, and the average Clinical Global Impressions-Improvement ratings indicated that patients were 'much improved'. These promising initial results merit further investigation in a larger, randomized-controlled trial.

Impact of Stimulant Pharmacotherapy on Sleep Quality

Sleep disturbances may cause distress among individuals with attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the impact of stimulant pharmacotherapy for ADHD on sleep in adults. These post hoc analyses included sleep data collected with the Pittsburgh Sleep Quality Index (PSQI), a self-rated questionnaire, from 831 adults with DSM-IV-TR-defined ADHD in 2 large, randomized, double-blind, placebo-controlled, forced-dose titration studies of lisdexamfetamine (N = 420; conducted from May 25, 2006, to November 16, 2006) and triple-bead mixed amphetamine salts (MAS) (N = 411; conducted from April 25, 2005, to November 4, 2005). Change from baseline to endpoint in PSQI clinically meaningful change categories (ie, "decrease," "no change," or "increase") was analyzed by treatment group in each study using the χ² test. The Cochran-Mantel-Haenszel method was used (1) to determine whether there was a statistically significant difference in Clinical Global Impressions-Improvement (CGI-I) score of 1 or 2 (improved) versus > 2 (not improved) relative to a decrease or an increase in PSQI and (2) to analyze shifts from good sleep at baseline (PSQI ≤ 5) to poor sleep at endpoint (PSQI > 5). Impaired sleep (PSQI score > 5) relative to baseline was demonstrated in 8.3% and 9.7% of the treatment and placebo groups, respectively (P = .18), in the MAS study and 7.7% and 8.2%, respectively (P = .03), in the lisdexamfetamine study. Clinically meaningful change in baseline to endpoint PSQI was not statistically significantly different between treatment and placebo groups in either study. A significant difference in CGI-I 1 and 2 relative to an increase or decrease in PSQI was found in both the triple-bead MAS (P < .0001) and the lisdexamfetamine (P = .0008) trials. More subjects with improved CGI-I rating of 1 or 2 had improvement in PSQI than had worsening. Approximately one-third of subjects receiving treatment or placebo had clinically meaningful sleep improvement, emphasizing that change in sleep quality during treatment may not necessarily be related to stimulant therapy. When managing complaints of sleep difficulties in ADHD subjects, clinicians should undertake a broad assessment and consider underlying conditions that may contribute to sleep disruption. clinicaltrials.gov Identifiers: NCT00334880 and NCT00152022.

Tinnitus Handicap Inventory for Evaluating Treatment Effects

To determine the minimum change of the Tinnitus Handicap Inventory (THI) score that could be considered clinically relevant, the authors compared the absolute change of the THI with the Clinical Global Impression–Improvement (CGI-I) score. International studies register with standardized data collection. Tinnitus Research Initiative (TRI). Two hundred ten patients of the TRI database were eligible for this study. In the first analysis, the THI score change and CGI-I ratings were compared with equipercentile linking. In a second analysis, the authors categorized the CGI-I into the 4 groups much better or better, minimally better, no change, and worse and calculated the corresponding differences of the THI score and the effect sizes. An effect size separating the minimally better and the no-change groups was chosen, and the referring THI mean score difference was calculated. According to the linking method, a CGI-I value of 3 (minimally better) corresponded to a THI score reduction of 6 to 16, whereas the CGI-I value of 4 (no change) corresponded to the range between improvement by 5 points and worsening by 4 points. For separating the no-change and minimally better groups, an effect size d = 0.5 was determined, resulting in a minimal clinically relevant difference of ΔTHI = 7. Two different methods yielded comparable results in identifying a reduction in the THI score of 6 and 7 points, respectively, as the minimal clinically relevant change. This study provides a first orientation for sample size calculations and for planning the design of future studies.