Clinician-rated Clinical Global Impression Research Articles

Efficacy of tPBM on ADHD symptoms and Executive Function Deficits in Adults with high-functioning Autism Spectrum Disorder

IntroductionExecutive function (EF) deficits are often associated with Autism Spectrum Disorder (ASD), even in the absence of Attention Deficit Hyperactivity Disorder (ADHD) diagnosis. To date, no approved medication treatments exist for EF deficits associated with ASD.ObjectivesTo assess the efficacy of transcranial photobiomodulation (tPBM) on EF in adults with ASD.MethodsAdults (18-59) with high-functioning (HF)-ASD received twice a week tPBM for 8 weeks in an open-label single group design. ASD and EF deficits were assessed by clinician-rated Clinical Global Impression Scale and patient-rated scales of Behavior Rating Inventory of Executive Function-Adult (BRIEF-A).ResultsEleven participants were enrolled. Ten participants completed the study. Nine participants who completed the study had comorbid ADHD diagnosis. All 10 participants were included in efficacy analyses of EF deficits. Statistically significant improvements in executive function deficits were found in BRIEF-A total score and in subdomains of Inhibition, Emotional Control, Planning and Organization, Organization of Materials, Behavioral Regulation, Metacognitive Index and Global Executive Control. All participants were found to have mild to moderate improvement in their ADHD symptom severity per clinician rated CGIs. Statistically significant improvements in ADHD symptoms were noted in self-rated scales. No adverse events required changes in tPBM protocol.ConclusionstPBM is a safe and feasible treatment approach that has the potential to treat core features of ASD. Further research is necessary and warranted.DisclosureThis work is funded by Alan and Lorraine Bressler Clinical and Research Program for Autism Spectrum Disorder and the MGH Pediatric Psychopharmacology Council Fund.

7.1 RANDOMIZED CONTROLLED TRIAL OF MULTINUTRIENTS FOR ADHD WITH EMOTIONAL DYSREGULATION

This session aims to examine the efficacy of broad-spectrum multinutrients for ADHD and emotional dysregulation. In the Micronutrients for ADHD in Youth (MADDY) randomized controlled trial, unmedicated children (N = 135) aged 6-12 years with ADHD and emotional dysregulation (based on parent reports) at 3 sites (Oregon, Ohio, Canada) were randomized to a 36-ingredient multinutrient supplement (vitamins + minerals) or placebo (3:2 ratio) for 8 weeks. The primary outcomes were the clinician-rated Clinical Global Impression–Improvement (CGI-I; 1 or 2 = responder), and the parent-rated Child and Adolescent Symptom Inventory-5 (CASI-5) composite score comprised of ADHD, ODD, DMDD, and peer-conflict symptoms, including impairment scores for each. A teacher also completed the CASI-5. With a mean age of 9.8 years, 93% (N = 126) of the 135 randomized children comprised the intention-to-treat population. Participants’ demographic and baseline clinical characteristics were well matched between treatment groups, with no significant differences (all p > 0.05). On the CGI-I, 54% of those assigned micronutrients vs 18% of the placebo group were responders (Cramér’s V = 0.37; p < 0.001). However, parent-rated CASI-5 composite scores did not differ between groups (p = 0.70); both improved from baseline (p < 0.01). Teacher reports showed significant between-group difference favoring micronutrients on the Peer Conflict subscale, which was 0.13 points lower for micronutrients (95% CI, –0.26 to –0.01, p = 0.04; Cohen’s d = 0.16). The micronutrient group grew 6 mm more than the placebo group (p = 0.002; Cohen’s d = 1.15). Blinding was maintained. Micronutrients showed global improvement over placebo by blinded clinician rating and teacher reports of peer conflict, but not by parent report on the CASI-5 in children with ADHD and irritability. The micronutrient group showed greater height growth velocity. Micronutrients were well tolerated, and the majority of children adhered to the treatment. This randomized controlled trial replicates the efficacy reported for ADHD in 2 smaller RCTs of a similar formula, containing all vitamins and known essential minerals in therapeutic amounts between the Recommended Dietary Allowance and Tolerable Upper Intake Level.

Repetitive transcranial magnetic stimulation (rTMS) for depression: outcomes in a United Kingdom (UK) clinical practice

Objective: The aim of this paper is to present the outcomes data from the largest United Kingdom’s (UK) National Health Service (NHS) clinical rTMS service treating treatment resistant depression (TRD).Methods: The study was a retrospective investigation of routinely collected data on patients receiving rTMS between 2015 and 2017. Measures used were the clinician-rated Clinical Global Impression (CGI) and Hamilton Depression Rating Scale (HAM-D), and patient rated Beck Depression Inventory (BDI). The outcome data of 73 patients with TRD were analysed. The sample included patients with co-morbid psychiatric diagnosis.Results: Response and remission rates, respectively, were 40.4% and 25.5% for the HAM-D; 35.6% and 20.8% for the BDI; and 51.1% and 52.1% for the CGI. Effect sizes were medium (0.54, 0.52 and 0.56, respectively).Conclusions: The results show that a UK-based clinical service achieves similar results to those published internationally and that clinical rTMS can have significant impact on symptoms of depression in many patients with TRD. Health services are under pressure to make financial savings, investment in rTMS could reduce the long-term treatment costs associated with TRD.

Ketamine Infusion (KI) in Treatment Resistant Depression (TRD): Retrospective Clinical Data Analysis

Objective: The aim of this paper is to present the clinical data analysis results from a service delivering ketamine infusion, repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy for people with treatment resistant depression (TRD). Methods: The study was a retrospective investigation of routinely collected data on patients receiving ketamine infusion between 2017 and 2019. Measures used were the clinician-rated Clinical Global Impression (CGI) and self-reported Beck Depression Inventory (BDI) and Quick Inventory of Depressive Symptomatology (QIDS-SR). The outcome data of 28 patients with TRD were analysed. A minimum course of treatment was defined as three ketamine infusions. Results: Response combined with partial response, response, and remission rates respectively were 42.3%, 23.1% and 4.2% for the BDI; 18.2%, 9.1% and 0% for the QIDS-SR; 50%, 18.2% and 4.6% for the CGI. There was a statistically significant improvement on the BDI with a medium effect size (0.63). There was not a significant improvement in the CGI or QIDS-SR. Conclusions: The results show a mixed picture the impact ketamine on symptoms of depression in TRD over the course of multiple infusions. The results need to be viewed in the context of clinical outcome data collection: outcome scores are taken prior to treatment and so are at a point when ketamine is not having an active effect. The findings can inform the availability of ketamine infusion as a treatment option for TRD where treatment adhering to national guidelines has not succeeded. A qualitative investigation of the experience of people receiving ketamine would provide further insights.

Repetitive Transcranial Magnetic Stimulation (rTMS) in Treatment Resistant Depression: Retrospective Data Analysis from Clinical Practice

Objective: The aim of this paper is to present the service data results from a clinical repetitive Transcranial Magnetic Stimulation (rTMS) service treating treatment resistant depression (TRD). Methods: The study was a retrospective investigation of routinely collected data on patients receiving rTMS between 2015 and 2018. Measures used were the clinician-rated Clinical Global Impression (CGI) and Hamilton Depression Rating Scale (HAM-D), and patient rated Physical Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder 7 (GAD-7). The outcome data of 144 patients with TRD was analysed. The sample included patients with co-morbid psychiatric diagnosis. Results: Response and remission rates respectively were 34.6% and 20.6% for the HAM-D; 10% and 28.6% for the PHQ-9; 31% and 31.8% for the CGI; and 24.6% and 28.8% for GAD-7. Effect sizes were mostly medium (0.48, 0.27, 0.51, 0.43 respectively). GAD-7 reliable change improvement was 56.1% and PHQ-9 reliable change improvement was 40%. There was a medium positive correlation between anxiety (GAD-7) and depression recovery (HAM-D), r = 0.31, n = 46, p = 0.039, with lower pre-treatment anxiety associated with lower post-treatment HAM-D scores. Conclusions: TRD patients with low pre-treatment anxiety levels respond to treatment better than those with high pre-treatment anxiety. The results show that a clinical rTMS service can have a significant impact on symptoms of depression and anxiety in TRD. The findings support wider availability of rTMS as a treatment option for people with TRD.

Repetitive Transcranial Magnetic Stimulation (rTMS) for depression: outcomes in a United Kingdom (UK) clinical practice

Objective: The aim of this paper is to present the outcomes data from the largest United Kingdom's (UK) National Health Service (NHS) clinical rTMS service treating treatment resistant depression (TRD). Methods: The study was a retrospective investigation of routinely collected data on patients receiving rTMS between 2015 and 2017. Measures used were the clinician-rated Clinical Global Impression (CGI) and Hamilton Depression Rating Scale (HAM-D), and patient rated Beck Depression Inventory (BDI). The outcome data of 73 patients with TRD were analysed. The sample included patients with co-morbid psychiatric diagnosis. Results: Response and remission rates, respectively, were 40.4% and 25.5% for the HAM-D; 35.6% and 20.8% for the BDI; and 51.1% and 52.1% for the CGI. Effect sizes were medium (0.54, 0.52 and 0.56, respectively). Conclusions: The results show that a UK-based clinical service achieves similar results to those published internationally and that clinical rTMS can have significant impact on symptoms of depression in many patients with TRD. Health services are under pressure to make financial savings, investment in rTMS could reduce the long-term treatment costs associated with TRD.

Aripiprazole for Irritability in Asian Children and Adolescents with Autistic Disorder: A 12-Week, Multinational, Multicenter, Prospective Open-Label Study.

We investigated the effectiveness and tolerability of aripiprazole in the treatment of irritability in Asian children and adolescents (6-17 years) with autistic disorder in a 12-week, multinational, multicenter, open-label study. Sixty-seven subjects (10.0 ± 3.1 years old, 52 boys) were enrolled and treated with flexibly dosed aripiprazole for 12 weeks (mean dose, 5.1 ± 2.5 mg; range 2-15 mg). Aripiprazole significantly reduced the mean caregiver-rated scores for the Irritability, Lethargy/Social Withdrawal, Stereotypy, Hyperactivity, and Inappropriate Speech subscales of the Aberrant Behavior Checklist from baseline to week 12 (p < 0.001 for all subscales). Clinician-rated Clinical Global Impression Severity of Illness scale score also improved from baseline through week 12 (p < 0.001). The most common adverse event was weight gain and no serious adverse event related to aripiprazole treatment was noted. Our results suggest that aripiprazole is effective and generally tolerable in the treatment of irritability in Asian children and adolescents with autistic disorder. Further studies with larger sample sizes and longer treatment durations are required.

A naturalistic, multi-site study of repetitive transcranial magnetic stimulation therapy for depression

BackgroundRepetitive transcranial magnetic stimulation (rTMS) was approved in 2008 in the United States, and there are relatively few studies describing its use in regular clinical practice since approval. MethodsFrom April 2011 to October 2014, ten sites within the National Network of Depression Centers (NNDC) provided data on 62 evaluable patients with a depressive episode. Treatment was determined naturalistically. Response was assessed by the Quick Inventory of Depressive Symptoms, Self-Report (QIDS-SR) as the primary outcome, and the Patient Health Questionnaire-9 (PHQ-9) and the clinician-rated Clinical Global Impression (CGI) as secondary depression measures. ResultsEnrolled patients exhibited significant treatment resistance, with 70.2% reporting more than 4 prior depressive episodes. Most patients received treatment with standard parameters (10Hz over the left dorsolateral prefrontal cortex), although 22.6% of the patients received 1 or 5Hz stimulation at some point. Over 6 weeks of treatment, response and remission rates were 29.4% and 5.9%, respectively, for the QIDS-SR; 39.2% and 15.7%, respectively, for the PHQ-9; and 50.9% and 17.9%, respectively, for the CGI. Moderator analyses revealed no effect of prior depressive episodes, history of ECT or gender, although early life stress predicted a better response to rTMS therapy. LimitationsThe study was an open-label, registry trial, with relatively coarse clinical data, reflecting practice only in academic, depression-specialty centers. Because of the relatively small size and heterogeneity of the sample, type 2 errors are possible and positive findings are in need of replication. ConclusionrTMS demonstrates effectiveness in clinical practice within the NNDC, although remission rates appear slightly lower in comparison with other recent naturalistic studies.

The effects of physical activity in the acute treatment of bipolar disorder: A pilot study

Background Physical activity has demonstrated efficacy in depression and anxiety, but its potential in the management of bipolar disorder is yet unexplored. This study is a pilot investigation into the effectiveness of an adjunctive walking program in the acute treatment of bipolar disorder. Methods This is a retrospective cohort study of all patients admitted over a 24-month period to a private psychiatric unit with a primary diagnosis of bipolar disorder (ICD-10). All patients were invited to participate voluntarily in a walking group during their admissions. Those who reliably attended the walking group (participants) were compared against those who did not attend (non-participants), using the clinician-rated Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I) scales and the self-reported 21-item Depression Anxiety Stress Scales (DASS) as primary outcome measures. Results There were 24 admissions for participants and 74 admissions for non-participants. The two groups did not differ significantly in patient demographics or admission CGI and DASS measures, except for a lower DASS Stress subscore for participants ( p = 0.049). At discharge, the inter-group differences in CGI measures remained non-significant, but participants had significantly lower scores than non-participants for DASS ( p = 0.005) and all its subscales (Depression p = 0.048, Anxiety p = 0.002, Stress p = 0.01). Limitations Methodological limitations include a retrospective design, small sample size, lack of randomisation or control, and indirect measure of manic symptoms. Conclusions The results of this trial provide preliminary support for a therapeutic role of physical activity in bipolar disorder, and warrant further investigation with randomised controlled trials.

Modafinil in children and adolescents with attention-deficit/hyperactivity disorder:a preliminary 8-week, open-label study

ABSTRACTObjective: In a 4-week, double-blind, placebo-controlled study, the attention-promoting agent modafinil improved symptoms of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents and was well tolerated. To assess the continued efficacy of modafinil and obtain additional safety data, an 8-week, open-label study was conducted as an extension to the double-blind study.Method: Two hundred and twenty children and young adolescents (age range, 6–14 years) with ADHD who had completed 4 weeks of the double-blind period or had withdrawn for reasons other than an adverse event were enrolled. Patients received individually titrated doses of modafinil (100–400 mg), administered once daily or as a divided dose. Patients visited the clinic at open-label weeks 2, 4, and 8 for assessments of efficacy. Efficacy was assessed using the parent-or clinician-completed ADHD Rating Scale-IV (ADHD-RS-IV) Home Version, the parent-completed Conners' ADHD/DSM-IV Scale Parent Version (CADS-P), and the clinician-rated Clinical Global Impression of Improvement (CGI-I) scale. Adverse events were monitored.Results: Modafinil improved symptoms on all ADHD rating scales and subscales during the open-label extension. Mean change (baseline to final visit) in Total score on the ADHD-RS-IV was −14.6 (95% CI: −16.40 to −12.70); and −7.6 (95% CI: −8.65 to −6.62) and −6.9 (95% CI: −7.90 to −5.94) in the Inattention and Hyperactivity–impulsivity scores, respectively. The mean Total score [SD] on the CADS-P decreased from baseline (74.4 [10.3]) to the final visit (63.2 [13.1]) (change: −11.2, 95% CI: −13.08 to −9.65). Fiftythree percent of patients were rated as much or very much improved on the CGI-I. Insomnia (13%) and headache (10%) were the most common adverse events. No clinically meaningful changes were observed in physical examination findings, electrocardiography, blood pressure, pulse, or body temperature. Clinically significant changes (increase or decrease) in body weight of 7% or more were observed for 30 patients (14%), with decreases (mean, 3.2 kg) reported for 22 patients (10%) and increases (mean, 3.7 kg) reported for eight patients (4%).Conclusion: Modafinil remained efficacious and well tolerated in children with ADHD, improving ADHD symptoms and overall clinical condition during the open-label study. Limitations of the study include open-label dosing and lack of a placebo control.

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Venlafaxine in the Treatment of Premenstrual Dysphoric Disorder

From 3% to 5% of women of reproductive age develop functional impairment of the degree found in premenstrual dysphoric disorder (PMDD)-a severe form of premenstrual syndrome. Changes in mood, behavior, and appetite suggest that central serotonergic activity has a role in the development of PMDD. Antidepressants that inhibit serotonin reuptake have proved to be a consistently effective treatment for PMDD in randomized, double-blind trials, but a sizable number of patients fail to respond. This study evaluated venlafaxine, a new antidepressant that selectively inhibits reuptake of both serotonin and norepinephrine. Using a randomized, double-blind, placebo-controlled design, 164 women given a diagnosis of PMDD, who were free of other major psychiatric disorders, were assigned to receive venlafaxine in a daily dose of 50 to 200 mg or placebo over four menstrual cycles. Premenstrual symptoms were evaluated by a daily symptom report (DSR) and the Hamilton Rating Scale for Depression. Apart from meeting criteria for PMDD, the participants were 18 to 45 years of age, had had regular cycles for the past 6 months, and probably had ovulated. Active medication or placebo was given throughout the entire menstrual cycle. Of 157 evaluable patients, 56 withdrew during the 4-month treatment phase-roughly 35% of those in each treatment group. There were no serious adverse events. Total DSR scores indicated significantly greater improvement with venlafaxine than with placebo. The active drug reduced symptoms of PMDD in the first treatment cycle by 42%, compared with 14% for placebo recipients, and improvement increased in the second cycle. Venlafaxine remained significantly more effective than placebo in all four double-blind treatment cycles. DSR postmenstrual scores were comparable in the two groups. Venlafaxine provided improvement in emotion, function, pain, and physical symptoms but not in appetite. Hamilton depression scores also were significantly improved in the venlafaxine group. Rates of treatment response, with at least a 50% reduction from the pretreatment baseline in total premenstrual DSR scores, were 60% in the venlafaxine group and 35% for placebo patients. Analysis of Hamilton depression scores yielded very similar results. Whichever test was used, symptom remission was observed substantially more often in patients given venlafaxine. All these findings were ratified by the clinician-rated Clinical Global Impression scale. The new antidepressant venlafaxine, which blocks reuptake of serotonin and norepinephrine, seems to be an effective means of treating PMDD. Responses occur rapidly and treatment is generally well tolerated. Additional study may show that treatment only in the symptomatic luteal phase is a reasonable approach.

An open naltrexone treatment study in pathological gambling disorder.

The present study was designed to test the short-term efficacy and safety of naltrexone in the treatment of pathological gambling disorder. Seventeen subjects (seven men, 10 women) who fulfilled DSM-IV criteria for pathological gambling disorder, and were free from other Axis I diagnoses by Structured Clinical Interview for DSM-III-R screening, participated in a 6-week open naltrexone flexible dose trial. Gambling symptom change was assessed with the patient-rated Clinical Global Impression (CGI) Scale, the clinician-rated CGI and the Gambling Symptom Assessment Scale. Side-effects were monitored weekly and liver function tests biweekly. Naltrexone reduced urges to gamble and gambling behaviour. The mean change in gambling frequency per week was 1.40 +/- 0.28 episodes per week; the mean change in dollars lost per week was $66.95 +/- 13.77; and the mean change in clinician-rated CGI Improvement was 0.40 +/- 0.04. Of those who responded to the medication, the majority had done so by the end of the fourth week. Men responded to naltrexone as well as women. The average naltrexone dose required for effective symptom control was 157 mg/day. Nausea was common during the first week (47%). The present findings provide evidence that naltrexone may be effective in the treatment of pathological gambling disorder. The present report is preliminary and controlled trials are needed to confirm these findings.

Tacrine in Alzheimer's Disease-Reply

<h3>In Reply.</h3> —Our tacrine study was designed to support preliminary results from a preceding enrichment trial¹and to define dose-response characteristics using doses from 20 to 80 mg/d. The a priori hypothesis (as indicated on page 2525) addressed whether tacrine improves patient response on the Alzheimer's Disease Assessment Scale (ADAS) cognitive and the clinician-rated Clinical Global Impression of Change (CGIC). The ADAS cognitive has been validated in Alzheimer's disease and demonstrated sensitivity to modest drug effects and cognitive deterioration over time.²However, the clinician-rated CGIC had not been validated in this patient population.³Therefore, our primary focus on ADAS cognitive reflected uncertainty in use of the CGIC when the study was designed. The sample size was set to provide sufficient power to detect ADAS cognitive effects based on previous studies of tacrine.¹ Primary analyses based on "evaluable completers" were most appropriately presented in the original publication.

A Controlled Trial of Tacrine in Alzheimer's Disease

To compare efficacy and safety of tacrine hydrochloride with placebo in patients with probable Alzheimer's disease. A 12-week, double-blind, placebo-controlled, parallel-group study. Outpatients at 23 centers. Men and women with probable Alzheimer's disease, at least 50 years old, mildly to moderately impaired, without other significant medical conditions. In the initial 6 weeks, patients received placebo, 20 mg/d of tacrine, or 40 mg/d of tacrine. In the second 6 weeks, half received the same treatment and half increased tacrine dose: those receiving placebo increased to 20 mg/d, those receiving 20 mg/d increased to 40 mg/d, and those receiving 40 mg/d increased to 80 mg/d. Alzheimer's Disease Assessment Scale (ADAS) cognitive component and clinician-rated Clinical Global Impression of Change (CGIC). Four hundred sixty-eight patients entered. After 12 weeks, dose-related improvement was significant on the ADAS cognitive (P = .014), clinician-rated CGIC (P = .014), and caregiver-rated CGIC (P = .006). Comparison of 80 mg/d with placebo showed significant improvement on the ADAS cognitive (P = .015), clinician-rated CGIC (P = .016), and caregiver-rated CGIC (P = .028). Significant effects appeared as early as 6 weeks on the ADAS cognitive and caregiver-rated CGIC. Among patients receiving 80 mg/d of tacrine, 51% achieved a four-point or greater improvement of the ADAS cognitive component after 12 weeks of treatment. Reversible asymptomatic transaminase elevations greater than three times normal occurred in 25% of patients. Other treatment-related events included nausea and/or vomiting (8%), diarrhea (5%), abdominal pain (4%), dyspepsia (3%), and rash (3%). These results confirm the efficacy and safety of tacrine in some patients with Alzheimer's disease. After 12 weeks, the magnitude of the treatment effect is clinically important and recognized by the physician and caregiver. Liver toxicity is reversible and easily detected by weekly alanine aminotransferase determinations.