Explore the vast range of titles available.

Riluzole is a glutamatergic modulator of particular interest in autism spectrum disorder (ASD). In this 12-week randomized, double-blind, placebo-controlled, crossover pilot study we evaluated the safety and tolerability of 5-week of adjunctive riluzole treatment (vs. 5-week of placebo, with 2-week washout period) targeting ASD-associated drug-refractory irritability in eight individuals age 12–25 years. All participants tolerated riluzole 200 mg per day, however there were no statistically significant findings for the overall treatment effect, the treatment effect by week within period of the study, or a cross-over effect across the periods of the study on the Clinical Global Impression Improvement Scale or the Aberrant Behavior Checklist Irritability subscale. The results of this trial indicate that 5-week of riluzole treatment was well tolerated, but had no significant effect on the target symptoms. Trial Registration ClinicalTrials.gov Identifier NCT02081027, Registered 5 August 2013, First participant enrolled 19 September 2013.

Building on prior work using Tom Dishion's Family Check-Up, the current article examined intervention effects on dysregulated irritability in early childhood. Dysregulated irritability, defined as reactive and intense response to frustration, and prolonged angry mood, is an ideal marker of neurodevelopmental vulnerability to later psychopathology because it is a transdiagnostic indicator of decrements in self-regulation that are measurable in the first years of life that have lifelong implications for health and disease. This study is perhaps the first randomized trial to examine the direct effects of an evidence- and family-based intervention, the Family Check-Up (FCU), on irritability in early childhood and the effects of reductions in irritability on later risk of child internalizing and externalizing symptomatology. Data from the geographically and sociodemographically diverse multisite Early Steps randomized prevention trial were used. Path modeling revealed intervention effects on irritability at age 4, which predicted lower externalizing and internalizing symptoms at age 10.5. Results indicate that family-based programs initiated in early childhood can reduce early childhood irritability and later risk for psychopathology. This holds promise for earlier identification and prevention approaches that target transdiagnostic pathways. Implications for future basic and prevention research are discussed.

Women diagnosed with premenstrual dysphoric disorder (PMDD) report significant symptom relief when treated with selective serotonin reuptake inhibitors, but few studies have addressed the possibility of capturing this effect in behavioral, laboratory-based tests. This study examined the effects of intermittent treatment with escitalopram (vs. placebo) on a behavioral measure of impulsivity and inattentiveness in women reporting high levels of premenstrual irritability and anger. Participants (  = 27) rated cardinal PMDD mood symptoms over three menstrual cycles using Visual Analogue Scales. In Cycles 2 and 3, participants displaying cyclicity with respect to the irritability/anger item received escitalopram (20 mg) or placebo in a randomized, single-blind, crossover design. The participants completed the Conners Continuous Performance Test (CPT 3) in the luteal phase of the intervention cycles. Additionally, they filled out the UPPS Impulsive Behavior Scale, once in the luteal phase and once in the follicular phase of the placebo cycle. In line with previous reports, escitalopram caused a significant reduction in self-rated irritability and anger in the luteal phase. When on escitalopram, the participants demonstrated a lower frequency of anticipatory responses and greater consistency in response speed in the CPT 3. With respect to self-reported impulsivity, participants reported higher levels of urgency and lower levels of sensation seeking in the luteal placebo phase versus the follicular phase. The finding that escitalopram impacted the outcome of the CPT 3 test in women with premenstrual irritability highlights the possible role of impulsivity in this condition.

This study examines the effect of amantadine on irritability in persons in the post-acute period after traumatic brain injury (TBI). There were 168 persons ≥6 months post-TBI with irritability who were enrolled in a parallel-group, randomized, double-blind, placebo-controlled trial receiving either amantadine 100 mg twice daily or equivalent placebo for 60 days. Subjects were assessed at baseline and days 28 (primary end-point) and 60 of treatment using observer-rated and participant-rated Neuropsychiatric Inventory (NPI-I) Most Problematic item (primary outcome), NPI Most Aberrant item, and NPI-I Distress Scores, as well as physician-rated Clinical Global Impressions (CGI) scale. Observer ratings between the two groups were not statistically significantly different at day 28 or 60; however, observers rated the majority in both groups as having improved at both intervals. Participant ratings for day 60 demonstrated improvements in both groups with greater improvement in the amantadine group on NPI-I Most Problematic (p<0.04) and NPI-I Distress (p<0.04). These results were not significant with correction for multiple comparisons. CGI demonstrated greater improvement for amantadine than the placebo group (p<0.04). Adverse event occurrence did not differ between the two groups. While observers in both groups reported large improvements, significant group differences were not found for the primary outcome (observer ratings) at either day 28 or 60. This large placebo or nonspecific effect may have masked detection of a treatment effect. The result of this study of amantadine 100 mg every morning and noon to reduce irritability was not positive from the observer perspective, although there are indications of improvement at day 60 from the perspective of persons with TBI and clinicians that may warrant further investigation.

Irritability, a state of excessive reactivity to negative emotional stimuli, is common in individuals with autism spectrum disorder (ASD). Although it has a significant negative impact of patients' disease severity and quality of life, the neural mechanisms underlying irritability in ASD remain largely unclear. We have previously demonstrated that male mice lacking the Coiled-coil and C2 domain containing 1a (Cc2d1a) in forebrain excitatory neurons recapitulate numerous ASD-like behavioral phenotypes, including impaired social behaviors and pronounced repetitive behaviors. Here, using the bottle-brush test (BBT) to trigger and evaluate aggressive and defensive responses, we show that Cc2d1a deletion increases irritability-like behavior in male but not female mice, which is correlated with reduced number of oxytocin (OXT)-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Intranasal OXT administration or chemogenetic activation of OXT neurons in the PVN rescues irritability-like behavior in Cc2d1a conditional knockout (cKO) mice. Administration of a selective melanocortin receptor 4 agonist, RO27-3225, which potentiates endogenous OXT release, also alleviates irritability-like behavior in Cc2d1a cKO mice, an effect blocked by a specific OXT receptor antagonist, L-368,899. We additionally identify a projection connecting the posterior ventral segment of the medial amygdala (MeApv) and ventromedial nucleus of the ventromedial hypothalamus (VMHvl) for governing irritability-like behavior during the BBT. Chemogenetic suppression of the MeApv-VMHvl pathway alleviates irritability-like behavior in Cc2d1a cKO mice. Together, our study uncovers dysregulation of OXT system in irritability-like behavior in Cc2d1a cKO mice during the BBT and provide translatable insights into the development of OXT-based therapeutics for clinical interventions.

AbstractObjectiveIrritability is one of the most frequent concerns in pediatric mental health and a predictor of long-term psychopathology and burden. This article aims to provide a comprehensive review of non-episodic irritability along with evidence-based clinical recommendations for pediatric care professionals. SourcesA narrative review was conducted based on the literature from the last 10 years and additional key studies. Observational studies, randomized controlled trials, systematic reviews, and meta-analyses were considered. Summary of the findingsNon-episodic irritability is a transdiagnostic construct associated with several mental disorders. Research on etiological pathways suggests that irritability may involve distinct mechanisms, moderate heritability, and genetic associations with attention-deficit/hyperactivity disorder (ADHD), and depression. Clinical manifestations vary across different developmental stages, and distinguishing pathological from normative irritability may be challenging. Although there is no gold-standard measure, validated instruments are available. Despite recent advances, evidence-based treatment remains limited. Evidence supports psychosocial interventions that integrate parent- and child-focused components, as well as the use of stimulants for patients with comorbid ADHD. Antipsychotics are effective in reducing irritability in children with autism spectrum disorder. However, its use requires caution in non-autistic youth with irritability without a diagnosable disorder or with oppositional defiant disorder due to inconclusive efficacy and potential adverse effects. ConclusionsAlthough publications on non-episodic irritability have increased, the evidence remains relatively nascent. Further research is needed to advance the knowledge on underlying mechanisms, enhance clinical recognition, identify effective interventions, and support the development of new treatments, ensuring that irritability is adequately addressed in clinical practice.

Background Our objective was to compare self‐ and parent‐reported irritability in youths with anxiety disorders, healthy youths, and those with mood disorders characterized by irritability. Irritability is a common but relatively understudied psychiatric symptom in child and adolescent anxiety disorders. In anxious youths, little is known about the severity of irritability, its impact on functioning, or the effect of informant source on reports of irritability. Methods We compared parent‐ and self‐report forms of the Affective Reactivity Index (ARI), a validated measure of irritability, in youths ages 8–17 years with no psychopathology (healthy comparison, HC; n = 38), anxiety disorders (ANX; n = 42), bipolar disorder (BD; n = 35), or severe mood dysregulation (SMD; n = 61; a phenotype characterized by chronic, severely impairing irritability). Results Irritability was significantly higher in ANX than HC youths by both parent and self‐report (partial η2 = 0.24 and 0.22, respectively, P's < 0.001). Informant effects differed among ANX, BD, and SMD. Overall, parent‐reported irritability was higher in BD with comorbid anxiety disorders and SMD with or without comorbid anxiety disorders than ANX (P's < 0.007), but self‐reported irritability was not significantly different among the three patient groups. Discussion By both parent and self‐report, youths with anxiety disorders exhibit significantly more irritability and associated impairment than healthy subjects. Self‐reported irritability in youths with anxiety disorders is comparable to that observed in youths with severe mood disorders, although parental reports of irritability differ among the disorders. Future research should examine the pathophysiology of anxiety‐associated irritability, as well as its prognostic and treatment implications.

Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by social and language deficits and by repetitive behaviors and interests. Irritability/aggression is a significant comorbid symptom in this population, which greatly impacts burden of care. This study examined the effect of divalproex sodium for irritability/aggression in children and adolescents with ASD. This was a 12-week randomized, double-blind, placebo-controlled trial. All efficacy measures were obtained by an independent evaluator blinded to randomization condition and side effects. A total of 55 subjects gavetheir consent and 27 were randomized in a 1 : 1 manner (mean age 9.46±2.46, mean nonverbal IQ 63.3±23.9). Two subjects from the active group and one subject from the placebo group discontinued the study because of either a lack of efficacy or side effects (increased irritability). Primary outcome measures were Aberrant Behavior Checklist-Irritability subscale and Clinical Global Impression-Improvement, which focused on irritability. Overall, 62.5% of divalproex subjects vs 9% of placebo subjects were responders (CGI-irritability OR: 16.7, Fisher's exact p =0.008). A statistically significant improvement was also noted on the ABC-Irritability subscale ( p =0.048). There was a trend for responders to have higher valproate blood levels compared with nonresponders. This study suggests the efficacy of divalproex for the treatment of irritability in children and adolescents with ASD. Larger sample follow-up studies are warranted.