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Seltorexant, an investigational drug being developed by Johnson & Johnson, met all primary and secondary endpoints in a phase 3 trial of patients with major depressive disorder (MDD) with insomnia symptoms, the company has announced. Seltorexant is an investigational potential first-in-class selective antagonist of the human orexin 2 receptor being studied for the adjunctive treatment of MDD with insomnia symptoms. Its selective mechanism of action means it has the potential to improve both mood and sleep symptoms associated with depression. The phase 3 MDD3001 study was a multicenter, randomized, double-blind trial comparing the efficacy and safety of 20-mg oral seltorexant once daily with placebo, added to background selective serotonin reuptake inhibitor/serotonin and norepinephrine reuptake inhibitor (SSRI/SNRI) therapy, for improving depressive symptoms in adult and elderly patients with MDD with insomnia symptoms. In the study, seltorexant led to "statistically significant and clinically meaningful" improvement in depressive symptoms based on the Montgomery-Asberg Depression Rating Scale total score, as well as improved sleep disturbance outcomes, in patients with moderate to severe depression and severe sleep disturbance who had a prior inadequate response to SSRI/SNRI antidepressants alone, the company announced in a statement. Consistent with previous trials of seltorexant, the drug was safe and well-tolerated, with similar rates of common adverse events seen in both treatment groups. "Depression is a leading cause of disability worldwide and shares a strong link with sleep disturbances. In MDD, insomnia symptoms exacerbate the risk of depressive relapse, increase healthcare costs, and impact quality of life, and it often goes undertreated despite being one of the most common residual symptoms," Andrew Krystal, MD, professor of psychiatry, University of California, San Francisco Weill Institute for Neurosciences, said in the statement. "Seltorexant has the potential to fill a significant unmet need for new therapies to treat patients experiencing depression and insomnia and, most importantly, to improve outcomes and quality of life for these patients," Krystal added. The topline results are being presented at the American Society of Clinical Psychopharmacology (ASCP) 2024 Annual Meeting, underway in Miami, Florida. The positive phase 3 data follow earlier promising data reported in 2022, as reported by Medscape Medical News. Note: This article originally appeared on Medscape

Keypoint: An expert shares some lessons learned from prior research on the treatment and suggestions for a way forward at the 2024 ASCP Annual Meeting. CONFERENCE REPORTER “The pharmacopoeia on the depressive phase of bipolar disorder, from a regulatory standpoint, is really quite limited in comparison to other phases of illnesses and other mental illnesses. Antidepressants for use in bipolar disorder have a very limited evidence base, and concern always remains for associated destabilization. I would argue that our studies need to develop more narrow precision.” Mark A. Frye, MD, served as chair of a panel of experts who discussed the potential of modafinil/armodafinil as a treatment for bipolar disorder targeting cognition, depression, and sleep circadian rhythm at the 2024 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting. Frye is a consultant in the Department of Psychiatry & Psychology and a professor of psychiatry at Mayo Clinic College of Medicine. In his individual presentation, titled “Modafinil / armodafinil in bipolar disorder: lesson learned, roadmap forward,”1 Frye shared that, despite mixed results in clinical trials, recent meta-analyses suggest that armodafinil (R-modafinil), which is currently approved for managing excessive sleepiness in conditions like shift work disorder and narcolepsy,2 may still hold potential as a treatment option for bipolar 1 depression.1 According to Frye, mrmodafinil works as a wakefulness-promoting agent by inhibiting dopamine transport at low affinity. This mechanism of action is different from the typical treatments for bipolar depression involving mood stabilizers and antipsychotics. Existing treatments, such as quetiapine and cariprazine, have traditionally been used for both acute mania and depression (bimodal mood stabilization) or in combination with antimanic agents, like the olanzapine-fluoxetine combination.1 However, Frye said, the development of armodafinil as a treatment for bipolar 1 depression faced significant challenges. Two out of 3 phase 3 clinical trials did not demonstrate a clear benefit over placebo, leading to the discontinuation of the development program. Despite these setbacks, a meta-analysis reported that both modafinil and armodafinil could be efficacious and safe for treating bipolar 1 depression.1 Frye stated that 1 of the key issues in these trials was the heterogeneity of the patient population, particularly regarding the use of mood stabilizers. The varied composition of mood stabilizers among participants might have affected the trials’ ability to detect a significant difference between armodafinil and placebo. According to Frye, this variability, which was initially seen as a strength for generalizability and community translation, may have inadvertently limited the studies’ sensitivity to armodafinil’s effects.1 Given these findings, Frye reported that researchers are advocating for a fully powered clinical trial with a more targeted approach. Such a trial would focus on identifying patient characteristics that predict a favorable response to armodafinil. Factors like atypical depressive symptoms, circadian rhythm disruptions, cognitive issues, and specific therapeutic combinations need to be considered to better tailor treatment to individual patient needs.1 “A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with armodafinil,” Frye concluded. “Additional research is warranted and necessary to better identify clinical predictors…that would provide optimized, individualized therapeutics for bipolar depression and or cognitive enhancement in bipolar disorder.” Frye was joined in this panel by Katherine E. Burdick, PhD, and Ellen Frank, PhD. Burdick is Jonathan F. Borus, MD, Distinguished Chair in Psychiatry and vice chair for research in the Department of Psychiatry at Brigham and Women’s Hospital, and a professor at Harvard Medical School. Frank is a distinguished professor emeritus in the Department of Psychiatry at the University of Pittsburgh School of Medicine and chief scientific officer at Health Rhythms Inc. In the overall panel presentation, Frye, Burdick, and Frank reviewed the methodological limitations associated with developing modafinil/armodafinil for bipolar depression and discussed cognitive impairment and circadian rhythm issues in bipolar disorder as targets for modafinil/armodafinil. Note: This article originally appeared on Psychiatric Times

Neuropsychiatric symptoms, including nightmares and hallucinatory "daymares," may be a more important aspect of systemic lupus erythematosus (SLE) than formerly recognized, according to a qualitative mixed methods study published in The Lancet Discovery Science's eClinicalMedicine. The findings suggested these neuropsychiatric symptoms can sometimes present as prodromal and other times act as an early warning system for a forthcoming flare. "For clinicians, the key point is to be aware that neurological and psychiatric symptoms are much more common in patients with lupus and other autoimmune systemic rheumatic diseases than previously thought," lead author Melanie Sloan, PhD, of the Department of Public Health and Primary Care at the University of Cambridge in Cambridge, England, told Medscape Medical News. "If clinicians — and some do already — could all ask about and document these symptoms for each patient, the usual progression of symptoms in a flare can then be monitored, and patients could be supported and treated at an earlier stage," Sloan said. "Another key point is to consider systemic autoimmune diseases at an early stage if a patient presents with multiple seemingly unconnected symptoms, which often include both physical and mental health symptoms." Alfred Kim, MD, PhD, an associate professor of medicine in rheumatology at Washington University School of Medicine in St. Louis, Missouri, noted the difficulty of determining what neuropsychiatric symptoms may be linked to lupus vs those occurring independently or as part of a different condition. "There is some controversy about whether the neuropsychiatric manifestations that we have long attributed to lupus actually are due to lupus," Kim told Medscape Medical News. Kim was part of a group that published a review on potential mechanisms underlying neuropsychiatric symptoms described by a committee of the American College of Rheumatology. Since that committee's findings, "we have long assumed that if we saw these symptoms, the best explanation was lupus," Kim said. "The problem is that, in the real world, we can see many of these manifestations in patients with lupus that do not get better with lupus meds. This opens up the very real possibility that another etiology is at play." Kim noted that mood disorders such as depression and anxiety may be part of the neuropsychiatric SLE criteria, but they failed to correlate with overall lupus disease activity in a cohort he evaluated. That makes it hard to distinguish whether those neuropsychiatric symptoms can actually be attributed to lupus. "Probably the more accurate interpretation is that there may be certain symptoms, such as nightmares, that indicated a prodrome of lupus," he said. "Whether these are actually lupus symptoms is debatable to me." There remains value in initiating discussions about these symptoms with patients, however, because the stigma associated with neuropsychiatric symptoms may prevent patients from bringing them up themselves. "It is important to remember that many of these patients, in common with other chronic diseases, will often have had long and traumatic journeys to diagnosis," including having been misdiagnosed with a psychiatric condition, Sloan said. "Many of the patients then lose trust in doctors and are reluctant to report symptoms that may lead to another misdiagnosis." Clinicians may also be reluctant to bring up these symptoms, but for different reasons. Their reluctance may stem from insufficient time to discuss the symptoms or not having the support available to help the patients with these particular problems, Sloan said. The invisible nature of these symptoms, which lack biomarkers, makes them harder to identify and makes listening to patients more important, she added. Study Details In planning for the study, the researchers first searched the existing literature for studies involving neuropsychiatric symptoms in patients with systemic autoimmune rheumatic diseases (SARDs). "The literature indicated frequent underreporting and misattributions of neuropsychiatric symptoms in SLE and other SARD patients, and clinician-patient discordance in neuropsychiatric symptom attribution," the authors reported. During 2022-2023, the researchers conducted two surveys, one with 676 adult patients with SLE and one with 400 clinicians, recruited through social media, online patient support groups, and professional networks. All patients self-reported an SLE diagnosis that the researchers did not independently confirm. The patients were predominantly White (80%) and female (94%), ranging in age from 18 to over 70, with most falling between ages 40 and 69. Most patients lived in the United Kingdom (76%) or Europe (15%). The clinicians included 51% rheumatologists, 24% psychiatrists, 13% neurologists, 5% rheumatology nurses, 3% primary care physicians, and 7% other clinicians. Nearly half of the clinicians (45%) were from the United Kingdom, with others from the United States or Canada (16%), Europe (17%), Asia (9%), Latin America (8%), Australia or New Zealand (3%), or elsewhere (3%). The patient surveys asked whether they had experienced any of the 29 neuropsychiatric symptoms. For the symptoms that patients had experienced at least three times in their lives, the survey asked when they first experienced the symptom in relation to their SLE onset or other SLE symptoms: Over a year before, within a year of (on either side), 1-4 years after, or more than 5 years after onset/other symptoms. "Other quantitative data included timings of disrupted dreaming sleep in relation to hallucinations for those patients reporting experiencing these," the authors wrote. The researchers also conducted videoconference interviews with 50 clinicians, including 20 rheumatologists, and 69 interviews with patients who had a systemic autoimmune rheumatic disease, including 27 patients with SLE. Other conditions among those interviewed included inflammatory arthritis, vasculitis, Sjögren disease, systemic sclerosis, myositis, undifferentiated and mixed connective tissue diseases, and polymyalgia rheumatica. During interviews, the term "daymare" was used to discuss possible hallucinations. Linking Neuropsychiatric Symptoms and Disease Four themes emerged from the analysis of the surveys and interviews. First, despite many rheumatologists stating that it was an "established theory" that most neuropsychiatric symptoms related to SLE would initially present around the time of diagnosis or disease onset, the findings from patients and interviews with psychiatrists did not align with this theory. The first presentation of each neuropsychiatric symptom only occurred around the onset of other SLE symptoms, about one fifth to one third of the time. In fact, more than half of the patients with SLE who had experienced hallucinations or delusions/paranoia said they occurred more than a year after they first experienced their other SLE symptoms. Patient experiences differed in terms of whether they believed their neuropsychiatric symptoms were directly related to their SLE or other rheumatic disease. Some did attribute the symptoms, such as hypomania, to their rheumatic illness, while others, such as a patient with major depression, did not see the two as linked. A second theme focused on pattern recognition of neuropsychiatric symptoms and the onset of a disease flare. "For example, several patients described how they felt that some types of depressive symptoms were directly attributable to active inflammation due to its time of onset and differences in type and intensity compared to their more 'reactive' low mood that could be more attributable to a consequence of psychological distress," the authors wrote. Another common report from patients was experiencing a sudden, intense fatigue that coincided with a flare and differed from other types of fatigue. Some patients could recognize that a flare was coming because of familiar neuropsychiatric symptoms that acted like an "early warning system." Often, however, these symptoms "were absent from current diagnostic guidelines and only rarely identified by clinician interviewees as related to SLE/NPSLE," the authors found. "These neuropsychiatric prodromal symptoms were reported as sometimes preceding the more widely recognized SLE and other SARD symptoms such as joint pain, rashes, and other organ involvement." These symptoms included sudden changes in mood (usually a lowering but sometimes mania), increased nightmares, a "feeling of unreality," or increased sensory symptoms. Other patients, on the other hand, had not considered a link between neuropsychiatric symptoms and their rheumatic disease until the interview, and many of the clinicians, aside from psychiatrists and nurses, said they had little time in clinic to gather information about symptom progression. Nightmares and Daymares A third theme centered on disrupted dreaming sleep, nightmares, and "daymares" as a prodromal symptom in particular. Some patients had already drawn a connection between an oncoming flare of their disease and these dreaming-related symptoms, while others had not considered a link until the interviews. "Several SLE patients recounted flares consistently involving the segueing of increasingly vivid and distressing nightmares into distorted reality and daytime hallucinations," the authors reported. Flare-related nightmares in particular "often involved being attacked, trapped, crushed, or falling." Patients tended to be more forthcoming about hallucinatory experiences when the term "daymare" was used to describe them, and they often related to the idea of feeling "in-between asleep and awake." Only one of the rheumatologists interviewed had considered nightmares as potentially related to SLE flares, and several appeared skeptical about a link but planned to ask their patients about it. Most of the specialists interviewed, meanwhile, said they often discussed sleep disruption with patients. "There was agreement that recognizing and eliciting these early flare symptoms may improve care and even reduce clinic times by averting flares at any earlier stage, although some rheumatologists were clear that limited appointment times meant that these symptoms would not be prioritized for discussion," the authors wrote. Though Kim acknowledged the possibility of nightmares as prodromal, he noted other ways in which nightmares may be indirectly linked to lupus. "Trauma is a major risk factor for lupus," Kim said, with multiple studies showing childhood traumatic experiences and even posttraumatic stress disorder to be risk factors for lupus. "Whether nightmares represent a traumatic event or prior traumatic events is not clear to me, but one could hypothesize that this may be a manifestation of trauma," Kim said. In addition, nightmares represent a sleep disorder that can substantially reduce sleep quality, Kim said, and poor sleep is also associated with lupus. "One has to wonder whether disruptive dreaming sleep is one of several specific manifestations of poor sleep quality, which then increases the risk of lupus in those patients," Kim said. Misattribution of Neuropsychiatric Symptoms The final theme to emerge from the findings was patients had been misdiagnosed with psychiatric or psychosomatic conditions shortly before getting their rheumatic disease diagnosis. One patient, for example, reported being diagnosed with borderline personality disorder just 6 months before their lupus diagnosis at age 19 and noticed that the symptoms of one "got under control" when the symptoms of the other did. "Early misattributions of SARD symptoms to primary psychiatric or psychosomatic conditions were frequently reported to have delayed SARD diagnosis and led to future misattributions," the authors reported. "Whilst some of these misdiagnoses likely reflect the widespread lack of knowledge and limited definitive tests for SLE, it is plausible that some early SLE neurological and/or psychiatric symptoms may represent a neuropsychiatric prodrome for SLE itself." Kim agreed that misattribution of symptoms to other diagnoses is common with lupus and a common reason for delays in diagnosis, even with symptoms that are not neuropsychiatric. The findings in this study broaden "the type of symptoms we need to put on our radar pre-diagnosis," Kim said. "We just also have to be aware that these prodromal symptoms are not diagnostic for lupus, though." Sloan cited earlier work in recommending an "ABC" approach to improving clinician-patient relationships: "Availability is being accessible when patients need them, Belief is demonstrating belief and validating patient self-reports of symptoms, and Continuity is when the same clinician sees the same patient each clinic visit to build up a trusting relationship." She also noted the importance of asking about and normalizing the existence of these symptoms with rheumatic diseases. Note: This article originally appeared on Medscape

The US Department of Justice (DOJ) officially moved to reclassify marijuana as a Schedule III controlled substance on Thursday, marking a major shift in US policy on cannabis that has been years in the making. The DOJ issued a notice of proposed rulemaking to the Federal Register, which jumpstarts a 60-day public comment period, followed by a possible review from an administrative judge. "This proposal starts the process, where the Drug Enforcement Administration will gather and consider information and views submitted by the public, in order to make a determination about the appropriate schedule. During that process, and until a final rule is published, marijuana remains a schedule I controlled substance," a statement released May 16 by the DOJ reads. A DOJ spokesperson told Medscape Medical News that although the proposed rule was submitted this week, it is unclear how long it will take for it to officially appear on the Federal Register site. The official filing is the latest step in a process that began in October 2022 with a directive from President Joe Biden to the US Attorney General and the Secretary of Health and Human Services (HHS) to conduct a scientific review of marijuana scheduling under federal law. A 2023 report from the US Food and Drug Administration, part of HHS, determined that marijuana has a legitimate medical use and should be moved from a Schedule I controlled substance to Schedule III. In early May 2024, the US Drug Enforcement Agency (DEA) announced plans to follow that recommendation, as reported by Medscape Medical News. The DEA defines Schedule I drugs as those with no currently accepted medical use and a high potential for abuse. That class includes heroin, LSD, and ecstasy. Schedule III drugs have a moderate to low potential for physical and psychological dependence and have a currently accepted medical use. This class includes ketamine, acetaminophen with codeine, and buprenorphine. Even though the manufacturing, distribution, sale, and use of marijuana has long violated federal law, 38 states and Washington, DC, have legalized medical cannabis, and 24 states and DC have legalized its recreational use. Under the proposed rule, medical cannabis can be legally prescribed in states that have legalized the drug for that use. The manufacture, distribution, and possession of recreational marijuana would remain illegal under federal law. In a video and statement released Thursday, President Joe Biden called the step "monumental." "At my request, and guided by science and evidence, HHS and DOJ have studied the drug's medical use and abuse and dependency potential and are recommending rescheduling, concluding reclassification would remove barriers to critical research," Biden said. Note: This article originally appeared on Medscape

For many people navigating the stresses of the COVID-19 pandemic, temporary relief came in the form of a stiff drink. In the United States, the pandemic years were accompanied by the largest increase in alcohol sales in more than half a century and a surge in cases of alcohol-associated liver disease (ALD). Yet the pandemic merely accelerated a trend that was decades in the making. Statistics from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) show that from 2000 to 2019, deaths due to alcohol-associated liver cirrhosis grew by 47%. Globally, ALD is now the leading cause of preventable liver-related morbidity and mortality. "This increasing trend is due to a number of factors, including an increase in global alcohol consumption, increase in alcohol consumption and binge drinking among women, social media and increased exposure of youth to alcohol-related ads, more people using alcohol as a way to cope, among other reasons," Bubu Banini, MD, PhD, assistant professor in the Section of Digestive Diseases at Yale School of Medicine and a hepatologist at Yale Medicine, New Haven, Connecticut, told Medscape Medical News. For gastroenterologists treating ALD, gaining an understanding of a patient's alcohol consumption is crucial for distinguishing it from other conditions and tailoring subsequent interventions. "Unfortunately, there are no accurate diagnostic tests for ALD; thus, history and honest reporting of alcohol use are essential," Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. "ALD and metabolic dysfunction–associated steatotic liver disease (MASLD) are indistinguishable biochemically and histologically. Many patients with ALD also have risk factors for MASLD, which highlights the importance of an accurate alcohol-use history." Effectively treating ALD often means simultaneously treating alcohol use disorder (AUD), a common and chronic condition with varying grades of severity. The sooner AUD treatment can begin, the better the prognosis is for patients with ALD. A retrospective analysis of veterans with cirrhosis found that behavioral and/or pharmacotherapy‐based AUD treatment was associated with a significant reduction in incident hepatic decompensation and long‐term all‐cause mortality. Yet, getting patients to openly and accurately discuss their alcohol consumption can be difficult. "Research suggests that people tend to underreport their alcohol consumption, whether intentionally or not," George F. Koob, PhD, director of the NIAAA, told Medscape Medical News. "For instance, when people are asked to keep diaries of how much they drink, they tend to report more alcohol use in the diaries than when interviewed in person. This is particularly true for heavier drinkers." Many gastroenterologists are falling short in addressing problematic drinking in patients with ALD. Survey results indicate that although nearly all hepatology and gastroenterology providers routinely ask patients about alcohol use, most don't regularly use validated screening questionnaires, are uncomfortable treating AUD due to a lack of addiction education, have suboptimal knowledge about AUD pharmacotherapies and are unlikely to prescribe them, and generally demonstrate low rates of adherence to practice guidelines. Experts say that gastroenterologists can meet these challenges by adopting a few techniques for discussing and treating AUD. Choose Brief, Effective Screening Tools The American College of Gastroenterology's guidelines on ALD recommend that standardized screening for AUD be incorporated at every medical encounter. The United States Preventive Services Task Force recommends the Alcohol Use Disorders Identification Test–Consumption, which consists of three questions related to drinking frequency and quantity, or the NIAAA's Single Alcohol Screening Question, which asks "How many times in the past year have you had (four for women, or five for men) or more drinks in a day?" When a patient screens positive, clinicians should follow-up with a more thorough risk assessment. Experts also advise clinicians to incorporate into their screening practices biomarker tests that can detect alcohol across windows of time, spanning from hours (blood alcohol) to months (hair ethyl glucuronide). A 2021 systematic review found that biomarkers provided a substantially more accurate accounting of alcohol consumption than self-reporting among those with AUD. Patients should be informed ahead of time they'll be screened with a biomarker assessment, so they don't feel as if the tool is a de facto lie detector test, said Ponni V. Perumalswami, MD, MS, associate professor of medicine in the Division of Gastroenterology and Hepatology at the University of Michigan, Ann Arbor, Michigan, and coauthor of a recent review on optimizing the care of ALD. "We want patients to feel aligned and that we are working together to provide all-around support," Perumalswami told Medscape Medical News. Engage in Open, Supportive Discussions With Patients Once AUD has been identified via screening, clinicians can rely on practical communication strategies to move patients toward the most-appropriate interventions. Clinicians should determine whether patients have any special considerations holding them back from fully disclosing alcohol consumption, said Lewis Nelson, MD, MBA, DFASAM, an addiction medicine specialist and chair of Emergency Medicine at Rutgers New Jersey Medical School, Newark, New Jersey. "There may be issues of insurance, with people in their family finding out, or religious implications, among other things, that keep people from discussing this," he said. Simonetto advised taking a compassionate, empathetic approach in these initial conversations. "It's important to avoid stigmatizing words such as 'alcoholic' or 'alcoholic liver disease' to create a supportive, nonjudgmental environment and to ask clear, direct questions," he said. "It's also important to respect patients' autonomy and to accept resistance without confrontation." Banini recommended putting the disease in a clinical context when talking with patients. "Setting the tone and having patients understand that AUD is a common medical condition that can happen to anyone and that there are personalized, evidence-based treatment options that can be helpful in recovery might make them more comfortable in opening up about their alcohol use," she said. The NIAAA's Koob pointed to the Screening, Brief Intervention, and Referral to Treatment (SBIRT) model as an evidence-based approach that clinicians can adopt to identify and work with patients "who may be using alcohol in ways that are harmful to their health." Information on SBIRT and other materials are available in the NIAAA Healthcare Professional's Core Resource on Alcohol, he noted. Get Comfortable With AUD Therapies A 2019 analysis of over 66,000 patients with alcohol-associated cirrhosis found that only 10% had undergone face-to-face visits with mental health or substance abuse specialist, and just 0.8% received a US Food and Drug Administration (FDA)–approved relapse prevention medication. "There's no prescribing restrictions around treatment for AUD," Perumalswami said. "This begs the question: Can we get more providers engaged in this space to be offering these medications with growing comfort? There's a lot of discussion in the gastroenterology and hepatology fields about wanting to see us collectively as a group be offering more." The FDA has approved three medications for AUD, namely, naltrexone, disulfiram, and acamprosate, Koob said. "Given the possibility of hepatotoxicity with disulfiram, it is not recommended for patients with ALD. Use of the other two medications should be made after careful consideration of the risks for an individual patient," he added. Timing is of the essence in offering these treatments, as patients with ALD can still reap their benefits even after disease onset, Koob said. A 2022 retrospective cohort study of patients with AUD found that addiction pharmacotherapy significantly decreased the incidence of hepatic decompensation among a subset of those with cirrhosis, he noted. Best practice is for patients to have at least one alcohol-related follow-up within 30 days of starting an AUD medication and to be reevaluated on a quarterly basis thereafter. Build Relationships With Other Providers The management of psychiatric and behavioral therapies can be more complicated. "It isn't realistic for us to ask all gastroenterologists and hepatologists to have these behavioral skills and do all of this themselves," Perumalswami said. "This should be about figuring out your comfort level, building your capacity if you're interested, but also having relationships with behavioral health providers and asking them to be important parts of our practices and systems." Here too, the need for greater intervention is clear. AUD is among the most undertreated psychiatric disorders. A 2023 review article estimated that 40%-60% of patients with AUD have concurrent mental illness. Partnering with an addiction specialist is recommended to formally evaluate these patients and to determine the proper psychiatric care pathway and whether it entails outpatient, residential, or medically managed inpatient service. However, gastroenterologists should maintain realistic expectations for their patients with ALD who seek these treatments, said addiction medicine specialist Nelson. "Remember that the very definition of addiction is compulsive use despite harm," Nelson told Medscape Medical News. "I'm not trying to minimize our roles. It's a big step. But addiction physicians have no magic bullet to get people to stop drinking. You simply present them with information about the risks of continued use and their treatment options, which they need to use to make a decision. You just hope that you can get through to them." Gastroenterologists may want to partner with or refer patients to psychiatric/behavioral care providers. The NIAAA's Alcohol Treatment Navigator and the Substance Abuse and Mental Health Services Administration's FindTreatment.gov offer tools to help find substance providers and programs.

Keypoint: A recent study analyzed longitudinal data of patients with schizophrenia or major depressive disorder to rank treatment regimens in terms of weight gain, adverse effects, and response to treatment. Individuals with psychiatric diagnoses are especially vulnerable to experiencing obesity or rapid, undesirable weight gain due to psychotropic medications.1 Mental health treatment strategies often include polypharmacy; however, previous research on drug-induced weight gain mainly focused on monotherapy and is therefore not applicable. Investigators analyzed longitudinal data of 832 inpatients with ICD-10 diagnoses of either schizophrenia (n = 282) or major depressive disorder (n = 550) to rank treatment regimens in terms of weight gain, adverse effects, and response to treatment. These data were complemented by data from 3180 students aged 18 to 22 years, which the investigators used to identify factors for early detection and prevention of obesity and mental health disorders. Following 3 weeks of treatment, 47.7% of patients with schizophrenia and 54.9% of patients with major depressive disorder showed 2 kg or more in weight gain.2 Starting weight (r = 0.115), concurrent medications (r = 0.176), and increased appetite (r = 0.275) were major predictive factors. When investigators compared monotherapy (n = 409) with polypharmacy (n = 399), they found significant issues associated with polypharmacy, including increased weight gain (P = .0005), more severe adverse effects (P = .0011), and lower response rates (schizophrenia: P = .0008; major depressive disorder: P = .0101). The student data established that obesity often begins early in life, is interconnected with personality traits such as “defeatism,” and increases the risk of developing psychosomatic disturbances, mental health problems, or somatic illnesses. Results also demonstrated ways to successfully counteract weight gain during the early stages of treatment, even though the data did not create a comprehensive and applicable model of said weight gain. The investigators listed 8 questions for their research project to address, which could then be translated into clinical practice, including the following: To what extent is obesity more prevalent among psychiatric patients compared with the general population? To what extent do psychotropic drugs induce unwanted weight gain? What are the differences in drug-induced weight gain between patients with schizophrenia (antipsychotics) and patients with major depressive disorder (antidepressants)? What are the differences between monotherapy and polypharmacy for drug-induced weight gain? What is the severity of the adverse effects that cooccur with drug-induced weight gain? What factors might predict drug-induced weight gain? To what extent does obesity start developing in early life? What factors might influence obesity in early life? This study identified several major factors that contribute to drug-induced unwanted weight gain, thereby suggesting clinically easily realizable ways of avoiding such weight gain. On average, patients receiving treatment via polypharmacy took 4.19 ± 1.92 medications, consisting of 3.08 ± 1.81 psychotropic drugs, 0.74 ± 1.15 medications that alleviate adverse effects, and 0.37 ± 0.83 other somatic medications. Also of interest was the comparison between monotherapy (n = 409) and polypharmacy (n = 399), as far more patients with major depressive disorder (56.0%) were assigned to a polypharmacy regimen than patients with schizophrenia. (32.3%). Upon performing correlation analyses, investigators found several significant interrelations between weight gain and variables that reached significance in an explorative generalized linear regression model: (1) starting weight (r = 0.11469; P = .0117); (2) number of concurrent psychotropic drugs (r = 0.16553; P = .0002); and (3) a treatment-induced “increased appetite” from the treatment outset (r = 0.27525; P < .0001). Male patients showed higher average weight gains than female patients, although the differences did not reach statistical significance. Furthermore, there was a strong correlation between unwanted weight gain and the number of concurrent psychotropic medications (r = 0.16553; P = .0002). When comparing psychotherapy to pharmacotherapy, the investigators noted that patients who received psychotherapy alone experienced only minor adverse effects (n = 24), followed by patients receiving monotherapy (n = 409); however, patients receiving polypharmacy reported more severe adverse effects (n = 399). They noted the significant difference between monotherapy and polypharmacy (P = .0011). Additionally, the data of 3180 students aged 18 to 22 years made it clear that overweight and obesity often begin early in life among those affected, and are interconnected with personality traits, while increasing the risk of developing psychosomatic disturbances, mental health problems, or somatic illnesses. The student data also cleared the way for applications aiming at the early detection and prevention of overweight and obesity. “Given these results, we think psychiatry has developed to a significant extent in the wrong direction over the past 15 years. In particular, it seems to be time for psychiatry to reconsider its treatment strategies, which are far too one-sidedly fixated on psychopharmacology and pay far too little attention to alternative options, especially in mild cases,” the study authors wrote.1 “Most importantly, the polypharmacy approach to treating [patients with major depressive disorder] or [schizophrenia] can in no way—not even rudimentarily—solve the problem that there is no causal therapy in psychiatry.” Note: This article originally appeared on Psychiatric Times

Keypoint: A study assessed the associations between the use of ADHD medications and CVD over the course of 14 years. Here's what the investigators found. Recent decades have seen increased medication use for attention-deficit/hyperactivity disorder (ADHD), including both stimulants and nonstimulants. However, long-term effects of ADHD medications on the cardiovascular system are not fully understood. There is limited evidence on whether long-term use is associated with an increased risk of cardiovascular disease (CVD), with most prior studies having an average follow-up time of no more than 2 years. This study used the nationwide health registers in Sweden to assess the associations between the use of ADHD medications and CVD over the course of 14 years. The Study Zhang L, Li L, Andell P, et al. Attention-deficit/hyperactivity disorder medications and long-term risk of cardiovascular diseases. JAMA Psychiatry. 2024;81(2):178-187. Study Funding L. Zhang: Grants from Swedish Research Council for Health, Working Life, and Welfare H. Larsson: European Union’s Horizon 2020 research and innovation program under grant agreement Study Objectives To assess the association between long-term use of ADHD medication and the risk of CVD. Methodology This was a population-based case-control study looking at all individuals in Sweden aged 6 to 64 years who either had an incident diagnosis of ADHD or had been prescribed ADHD medication between January 1, 2007 and December 31, 2020. Excluded from the study were patients with a previous CVD diagnosis, those who used ADHD medication for other indications, and those who had emigrated or died before the baseline. In this study, the investigators defined baseline (cohort entry) as the date of incident ADHD diagnosis or ADHD medication dispensation, whichever event came earlier. Patient demographics including diagnosis, medication dispensation history, socioeconomic factors, and death information were obtained from multiple Swedish nationwide registries: the Swedish National Inpatient Register, the Swedish Prescribed Drug Register, the Longitudinal Integrated Database for Health Insurance and Labor Market Studies, and the National Cause of Death Register. CVD diagnosis was defined by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) and included ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease. Each patient case—that is, a patient with ADHD who received a CVD diagnosis after initiation of ADHD medication—was matched with up to 5 controls who did not receive a CVD diagnosis. Patient cases and controls were matched based on age, sex, and calendar time to ensure similar lengths of follow-up. Each patient was followed for up to 14 years. The primary exposure was cumulative duration of ADHD medication use, and the primary outcome was incident CVD. Conditional logistic regression analyses were used to estimate odds ratios for the associations between cumulative durations of ADHD medication use and incident CVD. The crude odds ratios were adjusted for all matching variables, which included age, sex, and calendar time. The adjusted odds ratios (AORs) were additionally controlled for country of birth (Sweden vs another country), highest educational level, and diagnoses of somatic and psychiatric comorbidities before baseline. Study Results The study’s treatment effect showed that longer use of ADHD medications was associated with increased CVD risk compared with nonuse (1 to ≤ 2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤ 3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤ 5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and > 5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Specifically, there was a significant association of long-term ADHD medication use with hypertension (AOR, 1.72 [95% CI, 1.51-1.97] for 3 to ≤ 5 years) and arterial disease (AOR, 1.65 [95% CI, 1.11-2.45] for 3 to ≤ 5 years). There were no statistically significant associations for arrhythmias, heart failure, ischemic heart disease, thromboembolic disease, or cerebrovascular disease. Throughout the study’s follow-up, each 1-year increase in the use of ADHD medications correlated with a 4% increased association of CVD (95% CI, 1.03-1.05) and an 8% increased association in the first 3 years (95% CI, 1.04-1.11). There was a rapid increase in association for the first 3 cumulative years, but the association stabilized thereafter. The association between CVD and ADHD medications increased with higher average defined daily doses (DDDs; eg, 30 mg methylphenidate or 80 mg atomoxetine), with a statistically significant risk found only among individuals with a mean dose of at least 1.5 times the DDD. Researchers found a 4% increased risk for individuals receiving 1.5 to 2 times the DDD, whereas they found a 5% increased risk for individuals receiving more than 2 times the DDD. Looking at specific classes of ADHD medications, atomoxetine’s association with CVD was significant only for the first year of use, with an AOR of 1.07 (95% CI, 1.01-1.13). For methylphenidate use vs no use, the AOR was 1.20 (95% CI, 1.10-1.31) for 3 to 5 or fewer years. For greater than 5 years, the AOR was 1.19 (95% CI, 1.08-1.31). The data for lisdexamfetamine use vs no use showed an AOR of 1.23 (95% CI, 1.05-1.44) for 2 to 3 or fewer years. Across groups, researchers observed similar associations in females and males. Conclusions The results of this population-based case control study suggest that long-term ADHD medication use was associated with an increased risk of CVD, specifically hypertension and arterial diseases. The observed risk of CVD was greater when stimulant medications were used in comparison with nonstimulant medications to treat ADHD. There was also a significant association between the cumulative duration of ADHD medication use and increased risk of CVD. Practical Applications Long-term use of ADHD medications is associated with CVD. It is important to weigh the risks and benefits of this treatment modality with every patient. It is also important to closely monitor patients for the signs and symptoms of CVD in those who are taking these medications. Bottom Line This nested case-control study followed patients for 14 years and found that long-term ADHD medication use was associated with CVD, specifically hypertension and arterial diseases. Note: This article originally appeared on Psychiatric Times

Welcome everyone. I'm Dr. John White. I'm the chief medical officer at WebMD. Does your biologic sex impact your health? Does it have any play in how you're diagnosed, how you're treated in terms of what symptoms you have? Of course it does. We all know that. But that's not something that many people believed 5, 10 years ago, certainly not 20 years ago. And it was only because of leaders like my guest today, Phyllis Greenberger, who really championed the need for research on women's health. She has a new book out, which I love. It's called Sex Cells: the Fight to Overcome Bias and Discrimination in Women's Healthcare. Please welcome my very good friend, Phyllis Greenberger. Thank you. Phyllis. It's great to see you today. It's great to see you as well. Now, you and I have been talking about this for easily 2 decades. At least. And some people think, oh, of course it makes sense. Although I saw you disagreeing that not everyone still believes that. But what has been that journey? Why has it been so hard to make people understand, as you point out early on in your book, women are not smaller men? I think the basic reason was that it was just believed that men and women were the same except for their reproductive organs. So minus the reproductive organs, whether it was a device, a diagnostic, or therapeutic, if it was used and successful on a male, that it would be successful on a female. We're really very far from understanding the differences, and there's still a lot of distrust and disbelief and ignorance about it. And so there's still a long way to go. But you talk about that in the book, that there's still a long way to go. Why is that? What's the biggest obstacle? Is it just misinformation, lack of information? People don't understand the science? There's still resistance in some areas. Why is that? I think it's misinformation, and I gave a presentation, I don't know how many years ago, at least 20 years ago, about the curriculum. And at the time, there was no women's health in the curriculum. It was health. So if it was on cardiovascular issues or on osteoporosis, it was sort of the basic. And at the time, there would maybe be one woman whose job was women's health, and she'd have an office, and otherwise there was nothing. And maybe they talked about breast cancer, who knows. But I spoke to someone just the other day, in view of all the attention that the book is getting now, whether that's changed, whether it's necessary and required. And she said it's not. So, it's not necessarily on the curriculum of all research and medical institutions, and even if women's health, quote unquote, is on the curriculum, it doesn't mean that they're really looking at sex differences. And the difference is obvious. I mean, gender is really, it's a social construct, but biological sex is how disease occurs and develops. And so if you're not looking, and because there's so little research now on sex differences that I don't even know, I mean, how much you could actually teach. So what needs to change? This book is a manifesto in many ways in how we need to include women; we need to make research more inclusive of everyone. But we're not there yet. So what needs to change, Phyllis? During this whole saga of trying to get people to listen to me and to the society, we really started out just looking at clinical trials and that, as you mentioned, I mean, there are issues in rural communities. There's travel issues for women and child care. There's a lot of disbelief or fear of clinical trials in some ethnicities. I do think, going to the future, that technology can help that. I mean, if people have broadband, which of course is also an issue in rural areas. What could women do today? What should women listeners hear and then be doing? Should they be saying something to their doctor? Should they be asking specific questions? When they interact with the health care system, how can they make sure they're getting the best care that's appropriate for them when we know that sex cells matter? Well, that's a good question. It depends on, frankly, if your doctor is aware of this, if he or she has learned anything about this in school, which, I had already said, we're not sure about that because research is still ongoing and there's so much we don't know. So I mean, you used to think, or I used to think, that you go to, you want a physician who's older and more experienced. But now I think you should be going to a physician who's younger and hopefully has learned about this, because the physicians that were educated years ago and have been practicing for 20, 30 years, I don't know how much they know about this, whether they're even aware of it. Phyllis, you are a woman of action. You've lived in the DC area. You have championed legislative reforms, executive agendas. What do you want done now? What needs to be changed today? The curriculum is going to take time, but what else needs to change? That's a good question. I mean, if curriculum is going to take a while and you can ask your doctor if he prescribes the medication, whether it's been tested on women, but then if it hasn't been tested on women, but it's the only thing that there is for your condition, I mean, so it's very difficult. The Biden administration, as you know, just allocated a hundred million dollars for women's health research. What do you hope to accomplish with this book? Well, what I'm hoping is that I spoke to someone at AMWA and I'm hoping – and AMWA is an association for women medical students. And I'm hoping that's the audience. The audience needs to be. I mean, obviously everybody that I know that's not a doctor that's read it, found it fascinating and didn't know a lot of the stuff that was in it. So I think it's an interesting book anyway, and I think women should be aware of it. But really I think it needs to be for medical students. And to your credit, you built the Society for Women's Health Research into a powerful force in Washington under your tenure in really promoting the need for Office of Women's Health and Research in general. The book is entitled Sex Cells, the Fight to Overcome Bias and Discrimination in Women's Healthcare. Phyllis Greenberger, thank you so much for all that you've done for women's health, for women's research. We wouldn't be where we are today if it wasn't for you. So thanks. Thank you very much, John. Thank you. I appreciate the opportunity. This interview originally appeared on WebMD on May 23, 2024 Note: This article originally appeared on Medscape

What is dialectical behavior therapy (DBT)? Dialectical behavior therapy (DBT) is a type of talk therapy (psychotherapy). It’s based on cognitive behavioral therapy (CBT), but it’s specially adapted for people who experience emotions very intensely. Cognitive behavioral therapy (CBT) is a type of talk therapy that helps people understand how thoughts affect emotions and behaviors. “Dialectical” means combining opposite ideas. DBT focuses on helping people accept the reality of their lives and their behaviors, as well as helping them learn to change their lives, including their unhelpful behaviors. Dialectical behavior therapy was developed in the 1970s by Marsha Linehan, an American psychologist. What is dialectical behavior therapy (DBT) used for? Dialectical behavior therapy (DBT) is especially effective for people who have difficulty managing and regulating their emotions. DBT has proven to be effective for treating and managing a wide range of mental health conditions, including: Borderline personality disorder (BPD). Self-harm. Suicidal behavior. Post-traumatic stress disorder (PTSD). Substance use disorder. Eating disorders, specifically binge eating disorder and bulimia. Depression. Anxiety. It’s important to note that the reason DBT has proved effective for treating these conditions is that each of these conditions is thought to be associated with issues that result from unhealthy or problematic efforts to control intense, negative emotions. Rather than depending on efforts that cause problems for the person, DBT helps people learn healthier ways to cope. DBT skills aim to help enhance your capabilities in day-to-day life. The four skills your therapist will teach include: Mindfulness: This is the practice of being fully aware and focused in the present instead of worrying about the past or future. Distress tolerance: This involves understanding and managing your emotions in difficult or stressful situations without responding with harmful behaviors. Interpersonal effectiveness: This means understanding how to ask for what you want and need and setting boundaries while maintaining respect for yourself and others. Emotion regulation: This means understanding, being more aware of and having more control over your emotions. Source: Cleveland Clinic

Teens with classmates who have a mental illness have a significantly greater risk for a psychiatric diagnosis later in life, even after controlling for parents' mental health history and other factors, a new study suggested. The research provides new evidence that adolescents within a specific peer network may possibly "transmit" mental disorders such as depression and anxiety to each other, the investigators noted. Having a classmate with a mental illness was associated with a 3% higher risk for subsequent psychiatric diagnosis, researchers found. The risk was highest — 13% — in the first year of follow-up and was strongest for mood, anxiety, and eating disorders. The study is said to the be the largest to date on the topic, including data on more than 700,000 ninth graders in Finland who were followed for up to 18 years. At least one expert noted that the numbers are higher than he would have expected, but the investigators were quick to caution the study doesn't prove having a classmate with a mental illness leads to later psychiatric diagnosis among peers. "The associations observed in the study are not necessarily causal," lead investigator Jussi Alho, PhD, a postdoctoral researcher at the University of Helsinki, Helsinki, Finland, told Medscape Medical News. "The study did not investigate the mechanisms that explain the observed associations." The results were published online on May 22 in JAMA Psychiatry. Few Data Previous studies have reported a clustering of mood symptoms, eating disorders, and other psychiatric illnesses among adolescent and adult social networks. But most involve self-selected peer groups. "Investigating the transmission of mental disorders is especially important in childhood and adolescence," the authors noted. "Yet, despite a few survey studies reporting that adolescents may experience increased mental health symptoms when exposed to friends or peers with mental health problems, large-scale studies on the potential peer influences of mental disorders in youth are lacking," the authors wrote. Researchers used a database of 713,809 students in the ninth grade, about half boys and half girls. All were born between January 1, 1985, and December 31, 1997. About 47,000 were excluded as they had a mental disorder diagnosis before the study began. Some 666,000 students in 860 schools were followed from ninth grade until the first diagnosed mental disorder, death, emigration, or the end of the study in 2019. Median follow-up was 11.4 years. Diagnoses were gathered from Finnish registries for inpatient, outpatient, and primary care and included ICD-9 and ICD-10 diagnoses for substance misuse disorders, schizophrenia spectrum disorders, mood disorders, anxiety disorders, eating disorders, emotional and social-functioning disorders, and hyperkinetic and conduct disorders. The authors adjusted for sex, birth year, school and ninth-grade class size, area-level urbanicity, area-level morbidity, area-level education, area-level employment rate, parental educational level, and parental mental health, with a random intercept per school. Dose-Response Relationship Overall, a quarter (167,227) of the students were diagnosed with a mental disorder. The risk of being diagnosed with any mental disorder was 3% higher during the entire follow-up period (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04). Risk was highest in the first year of follow-up (HR, 1.13; 95% CI, 1.08-1.18) and then rose again in years 4 and 5, when the risk was 5% higher with one diagnosed classmate and 10% higher with more than one diagnosed classmate. The risk was significantly increased for mood, anxiety, and eating disorders in each follow-up time window. Investigators also noted a dose-response relationship: The more classmates with a psychiatric illness, the greater the risk for later mental illness. "These findings suggest that mental disorders may be transmitted within adolescent peer networks," the authors wrote. The researchers chose to describe the spread of mental disorders among peer classmates as "transmission" in part because it has been previously used in the literature, Alho said. Alho said the researchers also believe that transmission is an accurate term to describe the potential mechanisms by which mental disorders may spread. The authors hypothesized that more students might be diagnosed when disorders are normalized, through increased awareness and receptivity to diagnosis and treatment. Conversely, the rate of disorders might also have increased — especially in the first year of follow-up — if there were no students in the peer network who had been diagnosed, the authors added. Without an example, it might discourage a student to seek help. The authors also noted that it's "conceivable that long-term exposure to a depressive individual could lead to gradual development of depressive symptoms through the well-established neural mechanisms of emotional contagion." New Direction for Treatment? Commenting on the findings for Medscape Medical News, Madhukar H. Trivedi, MD, the Betty Jo Hay Distinguished Chair in Mental Health at UT Southwestern Medical School, Dallas, said that the theory that having classmates with psychiatric illness could normalize these conditions has merit. Once someone is diagnosed or receives treatment, "their peers kind of get implicit permission to be able to then express their own symptoms or express their own problems, which they may have been hiding or not recognized," he said. However, Trivedi disagreed with the authors' suggestion that the rate of disorders might also have increased if no classmates had received a psychiatric diagnosis, noting that it was unlikely that a student would not have been exposed to depression, anxiety, or another mood disorder — through a peer or family member — given how common those illnesses are. "The numbers are slightly higher than I would have expected," Trivedi said, adding that peer influence having that type of impact "is something that has not been shown before." The study is notable for its use of comprehensive registries, which helped solidify the data integrity, Trivedi said, and the results offer some potential new directions for treatment, such as adding peer support. That has been found useful in adult treatment but has been less utilized with adolescents, he said. The study was funded by the European Union and the Academy of Finland. The authors reported no relevant financial relationships. Note: This article originally appeared on Medscape

Keypoint:Polypharmacy is often overlooked in patients with significant traumatic brain injury. How can you best manage medication in these patients? The issue of polypharmacy is often overlooked in patients with significant traumatic brain injury (TBI). In the acute setting—which includes the emergency department, critical care unit, and hospital floor—attention is appropriately fixed on survival and medical stabilization. To that end, interventions range from neurosurgical to pharmacological. In a typical severe TBI scenario, it is not unusual for a patient to undergo multiple surgical procedures (eg, craniotomy/craniectomy, ventricular drains, various orthopedic procedures to address polytrauma, tracheostomy, gastrostomy tube placement). The science behind the acute management of TBI is evolving, and any intervention that improves survival and reduces long-term morbidity is worthwhile. But as patients recover, many of the pharmacological interventions become counterproductive and should be discontinued. TBI is increasingly recognized as a chronic disease with chronic impairments. Therefore, the majority of care for the patient with TBI occurs post hospital. This care is often highly fragmented and many opportunities to reduce medications and avoid polypharmacy and comorbidity can be missed. Many categories of medication frequently used in patients with TBI can contribute to polypharmacy. Some medications sedate and cloud the sensorium, potentially limiting recovery. This group includes antipsychotics, anxiolytics, antiepileptics, and opiates. Another group includes preventive medications, whether for deep venous thrombosis (DVT) and pulmonary embolism (PE), seizures, or headaches. Yet another group might be referred to as convenience medication; for example, as-needed antiemetics. There are also medications directed at specific and frequent associated conditions such as syndrome of inappropriate antidiuretic hormone secretion (SIADH), cerebral salt wasting, autonomic dysfunction, neurogenic bowel/bladder, and so on. This article will attempt to address each medication briefly. What is important for clinical practitioners to know is that every successive evaluation is an opportunity to reexamine the medication list for necessity. Some of the most problematic contributors to polypharmacy are the most common: sedating medications. Antipsychotics, typically used in acute settings to manage behavioral complications of TBI, or in rare cases actual psychosis, are generally detrimental to TBI recovery in the long term, unless the patient is diagnosed with psychosis. Similarly, benzodiazepines are generally detrimental unless used for very specific and time-limited purposes such as obtaining diagnostics, performing procedures, and the like. In addition, like opiates, the addictive potential of these medications in a patient with TBI and associated impulsivity is high. Opiate medications are unfortunately frequently necessary in patients with TBI, at least temporarily, as there is frequently associated polytrauma. These medications carry known and varied risks as mentioned, including addictive potential. Awareness of the individual risks of each of these medications, as well as the cumulative effects of polypharmacy involving multiple agents, is paramount. Recovery from TBI is already difficult for a patient combating impaired sensation due to impairments in vision, proprioception, balance, spatial awareness, language, vertigo, and so on. Unnecessary sedation from medication does not improve the process. Antiepileptic medication is frequently initiated prophylactically during acute care for any patient who has a TBI with intracranial bleeding, and continued use is appropriate for patients who do experience seizure disorder post TBI. However, in patients without a history of seizure post TBI, guidelines suggest that this is not recommended beyond 7 days.1 Many antiepileptics have significant drug-drug interactions, pharmacokinetic impact, and other adverse effects. Older antiepileptics such as carbamazepine, oxcarbazepine, phenytoin, and phenobarbital have significant effects on cytochrome P450 enzymes. This leads to pharmacokinetic effects and risk for changes in serum drug levels. Valproic acid can similarly affect circulating drug levels through other mechanisms. Newer antiepileptics have less dramatic effect on serum drug levels but many remain hepatically metabolized, and therefore drug levels should be monitored and dosage adjusted. Fortunately, levetiracetam, considered a first-line agent by many for management of epilepsy post TBI, does not frequently alter the serum level of other drugs in clinical practice. In addition to seizure prophylaxis or management, some of these medications are also commonly used for various other purposes in the TBI population, including headache prevention (eg, topiramate), behavioral intervention (eg, lamotrigine, valproic acid), or neurogenic pain management (eg, gabapentin, pregabalin). These can be effective and beneficial, but as patients improve clinically over time, ongoing use should be addressed. Many patients with TBI suffer from immobility as a consequence, whether transiently or long term. In either instance, acute immobility confers risk for DVT/PE, which some patients do experience during their illness.2 Patients are commonly discharged on prophylaxis for treatment of DVT/PE. This may be with either heparin, low molecular weight heparin, warfarin, or one of the novel anticoagulants. All these medications carry their own adverse effect profiles, and many have significant polypharmacy risks due to drug-drug interactions and pharmacokinetic impacts. In cases where a patient’s mobility improves, prophylaxis should be discontinued appropriately. Other individuals with anticipated long-term immobility still do not benefit from prophylaxis indefinitely, because the risk for DVT/PE in this context wanes over time. Appropriate guidelines related to the duration of treatment for DVT or PE should be adhered to, with medication discontinued when appropriate.3 TBI is also frequently associated with other secondary complications. Disorders of homeostasis such as the SIADH or cerebral salt wasting can result in the addition of fluid restriction or the use of salt tabs and/or fludrocortisone. It is not uncommon for this condition to remain unresolved at the time of discharge from the hospital. However, most often this condition will resolve over time with recovery, and these interventions can then be discontinued. Various other medications, used during acute care to manage hypertension, hyperglycemia, nausea/vertigo, and so on, are frequently prescribed at the time of discharge. With patient improvement, these can also unnecessarily contribute to polypharmacy. This list is exhaustive, but the primary objective here is to highlight the beneficial role of a care provider paying close attention during each visit to the medication list and the ongoing indications (or lack thereof). Finally, as patients proceed through the recovery process, still other medications can be added. Antidepressants, headache prevention or abortive medications, antiepileptics, and many others may be clinically indicated, some even permanently. However, in all cases, vigilance on behalf of all treatment providers as to the polypharmacy concerns remains vital.

Keypoint: A more useful measure than BMI or waist circumference? Researchers analyzed the association between weight-adjusted waist index and depressive symptoms. CASE VIGNETTE “Ms Gray” is a 42-year-old Caucasian female with a 15-year history of recurrent, severe major depressive disorder (MDD) with psychotic features. She also has significant symptoms of anxiety. She does not smoke, drink alcohol, or use illicit drugs. She meets the criteria for obesity, with a current body mass index (BMI) of 33. She currently takes a selective serotonin reuptake inhibitor and sees a psychologist for cognitive-behavioral therapy. At an outpatient clinic visit, she reports increased interest in exercise. She says she plans to walk in the morning with a neighbor friend. She asks about the potential beneficial effects of exercise on her depression. As her psychiatrist, how would you respond? Depression is the leading cause of disability worldwide.1 Obesity is a replicated risk factor for the onset of depressive symptoms, with a magnitude of >50%.2 Conventional measures of obesity include BMI and waist circumference (WC). However, BMI does not distinguish between visceral fat and muscle mass; similarly, WC does not distinguish between visceral and subcutaneous fat. Weight-adjusted waist index (WWI) has been proposed as a new index of obesity reflecting central obesity, which standardizes WC to better reflect adiposity and muscularity.3 However, the relationship between WWI and depressive symptoms is unknown. The Current Study Liu and colleagues4 investigated associations between WWI and depressive symptoms in the National Health and Nutrition Examination Survey (NHANES) and made comparisons with traditional obesity indices. NHANES data are freely available in the public domain. Data were included for 32,374 participants from 7 2-year cycles (2005 to 2018). Exclusion criteria were age <20 years, pregnancy, and missing data on WC, weight, and/or depressive symptoms. WWI is calculated as the ratio of WC (in cm) to the square root of weight (in kg) (ie, WWI = WC / √ [Weight]). Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9). Additional covariates included age, sex, race/ethnicity, smoking, diabetes, hypertension, alcohol consumption, household income, education level, lipid panel, WC, BMI, and the poverty rate. Differences in demographic variables by WWI quartiles were investigated with t-tests and chi-square tests. Linear associations between WWI, WC, BMI, and depressive symptoms were analyzed using weighted multiple linear regression and logistic regression. The mean participant age was 50 years, 50% of participants were male, and 43% were non-Hispanic white. The mean WWI was 11.1 ± 0.9. There were 2810 participants (9%) with PHQ-9 scores ≥10, which was used as the definition of depressive symptoms. Higher quartiles of WWI were more likely to be female, non-Hispanic white, Mexican American, and smokers, and to drink more alcohol and have diabetes and hypertension. Higher WWI was also associated with higher total and LDL cholesterol, triglycerides, BMI, and WC, and lower education and HDL cholesterol. In a regression model adjusting for age, sex, race/ethnicity, smoking, diabetes, hypertension, alcohol consumption, household income, education level, lipid panel, and the poverty rate, the WWI (as a continuous measure) was associated with depressive symptoms (OR=1.18, 95% CI 1.05-1.34) more strongly than either BMI or WC (OR=1.01 for both). Participants in the highest (versus lowest) quartile of WWI were almost 1.5 times more likely to have depressive symptoms, after controlling for potential confounders (OR=1.49, 95% CI 1.14-1.96). Subgroup analyses indicated that this association was not moderated by age, sex, race/ethnicity, smoking, diabetes, or hypertension. Study Conclusions The investigators concluded that WWI was robustly associated with depressive symptoms with a significantly higher magnitude than either BMI or WC. Study strengths include the use of a large, nationally representative study sample and consideration of many potential confounding factors. Study limitations include the cross-sectional design (which limits causal inferences), the use of a self-report depression measure, and the absence of information on the duration of depressive symptoms and antidepressant treatments. The Bottom Line The weight-adjusted weight index was a stronger predictor of depressive symptoms than either BMI or WC. The WWI represents a potentially useful measure in clinical practice. Note: This article originally appeared on Psychiatric Times