Clinical Global Impressions-Improvement Score Research Articles

Relationships between clinical scales and binge eating days in adults with moderate to severe binge eating disorder in two Phase III studies.

ObjectivesIn two Phase III studies, lisdexamfetamine dimesylate (LDX) reduced binge eating (BE) days/week in adults with moderate to severe binge eating disorder (BED) and was associated with improvement based on the Clinical Global Impressions–Improvement (CGI-I) scale. In this study, post hoc analyses examined the relationships between clinical observations and clinical rating scales in individuals with BED.Clinical trial registrationNCT01718483 (ClinicalTrials.gov/ct2/show/NCT01718483); NCT01718509 (ClinicalTrials.gov/ct2/show/NCT01718509).MethodsTwo 12-week, double-blind, placebo-controlled studies randomized (1:1) adults meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, BED criteria and with protocol-defined moderate to severe BED (study 1, N=383; study 2, N=390) to placebo or dose-optimized LDX (50 or 70 mg). Assessments included the number of BE days/week, CGI–Severity (CGI-S) and CGI-I scores, and Yale-Brown Obsessive Compulsive Scale modified for Binge Eating (Y-BOCS-BE) total scores. For these post hoc analyses, data were pooled across studies and treatment arms. Statistical assessments included Spearman correlations and equipercentile linking analyses (ELA). Reported P-values are nominal (descriptive and not adjusted for multiplicity).ResultsAt baseline, nominally significant correlations with CGI-S scores were reported for BE days/week (r=0.374; P<0.0001) and Y-BOCS-BE total scores (r=0.319; P<0.0001). Baseline ELA for CGI-S further characterized this relationship: a CGI-S score of 4 (moderately ill) corresponding to 3.504 BE days/week and a Y-BOCS-BE total score of 18.6. Nominally significant correlations with CGI-I scores were reported for changes from baseline at study endpoint for BE days/week (r=0.647; P<0.0001) and Y-BOCS-BE total scores (r=0.741; P<0.0001). ELA for CGI-I scores at study endpoint showed that a CGI-I score of 1 (very much improved) corresponds to a reduction from baseline of 4.504 BE days/week and 19.4 points for Y-BOCS-BE total score.ConclusionThese post hoc analyses suggest that indices of global disease severity and improvement positively correlate with BE behavior and with obsessive and compulsive features of BED, measured by the Y-BOCS-BE, supporting the clinical relevance of BED treatment outcomes.

Efficacy, acceptability, and safety of adjunctive aripiprazole in treatment-resistant depression: a meta-analysis of randomized controlled trials.

BackgroundTreatment-resistant depression (TRD) is common and potentially life-threatening in adults, and the benefits and risks of adjunctive aripiprazole in these patients remain controversial. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy, acceptability, safety, and quality of life of adjunctive aripiprazole in patients with TRD.MethodsRCTs published in PubMed, Web of Science, and Embase were systematically reviewed to evaluate the efficacy and safety profiles of TRD patients who were treated with adjunctive aripiprazole. The main outcome measures included response rate, remission rate, changes from baseline in Montgomery–Asberg Depression Rating Scale (MADRS), Clinical Global Impression-severity (CGI-S), Clinical Global Impression-improvement (CGI-I), 17-Item Hamilton Rating Scale for Depression (HAM-D17), Sheehan Disability scale (SDS), and Inventory of Depressive Symptomatology Self-Report Scale (IDS-SR), discontinuation due to adverse events, and adverse events. Risk ratio (RR) or weight mean difference with 95% confidence intervals (CIs) were pooled using a fixed-effects or random-effects model according to the heterogeneity among studies.ResultsA total of 8 RCTs involving 2,260 patients were included in this meta-analysis. Adjunctive aripiprazole was associated with a significantly higher remission rate (RR =1.64, 95% CI: 1.42 to 1.89; P<0.001) and response rate (RR =1.45, 95% CI: 1.13 to 1.87; P=0.004) than other treatments. Moreover, adjunctive aripiprazole had greater changes in MADRS score, CGI-S score, CGI-I score, HAM-D17 score, SDS score, and IDS-SR score. There were more patients treated with adjunctive aripiprazole who discontinued their treatments due to adverse events. The incidence of adverse events was significantly higher in the adjunctive aripiprazole group than in other treatment groups.ConclusionThe adjunctive aripiprazole showed benefits in improving the response rate, remission rate, and the quality of life in patients with TRD. However, clinicians should interpret these findings with caution due to the evidence of potential treatment-related side effects.

SHP465 Mixed Amphetamine Salts in the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: Results of a Randomized, Double-Blind Placebo-Controlled Study.

Objective: The aim of this study was to evaluate the efficacy, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).Methods: This randomized, double-blind dose-optimization study enrolled children and adolescents (6–17 years) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision ADHD criteria and having baseline ADHD Rating Scale IV (ADHD-RS-IV) total scores ≥28. Participants were randomized 1:1 to placebo or dose-optimized SHP465 MAS (12.5–25 mg) for 4 weeks. Total score change (baseline to week 4) on the ADHD-RS-IV (primary endpoint) and the Clinical Global Impressions-Improvement (CGI-I) scale score at week 4 (key secondary endpoint) were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments (secondary endpoints) included treatment-emergent adverse events (TEAEs) and vital sign changes.Results: Of 264 randomized participants (placebo, n = 132; SHP465 MAS, n = 132), 234 (placebo, n = 118; SHP465 MAS, n = 116) completed the study. The least squares mean (95% confidence interval) treatment difference significantly favored SHP465 MAS over placebo for ADHD-RS-IV total score change from baseline to week 4 (−9.9 [−13.0, −6.8]; p < 0.001; effect size = 0.80) and CGI-I score at week 4 (−0.8 [−1.1, −0.5]; p < 0.001; effect size = 0.65). TEAE frequency was 46.6% (61/131) with placebo and 67.4% (89/132) with SHP465 MAS; no serious TEAEs were reported. TEAEs reported at a frequency of ≥5% and ≥2 times the placebo rate were decreased appetite, insomnia, irritability, nausea, and decreased weight. Mean ± standard deviation increases (baseline to final on-treatment assessment) were higher with SHP465 MAS than placebo for pulse (5.7 ± 11.78 vs. 0.7 ± 10.79), systolic blood pressure (3.8 ± 9.15 vs. 2.1 ± 8.72), and diastolic blood pressure (4.0 ± 8.23 vs. 0.5 ± 7.45).Conclusions: SHP465 MAS demonstrated superiority over placebo in improving ADHD symptoms and global functioning in children and adolescents with ADHD. The safety and tolerability profile of SHP465 MAS was consistent with that of SHP465 MAS in adults and other long-acting psychostimulants in children and adolescents.

Treatment of Children and Adolescents with Attention Deficit Hyperactivity Disorder and/or Tourette's Disorder with Clonidine Extended Release.

We aimed to assess the effectiveness and safety of clonidine extended release (ER) treatment in Korean youth with ADHD and/or Tourette's disorder. We retrospectively reviewed the medical records of 29 children and adolescents treated with clonidine ER. The effectiveness were retrospectively measured at baseline and after 4 and 12 weeks based on the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scores. Safety was evaluated at each visit based on spontaneous reports from the subjects or from their parents/guardians. Significant decreases in the CGI-S scores for both ADHD (F=23.478, p<0.001, partial η2=0.540) and tic symptoms (F=15.137, p<0.001, partial η2=0.443) were noted over 12 weeks. The most common adverse event was somnolence (n=9, 31.0%) and life-threatening adverse effects were not observed. Our results provide preliminary evidence for the effectiveness and safety of clonidine ER.

Clinical Implications From the Treatment of Severe Childhood Aggression (TOSCA) Study: A Re-Analysis and Integration of Findings

The Treatment of Severe Childhood Aggression (TOSCA) project examined augmentation of stimulant treatment and parent training (PT) with risperidone for severe physical aggression. This article summarizes the clinical implications; reanalyzes the data to examine the utility of 4 criteria for deciding to augment; and presents a treatment algorithm. The newly analyzed 4 criteria for augmenting after 3 weeks of stimulant and PT treatment consisted of not meeting a Clinical Global Impressions-Improvement (CGI-I) score of 1 and a normal score (≤15) on the Nisonger Child Behavior Rating Form Disruptive-Total (D-Total); a CGI-I score of 1 or 2 plus 25% improvement in D-Total score; a D-Total score no higher than 15; and a CGI-Severity score of 3 (mild) or better. Effect sizes were calculated. Prior TOSCA publications were reviewed for clinically relevant findings. All 4 criteria resulted in medium or better effect sizes (d= 0.59-0.72) when comparing risperidone with placebo. Providing risperidone to children who did not reach a CGI-I score of 1 plus a D-Total score no higher than 15 resulted in the greatest benefit. In addition, a review of clinically relevant data suggests that stimulant plus PT shows further improvement after 3 weeks even without augmentation. For those children who did not attain a CGI-I score of 1 and a D-total score no higher than 15, adding risperidone maximized the number of children benefitting from treatment and the average amount of benefit. Unless clinical circumstances dictate otherwise, practitioners should delay an antipsychotic drug for at least 1 month after the optimal stimulant dose is achieved and PT has commenced. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov; NCT00796302.

Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial.

Conventional antidepressant treatments result in symptom remission in 30% of those treated for major depressive disorder, raising the need for effective adjunctive therapies. Inflammation has an established role in the pathophysiology of major depressive disorder, and minocycline has been shown to modify the immune-inflammatory processes and also reduce oxidative stress and promote neuronal growth. This double-blind, randomised, placebo-controlled trial examined adjunctive minocycline (200 mg/day, in addition to treatment as usual) for major depressive disorder. This double-blind, randomised, placebo-controlled trial investigated 200 mg/day adjunctive minocycline (in addition to treatment as usual) for major depressive disorder. A total of 71 adults with major depressive disorder ( Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) were randomised to this 12-week trial. Outcome measures included the Montgomery-Asberg Depression Rating Scale (primary outcome), Clinical Global Impression-Improvement and Clinical Global Impression-Severity, Hamilton Anxiety Rating Scale, Quality of Life Enjoyment and Satisfaction Questionnaire, Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool. The study was registered on the Australian and New Zealand Clinical Trials Register: www.anzctr.org.au , #ACTRN12612000283875. Based on mixed-methods repeated measures analysis of variance at week 12, there was no significant difference in Montgomery-Asberg Depression Rating Scale scores between groups. However, there were significant differences, favouring the minocycline group at week 12 for Clinical Global Impression-Improvement score - effect size (95% confidence interval) = -0.62 [-1.8, -0.3], p = 0.02; Quality of Life Enjoyment and Satisfaction Questionnaire score - effect size (confidence interval) = -0.12 [0.0, 0.2], p < 0.001; and Social and Occupational Functioning Scale and the Range of Impaired Functioning Tool score - 0.79 [-4.5, -1.4], p < 0.001. These effects remained at follow-up (week 16), and Patient Global Impression also became significant, effect size (confidence interval) = 0.57 [-1.7, -0.4], p = 0.017. While the primary outcome was not significant, the improvements in other comprehensive clinical measures suggest that minocycline may be a useful adjunct to improve global experience, functioning and quality of life in people with major depressive disorder. Further studies are warranted to confirm the potential of this accessible agent to optimise treatment outcomes.

Predictors of treatment response and drop out in the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study

The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) compared the efficacy of risperidone, olanzapine, and molindone over 8 weeks in 119 youths age 8–19 years with early-onset schizophrenia or schizoaffective disorder. From this large dataset, we examined predictors of treatment response and drop out using stepwise regression and receiver operating characteristics curve (ROC) analysis. Treatment response was defined as having both a ≥ 20% improvement in Positive and Negative Syndrome Scale (PANSS) score and a Clinical Global Impression-Improvement (CGI-I) score < 3. More severe baseline symptoms, having a history of being in an early education program, and previous prescription of a mood stabilizer increased the likelihood of responding to treatment. Anhedonia and poor community functioning predicted a reduction in symptom severity on the PANSS. Random assignment to different antipsychotic treatment was not predictive of outcome. Parental report of aggressive behaviors at baseline and being African American were associated with a greater likelihood of drop out. Our results suggest youth with more severe psychotic symptoms are most likely to benefit from treatment with antipsychotics and that aggressive youth may require additional support to improve treatment adherence. Further investigation is needed to understand potentially modifiable predictors of response like early education programs.

Effects of 10 Hz Repetitive Transcranial Magnetic Stimulation of the Left Dorsolateral Prefrontal Cortex in Disorders of Consciousness.

While repetitive transcranial magnetic stimulation (rTMS) has been applied in treatment of patients with disorders of consciousness (DOC), a standardized stimulation protocol has not been proposed, and its therapeutic effects are inconsistently documented. To assess the efficacy of rTMS in improving consciousness in patients with persistent minimally conscious state (MCS) or unresponsive wakefulness syndrome (UWS), previously known as vegetative state (VS). A prospective single-blinded study, with selected subjects, was carried out. In total, 16 patients (5 MCS and 11 VS/UWS) with chronic DOC were included. All patients received active 10 Hz rTMS at the left dorsolateral prefrontal cortex (DLPFC), at one session per day, for 20 consecutive days. A single daily session of stimulation consisted of 1,000 pulses (10 s of 10 Hz trains; repeated 10 times with an inter-train interval of 60 s; and 11 min and 40 s for total session). The main outcome measures were changes in the total score on the JFK Coma Recovery Scale-Revised (CRS-R) scale. Additional measures were the impressions of caregivers after the conclusion of the interventions, which were assessed using the Clinical Global Impression-Improvement (CGI-I) scale. The CRS-R scores were increased in all 5 MCS patients and 4 of 11 VS/UWS patients, while a significant enhancement of CRS-R scores was observed compared to the baseline in all participants (p = 0.007). However, the improvement was more notable in MCS patients (p = 0.042) than their VS/UWS counterparts (p = 0.066). Based on the CGI-I scores, two patients improved considerably, two improved, six minimally improved, six experienced no change, and none deteriorated. Good concordance was seen between the CGI-I result and the increases in CRS-R scores. Treatment of 10 Hz multisession rTMS applied to the left DLPFC is promising for the rehabilitation of DOC patients, especially those in MCS. Further validation with a cohort of a larger sample size is required.

A Randomized, Double-Blind Placebo-Controlled Trial on Effectiveness and Safety of Celecoxib Adjunctive Therapy in Adolescents with Acute Bipolar Mania.

Recent studies have focused on the role of inflammatory cascades as one of the possible etiologic factors of bipolar disorder. We hypothesize that celecoxib, through its anti-inflammatory properties, may have a therapeutic role in acute bipolar mania. Forty-two adolescent inpatients with the diagnosis of acute bipolar mania participated in a parallel, randomized, double-blind controlled trial, and 40 patients underwent an 8-week treatment with either celecoxib (100 mg twice daily) or placebo as an adjunctive treatment to lithium and risperidone. Patients were evaluated using Young Mania Rating Scale (YMRS) at baseline and weeks 2, 4, and 8. The primary outcome measure was to assess the efficacy of celecoxib compared with placebo in improving mania symptoms. General linear model repeated measures showed significant effect for time × treatment interaction on YMRS scores [F (2.54, 96.56) = 3.21, p = 0.03]. Significantly greater improvement was observed in YMRS scores in the celecoxib group compared with the placebo group from baseline YMRS score at week 8 (p = 0.04). Although a 35% greater response to treatment (considering a Clinical Global Impressions-Improvement score of ≤2, very much/much improved) was observed in the celecoxib group compared with the placebo group, the difference did not reach the statistical significance level (p = 0.09). No serious adverse event was reported. Celecoxib may be an effective adjuvant therapy in treatment of manic episodes (without psychotic features) of adolescents with bipolar mood disorder. The mood-stabilizing role of this drug might be mediated through its action on inflammatory cascades.

Open-Label Trial of Vitamin D3 Supplementation in Children with Autism Spectrum Disorder

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume X, Number x, 2016 a Mary Ann Liebert, Inc. Pp. 1–10 DOI: 10.1089/cap.2015.0159 Original Article Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism Robert L. Hendren, DO, 1 S. Jill James, PhD, 2 Felicia Widjaja, MPH, 1 Brittany Lawton, BS, 1 Abram Rosenblatt, PhD, 1 and Stephen Bent, MD 1 Abstract Objective: Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress. We sought to determine if methyl B12, a key metabolic cofactor for cellular methylation reactions and antioxidant defense, could improve symptoms of ASD. Methods: A total of 57 children with ASD were randomly assigned to 8 weeks of treatment with methyl B12 (75 lg/kg) or saline placebo every 3 days in a subcutaneous injection. The primary outcome measure was overall improvement in symptoms of ASD as measured by the Clinical Global Impressions-Improvement (CGI-I) score. Secondary outcome mea- sures included changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Laboratory measures of methionine methylation and antioxidant glutathione metabolism were assessed at baseline and 8 weeks. Results: A total of 50 children (mean age 5.3 years, 79% male) completed the study. The primary outcome measure – the clinician rated CGI-I score – was statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2–0.2, p = 0.005). Clinical improvement among children treated with methyl B12 was positively correlated with increases in plasma methionine ( p = 0.05), decreases in S-adenosyl-l- homocysteine (SAH) ( p = 0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH ( p = 0.007), indi- cating an improvement in cellular methylation capacity. No improvements were observed in the parent-rated ABC or SRS. Conclusions: Methyl B12 treatment improved clinician-rated symptoms of ASD that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity. Clinical Trial Registry: Efficacy Study of Subcutaneous Methyl B12 in Children with Autism: NCT01039792 (clinical trials.gov1). Introduction with autism had significantly lower plasma methionine, S- adenosylmethionine (SAM), homocysteine, cystathionine, cysteine, and total glutathione as well as significantly higher levels of S-adenosyl-l-homocysteine (SAH), adenosine, and oxidized gluta- thione. These laboratory changes were consistent with increased oxidative stress and impaired methylation capacity in children with ASD ( James et al. 2004). As shown in Figure 1, these abnormalities are related to three interconnected metabolic pathways known col- lectively as methionine transmethylation/transsulfuration metabo- lism (Hirsch et al. 2008; Kalinina et al. 2014; Watson et al. 2014). A second study in 2006 of 80 children with ASD and 73 controls again demonstrated the same pattern of methylation deficit and oxidative stress ( James et al. 2006). A more recent study in 2012 examined 68 children with ASD, 40 unaffected siblings, and 54 age- matched unaffected, unrelated control children. Reduced methyla- tion capacity was associated with DNA hypomethylation and reduced glutathione antioxidant defense in the children with ASD but not in their unaffected siblings or control children (Melnyk et al. A utism spectrum disorder (ASD) is a complex neurodeve- lopmental disorder characterized by deficits in social inter- action and restricted, repetitive patterns of behavior that now affects 1 in 68 children (Developmental Disabilities Monitoring Network Surveillance Year Principal and Centers for Disease Control and Prevention 2014). ASD has a significant genetic component, with up to 25% of cases being caused by an identifiable genetic defect (Huguet et al. 2013). However, two recent epide- miologic studies have concluded that environmental influences have a greater contribution than genetic factors in the etiology of autism (Hallmayer et al. 2011; Sandin et al. 2014). Many metabolic processes have shown specific deficits in children with ASD, including both cellular methylation and glutathione- mediated antioxidant defense (Rossignol and Frye 2012). In 2004, James et al. reported findings of a small study of 20 children with autism compared with 33 healthy controls, and found that children Department of Psychiatry, University of California, San Francisco, California. Arkansas Children’s Hospital Institute, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Funding: This study was supported by a grant from Autism Speaks (grant #3031 to Dr. Hendren).

Moderators and predictors of response to behavior therapy for tics in Tourette syndrome.

To examine moderators and predictors of response to behavior therapy for tics in children and adults with Tourette syndrome and chronic tic disorders. Data from 2 10-week, multisite studies (1 in children and 1 in adults; total n = 248) comparing comprehensive behavioral intervention for tics (CBIT) to psychoeducation and supportive therapy (PST) were combined for moderator analyses. Participants (177 male, 71 female) had a mean age of 21.5 ± 13.9 years (range 9-69). Demographic and clinical characteristics, baseline tic-suppressing medication, and co-occurring psychiatric disorders were tested as potential moderators for CBIT vs PST or predictors of outcome regardless of treatment assignment. Main outcomes measures were the Yale Global Tic Severity Scale Total Tic score and the Clinical Global Impression-Improvement score assessed by masked evaluators. The presence of tic medication significantly moderated response to CBIT vs PST (p = 0.01). Participants showed tic reduction after CBIT regardless of tic medication status, but only participants receiving tic medication showed reduction of tics after PST. Co-occurring psychiatric disorders, age, sex, family functioning, tic characteristics, and treatment expectancy did not moderate response. Across both treatments, greater tic severity (p = 0.005) and positive participant expectancy (p = 0.01) predicted greater tic improvement. Anxiety disorders (p = 0.042) and premonitory urge severity (p = 0.005) predicted lower tic reduction. Presence of co-occurring attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, or anxiety disorders did not moderate response to CBIT. Although participants on tic medication showed improvement after CBIT, the difference between CBIT and PST was greater for participants who were not on tic-suppressing medication. The child and adult CBIT studies are listed on clinical trials.gov (NCT00218777 and NCT00231985, respectively). This study provides Class I evidence that CBIT is effective in reducing tic severity across subgroups of patients with chronic tic disorders, although the difference between treatments was smaller for participants on tic-suppressing medications, suggesting reduced efficacy in this subgroup.

The Utility of Low-Dose Aripiprazole for the Treatment of Bipolar II and Bipolar NOS Depression.

Despite initial reports of efficacy in bipolar depression, multicenter trials did not show aripiprazole to be better than placebo, possibly because the doses used were too high, leading to lower efficacy and high dropout rates. This study evaluated the effects of low-dose aripiprazole. Extensive clinical experience has suggested that doses beyond 5 mg are rarely efficacious. Data were gathered from patients with bipolar II or bipolar not otherwise specified depression using a retrospective chart review. Efficacy was assessed with the Clinical Global Impression-Improvement score. Patients who had at least 2 trials of aripiprazole were included in a retrospective off-on-off-on experimental design. All patients were on other medications when aripiprazole was started. Patients were treated with doses of 1 to 5 mg. On average, patients were rated improved or very much improved compared with baseline. Sixteen of 211 patients worsened or experienced no change. Forty-four patients (21%) discontinued due to adverse effects. The group of patients who underwent off-on-off-on trials experienced statistically significant improvement when they started and restarted aripiprazole, and statistically significant worsening when they discontinued it. When treating bipolar II or bipolar not otherwise specified depression, low doses of aripiprazole, 5 mg or less, may be more effective and better tolerated than higher ones. Clinicians should start treatment with a very low dose and give patients time to respond.

What does the MADRS mean? Equipercentile linking with the CGI using a company database of mirtazapine studies

BackgroundLittle is known about the clinical relevance of the Montgomery Asberg Depression Rating Scale (MADRS) total scores. It is unclear how total scores translate into clinical severity, or how commonly used measures for response (reduction from baseline of ≥50% in the total score) translate into clinical relevance. Moreover, MADRS based definitions of remission vary. MethodsWe therefore compared: a/ the MADRS total score with the Clinical Global Impression – Severity Score (CGI-S) b/ the percentage and absolute change in the MADRS total scores with Clinical Global Impression – Improvement (CGI-I); c/ the absolute and percentage change in the MADRS total scores with CGI-S absolute change. The method used was equipercentile linking of MADRS and CGI ratings from 22 drug trials in patients with Major Depressive Disorder (MDD) (n=3288). ResultsOur results confirm the validity of the commonly used measures for response in MDD trials: a CGI-I score of 2 (‘much improved’) corresponded to a percentage MADRS reduction from baseline of 48–57%, and a CGI-I score of 1 (‘very much improved’) to a reduction of 80–84%. If a state of almost complete absence of symptoms were required for a definition of remission, a MADRS total score would be <8, because such scores corresponded to a CGI-S score of 2 (‘borderline mentally ill’). Limitations: Although our analysis is based on a large number of patients, the original trials were not specifically designed to examine our research question. ConclusionsThe results might contribute to a better understanding and improved interpretation of clinical trial results in MDD.

Aripiprazole in the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorder in Japan: A Randomized, Double-blind, Placebo-controlled Study

We evaluated the efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents (6–17 years) with autism spectrum disorder (ASD) in a randomized, double-blind, placebo-controlled 8-week study in Japan. Patients received flexibly dosed aripiprazole (1–15 mg/day) or placebo. Ninety-two patients were randomized to placebo (n = 45) or aripiprazole (n = 47). Aripiprazole produced a significant improvement in the mean parent/caregiver-rated Aberrant Behavior Checklist Japanese Version irritability subscale score relative to placebo from week 3 through week 8. Administration of aripiprazole provided significantly greater improvement in the mean clinician-rated Clinical Global Impression-Improvement scores than placebo from week 2 through week 8. All patients randomized to aripiprazole completed the study, and no serious adverse events were reported. Three patients in placebo group discontinued. Aripiprazole was effective and generally safe and well-tolerated in the treatment of irritability associated with ASD in Japanese children and adolescents.

Identifying predictive clinical characteristics of the treatment efficacy of mirtazapine monotherapy for major depressive disorder.

BackgroundMirtazapine, which is classified as a noradrenergic and specific serotonergic antidepressant, is widely prescribed for the treatment of major depressive disorder. The potential predictive factors of the efficacy of mirtazapine and the tolerability based on the incidence of oversedation and jitteriness/anxiety syndrome were evaluated.Patients and methodsPatients with major depressive disorder were retrospectively investigated. Study subjects comprised 68 patients with depression who received mirtazapine as an initial antidepressant at the Department of Psychiatry of the Tokyo Women’s Medical University Hospital from September 2009 to March 2013. The efficacy of mirtazapine monotherapy was evaluated based on the Clinical Global Impression Improvement score. Clinical characteristics were compared between remission and nonremission groups to determine the factors predicting the efficacy. Moreover, discontinuation rates due to adverse effects, including oversedation and jitteriness/anxiety syndrome, were examined, and the effects of confounding factors were evaluated.ResultsThe remission rate of mirtazapine monotherapy was 36.8% among the 68 enrolled subjects. The mean final doses in the remission and nonremission groups were 27.6±13.5 mg and 26.0±14.1 mg, respectively, and there was no significant difference between them. Multiple logistic analyses revealed that the absence of guilt (odds ratio [OR] =0.15; 95% CI [1.66–37.24], P=0.006) and the presence of psychomotor retardation (OR =4.30; 95% CI [1.30–16.60], P=0.016) were significantly related to the efficacy of mirtazapine monotherapy. The discontinuation rates due to oversedation and jitteriness/anxiety syndrome were 13.2% and 11.8%, respectively. Age did not differ significantly between patients with or without oversedation or jitteriness/anxiety syndrome (P=0.078 and P=0.579, respectively).ConclusionThe absence of guilt and the presence of psychomotor retardation may predict the efficacy of mirtazapine, and mirtazapine may be tolerable for all ages.

AUGMENTATION STRATEGIES FOR TREATMENT-RESISTANT ANXIETY DISORDERS: A SYSTEMATIC REVIEW AND META-ANALYSIS.

A systematic review and meta-analysis was conducted to explore the efficacy of medication augmentation strategies compared to control treatments in patients who have had a partial or no response to initial treatment for generalized anxiety disorder, social anxiety disorder, and panic disorder. Double-blind controlled trials of medication augmentation in adult treatment-resistant anxiety disorders conducted between January 1990 and January 2015 were systematically reviewed and evaluated by two independent raters. The search identified 625 articles; 610 were excluded following abstract review and 15 had full-text screening. Studies had to include a definition of treatment resistance, exclude concomitant medications, and have a parallel or crossover design. Data extraction forms were completed in duplicate. Six studies were included in the meta-analysis. Effect estimates were calculated using random effects modeling; heterogeneity was assessed and subgroup and sensitivity analyses were completed. Primary outcome was response, defined by Clinical Global Impression-Improvement score of ≤2. Augmentation was not associated with an increased risk of response, as compared with placebo (RR = 1.08, 95% CI = 0.94-1.24). A small significant effect was found in reduction in symptom severity: standard mean difference = -0.32, 95% CI = -0.56 to -0.08. No significant differences between augmentation with medication versus placebo were found in ratings of functional impairment and dropouts due to adverse events. Augmentation does not appear to be beneficial in treatment-resistant anxiety disorders. These results may be limited by small study samples, and a small number of overall studies in the analysis.

A retrospective study of predictive factors for effective aripiprazole augmentation of antidepressant therapy in treatment-resistant depression.

BackgroundSeveral studies have evaluated the efficacy and tolerability of aripiprazole for augmentation of antidepressant therapy for treatment-resistant depression (TRD). Here, we investigated the efficacy of aripiprazole augmentation for TRD including both major depressive disorder and bipolar disorder and the clinical predictors of treatment efficacy in a Japanese population.MethodsEighty-five depressed Japanese patients who underwent aripiprazole augmentation therapy after failing to respond satisfactorily to antidepressant monotherapy were included in the study. Treatment responses were evaluated based on Clinical Global Impression Improvement scores assessed 8 weeks after initiation of aripiprazole administration. We compared demographic and diagnostic variables, psychiatric medication variables, and clinical variables between remission and nonremission groups.ResultsThe aripiprazole augmentation remission rate was 36.5%. Multiple logistic regression analysis indicated that aripiprazole augmentation was significantly more effective for bipolar depression than for major depressive disorder, and both absence of comorbid anxiety disorders and current episode duration >3 months were significantly associated with the efficacy of aripiprazole augmentation.ConclusionPolarity of depression, comorbidity of anxiety disorders, and current episode duration may predict the efficacy of aripiprazole augmentation for TRD including both major depressive disorder and bipolar disorder. Among them, comorbidity of anxiety disorders was significantly related to the efficacy for TRD including only major depressive disorder. Additional studies are needed to examine the association between the efficacy of aripiprazole augmentation and bipolarity, and these findings should be validated further in a prospective study.

Efficacy of Long-Acting Injectable Antipsychotics in Adolescents.

The number of long-acting injectable antipsychotics (LAIA) has increased in recent years. The safety and efficacy of that treatment are not established in children. This study aims to address this gap of information by studying such treatments in a case series. This retrospective chart review of patients identified by the investigators at an academic acute inpatient psychiatric unit included all patients from the past 24 months who required new initial treatment with LAIA. This study included a case series of the nine patients along with Clinical Global Impression-Severity (CGI-S) scores from admission and discharge and Clinical Global Impression-Improvement (CGI-I) scores. Other observations included the presentation of primary psychiatric diagnosis, psychiatric and medical comorbidities, age, sex, previous and LAIA psychiatric medications, reasoning for LAIA treatment, adverse events, CGI-S and CGI-I scores, and outpatient resources utilized to continue treatment. The case series included two females and seven males within the ages of 14-17 years. Of those patients, five were treated with paliperidone palmitate, one treated with risperidone, one treated with fluphenazine, and one treated with aripiprazole. Primary psychiatric diagnosis of the patients in the case series included five with schizophrenia, one with schizoaffective disorder, one with bipolar affective disorder-type I, one with bipolar affective disorder-not otherwise specified, and one with mood disorder-not otherwise specified. In all nine cases, noncompliance was a consideration in treatment with LAIA. Frequent running away and severity of illness were also considerations in one case each. All of the patients required community resources with injectable services. This study describes initiation of treatment with LAIA in 14-17-year olds in an acute inpatient psychiatric unit with serious mental illness. This study also demonstrates the need for outpatient community resources with the ability to provide long-acting injectable medication. Limitations of this study include a small patient population, other factors changing CGI-S and CGI-I scores beyond the medication, and the nature of the study as a retrospective chart review. This study did not compare medications between each other. Maintenance dosing and long-term safety were beyond the scope of this study. Future directives for safety studies, open-label trials, and randomized double-blinded control trails in the pediatric population would be needed.

Randomized, Placebo-Controlled Trial of Methyl B12 for Children with Autism.

Children with autism spectrum disorder (ASD) have been reported to have reduced ability to methylate DNA and elevated markers of oxidative stress. We sought to determine if methyl B12, a key metabolic cofactor for cellular methylation reactions and antioxidant defense, could improve symptoms of ASD. A total of 57 children with ASD were randomly assigned to 8 weeks of treatment with methyl B12 (75 μg/kg) or saline placebo every 3 days in a subcutaneous injection. The primary outcome measure was overall improvement in symptoms of ASD as measured by the Clinical Global Impressions-Improvement (CGI-I) score. Secondary outcome measures included changes in the Aberrant Behavior Checklist (ABC) and the Social Responsiveness Scale (SRS). Laboratory measures of methionine methylation and antioxidant glutathione metabolism were assessed at baseline and 8 weeks. A total of 50 children (mean age 5.3 years, 79% male) completed the study. The primary outcome measure - the clinician rated CGI-I score - was statistically significantly better (lower) in the methyl B12 group (2.4) than in the placebo group (3.1) (0.7 greater improvement in the methyl B12 group, 95% CI 1.2-0.2, p = 0.005). Clinical improvement among children treated with methyl B12 was positively correlated with increases in plasma methionine (p = 0.05), decreases in S-adenosyl-l-homocysteine (SAH) (p = 0.007) and improvements in the ratio of S-adenosylmethionine (SAM) to SAH (p = 0.007), indicating an improvement in cellular methylation capacity. No improvements were observed in the parent-rated ABC or SRS. Methyl B12 treatment improved clinician-rated symptoms of ASD that were correlated with improvements in measures of methionine metabolism and cellular methylation capacity. Clinical Trial Registry: Efficacy Study of Subcutaneous Methyl B12 in Children with Autism: NCT01039792 ( clinicaltrials.gov1 ).

The efficacy and safety of 10 mg vortioxetine in the treatment of major depressive disorder: a meta-analysis of randomized controlled trials.

BackgroundVortioxetine is an investigational multimodal antidepressant. We conducted this meta-analysis to assess the efficacy and safety of 10 mg vortioxetine in the treatment of major depressive disorder (MDD).MethodsRandomized controlled trials (RCTs) published in PubMed, Web of Science, Embase, and ClinicalTrials.gov were systematically reviewed to assess the treatment effects and safety profiles of patients with MDD who were treated with 10 mg vortioxetine. The outcome measures included response rate, remission rate, changes from baseline in Montgomery–Asberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Depression (24-items) (HAM-D24), Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Improvement (CGI-I) scores. Results were expressed with risk ratio or weighted mean difference with 95% confidence intervals. Pooled results were calculated using a fixed-effects model or a random-effects model according to the heterogeneity among included trials.ResultsSix RCTs with a total of 1,801 patients met the inclusion criteria and were included in this meta-analysis. The 10 mg vortioxetine dose significantly increased the response rate and remission rate in the treatment of MDD compared with placebo. Moreover, there was a statistically significant reduction from baseline in the MADRS, HAM-D24, CGI-S, and CGI-I scores with 10 mg vortioxetine vs placebo. The incidence of treatment-emergent adverse events such as nausea, vomiting, constipation, and hyperhidrosis was higher in the 10 mg vortioxetine group than in the placebo group.ConclusionVortioxetine 10 mg can significantly increase the response rate and remission rate, and reduce the MADRS, HAM-D24, CGI-S, and CGI-I scores in patients with MDD with an acceptable risk of treatment-emergent adverse events. Further well-conducted, large-scale trials are needed to validate these findings.