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The world is facing an era of climate crisis. The year 2023 was the warmest on record since the Industrial Revolution, underscoring the undeniable evidence of ongoing global warming. This presents a critical issue, as global average temperatures have now surpassed the 1.5 °C threshold established by the Paris Agreement in 2015 on multiple occasions and in various regions across the globe. The current trajectory is concerning, with predictions indicating that temperatures will continue to rise if no action is taken. The recent Conference of Parties (COP) 28 United Nations Climate Change Conference in Dubai, United Arab Emirates, resulted in a consensus among parties to initiate an energy transition toward a phaseout of fossil fuels. This is a crucial step, as fossil fuels are a major source of greenhouse gases, pollution, and global warming. The ramifications of rising temperatures are profound, affecting the planet, states, communities, and individuals in diverse and interconnected ways. Climate is a complex system characterized by multiple pathways of development, alternating periods of gradual and rapid change, feedback loops and nonlinear dynamics, thresholds, tipping points, and shifts among pathways.2 In a globalized society, all is intertwined. Ecosystems are subjects in a complex network of interactions, and each part of the world that is affected by the effects of climate change has consequences on the others. In the context of climate change, these characteristics can lead to acute, subacute, and chronic environmental events and changes. The impact of climate change–related events can vary, from acute to chronic occurrences that are experienced directly or indirectly. Acute events are the fast-onset disasters, such as extreme weather events (eg, typhoons, cyclones, floods, wildfires, heat waves), while the subacute events are the slow-onset events such as droughts. Chronic events refer to slow environmental changes, such as the rise of sea levels and, in the future, the disappearance of islands (eg, the Pacific Islands) or cities, loss of biodiversity, and/or mass extinction. All these events entail both direct and indirect impacts that can coexist, overlap, and be nested within each other. The influence of these events on mental health and well-being can also be direct or indirect. Individuals can be directly affected by experiencing climate-related extreme events such as floods and tornadoes. This exposure involves a physical risk and, at first, attempting to survive the disaster, which may cause trauma or death, exposure to vector-borne diseases and disaster-related pathologies, as well as mental diseases like trauma, depression and other mood disorders, anxiety disorder, substance abuse, and suicide. Additionally, witnessing the calamities, living near the affected area, and learning about an event, even from a distance, are all ways an individual may experience indirect repercussions from climate events. The experience of subacute and chronic events also leads to onset of the so-called psychoterratic syndromes, emotional states specifically correlated with living or witnessing climate change. These emotions include solastalgia, eco-anxiety, eco-grief, eco-trauma, climate anxiety, and ecological posttraumatic stress disorder (PTSD), as well as denial and apathy. All the extreme and slow-onset events carry societal costs in terms of population mental health, premature deaths, reduced well-being, breakdown of communities or societies, disruption to socioeconomic and political conditions, and increased forced migration and conflicts. Additionally, different individuals may experience climate change in different ways. Vulnerable individuals or populations may be particularly sensitive to these types of events and may be more prone to developing psychiatric disorders. Vulnerable groups include women, youth, and the elderly, individuals with preexisting physical or mental illnesses, Indigenous populations, and individuals with low socioeconomic status. Some scientists studying the climate and eco-activists may be more exposed to climate-related information and, therefore, more sensitive to its impact. Environmental Determinants The mind and the planet are connected deeply, on multiple levels, and in a complex way. Numerous climate determinants have been linked to mental health, and understanding this is crucial for promoting well-being and developing effective interventions to address mental health challenges in these times of climate crisis. The determinants of mental health operate at 4 levels (Figure), interact with each other, and are influenced by various protective and risk factors. The determinants of health are defined as the range of personal, social, economic, and environmental factors that influence physical and mental health. Recognizing the environment as a significant factor affecting individual health entails acknowledging the importance of the environment as a determinant of mental health. The environmental determinant is both from nature (the non-human element that includes geographical areas and encompasses the interactions among all living species, as well as the elements and phenomena present in Earth’s lands, waters, and biodiversity) and from the built environment (human-made surroundings that serve as the backdrop for human activities like living, working, and recreation).8 In the era of climate change, environmental determinants can influence each of the 4 levels of mental health. At the personal level, an increasing number of individuals are exposed to the effects of climate change, both extreme and slow-onset events. These have an impact on mental health, especially in vulnerable individuals. Disconnection from the natural environment and increased urbanization also contribute to environmental influences on personal health. Living in the city is a risk factor due to the adverse effects of air pollution, noise pollution, and distance from green environments. At the family and community levels, having low socioeconomic status, being a member of an already at-risk group, and seeing one’s homeland and community places being threatened by climate change can be a risk factor for adverse climate effects. Protective community factors are given by the level of closeness and cohesion within a group following a disaster and being together and coping through pro-environmental actions. At the society level, indirect psychosocial impacts are triggered by weather disasters, infrastructure damages, or the experience of economic hardship.3 Furthermore, the escalation of climate change may push the planet past critical thresholds, potentially leading to societal collapse. However, the economic and political aspects of society may cooperate for mitigation of climate change. For example, during COP 28, a “loss and damage fund” was established to address the damage of climate disasters and to support the vulnerable communities that are affected by it. Ecotherapy Nature is an environmental determinant of mental health and well-being. Numerous studies suggest that experiences in nature can be beneficial for health and well-being. Nature is effective for mitigating medical disorders such as hypertension and cardiovascular disease, obesity, diabetes, postsurgical recovery, and sleep disturbance, and can help increase attentiveness, brain capacity, and creativity. Much evidence suggests that spending time in nature has mental health benefits and can decrease the risk of mental illnesses and psychosocial conditions like mood disorders, depression, anxiety disorder, stress, and PTSD. For children, spending time in nature is beneficial for behavioral disorders such as attention-deficit/hyperactivity disorder and for lowering the risk of onset of psychiatric disorders in older age. Activities in nature come in many forms, including therapeutic horticulture, pet therapy, therapeutic use of agricultural landscapes and farming practices, conservation work, physical exercise outdoor in parks and the countryside, nature-related arts and crafts, and specific ecotherapy techniques. Although many of these activities can be done alone, they may also be done socially to increase the sense of community and cohesion in a specific group. In general, spending time in nature is beneficial for physical, mental, and emotional health, so clinicians should encourage patients to engage in these types of activities. Being aware of the effects of climate change can also lead individuals to get more involved in pro-environmental behaviors. These actions may involve activism in environmental organizations, non-activist behavior in the public sphere (eg, petitioning on environmental issues), private actions (eg, saving energy, purchasing recycled goods), and organizational behavior (eg, product design). The more these actions are perceived as meaningful, the stronger their positive impact on subjective well-being will be. This type of behavior benefits not only the individual but also the community and the entire planet. The connection that occurs between climate change and individuals can be positive when it starts consciously from the individuals themselves. Concluding Thoughts Being aware of climate change adds a layer of complexity to discussions surrounding individual well-being and mental health. Mental health is influenced not only by individual biology, but also by social, ecological, and environmental determinants. Recognizing and addressing these connections comprehensively is essential for promoting individual and collective well-being. Mental health clinicians must be aware of the effects of climate change on mental health in individuals and communities and they must encourage individuals to engage in ecotherapy techniques, pro-environmental behaviors, and behaviors promoting social and community cohesion. Note: This article originally appeared on Psychiatric Times .

Keypoint: Judith Joseph, MD, MBA, shares her journey of balancing clinical work with social media mental health advocacy. CLINICAL CONVERSATIONS With a mission of “Bridging the gap between advanced research and real-world understanding,” Judith Joseph, MD, MBA, finds opportunities to better herself, the field of psychiatry, and mental health education for the general public. In fact, based on her reach and success, the US House of Representatives recently acknowledged her popular presence on social media, where she leverages her experience, clinical research, and expertise to help patients as well as to advocate for better treatments. Joseph, who is a clinical assistant professor in the department of Child and Adolescent Psychiatry at New York University’s Langone Medical Center, also serves as a medical board member for the national nonprofit organization Let’s Talk Menopause and chair of the Women in Medicine Board at Columbia University Vagelos College of Physicians and Surgeons. She is also the principal investigator at Manhattan Behavioral Medicine, where she has been part of more than 60 clinical trials and has mentored numerous early career investigators, and she has worked as a child and adolescent and adult psychiatrist. Psychiatric Times invited Joseph to share her journey, lessons learned, and hopes for the future of psychiatry. Psychiatric Times: How did your social media journey begin? Judith Joseph, MD, MBA: When I was a first-year fellow at New York University in the department of child and adolescent psychiatry, a reporter came to the psychiatric emergency department and interviewed me about the services that were being offered. When I read the article, I was disappointed in my interview, and I asked the director of education at my fellowship if the department would enroll me in a media training course. My director’s response was a Socratic one. He said, “Judith, you should develop the course yourself. And then when you finish writing the course, you should teach it to the rest of us.” Initially I thought that he was joking, but he wasn’t. In fact, he suggested that I focus on media training as the topic of my second year senior project during my fellowship program. I wrote the course after doing extensive research in journalism and medical media reporting, and then I taught the course to the NYU child psychiatry fellows and NYU film undergraduate students who were taking CAMS (Child and Adolescent Mental Health Studies Minor) courses at NYU. The course is titled “Meet The Press,” and I am in my tenth year teaching this course at NYU. During this course, I teach doctors and health care professionals how to give press interviews. The first half of the course is skills based in which I teach specific tools and skills, and the second half of the course is practical and consists of videotaped mock press interviews during which the doctors learn how to implement the tools that were taught in the first half of the course. We play back the video mock interviews to the class in real-time so that their peers and I can give them constructive feedback. I started to become active on social media so that I could teach my students. I had no idea that I would have this much personal and career success in such a short period of time. Teaching this course opened up so many opportunities for me. I used my media skills to give press interviews with local radio and news stations, and eventually I found myself as a regular medical media expert, appearing from 2017 through the present on national television shows such as the Today Show, Dr Oz, ABC News, and many more. This exposure led to consulting work as a medical writer. I worked on a fiction series, The Crowded Room, starring and produced by Tom Holland for Apple TV. I also have served as a true crime mental health expert for Investigation Discovery’s show “Crimes Gone Viral” for the past 4 years. After 2021, people were increasingly getting their information from social media platforms. To teach young doctors how to use social media, I first had to understand social media. So I did the work and began to research how to create evidence-based entertaining content (edutainment). Now the course includes how to create social media content that is evidence-based. I also recently updated the course to include how to give podcast interviews and social media “Live” interviews in addition to traditional television press interviews. I started to become active on social media so that I could teach my students. I had no idea that I would have this much personal and career success in such a short period of time. My social media reels went viral, and within 2 years I had almost 1 million followers across TikTok, Instagram, Facebook, and Threads. My social media advocacy and research led me to receiving a US House of Representatives Proclamation in June 2023. I was nominated by Congresswoman Sheila Cherfilus-McCormick in honor of Caribbean American Heritage Month and invited to Vice President Kamala Harris’s reception at the White House after my proclamation was read before Congress. Most recently I teamed up with Fides, an advocacy group within the World Health Organization, to help other health professionals around the world combat online misinformation by becoming leading voices for health care advocacy. PT: What have been some of the pros and cons of being a popular psychiatric clinician on social media? Joseph: There are so many benefits to being online because we are highly skilled and highly trained medical doctors. Becoming a content creator has allowed me to start my own mental health podcast, The Vault, and has created opportunities for me to work and partner with brands that I love. I am not an influencer, I am a “physician content creator,” and what I am doing helps to inform millions of people every day. I still have a research lab and a clinical practice where I see one patient at a time. But, using my iPhone, in 60 seconds I can create a reel that helps millions of people all over the world. Doctors belong on social media because we know how to provide information in ways that are responsible and evidence-based. If we don’t dominate the mental health social media space, then less educated, less informed, and less reputable individuals will take up the space. This is dangerous, because there is so much misinformation online. The only significant negative aspect that I have identified to being online as a professional is that you get a lot of trolls. However, the network at Fides provides guidelines and support for dealing with trolls. When I first started to ramp up my online content, some of my colleagues told me that no one would take me seriously as a researcher and psychiatrist if I became an “influencer.” My response was that I am not an influencer, I am a “physician content creator,” and what I am doing helps to inform millions of people every day. I still have a research lab and a clinical practice where I see one patient at a time. But, using my iPhone, in 60 seconds I can create a reel that helps millions of people all over the world. Some of those same colleagues who once criticized me have since apologized and have asked me for advice on how to build their online presence. I help them because I want more doctors online. We need to take up this space, because we are the most qualified to have these platforms. In addition, the social media advocacy has led me to experience so much growth in my lab; our lab space and team have since doubled. I will be offering the media course to all providers this year. Individuals can sign up for my newsletter to learn how they can attend this course virtually from anywhere in the world. PT: You mentioned your lab—Manhattan Behavioral Medicine. How did you get started in clinical research? Joseph: Before I was a resident in psychiatry, I was a resident in anesthesiology at Columbia University Medical Center. I loved intubating, doing IVs, and lumbar punctures. I loved the work, but I missed talking to patients and I missed working in teams. I was fortunate to leave my anesthesiology residency at Columbia 2 years into my training and to secure a spot in psychiatry residency at Columbia. I immediately loved psychiatry, but I missed the procedures. Clinical research in psychiatry allowed me to still use my hands and practice psychiatry. In my lab, Manhattan Behavioral Medicine, I do ECGs, blood draws, insert IVs, and administer subcutaneous injections and intranasal medications daily. We even do lumbar punctures when we test cerebrospinal fluid for dementia studies. Some of our studies require EEGs and pulmonary function tests. I love learning new skills and sharpening old skills. We recently opened a third office, where we are focusing on psychedelic studies, involving psilocybin-like compounds and ketamine. This is a very exciting time for psychiatry, and some of the drugs we investigated via clinical research are proving to be important agents in psychiatry, included the recently approved brexanolone (Zulresso) and zuranolone (Zurzuvae) for postpartum depression and xanomeline-trospium (KarXT) for schizophrenia, scheduled to be reviewed by the US Food and Drug Administration in September 2024. PT: What advice would share with clinicians who are interested in pursuing clinical research? Joseph: My advice for residents who are interested in clinical research is that they get involved in clinical research as a resident in training and then look for jobs in labs after your training so that you can work with established principal investigators. I have research mentors from my residency that I still keep in touch with. If you have completed training and you are looking to become involved in clinical research, consider taking a job at a clinical research site where you can train under a principal investigator. I love training new sub-investigators as the principal investigator of Manhattan Behavioral Medicine. PT: Among your passions is menopause advocacy. Can you tell us about your work with Let’s Talk Menopause? Joseph: I became heavily active with Let’s Talk Menopause because Black women go through menopause sooner than other women, and menopause lasts longer and with more severe symptoms than other women. I am on the board for Let’s Talk Menopause, and I am the only board member who has not gone through menopause. I am also the only Black board member. Black women have some of the scariest rates of postpartum depression, postpartum suicide, postpartum complications, perinatal death, and negative perimenopause/menopause outcomes. There is a saying in the Black community: “Black Don’t Crack.” Unfortunately, this is not true in regards to health outcomes. Black women have some of the scariest rates of postpartum depression, postpartum suicide, postpartum complications, perinatal death, and negative perimenopause/menopause outcomes. My patients who experience physical and mental health symptoms related to menopause benefit from hormone replacement therapy (HRT) and other interventions like psychotherapy and cognitive behavioral therapy for sleep. Some patients benefit from antidepressants and sleep aides. However, most people are not offered HRT, and this is problematic. According to a 2019 Mayo Clinic survey of resident physicians, only 6.8% felt adequately prepared for managing the treatment of women in menopause and only 58% of the participants had up to one lecture about menopause during residency training. This gap of knowledge in medical providers plays a large role in the lack of menopause competency in health care. In addition, many patients going through perimenopause and menopause are misdiagnosed as having major depressive disorders because of the similarity of the symptoms. They present to their doctors with cognitive concerns, identity loss, sadness, moodiness, anxiety and insomnia—symptoms that may occur in both major depressive disorder and in perimenopause. Often, these patients do not have a primary major depressive episode; they are experiencing mood symptoms related to hormonal fluctuations. The disconnect in physician knowledge is largely due to the fact that the 2002 Women’s Health Initiative study was misleading and concluded that HRT had risks that far outweighed the benefits. This statement has since been debunked, but the message that HRT was harmful was so pervasive in health care that doctors stopped prescribing it and patients have suffered as a result. Let’s Talk Menopause educates women for free via webinars, events, and social media content. In addition, advocacy is a large part of our mission and activities. We recently advocated alongside Congresswoman Yvette Clarke in front of Congress to support the MREA (Menopause Research and Equity Act).I also developed the T.I.E.S. Method to help patients identify the mental health symptoms of menopause and how to discern them from primary mental health conditions. PT: On the other end of the spectrum, much has been said about the mental health crisis in youth. As a clinical psychiatrist, what has been your experience? Joseph: I am a child psychiatrist who also treats adults, and can report that this issue is not just in children, it is happening across all ages. The post-pandemic mental health crisis seems to be worsening and people do not have access to quality mental health care. Recently I have been working with US Representative Ro Khanna and other mental health advocates to address the crisis in youth. One of the suggestions that I have made is to focus on funding mental health services and education in schools. We need to approach this from a preventative approach and teach children how to use social media responsibly, how to regulate their mood, and how to determine if relationships are harmful. We need to provide these types of workshops in the workplace for adults as well. Preventing mental health issues is where we should focus our efforts, because the reality is that it will take decades to create and disseminate new therapists and mental health professionals. The shortage of professionals is far too great, and 1 in 3 Americans lives in an area where there is a shortage of these professionals. Moreover, minority mental health is often overlooked in adults and youth. There are very few Black therapists compared with other therapists, and this creates a barrier to care. For this reason, I create social media content that directly addresses Black patient populations so that they are informed and are receiving support and resources from a cultural competency perspective. When I was a resident, I received a SAMHSA minority health grant to focus on cultural competency in the Black community, and I use what I learned during that grant period to create evidence-based content to support my community. I have also done several events with the Congressional Black Caucus around Black mental health in children and adults. PT: Another area of interest of yours is high functioning depression (HFD). Can you tell us more about this condition and what you have found in your research? Joseph: I am very excited about my research in HFD. In this post-pandemic period, we are learning about patients who have hidden conditions, like HFD which is often masked by busyness. HFD affects highly visible successful figures as well as everyday individuals. People with high functioning depression may include the chief executive officer who runs her company and masks her symptoms in light of grave financial uncertainty; or the famous sports figure who has to bring home a win for his franchise. Think of the teacher who works through lunch to grade his students’ papers on time so that they pass the state exams or the single working mom who stretches the dollar to make sure her kids are fed and gets them to school on time every day despite a lack of support. I also think that many health care professionals, specifically doctors, suffer from HFD. People with HFD push through painful situations to meet or exceed their performance expectations. Those with HFD often report symptoms of anhedonia. Although individuals with HFD have some symptoms of depression (eg, poor sleep, low energy, or self-doubt), their symptoms do not meet the DSM 5 criteria for major depressive disorder because the individuals exceed basic functioning; they push through pain and they don’t always identify as being emotionally distressed. This is why HFD often goes unnoticed by medical providers and mental health professionals; clinicians are looking for a lack or loss of functioning, and these patients do not have that. HFD is contagious, not in the way that a virus spreads, but in the way that unhealthy habits may rub off on those around us. Think about the boss who works themselves and their team to the bone, or the parent who never seems satisfied with their child’s academic progress; this can spread, if not contained. If we can contain HFD and its most insidious symptom, anhedonia, we can hopefully put an end to this epidemic and spread joy instead. My research and upcoming book on the topic shares evidence-based tools for combating symptoms of anhedonia so that life feels more meaningful and purposeful. The book and research findings are set to be released in March 2025. In the meantime, the High Functioning Blog on my website offers the high functioning depression scale and the anhedonia scale to learn more about the symptoms. I also have a free weekly newsletter that provides evidence-based tips on how to improve mental health. Note: This article originally appeared on Psychiatric Times .

We recently shared a clinical case drawn from a family medicine practice about the effect of adverse childhood experiences (ACEs) on health. The widespread epidemiology and significant health consequences require a focus on the prevention and management of ACEs. The Centers for Disease Control and Prevention published an important monograph on ACEs in 2019. Although it is evidence based, most of the interventions recommended to reduce ACEs and their sequelae are larger policy and public health efforts that go well beyond the clinician's office. Important highlights from these recommended strategies to reduce ACEs include: Strengthen economic support for families through policies such as the earned income tax credit and child tax credit. Establish routine parental work/shift times to optimize cognitive outcomes in children. Promote social norms for healthy families through public health campaigns and legislative efforts to reduce corporal punishment of children. Bystander training that targets boys and men has also proven effective in reducing sexual violence. Facilitate early in-home visitation for at-risk families as well as high-quality childcare. Employ social-emotional learning approaches for children and adolescents, which can improve aggressive or violent behavior, rates of substance use, and academic success. Connect youth to after-school programs featuring caring adults. But clinicians still play a vital role in the prevention and management of ACEs among their patients. Akin to gathering a patient's past medical history or family history is initiating universal ACE screening in practice and exploring related topics in conversation. The ACEs Aware initiative in California provides a comprehensive ACE screening clinical workflow to help implement these conversations in practice, including the assessment of associated health conditions and their appropriate clinical follow-up. While it is encouraged to universally screen patients, the key screenings to prioritize for the pediatric population are "parental depression, severe stress, unhealthy drug use, domestic violence, harsh punishment, [and] food insecurity." Moreover, a systematic review by Steen and colleagues shared insight into newer interpretations of ACE screening which relate trauma to "[...] community violence, poverty, housing instability, structural racism, environmental blight, and climate change." These exposures are now being investigated for a connection to the toxic stress response. In the long term, this genetic regulatory mechanism can be affected by "high doses of cumulative adversity experienced during critical and sensitive periods of early life development — without the buffering protections of trusted, nurturing caregivers and safe, stable environments." This micro and macro lens fosters a deeper clinician understanding of a patient's trauma origin and can better guide appropriate clinical follow-up. ACE-associated health conditions can be neurologic, endocrine, metabolic, or immune system–related. Early diagnosis and treatment of these conditions can help prevent long-term healthcare complications, costly for both patient and the healthcare system. After the initial clinical assessment, physicians can educate patients about the ways that ACE-associated health conditions are a consequence of toxic stress exposure. From there, physicians should rely on a broader integrated health team, within the health system and the community to offer clinical interventions and services to mitigate patients' toxic stress. The ACEs Aware Stress Buster wheel highlights seven targets to strategize stress regulation. This wheel can be used to identify existing protective factors for patients and track treatment progress, which may buffer the negative impact of stressors and contribute to health and resilience. The burden of universal screenings in primary care is high. Without ACE screening, however, the opportunity to address downstream health effects from toxic stress may be lost. Dubowitz and colleagues suggest ways to successfully incorporate ACE screenings in clinical workflow: Utilize technology to implement a streamlined referral processing/tracking system Train clinicians to respond competently to positive ACE screens Gather in-network and community-based resources for patients In addition, prioritize screening for families with children younger than 6 years of age to begin interventions as early as possible. Primary care clinicians have the unique opportunity to provide appropriate intervention over continual care. An intervention as simple as encouraging pediatric patient involvement in afterschool programs may mitigate toxic stress and prevent the development of an ACE-associated health condition. Note: This article originally appeared on Medscape.

An extended-release oral tablet formulation of ketamine has shown promise for treatment-resistant depression (TRD) results of a phase 2 proof-of-concept study suggest. In the trial, twice weekly dosing of extended-release ketamine led to statistically significant and clinically meaningful improvement in depressive symptoms. Overall tolerability was "excellent," researchers reported, and common side effects commonly associated with intravenous or intranasal ketamine such as dissociation, sedation, and increased blood pressure were "minimal." "Having a tablet formulation makes it possible for patients to be safely dosed at home and would increase the number of patients who could be treated at any one time," study investigator Paul Glue, MBChB, MD, with University of Otago, Dunedin, New Zealand, told Medscape Medical News. The study was published online on June 24 in Nature Medicine. Challenging Condition TRD poses a significant challenge. "We've known for over 20 years that ketamine, a drug originally developed as an anaesthetic, is also a fast-acting antidepressant," Glue said. However, when injected or administered as a nasal spray, it has "quite marked side effects," which means it that has to be administered in a clinic, and patients need to remain in clinic for 2 hours or so after dosing, Glue added. Several small studies have shown that ketamine still works as an antidepressant when taken orally, although it still produces some dissociation. "If ketamine is formulated as an extended-release tablet (where it takes approximately 10 hours to release), most ketamine is metabolized in the liver before it can get into the circulation. It still is effective as an antidepressant because its metabolites are the main drivers of its antidepressant effects. However, the lower blood ketamine levels mean patients experience few or no side effects," said Glue. The current phase 2 trial tested the efficacy and safety of an extended-release oral ketamine tablet (R-107) in adults with TRD and Montgomery–Asberg Depression Rating Scale (MADRS) scores ≥ 20. During an open-label phase, 231 participants received 120 mg/d of R-107 for 5 days. The 168 responders, identified by MADRS scores ≤ 12 and a reduction of 50% or more, were randomly assigned to double-blind twice-weekly treatment with R-107 at doses of 30, 60, 120, or 180 mg or placebo, for a further 12 weeks. The study met its primary objective, with the 180-mg R-107 group demonstrating a significant reduction in MADRS scores compared with placebo (mean difference, -6.1; P = .019). Seventy-one percent of patients in the placebo group experienced a relapse into depression after 13 weeks compared with 43% of patients who received twice weekly oral ketamine. There were no changes in blood pressure and minimal reports of sedation and dissociation. The most common adverse events were headache, dizziness, and anxiety. More Convenient, Tolerable Several experts offered perspective on the analysis in a statement from the UK-based nonprofit Science Media Centre, which was not involved with the conduct of this study. Paul Keedwell, PhD, consultant psychiatrist and fellow of the Royal College of Psychiatrists, said that this "novel study further underlines the impressive antidepressant effect of ketamine, but in the much more convenient and acceptable form of a slow-release tablet." "In addition, the researchers demonstrated a major upside of oral ketamine — that side effects did not separate significantly from placebo," Keedwell said. He added that the study also addressed the "thorny issue of maintaining improvement after the initial response. Their results suggest that many will continue to do well with longer-term treatment, provided higher doses are used, but more research is needed with higher numbers of patients." "A potential downside of taking oral ketamine is that there are likely to be large individual differences in absorption and metabolism, so further research is needed to determine the ideal dosing regime," Keedwell noted. Also weighing in, Rupert McShane, MD, psychiatrist at the University of Oxford, United Kingdom, said that the results are "good enough to justify the larger phase 3 trials that will be necessary for a license for the 180-mg twice weekly dose." "Given the ease with which people may choose to take two tablets if they do not benefit from one tablet, regulators may be interested in the benefits and risks of higher doses," McShane commented. The study was sponsored by Douglas Pharmaceuticals, which is developing R-107. Glue is named on a patent for the extended-release ketamine formulation. A complete list of author disclosures is available with the original article. Keedwell reports no relevant conflicts of interest. McShane runs a clinic in Oxford providing ketamine as a treatment for depression, runs an academic conference about ketamine, and is leading a proposal for intravenous ketamine to be repurposed as an alternative to ECT. Note: This article originally appeared on Medscape.

Keypoint: An expert discusses this comorbidity, plus the effects of semaglutide and other GLP-1 agonists on this patient population. CLINICAL CONVERSATIONS Psychiatric Times® sat down with Elizabeth Wassenaar, MD, MS, CEDS-S, DFAPA, regional medical director of the Eating Recovery Center in Denver, Colorado, to discuss the comorbidity of eating disorders and addiction, as well as the effects of semaglutide and other GLP-1 agonists on patients with eating disorders. Psychiatric Times: How common is the comorbidity of eating disorders and addiction? How might the neurobiological pathways implicated in eating disorders intersect with those involved in addiction, and what implications does this have for the use of medications like semaglutide in managing these overlapping conditions? Elizabeth Wassenaar: The lifetime co-occurrence of eating disorders and substance use disorders was reported to be 21.9% in 2019,1 and some studies report that up to 50% of individuals with an eating disorder will abuse substances. The most commonly misused substances were tobacco, caffeine, and alcohol, and female-identifying patients with binge-purge eating disorders were most commonly affected. There are common neurobiological pathways implicated in eating disorders and substance use disorders, especially dopamine and endogenous opiate pathways. There is evidence that GLP-1 receptors also exist in reward areas of the brain and decrease rewards related to eating, including anticipation of food. GLP-1 receptor agonists' impact on dopamine may also have implications for addictive processes in the brain. PT: Research suggests that semaglutide and other GLP-1 agonists may influence appetite regulation and weight management, which are significant components of eating disorder pathology. How does the mechanism of action of these drugs impact individuals with eating disorders or addiction, considering the potential for weight loss and its effect on appetite regulation? Wassenaar: GLP-1 receptor agonists work in the brain to suppress appetite and increase feelings of fullness, which is how they act for individuals who take them to manage their type 2 diabetes. We are beginning to notice patients who are vulnerable to disordered eating and/or relapse of their eating disorder following the initiation of GLP-1 receptor agonist medications. PT: There is potentially a link between addiction-related neurobiological changes and disordered eating behaviors. How do you navigate the complexities of treating patients with both addiction and eating disorders, particularly concerning medications like semaglutide and other GLP-1s that may influence these underlying neural pathways? Wassenaar: The impact of drugs like semaglutide on mental health is not yet well understood. We do not yet understand which patients are vulnerable to the negative impact of these medications versus which patients may find mental health benefits. PT: How do you assess the risk of addiction or misuse associated with semaglutide and other GLP-1 agonists when considering their use in treatment plans for patients with eating disorders? Wassenaar: The biggest risk that I have seen is precipitating a severe eating disorder and medical complications of malnutrition. Eating disorders are one of the most fatal mental illnesses, and prescribing a medication that has the potential to trigger this is very concerning. With the opiate crisis, many practitioners thought they were being helpful and addressing pain in ways that provided better care. It was not until years and decades later we learned the tragic dark side of prescription opiate pain medications and how they could trigger the mental illness of addiction, and now we are dealing with the fallout of this prescribing practice. I worry that GLP-1 RAs could have a similar impact on eating disorders, in that we will not know the true harm for many years, and by then, countless individuals will have suffered from preventable mental illness. Dr Wassenaar is the regional medical director of the Eating Recovery Center in Denver, Colorado. Note: This article originally appeared on Psychiatric Times.

A history of traumatic brain injury (TBI) is associated with a 33% increased risk for schizophrenia and a 78% increase in bipolar disorder (BD), with the strongest link in older adults, women, and those with severe TBI, new research suggested. "Findings indicate that TBI is a risk factor for both schizophrenia and [BD] with differential impact by age, severity, and sex, and that this association cannot be explained by familial confounding alone," investigators led by Kai-Yuan Cheng, MD, PhD, of the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, wrote. "The associations between TBI with schizophrenia and [BD] risks call on clinicians to monitor clinical course and potential psychiatric symptoms in people with a history of TBI, particularly the vulnerable groups identified in our study," they added. The study was published online on June 2, 2024, in Psychiatry Research. Conflicting Findings TBI is associated with elevated risk for several psychiatric conditions, including depression, anxiety, posttraumatic stress disorder, and suicidality, but evidence linking TBI to the risk for schizophrenia and BD has been based largely on small studies and yielded conflicting results. The researchers identified 4184 individuals with schizophrenia and 18,681 with BD from Swedish national registries. Patients were aged ≥ 15 years at first diagnosis and born between 1973 and 1998. Controls included 20,920 controls with schizophrenia and 93,405 patients with BD who were matched with controls by birth year, sex, and birthplace. They also matched cases with siblings who had neither disorder. Those with schizophrenia were predominantly men (66% in the case-control group and 57% in the sibling group), while women predominated in the BD samples (66% in case-controls and 56% in the sibling group). Within all samples, the proportion of individuals who had experienced TBI was consistently higher among cases vs control individuals. In the nested case-control samples, experiencing any TBI was associated with a significantly higher risk for schizophrenia (incidence rate ratio [IRR], 1.33) and BD (IRR, 1.78; both P < .001). Moderate and severe TBI vs mild TBI were associated with higher relative risk for schizophrenia and BD, and later age vs earlier age at first TBI (≥ 15 years) was associated with a higher risk for both conditions. "A dose-response relationship is an important element in establishing a causal relationship as it yields evidence of potential biological plausibility and gradient," the researchers wrote. The sibling comparison samples, designed to adjust for familiar confounding, yielded hazard ratios (HRs) that complemented findings, with TBI remaining significantly associated both with schizophrenia and BD (adjusted HR [aHR], 1.38; P = .002 and aHR, 1.55; P < .001, respectively). Severity and later age of TBI were also associated with stronger risks for both conditions. The association between TBI and BD was significantly stronger in women vs men, which applied to any TBI exposure and TBI sustained at different ages. However, the pattern of excess risk for women in schizophrenia was not statistically significant. Limitations included the fact that primary care diagnoses were not included in the data, and outpatient diagnoses were only recorded from 2001 — which may have led to missing milder TBI exposures and some outcome diagnoses. In addition, data on family design were not comprehensive, and siblings born at different times may not have grown up in the same environment. Lastly, it was not possible to completely rule out the potential biases of residual confounding effects — especially reverse causality. The researchers suggested the findings underscore the need for further research establishing a "clear pathophysiological mechanism" between TBI and severe mental illness. Note: This article originally appeared on Medscape.

Keypoint: Do physical health conditions in childhood affect ADHD symptoms at age 17 years? Researchers investigated these associations in a large cohort study. CASE VIGNETTE “Kate” is a 17-year-old Caucasian female with a history of attention-deficit/hyperactivity disorder (ADHD), diagnosed at age 10 years. She presented with primarily inattentive symptoms and minimal issues with hyperactivity or impulsivity. She has a history of myopia and has worn eyeglasses since age 13 years. She was also diagnosed with asthma at age 6 years. Her body mass index is in the 40th percentile. Kate had a positive response to treatment with methylphenidate, which she continues to take, although she is still sometimes easily distracted. At an outpatient visit, her mother asks whether Kate’s asthma could impact on her ADHD symptoms. As Kate’s psychiatrist, how would you respond? Increasing evidence suggests that ADHD is associated with physical comorbidities, including asthma and obesity.1 A recent birth cohort study found cross-sectional associations between ADHD symptoms, asthma, and sleep problems in early and middle childhood and adolescence.2 There may be a bidirectional association between ADHD and physical conditions, as well as common underlying risk factors.3 Few studies have investigated longitudinal associations between ADHD and physical conditions. The Current Study Reed and colleagues4 used a large-scale population-representative sample to investigate the hypothesis that the cumulative number of physical health conditions across childhood are associated with ADHD symptoms in adolescence (age 17 years), controlling for cumulative environmental risk, ADHD medications, and ADHD symptoms at age 3 years. The authors used data from the Millennium Cohort Study, which contains longitudinal data on > 19,000 UK families with children born between 2000 and 2002. Data have been collected in 7 waves, at ages 9 months and 3, 5, 7, 11, 14, and 17 years. Only the first sibling in each family was included. Participants were also excluded if data on the biological mother was unavailable, if physical health predictor variables were missing, or if outcome data at age 17 years was missing. The present study included 8059 participants. The parent-reported hyperactivity/inattention subscale of the Strengths and Difficulties Questionnaire (SDQ), which predicts ADHD diagnosis,5 was collected at age 17 years, and SDQ score at age 3 years was also included as a potential confounding factor. Approximately 174 children in the cohort were diagnosed with ADHD by age 17 years. Parents were asked about their child’s physical health at each wave, including diagnoses and hospitalizations. Physical conditions were grouped into 4 clusters: Sensory (eyesight, hearing) Atopic (eczema, asthma, hay fever) Neurological (epilepsy, sleep problems, movement problems, stutter) Cardiometabolic (obesity, diabetes, heart problems) Risk factors were grouped into 5 cumulative risk indices: Prenatal Perinatal Postnatal environment Postnatal maternal well-being Socioeconomic status and demographics At age 14 years, data on ADHD medications were also obtained. Data were analyzed using stepwise multiple linear regression to analyze the relationship between physical health clusters and ADHD symptoms at age 17 years, controlling for environmental risk indices, ADHD medications, and SDQ score at age 3 years. Binary logistic regression models were also used with ADHD diagnosis as the outcome. Approximately 91 children were taking ADHD medication, and the average SDQ score at age 17 years was 2.6. After adjusting for confounders, sensory and neurological clusters were significantly associated with ADHD symptoms as a continuous measure at age 17 years (β=0.06 for each), and the model explained 21% of the variance. In binary logistic regression analyses, both the sensory cluster (OR=1.31, 95% CI 1.04-1.65) and the neurological cluster (OR=1.94, 95% CI 1.48-2.53) predicted ADHD diagnosis. The odds of an ADHD diagnosis approximately doubled with each additional neurological condition. Study Conclusions The investigators concluded that this was the first study to analyze the longitudinal association between physical conditions in childhood and ADHD symptoms. Sensory and neurological clusters, but not the atopic or cardiometabolic clusters, were significant predictors of hyperactivity/inattention symptoms at age 17 years. Participants with predating neurological issues were almost 2 times more likely to have an ADHD diagnosis at age 17 years. Study strengths included the large cumulative sample size, the availability of longitudinal data, and consideration of potential confounding effects of environmental risk factors and ADHD medications. Limitations include that the SDQ is not designed as a screening instrument for ADHD, and only a small subset of participants had been clinically evaluated for ADHD. The investigators did not explore ADHD symptoms as predictors of physical health (the reverse relationship). Data were not available to analyze the effect of parental history of ADHD on these associations. The Bottom Line Findings suggest possible biological commonalities between physical disorders in childhood and ADHD symptoms in adolescence. Clinicians should monitor for symptoms of hyperactivity and inattention in children with sensory and neurological disorders. Note: This article originally appeared on Psychiatric Times

Gray matter volume, BDNF and cytokine levels, and depressive symptoms partially mediate the cognitive decline associated with loneliness. Risk Factors for Cognitive Decline Loneliness contributes to both psychological risk factors for cognitive decline and structural brain changes that are linked to dementia, according to study results published in Brain Behavior and Immunity. Given that older adults are more susceptible to loneliness, targeted interventions for this vulnerable population are needed to prevent adverse health impacts. Previous research has established a relationship between loneliness and poorer mental and physical health outcomes, particularly among older adults. However, few studies have examined the neurobiological mechanisms underlying loneliness in adults aged 65 and older, and how these changes may impact cognitive function. To investigate this further, researchers used data from the Rush Memory and Aging Project (RMAP) determine whether the psychobiological conditions of loneliness increase the risk for cognitive decline among adults aged 65 and older. To measure loneliness, participants completed a modified version of the de Jong-Gierveld Loneliness Scale. The researchers assessed 5 cognitive domains: episodic memory, semantic memory, working memory, visuospatial ability, and processing speed. Additionally, the researchers examined levels of proinflammatory cytokines and brain-derived neurotrophic factor (BDNF), depressive symptoms, and total gray matter volume as potential contributing factors to the relationship between loneliness and cognition. A total of 2130 participants had complete data for loneliness, depressive symptoms, and cognitive measures. Among these participants, 73% were women, 93% were White, 5% were Hispanic, and they were 80.1 years of age, on average. However, the sample size was reduced for the analyses that evaluated cytokines (n=414-423), BDNF (n=272), and gray matter volume (n=664). The researchers found that loneliness was negatively associated with episodic memory (β= -0.1; SE, 0.01; t = -73; P <.001), semantic memory (β= -0.06; SE, 0.01; t = -5.9; P <.001), working memory (β= -0.06; SE, 0.00; t = -5.9; P <.001), visuospatial ability (β= -0.07; SE, 0.01; t = -7.25; P <.001), processing speed (β= -0.08; SE, 0.01; t = -3.86; P <.001), and global cognition (β= -0.06; SE, 0.01; t = -8.32; P <.001). The researchers then evaluated potential pathophysiological pathways that may explain the relationship between loneliness and cognition. The researchers observed a significant, positive correlation between BDNF levels and all cognitive domains (all P <.001). When BDNF was added to the linear mixed model, there was a 3-way interaction between BDNF, time, and loneliness (β=0.05; SE, 0.02; P <.05) and a likelihood ratio test indicated that adding BDNF to the model significantly improved the model’s prediction (χ2=6.59; P =.01). Similarly, the researchers observed a 3-way interaction between cytokine levels, time, and loneliness (β= -0.12; SE, 0.05; P <.05) Total gray matter volume was also a significant mediator of the relationship between cognition and loneliness, with the exception of working memory, accounting for 15% to 25% of the observed relationship. Further, depressive symptoms were a mediating factor for all cognitive domains except visuospatial ability. The mediating effect of depressive symptoms explained 12% of the relationship between loneliness and episodic memory, 17% of processing speed, 41% of visuospatial ability, and 15% of global memory. Study authors concluded, “As demonstrated in this study, loneliness is related not only to psychological risk factors of cognitive decline, such as depression but also to structural changes in the brain that are significant predictors of dementia.” Study limitations include the fact that the observed significant associations between longitudinal scores of loneliness and cognitive decline had a small effect size, the sample size was smaller for participants with neuroimaging and measures of loneliness and depressive symptoms, and most MAP participants were White. Note: This article originally appeared on Psychiatry Advisor

Adults with posttraumatic stress disorder (PTSD) have smaller cerebellums than unaffected adults, suggesting that this part of the brain may be a potential therapeutic target. According to recent research on more than 4000 adults, cerebellum volume was significantly smaller (by about 2%) in those with PTSD than in trauma-exposed and trauma-naive controls without PTSD. "The differences were largely within the posterior lobe, where a lot of the more cognitive functions attributed to the cerebellum seem to localize, as well as the vermis, which is linked to a lot of emotional processing functions," lead author Ashley Huggins, PhD, said in a news release. "If we know what areas are implicated, then we can start to focus interventions like brain stimulation on the cerebellum and potentially improve treatment outcomes," said Huggins, who worked on the study while a postdoctoral researcher in the lab of Rajendra Morey, MD, at Duke University, Durham, North Carolina, and is now at the University of Arizona, Tucson. While the cerebellum is known for its role in coordinating movement and balance, it also plays a key role in emotions and memory, which are affected by PTSD. Smaller cerebellar volume has been observed in some adult and pediatric populations with PTSD. However, those studies have been limited by either small sample sizes, the failure to consider key neuroanatomical subdivisions of the cerebellum, or a focus on certain populations such as veterans of sexual assault victims with PTSD. To overcome these limitations, the researchers conducted a mega-analysis of total and subregional cerebellar volumes in a large, multicohort dataset from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA)-Psychiatric Genomics Consortium PTSD workgroup that was published online on January 10, 2024, in Molecular Psychiatry. They employed a novel, standardized ENIGMA cerebellum parcellation protocol to quantify cerebellar lobule volumes using structural MRI data from 1642 adults with PTSD and 2573 healthy controls without PTSD (88% trauma-exposed and 12% trauma-naive). After adjusting for age, gender, and total intracranial volume, PTSD was associated with significant gray and white matter reductions of the cerebellum. People with PTSD demonstrated smaller total cerebellum volume as well as reduced volume in subregions primarily within the posterior cerebellum, vermis, and flocculonodular cerebellum than controls. In general, PTSD severity was more robustly associated with cerebellar volume differences than PTSD diagnosis. Focusing purely on a "yes-or-no" categorical diagnosis didn't always provide the clearest picture. "When we looked at PTSD severity, people who had more severe forms of the disorder had an even smaller cerebellar volume," Huggins explained in the news release. Novel Treatment Target PTSD These findings add to "an emerging literature that underscores the relevance of cerebellar structure in the pathophysiology of PTSD," the researchers noted. They caution that despite the significant findings suggesting associations between PTSD and smaller cerebellar volumes, effect sizes were small. "As such, it is unlikely that structural cerebellar volumes alone will provide a clinically useful biomarker (eg, for individual-level prediction)." Nonetheless, the study highlights the cerebellum as a "novel treatment target that may be leveraged to improve treatment outcomes for PTSD," they wrote. They noted that prior work has shown that the cerebellum is sensitive to external modulation. For example, noninvasive brain stimulation of the cerebellum has been shown to modulate cognitive, emotional, and social processes commonly disrupted in PTSD. Commenting on this research for Medscape Medical News, Cyrus A. Raji, MD, PhD, associate professor of radiology and neurology at Washington University in St. Louis, Saint Louis, Missouri, noted that this "large neuroimaging study links PTSD to cerebellar volume loss." "However, PTSD and traumatic brain injury frequently co-occur, and PTSD also frequently arises after TBI. Additionally, TBI is strongly linked to cerebellar volume loss," Raji pointed out. "Future studies need to better delineate volume loss from these conditions, especially when they are comorbid, though the expectation is these effects would be additive with TBI being the initial and most severe driving force," Raji added. The research had no commercial funding. Author disclosures are listed with the original article. Raji is a consultant for Brainreader, Apollo Health, Pacific Neuroscience Foundation, and Neurevolution Medicine LLC. This article originally appeared on Medscape

Prevention-based interventions are effective in increasing cannabis risk perception and reducing cannabis use among adolescents. Increased knowledge and a greater perception of cannabis risk in adolescents are associated with decreased current usage and reduced intentions for future use, according to study results published in the Journal of Adolescent Health. While prevention-based interventions were generally effective in enhancing knowledge and perception of cannabis risk, legislative changes demonstrate considerable heterogeneity in outcomes. Cannabis remains the predominantly used illicit substance by adolescents on a global scale, and given recent legislative changes to cannabis legalization, investigators aimed to establish a comprehensive understanding of adolescents’ general knowledge and perception of risk for cannabis and whether legislation impacted these variables. The investigators conducted a systematic literature review by searching publication databases from inception to February 2022 for articles that reported on cannabis knowledge and its risk perception among children and adolescents (10 to 18 years of age). Levels of evidence for each study included were determined using the Center for Evidence Based Medicine’s framework, with Level 1A (systematic review of randomized controlled trials) representing the highest level of evidence and Level 5 (expert opinion, physiology bench research, or “first principles”) being the lowest. A total of 133 articles were included in the final analysis. Most studies (n=93) were categorized as evidence grade level 2C, involving outcome studies from large database registries and population-based data, while 22% (n=30) met the criteria for level 2B studies, which includes cohort studies and lower-quality RCTs. Over 90% of the studies were conducted in high-income countries (eg, United States, Canada, Australia, England, France), with limited representation from upper and lower middle-income countries. Overall, increased awareness and knowledge regarding the perceived risk for cannabis among adolescents was frequently associated with reduced current usage and future use intentions of cannabis. Studies investigating associations over time demonstrated a rise in adolescent cannabis use alongside a decline in risk perception. However, the investigators observed that prevention interventions frequently improved knowledge and risk perception among these adolescents. For example, a Psychostimulant and Cannabis Module led to significantly higher levels of cannabis-related knowledge in intervention groups compared with controls, even at 10 months post-intervention (P <.001). Additionally, a life-skills training program with a drug education unit for middle school students resulted in reduced lifetime (P =.05) and recent (P <.03) marijuana use 2 years after intervention, relative to controls. In contrast, legislative changes led to heterogeneous knowledge and risk perception outcomes. Medicinal marijuana legislation consistently demonstrated a reduction in risk perception among adolescents, while studies that evaluated recreational marijuana legislation observed significant variability in both knowledge and use outcomes. Notably, studies that assessed adolescents’ knowledge and perception of risks associated with cannabis use as a primary outcome revealed that a lack of comprehensive understanding regarding the health implications of marijuana usage was consistently associated with higher rates of current usage and intentions for future use. Review authors concluded, “[T]argeted public health strategies that seek to increase cannabis-related knowledge among youth and disseminate information about the potential health harms of cannabis use should continue and be prioritized as a means of protecting youth and mitigating rates of cannabis use in adolescents.” The findings of this review may be limited by the inclusion of manuscripts exclusively published in English, and the high risk for bias found in 95% of included studies. This article originally appeared on Psychiatry Advisor

Heavy secondhand smoke exposure was positively associated with a higher risk of developing severe headaches or migraine in adults who never smoked. Among adults who never smoke, heavy secondhand smoke exposure is positively associated with severe headaches or migraine, according to study findings published in the journal Headache. To determine if an association exists between secondhand smoke exposure and severe headaches or migraine, validated by serum cotinine levels, among adults who never smoked, researchers conducted a cross-sectional study and collected data via the 1999-2004 National Health and Nutrition Examination Survey (NHANES). Serum cotinine levels exceeding 10 ng/mL were frequently observed in current smokers, establishing a threshold value. To be classified as nonsmoker, individuals must have smoked fewer than 100 cigarettes in their lifetime, abstained from nicotine-containing products for the past 5 days, and had serum cotinine levels of 10 ng/mL or less. The researchers determined migraine headache status by asking participants whether they have experienced severe headaches or migraine during the previous 3 months. After excluding participants, a total of 4560 individuals (median age, 43; female 60.1%; 71.5% White) who had completed the NHANES survey were included in the final analysis. Among participants, 919 (20%) self-reported experiencing severe headaches or migraine. After accounting for relevant covariates, the researchers observed a significant association between high levels of secondhand smoke exposure and an increased risk for severe headaches or migraine (odds ratio [OR], 2.02; 95% CI, 1.19-3.43). In contrast, low secondhand smoke exposure demonstrated no significant association with severe headaches or migraine (OR, 1.15; 95% CI, 0.91-1.47). When compared with individuals with no secondhand smoke exposure, those with a body mass index (BMI) less than 25 and those who were sedentary (P =.016) showed a significant association with both low secondhand smoke exposure (OR, 2.15; 95% CI, 1.54-2.99) and heavy secondhand smoke exposure (OR, 2.60, 95% CI; 1.25-5.42) and severe headache or migraine. Among individuals with a BMI of 25–30, no significant association was found between low secondhand smoke exposure (OR, 0.77; 95% CI, 0.51-1.15) or heavy secondhand smoke exposure (OR, 1.14; 95% CI, 0.47-2.76). The results indicated a distinct linear association between the natural logarithm of serum cotinine and the occurrence of severe headaches or migraine (P =.335 for nonlinearity). In sensitivity analyses, which excluded active smokers with serum cotinine concentrations more than 3 ng/mL, participants on specific medications, and after multiple imputations, the association persisted with a slight decrease in the odds ratio value. The study has several limitations including the inability to establish a causal relationship between secondhand smoke exposure and severe headache or migraine. Moreover, the half-life of serum cotinine is 15-40 hours, which can only reveal recent secondhand smoke exposure. “These findings underscore the harmful impact of [secondhand smoke] exposure on the nervous system and serve as a reminder to avoid prolonged exposure to tobacco smoke,” the researchers concluded. This article originally appeared on Neurology Advisor