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Riding on a judicial victory challenging the US Drug Enforcement Administration's (DEA's) denial of a petition to move psilocybin from schedule I to schedule II, the plaintiffs said they will soon be back in court to try to force the agency to allow the use of the psychedelic under state right-to-try laws, which aim to provide terminally ill patients with access to experimental treatments that have not yet been fully approved by the US Food and Drug Administration (FDA). The petition is just one avenue being pursued by the Seattle, Washington-based AIMS Institute, which is seeking to use the drug to help ease anxiety in patients with cancer. Last fall, in a scathing response to the DEA, a three-judge panel of the US Court of Appeals for the Ninth Circuit told the agency that it had failed to follow its own procedures and had obfuscated how it came to the conclusion that the petition, filed in 2022 by Sunil Aggarwal, MD, and AIMS, should be denied. The court said the DEA needed "to either clarify its pathway for denying Aggarwal's petition" or, alternatively, to "reevaluate Aggarwal's petition on an open record." The Ninth Circuit response renders moot a lawsuit filed by Aggarwal to force a DEA explanation of its refusal to reschedule psilocybin. Shane Pennington, an attorney with Porter Wright who is representing AIMS, said, "it's a huge deal to have DEA's denial of a rescheduling petition declared unlawful and set aside." "The only thing we didn't get is we wanted the court to direct them to send the petition to the FDA as the statute requires," Pennington told Medscape Medical News. The 'Right Thing' to Do The court also did not order the DEA to respond or to do so within any set period. But if the DEA delays "too much," AIMS has the right to go back to court and demand action, Pennington said. "I suspect that if they haven't done anything in 6 months to a year, the court would be frustrated by that," he added. Attorney Kathryn Tucker, director of advocacy for the National Psychedelics Association, who has also been representing AIMS, said her clients are happy with the Ninth Circuit response. However, they wish the judges had been more directive with the DEA, Tucker told Medscape Medical News. "We are at a moment where one would hope that the agency will finally stop obstructing and delaying and do the right thing," she said. Mason Marks, MD, project lead of the Project on Psychedelics Law and Regulation at Harvard Law School's Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics, said he does not expect the DEA to approve the rescheduling petition, but that the agency may provide "a more detailed response that actually has some more substance to it." Marks cites the DEA's long history of refusing to reschedule cannabis, saying it "doesn't really bode well for people who are advocating to reschedule psilocybin." The agency will likely only reconsider psilocybin when there is an FDA-approved product that it can reschedule, said Marks. For instance, when the FDA approved the cannabis-derived drug Epidiolex in 2018, the DEA moved it to schedule V several months later. Compass Pathways is developing a psilocybin product, which is currently being tested in trials for treatment-resistant depression. That drug may not be approved until 2027 at the earliest, said Marks. If it were to be approved, "the DEA would reschedule that particular formulation of psilocybin, but that formulation alone," he said. "It just doesn't seem like there's any possibility that the agency would willingly do anything else before then," said Marks. Next Best Chance Tucker said that the next best chance to pressure the agency is through another suit brought by AIMS that seeks to allow use of psilocybin under state right-to-try laws. In 2021, the DEA denied AIMS' request to waive Controlled Substances Act prohibitions against psilocybin use, citing right-to-try laws. AIMS then sued, and the Ninth Circuit in 2022 threw out the case on a technicality. But AIMS had an avenue to reframe its arguments, and the case is now again pending before the Ninth Circuit, which is one of the courts that adjudicates administrative law. AIMS and the federal government are submitting briefs, and arguments could be heard as soon as summer 2024, said Tucker. For a treatment to be eligible for right-to-try, it must have completed an FDA-approved phase 1 clinical trial; be in an active trial that would form the basis of an application for approval or already is part of an approval application; and be in ongoing active development or production and not discontinued by the manufacturer or placed on clinical hold. Psilocybin meets all of these conditions, said Tucker. "A single guided treatment with psilocybin therapy for a dying cancer patient has been shown time and again to bring immediate, substantial, and sustained relief. The right to try argument is very strong," she said. Forty-one states have passed right-to-try laws. Pennington said that AIMS will argue that the federal right-to-try law, which sets a template for states, trumps the Controlled Substances Act. The plaintiffs are asking the court to declare the DEA's refusal to create a pathway for psilocybin use under those right-to-try statutes to be unlawful, said Pennington. "I believe we will prevail," said Tucker. However, Tucker is also a realist. "There is no quick path to victory here," she said. Easing Psychological Suffering She also noted that several pieces of legislation have been introduced in the US Congress that could help facilitate research and allow compassionate use of psychedelic therapies like psilocybin and 3,4-methylenedioxy methamphetamine (MDMA). The Breakthrough Therapies Act (Senate Bill 689) would expedite the transfer of substances that receive breakthrough therapy designation from the FDA from schedule I to schedule II. So far, both psilocybin and MDMA have been designated as breakthrough therapies. The bill has not received any congressional action since its March 2023 introduction. Similarly, the Right-to-Try Clarification Act (House Bill 1825) has not seen any action since its introduction. That legislation would specifically exempt drugs eligible for right-to-try from restrictions under the Controlled Substances Act (CSA). Congressional pressure will not likely move the needle, said Marks. He has argued for reform of the CSA. It would make more sense "to have a public health agency making decisions that at least in theory should primarily be directed at improving public health," he noted. Arguably, scheduling does not prevent the harms associated with substance use, Marks added. "Scheduling hasn't prevented opioid overdose deaths. I don't know that there's any evidence to suggest that scheduling improves safety in any meaningful way. It does, however, inhibit the ability to do research." Tucker said she will keep pushing on every available front. "The obvious gap in the palliative care toolbox is a tool for the relief of nonphysical suffering, and psilocybin is that tool." "It's really essential that everyone in patients' rights, hospice and the palliative care movement stand up and insist that it be available sooner rather than later," Tucker added. Note: This article originally appeared on Medscape

COMMENTARY The trauma inflicted during the Hamas attack on October 7, 2023, is being experienced by vulnerable individuals worldwide, as Ofrit Shapira-Berman, PhD, a psychoanalyst supporting victims and their families, explains in our conversation. In the immediate area of conflict, not only Israelis but also Palestinians are being held hostage by Hamas and the perpetrators of the violent attacks, as they continue to bring death and destruction on the residents of Gaza and the individuals in Israel mourning their losses and waiting for the 136 men, women, and children being held hostage. Adding insult to injury, many Jewish individuals have felt the impact of rising antisemitism worldwide. The hate and the rhetoric have caused harm to innocent individuals on both sides and impact humanitarian relief and healing. The trauma is multiplied by history of the Holocaust (many Holocaust survivors live in Israel, some of whom were victims of the October 7 attacks and/or witnessed the violence in a land they had deemed safe), and the shocking willingness of much of the world to look away from the genocide that was perpetrated against the Jews. The widespread, ideologically fueled denial of sexual violence perpetrated by Hamas as well as the International Court of Justice taking up a charge of genocide against Israel with no probable cause has added to the trauma. An expert on international law who has represented Palestinian interests has noted that sometimes an accusation of genocide becomes an incitement to genocide.1 This undoubtedly adds to fear and trauma. Fostering resiliency involves acknowledging the trauma and finding ways to move forward. Fortunately, there are outlets. For those seeking legal recourse against hate speech misrepresented as free speech, there is a movement to seek civil damages for the harms caused by such speech. For those treating or consulting to clinicians treating victims and survivors, in addition to the therapeutic approaches outlined by Dr Shapira-Berman, engaging patients in creativity can be one way of helping them grieve.3 Hyman Bloom’s Child in the Garden, painted in the immediate aftermath of the Holocaust, can serve as a model for such therapeutic exploration through art. Harold J. Bursztajn, MD: What has been the impact on the bereaved, families of hostages, and traumatized victims of kidnapping, rape, and humiliation? Ofrit Shapira-Berman, PhD: The trauma is so profound and unprecedented—it seems to be very different from “regular” losses normally endured by people. It is partly because each of the victims had endured multiple traumas, simultaneously. For example, people at the kibbutzes were locked in their shelters for hours. They heard terrorists outside their homes shout in Arabic, they heard the shooting all around them, they were shot at, and their homes were invaded. They witnessed their loved ones being shot, wounded, and killed. At the extreme, their loved ones were abused and slaughtered right before their eyes. Many houses were burned with the victims in them as an attempt to make them run out—then they were murdered. In the community WhatsApp group, members of the community were texting—crying for help and reporting what was going on—so everyone was exposed to all the various atrocities that took place. People who survived the attack emerged with their world shattered, in terms of their trust and morals. Everything they have ever believed in was completely shattered. Terrorists were able to invade their homes, the army did not appear for hours on end, so their trust is totally shattered. In terms of morals, the fact that human beings could be so cruel—abuse, slaughter, cutting off people’s limbs, gouging their eyes, and burning children alive, then eating, drinking, and laughing before and after—is something no human mind can contain. The effects of such horrific acts lead the survivors not only to doubt the possibility of living with their neighbors, but to doubt humanity as a whole. The same can be said for the survivors of the NOVA Festivals. The things they witnessed and experienced are outside of one’s imagination, and 2 of the things they refer to are 1) the extent of the terrorists’ cruelty and 2) the fact that the terrorists were smiling as they were slaughtering people. It seems that the Hamas’ sadism was one of the main factors that extinguished Israelis’ trust in humanity. I presume that it goes as far as “humanity” because the atrocities were so horrific. It magnifies one’s shattered trust. Bursztajn: What has been the impact of denial of the Hamas attack (eg, the refusal—including from feminist organizations around the world—to acknowledge the rape of Israeli women and the United Nations’ delay in investigating Hamas)? Is such denial and suppression of conversation foreseeably harmful to survivors? Shapira-Berman: The Holocaust is a fundamental aspect of the Jewish and Israelis’ ethos. This ethos has 3 basic components: 1) the hatred of Jews merely for being Jewish, 2) the determination and cruelty of the Nazis, and 3) the silence of the world, at least for a long time. Jews were left to be burned, murdered in the gas chambers, and prisoned and tortured in the camps. Eventually, the world stepped in, but for many, it was too little and too late. The events of October 7, 2023, brought to the surface the Holocaust as a common metaphor. Of course, there are significant differences. Jews have a state and an army, and the Hamas, however vicious they are, are not an existential danger. However, the silence of the world and the apparent antisemitism is a dark reminder of those days. Surviving such horrific violence, only to be blamed for it, is an additional trauma to what was already suffered by the victims. The world’s avoidance and reluctance to condemn the Hamas and other terrorists, and to acknowledge brutal rape, adds to what the Hamas did on October 7. It is not an exaggeration to suggest that this silence is an additional act of killing of the survivors’ minds and psyches. Bursztajn: How have victims of the Hamas attack, and Israelis in general, shown resilience? How can such resilience be effectively supported? Shapira-Berman: The civilians’ resilience and resourcefulness were extraordinary—both from those exposed to the atrocities and from those who lived elsewhere. People in the kibbutzes fought fiercely and with endless courage, often endangering their own lives, in their attempts to save other members of their community. For hours, they fought thousands of terrorists who invaded their homes, all alone, until the Israel Defense Forces (IDF) special forces arrived. The resilience could be seen in some of the most famous footage that was published of an 84-year-old woman who was kidnapped and taken to Gaza and was seen sitting among her kidnappers with a thin, serene, almost smile on her face. It was such an extraordinary sight that people wondered whether she was suffering from dementia. Her children said she was as lucid as possible and that this was an expression of her strengths and resilience. The civilian population showed its resilience by organizing, immediately, and setting up a war room, replacing almost all of the formal authorities, within hours of Saturday morning. Thousands of civilians not only joined the army, but started gathering food, clothing, and all other necessities for the victims of the attack who had been evacuated from their homes. Some of them went to the south to save the injured. Civilians, who were on the verge of a civil war for 10 months prior to October 7 after the political coup of Netanyahu’s government, united immediately in their support of the victims, the survivors, the bereaved families, and the combat soldiers fighting in the south. The victims themselves were able to hold in their rage and express their unity with the rest of the Israeli society and the IDF, although they did feel betrayed by the “state” and the army. With much dignity, they have been able to postpone whatever needs to be examined until after the war. Israelis’ reliance can, and should, be supported by a global recognition of the atrocities and the horrible suffering they endured. Such recognition and acknowledgment act as empathic witnessing—the opposite of the ignorant and indifferent bystander. Bursztajn: What are effective treatments for trauma like this? Can individuals who have suffered in different ways benefit from different forms of treatment? Shapira-Berman: Therapists have mainly been using the following interventions: Support: recognition and acknowledgement of the atrocities, their effects, and the individuals’ attempts to survive them -Short-term therapy: both dynamic and cognitive behavioral therapy (CBT)/eye movement desensitization and reprocessing (EMDR) Long-term therapy: both analytic and trauma informed; survivors, bereaved family members, and the hostages who are back are just beginning these therapies now For NOVA Festival survivors, specific locations were opened in which various kinds of alternative methods were combined with the more classical ones. In addition to these methods, these places employed therapies that focus on psychedelic drug usage, as many of the NOVA survivors had been using them at the party. Bursztajn: How has the denial of Hamas horrors, including the systematic rapes of Israeli women, impacted victims of sexual violence worldwide and of other recent genocides (ranging from the Shoah to Biafra and beyond), as well as emboldened antisemitism and racism? What can be done to detoxify this worldwide impact? Shapira-Berman: I think this is one of the most painful aspects of the October 7 events. I find this issue of sexual abuse to be the most difficult of all for the Israeli citizens to contain. Most say, “I cannot handle this. This is too much for me.” I think its effect on women in general, but especially Jewish women, is horrible. What can we think now, other than that our lives do not matter, women’s lives do not matter, and Jewish women’s lives do not matter at all? I cannot believe that if American women were raped, as a war crime, the world would react in the same way. This is being understood in Israel as another manifestation of antisemitism, and it should be addressed as such. I think it is not only women’s organizations that should be approached. I refuse to see sexual violence as a “women’s issue.” It is a human issue and should be addressed as one. Men who rape women (and other men as well, as was the case on October 7) should be perceived and judged as war criminals, and those who perceive themselves as the gatekeepers of the moral civilization should all stand up and shout, no more. The violence that took place on October 7 should not be regarded as a problem of the Israelis, but as a problem of the whole world. World leaders who permit such violence are bringing the world nearer to its end. How to detoxify the effects of double standards relative to Israeli self-defense efforts? For instance, what does it mean to the survivors you are treating that some American politicians insist that conditions be placed on military assistance to Israel that were not placed in instances such as aid to the Iraqi army in liberating Mosul from ISIS? Bursztajn: How can restorative justice be helpful in the face of such trauma? How might restorative justice be achieved? Shapira-Berman: I cannot see it happening in the near future. No survivor will be able to forgive the Hamas and those who support them for any of the horrific things that took place on October 7. Bursztajn: Is there anything else you would like to share with your colleagues in the United States? Shapira-Berman: No therapist can allow herself, or himself, to stay silent or to remain an innocent/ignorant bystander when children are being burned alive; people are having their limbs cut off while they are still alive; women are being raped, abused, and then murdered; men’s genitals are being cut off; and innocent people are being kidnapped and taken to Gaza. This amounts to keeping silent while another Holocaust takes place. No nation should ever suffer such atrocities. Therapists who dedicate their lives to the suffering and healing of others but do not stand with the people of Israel at the moment are hypocrites, to say the least. They should all remember: Not reaching out for the victims is strengthening the abusers. On October 7, the abusers were the Hamas and other terrorists, and the victims were the people of Israel. There is no justification, and there should never be any justification, for such atrocities. Note: This article originally appeared on Psychiatric Times®. The opinions expressed in commentaries are those of the participants and do not necessarily reflect the opinions of Psychiatric Times®.

Benzodiazepines are known to lead to dependency quickly and have numerous side effects. Long-term use is not recommended. However, if there is a long-term prescription, the goal should be to end therapy with these tranquilizers. However, discontinuation could have unexpected consequences, as US researchers reported in JAMA Network Open. In a registry study, patients who discontinued benzodiazepines after long-term therapy had an increased risk for death in the following 12 months. Whether there is a causal relationship between discontinuation of therapy and increased mortality rate or whether it is just the temporal coincidence of two phenomena cannot be answered by the study. Risks Are Downplayed "Under no circumstances should it be concluded from the results of this study that it is appropriate to continue long-term benzodiazepine therapy," warned Dirk Wedekind, MD, head of the Addiction Medicine Department the University Medical Center Göttingen's Department of Psychiatry and Psychotherapy in Germany, in response to inquiries from Medscape Medical News. "Long-term use of benzodiazepines is associated with risks that, in my opinion, are downplayed in this study," he said. In addition to rapid tolerance development and associated dependency, benzodiazepines carry the risk for various physical, psychological, and cognitive side effects. Sedation, daytime drowsiness, and sleepiness with impaired attention and reaction time, muscle weakness, lethargy, ataxia, confusion, depression, and dizziness are frequent. The risk for falls is significantly increased. A connection with the onset of Alzheimer's dementia is also frequently discussed. "Only in individual cases, when other drug strategies are not an option at all, is it indicated to treat with benzodiazepines long-term. Otherwise, these substances, as useful as they are acutely, must be discontinued after a few weeks," Wedekind emphasized. Long-Term Prescriptions The US Food and Drug Administration and German professional associations strictly advocate that benzodiazepines not be used as permanent medication. However, long-term therapy is "often medical reality," said Wedekind. "There are also many patients in Germany with long-term prescriptions that are not appropriate." The Federal Joint Committee has greatly restricted the ability to prescribe at the expense of statutory health insurance funds. A prescription is only possible for short-term therapy. "Therefore, the prescription of benzodiazepines on a private prescription in Germany is enormously high," said Wedekind. Benzodiazepine Dependence Unnoticed Estimates suggest that there are 1.2-1.5 million people with benzodiazepine dependence in Germany. "The number of benzodiazepine-dependent individuals whose addiction was induced by medical prescription over too long a period is estimated to be about half as high as that of alcohol-dependent individuals in Germany. This is a relevant problem that is little discussed, also because a patient taking benzodiazepines permanently does not appear intoxicated when handled," said Wedekind. For their registry study, Donovan T. Maust, MD, of the Department of Psychiatry at the University of Michigan in Ann Arbor, and his colleagues relied on US health insurance data for more than 350,000 patients who underwent long-term medically prescribed therapy with benzodiazepines. If patients did not refill a prescription for the tranquilizers within 31 consecutive days within 6 months, this was considered the termination of therapy. How to Discontinue? There was no evidence about the circumstances under which the medication was terminated, however. "These medications must be tapered slowly to avoid causing severe withdrawal symptoms, which can lead to impaired consciousness, confusion, and delirium. Abrupt discontinuation of long-term, even low-dose benzodiazepine therapy is a health risk, which understandably would be associated with increased mortality and would be a medical error," said Wedekind. The research group at the University of Michigan reported that the mortality risk of insured individuals who discontinued benzodiazepine therapy was 1.6 times higher in the following year than in those who continued therapy. Whether the patients were simultaneously treated with opioids did not play a role. The absolute increase in risk was 2.1% without and 2.4% with concurrent opioid use. "People who take sedatives such as benzodiazepines for the long term are also much more likely to take high-potency pain medications such as opioids," said Wedekind. Suicide Attempts and Overdoses The researchers observed comparable increases in risk for other endpoints such as nonfatal overdoses, suicide attempts or self-inflicted injuries, suicidal ideation, and treatments in an emergency department. Given the increased risks for overdoses and mortality associated with the prescription of benzodiazepines, especially when prescribed concurrently with opioids, the researchers assumed that discontinuing the sedatives would be associated with a reduction in mortality risk. This hypothesis was not confirmed. Rather, the study suggests that discontinuing benzodiazepine therapy in patients who have been prescribed them long term is associated with unforeseen risks. Efforts to promote the discontinuation of these medications should carefully weigh the potential risks of discontinuation against the continuation of treatment, wrote Maust and his colleagues. Qualified Detoxification "Simply continuing to prescribe benzodiazepines cannot, of course, be a medical standard," said Wedekind. It is important to identify patients with long-term use or dependence on benzodiazepines and refer them to qualified medical treatment. Withdrawal effects may emerge if detoxification is not slow enough. Or patients may resort to other sedative substances such as cannabis or alcohol after stopping benzodiazepines, the US authors wrote. "Therefore, these patients need qualified detoxification and rehabilitation therapy in a suitable institution," said Wedekind. This detoxification must last long enough for patients with long-term use, because "the longer and higher the dosage, the longer and more problematic the detoxification process." This article originally appeared on Medscape

Psychotherapy for posttraumatic stress disorder (PTSD) is as effective in cases involving multiple traumatic events as it is in those with a single trauma, a new meta-analysis of randomized clinical trials (RCTs) showed. Investigators said this is the first study of its kind to compare the efficacy of psychological interventions in single-event PTSD vs multiple-event PTSD. When compared with control conditions at the treatment endpoint, moderate benefits were reported in both groups of patients, with little difference between the two. Researchers also found that trauma-focused cognitive behavioral therapy (CBT) was more effective than non-trauma–based psychotherapy for PTSD with multiple traumatic events. "Some therapists believe that trauma-focused interventions are not appropriate for individuals who have been through multiple traumas," investigators, led by Thole Hoppen, PhD, of the University of Münster in Münster, Germany, said. "The finding of this meta-analysis could be used in therapist training to highlight the large body of evidence that contradicts such misconceptions." A Vulnerable Population Hoppen and his team analyzed the results of 137 RCTs with 10,600 individuals (54% female, mean age, 40). The trials compared the efficacy by time — short-term or treatment endpoint, mid-term or ≤ 5 months, or long-term or > 5 months — of different types of psychotherapy vs one another or vs control treatment on PTSD symptoms stemming from single or multiple events. Trials involving individuals with comorbid PTSD and substance abuse orders or comorbid traumatic brain injury were excluded from the analysis, and clinician-administered PTSD outcome assessments were prioritized over self-report-based ones when both were reported. At treatment endpoint, psychotherapy was highly efficacious for PTSD when compared with passive control conditions in both samples with single-trauma events and multiple trauma events, with no statistically significant difference in efficacy. When analyzing benefits of specific psychotherapies in multiple trauma trials, trauma-focused CBT and eye movement desensitization and reprocessing therapy offered similar short-term results, while trauma-focused CBT yielded larger efficacy than non-trauma–focused interventions. Investigators noted that because multiple traumas can be associated with worse PTSD presentation, "the finding that this vulnerable population nevertheless responds well to intervention is encouraging." Dispelling Misconceptions In an accompanying editorial, Maria Bragesjö, PhD, Karolinska Institutet, Stockholm, Sweden, noted that the study advances clinicians' understanding of PTSD treatment and "serves as a powerful catalyst, challenging prevailing stigmas and misconceptions." She added that by "dispelling misconceptions about the efficacy of trauma-focused interventions for individuals with multiple trauma histories, this meta-analysis contributes substantially to reshaping the landscape of PTSD treatment strategies, fostering a more comprehensive and inclusive treatment approach." Limitations of the meta-analysis included a shortage of studies that reported the number of total traumatic events and more detailed information about treatment effects. This article originally appeared on Medscape

Childhood trauma, such as sexual, physical, or emotional abuse, or neglect, is associated with chronic pain later in life. Adults with a history of childhood trauma such as sexual, physical, or emotional abuse, or neglect, have a higher risk for both pain and pain-related disability, according to study findings published in the European Journal of Psychotraumatology. Adverse childhood experiences (ACEs) have been previously associated with pain in adulthood, but it has remained unclear what types and degrees of exposure to ACE may increase the risk for chronic pain and pain-related disability later in life. Previous analyses have included small sample sizes, unclear exposure and outcome definitions, and inconsistent inclusion of comparison groups. To evaluate the associations between exposure to ACEs and chronic pain and pain-related disability in adults, researchers conducted a systematic review and meta-analysis. The researchers identified 85 cross-sectional observational studies, of which 57 were included in meta-analyses, with a population of 826,452 individuals (mean age, 44). The studies reported on ACEs during childhood including abuse and neglect (direct exposure) to other household and socioeconomic (indirect) exposures. The studies further reported musculoskeletal disorders and/or nonmusculoskeletal chronic pain, such as headache, migraine, fibromyalgia, and irritable bowel syndrome, as defined by the International Association for the Study of Pain (IASP), and quantified any associated disability. The likelihood of reporting chronic pain conditions later in life was significantly higher among individuals exposed to direct childhood ACEs (adjusted odds ratio [aOR], 1.45; 95% CI, 1.38-1.53), including neglect (aOR, 1.38; 95% CI, 1.15-1.66), sexual abuse (aOR, 1.37; 95% CI, 1.25-1.49), and emotional abuse (aOR, 1.56; 95% CI, 1.36-1.78) compared with those with ACE. Individuals who had experienced childhood physical abuse were more likely to report not only chronic pain (aOR, 1.50; 95% CI, 1.39–1.64) but also pain-related disability (aOR, 1.46; 95%CI, 1.03–2.08). This result was not influenced by sensitivity analysis. The researchers also found that exposure to any ACE, including indirect exposures, had higher odds of developing any of a variety of musculoskeletal and nonmusculoskeletal pain conditions (aOR, 1.53; 95% CI, 1.42–1.65), as well as pain-related disability (aOR, 1.29; 95% CI, 1.01–1.66), in adulthood. No significant association was identified between pooled estimates for chronic pain or pain-related disability outcome and measured covariate such as country, setting, or year of publication. Study limitations included the potential lack of accuracy of self-reported ACEs and the cross-sectional designs of the included studies that did not differentiate between cause and effect and are prone to selection and recall bias. The researchers suggested that these results underscore the need for trauma-informed care for chronic pain in adults. They concluded, “Over 1 billion children — half of all children in the world — are exposed to physical, sexual, or emotional violence or neglect each year. The endemic magnitude of ACEs, their health consequences, and their combined attributable costs … compel urgent action.” Note: This article originally appeared on Psychiatry Advisor

In-utero exposure to prescription stimulants is not associated with an increased risk for neurodevelopmental disorders in children. Exposure to amphetamine/dextroamphetamine and methylphenidate in utero is not meaningfully associated with an increased risk for childhood neurodevelopmental disorders (NDDs), according to study results published in JAMA Psychiatry. These findings may help inform treatment for pregnant individuals who depend on prescription stimulants for daily functioning. Stimulant medications cross the placenta and can increase the concentrations of norepinephrine and dopamine, which are known to play an important role in fetal neurodevelopment. However, it is unclear whether amphetamine treatment for pregnant individuals poses a risk for childhood NDDs. Therefore, researchers performed a cohort study using national Medicaid data from 2000 to 2018 and MarketScan data from 2003 to 2020. The researchers identified pregnant individuals who filled prescriptions for amphetamine/dextroamphetamine and methylphenidate in the second half of pregnancy (week 19 to delivery) to assess the association between stimulant use for attention-deficit/hyperactivity disorder (ADHD) during pregnancy and neurodevelopmental outcomes. Children from these pregnancies were monitored from birth until their continuous enrollment ended, they developed a NDD, the study period ended, or they died (whichever came first). The primary outcome of any NDD was defined as a composite of autism spectrum disorder (ASD), ADHD, specific learning disorders, developmental speech or language disorder, developmental coordination disorder, intellectual disability, and behavioral disorder. The analyses included 4,317,502 pregnancies from both the Medicaid and MarketScan cohorts, and pregnant individuals had a mean age of 25.2 (SD, 6.0) and 31.6 (SD, 4.6) years at enrollment, respectively. During the second half of pregnancy, 7065 individuals were exposed to amphetamine/dextroamphetamine and 1123 were exposed to methylphenidate. Upon controlling for confounding variables, exposure to amphetamine/dextroamphetamine was not found to be significantly correlated with neurodevelopmental outcomes. The hazard ratios (HRs) were 0.80 (95% CI, 0.56-1.14) for ASD, 1.07 (95% CI, 0.89-1.28) for ADHD, and 0.91 (95% CI, 0.81-1.02) for any NDD. In the subset of patients with maternal ADHD diagnoses, risk elevation for these outcomes was not evident in either crude or adjusted analyses. Relative to individuals who ceased amphetamine use before pregnancy, the researchers observed no significant associations between amphetamines and ADHD and any NDD, while the adjusted HR for ASD was 1.35 (95% CI, 0.84-2.15) for early exposure and 1.81 (95% CI, 1.04-3.12) for late exposure. Overall, there were no meaningful associations between amphetamine exposure and ADHD and composite NDDs. When examining pregnancies exposed to methylphenidate, initial estimates indicated a 2- to 3-fold increase in ASD, ADHD, and composite NDDs. However, these estimates were greatly reduced after adjusting for confounding factors. The adjusted HRs for exposure during late pregnancy were 1.06 (95% CI, 0.62-1.81) for ASD, 1.43 (95% CI, 1.12-1.82) for ADHD, and 1.15 (95% CI, 0.97-1.36) for NDD overall. The associations were even weaker in analyses that included only mothers with ADHD and those who discontinued methylphenidate use before pregnancy. Study authors concluded, “Given the recent rise in use of stimulant medications for ADHD in adults and during pregnancy, these results are reassuring for patients who depend on these medications throughout pregnancy for control of debilitating ADHD symptoms that interfere with daily functioning.” These study findings may be limited by potential outcome misclassification and substantial attrition due to insurance disenrollment. Additionally, as prescription stimulants for ADHD can be used as needed, evidence of dispensing may not accurately indicate consumption. This article originally appeared on Psychiatry Advisor

A higher risk was seen with increasing somatic symptoms during early to mid adolescence. HealthDay News — Persistent withdrawn symptoms and increasing somatic symptoms during early to mid adolescence are associated with an increased risk for suicidal thoughts in mid adolescence, according to a study published online Jan. 25 in JAMA Network Open. Akito Uno, M.D., from the University of Tokyo, and colleagues assessed which categories and trajectories of psychopathological and behavioral symptoms are associated with suicidal thoughts in adolescence. The analysis included data from three waves of the Tokyo Teen Cohort study (2,780 adolescents) conducted at ages 10, 12, and 16 years from October 2012 to September 2021. The researchers found that 8.2 percent of participants had suicidal thoughts. When adjusting for each symptom trajectory and confounders, adolescents with persistent high withdrawn symptoms (odds ratio, 1.88) and increasing somatic symptoms (odds ratio, 1.97) had a significantly higher risk for suicidal thoughts versus adolescents without these symptoms. For the risk for suicidal thoughts, there was no interaction between these symptom trajectories. “A wide range of people involved in adolescent health should pay attention to the suicidal risk associated with these symptoms and consider the possibility of providing psychosocial support, particularly when the symptoms persist or increase in the longitudinal follow-up,” the authors write. This article originally appeared on Psychiatry Advisor

Single exercise sessions of 30 minutes or less led to small, but significant, improvements in ADHD core symptoms and executive function among adolescents. A single session of exercise had small effect-size improvements in core symptoms and executive function among adolescents with attention-deficit/hyperactivity disorder (ADHD), according to results from a systematic review and meta-analysis published in the Journal of Attention Disorders. In particular, high-intensity interval training, single exercise sessions of 30 minutes or less, and cycling exercises were most effective for symptom improvement. While medications for ADHD are effective in improving attention, hyperactivity, and executive function in ADHD, these therapies can have adverse side effects and recent drug-shortages have left many patients without an effective treatment option. To investigate the utility of exercise interventions for ADHD symptoms, investigators conducted a systematic review and meta-analysis of publication databases from inception through July 2023 for randomized controlled trials (RCTs) or crossover RCTs that included adolescents with ADHD who underwent a single session of exercise intervention (aerobic, resistance, or aerobic + resistance) for ADHD symptom management. The investigators included a total of 13 studies with a pooled sample size of 437 participants, who were primarily boys/men (71.6%) with a mean age range of 10 to 24 years. Core symptoms of ADHD (inattention and impulsivity) were primarily assessed with Conner’s Continuous Performance Test and the Barkley Adult ADHD Rating Scale-Modified, while executive function was evaluated with the Stroop Test and Flanker Task. All single exercise sessions were open chain (eg, swimming, cycling, running), were moderate to vigorous in intensity, and ranged from 10 to 40 minutes in duration. Control groups mainly watched videos. The investigators found that single-session exercise had small effect-size improvements in core symptoms of hyperactivity and attention (standardized mean difference [SMD], 0.35; 95% CI, 0.08-0.63; P =.01) and executive function (SMD, 0.28; 95% CI, 0.13-0.43; P =.00) among adolescents with ADHD. When stratified by age, the investigators observed small effect-size improvements in core symptoms and executive function among participants aged 10 to 13 years (standardized mean difference [SMD], 0.30; 95% CI, 0.12-0.48; P =.00) and 18 to 24 years (SMD, 0.42; 95% CI, 0.12-0.72; P =.01). However, single-session exercise did not significantly improve ADHD symptoms among participants 14 to 17 years of age (SMD, 0.16; 95% CI, -0.08 to 0.40; P =.65). When stratified by exercise type, high-intensity interval training was more effective in improving core symptoms and executive function (SMD, 0.44; 95% CI, 0.08-0.80; P =.02) relative to moderate-intensity continuous training (SMD, 0.27; 95% CI, 0.13-0.41; P =.00). Additionally, exercise sessions under 30 minutes were more effective (SMD, 0.35; 95% CI, 0.19-0.51; P =.00) than sessions of 30 minutes or more (SMD, 0.22; 95% CI, 0.00-0.44; P =.05), and cycling led to greater symptom improvements (SMD, 0.40; 95% CI, 0.17-0.63; P =.00) than running (SMD, 0.11; 95% CI, -0.04 to 0.27; P =.91). The investigators concluded, “This study supports the role of exercise in improving core symptoms and executive functioning in adolescent ADHD and provides additional evidence-based treatment options for a large number of adolescent patients with ADHD who are not amenable to medication.” These findings may be limited by the small number of relevant studies and heterogeneity in the reliability and sensitivity of assessment standards. Note: This article originally appeared on Psychiatry Advisor

Iloperidone, a second-generation antipsychotic used to treat schizophrenia, appears to be safe and effective in the treatment of bipolar mania, new research suggested. Results of the phase 3 randomized double-blind placebo-controlled trial show patients with bipolar mania who received iloperidone had significantly greater change from baseline to 4 weeks on the Young Mania Rating Scale (YMRS) compared with placebo, an improvement detected as early as 14 days from the initial dose. The incidence of akathisia and extrapyramidal symptoms (EPS) was low in the treatment group, and the medication was well-tolerated. "This study provides evidence that iloperidone improves the symptoms of bipolar mania in adults and can be a useful treatment option for people with bipolar disorder," the investigators, led by Rosarelis Torres, PhD, of Vanda Pharmaceuticals Inc., and colleagues wrote. The study was published online on January 15 in the Journal of Clinical Psychiatry. Early Improvement Iloperidone was first approved by the US Food and Drug Administration in 2009 for treatment of schizophrenia. The current study included 414 participants (mean age, 43 years; 56% male) across 17 US and international sites. Patients with psychotic features received a fixed daily dose of 24 mg of iloperidone (n = 206) or placebo (n = 208). Participants completed a screening period of up to 7 days before randomization, followed by a 1-day baseline evaluation period and a 28-day treatment phase. The primary efficacy endpoint was change from baseline to week 4 on the YMRS (vs placebo), while secondary efficacy endpoints included change from baseline on the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales (CGI-S and CGI-C, respectively). Compared with placebo, iloperidone was associated with significant improvement of mania symptoms at week 4, with a mean reduction on the YMRS scale of −4.0 (P = .000008), and significant decreases on the CGI-S (mean, −0.4; P = .0005) and CGI-C scales (mean, −0.5; P = .0002). Statistically significant differences between iloperidone and placebo were observed as early as day 14 and continued through days 21 and 28. Post hoc analyses found no difference in efficacy even when patients who had received benzodiazepines were excluded, regardless of the presence or absence of psychotic features at baseline. Favorable Akathisia Profile As for safety, 68% of patients in the iloperidone group experienced at least one adverse event, compared with 49% of patients in the placebo group. Patients in the treatment group had a higher rate of withdrawal from the study than those in the placebo group (32.9% vs 27.1%), and more patients in the iloperidone group experienced treatment-emergent adverse events (TEAEs) leading to study drug discontinuation (8.7% vs 5.3%). However, no TEAEs associated with discontinuation occurred in more than two patients in either group, and none of the participants experienced any AE leading to death. The most common adverse events (AEs) were tachycardia (18%), dizziness (11%), dry mouth (9%), increased alanine aminotransferase (7%), nasal congestion (6%), weight gain (6%), and somnolence (5%). Five serious AEs were reported in four participants in the treatment group and one in the placebo group. Two were identified as related to the study medication. These included sedation and spontaneous penile erection. Changes from baseline in clinical laboratory parameters were not largely different between the groups, but there were post-randomization changes in QT interval in three iloperidone patients. The incidence of orthostatic response was also higher for iloperidone vs placebo. Although "much improved compared to early antipsychotics, SGAs can still cause considerable adverse motor side effects," the authors wrote. "However, among all SGAs, iloperidone's akathisia profile is favorable." Antipsychotic-induced akathisia has been reported more frequently in patients with bipolar disorder than in those with schizophrenia treated with the same medication, investigators noted. One study limitation is the fact that long-term efficacy in the prevention of manic or depressive episodes was not assessed. Potential Second-Line Treatment Commenting on the study for Medscape Medical News, Richard Louis Price, MD, assistant professor of psychiatry, at Weill Cornell Medical College, New York City, said the findings suggest iloperidone may be "modestly effective" for patients with bipolar 1 mania or mixed episodes. "It's helpful to have new treatment options, especially for patients who have difficulty tolerating other agents," said Price, who was not involved with the study. Also commenting on the research for Medscape Medical News, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, noted iloperidone's "interesting antipsychotic pharmacodynamic," highlighting the drug's high-binding affinity for serotonin 5HT2A and dopamine D2 and D3 receptors, as well as the noradrenergic α1 receptors. The drug's profile "suggests benefit in manic features and agitation, perhaps with a lower propensity to EPS, which is especially important in persons at higher risk, like persons living with bipolar disorder," McIntyre said. McIntyre, who was not involved with the study, added iloperidone could be a second-line therapy because of its tolerability profile, provided the study results can be replicated. "When considering alternatives with similar efficacy, absence of titration (or simple titration) minimal to no weight gain, no orthostatic hypotension, and no potential concerns with QT, those alternatives would have to be considered first-line, assuming that the study results are replicated," he said. Note: This article originally appeared on Medscape

TOPLINE: In 2022, approximately 13% of mental health specialists switched to practicing exclusively via telemedicine, with rates highest among psychiatric nurse practitioners and clinicians working in densely populated areas, and with females more likely than males to switch, new research revealed. METHODOLOGY: Researchers used health insurance claims from OptumLabs Data Warehouse for commercial insurance and Medicare Advantage enrollees for the years 2019 and 2022 after the start of the pandemic. They identified mental health specialists (psychiatrists, psychologists, social workers, and psychiatric mental health nurse practitioners [PMHNPs]) who had at least 30 visits and five patients in both years and conducted less than 25% of visits virtually in 2019. The study investigated the likelihood of providing "telemedicine-only" care in 2022, defined as conducting more than 95% of visits virtually. For each clinician, the study captured specialty, sex, region, age range of patient population, proportion of patients with severe mental illness, and median house value and population where most of their patients resided. TAKEAWAY: Among 51,309 mental health specialists included in the analysis, 13.0% provided telemedicine-only care in 2022. The adjusted rate was highest among PMHNPs (18.7%; 95% CI, 17.1%-20.3%) and lowest among psychiatrists (9.1%; 95% CI, 8.6%-9.7%). Characteristics associated with a greater likelihood of switching to telemedicine only included being female (adjusted rate, 14.0% vs 11.1% for males; P < .001), working in counties in the top (vs lowest) quartile of housing value (16.6% vs 8.8%; P < .001), and having the highest (vs lowest) population density (16.0% vs 8.8%; P < .001). Clinicians with a pediatric focus and those with an older adult focus (6.7%; 95% CI, 6.0%-7.5% and 6.5%; 95% CI, 5.6%-7.4%, respectively) were significantly less likely than general clinicians (14.1%; 95% CI, 13.8%-14.4%; P < .001) to have a telemedicine-only practice. IN PRACTICE: It's unclear how telemedicine-only clinicians will navigate Medicare and Medicaid changes, taking effect in 2025, that will require patients to get an annual in-person visit to continue receiving telemedicine visits for mental illness, the researchers wrote. They add that in-person requirements for visits and prescribing may "cause care interruptions, particularly for conditions such as opioid use disorder." LIMITATIONS: As the analysis included only clinicians treating patients with commercial insurance or Medicare Advantage, results may not be generalizable. Researchers were unable to determine where clinicians physically practiced. Given the shortage of mental health clinicians, future research should explore whether a virtual-only model affects clinician burnout or workforce retention. DISCLOSURES: The study was supported by the National Institute of Mental Health. Hailu reported no relevant conflicts of interest. The disclosures of the other investigators can be found in the paper.

TOPLINE: Prescriptions for Schedule II (C-II) stimulants and nonstimulant attention-deficit/hyperactivity disorder (ADHD) medications significantly increased in the United States during the COVID-19 pandemic, particularly in young adults and females, results of a cross-sectional study showed. METHODOLOGY: Using the National Prescription Audit commercial database, which captures more than 94% of US outpatient prescription drug activity, researchers examined US trends in prescriptions dispensed before (April 2018-March 2020) and during (April 2020-March 2022) the COVID-19 pandemic. Researcher analyzed monthly incident prescriptions for oral formulations of drugs in five classes (antidepressants, benzodiazepines, C-II stimulants, nonstimulant ADHD drugs, and buprenorphine products labeled as medications for opioid use disorder [MOUD]), dispensed to a patient with no prescriptions within the same drug class in the prior 12 months. For each drug class, investigators ranked the three highest-volume prescriber specialties and identified the top two drugs dispensed. TAKEAWAY: After an initial drop in dispensing across all drugs examined, including significant decreases for ADHD drugs and buprenorphine MOUD, prescriptions increased during the pandemic for C-II stimulants (14%) and nonstimulant ADHD drugs (32%), most notably among adults aged 20-39 years (30% and 81%, respectively) and women (25% and 59%, respectively). Among specialties, the largest increases were for prescriptions written by nurse practitioners across all drug classes, ranging from 7% for benzodiazepines to 78% for buprenorphine MOUD. Trends in prescriptions dispensed for antidepressants and benzodiazepines did not significantly change as was the case for buprenorphine MOUD, possibly because telemedicine prescribing flexibilities allowed clinicians to continue to diagnose and start treatment for OUD, the authors wrote. In the C-II stimulant class, amphetamine-dextroamphetamine increased more than methylphenidate, whereas among nonstimulant ADHD medications, there was an increase for atomoxetine but not for guanfacine extended release. IN PRACTICE: Increases in ADHD medication prescriptions during the pandemic "underscore the need for robust policies to address unmet needs while balancing public health concerns" wrote the authors, adding that future research "should prioritize clinical ADHD guideline development" to define treatment appropriateness. LIMITATIONS: Prescriptions dispensed outside the defined timeframe (during the previous year) may have been misclassified as an incident. The study could not determine causal relationships between drug utilization patterns and effects of the pandemic. Dispensed prescription data may not reflect demand or medical need during periods of drug shortage. The data did not contain information on race. Note: This article originally appeared on Medscape

Schizophrenia is far-reaching, affecting individuals, families, and society. Schizophrenia has been called “the worst disease affecting mankind” (1). It is a complex neuropsychiatric disorder, with multiple clinical features. These include cognitive impairment and deficits, mood symptoms, and psychiatric symptoms (hallucinations and delusions). It is also arguably the diagnosis that carries the greatest degree of stigma. For many years, schizophrenia was untreatable, until the discovery of antipsychotic medications in the 1950s. These first-generation antipsychotic medications offered hope, but many people were left with either a lack of efficacy or intolerable side effects. Today, thanks to the newer second-generation antipsychotic medications, and clozapine for treatment-resistance, the odds for recovery from schizophrenia are possible for many. The absence of insight is one of the most serious symptoms that prevents an individual with schizophrenia from receiving treatment. A lack of insight is called anosognosia. It is common in schizophrenia and other serious mental illness. It is more than denial, it is a firm and false belief that the affected individual is not sick and does not need medical treatment. Many people with schizophrenia develop delusions and believe things a mentally healthy person would find absurd. In the movie, A Beautiful Mind, while struggling with schizophrenia, Nobel Prize-winning mathematician John Nash believes that a microchip has been inserted in his body by the FBI because he is on a special mission. When a person begins their journey on a downward spiral into schizophrenia, especially untreated schizophrenia, the following are some consequences: Individuals become tortured with delusions and hallucinations Symptoms of schizophrenia can undermine a person’s life and can take away what matters most, such as a college education, pursuing a career, establishing relationships, buying a house, and raising a family. A person with schizophrenia often neglects personal hygiene and becomes malodorous. Many live in fear of the hallucinations raging inside their minds and feel detached from reality. Despite this, many will never seek out treatment until they are involuntarily hospitalized, which state laws allow. Psychiatric hospitalizations, which can often be avoided with early intervention, can be very costly ($1500 to $3000 a day depending on the location. Families are fractured Families of individuals struggling with schizophrenia often wonder what they did wrong, though schizophrenia is a genetic disorder, and no one is at fault. Parents may feel burdened by the many hours of care they have to provide, traveling to doctors’ appointments, researching how to best help their loved one, and having long and frustrating conversations to try and convince him or her they need treatment. Some parents who refuse to allow a delusional, violent, and unpredictable son or daughter to live in their home are struck by guilt, wondering if they did the right thing. Hundreds of billions of dollars annually in cost to society Schizophrenia incurs high direct and indirect costs to society that are expensive. Multiple hospitalizations, a lifetime of regular outpatient visits, legal costs (arrests, court hearings, re-incarceration due to a relapse) and lifetime disability (payments for room and board) add up to a huge cost. But, notably, if a person is identified earlier, they will have a better outcome. Full adherence to antipsychotic medication can prevent relapse (similar to full adherence to insulin in people with diabetes), and many who stick to their treatment plan may regain healthy minds return to their baseline, and contribute to society. Homelessness and substance use Untreated schizophrenia may lead to self-medicating with illicit substances, which can cause recurrence of psychosis and sabotage recovery. It is a daunting task to care for persons with schizophrenia who are addicted to substances. Many will become homeless, with cognition too impaired to hold even a simple job. People with schizophrenia are vastly overrepresented in the homeless community (2). The legal and prison systems When deinstitutionalization began in the '60s, funding and programs for those with developmental disabilities such as autism and Down’s Syndrome were made available. However, people with schizophrenia were not adequately covered by health insurance, often ending up on the streets, or in jail for crimes stemming from abnormal behavior triggered by the illness. Today, people with schizophrenia are also vastly overrepresented in jails and prisons (3). The pharmaceutical industry Hundreds of millions of dollars have been spent to search for a cure for schizophrenia, or at least better medication options with greater efficacy and fewer side effects than first-generation antipsychotics. Clozapine was approved by the FDA in 1989 and remains the antipsychotic drug with the highest efficacy after several decades, although it can have several safety and tolerability issues. Research continues with the hope that future medications will not only address the psychotic symptoms of schizophrenia, such as hallucinations and delusions, but also cognitive deficits (in memory, attention, or decision-making) and negative symptoms such as apathy, lack of motivation, inability to socialize, anhedonia, and blunted facial expression. Though a few medications are in the pipeline, their efficacy will not be known until the controlled clinical trials are completed and examined by the FDA for possible approval (4,5). The effects of suicide There is a very high suicide rate in people with schizophrenia. The rate of suicide in persons with schizophrenia is 4 to 13 percent (6). Studies report up to 10,000 percent higher death rates from suicide in young people with schizophrenia compared with the same age group in the general population (7). This is tragic for young people just starting their lives and is difficult to prevent. There is hope that the recent initiation of the 988 crisis hotline will offer more people struggling with suicide much-needed support (8). There is hope Despite the devastating impacts of schizophrenia, there is hope. Today, many people with ongoing treatment for schizophrenia (usually by committing to taking antipsychotic medication for life) reclaim their lives, work, attend college, and enjoy meaningful relationships again. Persons affected by schizophrenia can achieve remission by avoiding any further psychotic relapses after the initial hospitalization with uninterrupted adherence made possible through long-acting injectable antipsychotics (with no need for pills) that can be given once every one to six months. Unfortunately, the vast majority of persons with schizophrenia who improve significantly during their first hospitalization are discharged on pills, which they often do not take regularly, leading to multiple relapses that can destroy more brain cells and render the person disabled. Prompt and efficacious treatment with 100 percent adherence to antipsychotic medications can heal people with schizophrenia, enable them to return to their baseline functioning (like school or work) and bring families back together again. This will also avoid rehospitalization, re-incarceration, suicide, homelessness, and exorbitant costs to society. Recovery from schizophrenia is a win-win for patients, their families, and society. Note: This article originally appeared on Psychology Today