Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function.

There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development.

Characterization of sleep habits and medication outcomes for sleep disturbance in children and adults with Angelman syndrome.

The objectives of this study were to characterize the sleep habits of 50 clinically referred individuals with Angelman syndrome (AS) and to retrospectively compare the effectiveness/tolerability of the three most commonly prescribed sleep medications in the sample. An experienced physician assigned a Clinical Global Impressions-Severity scale (CGI-S) score for each subject's AS-specific symptoms. Caregivers completed the Child Sleep Habits Questionnaire (CSHQ; screen for sleep problems in school-aged [4-10 years] children), a screening assessment for sleep problems. Caregivers provided information about medication trials targeting disturbed sleep, with the physician assigning a CGI-Improvement scale (CGI-I) score for each trial. Linear regression showed significant negative association between age and CSHQ score. In their lifetime, 72% of participants had taken a medication for sleep, most commonly melatonin, clonidine and trazodone. The majority continued these for 6 months or longer. With these medications, many demonstrated significant improvement in sleep disturbances, with no difference in odds of improvement between medications. Disturbed sleep was common in this cohort and significantly worse in younger-aged participants. The majority received at least one medication trial for disturbed sleep and each of the most commonly prescribed medication was effective for a substantial percentage of participants. Most participants remained on medication for at least 6 months, suggesting favorable tolerability.

Prevalence and factors associated with overweight, obesity, and hypertension in a large clinical sample of adults with autism spectrum disorder.

Adults with autism spectrum disorder (ASD) are at risk for excess bodyweight and hypertension, yet the prevalence of and clinical predictors for these health conditions remain unknown. The objective of this study was to assess the prevalence of overweight, obesity, and hypertension in a large clinical sample of adults with a confirmed diagnosis of ASD and to examine potential clinical predictors. This retrospective chart review study included adult subjects (≥ 20 years) with ASD who had been seen within the past 5 years at a multidisciplinary developmental disorders clinic. Data collected from the electronic health record included age, sex, race and ethnicity, cognitive ability, language ability, body mass index (BMI), hypertension, and use of second generation antipsychotic medications (SGAs). Of 622 adults with a confirmed diagnosis of ASD potentially eligible for the study, 483 (78%) had one or more notes in their records from the past 5 years. Those with recent notes were 23% female, 89% White, and had a mean (SD) age of 28.1 (7.1) years. Overall prevalence estimates for adults represented by this predominantly male, White, and young clinical sample were 28% (95% CI 24%, 32%) for overweight (BMI 25-29.9 kg/m2), 35% (95% CI 31%, 40%) for obesity (≥ 30 kg/m2), and 11% (95% CI 9%, 15%) for hypertension. Controlling for age and sex, intellectual disability (ID) was significantly associated with BMI (p = 0.003) but not hypertension (p = 0.69); those with moderate or more severe ID had a mean BMI that was 2.26 kg/m2 (95% CI 0.96, 3.57) lower than those with no ID. Controlling for age and sex, neither language ability, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) subtype of autism, nor past or current use of SGAs were significantly associated with BMI or hypertension. The study identified a high prevalence of overweight and obesity in adults with ASD consistent with the prevalence of these medical comorbidities in the U.S. population.

Repetitive Thoughts and Repetitive Behaviors in Williams Syndrome.

The purpose of the study was to characterize repetitive phenomena in Williams syndrome (WS). The parents of 60 subjects with WS completed the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) or Children's Y-BOCS, the Yale Global Tic Severity Scale, the Stereotyped Behavior Scale, and the Spence Children's Anxiety Scale-Parent Version. Nineteen males and 41 females participated in the study. Six subjects (10%) had obsessions only, six (10%) had compulsions only, and eleven (18%) had at least one obsession and at least one compulsion. None of the subjects had tics. Fifty subjects (83.3%) endorsed at least one stereotypy. Increased anxiety was associated with increased severity of obsessions, but not severity of compulsions or stereotypies.

A randomized double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in children and adolescents with autism spectrum disorder.

This study was a 10-week double-blind, placebo-controlled pilot trial of mirtazapine for anxiety in youth with autism spectrum disorder (ASD). Participants were ages 5 to 17 years with ASD and clinically significant anxiety (Pediatric Anxiety Rating Scale [PARS] score ≥10). Thirty participants were randomized to mirtazapine (7.5-45 mg/day) or placebo in a 2:1 ratio. The co-primary outcome measures were the PARS and the Clinical Global Impressions-Improvement subscale (CGI-I). Mirtazapine resulted in a statistically significant within group decrease in anxiety on the PARS (ES 1.76, p < 0.001). The improvement in PARS score for mirtazapine versus placebo was clinically meaningful but not statistically significant (ES = 0.63, p = 0.64). Forty-seven percent of participants assigned to mirtazapine (95% CI 22%: 74%) and 20% assigned to placebo (95% CI 2%: 60%) were rated "much improved" (CGI-I = 2) or "very much improved" (CGI-I = 1) for anxiety, p = 0.46. No statistically significant differences in mean 10-week changes between mirtazapine and placebo occurred on any outcome measure. There were no statistically significant differences in adverse effect frequency between mirtazapine and placebo. The results are consistent with mirtazapine's safety and tolerability and meet three of four pre-specified indicators of efficacy (statistically significant change in total PARS score for mirtazapine, numerically greater reduction in total PARS score for mirtazapine than placebo, numerically higher number of responders to mirtazapine than placebo, but not greater than 50% of participants receiving mirtazapine rated as responders). Implementation of a larger randomized controlled trial of mirtazapine for the treatment of anxiety in this population is supported.Clinical trial registration information: Mirtazapine Treatment of Anxiety in Children and Adolescents with Pervasive Developmental Disorders; https://clinicaltrials.gov ; NCT01302964.

Parent Description of Anxiety in Angelman Syndrome.

Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and quantitative assessments were used to evaluate for anxiety in 50 subjects with AS. In-person evaluations assessed behaviors concerning for anxiety and circumstances wherein they occurred. Caregivers completed anxiety and other behavioral rating scales. Caregiver responses were categorized and compared to items from anxiety rating scales. The most common behavioral manifestation of anxiety was "aggression." The most common circumstance was "separation from caregiver/parent." Subjects had elevated scores on anxiety, irritability and hyperactivity scales with lower mean scores among subjects with a maternal deletion. The Pediatric Anxiety Rating Scale best captured behaviors described by caregivers. Existing anxiety scales should be adapted for use in AS.

Selective Serotonin Reuptake Inhibitors for the Treatment of Depression in Adults with Down Syndrome: A Preliminary Retrospective Chart Review Study.

BACKGROUND: Depression is a common psychiatric comorbidity in individuals with Down syndrome (DS), particularly adults, with an estimated lifetime prevalence of at least 10%. The current literature on the treatment of depression in adults with DS is limited to case series published more than two decades ago, prior to the widespread use of modern antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). The purpose of this retrospective chart review study was to examine the effectiveness, tolerability, and safety of SSRIs for depression in adults with DS. METHODS: Medical records of 11 adults with DS and depression were reviewed. Assignment of scores for severity (S) of symptoms of depression and improvement (I) of symptoms with treatment with an SSRI was made retrospectively using the Clinical Global Impression Scale (CGI). Demographic and clinical characteristics of the study population, SSRI name, dose, and duration of treatment; and adverse effects were also recorded. RESULTS: All 11 patients (7 male, 4 female; mean age = 27.2 years, range 18-46 years) completed a 12-week treatment course with an SSRI. The median duration of time after initiation of the SSRI covered by record review was 2.1 years, with a range of 24 weeks to 6.7 years. Nine of the 11 patients (82%; 95% CI 52%, 95%) were judged responders to SSRIs based on a rating of "much improved" or "very much improved" on the CGI-I after 12 weeks of treatment (median time of follow-up was 14.4 weeks, with a range of 12.0-33.0 weeks). Adverse effects occurred in four patients (36%). The most common adverse effects were daytime sedation and anger. CONCLUSIONS: In this preliminary retrospective study, the majority of patients responded to a 12-week course of SSRI treatment and some tolerated long-term use. Controlled studies are needed to further assess the efficacy, tolerability, and safety of SSRIs for the treatment of depression in adults with DS.

Beyond the brain: A multi-system inflammatory subtype of autism spectrum disorder.

An immune-mediated subtype of autism spectrum disorder (ASD) has long been hypothesized. This article reviews evidence from family history studies of autoimmunity, immunogenetics, maternal immune activation, neuroinflammation, and systemic inflammation, which suggests immune dysfunction in ASD. Individuals with ASD have higher rates of co-morbid medical illness than the general population. Major medical co-morbidities associated with ASD are discussed by body system. Mechanisms by which FDA-approved and emerging treatments for ASD act upon the immune system are then reviewed. We conclude by proposing the hypothesis of an immune-mediated subtype of ASD which is characterized by systemic, multi-organ inflammation or immune dysregulation with shared mechanisms that drive both the behavioral and physical illnesses associated with ASD. Although gaps in evidence supporting this hypothesis remain, benefits of this conceptualization include framing future research questions that will help define a clinically meaningful subset of patients and focusing clinical interactions on early detection and treatment of high-risk medical illnesses as well as interfering behavioral signs and symptoms across the lifespan.

Aberrant cerebellar connectivity in bipolar disorder with psychosis.

BACKGROUND: The cerebellum, which modulates affect and cognition in addition to motor functions, may contribute substantially to the pathophysiology of mood and psychotic disorders, such as bipolar disorder. A growing literature points to cerebellar abnormalities in bipolar disorder. However, no studies have investigated the topographic representations of resting state cerebellar networks in bipolar disorder, specifically their functional connectivity to cerebral cortical networks. METHODS: Using a well-defined cerebral cortical parcellation scheme as functional connectivity seeds, we compared ten cerebellar resting state networks in 49 patients with bipolar disorder and a lifetime history of psychotic features and 55 healthy control participants matched for age, sex, and image signal-to-noise ratio. RESULTS: Patients with psychotic bipolar disorder showed reduced cerebro-cerebellar functional connectivity in somatomotor A, ventral attention, salience, and frontoparietal control A and B networks relative to healthy control participants. These findings were not significantly correlated with current symptoms. CONCLUSIONS: Patients with psychotic bipolar disorder showed evidence of cerebro-cerebellar dysconnectivity in selective networks. These disease-related changes were substantial and not explained by medication exposure or substance use. Therefore, they may be mechanistically relevant to the underlying susceptibility to mood dysregulation and psychosis. Cerebellar mechanisms deserve further exploration in psychiatric conditions, and this study's findings may have value in guiding future studies on pathophysiology and treatment of mood and psychotic disorders, in particular.

Rapid mood-elevating effects of low field magnetic stimulation in depression.

BACKGROUND: We previously reported rapid mood elevation following an experimental magnetic resonance imaging procedure in depressed patients with bipolar disorder (BPD). This prompted the design, construction, and testing of a portable electromagnetic device that reproduces only the rapidly oscillating (1 kHz, <1 V/m) electromagnetic field of the experimental procedure, called low field magnetic stimulation (LFMS). METHODS: We used a randomized, double blind, sham controlled treatment protocol to study the effects of LFMS in a large group of stably medicated, depressed patients with either BPD (n = 41) or major depressive disorder (n = 22). Subjects received a single, 20-minute treatment. Change in mood was assessed immediately afterward using a visual analog scale (VAS), the 17-item Hamilton Depression Rating Scale (HDRS-17), and the Positive and Negative Affect Schedule scales. RESULTS: Substantial improvement (>10% of baseline) in mood was observed following LFMS treatment relative to sham treatment for both diagnostic subgroups for our primary outcomes, the VAS and the HDRS-17. These differences were not statistically significant in primary analyses stratifying by diagnosis but were significant in secondary analyses combining data across the two diagnostic groups (p = .01 VAS, p = .02 HDRS-17). Rapid improvement in mood was also observed using the Positive and Negative Affect Schedule scales as secondary measures (positive affect scale p = .02 BPD, p = .002 combined group). A finite element method calculation indicates a broad penetration of the LFMS electric field throughout the cerebral cortex. CONCLUSIONS: Low field magnetic stimulation may produce rapid changes in mood using a previously unexplored range of electromagnetic fields.