Editorial on common mental health disorders and cognitive decline in a longitudinal Down syndrome cohort.

This editorial discusses a study by Idris and colleagues, where the authors investigated the impact of common mental disorders (CMDs) among patients with Down syndrome, with respect to development of clinical features of Alzheimer's disease.

Atypical alpha band microstates produced during eyes-closed resting state EEG in autism.

Electroencephalogram (EEG) microstates, which represent quasi-stable patterns of scalp topography, are a promising tool that has the temporal resolution to study atypical spatial and temporal networks in autism spectrum disorder (ASD). While current literature suggests microstates are atypical in ASD, their clinical utility, i.e., relationship with the core behavioural characteristics of ASD, is not fully understood. The aim of this study was to examine microstate parameters in ASD, and examine the relationship between these parameters and core behavioural characteristics in ASD. We compared duration, occurrence, coverage, global explained variance percentage, global field power and spatial correlation of EEG microstates between autistic and neurotypical (NT) adults. Modified k-means cluster analysis was used on eyes-closed, resting state EEG from 30 ASD (10 females, 28.97 ± 9.34 years) and 30 age-equated NT (13 females, 29.33 ± 8.88 years) adults. Five optimal microstates, A to E, were selected to best represent the data. Five microstate maps explaining 80.44% of the NT and 78.44% of the ASD data were found. The ASD group was found to have atypical parameters of microstate A, C, D, and E. Of note, all parameters of microstate C in the ASD group were found to be significantly less than NT. While parameters of microstate D, and E were also found to significantly correlate with subscales of the Ritvo Autism Asperger Diagnostic Scale - Revised (RAADS-R), these findings did not survive a Bonferroni Correction. These findings, in combination with previous findings, highlight the potential clinical utility of EEG microstates and indicate their potential value as a neurophysiologic marker that can be further studied.

Prevalence of Psychotropic Medication Use and Psychotropic Polypharmacy in Autistic Adults With or Without Intellectual Disability.

The aim of this study was to compare the rates of psychotropic medication use and psychotropic polypharmacy between autistic adults with and without intellectual disability (ID) and to examine factors associated with psychotropic medication use and psychotropic polypharmacy in autistic adults, stratified by the presence of ID. We conducted a retrospective medical chart review of outpatients with an autism diagnosis aged 18 years and older. The rates of psychotropic medication use and psychotropic polypharmacy were compared between autistic adults with and without ID. Subsequently, logistic regression analyses were performed to identify factors associated with psychotropic medication use and psychotropic polypharmacy in autistic adults with ID and those without ID, respectively. The rates of prevalence of psychotropic medication use and polypharmacy were significantly higher in participants with ID than those without ID (78.6% vs. 58.8% and 49.3% vs. 31.2%; p-values < 0.05). Age, gender, race, residence, presence of mood disorders, presence of schizophrenia, absence of anxiety disorder, number of psychiatric comorbidities, and presence of behaviors that challenge were significantly associated with these outcomes, depending on the presence/absence of ID. The need to optimize pharmacotherapy in autistic adults, stratifying by the presence of ID, is highlighted.

Assessing for autism in adult psychiatry.

This editorial discusses a study by Nyrenius and colleagues in which they investigated rates of co-occurring psychiatric conditions and functioning in a population of adults referred to a Swedish psychiatric out-patient clinic, comparing those meeting DSM-5 diagnostic criteria for autism with their non-autistic peers.

Psychiatric manifestations of Kleefstra syndrome: a case report.

Background: Kleefstra syndrome is a rare genetic condition, which affects at least 1 in 120,000 individuals who have a neurodevelopmental disorder, characterized by the core clinical phenotype of intellectual disability, hypotonia, severe speech delay, and distinct facial characteristics with additional clinical features including sleep disturbance, overweight, psychiatric disorders, and autism spectrum disorder. To date, a limited number of case reports of Kleefstra syndrome with psychiatric manifestations have been reported. Case presentation: We reported a case of a 35-year-old male diagnosed with Kleefstra syndrome, who also had diagnoses of autism spectrum disorder and moderate to severe intellectual disability. He exhibited various psychiatric manifestations, including temporarily manic-like symptoms, excessive eating/overweight, addictive/gambling behaviors, inappropriate and unsafe internet use, sleep disturbance, rigid routines, and behaviors that challenged in the form of meltdowns. These symptoms were eventually relatively successfully managed with a combination of non-pharmacological and pharmacological treatments. Conclusion: To our knowledge, there is only a limited number of case reports that detail patients with Kleefstra syndrome exhibiting various psychiatric manifestations. Our report adds further knowledge to the paucity of literature and highlights the effectiveness of a combination of non-pharmacological and pharmacological treatments for behavioral/psychiatric difficulties in Kleefstra syndrome.

Nabilone treatment for severe behavioral problems in adults with intellectual and developmental disabilities: Protocol for a phase I open-label clinical trial.

Severe behavioral problems (SBPs) are common contributors to morbidity and reduced quality of life for adults with intellectual and developmental disabilities (IDD) and their families. Current medications for SBPs show equivocal effectiveness and are associated with a high risk of side effects. New and safe treatments are urgently needed. While preliminary studies suggest that medical cannabinoids, particularly the synthetic cannabinoid nabilone, are plausible treatment options for SBPs in adults with IDD, data on the tolerability, safety and efficacy of nabilone in this population has never been investigated. Thus, we propose this first-ever Phase I pre-pilot open-label clinical trial to obtain preliminary data on the adherence, tolerability and safety profiles of nabilone in adults with IDD, and explore changes in SBPs pre- to post-treatment. We hypothesize that nabilone has favorable tolerability and safety profile for adults with IDD. The preliminary results will inform the next-stage pilot randomized controlled trials, followed by fully powered clinical trials eventually. This research helps fill the evidence gap in the use of cannabinoids in individuals with IDD to meet the needs of patients, families, and service providers.

Roadblocks and detours on pathways to a clinical diagnosis of autism for girls and women: A qualitative secondary analysis.

BACKGROUND: Autism is not always considered for girls and women until later along their clinical diagnostic pathways. Misdiagnosis or late diagnosis can pose significant disadvantages with respect to accessing timely health and autism-related services and supports. Understanding what contributes to roadblocks and detours along clinical pathways to an autism diagnosis can shed light on missed opportunities for earlier recognition. OBJECTIVE: Our objective was to examine what contributed to roadblocks, detours, and missed opportunities for earlier recognition and clinical diagnosis of autism for girls and women. DESIGN: We conducted a qualitative secondary analysis using data from a Canadian primary study that examined the health and healthcare experiences of autistic girls and women through interviews and focus groups. METHODS: Transcript data of 22 girls and women clinically diagnosed with autism and 15 parents were analysed, drawing on reflexive thematic analysis procedures. Techniques included coding data both inductively based on descriptions of roadblocks and detours and deductively based on conceptualizations of sex and gender. Patterns of ideas were categorized into themes and the 'story' of each theme was refined through writing and discussing analytic memos, reflecting on sex and gender assumptions, and creating a visual map of clinical pathways. RESULTS: Contributing factors to roadblocks, detours, and missed opportunities for earlier recognition and diagnosis were categorized as follows: (1) age of pre-diagnosis 'red flags' and 'signals'; (2) 'non-autism' mental health diagnoses first; (3) narrow understandings of autism based on male stereotypes; and (4) unavailable and unaffordable diagnostic services. CONCLUSION: Professionals providing developmental, mental health, educational, and/or employment supports can be more attuned to nuanced autism presentations. Research in collaboration with autistic girls and women and their childhood caregivers can help to identify examples of nuanced autistic features and how context plays a role in how these are experienced and navigated.

Machine learning approaches for electroencephalography and magnetoencephalography analyses in autism spectrum disorder: A systematic review.

There are growing application of machine learning models to study the intricacies of non-linear and non-stationary characteristics of electroencephalography (EEG) and magnetoencephalography (MEG) data in neurobiologically complex and heterogeneous conditions such as autism spectrum disorder (ASD). Such tools have potential diagnostic applications, and given the highly heterogeneous presentation of ASD, might prove fruitful in early detection and therefore could facilitate very early intervention. We conducted a systematic review (PROSPERO ID#CRD42021257438) by searching PubMed, EMBASE, and PsychINFO for machine learning approaches for EEG and MEG analyses in ASD. Thirty-nine studies were identified, of which the majority (18) used support vector machines for classification; other successful methods included deep learning. Thirty-seven studies were found to employ EEG and two were found to employ MEG. This systematic review indicate that machine learning methods can be used to classify ASD, predict ASD diagnosis in high-risk infants as early as 3 months of age, predict ASD symptom severity, and classify states of cognition in ASD with high accuracy. Replication studies testing validity, reproducibility and generalizability in tandem with randomized controlled trials in ASD populations will likely benefit the field.

Addressing Metabolic Comorbidity in Individuals With Intellectual and Developmental Disability on Antipsychotics: A Clinical Case Series.

PURPOSE/BACKGROUND: Individuals with intellectual and developmental disabilities (IDDs) are at increased risk for serious metabolic comorbidities, which is further exacerbated by the high rate of antipsychotic use in this population. There is currently a lack of literature on effective treatment options for antipsychotic-induced weight gain and metabolic abnormalities in IDD. This case series reports on the clinical use of metformin in patients with IDD on antipsychotics. METHODS/PROCEDURES: We conducted a retrospective review of patients in a novel clinical service at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada for adults with IDD experiencing antipsychotic-related weight gain and other metabolic aberrations. Charts were reviewed for weight and other metabolic outcome measures before and after commencing metformin treatment. FINDINGS/RESULTS: In 11 patients referred to this clinic, the mean weight loss while on metformin treatment was 11.1 kg, with over 50% of the sample achieving clinically meaningful weight loss of >7%. Additional adaptive changes were observed for fasting glucose, glycated hemoglobin, triglyceride, and high-density lipoprotein cholesterol levels. IMPLICATIONS/CONCLUSIONS: In line with its use in severe mental illness, metformin may be a safe, effective, and accessible treatment option for patients with IDD experiencing metabolic adverse effects of antipsychotic medication. Further research and randomized controlled trials are needed to examine the efficacy of metformin in this population.

Resting state electroencephalography microstates in autism spectrum disorder: A mini-review.

Atypical spatial organization and temporal characteristics, found via resting state electroencephalography (EEG) microstate analysis, have been associated with psychiatric disorders but these temporal and spatial parameters are less known in autism spectrum disorder (ASD). EEG microstates reflect a short time period of stable scalp potential topography. These canonical microstates (i.e., A, B, C, and D) and more are identified by their unique topographic map, mean duration, fraction of time covered, frequency of occurrence and global explained variance percentage; a measure of how well topographical maps represent EEG data. We reviewed the current literature for resting state microstate analysis in ASD and identified eight publications. This current review indicates there is significant alterations in microstate parameters in ASD populations as compared to typically developing (TD) populations. Microstate parameters were also found to change in relation to specific cognitive processes. However, as microstate parameters are found to be changed by cognitive states, the differently acquired data (e.g., eyes closed or open) resting state EEG are likely to produce disparate results. We also review the current understanding of EEG sources of microstates and the underlying brain networks.

Motor cortical plasticity in adolescents with early onset schizophrenia: A TMS-EMG study assessing the perturbation effect of intermittent and continuous theta burst stimulation.

BACKGROUND: Neuroplasticity in adolescents is distinct from that of adults. Literature pertaining to neuroplasticity in schizophrenia is limited to adult populations. AIM: We aimed to assess baseline (or resting) cortical excitability and cortical plasticity in adolescents with schizophrenia using the transcranial magnetic stimulation-electromyography (TMS-EMG) protocol. METHODS: Twenty adolescent cases with schizophrenia and 20 age and gender matched healthy controls were studied using a crossover design. Single pulse TMS elicited resting motor threshold (RMT) and motor evoked potentials (MEPs) were assessed. Cortical plasticity was determined by tracking MEPs after a single session continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) up to 120 min at 12 intervals. RESULTS: Baseline (or resting) cortical excitability was found to be significantly lower in cases compared with controls. Response patterns to cTBS and iTBS were similar between the crossover. While cTBS led to inhibitory response, iTBS had an excitatory effect in both the groups. In the cases, while cTBS led to significantly greater initial inhibitory response, iTBS led to significantly lower excitatory response, compared with controls. The time taken to return to baseline excitability was significantly longer after receiving cTBS for cases, compared with controls. CONCLUSIONS: iTBS and cTBS lead to excitatory and inhibitory response, representing classical long-term depression and long-term potentiation effects, respectively, in both cases and controls. We conclude that adolescents with schizophrenia have significantly lower baseline (resting) cortical excitability as well as significantly greater inhibitory plasticity; excitatory plasticity is significantly lower.

The metabolic adverse effects of antipsychotic use in individuals with intellectual and/or developmental disability: A systematic review and meta-analysis.

OBJECTIVE: Individuals with intellectual and/or developmental disability (IDD) are often prescribed antipsychotics (APs). However, despite their known propensity to cause metabolic adverse effects, including weight gain, diabetes, and increased risk of cardiovascular events, there is currently a limited body of literature describing the metabolic consequences of AP use in this population. METHODS: We searched MEDLINE, EMBASE, PsychINFO, CENTRAL, and CINAHL databases to identify all randomized trials that reported on the metabolic effects of APs in individuals with IDD. Random effects meta-analyses were used to examine weight gain as both a continuous and dichotomous outcome. RESULTS: Eighteen randomized trials met our inclusion criteria with a total of 1376 patients across a variety of IDDs. AP use was associated with significantly greater weight gain compared with placebo (Continuous: mean difference = 1.10 kg, [0.79, 1.40], p < 0.00001, I2  = 54%; Dichotomous: odds ratio = 3.94, [2.15, 7.23], p < 0.00001, I2  = 0). Sub-group analysis revealed no significant effect of AP type. Data regarding the effects of APs on other metabolic outcomes were limited. CONCLUSION: This review (PROSPERO # CRD42021255558) demonstrates that AP use is associated with significant weight gain among patients with IDD. Concerningly, most reported studies were in children and adolescents, which sets up an already vulnerable population for adverse medical sequalae at an early age. There was also a lack of long-term studies in adults with IDD. Further studies are required to better understand how AP use affects metabolic parameters in this group of individuals.

NAA/Glu Ratio Associated with Suicidal Ideation in Pilot Sample of Autistic Youth and Young Adults.

Suicidality is increased in autism spectrum disorder (ASD), yet effective interventions are lacking. Developing biologically based approaches for preventing and treating suicidality in ASD hinges on the identification of biomarkers of suicidal ideation (SI). Here, we assessed magnetic resonance spectroscopy (MRS) markers of glutamatergic neurotransmission in ASD youth and young adults. Twenty-eight ASD participants (16-33 years) underwent 1H-MRS, and metabolites were quantified using LCModel. N-acetylaspartate (NAA), glutamate (Glu), and the NAA/Glu ratio from the left dorsolateral prefrontal cortex were compared between ASD SI+ (n = 13) and ASD SI- (n = 15) participants. We found that ASD SI+ participants had a higher NAA/Glu ratio compared ASD SI- participants. The NAA/Glu ratio also predicted SI and significantly discriminated between ASD SI+/SI- participants. All analyses including NAA and Glu alone were non-significant. Here, we provide preliminary evidence for the importance of NAA/Glu in ASD with SI, with implications for biomarker discovery. Further mechanistic research into risk and interventional approaches to address SI in ASD are needed.

Cross-frequency coupling in psychiatric disorders: A systematic review.

Cross-frequency coupling (CFC), an electrophysiologically derived measure of oscillatory coupling in the brain, is believed to play a critical role in neuronal computation, learning and communication. It has received much recent attention in the study of both health and disease. We searched for literature that studied CFC during resting state and task-related activities during electroencephalography and magnetoencephalography in psychiatric disorders. Thirty-eight studies were identified, which included attention-deficit hyperactivity disorder, Alzheimer's dementia, autism spectrum disorder, bipolar disorder, depression, obsessive compulsive disorder, social anxiety disorder and schizophrenia. The systematic review was registered with PROSPERO (ID#CRD42021224188). The current review indicates measurable differences exist between CFC in disease states vs. healthy controls. There was variance in CFC at different regions of the brain within the same psychiatric disorders, perhaps this could be explained by the mechanisms and functionality of CFC. There was heterogeneity in methodologies used, which may lead to spurious CFC analyses. Going forward, standardized methodologies need to be established and utilized in further research to understand the neuropathophysiology associated with psychiatric disorders.

Assessing and stabilizing atypical plasticity in autism spectrum disorder using rTMS: Results from a proof-of-principle study.

OBJECTIVES: Emerging evidence implicates atypical plasticity in the neurophysiology of autism spectrum disorder (ASD). Specifically, autistic people demonstrated hyperplasticity in response to theta-burst stimulation (TBS). We hypothesized that autistic adults would display hyperplasticity to TBS and that repetitive transcranial magnetic stimulation (rTMS) - which potentiates brain inhibitory mechanisms - would 'stabilize' hyperplasticity. METHODS: Using a randomized, cross-over design, plasticity was assessed using TBS in the left motor cortex (M1) in 31 autistic adults and 30 sex-, intelligence quotient-, and age-matched controls. Autistic adults (n = 29) were further randomized (1:1) to receive a single session of active (n = 14) or sham (n = 15) rTMS (6000 pulses at 20 Hz) over left M1 and plasticity was reassessed on the next day following rTMS. RESULTS: Both long-term potentiation (LTP) and long-term depression (LTD) were significantly increased in the ASD group, indicating hyperplasticity. Active, but not sham rTMS, attenuated LTD in autistic adults. CONCLUSIONS: We provided further evidence for the presence of brain hyperplasticity in ASD. To our knowledge, this is the first study to show preliminary evidence that an excessive LTD in ASD can be 'stabilized' using rTMS. Such 'stabilizing' effect of rTMS on LTP was not observed, likely due to small sample size or a more specific 'attenuating' effect of rTMS on LTD, compared to LTP. SIGNIFICANCE: These findings indicate atypical brain inhibitory mechanisms behind hyperplasticity in ASD. Utilizing a larger sample, future replication studies could investigate therapeutic opportunities of 'mechanism-driven' rTMS.

Modulation of Dorsolateral Prefrontal Cortex Glutamate/Glutamine Levels Following Repetitive Transcranial Magnetic Stimulation in Young Adults With Autism.

Altered excitatory and inhibitory neurotransmission has been implicated in autism spectrum disorder (ASD). Interventions using repetitive transcranial magnetic stimulation (rTMS) to enhance or inhibit cortical excitability are under study for various targets, though the mechanistic effects of rTMS have yet to be examined in ASD. Here, we examined whether an excitatory rTMS treatment course modulates glutamatergic (Glx) or γ-aminobutyric acid (GABA) metabolite levels in emerging adults with ASD. Twenty-eight participants with ASD and executive function impairment [23.3 ± 4.69 years; seven-female] underwent two magnetic resonance spectroscopy (MRS) scans of the left dorsolateral prefrontal cortex (DLPFC). MRS scans were acquired before and after participants with ASD were randomized to receive a 20-session course of active or sham rTMS to the DLPFC. Baseline MRS data was available for 19 typically developing controls [23.8 ± 4.47 years; six-female]. Metabolite levels for Glx and GABA+ were compared between ASD and control groups, at baseline, and metabolite level change, pre-to-post-rTMS treatment, was compared in ASD participants that underwent active vs. sham rTMS. Absolute change in Glx was greater in the active vs. sham-rTMS group [F (1, 19) = 6.54, p = 0.02], though the absolute change in GABA+ did not differ between groups. We also examined how baseline metabolite levels related to pre/post-rTMS metabolite level change, in the active vs. sham groups. rTMS group moderated the relation between baseline Glx and pre-to-post-rTMS Glx change, such that baseline Glx predicted Glx change in the active-rTMS group only [b = 1.52, SE = 0.32, t (18) = 4.74, p < 0.001]; Glx levels increased when baseline levels were lower, and decreased when baseline levels were higher. Our results indicate that an interventional course of excitatory rTMS to the DLPFC may modulate local Glx levels in emerging adults with ASD, and align with prior reports of glutamatergic alterations following rTMS. Interventional studies that track glutamatergic markers may provide mechanistic insights into the therapeutic potential of rTMS in ASD. Clinical Trial Registration: Clinicaltrials.gov (ID: NCT02311751), https://clinicaltrials.gov/ct2/show/NCT02311751?term=ameis&rank=1; NCT02311751.

Pharmacogenomic Studies in Intellectual Disabilities and Autism Spectrum Disorder: A Systematic Review.

BACKGROUND: Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to treat aberrant behaviors and mood symptoms, frequently resulting in polypharmacy and drug-related adverse effects. Pharmacogenomic (PGx) studies with ASD and/or ID (ASD/ID) have been scarce despite the promise of optimizing treatment outcomes. We reviewed the literature on PGx studies with antipsychotics and antidepressants (e.g., treatment response and adverse effects) in ASD/ID. METHODS: We performed a systematic review using MEDLINE, Embase, and PsycINFO, including peer-reviewed original articles in English referring to PGx in the treatment of ASD/ID in any age groups (e.g., treatment response and adverse effects). RESULTS: A total of 28 PGx studies using mostly candidate gene approaches were identified across age groups. Notably, only 3 studies included adults with ASD/ID while the other 25 studies focused specifically on children/adolescents with ASD/ID. Twelve studies primarily investigated treatment response, of which 5 and 6 studies included patients treated with antipsychotics and antidepressants, respectively. Most interesting results for response were reported for 2 sets of candidate gene studies, namely: (1) The DRD3 Ser9Gly (rs6280) polymorphism was examined in patients treated with risperidone in 3 studies, 2 of which reported an association with risperidone treatment response and (2) the SLC6A4 5-HTTLPR polymorphism and treatment response to antidepressants which was investigated in 4 studies, 3 of which reported significant associations. In regard to side effects, 9 of 15 studies focused on hyperprolactinemia in patients treated with risperidone. Among them, 7 and 5 studies examined the impact of CYP2D6 and DRD2 Taq1A polymorphisms, respectively, yielding mostly negative study findings. CONCLUSIONS: There is limited data available on PGx in individuals with ASD/ID and in particular in adults. Given the potential for PGx testing in improving treatment outcomes, additional PGx studies for psychotropic treatment in ASD/ID across age groups are warranted.