Keypoint: Men have a higher ASD heritability estimate than women, even after controlling for birth year and parental age. The heritability of autism spectrum disorder (ASD) is higher among men than women, according to new research published in JAMA Psychiatry. Given these findings, study authors discuss the possible scenarios that may explain the observed sex differences in the genetic variance of ASD. It has been widely established that ASD is more prevalent among boys and men than girls and women. However, previous genetic research has not fully elucidated estimates of ASD heritability by sex using a large, population-based database. To this aim, investigators conducted a population-based familial heritability analysis using Swedish national register data. The investigators identified non-twin siblings and cousins born in Sweden between January 1, 1985, and December 31, 1998 and followed up all individuals until they reached 19 years of age to optimize detection of ASD diagnoses. International Classification of Diseases (ICD) codes were used to confirm ASD diagnoses from specialist care or inpatient treatment. The primary outcome of interest was an ASD heritability estimation a result of sex-specific additive genetics, shared environmental effects, and a common residual term. The investigators included 1,047,649 individuals in 456,832 families for analysis, 48.62% of which were women (n=509,366). By 19 years of age, 12,226 individuals (1.17%) were diagnosed with ASD, including 8128 men (1.51%) and 4098 women (0.80%). The investigators observed a higher cumulative rate of ASD diagnoses for men compared with women. Additionally, ASD diagnoses were higher among individuals born between 1995 and 1998 (n=5327; 2.36%) relative to those born between 1985 and 1989 (n=1891; 0.46%). For all statistic models, the shared environmental contributions to ASD heritability were close to 0 and not statistically significant, suggesting that the sex differences in ASD prevalence are instead due to genetic variance. In heritability estimates, overall autism heritability was estimated at 82.6% (95% CI, 78.7%-86.4%) after controlling for birth year and parental age. However, sex-specific heritability was 87.0% for men (95% CI, 81.4%-92.6%) and 75.7% for women (95% CI, 68.4%-83.1%), resulting in an 11.3% (95% CI, 1.0%-21.6%) difference. Although researchers are unable to definitively determine the underlying reasons for these sex differences, the study authors posit that the greater prevalence of ASD among men may be due to additive genetic sources or an increased vulnerability to the same genetic contributions. The present findings indicate a modest, but statistically significant, difference in autism heritability between men and women. The investigators concluded, “The skewed sex ratio in ASD may, partly, be explained by differences in genetic variance between sexes.” These results may be limited, as the investigators included only the first 3 siblings or cousins born from each family and the analyses rely on untestable assumptions about the independence of case ascertainment and the separation of genetic and environmental factors. Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of author disclosures. Note: This article originally appeared on Psychiatry Advisor

Keypoint: Although most effective for symptoms, medications are also tied to adverse effects. HealthDay News — Medication therapy remains an important treatment for children with attention-deficit/hyperactivity disorder (ADHD), according to a review published online March 25 in Pediatrics. Bradley S. Peterson, M.D., from the Institute for the Developing Mind at Children’s Hospital Los Angeles, and colleagues conducted a systematic literature review to identify effective treatment of ADHD. Based on 312 included studies, treatments were classified as medication, psychosocial interventions, parent support, nutrition and supplements, neurofeedback, neurostimulation, physical exercise, complementary medicine, school interventions, and provider approaches. ADHD symptoms were improved with several treatments, although medications had the strongest evidence base for improving outcomes, including disruptive behaviors and broadband measures. However, medications were associated with adverse events. “The paucity of head-to-head studies comparing treatments precludes research-based recommendations regarding which is likely to be most helpful and which should be tried first, and decisions need to be based on clinical considerations and patient preferences,” the authors write. Note: This article originally appeared on Psychiatry Advisor

Keypoint: A third of adults with ADHD experience some form of work disability. Attention-deficit/hyperactivity disorder (ADHD) medication use is associated with a lower risk for hospitalizations – both psychiatric and nonpsychiatric – and suicidal behavior, according to study results published in JAMA Network Open. Although pharmacotherapy is the primary treatment recommendation for ADHD, there are ongoing concerns about its long-term effectiveness and safety, particularly regarding its potential effect on cardiovascular health and the risk of inducing psychosis. To this aim, researchers conducted a prospective population-based cohort study to evaluate the relationship between ADHD medication use and both hospitalization outcomes and work disability. The researchers used data from Swedish national registers to identify individuals 16 to 65 years of age who were residing in Sweden and diagnosed with ADHD between January 2006 and December 2021. The primary exposure was ADHD medication use, confirmed via Anatomical Therapeutic Chemical codes. The primary outcomes of interest included psychiatric hospitalizations, attempts of suicide or suicide-related deaths, hospitalizations for nonpsychiatric reasons, and instances of work disability (defined as instances of sickness absence lasting over 14 days or the issuance of a disability pension of any level). Both ADHD diagnoses and outcomes were verified using International Classification of Diseases (ICD) codes. A total of 221,714 individuals were included for analysis. On average, individuals were 25 years of age at baseline and 54.6% (n=120,968) were boys/men. Over half of the individuals (56.5%) presented with psychiatric comorbidities, which primarily consisted of anxiety or stress-related disorders (24%) and depression or bipolar disorders (19.5%). The majority of participants (61%) possessed a low level of education, though this was largely attributed to the group’s relatively young age. The researchers found that methylphenidate was the most commonly used ADHD medication, as it was utilized by 68.5% (n=151,837) of individuals. Lisdexamphetamine was the second most common (35.2%; n=78,106), followed by polytherapy (27.1%; n=60,102) and atomoxetine (15.6%; n=34,631). Over the 15-year study period, 25.6% (n=56,704) of individuals experienced psychiatric hospitalization. The risk for psychiatric hospitalization was significantly lower among individuals using amphetamine (adjusted hazard ratio [aHR], 0.74; 95% CI, 0.61-0.90; P =.003), lisdexamphetamine (aHR, 0.80; 95% CI, 0.78-0.82; P <.001), ADHD polytherapy (aHR, 0.85; 95% CI, 0.82-0.88; P <.001), dexamphetamine (aHR, 0.88; 95% CI, 0.83-0.94; P <.001), and methylphenidate (aHR, 0.93; 95% CI, 0.92-0.95; P <.001), relative to periods when ADHD medications were not used. The risk for suicidal behavior was also significantly lower among those using dexamphetamine (aHR, 0.69; 95% CI, 0.53-0.89; P =.004), lisdexamphetamine (aHR, 0.76; 95% CI, 0.68-0.84; P <.001), ADHD polytherapy (aHR, 0.85; 95% CI, 0.74-0.98; P =.02) and methylphenidate (aHR, 0.92; 95% CI, 0.86-0.98; P =.007). The ADHD medications associated with a lower risk for nonpsychiatric hospitalizations included amphetamine (aHR, 0.62; 95% CI, 0.45-0.84; P =.002), lisdexamphetamine (aHR, 0.64; 95% CI, 0.61-0.67; P <.001), polytherapy (aHR, 0.67; 95% CI, 0.62-0.72; P <.001), dexamphetamine (aHR, 0.72; 95% CI, 0.65-0.80; P <.001), methylphenidate (aHR, 0.80; 95% CI, 0.78-0.82; P <.001), and atomoxetine (aHR, 0.84; 95% CI, 0.78-0.90; P <.001). Additionally, the researchers evaluated work disability among a subset of 189,380 participants and found that 30% faced work disability over a 6-year follow-up period. Atomoxetine was associated with a marginally lower risk for work disability (aHR, 0.89; 95% CI, 0.82-0.97), particularly in adolescents and young adults aged 16 to 29 years (aHR, 0.82; 95% CI, 0.73-0.92). Conversely, the use of polytherapy was associated with an increased risk for work disability (aHR, 1.12; 95% CI, 1.05-1.20). “Considering the high prevalence of psychiatric comorbidity in persons with ADHD, these results suggest that ADHD medication use can reduce morbidity in adolescents and adults with ADHD,” the researchers concluded. Study limitations include limited adjustment for psychiatric conditions, incomplete clinical data due to the reliance on nationwide registers, and a lack of accurate data regarding nonpharmacological treatments, work disability (beyond the study definition), and suicide attempts that did not lead to hospital admission. Note: This article originally appeared on Psychiatry Advisor

Autism spectrum disorder (ASD) is a complex developmental condition involving persistent challenges with social communication, restricted interests, and repetitive behavior. While autism is considered a lifelong disorder, the degree of impairment in functioning because of these challenges varies between individuals with autism. Diagnosis of Autism Spectrum Disorders Early signs of this disorder can be noticed by parents/caregivers or pediatricians before a child reaches one year of age. However, symptoms typically become more consistently visible by the time a child is 2 or 3 years old. In some cases, the functional impairment related to autism may be mild and not apparent until the child starts school, after which their deficits may be pronounced when amongst their peers. Social communication deficits may include: Decreased sharing of interests with others Difficulty appreciating their own & others' emotions Aversion to maintaining eye contact Lack of proficiency with use of non-verbal gestures Stilted or scripted speech Interpreting abstract ideas literally Difficulty making friends or keeping them Restricted interests and repetitive behaviors may include: Inflexibility of behavior, extreme difficulty coping with change Being overly focused on niche subjects to the exclusion of others Expecting others to be equally interested in those subjects Difficulty tolerating changes in routine and new experiences Sensory hypersensitivity, e.g., aversion to loud noises Stereotypical movements such as hand flapping, rocking, spinning Arranging things, often toys, in a very particular manner Parent/caregiver/teacher concerns about the child's behavior should lead to a specialized evaluation by a developmental pediatrician, pediatric psychologist, child neurologist and/or a child & adolescent psychiatrist. This evaluation involves interviewing the parent/caregiver, observing, and interacting with the child in a structured manner, and sometimes conducting additional tests to rule out other disorders. In some ambiguous cases, the diagnosis of autism may be deferred, but otherwise an early diagnosis can greatly improve a child's functioning by providing the family early access to supportive resources in the community. The first step is seeking an evaluation. Most parents start with their pediatrician who is checking on developmental milestones. If your child is under the age of 3 years, you can obtain an evaluation through your local early intervention system. If your child is over the age of 3, you can get an evaluation through your local school (even if your child does not go there). Risk Factors The current science suggests that several genetic factors may increase the risk of autism in a complex manner. Having certain specific genetic conditions such as Fragile X Syndrome and Tuberous Sclerosis has been identified as conferring a particularly increased risk for being diagnosed with autism. Certain medications, such as valproic acid and thalidomide, when taken during pregnancy, have been linked with a higher risk of autism as well. (CDC) Having a sibling with autism also increases the likelihood of a child being diagnosed with autism. Parents being older at the time of pregnancy is additionally linked with greater risk of autism. Contrary to popular belief, vaccines have not been shown to increase the likelihood of an autism diagnosis, and race, ethnicity or socioeconomic status does not seem to have a link either. Male children tend to be diagnosed with autism more often than those assigned female sex at birth, albeit this ratio is changing over time. Treatment While there is no "cure" for autism, there are several effective interventions that can improve a child's functioning: Applied behavioral analysis: It involves systematic study of the child's functional challenges, which is used to create a structured behavioral plan for improving their adaptive skills and decreasing inappropriate behavior Social skills training: Done in group or individual settings, this intervention helps children with autism improve their ability to navigate social situations Speech & language therapy: It can improve the child's speech patterns and understanding of language Occupational therapy: This address adaptive skills deficits with activities of daily living, as well as problems with handwriting Parent management training: Parents learn effective ways of responding to problematic behavior and encouraging appropriate behavior in their child. Parent support groups help parents cope with the stressors of raising a child with autism Special education services: Under an Individual Education Plan provided by their school, which accommodates for their social communication deficits, restricted interests, and repetitive behaviors, children with autism can achieve their fullest potential academically. This includes special day classes for very young children to address language, social, and life skills. Treating co-occurring conditions: Children with autism experience insomnia, anxiety, and depression more often than peers without autism. They also more often have ADHD. Children with autism may have intellectual disability and this needs to be addressed. The impact of these conditions can be reduced with the proper services, which include all of the above, in addition psychotherapy and/or medication treatment Medication: A child psychiatrist can evaluate for co-morbid depression, anxiety, and impulsivity. If appropriate medications can be helpful. For example, autism-related irritability can be reduced by medications such as aripiprazole and risperidone (the two medications approved by the Food and Drug Administration for irritability associated with autism), prescribed judiciously by a knowledgeable clinician in collaboration with the child's parents. Several complementary and alternative interventions involving special diets and supplements have been tried over the years by parents/caregivers seeking ways to help their child with autism function better. To date compelling evidence has not been found to clearly recommend any such specific interventions. Research into these types of interventions continues, and parents/caregivers interested in them should discuss them with their child's treating clinician. Tips For Parents Learn as much as possible about autism spectrum disorder Provide consistent structure and routine Connect with other parents of children with autism Seek professional help for specific concerns Take time for yourself and other family members Having a child with autism affects the whole family. It can be stressful, time-consuming and expensive. Paying attention to the physical and emotional health of the whole family is important. Many national and local advocacy organizations provide information, resources and support to individuals with autism spectrum disorder and their families. A few are listed in the Resources section. Related Conditions Attention-deficit/hyperactivity disorder Social communication disorder Specific learning disorder Intellectual disability Source: American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Washington, DC: American Psychiatric Association Publishing.CDC. (2021, April 29). Autism Spectrum Disorder (ASD). Retrieved August 19, 2021, from: https://www.cdc.gov/ncbddd/autism/index.html

At a Glance Autism is a neurodevelopmental disorder that affects how people interact, communicate, and learn. Making early autism screening part of routine health care helps connect families to support and services as early as possible. Despite American Academy of Pediatrics guidelines, only a small fraction of pediatricians reported screening for autism at well-child visits. NIMH-supported efforts to close the gap between science and practice have yielded key insights into effective strategies for expanding early autism screening. Researchers are identifying new tools for detection, new models for delivering services, and new strategies for embedding early autism screening and rapid referral into routine health care. As many parents of young children know all too well, visits to the pediatrician typically involve answering a series of questions. Health care providers may ask about the child’s eating and sleeping habits or about their progress toward walking, talking, and many other developmental milestones. Increasingly, they’re also asking questions that could help identify early signs of autism. Autism is a neurodevelopmental disorder that affects how people interact, communicate, behave, and learn. It is known as a “spectrum” disorder because there is wide variation in the type and severity of symptoms people experience. Today, thanks to research focused on embedding routine screening in well-baby checkups, the early signs of autism can be identified in children as young as 12–14 months. These efforts, many supported by the National Institute of Mental Health (NIMH), show that making early autism screening part of routine health care can have a significant impact on children and families, helping connect them to support and services as early as possible. “This progress wasn’t inevitable or linear,” explains Lisa Gilotty, Ph.D., Chief of the Research Program on Autism Spectrum Disorders in the Division of Translational Research at NIMH. “Rather, it’s part of an evolving story that reflects the persistent, collective efforts of researchers and clinicians working to translate science into practice.” Identifying the disconnect The modern concept of autism as a neurodevelopmental disorder first emerged in the 1940s and coalesced into a diagnostic label by the 1980s. Diagnostic criteria evolved over time and, by the early 2000s, clinicians had evidence-based tools they could use to identify children with autism as early as 36 months. At the same time, evidence suggested that parents may notice signs even earlier, in the child’s second year of life. “Reducing this gap—between observable signs and later identification and diagnosis—became an urgent target for researchers in the field,” said Dr. Gilotty. “The research clearly showed that kids who were identified early also had earlier access to supports and services, leading to better health and well-being over the long term.” Researcher Diana Robins, Ph.D. , then a doctoral student, wondered whether an evidence-based early screening tool might help close the gap. With support from NIMH , Robins and colleagues developed the Modified Autism Checklist for Toddlers (M-CHAT) , which they introduced in 2001. They aimed to provide pediatricians with a simple screening measure that could identify children showing signs of autism as early as 24 months. The science behind early screening continued to build and gain momentum over the next few years. By the mid-2000s, researchers were exploring the possibility of using various developmental screening tools—such as the Communication and Symbolic Behavior Scales, First Year Inventory, and Ages & Stages Questionnaires—to identify early signs of autism. A young adult working on a computer gear with the text “Adults on the autism spectrum can benefit from services and supports that improve health and well-being across the lifespan.” The link points to nimh.nih.gov/autism. The growing body of evidence did not go unnoticed. In 2006, the American Academy of Pediatrics (AAP) issued evidence-based guidelines recommending autism-specific screening for all children at the 18-month visit. In a later update, they recommended adding another autism-specific screening at the 24-month visit, recognizing that some children may start showing signs a bit later in development. To the research community, these new guidelines signified a huge step forward for science-based practice. But this sense of progress was soon dashed by reality. When researchers actually surveyed health care providers, they found that very few knew about or followed the AAP guidelines. For example, in a 2006 study , 82% of pediatricians reported screening for general developmental delays, but only 8% reported screening for autism. Most of the pediatricians said they weren’t familiar with autism-specific screening tools, and many also cited a lack of time as a significant barrier to screening. The disconnect between science and practice prompted concern in the research community. A series of conversations in scientific meetings and workshops led to a crystallizing moment for the staff at NIMH. “There was a period of several years in which researchers would go off and do unfunded work and then bring it back to these meetings and say, ‘This is what I've been working on,’” said Dr. Gilotty. “It was an impetus for those of us at NIMH to say, ‘We’re going to do something about this.’” Bridging the gap Gilotty worked with colleagues Beverly Pringle, Ph.D., and Denise Juliano-Bult, M.S.W., who were part of NIMH’s Division of Services and Intervention Research (DSIR) at the time, to synthesize several file drawers’ worth of different measures, meeting notes, and research papers and distill them into an NIMH funding announcement. The announcement, issued in 2013, focused on funding for autism services research in three critical age groups: toddlers , transition-age youth , and adults . NIMH ultimately funded five 5-year research projects that specifically examined screening and services in toddlers. The projects focused on interventions that emphasized early screening and connected children to further evaluation and services within the first two years of life. In 2014, Denise Pintello, Ph.D., M.S.W., assumed the role of Chief of the Child and Adolescent Research Program in DSIR. She directed the research portfolio that included these projects, which sparked an idea: “It was such an exciting opportunity to connect these researchers because the projects were all funded together as a cluster,” she said. “I thought, ‘Let’s encourage these exceptional researchers to work closely together.’” At NIMH’s invitation, the researchers on the projects united to form the ASD Pediatric, Early Detection, Engagement, and Services (ASD PEDS) Research Network. Although the ASD PEDS researchers were using different research approaches in a range of settings, coming together as a network allowed them to share knowledge and resources, analyze data across research sites, and publish their findings together . The researchers also worked together to identify ways that their data could help address noticeable gaps in the evidence base. Building on the evidence Together, the ASD PEDS studies have screened more than 109,000 children, yielding critical insights into the most effective strategies for expanding early autism screening. For example, an ASD PEDS study led by Karen Pierce, Ph.D. , showed the effectiveness of integrating screening, evaluation, and treatment (SET) in an approach called the Get SET Early model. Working with 203 pediatricians in San Diego County, California, Pierce and colleagues devised a standardized process that the providers could use to screen toddlers for autism at their 12-, 18-, and 24-month well-child visits. The researchers also developed a digital screening platform that scored the results automatically and gave clear guidelines for deciding when to refer a child for further evaluation. These improvements boosted the rate at which providers referred children for additional evaluation and sped up the transition from screening to evaluation and services. The study also showed that autism can be identified in children as young as 12–14 months old, several years earlier than the nationwide average of 4 years. This and other studies showed that incorporating universal early screening for autism into regular health care visits was not only feasible but effective. Working closely with health care providers allowed researchers to build trust with the providers and address their concerns. “There is this sense that if you sit down and really talk with pediatricians, you can bring them into the fold,” said Dr. Gilotty. “Once you get some key people, you get a few more and a few more, and then it becomes something that ‘everybody’ is doing.” Meeting the need At the same time, the ASD PEDS studies have also explored ways to reach families with young children outside of primary care settings. Numerous studies have shown that some families are much less likely to have access to early screening and evaluation, including non-English-speaking families, families with low household incomes, and families from certain racial and ethnic minority groups. “Screening is most effective when everyone who needs it has access to it,” said Dr. Pintello. “Addressing these disparities is a critical issue in the field and NIMH’s efforts have prioritized focusing on underserved families.” One way to accomplish this is to integrate standardized universal screening into systems that are already serving these families. For example, in one study, ASD PEDS investigators Alice Carter, Ph.D. , and Radley Christopher Sheldrick, Ph.D. , worked with the Massachusetts Department of Public Health to implement an evidence-based screening procedure at three federally funded early intervention sites. The researchers developed a multi-part screening and diagnosis process that included both clinicians and caregivers as key decision-makers. They hypothesized that this standardized process would minimize procedural variations across the early intervention sites and help to reduce existing disparities in ASD screening and diagnosis. The results suggested their hunch was correct. All three study sites showed an increase in the rate of autism diagnosis with the new procedure in place, compared with other intervention sites that served similar communities. Importantly, the standardized procedure seemed to address existing disparities in screening and diagnosis. The increased rate of diagnosis observed among Spanish-speaking families was more than double the increase observed among non-Spanish-speaking families. Looking to the future Researchers are continuing to explore the best ways to put existing evidence-based screening methods into practice. At the same time, NIMH is also focused on research that seeks to develop new and improved screening tools. Evidence from neuroimaging and eye tracking studies suggests that, although the age at which observable features of autism emerge does vary, subtle signs can be detected in the first year of life. NIMH is supporting a suite of projects that aim to validate screening tools that can be used to identify signs of autism before a child’s first birthday. “In other words, are there measures we can use to identify signs even before parents and clinicians begin to notice them?” explained Dr. Gilotty. “This is the critical question because the earlier kids are identified, the earlier they can be connected with support.” These projects leverage sophisticated digital tools to detect subtle patterns in infant behavior. For example, researchers are using technology to identify patterns in what infants look at, the vocalizations they make, and how they move. They’re using technology to examine synchrony in infant–caregiver interactions. And they’re developing digital screening tools that can be administered via telehealth platforms. The hope is that new tools identified and validated in this first stage will go on to be tested in large-scale, real-world contexts, reflecting a continuous pipeline of research that goes from science to practice. “As a result of targeted research funded by NIMH over the last 10 years, we are seeing new tools for detection, new models for delivering services, and new strategies for embedding early screening and rapid referral into routine health care,” said Dr. Pintello. “I feel like it’s just the beginning of the story—we are just now seeing the impact of bringing science-based tools and practices into the hands of health care providers. Over the next few years, we hope that ongoing efforts to bridge science and practice will help us meet the unique needs of children at the exact time that they need services.” Note: This article originally appeared on NIMH

Keypoint: The device is designed to transcutaneously deliver low-level electrical stimulation to the skin behind the ears. The Food and Drug Administration (FDA) has cleared Modius Stress, a transdermal, home-use neurostimulation device that is indicated to treat the symptoms of generalized anxiety disorder in adults aged 22 and older, when used for approximately 4 weeks. The device is designed to transcutaneously deliver low-level electrical stimulation to the skin behind the ears, over the mastoid processes, through 2 self-adhesive electrode pads. The treatment is delivered for a period of 30 minutes before bed; users can engage in other activities while using the device. The prescription device includes a Modius headset, 150 electrode pads (enough for approximately 3 months use), alcohol cleansing wipes, and a micro USB charging cable. According to the Company, the clearance was granted based on data from two phase 3 trials conducted by Ulster University in the UK and Ireland and the Indian Center of Neurophysiology in India. Both were randomized, double-blind, sham-controlled trials that included patients diagnosed with generalized anxiety disorder. In the UK study, participants were instructed to use their allocated devices for 30 minutes per day for a 4-week duration at home. Results showed more patients in the Modius Stress group achieved a 4 point or more reduction in Generalized Anxiety Disorder (GAD)-7 score from the baseline visit to the week 4 visit compared with the sham group (75% [27 out of 36] vs 51% [20 out of 39], respectively). The Modius Stress group had a reduction of 5.41 in GAD-7 score vs a reduction of 3.96 in the sham group. Similar results were seen in the India study, where participants were asked to complete 20 sessions (30 minute duration) approximately 3 to 5 times per week. More participants in the Modius Stress arm achieved a 4 point or more reduction in GAD-7 score from baseline to the follow-up visit compared with the sham group (97% [33 out of 34] vs 24% [6 out of 25], respectively). The Modius Stress group had a reduction of 7.44 in GAD-7 score vs a reduction of 2.23 in the sham group (mean difference, -5.21 [95 CI, -6.57, -3.85]; P <.0001). “GAD affects an estimated 6.8 million adults in the US, over 3% of the population, with women twice as likely to be affected as men, according to the American Depression and Anxiety Association,” said Dr Jason McKeown, CEO of Neurovalens. “Modius Stress is a noninvasive device that treats the underlying issue to improve the lives of patients.” Note: This article originally appeared on MPR

Antidepressants differ in improving symptoms and preventing relapse of major depressive disorder (MDD) over a 2-year period, according to a nation-wide cohort study1 in Denmark. The study, designed to emulate a randomized controlled trial (RCT), compared long-term response of 17 antidepressants within their respective pharmacologic classes. Lars Vedel Kessing, MD, of the Copenhagen Affective Disorder Research Center, Psychiatric Center Copenhagen, and colleagues point out that clinical trials of antidepressants are commonly conducted against placebo, with few comparing active agents and fewer extending beyond short-term assessment of acute effects. They reference a comprehensive, systematic review and meta-analysis2 of 522 trials comprising 21 different antidepressants that differentiated some by acute treatment response, but point out that the need remains for comparisons by long-term effect. "Although antidepressants also reduce relapse rates, there is no consensus on which antidepressants should be preferred as a first option for long-term use," Kessing and colleagues assert. The present study, the investigators describe, "presents for the first time systematic, population-based, nationwide data on comparative 2-year long-term response within 6 antidepressant drug classes and 17 different antidepressants in patients with a first diagnosis of MDD in psychiatric hospital settings." Differentiating Antidepressants by Long-Term Response The investigators accessed Danish national health care records from between 1995 and 2018 to identify 106,920 patients treated for a first diagnosis of a single depressive episode or recurrent depressive disorder who then obtained a prescribed antidepressant. The cohort excluded patients with additional mental health disorder diagnoses and those who initially obtained multiple prescriptions, or who had antidepressants or antipsychotics prescribed 1 and 5 years prior to the index diagnosis. The antidepressants were compared within pharmacologic classes, and within each to a reference medication. Sertraline was the reference in both the selective serotonin reuptake inhibitor (SSRI) and noradrenalin reuptake inhibitor (NARI) classes, following Danish National Board of Health guidelines associating sertraline with fewer drug interactions, less association with cardiac effects, and greater safety during breast feeding. Although 8 pharmacologic classes were identified, the comparative analysis was not conducted when the sample size was less than 100. Six classes were used in the final analysis—then excluding monoamine oxidase inhibitors (MAOIs) versus sertraline, as well as bupropion versus sertraline. In addition to the SSRI and NARI, the classes were serotonin and noradrenalin reuptake inhibitors (SNRIs), venlafaxine reference, adrenergic receptor inhibitors (NaSSAs), mirtazapine reference, tricyclic antidepressants (TCAs), amitriptyline reference, and “other,” with sertraline reference. The study's primary measure was non-response, defined as switch to or add-on of another antidepressant, an antipsychotic or lithium, or inpatient hospitalization for depression. The analyses yielded estimated risk, risk difference, and relative risk (RR) of non-response for each antidepressant against the corresponding reference during a 2-year follow-up. Kessing and colleagues report that within the SSRIS, there was no statistically significant difference in absolute or relative risk difference between citalopram and the reference sertraline—but that in comparison with sertraline, there was statistically significantly higher RR of non-response with fluoxetine (1.13 [95% CI 1.10-1.17]), paroxetine (1.06, 1.01-1.10), and escitalopram (1.22, 1.18-1.25). In other analyses: Sertraline ranked higher, with less risk of non-response, than reboxetine in the NARI class. Venlafaxine ranked higher than duloxetine in the SNRI class. Mirtazapine ranked higher than mianserin in the NaSSA class. Imipramine was not statistically different from amitriptyline, which ranked higher than nortriptyline, clomipramine, and dosulepin in the TCA class. Sertraline ranked higher than agomelatine and vortioxetine in the "other" class. Contrasting Antidepressant Assessments Kessing and colleagues contrast some findings with those from a previous comparison2 of antidepressants by meta-analysis of short-term trials—typically 8 weeks—conducted by Andrea Cipriani, MD, of the Department of Psychiatry at the University of Oxford, and colleagues. Cipriani's group found, for example, no statistically significant differences in odds ratios (OR) of response between sertraline and other SSRIs, or between sertraline and reboxetine, agomelatine, or vortioxetine. There was also no statistically significant difference between the TCAs amitriptyline and clomipramine. In addition to the principal differences in these studies of short- and long-term treatment durations, Kessing and colleagues point out that their "real-world," naturalistic, register-based data minimized selection bias as well as recall bias. They also note that the meta-analysis encountered variations between clinical trials in design and cohort criteria and had relatively low statistical power available for some of the comparisons. Cipriani discussed this latest comparison of antidepressants and its focus on longer-term treatment with Psychiatric Times®. According to Cipriani, the findings that antidepressants are not all created equal for the maintenance treatment of depression and that there are differences within the same drug class, "is in line with what we found for the acute treatment of depression in our previous network meta-analyses of randomized controlled trials." Although their meta-analysis of all RCTs, including antidepressants versus placebo, revealed few differences in rates of response, subsequent analysis of only the head-to-head comparative trials did reveal diversity in range of efficacy and dropout patterns. In that analysis, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were the most effective; and fluoxetine, fluvoxamine, reboxetine, and trazadone were the least efficacious. Cipriani commented on the differences between RCTs and "real world" observations as a basis for comparing efficacy of agents. A principal distinction, he pointed out, is that RCTs apply strict inclusion and exclusion criteria and are designed primarily to assess relative effects. "Some studies have aimed to explore and quantify potential differences in drug effects between RCTs and observational real-world studies for the treatment of depression with selected antidepressants—ie, venlafaxine and duloxetine," Cipriani noted. "Differences in effect sizes between these real-world studies and RCTs were found, but it remains unclear whether they were due to differences in study populations—selected in RCTs versus unselected in real-world studies—or due to other factors. This is relevant, as lack of representativeness might impact the generalizability of RCT findings to real-world populations, particularly when there are important differences in the distribution of effect modifiers between RCT and RW patient populations." Cipriani anticipates that additional studies will help overcome the dichotomy between observational and randomized data, and appreciates that both contribute complementary information that can advance treatment. "The big challenge now is to move from estimating average effects at population level to predicting which is the best outcome for each individual patient, so we can personalize treatment and move a step forward in the field of precision psychiatry," Cipriani said. Keypoint: This article originally appeared on Psychiatric Times

Keypoint: During COVID-19, adolescents with high ACEs benefitted from in-person schooling. Among adolescents with adverse childhood experiences (ACEs), in-person schooling and coping behaviors were associated with significantly higher mental well-being during the COVID-19 pandemic, according to study results published in JAMA Network Open. Adolescent mental health has significantly deteriorated globally. With the onset of the COVID-19 pandemic, adolescents experienced disruptions to school and social routines, contributing to heightened anxiety, depression, and suicidal ideation. Mental health was particularly affected among adolescents with ACEs. However, relatively little is known about the factors which improve well-being of adversity-exposed adolescents. To this aim, researchers conducted a cross-sectional study of survey data from the Adolescent Brain Cognitive Development (ABCD) study during the COVID-19 pandemic. Adolescents 11 to 15 years of age who completed the COVID Rapid Response Research surveys of the ABCD study were included for analysis. The primary exposures were in-person schooling and 8 coping behaviors, including taking care of one’s body, exercising, engaging in healthy behaviors, neighborhood social distance activity, taking breaks from news, connecting with others online or by phone, and engaging in hobbies. Overall, 4515 adolescents were included in the analysis. On average, participants were 13.3 (SD, 0.88) years of age, 51% were girls, and 61% were White. Of the total sample, 1159 participants did not have ACEs, 3124 had 1 to 3 ACEs, and 232 experienced 4 or more ACEs. The investigators found adolescents with high ACEs had a significantly great improvement in positive affect (PA) scores with in-person schooling (B=5.55; 95% CI, 2.08-9.01) relative to adolescents with low-to-intermediate ACEs (B=1.27; 95% CI, 0.27-2.27). Additionally, in-person schooling was associated with lower perceived stress (PS) among adolescents with higher ACEs (B= -1.48; 95% CI, -2.69 to -0.28). For coping behaviors, adolescents with high ACEs benefitted from taking care of one’s body (PA: B=4.02; 95% CI, 1.39-6.66 and PS: B= -0.92; 95% CI, -1.84 to 0.00), exercising (PA: B=3.19; 95% CI, 0.46-5.92 and PS: B= -1.41; 95% CI, -2.40 to -0.43), and engaging in healthy behaviors (PA: B=4.07; 95% CI, 1.28-6.84 and PS: B= -1.01; 95% CI, -1.98 to -0.05). The researchers stated, “Among adolescents who had experienced high ACEs, in-person schooling, taking care of the body (stretching, meditating, and deep breathing), exercise, and engaging in healthy behaviors (eating healthy and sleeping well) were all associated with higher PA and lower PS scores.” Study authors concluded, “[W]e recommend that future studies build on these findings so that clinic and policy guidelines, as well as parents and educators, may identify protective factors to promote health equity and improved mental health among these adolescents at high risk of poor outcomes.” Limitations of the study include the variable timing of exploratory and outcome measures, lack of validated clinical associations for PA and PS scores, potential bias in ACE score reporting, limited generalizability due to the sample composition, insufficient power for analyzing high ACE exposure groups, and inability to investigate causal inferences due to the cross-sectional, observational design. Note: This article originally appeared on Psychiatry Advisor

People with autism spectrum disorder (ASD) face numerous healthcare disparities relative to their peers without ASD, as individuals with ASD often have reduced access to high-quality health care and experience lower satisfaction with patient-provider communication. Recent studies have begun to shed light on the unique obstetric challenges that people with ASD may experience during the perinatal period, although research on the intersectional experience of autism and pregnancy remains limited to date. “This population of childbearing people are unique in that they face multiple challenges such as unmet healthcare needs, communication issues, and experience more barriers to receiving appropriate education,” said Patricia D. Suplee PhD, RNC-OB, FAAN, associate professor at Rutgers University School of Nursing in Camden, New Jersey. Unique Challenges of Autism and Pregnancy Along with the physical, emotional, and service-related challenges that are associated with pregnancy more generally, people with ASD often experience additional perinatal difficulties compared to neurotypical individuals, according to Megan Freeth, MSc, PhD, professor of neurodevelopmental psychology and director of research and innovation in the Department of Psychology at the University of Sheffield in the United Kingdom. In a 2023 survey-based study published in the Journal of Autism and Developmental Disorders, Hampton et al compared the perinatal experiences of 384 individuals with ASD and 492 individuals without ASD. They found that those with ASD reported lower satisfaction with health care during perinatal medical encounters and were more likely to feel overwhelmed by the sensory aspects of childbirth. Although providers should avoid making assumptions about a patient’s sensory experience, Prof Freeth explained that many people with ASD can experience intense challenges with the sensory aspects of pregnancy.7 For example, they may have an extremely heightened sense of smell and taste, sensitivity to touch, or sensitivity to the lights and sounds of clinical environments. “For some, sensory experiences during birthing can result in feeling so overwhelmed that a disconnect from reality can be experienced,” she said. “Autistic people tend not to express emotional reactions in the same way as non-autistic people, and during birthing this can lead to clinical staff not realizing the severity of stress levels and can also exacerbate miscommunication, resulting in the autistic person not understanding their options and not having their preferences understood” by clinicians. Studies have also indicated that communication challenges could make it harder for individuals with ASD to ask providers for help during labor and the postpartum period. “Some autistic individuals may be unsure how to answer open-ended questions or convey how they are feeling during labor,” said Jane Donovan, PhD, RNC-MNN, assistant clinical professor at Drexel University College of Nursing and Health Professions in Philadelphia, Pennsylvania. “Additionally, during childbirth, there are numerous encounters with healthcare professionals and staff who have varying levels of experience and knowledge working with neurodiverse individuals, and these social encounters with unfamiliar people can be stressful for an autistic individual.” She noted that the stress and pain of labor can exacerbate communication differences for autistic individuals. Studies have also shown that individuals with ASD are more likely to experience postnatal depression and anxiety relative to their peers without ASD. Improving Obstetric Care and Outcomes in ASD In providing obstetric care to patients with ASD, Dr Donovan emphasized that providers need to recognize the vast diversity within this population. “It is essential to understand that autism is a spectrum condition with a great deal of variation among autistic individuals, and a provider’s view of autism should not be based on 1 patient,” she remarked. Dr Suplee offered the following recommendations for providers developing a care plan for autism and pregnancy: Assess each birthing person as an individual and do not assume that all patients with ASD will communicate or react the same way Do not make assumptions about how to provide intrapartum or postpartum care based on perceived client social interactions Learn how to interpret social cues and sensory overload and how to make appropriate accommodations to best meet the client’s needs10 Provide effective communication and tailor all education specifically to the client Discuss support services that can be incorporated during each phase of the client’s birthing journey Educate staff on what it means when a person experiences a heightened sensory perception of sound, light, or touch and what types of interventions can be utilized in these instances Prof Freeth noted, “Consistent support from the same team members throughout pregnancy is particularly valued by autistic people.” In addition, “Having clear, precise information provided in written form to supplement information provided via discussions tends to be helpful as some autistic people take a little longer than non-autistic people to process information and appreciate being able to go over key information again in their own time,” she explained. Other helpful adjustments may include options for individual or online classes or support groups — rather than large group-based formats — and allowing the presence of a patient advocate at appointments. Clinicians may need to take extra time to listen to the special concerns of these patients, especially regarding sensory issues. Providers and hospitals may also consider making small adjustments to the sensory environment, such as not having music playing or screens on in a waiting room, having the option to wait for appointments in a non-crowded space, or using a lamp for lighting instead of overhead lights, Prof Freeth recommended. Dr Donovan added that having sensory kits that contain items such as noise-canceling headphones, stress balls, sunglasses, and fidget toys available on obstetric units may help to ease sensory overload. “Implementing strategies to create a sensory-friendly environment in waiting rooms, examination areas, and on the labor and postpartum units can provide a more welcoming environment to neurodiverse individuals,” she stated. Given the high rates of comorbid mental health disorders among individuals with ASD, Dr Donovan advised that mental health screenings should be included in the plan of care for autism and pregnancy. Unmet Needs Experts point to the need for ongoing provider education and research to further understand and improve obstetric care for individuals with ASD. Ideally, such efforts would include “autistic-led training and co-production of service development whereby autistic people are involved in designing maternity services,” Prof Freeth suggested. She noted the need for research focused on the development and evaluation of such services, along with studies that would elucidate the lived experiences of pregnancy, birthing, and the postpartum period among people with ASD. Dr Donovan said she would like to see provider training programs focused on “interventions to facilitate communication and create sensory-friendly environments.” “Policies and protocols should be developed and used as guides when caring for birthing people with ASD during the intrapartum and postpartum periods,” Dr Suplee recommended. She cited the need for research exploring strategies for teaching new mothers with ASD about parenting skills and recognizing infant cues, as well as qualitative studies to “build evidence on how best to care for this population during the antepartum, intrapartum, and postpartum periods that will lead to improved maternal health outcomes.” Keypoint: This article originally appeared on Psychiatry Advisor

Tris Pharma Inc has announced a licensing agreement with Braingaze Ltd and the establishment of Tris Digital Health. Tris Digital Health will concentrate on developing and distributing digital diagnostic and therapeutic products for the treatment of attention-deficit/hyperactivity disorder (ADHD) and other neurological health disorders. Under the agreement, Tris Pharma—a biopharmaceutical company specializing in ADHD, pain, addiction, and neurological disorders—has gained exclusive rights to develop and market a digital diagnostic platform for ADHD in the United States and Canada by Braingaze, a digital health firm focusing on technology-driven solutions for cognitive disorders. According to Tris Pharma, the launch of Tris Digital Health and the licensing of Braingaze’s platform are to meet an unmet need for more objective diagnostic tools for ADHD. “Patients, caregivers, and physicians deserve better tools to support accurate ADHD diagnosis beyond the currently available options,” said Ketan Mehta, founder and CEO at Tris Pharma, in a press release. “We have launched Tris Digital Health to deliver on our long-term commitment to advance meaningful and beneficial health care for physicians, ADHD patients, and caregivers. We are delighted to partner with Braingaze to launch this important endeavor and look forward to offering practitioners in the United States and Canada the opportunity to use and evaluate the benefits of this digital ADHD diagnostic platform.” Braingaze's digital diagnostic tool for ADHD, which utilizes artificial intelligence and digital biomarkers, facilitates ADHD diagnosis in both children and adults by employing a computerized game and patented eye-tracking technology to assess attention levels. The results provide clinicians with probability and severity scores for individual patients with ADHD. “Tris analyzed multiple investigational ADHD digital diagnostic technologies and concluded that the Braingaze test substantially outperforms other tools designed to provide objective ADHD assessment and diagnosis,” said James Hackworth, brand division president at Tris Pharma, in a press release. “We look forward to validating this technology in US patients, with the goal of providing patients, their caregivers, and health care providers greater confidence in ADHD diagnoses to support improved outcomes.” The technology has already obtained the European CE Mark as a medical device and will undergo clinical trials in the United States under the guidance of the US Food and Drug Administration (FDA) to validate its efficacy for clinical use in North America. “We’ve received enthusiastic feedback from European physicians who tell us that our novel diagnostic test is an improvement over subjective tools they relied on until now,” said Laszlo Bax, CEO and co-founder of Braingaze, in a press release. “We are thrilled to partner with Tris, another leader in the ADHD space who has an exceptional track record with 4 commercialized medications, to extend the reach of our ADHD diagnostic solutions to patients who might benefit from it in the United States and Canada.” An estimated 129 million children and adolescents worldwide have ADHD. Here are some recent expert updates and discussions on ADHD as seen in Psychiatric Times®

The ketogenic diet shows promise in reducing the symptoms of bipolar disorder and schizophrenia and reversing metabolic syndrome, results of a new pilot study show. Participants who adhered to the high-fat, low-carb diet experienced a 30% reduction in psychiatric symptoms and an average 10% reduction in weight. "We're seeing huge changes," first author Shebani Sethi, MD, of Stanford University in Stanford, California said in a press release. "Even if you're on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, and the insulin resistance. I think that's very encouraging for patients." The findings were published online on March 27 in Psychiatric Research. Neuroprotective Effect? Recent research supports the hypothesis that psychiatric illness may stem, at least in part, from deficits in brain metabolism and that a keto diet may be neuroprotective by reducing inflammation and oxidative stress. The pilot study included 21 participants with schizophrenia (n = 5) or bipolar disorder (n = 16) who were aged 18-75 years. All were currently taking psychotropic medications. Participants were overweight (body mass index [BMI] ≥ 25) and had gained more than 5% of their body mass while taking psychotropic medication, or they had at least one metabolic abnormality, such as insulin resistance or dyslipidemia. At baseline, participants received a physical and psychiatric evaluation and 1 hour of instruction on how to implement the keto diet, which included 10% carbohydrate, 30% protein, and 60% fat. Investigators monitored blood ketone levels at least once a week and defined participants as keto-adherent if their levels were 0.5-5 mM for 80%-100% of the times they were measured. Health coaches checked in with participants for about 5-10 minutes each week to answer diet-related questions. Psychiatric assessments, which included mood rating and global functioning scales, were completed at baseline, 2 months, and at the end of the 4-month study. The research team tracked participants' adherence to the diet by weekly measurement of blood ketone levels. By the end of the trial, 14 patients had been fully adherent with the diet, six had been semi-adherent, and only one had been nonadherent. Higher ketone levels, suggesting greater adherence, correlated with better metabolic health. As measured by the Clinical Global Impression-Schizophrenia and Clinical Global Impression for Bipolar Disorder–Overall Severity, participants experienced a 31% reduction in symptom severity (P < .001). Overall, 43% (P < .02) of participants achieved recovery as defined by the Clinical Mood Monitoring Form criteria: 50% of the adherent group and 33% of those who were semi-adherent. Metabolic Benefits Initially, 29% of participants had metabolic syndrome and more than 85% had co-occurring medical conditions such as obesity, hyperlipidemia, or prediabetes. By the end of the study, none met criteria for metabolic syndrome. On average, participants experienced a 10% reduction in weight and BMI. Waist circumference was reduced by 11%, fat mass index dropped by 17%, and systolic blood pressure decreased by 6%. In addition, metabolic markers including visceral fat, inflammation, A1c, and insulin resistance also improved. All outcomes were significant at P < .001 except for systolic blood pressure, at P < .005. There was also a 20% reduction in triglycerides and a 21% increase in low-density lipoprotein cholesterol (both at P < .02). The study's limitations include its small sample size, the lack of control arm, and short duration. "Mental health and physical health are interconnected and addressing metabolic issues can complement psychiatric treatment to enhance overall well-being. Understanding the mechanisms and potential synergies between psychiatric treatment and metabolic improvements can also inform the development of more effective interventions," the researchers wrote. The study was funded by the Baszucki Group, Kuen Lau Fund, and the Obesity Treatment Foundation. The authors declare no competing interests. Note: This article originally appeared on Medscape

BUDAPEST, Hungary — Self-perceived loneliness during childhood is linked to a more than twofold increased risk for subsequent first-episode psychosis (FEP) — new findings that may point to a novel marker for the disorder. The association between loneliness and FEP "appears to extend beyond the effects of objective social isolation," said study presenter Covadonga M. Díaz-Caneja, MD, PhD, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Madrid, Spain, and "is particularly pronounced in females." "These findings suggest the potential of childhood loneliness as an early risk marker for psychosis that could help guide targeted interventions," she added. The results were presented here at the European Psychiatric Association 2024 Congress. Isolation a Major Risk Factor There are two components to isolation, both of which are "major risk factors" for morbidity, mortality, and the onset of mental disorders, said Díaz-Caneja. The first is "objective social isolation," which consists of a demonstrable lack of social connections, including social interactions, contacts, and relationships, while the other is a perceived sense of isolation, or "loneliness," defined as a "subjective feeling of distress associated with a lack of meaningful relationships," regardless of the amount of actual social contact an individual experiences. Childhood loneliness occurs before age 12 and is becoming increasingly prevalent, said Díaz-Caneja. A recent survey shows that approximately one third of children report they often feel lonely. Genetic and observational research has shown there is a bidirectional relationship between loneliness and psychosis and that patients with schizophrenia are more likely to report loneliness than the general population. Díaz-Caneja noted that there is no previous research that has assessed the potential association between childhood loneliness and subsequent psychosis. To investigate, the researchers conducted an observational, case-control study in seven university hospitals in Madrid. It included individuals aged 7-40 years, including FEP patients with a psychosis duration of less than 2 years, and healthy controls from the same geographic areas. They assessed childhood objective social isolation using the Premorbid Adjustment Scale and examined childhood loneliness with the single item: "Have you ever felt lonely for more than 6 months before the age of 12?" A range of measures and questionnaires were also administered to assess participants' symptom scores, alongside the Global Assessment of Functioning (GAF). Alone vs Lonely Two hundred eighty-five patients with FEP participated in the study. They had a mean age of 24.5 years, and 32.6% were female. The study also included 261 healthy controls (average age, 25.9 years; 48.7% female). After adjusting for age, gender, ethnicity, and socioeconomic status, loneliness during childhood was associated with a significantly increased risk for FEP (odds ratio [OR], 2.17; 95% CI, 1.40-3.51), which increased (OR, 2.70; 95% CI, 1.58-4.62) after further adjustment for objective social isolation. Further analysis revealed that in those who did not have objective social isolation in childhood, loneliness was associated with a significantly increased risk for FEP (OR, 2.68; 95% CI, 1.56-4.60). However, the relationship between loneliness and FEP was not significant in participants who were objectively socially isolated during childhood (OR, 0.33; 95% CI, 0.08-1.45). Compared with males, females reporting loneliness had a markedly increased risk for FEP (OR, 4.74; 95% CI, 2.23-10.05 vs OR, 1.17; 95% CI, 0.63-2.19). However, females had a reduced risk of receiving a diagnosis of schizophrenia spectrum disorder (OR, 0.155; 95% CI, 0.048-0.506), indicating that loneliness influenced the type of diagnosis, she noted. There was a significant positive relationship between loneliness in childhood and symptom scores in men, and a negative association with GAF scores in men. Díaz-Caneja noted that the study is preliminary and a "work in progress." The investigators plan to increase the sample size and will conduct more complex analyses, she said. "We also of course have to bear in mind that it is a cross-sectional study and that there may be some kind of recall biases [because] we are asking patients now about what happened in the past." She also noted that it's unclear whether the results can be extrapolated to individuals who are currently experiencing loneliness because "the determinants of loneliness 10 years ago or 15 years ago may be different." Note: This article originally appeared on Medscape