Clinical Global Impressions-Improvement Scale Research Articles

The Consequences of Discontinuing a Home Care Service for Patients with Severe Mental Illness After the COVID-19 Pandemic.

Continuity of care has been considered, as a key component of the treatment process, especially after discharge from the hospital. Establishing treatment continuity is critical to achieving successful treatment outcomes. Roozbeh Home Care Program was developed to ensure the continuity of care in patients with severe mental illness. This study aims to investigate the consequences of discontinuing a home care service including; relapse, readmission, service satisfaction, severity and disability, in patients with severe mental illness in Iran. Forty-three patients who received home care service for more than 6 months were included. They were assessed 3 and 6 months after receiving the service; and 12 months after the program discontinuation. There was a significant difference between the hospitalization rate during (0.42 ± 0.64) and 1 year after the program's discontinuation (0.65 ± 1.46). The majority of the caregivers (70%) were highly satisfied with the home care services. Among the patients who received the homecare services, 40.4% were highly satisfied; and 21.2% were moderately satisfied. There was no significant difference between disability (as measured by World Health Organization Disability Assessment Schedule), clinical improvement (as measured by Clinical Global Impression-Improvement Scale), or severity of illness (as measured by Clinical Global Impression Severity of the Illness Scale) during and 1 year after program's discontinuation. During the time of receiving the service, hospitalization rate was reduced. Patients and caregivers were satisfied with the service. Providing psychiatric services at home should be considered as a solution to maintain the continuity of care.

Early Antipsychotic Nonresponse as a Predictor of Nonresponse and Nonremission in Adolescents With Psychosis Treated With Aripiprazole or Quetiapine: Results From the TEA Trial.

To evaluate 1) whether early nonresponse to antipsychotics predicts nonresponse and nonremission, 2) patient and illness characteristics as outcome predictors, and 3) response prediction of 30-item Positive and Negative Syndrome Scale (PANSS-30) compared with 6-item PANSS (PANSS-6) and Clinical Global Impressions-Improvement Scale (CGI-I) in youths with first-episode psychosis. Post hoc analysis from a 12-week, double-blinded, randomized trial of aripiprazole vs extended-release quetiapine in adolescents (age 12-17 years) with first-episode psychosis was performed. Early nonresponse (week 2 or week 4) was defined as<20% symptom reduction (PANSS-30) (or<20% symptom reduction [PANSS-6] or CGI-I score 4-7 [less than "minimally improved"]). Nonresponse (week 12) was defined as<50% symptom reduction (PANSS-30). Nonremission (week 12) was defined as a score of >3 on 8 selected PANSS-items. Positive/negative predictive values (PPV/NPV) and receiver operating characteristics, binary logistic regression models, and PPV/NPV using PANSS-6 and CGI-I were analyzed. Of 113 randomized patients, 84 were included in post hoc analysis (mean [SD] age= 15.7 [1.3] years; 28.6% male). The 12-week symptom decrease was 31.9% [27.9%], most pronounced within the first 2 weeks (61.1% of total PANSS reduction). Response (27.4%) and remission (22.6%) rates were low. Results indicated that early nonresponse reliably predicted 12-week nonresponse (PPV: week 2, 82.2%; week 4, 90.0%) and nonremission (PPV: week 2, 80.0%; week 4, 90.0%); early nonresponse at week 4 was a statistically significant baseline predictor for 12-week nonresponse; and PANSS-6 had similar predictive significance as PANSS-30. However, outcomes were heterogeneous using CGI-I. In youths with first-episode psychosis showing early nonresponse to aripiprazole or extended-release quetiapine, switching antipsychotic drug should be considered. PANSS-6 is a feasible and clinically relevant alternative to PANSS-30 to predict 12-week nonresponse/nonremission. Tolerance and Effect of Antipsychotics in Children and Adolescents With Psychosis; https://www. gov/; NCT01119014.

Treatment-Resistant Mood Disorders in LGBTQ People

Objective: Individuals who identify as lesbian, gay, bisexual, transgender, or queer (LGBTQ) experience greater social exclusion and discrimination and higher rates of depression. Little is known about the clinical characteristics or treatment outcomes of LGBTQ people with severe mood disorders. We hypothesized that LGBTQ patients would present with distinct clinical features and that they might respond less favorably to electroconvulsive therapy (ECT).Methods: We performed a retrospective chart review (2018-2020) of 59 LGBTQ patients and 441 non-LGBTQ patients who received an acute ECT series for treatment-resistant illness (in 95%, a depressive episode by DSM-5 criteria). Clinical response was evaluated with the Clinical Global Impression Improvement (CGI-I) scale, self-rated Quick Inventory of Depressive Symptomatology (QIDS-SR), and QIDS-SR suicide item. Inverse probability of treatment weights were applied to regression models to balance baseline confounders.Results: LGBTQ status was associated with younger age, current suicide ideation, past suicide attempt, self-injurious behavior, posttraumatic stress disorder, personality disorder, tobacco smoking, past substance use disorder, and history of sexual abuse (all P < .05). LGBTQ and non-LGBTQ groups showed no significant differences in CGI-I score (odds ratio = 0.82, 95% CI = 0.48-1.40, P = .47), change in QIDS-SR total score (least-squares mean = -9.2 vs -8.1; F1,408 = 1.42; P = .24), or change in QIDS-SR suicide item (odds ratio = 1.83, 95% CI = 0.91-3.68, P = .09).Conclusions: LGBTQ people with treatment-resistant mood disorders presented with distinct clinical features, some of which have been previously linked with less favorable treatment outcomes. Nonetheless, LGBTQ and non-LGBTQ patients experienced similar clinically significant improvement with an acute ECT series. ECT should be considered for treatment-resistant depression regardless of an individual's sexual orientation or gender identity.

Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19–Related Olfactory Dysfunction

Recent studies suggest that theophylline added to saline nasal irrigation (SNI) can be an effective treatment for postviral olfactory dysfunction (OD), a growing public health concern during the COVID-19 pandemic. To evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19-related OD. This triple-blinded, placebo-controlled, phase 2 randomized clinical trial was conducted virtually between March 15 and August 31, 2021. Adults residing in Missouri or Illinois were recruited during this time period if they had OD persisting for 3 to 12 months following suspected COVID-19 infection. Data analysis was conducted from October to December 2021. Saline sinus rinse kits and bottles of identical-appearing capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) were mailed to consenting study participants. Participants were instructed to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities in the morning and at night for 6 weeks. The primary outcome was the difference in the rate of responders between the treatment and the control arms, defined as a response of at least slightly better improvement in the Clinical Global Impression-Improvement scale posttreatment. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT), the Questionnaire for Olfactory Disorders, the 36-Item Short Form Health Survey on general health, and COVID-19-related questions. A total of 51 participants were enrolled in the study; the mean (SD) age was 46.0 (13.1) years, and 36 (71%) participants were women. Participants were randomized to SNI with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study. At the end of treatment, 13 (59%) participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 10 (43%) in the placebo arm (absolute difference, 15.6%; 95% CI, -13.2% to 44.5%). The median difference for the UPSIT change between baseline and 6 weeks was 3.0 (95% CI, -1.0 to 7.0) for participants in the theophylline arm and 0.0 (95% CI, -2.0 to 6.0) for participants in the placebo arm. Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the 2 study arms. Eleven (50%) participants in the theophylline arm and 6 (26%) in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks. The difference in the rate of responders as measured by the UPSIT was 24% (95% CI, -4% to 52%) in favor of theophylline. This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19-related OD is inconclusive, though suggested by subjective assessments. Larger studies are warranted to investigate the efficacy of this treatment more fully. ClinicalTrials.gov Identifier: NCT04789499.

A naturalistic, 24-week, open-label, add-on study of vortioxetine in bipolar depression.

The efficacy of vortioxetine in major depressive disorder has been evaluated in many studies. However, there is a lack of studies assessing vortioxetine in bipolar depression. In 60 patients with bipolar depression, vortioxetine 10-20 mg daily was added to current mood stabilizing medication during 24-week, naturalistic, openlabel study. The most frequent mood stabilizers were lamotrigine, quetiapine, olanzapine, and valproates. The therapeutic efficacy was evaluated by the Clinical Global Impression - Improvement (CGI-I) and Clinical Global Impression - Severity (CGI-S) scales. Patients were classified as responding to vortioxetine when they achieved 1 or 2 points on the CGI-I scale at any stage of observation. The criterion of remission was defined as score 1 at the CGI-S. 73% of all patients (44/60) responded to vortioxetine and 52% (31/60) achieved clinical remission of depressive symptoms (in mean 8.97 ± 4.05 weeks). There were no significant associations between vortioxetine response/remission rates and: (1) the dose, (2) BD type, (3) clinical stage, (4) presence of rapid cycling, (5) history of psychotic symptoms, analyzed depressive symptoms, and (6) concomitantly used mood stabilizer. 4 patients (6.7%) stopped treatment due to adverse effects (nausea), and 7 patients (11.7%) discontinued treatment due to the phase switch. 14 patients (23%) experienced a loss of vortioxetine effectiveness after the initial response or remission. The results indicate relatively high rates of response and remission during 24-week treatment in depressed bipolar patients receiving vortioxetine concomitantly with a mood stabilizer. This may indicate that vortioxetine added to a mood stabilizer may constitute an efficient and well tolerated therapeutic option in bipolar depression.

C-reactive protein could predict the efficacy of SSRIs in clinical practice: A cohort study of large samples in the real world

BackgroundC-reactive protein (CRP) has been shown to predict antidepressant treatment outcomes in several trials, but they were limited to small-sample and strictly-restricted conditions. This study plans to verify if CRP can predict antidepressant efficacy in large samples in the real world. Methods918 depressed patients who had tested CRP were included, then were followed up through their outpatient visits or by telephone to obtain information about their medication therapy (SSRIs, SNRIs, MT, NaSSA) and assess efficacy using the Clinical Global Impressions–Improvement scale (CGII). Efficacy was classified as effective and ineffective and CRP was separated into the low CRP group (CRP <1 mg/L, n = 709) and the high CRP group (CRP ≥1 mg/L, n = 209).The efficacy was compared in different groups. ResultsUsing Kaplan-Meier survival analysis and Cox proportional regression model to analyze, it was discovered that SNRIs were more effective than SSRIs in treating patients with high CRP(HR = 1.652, p = 0.037,95 % CI:1.031–2.654), and SSRIs were more effective in treating patients with low CRP than those with high CRP (HR = 1.257, p = 0.047,95 % CI:1.003–1.574), while no difference in efficacy between the two groups was found in patients using SNRIs, MT, NaSSA. LimitationsSmall amounts of MT and NaSSA were included, and some factors that may affect CRP value have not been controlled. ConclusionCRP could predict the efficacy of SSRIs in the real world, depressed patients with high CRP may be more likely to respond poorly to SSRIs.

Association of Clinical and Demographic Characteristics With Response to Electroconvulsive Therapy in Mania

Knowledge of the effectiveness of electroconvulsive therapy (ECT) in the treatment of manic episodes is based on clinical experience, but empirical evidence is scarce. Moreover, prognostic factors associated with response to ECT in patients with mania are poorly understood. To investigate the response to ECT in patients with manic episodes. This nationwide, register-based observational cohort study was conducted using data from patients admitted to psychiatric departments in Sweden that reported data to the Swedish National Quality Registry for ECT (Q-ECT). Patients admitted to any hospital in Sweden and receiving ECT for a manic episode between 2012 and 2019 were considered for inclusion (605 individuals). The outcome, Clinical Global Impression Improvement scale (CGI-I) score, was available in 571 patients. Data from several national registers were combined to determine clinical and sociodemographic factors. Analysis of data occurred from April through September 2021. Patients treated with ECT for a mania were identified from the Q-ECT. Response to ECT was defined by a CGI-I score of 1 (very much improved) or 2 (much improved). Remission was defined as a Clinical Global Impression Severity scale (CGI-S) score of 1 (reference range or not ill) or 2 (minimally ill) within 1 week after ECT. Univariate and multivariable regression models were used to investigate associations of sociodemographic factors, psychopharmacology, and comorbidities with response. Among 571 patients with mania treated with ECT (211 [37.0%] men; median [IQR] age, 46 [31-59] years), 482 patients (84.4%) responded to ECT. Comorbid anxiety and obsessive-compulsive disorder (OCD) were associated with lower odds of response to ECT (adjusted odds ratio [aOR], 0.48; 95% CI, 0.25-0.90 and aOR, 0.17; 95% CI, 0.06-0.56, respectively). Patients who were markedly ill (aOR, 2.93; 95% CI, 1.23-7.00), severely ill (aOR, 2.60; 95% CI, 1.06-6.34), or among the most extremely ill (aOR, 7.94; 95% CI, 2.16-29.21) according to CGI-S score had higher odds of response than those with mild or moderate illness. This study found that ECT was associated with improvement for mania in clinical settings, with especially high response rates in patients with severe illness and those without comorbid anxiety or OCD.

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.

Findings from a pilot open-label trial of N-acetylcysteine for the treatment of pediatric mania and hypomania

BackgroundPediatric bipolar disorder is a highly prevalent and morbid disorder and is considered a prevalent public health concern. Currently approved treatments often pose the risk of serious side effects. Therefore, this study assessed the efficacy and tolerability of N-acetylcysteine (NAC), in children and adolescents with bipolar spectrum disorder.MethodsWe conducted a 12-week open-label trial of NAC for treatment of mania and hypomania in children and adolescents ages 5–17 with bipolar spectrum disorder including participants with full and subthreshold manic symptoms, accepting those with and without mixed states with co-occurring depression, and Young Mania Rating Scale scores ≥ 20 and < 40. Symptoms of mania and depression were assessed using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Children’s Depression Rating Scale (CDRS), and Clinical Global Impression (CGI) Severity (CGI-S) and Improvement (CGI-I) scales for mania and depression.ResultsThis study had a high drop-out rate with only 53% completing all 12 weeks. There was a significant reduction in YMRS, HDRS, and CDRS mean scores from baseline to endpoint. Of the 24 exposed participants, 54% had an anti-manic response measured by a reduction in YMRS ≥ 30% and 46% had a CGI-I mania score ≤ 2 at endpoint. Additionally, 62% of participants had an anti-depressive response measured by a reduction in HDRS ≥ 30%, 31% had an anti-depressive response measured by a reduction in CDRS ≥ 30%, and 38% had a CGI-I depression score ≤ 2 at endpoint.ConclusionsThese pilot open-label findings in a small sample provide preliminary data supporting the tolerability and safety of NAC in a pediatric population. The findings of this pilot scale study indicating improvement in mania and depression are promising, but require replication with a monotherapy randomized placebo controlled clinical trial and larger sample.Trial RegistrationClinicalTrials.gov Identifier: NCT02357290. First Registration 06/02/2015.

What Is the Minimum Clinically Important Change in Negative Symptoms of Schizophrenia? PANSS Based Post-hoc Analyses of a Phase III Clinical Trial.

IntroductionMinimum clinically important difference (MCID) is a measure that defines the minimum amount of change in an objective score of a clinical test that must be reached for that change to be clinically noticeable. We aimed to find the MCID for patients with predominantly negative symptoms of schizophrenia at its earliest occurrence.MethodsData of a 26-week long, double-blind study with 454 patients [Positive and Negative Symptom Scale Negative Factor Score (PANSS-FSNS) ≥24, Positive and Negative Symptom Scale Positive Factor Score (PANSS-FSPS) ≤ 19] treated with cariprazine 4.5 mg/d or risperidone 4 mg/d were analyzed. The Clinical Global Impression—Improvement scale was used to quantify minimum improvement (CGI-I = 3) and no clinical change (CGI-I = 4) on the PANSS-FSNS, and the MCID was estimated with the following methods: as the mean PANSS-FSNS changes corresponding to the first instance of minimal improvement across all visits (MCID1); as the difference between the PANSS-FSNS change associated with the first instance and the PANSS-FSNS changes associated with the last recorded clinically unchanged status across all visits (MCID2); with the effect size approach (MCID3); as the Youden Index based cut-off value between no clinical change and minimal improvement (MCID4); as the relative likelihood of minimal improvement (MCID5).ResultsThe MCID1 and MCID2 resulted in, respectively, a 3.8-point (18.5%) and a 1.5-point (7.3%) decrease from baseline severity on the PANSS-FSNS. Greater values were required for the MCID at later evaluation times. The cut-off between minimum improvement and no clinical change defined by the Youden Index was a−3-point (15%) change in the PANSS-FSNS. The effect size approach indicated the 1.5-point difference between minimally improved and unchanged patients to be a medium effect (ES = 0.6).ConclusionApplying different methods led to different results, ranging between 7.3 and 18.5% improvement from the baseline for the MCID at its earliest occurrence in patients with predominantly negative symptoms of schizophrenia.

Real-world use of inhaled nitric oxide therapy in patients with COVID-19 and mild-to-moderate acute respiratory distress syndrome.

BackgroundInhaled nitric oxide (iNO) has been studied in patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 when it may be too late to impact disease course. This article aims to describe real-world iNO use and outcomes in patients with COVID-19 with mild-to-moderate ARDS in the United States.MethodsThis was a retrospective medical chart review study that included patients who were ≥18 years old, hospitalized for COVID-19, met the Berlin ARDS definition, received iNO for ≥24 hours continuously during hospitalization, and had a partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (P/F ratio) of >100 to ≤300 mmHg at iNO initiation. Outcomes included oxygenation parameters, physician-rated Clinical Global Impression–Improvement (CGI-I) scale scores, and adverse events. Response to iNO was defined as >20% improvement in P/F ratio.ResultsThirty-seven patients at six sites were included. A P/F ratio of ≤100 was the most common reason for exclusion (n=146; 83% of excluded patients). The mean P/F ratio (SD) increased from 136.7 (34.4) at baseline to 140.3 (53.2) at 48 hours and 151.8 (50.0) at 72 hours after iNO initiation. The response rate was 62% (n=23). During hospitalization, no patient experienced adverse events, including methemoglobinaemia, airway injury, or worsening pulmonary oedema associated with iNO. At discharge, 54.0% (n=20) of patients improved or remained stable according to the CGI-I.ConclusionIn patients hospitalized with COVID-19 and mild-to-moderate ARDS, iNO was associated with improvement in the P/F ratio with no reported toxicity. This study provides additional evidence supporting a favourable benefit–risk profile for iNO in the treatment of mild-to-moderate ARDS in patients with COVID-19 infection.

Systematic Review and Meta-analysis: An Empirical Approach to Defining Treatment Response and Remission in Pediatric Obsessive-Compulsive Disorder.

A lack of universal definitions for response and remission in pediatric obsessive-compulsive disorder (OCD) has hampered the comparability of results across trials. To address this problem, we conducted an individual participant data diagnostic test accuracy meta-analysis to evaluate the discriminative ability of the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) in determining response and remission. We also aimed to generate empirically derived cutoffs on the CY-BOCS for these outcomes. A systematic review of PubMed, PsycINFO, Embase and CENTRAL identified 5,401 references; 42 randomized controlled clinical trials were considered eligible, and 21 provided data for inclusion (N = 1,234). Scores of≤2 in the Clinical Global Impressions Improvement and Severity scales were chosen to define response and remission, respectively. A 2-stage, random-effects meta-analysis model was established. The area under the curve (AUC) and the Youden Index were computed to indicate the discriminative ability of the CY-BOCS and to guide for the optimal cutoff, respectively. The CY-BOCS had sufficient discriminative ability to determine response (AUC= 0.89) and remission (AUC= 0.92). The optimal cutoff for response was a≥35% reduction from baseline to posttreatment (sensitivity= 83.9, 95% CI= 83.7-84.1; specificity= 81.7, 95% CI= 81.5-81.9). The optimal cutoff for remission was a posttreatment raw score of≤12 (sensitivity= 82.0, 95% CI= 81.8-82.2; specificity= 84.6, 95% CI= 84.4-84.8). Meta-analysis identified empirically optimal cutoffs on the CY-BOCS to determine response and remission in pediatric OCD randomized controlled clinical trials. Systematic adoption of standardized operational definitions for response and remission will improve comparability across trials for pediatric OCD.

Psychopharmacology in the Pediatric Oncology and Bone Marrow Transplant Units: Antidepressant Treatment.

Objectives: The aim of this study was to characterize the clinical profiles, tolerability, and efficacy of two groups of antidepressants, selective serotonin reuptake inhibitors (SSRIs), and the atypical antidepressant, mirtazapine, in children and adolescents treated in a large pediatric Hematology-Oncology center. Methods: A review of computerized medical charts of 32 pediatric patients with cancer, from December 2011 to April 2020, was conducted. Efficacy and tolerability of antidepressant medications were retrospectively analyzed. The Clinical Global Impressions-Severity (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) Scales were used to evaluate psychiatric symptoms severity before and following treatment, while the data on adverse events and drug-drug interactions were retrieved from the computerized medical records. Results: Thirty-two children and adolescents with cancer, 2-21 years of age (mean 14.1 ± 4.6 years), were treated with antidepressants. Fourteen patients (44%) received mirtazapine, whereas 18 patients (56%) received SSRIs: sertraline (25%), escitalopram (25%), or fluoxetine (6%). Treatment choice was dictated either by physician preference or informed by potential drug-drug interactions. The most common psychiatric diagnoses were major depressive disorders (47%), anxiety disorders (19%), and medication-induced psychiatric disorders (19%). The most common psychiatric-medical symptoms were depressed mood (94%) and anxiety (62%). CGI-S improved significantly (p < 0.05) between pretreatment and on-treatment assessments, with no statistically significant difference between SSRI and mirtazapine-treated patients. CGI-I scores at reassessment indicated improvement in most patients (84%). Adverse events of treatment were mild in all patients. Conclusions: The antidepressants used in this study, SSRIs and mirtazapine, were effective and well tolerated in children and adolescents with cancer and psychiatric comorbidities. Given the high rates of depression and anxiety in children with cancer, large-scale, multisite, prospective clinical trials of antidepressants are warranted.

Safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson's disease-Results of a multicenter open trial.

AimTo evaluate the effect of aripiprazole on psychosis and motor function in Japanese Parkinson's disease patients.MethodsPatients with Parkinson's disease and hallucinations and/or delusions were enrolled. They were administered aripiprazole 3 mg/day, with dosage increased or reduced as needed. Patients were evaluated using the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression‐Severity (CGI‐S) scale, and Clinical Global Impression‐Improvement scale for psychiatric response; Hoehn & Yahr staging and Unified Parkinson's Disease Rating Scale (UPDRS) part III for motor response; Mini‐Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) for cognitive response; and Schwab and England Activities of Daily Living scale for daily activities of patients, before and at 2, 4, and 12 weeks after initiation of open‐label aripiprazole administration. This study was registered at the University Hospital Medical Information Network Center (registration number: UMIN000007711).ResultsNine of the 24 enrolled patients discontinued the study. Among them, eight patients discontinued the trial on account of their worsening parkinsonian symptoms. There were no differences in age, disease duration, disease severity, and MMSE and FAB scores at baseline between patients who continued and discontinued the study. However, in patients who continued aripiprazole administration at 3 mg/day or less significantly improved BPRS, CGI‐S scale, and UPDRS parts I and III scores.ConclusionSignificant improvements in hallucinations and delusions can be expected, although aripiprazole may aggravate parkinsonism in Parkinson's disease patients. Low‐dose use of aripiprazole may be useful for managing Parkinson's disease patients with psychosis, but only with close observation of extrapyramidal symptoms.

Randomised controlled trials of mood stabilisers for people with autism spectrum disorder: systematic review and meta-analysis.

Despite the widespread use of psychotropic medications in people with autism spectrum disorder (ASD), there is limited evidence to suggest that psychotropic medications including mood stabilisers are effective in individuals with ASD. To carry out a systematic review and meta-analysis of randomised controlled trials (RCTs) that assessed the effectiveness of mood stabilisers in people with ASD. We searched the following databases: Cochrane Library, MEDLINE, Embase, CINAHL, PsycINFO, ERIC, DARE, and ClinicalTrials.gov. In addition, we hand-searched 12 relevant journals. We used the Cochrane Risk of Bias and Jadad scores to assess the quality of included RCTs. We carried out a meta-analysis using a random-effects model. We included eight RCTs (four on valproate, two on levetiracetam, and one each on lamotrigine and topiramate) that included a total of 310 people with ASD, primarily children. Outcomes were based on core and associated ASD symptoms including irritability and aggression but not bipolar disorder. Only two small studies (25%) from the same group showed definite superiority over placebo and one over psychoeducation alone. Meta-analysis of pooled data on the Aberrant Behaviour Checklist-irritability, Clinical Global Impression Scale-improvement, and Overt Aggression Scale (OAS)/OAS-modified did not show any significant inter-group difference. The rates of adverse effects did not show any significant inter-group difference. Given the methodological flaws in the included studies and the contradictory findings, it is difficult to draw any definitive conclusion about the effectiveness of mood stabilisers to treat either ASD core symptoms or associated behaviours. Robust large-scale RCTs are needed in the future to address this issue.PROSPERO registration: CRD42021255467 on 18 May 2021.

Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome

IntroductionRett syndrome (RTT) is a debilitating neurodevelopmental disorder with no approved treatments. Trofinetide is a synthetic analog of glycine–proline–glutamate, the N-terminal tripeptide of insulin-like growth factor 1. In a phase 2, placebo-controlled trial in 82 females with RTT aged 5–15 years, a significant (p ≤ 0.042) improvement over placebo was observed with the highest trofinetide dose (200 mg/kg twice daily [BID]) on three measures: Rett Syndrome Behaviour Questionnaire (RSBQ), Clinical Global Impression-Improvement (CGI-I), and RTT-Clinician Domain Specific Concerns-Visual Analog Scale (RTT-DSC-VAS). Trofinetide was well tolerated at all doses (50, 100, and 200 mg/kg BID). A phase 3 trial utilizing disease-specific and novel scales was designed to investigate the efficacy and safety of trofinetide in girls and women with RTT. MethodsThis 12-week, double-blind, randomized, placebo-controlled study (LAVENDER; NCT04181723) will evaluate trofinetide in 187 females, aged 5–20 years, with RTT. Co-primary endpoints are the RSBQ and CGI-I scales. Clinical domains of the CGI-I include communication, ambulation, hand use, seizures, attentiveness, and social (eye contact) and autonomic (breathing) aspects. Secondary endpoints will leverage four novel RTT-specific clinician ratings (derived from the RTT-DSC-VAS) of hand function, ambulation, ability to communicate, and verbal communication, and existing scales, to evaluate other core symptoms of RTT, quality of life and caregiver burden. A 40-week, open-label extension study will follow. DiscussionThis study was designed using disease-specific scales optimized to demonstrate changes in core symptoms of RTT and may provide the first phase 3 data demonstrating drug efficacy in individuals with RTT.Trial registration: Clinicaltrials.govNCT04181723

Subcortical volumetric alterations as potential predictors of methylphenidate treatment response in youth with attention-deficit/hyperactivity disorder.

Background:Patients with attention-deficit/hyperactivity disorder (ADHD) show structural alterations in the subcortical and dopaminergic regions of the brain. Methylphenidate is a first-line treatment for ADHD, and it is known to affect the subcortical and dopaminergic systems. The degree of pretreatment structural alterations in patients with ADHD may be an important factor in predicting methylphenidate treatment outcomes. The present study examined whether pretreatment volumetric alterations in the subcortical and dopaminergic regions predicted treatment response in youth with ADHD.Methods:This study included 67 youth with ADHD and 25 healthy controls. Youth with ADHD received 8 weeks of methylphenidate treatment. They completed baseline (pretreatment) T1-weighted structural MRI scans and underwent clinical assessments before and after methylphenidate treatment. The healthy controls also completed baseline structural MRI scans. We assessed volumetric alterations using relative volumes (volume of each region of interest/intracranial volume).Results:Among 67 youth with ADHD, 44 were treatment responders and 23 were nonresponders based on post-treatment scores on the Clinical Global Impression Scale–Improvement. Nonresponders had larger volumes in the bilateral amygdala and right thalamus than responders. Nonresponders also had larger volumes in amygdalar subregions (i.e., the bilateral lateral nucleus and right basal nucleus) and hippocampal subregions (i.e., the right hippocampal head and right molecular layer) relative to responders.Limitations:We did not collect post-treatment structural T1-weighted images, so volumetric changes related to methylphenidate treatment in youth with ADHD were undetermined.Conclusion:These findings suggest that pretreatment volumetric alterations in subcortical regions may serve as biomarkers for predicting methylphenidate treatment response in youth with ADHD.

Effect of Equine-Assisted Activities and Therapies on Cardiorespiratory Fitness in Children with Cerebral Palsy: A Randomized Controlled Trial.

Abstract Objectives: To determine the effects of an equine-assisted activities and therapies (EAAT) program on cardiorespiratory fitness (CRF) in children with cerebral palsy (CP). Design: An evaluator-blinded, parallel, two-arm, randomized controlled clinical trial with 1:1 randomization. Settings/Location: A tertiary university hospital and a local arena. Subjects: Forty-six children with CP (24 boys and 22 girls) classified as Gross Motor Function Classification System levels I, II, or III were included. Interventions: The EAAT program was conducted for 40 min twice a week for 16 weeks (32 lessons). Outcome measures: Clinical global impression scales, motor capacity, cardiopulmonary fitness, and habitual physical activity was measured on both groups before and after the 16-week period. Results: Changes in the Clinical Global Impression-Severity scale and Clinical Global Impression-Improvement scale scores were not different between the groups after the intervention. Analysis of covariance revealed statistically significant differences in Gross Motor Function Measure 66 (GMFM 66) (p < 0.05) and Pediatric Balance Scale (p < 0.001) in motor capacity and resting heart rate (HRrest) (p < 0.001) in CRF, between the EAAT group and the control group. Subgroup analysis using multiple linear regression analysis revealed that the GMFM 66 changes had a statistically significant effect on the HRrest changes in the EAAT group (p < 0.05). Conclusions: The present study showed decreased HRrest in children with CP after completing the 16-week EAAT program. This improvement was explained by the improvement of GMFM 66 in the EAAT group. Thus, EAAT may be among the endurance training programs that could be offered to children with CP to improve their CRF. Clinical Trial Registration number: NCT03870893.

N‐Acetylcysteine provides limited efficacy as treatment option for skin picking in Prader–Willi syndrome

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed genes in chromosome region 15q11-13. In addition to typical characteristics such as hyperphagia, PWS is evidenced by a certain behavioral phenotype. Common indicators are repetitive behaviors, temper tantrums, and self-injurious behaviors such as skin- and/or rectal picking. N-Acetylcysteine (NAC) was previously described as a promising therapeutic option for skin picking in PWS. In this case series, we retrospectively investigated the effect of pharmacotherapy with NAC in 14 individuals with PWS suffering from skin- and/or rectal picking. Treatment success was determined using the Clinical Global Impression-Improvement scale (CGI-I). The Clinical Global Impression-Efficacy index (CGI-EI) was used to put treatment success and side effects into perspective. Six of fourteen patients, all of which were female, showed improvement in symptoms (dosage 1800-2400 mg/day), whereas six patients did not show any change during treatment. Moreover, two male patients treated for solitary rectal picking showed new onset of skin picking. Across all cases, a CGI-I of 3 (corresponding to minimal improvement) was seen after 3 months of treatment, with a CGI-EI of 1.6 (corresponding to moderate efficacy). NAC remains a reasonable therapeutic option in certain cases of skin picking in PWS but provides only limited efficacy compared to previous studies on the topic. There was a higher rate of adverse drug reactions than previously reported. The results particularly suggest caution in future treatment in individuals with solitary rectal picking and reduced efficacy when coadministered with neuroleptics.

Long-term efficacy and safety of once-monthly Risperidone ISM® in the treatment of schizophrenia: Results from a 12-month open-label extension study

ObjectiveTo evaluate long-term efficacy, safety and tolerability of Risperidone ISM® in patients with schizophrenia, a multicenter, open-label extension of the PRISMA-3 study was conducted. MethodsEligible placebo (unstable) and Risperidone ISM® (stabilized) rollover patients from a previous 12-week double-blind phase and de novo stable patients received once-monthly intramuscular injections of Risperidone ISM® 75 or 100 mg for 12 months. The long term-efficacy assessment included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. Safety evaluation included treatment-emergent adverse events (TEAEs), injection site reactions (ISR), laboratory tests and several safety scales. ResultsAltogether, 215 patients entered the study (55 unstable, 119 stabilized and 41 stable patients). Most patients (74.9%) completed, and discontinuation rates were broadly similar across the study subgroups, mainly due to withdrawal of consent (12.1%). PANSS total and subscales scores decreased from baseline to endpoint in all groups, with the largest decrease for unstable patients. Improvement from baseline to 12 months was also shown for CGI-S and CGI-I scores for both unstable and stabilized patients; the CGI-S and CGI-I scores remained almost unchanged for the stable group. At least one treatment-related TEAE was reported in 39.1% of patients; the most common were headache (12.1%), hyperprolactinemia (9.8%) and asthenia (5.1%). ISR were reported in 8 (0.3%) patients; injection site pain score was low across the 2355 doses assessed. ConclusionRisperidone ISM® is an effective, safe, and well-tolerated long-term treatment of schizophrenia in adults, regardless of the initial disease severity or whether patients were previously treated with Risperidone ISM® during an acute exacerbation or switched from stable doses of oral risperidone.