Irritability Subscale Score Research Articles

Correlation between blood biomarkers and neuropsychiatric symptoms: Siriraj cohort, Thailand

AbstractBackgroundWe explored the relationship of neuropsychiatric symptoms (assesses by NPI) and Alzheimer disease pathophysiology from blood AB42/40, GFAB, NFL, and pTau181. We also investigated if age and cognition were related to these neuropsychiatric symptoms.Method222 subjects included 96 dementia, 66 MCI, and 60 normal controls (NC). Spearman correlation was used to calculation the correlation coefficient. Mann‐Whitney U test is used to compare biomarkers of those with and without subitem symptoms of NPI.ResultMean ages were 71.26±9.82 years old in dementia group, 68.83±8.01 years old in MCI group, and 59.28±9.22 years old in NC group. Sum of 12 NPI subscale scores showed significant low correlation (r=0.20‐0.29) were correlated with blood AB42/AB40, Ptau 181, NFL, and GFAB. Sum of 12 NPI subscale scores showed significant moderate correlation with age and global cognition (assessed by Thai mental state examination, TMSE). Blood pTau181 displayed low correlation with hallucination, depression, anxiety, apathy, and irritability subscale scores. There was a significant low correlation between blood AB42/AB40 and delusion and irritability subscale scores. Blood NFL showed low correlation with euphoria, a, apathy, disinhibition, irritability, and aberrant motor activity. Inflammation process appeared to be significantly related with psychosis, apathy, disinhibition, and irritability. After controlled by age and TMSE; only apathy and AMA NPI subscale scores were correlated to NFL and GFAB accordingly.ConclusionWe discovered that psychosis and mood factors of NP symptoms were related to blood pTau. While most frontal factors of NP symptoms showed significant relationship with axonal destruction and microglia activation/inflammation.This study was supported by grants from Health Systems Research Institute (HSRI), Thailand.

Decreased levels of L-selectin and platelet-endothelial cell adhesion molecule-1 in children with autism spectrum disorder.

This study aimed to ascertain the serum levels of selectins (E, L, P) and platelet-endothelial adhesion molecule-1 (PECAM-1) in preschool children with autism spectrum disorder (ASD) and to establish a comparison with the levels observed in healthy controls. The study included 34 children aged 2-7 years diagnosed with ASD (ASD group) and 34 randomly selected healthy children matched for age and sex to the ASD group. The children were free of any genetic or physical disease, clinically active infection, or medication use. The sociodemographic data form was completed by all parents. The Childhood Autism Rating Scale (CARS) and the Autism Behavior Checklist (ABC) were administered to the patient group, and the Aberrant Behavior Checklist (AbBC) was completed by the families of all children. Serum selectin (E, L, P) and PECAM-1 levels were measured using enzyme-linked immunosorbent assay (ELISA) kits. The results showed that the levels of both L-selectin (p = 0.007) and PECAM-1 (p = 0.019) were significantly lower in the ASD group than in the control group. No significant difference was observed between the groups concerning E-selectin and P-selectin levels (p > 0.05). It was observed that P-selectin variables were statistically significant in predicting the presence of ASD (p = 0.019). A remarkable inverse correlation was found between the AbBC irritability subscale score and L-selectin (r = -0.296, p = 0.014) and PECAM-1 (r = -0.276, p = 0. 023); the AbBC Lethargy-Social Withdrawal subscale score and E-Selectin (r = -0.239, p = 0.049), L-Selectin (r = -0.297, p = 0.014) and PECAM-1 (r = -0.264, p = 0.029); L-Selectin levels and the AbBC stereotypic behavior subscale (r = -0.248, p = 0.042). No statistically significant relationship was observed between selectins (E, L, P) and PECAM-1 levels and CARS scale, ABC subscale or total scores and age variables (p > 0.05). These study results suggest that L-selectin, P-selectin and PECAM-1 may play a role in the pathophysiology of ASD.

L -carnitine adjunct to risperidone for treatment of autism spectrum disorder-associated behaviors: a randomized, double-blind clinical trial.

The present study was designed to evaluate the efficacy and safety of l-carnitine as an adjuvant agent to risperidone in the treatment of autism spectrum disorder (ASD)-associated behaviors. In this study, 68 children with confirmed ASD were randomly allocated to receive either l-carnitine (150 mg/day) or matched placebo in addition to risperidone. We utilized the Aberrant Behavior Checklist-Community Edition scale (ABC-C) and a checklist of potential adverse effects to assess changes in behavioral status and safety profile at weeks 0, 5 and 10 of the trial. The primary outcome was defined as a change in the irritability subscale score. Sixty patients with similar baseline characteristics completed the trial period. Although scores of ABC-C subscales significantly decreased in both groups over the trial period, the combination of l-carnitine and risperidone resulted in more reduction on the irritability and hyperactivity subscales compared to the combination of risperidone and placebo ( P = 0.033 and P < 0.001, respectively). However, changes in lethargy, stereotypic behavior and inappropriate speech subscales were similar between groups. In conclusion, l-carnitine adjuvant to risperidone could improve irritability and hyperactivity features in children with ASD. Results of this study should be considered preliminary and further clinical trials with larger sample sizes and longer follow-up periods are warranted.

Aripiprazole in the real-world treatment for irritability associated with autism spectrum disorder in children and adolescents in Japan: 52-week post-marketing surveillance

BackgroundThe purpose of this study was to evaluate the post-marketing safety and effectiveness of aripiprazole in treating irritability in pediatric patients (6–17 years) with autism spectrum disorder (ASD) in actual clinical sites of Japan.MethodsIn this post-marketing surveillance, patients were enrolled into the multicenter, prospective, non-interventional, observational study for 52 weeks, and were dosed with aripiprazole (1–15 mg/day) under daily clinical settings in Japan.ResultsIn 510 patients, the continuation rate of aripiprazole treatment was 84.6% at day 168 (week 24) and 78.1% at day 364 (week 52). Adverse drug reactions (ADRs) occurred in 22.7% of patients (n = 116), and the most common ADRs were somnolence (9.4%), followed by weight increased (3.3%). At week 4, the mean change from baseline in the irritability subscale score for the Aberrant Behavior Checklist Japanese version (ABC-J) was − 5.7 ± 6.8 (n = 288). Based on multiple regression analysis, comorbid attention deficit and hyperactivity did not affect the ABC-J irritability subscale score at endpoint. At week 24, the mean change from baseline for the Strengths and Difficulties Questionnaire was − 3.3 ± 4.9 (n = 215) for the total difficulties score and 0.6 ± 1.7 (n = 217) for the prosocial behavior subscale score.ConclusionsAripiprazole was well tolerated and effective in the long-term treatment of irritability associated with ASD in Japanese pediatric patients in the real-world clinical practice.Trial registrationThis surveillance was registered with Clinical Trial.gov (no. NCT03179787) on June 7, 2017 (retrospectively registered).

Folinic Acid as Adjunctive Therapy in Treatment of Inappropriate Speech in Children with Autism: A Double-Blind and Placebo-Controlled Randomized Trial

This is a double-blind, placebo-controlled randomized trial to investigate the potential therapeutic effects of folinic acid/placebo as an adjuvant to risperidone on inappropriate speech and other behavioral symptoms of autism spectrum disorder (ASD). Fifty-five ASD children (age (mean ± standard deviation) = 13.40 ± 2.00; male/female: 35/20) were evaluated for behavioral symptoms at baseline, week 5, and week 10 using the aberrant behavior checklist-community (ABC-C). Folinic acid dosage was 2mg/kg up to 50mg per day for the entire course of the study. The repeated measures analysis showed significant effect for time × treatment interaction on inappropriate speech (F = 3.51; df = 1.61; P = 0.044), stereotypic behavior (F = 4.02; df = 1.37; P = 0.036), and hyperactivity/noncompliance (F = 6.79; df = 1.66; P = 0.003) subscale scores. In contrast, no significant effect for time × treatment interaction was found on lethargy/social withdrawal (F = 1.06; df = 1.57; P = 0.336) and irritability (F = 2.86; df = 1.91; P = 0.064) subscale scores. Our study provided preliminary evidence suggesting that folinic acid could be recommended as a beneficial complementary supplement for alleviating speech and behavioral symptoms in children with ASD.Clinical trial registeration: This trial was registered in the Iranian Registry of Clinical Trials ( www.irct.ir ; No. IRCT20090117001556N114).

Risperidone Combination Therapy With Propentofylline for Treatment of Irritability in Autism Spectrum Disorders: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Propentofylline is a xanthine phosphodiesterase inhibitor and adenosine reuptake blocker with neuroprotective effects linked to anti-inflammatory and antiexcitatory properties. This is a double-blind, placebo-controlled trial investigating the potential beneficial effects of propentofylline, as an adjunctive treatment with risperidone, on the severity and behavioral abnormalities of autism spectrum disorder (ASD). A total of 48 children with ASD were randomly allocated into 2 groups of risperidone (initiating at 0.5 mg/d) plus propentofylline (initiating at 300 mg/d) and risperidone plus placebo. The Aberrant Behavior Checklist-Community (ABC-C) and Childhood Autism Rating Scale (CARS) were used for the evaluation of ASD severity and behavioral disruptions at baseline, week 4, and week 10. Primary outcome measure of the study was ABC-C irritability subscale score, whereas CARS score along with other 4 subscales of ABC-C (lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech subscales) were considered as secondary outcome measures. Results from the general linear model repeated measures analysis demonstrated significant time-treatment interaction on irritability subscale (F1.55 = 3.45; P = 0.048) and CARS (F1.41 = 4.08; P = 0.034) scores. Compared with the placebo group, children receiving propentofylline showed greater improvements in the CARS score (P = 0.037) from baseline to the study endpoint. Our results found no significant time-treatment effect on other subscales of ABC-C. Two trial groups were comparable based on the frequency of adverse effects. Our findings demonstrated that adjunctive treatment with propentofylline is effective in alleviating disease severity and improving irritability in ASD patients. However, larger studies with longer durations are required to confirm these results.

Characterizing Early State Regulation in Preterm Infants.

To characterize state regulation and behavior of preterm infants after discharge from the neonatal intensive care unit (NICU). We recruited singleton infants born at ≤35 weeks of gestational age (GA) before NICU discharge. Parents completed surveys at discharge and 1, 3, and 6 months after discharge. Infant medical history was gleaned from the medical record. Surveys captured sociodemographic information and measures of infant state regulation (Baby Pediatric Symptom Checklist [BPSC]) and feeding behaviors. We calculated the median BPSC subscale scores at each time point and the proportion of infants with scores in the problem range (≥3/5). We explored longitudinal and cross-sectional correlates of BPSC scores. Fifty families completed the discharge questionnaire, and 42 (84%) completed the 6-month questionnaire. The median GA at birth was 34 weeks (IQR 30.1, 34.4 weeks); the median birth weight was 1930 g (IQR 1460, 2255 g). The median scores were above population norms for irritability and difficulty with routines. Twenty-one infants (40%) had irritability subscale scores in the problem range at 1 month, and 20 (38%) had problem scores on difficulties with routines. Only 9 infants (17%) had problem scores on the inflexibility subscale. Scores in all 3 domains showed different patterns from population norms from 1 to 6 months. BPSC scores were correlated with infant feeding behaviors at 1, 3, and 6 months. Scores for irritability and difficulty with routines among preterm infants were high compared with population norms and differed from normative values through 6 months after discharge. Preterm infants demonstrate problems with state regulation after NICU discharge that may require directed intervention.

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.

The autism inpatient collection: methods and preliminary sample description.

BackgroundIndividuals severely affected by autism spectrum disorder (ASD), including those with intellectual disability, expressive language impairment, and/or self-injurious behavior (SIB), are underrepresented in the ASD literature and extant collections of phenotypic and biological data. An understanding of ASD’s etiology and subtypes can only be as complete as the studied samples are representative.MethodsThe Autism Inpatient Collection (AIC) is a multi-site study enrolling children and adolescents with ASD aged 4–20 years admitted to six specialized inpatient psychiatry units. Enrollment began March, 2014, and continues at a rate of over 400 children annually. Measures characterizing adaptive and cognitive functioning, communication, externalizing behaviors, emotion regulation, psychiatric co-morbidity, self-injurious behavior, parent stress, and parent self-efficacy are collected. ASD diagnosis is confirmed by the Autism Diagnostic Observation Schedule – 2 (ADOS-2) and extensive inpatient observation. Biological samples from probands and their biological parents are banked and processed for DNA extraction and creation of lymphoblastoid cell lines.ResultsSixty-one percent of eligible subjects were enrolled. The first 147 subjects were an average of 12.6 years old (SD 3.42, range 4–20); 26.5 % female; 74.8 % Caucasian, and 81.6 % non-Hispanic/non-Latino. Mean non-verbal intelligence quotient IQ = 70.9 (SD 29.16, range 30–137) and mean adaptive behavior composite score = 55.6 (SD 12.9, range 27–96). A majority of subjects (52.4 %) were non- or minimally verbal. The average Aberrant Behavior Checklist - Irritability Subscale score was 28.6, well above the typical threshold for clinically concerning externalizing behaviors, and 26.5 % of the sample engaged in SIB. Females had more frequent and severe SIB than males.ConclusionsPreliminary data indicate that the AIC has a rich representation of the portion of the autism spectrum that is understudied and underrepresented in extant data collections. More than half of the sample is non- or minimally verbal, over 40 % have intellectual disability, and over one quarter exhibit SIB. The AIC is a substantial new resource for study of the full autism spectrum, which will augment existing data on higher-functioning cohorts and facilitate the identification of genetic subtypes and novel treatment targets. The AIC investigators welcome collaborations with other investigators, and access to the AIC phenotypic data and biosamples may be requested through the Simons Foundation (www.sfari.org).

Tolerability, Safety, and Benefits of Risperidone in Children and Adolescents with Autism: 21-Month Follow-up After 8-Week Placebo-Controlled Trial.

Risperidone has demonstrated efficacy for acute (8 week) and intermediate length (6 month) management of severe irritability and aggression in children and adolescents with autism. Less is known about the long-term effects of risperidone exposure in this population. We examined the tolerability, safety, and therapeutic benefit of risperidone exposure over a 1-2 year follow-up period. In a naturalistic study, 84 children and adolescents 5-17 years of age (from an original sample of 101) were assessed an average of 21.4 months after initial entry into a placebo-controlled 8 week trial of risperidone for children and adolescents with autism and severe irritability. They were assessed at baseline and at follow-up on safety and tolerability measures (blood, urinalysis, electrocardiogram [ECG], medical history, vital signs, neurological symptoms, other adverse events), developmental measures (adaptive behavior, intelligence quotient [IQ]), and standardized rating instruments. Treatment over the follow-up period, after completion of protocol participation, was uncontrolled. Statistical analyses assessed outcome over time with or without prolonged risperidone therapy. Two-thirds of the 84 subjects continued to receive risperidone (mean 2.47 mg/day, S.D. 1.29 mg). At follow-up, risperidone was associated with more enuresis, more excessive appetite, and more weight gain, but not more adverse neurological effects. No clinically significant events were noted on blood counts, chemistries, urinalysis, ECG, or interim medical history. Regardless of drug condition at follow-up, there was considerable improvement in maladaptive behavior compared with baseline, including core symptoms associated with autism. Height and weight gains were elevated with risperidone. Social skills on Vineland Adaptive Behavior Scale (VABS) improved with risperidone. Parent-rated Aberrant Behavior Checklist (ABC) Irritability subscale scores were reduced in those taking risperidone at follow-up. Several other measures of maladaptive behavior (some related to socialization) also showed improved functioning in association with risperidone on the ABC or on the Modified Real Life Rating Scale. Increased appetite, weight gain, and enuresis are risks associated with long-term risperidone. Our data suggest that these risks were balanced by longer-term behavioral and social benefits for many children over 1.8 years of ongoing treatment.

A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism

To assess the safety and efficacy of pioglitazone added to risperidone in the treatment of irritability in autistic disorder (AD), we conducted this study. In a 10-week, randomized, double-blind, parallel-group, placebo-controlled clinical trial, 44 outpatients of both genders aged 4–12 years with a diagnosis of AD and a score of ≥12 on the Aberrant Behavior Checklist-Community (ABC-C) irritability subscale were included. Mean change of ABC-C irritability subscale score as primary outcome, change in other ABC-C subscale scores and partial and complete responses were compared between two groups. Twenty patients completed the trial in each group. Level of reduction and effect of time×treatment interaction in the treatment group were significant for irritability (P=0.03), lethargy/social withdrawal (P=0.04) and hyperactivity/non-compliance (P=0.03) but not for stereotypic behavior and inappropriate speech subscales compared with the placebo group. Vomiting and headache were the most frequent reported side-effects. Results of this preliminary study indicate positive effects of pioglitazone compared with placebo in improving the behavioral symptoms of AD.

N-acetylcysteine as an adjunctive therapy to risperidone for treatment of irritability in autism: a randomized, double-blind, placebo-controlled clinical trial of efficacy and safety.

According to the proposed interference of N-acetylcysteine (NAC) with pathophysiologic processes of autistic disorders (ADs), we aimed to assess the effectiveness and safety of NAC as an adjunct to risperidone in the treatment of ADs in a randomized, double-blind, clinical trial. The participants were referred outpatients between 4 and 12 years of age with the diagnosis of ADs and a score of more than 12 on Aberrant Behavior Checklist-Community (ABC-C) Irritability subscale score. The participants were randomized into 2 groups. One group received risperidone plus NAC, and the other group received risperidone plus placebo. The dose of risperidone was titrated between 1 and 2.0 mg/d, and the dose of NAC was 600 to 900 mg/d. The main outcome was mean decrease in the ABC-C irritability subscale score from baseline at 5 and 10 weeks. Changes in other subscales were considered as secondary outcome measures. Forty patients completed the 10-week trial. Baseline characteristics including age, sex and body weight, as well as baseline scores in 5 subscales did not demonstrate statistically significant difference between the 2 groups. Repeated-measures analysis showed significant effect for time × treatment interaction in irritability (P = 0.01) and hyperactivity/noncompliance (P = 0.02) subscales. By week 10, the NAC group showed significantly more reduction in irritability (P = 0.02) and hyperactivity/noncompliance (P = 0.01) subscales scores. N-acetylcysteine can be considered as an adjuvant therapy for ADs with beneficial therapeutic outcomes.

A Randomized Double-Blind Placebo-Controlled Clinical Trial of Adjuvant Buspirone for Irritability in Autism

BackgroundThe brain serotonin level is decreased in individuals with autism. Buspirone is a 5-HT(1A) receptor agonist with antiaggressive effects increasing prosocial behaviors. MethodsWe conducted an 8-week randomized double-blind placebo-controlled clinical trial. Participants included 40 outpatient children and adolescents with autism. The patients took buspirone plus risperidone or risperidone plus placebo during 8 weeks. The patients were assessed at baseline, week 4, and week 8 using the Aberrant Behavior Checklist-Community Rating Scale. ResultsEighteen patients in the placebo group and 16 patients in the buspirone group completed this trial. The mean dose of buspirone was 6.7 (SD 2.7) mg/day. Irritability subscale score significantly decreased during this trial in both groups (buspirone group: declined from 25.7 [SD 5.7] to 16.3 [SD 8.5]; placebo group: declined from 24.7 [SD 7.6] to 18.2 [SD 7.7]). The Cohen d effect size was .45. Thirteen (81.2%) of 16 patients in the buspirone group and 7 (38.9%) of 18 patients in the placebo group showed a ≥30% decline in irritability score. The relative risk for treatment was 2.1. There were no serious adverse effects. The most common adverse effects in the buspirone group were increased appetite, drowsiness, and fatigue. ConclusionThis clinical trial supports that low dose buspirone plus risperidone is more effective than risperidone plus placebo for treating irritability in individuals with autism.

Regional Atrophy of the Insular Cortex Is Associated with Neuropsychiatric Symptoms in Alzheimer's Disease Patients

Background: Alzheimer's disease (AD) is a devastating illness that results in progressive cognitive decline and neuropsychiatric symptoms. The neuropsychiatric symptoms are associated with a rapid decline in cognition and activities of daily living and increased mortality, however the neuroanatomical localisation involved in the development of neuropsychiatric symptoms remains poorly understood. The aim of this study was to identify the association with the regional volume of the insular cortex and each neuropsychiatric symptom in patients with AD. Methods: Subjects diagnosed with AD (n = 40) were evaluated. Magnetic resonance images were obtained and the insular cortex was subdivided into four subregions through the central sulcus of the insula and bilaterally: right anterior insular cortex, right posterior insular cortex, left anterior insular cortex and left posterior insular cortex. The neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. A partial correlation analysis was performed. Results: A significant negative correlation existed between apathy, the irritability subscale score and the volume ratio of the bilateral anterior insular cortex and right posterior insular cortex (r = -0.457, -0.433 and -0.572, respectively, p = 0.032, 0.044 and 0.005, respectively). Conclusion: The findings suggest that the regional atrophy of the insular cortex is associated with neuropsychiatric symptoms in AD patients.

A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders

BackgroundThis study examined the efficacy and safety of N-acetylcysteine (NAC) augmentation for treating irritability in children and adolescents with autism spectrum disorders (ASD).MethodForty children and adolescents met diagnostic criteria for ASD according to DSM-IV. They were randomly allocated into one of the two groups of NAC (1200 mg/day)+risperidone or placebo+risperidone. NAC and placebo were administered in the form of effervescent and in two divided doses for 8 weeks. Irritability subscale score of Aberrant Behavior Checklist (ABC) was considered as the main outcome measure. Adverse effects were also checked.ResultsThe mean score of irritability in the NAC+risperidone and placebo+risperidone groups at baseline was 13.2(5.3) and 16.7(7.8), respectively. The scores after 8 weeks were 9.7(4.1) and 15.1(7.8), respectively. Repeated measures of ANOVA showed that there was a significant difference between the two groups after 8 weeks. The most common adverse effects in the NAC+risperidone group were constipation (16.1%), increased appetite (16.1%), fatigue (12.9%), nervousness (12.9%), and daytime drowsiness (12.9%). There was no fatal adverse effect.ConclusionsRisperidone plus NAC more than risperidone plus placebo decreased irritability in children and adolescents with ASD. Meanwhile, it did not change the core symptoms of autism. Adverse effects were not common and NAC was generally tolerated well.Trial registrationThis trial was registered at http://www.irct.ir. The registration number of this trial was IRCT201106103930N6

Riluzole as an Adjunctive Therapy to Risperidone for the Treatment of Irritability in Children with Autistic Disorder: A Double-Blind, Placebo-Controlled, Randomized Trial

A hyperglutamatergic state has been shown to play a possible role in the pathophysiology of autistic disorders. Riluzole is a glutamate-modulating agent with neuroprotective properties, which has been shown to have positive effects in many neuropsychiatric disorders. The aim of this study was to assess the efficacy and tolerability of riluzole as an adjunctive to risperidone in the treatment of irritability in autistic children who were not optimally responding to previous medications. This was a 10-week, randomized, double-blind, parallel-group, placebo-controlled trial. The study enrolled male and female outpatients aged 5-12years with a diagnosis of autistic disorder based on the DSM-IV-TR criteria and a score of ≥12 on the Aberrant Behavior Checklist-Community (ABC-C) irritability subscale who had discontinued other medications because of a lack of efficacy. Subjects received riluzole (titrated to 50 or 100mg/day based on bodyweight) or placebo in addition to risperidone (titrated up to 2 or 3mg/day based on bodyweight) for 10weeks. Patients were assessed at baseline, week 5, and week 10. The primary outcome measure was the difference in the change in the ABC-C irritability subscale score from baseline to week 10 between the two groups. We also compared changes in other ABC-C subscale scores and Clinical Global Impressions-Improvement (CGI-I) scale scores between the two groups. Forty-nine patients were enrolled in the study, and forty children completed the trial (dropouts: placebo=4, riluzole=5). A significantly greater improvement in the study primary outcome (the ABC-C irritability subscale score) was achieved by the riluzole-treated children compared with the placebo group (P=0.03). Patients in the riluzole group also showed significantly greater improvement on the lethargy/social withdrawal (P=0.02), stereotypic behavior (P=0.03), and hyperactivity/non-compliance subscales (P=0.005), but not on the inappropriate speech subscale (P=0.20) than patients in the placebo group. Eleven patients in the riluzole group and five patients in the placebo group were classified as responders based on their CGI-I scores [χ(2)(1)=3.750, P=0.05]. Children in the riluzole group experienced significantly more increases in their appetite and bodyweight than children in the placebo group by the end of the study. Riluzole add-on therapy shows several therapeutic outcomes, particularly for improving irritability, in children with autism. However, its add-on to risperidone also results in significantly increased appetite and weight gain.

Aripiprazole in the Treatment of Irritability in Pediatric Patients (Aged 6–17 Years) with Autistic Disorder: Results from a 52-Week, Open-Label Study

To report the long-term efficacy of aripiprazole in the treatment of irritability in children and adolescents (ages 6-17 years) with autistic disorder. This was a 52-week, open-label, flexible-dose (2-15 mg/day) study of aripiprazole for the treatment of children and adolescents with irritability associated with autistic disorder. Eligible subjects were enrolled from two 8-week randomized trials or were enrolled as de novo subjects. "Prior aripiprazole" subjects had received treatment with aripiprazole for 8 weeks before entering this study. Evaluation of efficacy, a secondary objective after evaluation of safety and tolerability in this study, was conducted using the caregiver-rated Aberrant Behavior Checklist-Irritability subscale and the clinician-rated Clinical Global Impression-Improvement score. Three hundred thirty subjects received treatment (de novo, n = 86; prior aripiprazole, n = 174; prior placebo, n = 70) and 199 subjects (60.3%) completed 52 weeks of treatment. At their last study visit, 38.2% of subjects were receiving concomitant central nervous system medications (commonly antidepressants, 13.4%; psychostimulants, 11.5%; antiepileptics, 5.9%). At week 52 (observed cases data set), the mean change from baseline in Aberrant Behavior Checklist Irritability subscale scores was -8.0 in de novo subjects and -6.1 in prior placebo subjects; prior aripiprazole subjects maintained symptom improvement that was achieved with treatment in the prior study. At endpoint, the majority of subjects had a Clinical Global Impressions-Improvement score of 2 (much improved) or 1 (very much improved). Aripiprazole reduced symptoms of irritability associated with autistic disorder in pediatric subjects ages 6-17 years who were studied for up to 1 year.

Aripiprazole

Aripiprazole is an atypical antipsychotic approved for the treatment of irritability associated with autistic disorder in pediatric patients aged 6-17 years. In two, randomized, double-blind, placebo-controlled studies in pediatric patients aged 6-17 years with irritability associated with autistic disorder, 8 weeks of treatment with aripiprazole 2-15 mg/day, compared with placebo, resulted in significant improvements in the Aberrant Behavior Checklist Irritability subscale score at endpoint (primary endpoint), and the mean Clinical Global Impression-Improvement score. Aripiprazole was generally well tolerated in this patient population in the two 8-week studies and a 52-week study, with most adverse events being mild to moderate in severity. Aripiprazole was associated with weight gain in both the short- and long-term studies; data from the long-term study indicated that the increase in bodyweight reached a plateau at 3-6 months.

Open-label add-on treatment trial of minocycline in fragile X syndrome

BackgroundFragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in fmr1 knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS.MethodsTwenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks.ResultsThe ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2).ConclusionsResults from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the fmr1 knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted.Trial registrationClinicalTrials.gov Open-Label Trial NCT00858689.

Fluoxetine Treatment of Alcoholic Perpetrators of Domestic Violence

Behaviorally based therapies for the treatment of perpetrators who initiate intimate partner violence (IPV) have generally shown minimal therapeutic efficacy. To explore a new treatment approach for IPV, we examined the effects of a selective serotonin reuptake inhibitor on the irritability subscale score of the Modified Overt Aggression Scale. This score served as a surrogate marker for the anger and physical aggression that characterize perpetrators of IPV. A 12-week, double-blind, randomized, placebo-controlled intervention study employing fluoxetine, alcohol treatment, and cognitive-behavioral therapy was performed. Sixty (46 men) non-court-mandated, DSM-IV-diagnosed alcoholic perpetrators of IPV with a history of at least 2 episodes of IPV in the year prior to participation in the study were evaluated. The primary outcome measure was the score on the irritability subscale of the Modified Overt Aggression Scale. Secondary measures included anxiety, depression, and ratings by the perpetrator's spouse/significant other. The study was conducted from January 2002 through December 2007. A repeated-measures analysis of variance using the irritability subscale scores obtained from perpetrators who completed the 12-week study (n = 24) showed a significant drug effect (F(1,21) = 12.09, P = .002). Last observation carried forward (F(1,32) = 4.24, P = .048) as well as intent-to-treat analysis (F(1,54) = 5.0, P = .034) also showed a significant drug effect. Spouses'/significant others' physical and nonphysical Partner Abuse Scale ratings showed a significant reduction of abuse over time (F(1,11) = 10.2, P = .009 and F(1,11) = 24.2, P = .0005, respectively). This is the first controlled study to show that a pharmacologic intervention employing a selective serotonin reuptake inhibitor, in conjunction with alcohol treatment and cognitive-behavioral therapy, can reduce measures of anger and physical aggression in alcoholic perpetrators of IPV.