Genetic syndromes are prevalent in patients with comorbid neurodevelopmental disorders and catatonia.

Catatonia occurs at high rates in idiopathic and syndromic neurodevelopmental disorders. At our institution's multidisciplinary catatonia clinic, clinical genetic testing (including microarray, fragile X PCR and methylation, autism/ID expanded panels, and exome sequencing) was commonly completed as part of clinical workup on patients with co-occurring neurodevelopmental disorders and catatonia (performed in 36/48 cases or 75%). This testing identified a pathogenic or likely pathogenic finding in 15/36 patients (42%). Testing identified a VUS (variant of uncertain significance) in 9/36 patients (25%). On review of the VUS findings, 4/9 were felt to be suspicious and potentially diagnostic. Testing was negative for 12/36 patients (33%). Many of the variants identified in this cohort were found in genes involved in gamma aminobutyric acid (GABA) and glutamatergic synaptic signaling; imbalances of these neurotransmitters are hypothesized to be drivers of catatonia. More work is needed to further characterize the molecular underpinnings of catatonia in the setting of neurodevelopmental disorders, including expanding genetic testing to larger cohorts in the future.

Management of Emotion Dysregulation and Outbursts in Children and Adolescents.

PURPOSE OF REVIEW: Emotion dysregulation and outbursts are very common reasons for referral to child and adolescent mental health services and a frequent cause of admission to hospitals and residential programs. Symptoms of emotion dysregulation and outburst are transdiagnostic, associated with many disorders, have the potential to cause severe impairment and their management presents a major challenge in clinical practice. RECENT FINDINGS: There are an increasing number of psychosocial interventions that demonstrate promise in improving emotion dysregulation and outbursts. Acute care systems to manage the most severely ill patients have limited best practice guidelines but program advancements indicate opportunities to improve care models. Pharmacotherapy may be of assistance to psychosocial interventions but must be used with caution due to potential adverse effects. Much remains to be discovered however evidence informed, targeted treatments for specific populations show potential for future improvements in outcomes.

Bipolar I disorder and major depressive disorder show similar brain activation during depression.

OBJECTIVES: Despite different treatments and courses of illness, depressive symptoms appear similar in major depressive disorder (MDD) and bipolar I disorder (BP-I). This similarity of depressive symptoms suggests significant overlap in brain pathways underlying neurovegetative, mood, and cognitive symptoms of depression. These shared brain regions might be expected to exhibit similar activation in individuals with MDD and BP-I during functional magnetic resonance imaging (fMRI). METHODS: fMRI was used to compare regional brain activation in participants with BP-I (n = 25) and MDD (n = 25) during a depressive episode as well as 25 healthy comparison (HC) participants. During the scans, participants performed an attentional task that incorporated emotional pictures. RESULTS: During the viewing of emotional images, subjects with BP-I showed decreased activation in the middle occipital gyrus, lingual gyrus, and middle temporal gyrus compared to both subjects with MDD and HC participants. During attentional processing, participants with MDD had increased activation in the parahippocampus, parietal lobe, and postcentral gyrus. However, among these regions, only the postcentral gyrus also showed differences between MDD and HC participants. CONCLUSIONS: No differences in cortico-limbic regions were found between participants with BP-I and MDD during depression. Instead, the major differences occurred in primary and secondary visual processing regions, with decreased activation in these regions in BP-I compared to major depression. These differences were driven by abnormal decreases in activation seen in the participants with BP-I. Posterior activation changes are a common finding in studies across mood states in participants with BP-I.

Safety and Efficacy of Paliperidone Palmitate in Pediatric Patients with Autism and Intellectual Disability.

This retrospective chart review examines the safety, tolerability and effectiveness of long acting injectable paliperidone palmitate (P-LAI) targeting irritability in twenty-six youth and transition-aged individuals with autism spectrum disorder (ASD) and/or intellectual disability (ID) over a 3-year window. Clinical response was evaluated via prospectively assigned Clinical Global Impressions Severity (CGI-S) and Improvement (CGI-I) scales as well as number of hospital presentations. P-LAI was well tolerated with only 3 patients stopping P-LAI due to side effects. The average duration of P-LAI treatment was 21.1 months. Difficulty with medication compliance was the most common reason for initiating P-LAI. There was a statistically significant improvement in CGI-I, CGI-S and hospital visits and no change in BMI noted. Given the potential difficulty of medication administration in this population, this evidence of safety, tolerability as well as preliminary data supporting effectiveness is an important addition to the literature regarding psychopharmacologic management of irritability in youth with ASD and ID.

Neurodevelopmental Disorders Including Autism Spectrum Disorder and Intellectual Disability as a Risk Factor for Delayed Diagnosis of Catatonia.

OBJECTIVE: Catatonia is a distinct and severe medical syndrome comprising motor, somatic, and psychiatric symptoms that is reported in upwards of 17% of young patients with autism spectrum disorders. Clinical experience indicates catatonia is often under-recognized in this clinical population. Here we characterize the clinical presentation of catatonia in patients with and without neurodevelopmental disorders (NDDs) including autism, including the time from symptom onset to diagnosis of catatonia. METHOD: Retrospective chart review of electronic medical records at a large, academic pediatric medical center identified 113 pediatric and young adult patients with a charted history of catatonia, as identified by an encounter diagnosis or problem list entry between September 2017 and September 2021. Workup, treatments, and diagnoses (psychiatric, neurodevelopmental, and genetic) were identified. RESULTS: We observed a clear and substantial delay in identification of catatonia in those with NDDs (diagnosis after 330 days for those without psychosis) compared with neurotypical patients (∼16 days). Psychiatry involvement was associated with shorter delays. CONCLUSION: Intellectual disability and autism are risk factors for significantly delayed diagnosis of catatonia. It is unknown whether delayed diagnosis contributes to the difficulty in treating catatonia in this patient population or whether the treatment difficulties relate instead to differential and ongoing biological mechanisms and underlying encephalopathy. Overall, these findings highlight the importance of increased recognition of catatonia symptoms in patients with NDDs and suggest early referral to psychiatric specialists may shorten the delay to diagnosis.

Systematic Review: Emotion Dysregulation in Syndromic Causes of Intellectual and Developmental Disabilities.

OBJECTIVE: To summarize the current state of the literature regarding emotion dysregulation (ED) in syndromic intellectual disabilities (S-IDs) in 6 of the most common forms of S-IDs-Down syndrome, fragile X syndrome (FXS), tuberous sclerosis complex, Williams syndrome, Prader-Willi syndrome, and Angelman syndrome-and to determine future research directions for identification and treatment of ED. METHOD: PubMed bibliographic database was searched from date of inception to May 2021. PRISMA 2020 guidelines were followed with the flowchart, table of included studies, list of excluded studies, and checklist provided. Filters applied included human research and English. Only original research articles were included in the final set, but review articles were used to identify secondary citations of primary studies. All articles were reviewed for appropriateness by 2 authors and summarized. Inclusion criteria were met by 145 articles (Down syndrome = 29, FXS = 55, tuberous sclerosis complex = 11, Williams syndrome = 18, Prader-Willi syndrome = 24, Angelman syndrome = 8). RESULTS: Each syndrome review was summarized separately and further subdivided into articles related to underlying neurobiology, behaviors associated with ED, assessment, and targeted intervention. FXS had the most thorough research base, followed by Down syndrome and Prader-Willi syndrome, with the other syndromes having more limited available research. Very limited research was available regarding intervention for all disorders except FXS. CONCLUSION: Core underlying characteristics of S-IDs appear to place youth at higher risk for ED, but further research is needed to better assess and treat ED in S-IDs. Future studies should have a standard assessment measure of ED, such as the Emotion Dysregulation Inventory, and explore adapting established curricula for ED from the neurotypical and autism spectrum disorder fields.

From Alert Child to Sleepy Adolescent: Age Trends in Chronotype, Social Jetlag, and Sleep Problems in Youth with Autism.

PURPOSE: Developmental changes in sleep in youth with autism spectrum disorder (ASD) are understudied. In non-ASD youth, adolescents exhibit a "night owl chronotype" (i.e., later sleep/wake timing) and social jetlag (i.e., shifts in sleep timing across school nights and weekends), with corresponding sleep problems. The purpose of this study is to evaluate age trends in chronotype, social jetlag, and sleep problems in high-risk youth with ASD. METHODS: Youth with ASD (N = 171), ages 5-21 years old, were enrolled at the time of admission to specialized psychiatric units. Caregivers reported children's demographic information, habitual sleep timing, and sleep problems. Multivariate analyses evaluated the effect of age on chronotype, social jetlag, and sleep problems and the effects of chronotype and social jetlag on sleep problems. Covariates and moderators included sex, race, verbal ability, autism symptom severity, supplemental melatonin, and pubertal status. RESULTS: Older age was associated with later chronotype, more social jetlag, fewer sleep anxiety/co-sleeping problems, fewer night waking and parasomnia problems, and more daytime alertness problems. The effect of age on chronotype was stronger for youth with greater social affective symptom severity. Mediation analyses showed that later chronotype statistically mediated the association between age and daytime alertness problems. CONCLUSIONS: Youth with ASD may exhibit night owl chronotype behavior and social jetlag as they enter adolescence. Shifts toward a later chronotype may be exacerbated by autism severity and may contribute to alertness problems and sleepiness during the day. Chronotype is modifiable and may be leveraged to improve daytime functioning in youth with ASD.

Results of a phase Ib study of SB-121, an investigational probiotic formulation, a randomized controlled trial in participants with autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by core impairments in social communication as well as restricted, repetitive patterns of behavior and/or interests. Individuals with ASD, which includes about 2% of the US population, have challenges with activities of daily living and suffer from comorbid medical and mental health concerns. There are no drugs indicated for the core impairments of ASD. As such, there is a significant need for the development of new medication strategies for individuals with ASD. This first-in-human placebo-controlled, double-blind, crossover study investigated the safety (primary objective) and efficacy of oral SB-121, a combination of L. reuteri, Sephadex® (dextran microparticles), and maltose administered once daily for 28 days in 15 autistic participants. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted. These results provide support for further clinical evaluation of SB-121 as a treatment in autistic patients. To evaluate the safety and tolerability of multiple doses of SB-121 in subjects with autism spectrum disorder. Single-center, randomized, placebo-controlled, double-blind, crossover trial. 15 patients with autism spectrum disorder were randomized and analyzed. Daily dosing of SB-121 or placebo for 28 days, followed by approximately a 14 day washout, then 28 days of dosing with other treatment. Incidence and severity of adverse events, presence of Limosilactobacillus reuteri and Sephadex® in stool, and incidence of bacteremia with positive L. reuteri identification. Additional outcomes include changes from baseline on cognitive and behavior tests as well as biomarker levels. Adverse event rates were similar between SB-121 and placebo, with most reported as mild. There were no severe or serious adverse events. No participants had features of suspected bacteremia or notable changes in vital signs, safety laboratory, or ECG parameters from baseline. There was a statistically significant increase from baseline in the Vineland-3 Adaptive Behavior Composite score (p = 0.03) during SB-121 treatment. There was a trend for increased social/geometric viewing ratio following SB-121 treatment compared to placebo. SB-121 was safe and well tolerated. SB-121-associated directional improvements in adaptive behavior measured by Vineland-3 and social preference as measured with eye tracking were noted.Trial registration: clinicaltrials.gov Identifier: NCT04944901.

Patterns in Medication Use for Treatment of Depression in Autistic Spectrum Disorder.

INTRODUCTION: Depression impacts many individuals with autism spectrum disorder (ASD), carrying increased risk of functional impairment, hospitalization, and suicide. Prescribing medication to target depression in patients with ASD occurs despite limited available systematic data describing medication management of depression in this population. PURPOSE: The purpose of this study is to discover prescribing patterns for individuals with MDD and ASD during this time period (2004-2012) to inform current and future prescribing practices with historical data. METHOD: Drawing from a large clinical database describing the prescribing practices in patients with ASD, we identified 166 individuals with ASD (mean age 14.5 ± 8.3 years old) who received medication targeting symptoms of depression. We report prescribing rates for specific drugs, drug treatment duration, and reasons for drug discontinuation when applicable. RESULTS: Sertraline, mirtazapine, and fluoxetine were the three most commonly prescribed medications to treat comorbid depression for this patient population. Among 241 drug starts, 123 (49%) drug treatments were continued at the final reviewed follow-up visit (average treatment duration of ± 0.72 years). The most common reason for discontinuation across all medications prescribed was loss of or lack of effectiveness. CONCLUSION: This study raises concern that standard of care pharmacological treatments for depression in individuals with ASD may be less effective than in neurotypical populations. There remains a need to develop effective interventions for depression specifically tailored to the needs of individuals with ASD.

A Collaborative Psychiatric-Genetics Inpatient Care Delivery Model Improves Access to Clinical Genetic Evaluation, Testing, and Diagnosis for Patients With Neurodevelopmental Disorders.

Neurodevelopmental disorders including autism spectrum disorder, intellectual disability, and global developmental delay are among the most common indications for referral to clinical genetics evaluation; and clinical genetic testing is indicated for people with neurodevelopmental disorders. There are known barriers to care in accessing clinical genetics evaluation for this patient population. We created a collaborative psychiatric-genetics consultation service and psychiatric-genetics outpatient clinic with the goal to improve care delivery to patients with neurodevelopmental disorders. Two years after the launch of this pilot program, our data demonstrate improved access to genetics evaluation with shorter wait times and fewer patients lost to follow-up. Perhaps most importantly, new genetic diagnoses changed medical care for the majority of patients.

Brief Report: Telehealth Satisfaction Among Caregivers of Pediatric and Adult Psychology and Psychiatry Patients with Intellectual and Developmental Disability in the Wake of Covid-19.

Telehealth has been shown to be both acceptable and effective in many areas of healthcare, yet it was not widely adopted prior to the SARS-CoV-2 (COVID-19) pandemic. Additionally, previous evaluations of telehealth for autism spectrum condition (ASC) and intellectual and developmental disability (IDD) populations are limited in both number and scope. Here, we investigated satisfaction amongst Psychology and Psychiatry patient caregivers at Cincinnati Children's Hospital Medical Center (CCHMC) after the onset of the COVID-19 pandemic. Results (640 responses) showed high rates of satisfaction across departments, appointment types, and diagnoses, with 92% indicating overall satisfaction with their appointment. There were, however, notable decreases in satisfaction among Group Therapy respondents, and those whose diagnosis was classified as Other.

Neocortical localization and thalamocortical modulation of neuronal hyperexcitability contribute to Fragile X Syndrome.

Fragile X Syndrome (FXS) is a monogenetic form of intellectual disability and autism in which well-established knockout (KO) animal models point to neuronal hyperexcitability and abnormal gamma-frequency physiology as a basis for key disorder features. Translating these findings into patients may identify tractable treatment targets. Using source modeling of resting-state electroencephalography data, we report findings in FXS, including 1) increases in localized gamma activity, 2) pervasive changes of theta/alpha activity, indicative of disrupted thalamocortical modulation coupled with elevated gamma power, 3) stepwise moderation of low and high-frequency abnormalities based on female sex, and 4) relationship of this physiology to intellectual disability and neuropsychiatric symptoms. Our observations extend findings in Fmr1-/- KO mice to patients with FXS and raise a key role for disrupted thalamocortical modulation in local hyperexcitability. This systems-level mechanism has received limited preclinical attention but has implications for understanding fundamental disease mechanisms.

Alteration of brain activation patterns in nonallergic rhinitis patients using functional magnetic resonance imaging before and after treatment with intranasal azelastine.

BACKGROUND: Although nonallergic rhinitis (NAR) patients tend to be more sensitive to chemical/olfactory stimuli, a suprathreshold olfactory response or the presence of specific olfactory receptor genes do not explain why their symptoms are triggered by such exposures. OBJECTIVE: To investigate differential neurogenic responses to azelastine in NAR patients, using functional magnetic resonance imaging (fMRI) in response to specific olfactory triggers. METHODS: A longitudinal study design on 12 subjects with a physician diagnosis of NAR previously demonstrated to be clinically responsive to intranasal azelastine (Astelin) was performed. Subjects underwent fMRI during exposure to unpleasant (hickory smoke) and pleasant (vanilla) odorants while off and then on azelastine for 2 weeks. The olfactory fMRI paradigm consisted of a visually triggered sniff every 21 seconds with synchronized delivery of a 4 second pulse of odorant. Each odorant was presented 18 times over 4-6-minute fMRI runs. Continuous fresh air was presented to wash out each odorant after presentation. RESULTS: Nonallergic rhinitis patients exhibited increased blood flow to several regions of the brain in response to both pleasant and unpleasant odorants, specifically in odor-sensitive regions, while off intranasal azelastine. Treatment with intranasal azelastine significantly attenuated blood flow to regions of the brain relevant to either olfactory sensation or sensory processing in response to these odorants compared with fresh air. CONCLUSION: The general reduction compared with increase in brain activation in NAR patients on versus off azelastine suggests that a possible effect of this medication may be reduction of brain responses to odorants.

Decades of Progress in the Psychopharmacology of Autism Spectrum Disorder.

Recent decades have been marked by a wave drug treatment research in autism spectrum disorder (ASD). This work has resulted in improved ability to treat commonly occurring behavioral challenges associated with ASD including most prominently irritability marked by aggression, self-injurious behavior, and severe tantrums. While treatment of interfering behavior has progressed in our field, there remain several areas of unmet medical need including most prominently a lack of any approved drug therapies for the core, defining symptoms of autism. We outline the progress to date in the field of autism drug treatment while taking a future look forward into how decades of work can inform better future steps in this field.

Recent Advances in the Pharmacological Management of Behavioral Disturbances Associated with Autism Spectrum Disorder in Children and Adolescents.

Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition affecting an estimated one in 36 children. Youth with ASD may have severe behavioral disturbances including irritability, aggression, and hyperactivity. Currently, there are only two medications (risperidone and aripiprazole) approved by the US Food and Drug Administration (FDA) for the treatment of irritability associated with ASD. Pharmacologic treatments are commonly used to target ASD-associated symptoms including irritability, mood lability, anxiety, and hyperactivity. However, evidence for the efficacy of many commonly used treatments is limited by the lack of large placebo-controlled trials of these medications in this population. Research into the pathophysiology of ASD has led to new targets for pharmacologic therapy including the neuroimmune system, the endocannabinoid system, and the glutamatergic neurotransmitter system. The goal of this review is to provide an overview of the current evidence base for commonly used treatments, as well as emerging treatment options for common behavioral disturbances seen in youth with ASD.

Use of fMRI in the study of chronic aphasia recovery after therapy: a case study.

PURPOSE: The role of intensity of aphasia therapy was investigated using functional magnetic resonance imaging (fMRI) to document changes in neural activation patterns associated with massed versus distributed therapy in an individual with chronic conduction aphasia. METHOD: Language therapy targeted word-finding deficits and phonological processing. fMRI scans were acquired at baseline, after massed therapy, and after distributed therapy. RESULTS: Treatment was effective, as demonstrated by increases in performance on standardized measures, narrative analysis, and task performance in the fMRI scanner. Task improvement across fMRI testing sessions corresponded with increases in fMRI blood oxygenation level dependent (BOLD) signal. Greatest behavioral gains and BOLD signal increases occurred after massed therapy, with slight gains accompanying distributed therapy. Increases in fMRI BOLD signal occurred after therapy in left basal ganglia and right hemisphere frontotemporal cortex. CONCLUSIONS: Intensity of aphasia therapy impacts the recovery process and warrants additional research. Basal ganglia and right hemisphere structures may be important neural substrates for aphasia recovery.

Brain-mapping techniques for evaluating poststroke recovery and rehabilitation: a review.

Brain-mapping techniques have proven to be vital in understanding the molecular, cellular, and functional mechanisms of recovery after stroke. This article briefly summarizes the current molecular and functional concepts of stroke recovery and addresses how various neuroimaging techniques can be used to observe these changes. The authors provide an overview of various techniques including diffusion-tensor imaging (DTI), magnetic resonance spectroscopy (MRS), ligand-based positron emission tomography (PET), single-photon emission computed tomography (SPECT), regional cerebral blood flow (rCBF) and regional metabolic rate of glucose (rCMRglc) PET and SPECT, functional magnetic resonance imaging (fMRI), near infrared spectroscopy (NIRS), electroencephalography (EEG), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS). Discussion in the context of poststroke recovery research informs about the applications and limitations of the techniques in the area of rehabilitation research. The authors also provide suggestions on using these techniques in tandem to more thoroughly address the outstanding questions in the field.

Pharmacological management of behavioral disturbances in children and adolescents with autism spectrum disorders.

Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition that, based on recent CDC estimates affects an estimated 1 in 59 American children. Behavioral treatments remain the mainstay of treatment for the core symptoms of ASD including communication deficits, social interaction deficits and repetitive behavior. However, youth with ASD may also have severe behavioral challenges including irritability, aggression, and hyperactivity. Currently there are only two medications (risperidone and aripiprazole) approved by the FDA for the treatment of irritability associated with ASD in children. Psychiatric comorbidities are common in youth with ASD, affecting up to 70% of affected children and adolescents. Given the burden of co-occurring disorders, medications are often employed to target symptoms such as irritability, anxiety, and hyperactivity. Other common co-occurring conditions including gastrointestinal disorders and sleep disorders may be improved with pharmacologic management. Evidence for the efficacy of many commonly used psychotropic medications in ASD is limited by the lack of large placebo-controlled trials in youth with ASD. This paper reviews the current literature regarding use of medications to address co-occurring conditions in children and adolescents with ASD as well as areas of emerging research.

Antidepressant-Induced Activation in Children and Adolescents: Risk, Recognition and Management.

The tolerability of antidepressants is poorly characterized in children and adolescents with depressive and anxiety disorders. Among adverse events that affect the tolerability of antidepressants in youth is activation, a cluster of symptoms that represent a hyperarousal event characterized by impulsivity, restlessness, and/or insomnia. This cluster of symptoms was first identified as a side effect of selective serotonin and selective serotonin norepinephrine inhibitors (SSRIs and SSNRIs) in the early 1990s; however, activation remains poorly characterized in terms of prevalence, risk factors, and pathophysiology. This article describes the pathophysiology of antidepressant-related activation, predictors of activation and its clinical management in youth with depressive and anxiety disorders who are treated with antidepressant medications.