Over the past 2 decades, the attention-deficit/hyperactivity disorder (ADHD) treatment spectrum has expanded to include intermediate-acting and long-acting treatments. Despite the advances in drug delivery technology for stimulant medications, short-acting stimulants remain widely prescribed for adults with ADHD.1,2 Understanding the diverse mechanisms and pharmacokinetic profiles of the currently available group of long-acting stimulant formulations will help clinicians tailor treatment to individual patient needs. In a recent Psychiatric Times® Expert Perspectives video series, Greg Mattingly, MD, associate clinical professor at Washington University School of Medicine in St Louis, Missouri, and president-elect of the American Professional Society of ADHD and Related Disorders (APSARD); and Oren Mason, MD, family physician at Attention MD in Grand Rapids, Michigan; had a wide-ranging discussion highlighting key points from a presentation they delivered at the 2023 APSARD annual meeting. They examined how the landscape of stimulant medications has evolved and how to improve the patient experience with stimulants. Ahead is a summary of key points and clinical insights from the discussion. Evolving Treatment Landscape for Adult Patients With ADHD As explained by Dr Mattingly, many long- acting medications achieve their duration of action by combining various ratios of immediate-release and extended-release components, which results in 2 peaks on the pharmacokinetic (PK) curve. “That first pulse [corresponds] to an immediate-release component, and the later pulses [are] delayed-release components that [occur] throughout the day… Formulations with immediate-release components usually have what we call a biphasic pharmacokinetic profile,” said Dr Mattingly. “[This means] that patients may potentially feel the on/off periods or the [adverse] effects of medicines [in a] coming-and-going [manner] rather than feeling the full duration of coverage.” Guidance for Prescribing Stimulants in Adults Within the past 15 to 20 years, the diagnosis of ADHD has increased to a greater extent for adults than for children and adolescents. In fact, a 2021 global systematic review and meta-analysis found a global prevalence of 8.83% in adults around the world. When treating adult patients with ADHD, Dr Mattingly noted that understanding various PK profiles can optimize treatment decision-making for patients with ADHD who may have disparate needs. He explained that for agents that contain a higher proportion of immediate-release medication, patients tend to exhibit greater early medication exposure relative to total exposure. “Typically, [this] is reflected by an earlier onset of action,” he said, “but perhaps [it does not have] sustained duration of action.” In comparison, Dr Mattingly said, “Formulations that have less drug available in immediate release but have more of the [medication acting in] extended release tend to give [the patient] a longer duration of coverage.” Dr Mattingly went on to describe multiple technologies that have different PK profiles. “They all need to be understood to optimize the outcomes for your patients,” he said. According to Dr Mattingly, advantages of long-acting formulations include: improving or augmenting symptom coverage throughout the day, potentially improving treatment response, helping with adherence, and potentially improving tolerability without having the on/off effect. He also added, “It’s breaking the barriers of stigma and improving privacy.” He concluded that currently, guidance is to shift away from short-acting agents whenever appropriate. Clinician and Patient Perspectives on Stimulants for ADHD Keeping the benefits of long-acting stimulants in mind, clinicians can improve the patient experience when treating adult ADHD. According to Dr Mason, the goal of treatment is to improve symptoms and to achieve functional remission, which is when the functional impairments begin to normalize. “In my experience, [although] people understand a small bit about ADHD, [patients] may not understand the full impact of ADHD on their lives,” said Dr Mason. “When we prescribe these medications, we should literally see the changes across [their full] spectrum of symptoms.” When treating adult patients with ADHD, Dr Mason explained that despite the benefits of long-acting stimulants, many patients ask for short-acting stimulant medications. “[They may have] concerns about cost or fear of the medications, hoping to limit their exposure to something they don’t understand,” said Dr Mason. “I think we have to explore it with people. There’s a lot of reassurance we can give. [We can explain] that these medications don’t change personality when properly administered, patients have overwhelmingly positive experiences to them, and a trial of [long-acting] medication may help educate them about the [benefits] that they might see from ADHD medication therapy.” In addition, it’s important for clinicians to consider medication duration. Dr Mason said that clinicians can give patients an expectation of what the average patient might experience; they will, however, need additional education to understand when a medication is wearing off. To achieve adequate duration, clinicians should begin with prescribing long-acting medications to achieve an all-day duration, according to Dr Mason. “An all-day duration is simply not going to [be achieved] with a short-acting medication, a medication [with effects that only last] for 4 to 6 hours,” said Dr Mason. “We let patients know what we expect the duration of benefit to be, and then we actually measure it. If the duration is inadequate, [we’ll] either switch to another long-acting preparation or, in some cases, we’ll add a short-acting booster to lengthen the duration of benefit.” He went on to explain that with many longer-acting preparations, there is an improvement in duration of benefit, not just in midday effect. “Through the titration optimization, we need to ask questions about both efficacy and duration of benefit. If we’re not able to obtain adequate duration of benefit from one long-acting medication, we have others that we can try. If no long-acting preparation gives the patient the duration necessary, we can add short-acting boosters in the afternoon.” Keeping in mind the appropriate utilization of stimulants and the avoidance of the overuse of short-acting formulations, Dr Mason highlighted current stimulant prescribing practices and clinician perspectives about treating adults with ADHD, explaining that there is a trend of improvement across the medical spectrum, despite the need for more improvement in the landscape.“ ADHD management spans a range of specialties, and [there are] different practices within each. We looked at a 2017 cross-sectional study across US-based health care professionals. For the purpose of the study, we’re going to talk about 4 specialties: psychiatrists, neurologists, primary care doctors, and psychiatric nurse care practitioners. When asked to identify which pharmacotherapy they prescribe as first-line treatment, short-acting stimulants were cited by 17% of psychiatrists and 29% to 36% of the other 3 groups. This means that there [are] a lot of short-acting stimulants being used primarily for ADHD right out of the gate. Psychiatrists are more likely than the other groups to prescribe long-acting stimulants.” In addition, health care professionals were asked how strongly they agree or disagree with the following statement: It’s difficult to determine optimal ADHD treatment regimen for adult patients. According to Dr Mason, there was a resounding yes from 45% of psychiatrists and 60% of primary care physicians, neurologists, and nurse practitioners. “This is an opportunity for education,” he said. “We need more awareness about the actual benefits of the [long-acting] medications, the deficiencies of short-acting medications relative to long-acting stimulants, and the opportunity to do better for our patients.” Despite the benefit patients can yield from ADHD medications, there are unmet needs that remain. According to Dr Mason, adequate duration of effect is an area in need of improvement, especially for adults with ADHD. “Clinicians should be aware of how the method of extending duration [with short-acting agents] influences drug pharmacokinetics,” he said. “Health care professionals have identified a need for guidance regarding stimulant medications for ADHD.” Dr Mattingly added that patients who misperceive the energizing effects of stimulants for clinical benefit may drive a preference for short-acting stimulants. As the role of long-acting medications within the spectrum of ADHD treatment continues to evolve, Dr Mason said that there is a need for more education related to the benefits of long-acting medications relative to short-acting stimulants to help improve patient outcomes. References 1. Cascade E, Kalali AH, Weisler RH. Short-acting versus long-acting medications for the treatment of ADHD. Psychiatry (Edgmont). 2008;5(8):24-27. 2. Mattingly GW, Wilson J, Ugarte L, Glaser P. Individualization of attention-deficit/hyperactivity disorder treatment: pharmacotherapy considerations by age and co-occurring conditions. CNS Spectr. 2021;26(3):202-221. doi:10.1017/S1092852919001822 Related Topic: ADHD Underappreciated in Older Adults

Antidepressant ARCELONA — The typical lag between treatment initiation with selective serotonin reuptake inhibitors (SSRIs) for depression and enhanced mood may be because of the time it takes to increase brain synaptic density, new imaging data suggest. In a double-blind study, more than 30 volunteers were randomly assigned to the SSRI escitalopram or placebo for 3-5 weeks. Using PET imaging, the investigators found that over time, synaptic density significantly increased significantly in the neocortex and hippocampus but only in patients taking the active drug. The results point to two conclusions said study investigator Gitta Moos Knudsen, MD, PhD, clinical professor and chief physician at the Department of Clinical Medicine, Neurology, Psychiatry and Sensory Sciences, at Copenhagen University Hospital, Copenhagen, Denmark. First, they indicate that SSRIs increase synaptic density in brain areas critically involved in depression, a finding that would go some way to indicating that the synaptic density in the brain may be involved in how antidepressants function, "which would give us a target for developing novel drugs against depression," said Knudsen. "Secondly, our data suggest synapses build up over a period of weeks, which would explain why the effects of these drugs take time to kick-in," she added. The findings were presented here at the 36th European College of Neuropsychopharmacology (ECNP) Congress, and simultaneously published online in Molecular Psychiatry. Marked Increase in Synaptic Density SSRIs are widely used for depression as well as anxiety and obsessive-compulsive disorder. It is thought they act via neuroplasticity and synaptic remodeling to improve cognition and emotion processing. However, the investigators note clinical evidence is lacking. For the study the researchers randomly assigned healthy individuals to either 20-mg escitalopram or placebo for 3-5 weeks. They performed PET with the 11C-UCB-J tracer, which allows imaging of the synaptic vesicle glycoprotein 2A (SV2A) in the brain, synaptic density, as well as changes in density over time, in the hippocampus and neocortex. Between May 2020 and October 2021, 17 individuals were assigned to escitalopram and 15 to placebo. There were no significant differences between two groups in terms of age, sex, and PET-related variables. Serum escitalopram measurements confirmed that all participants in the active drug group were compliant. When synaptic density was assessed at a single time point, an average of 29 days after the intervention, there were no significant differences between the escitalopram and placebo groups in either the neocortex (P = .41) or in the hippocampus (P = .26). However, when they performed a secondary analysis of the time-dependent effect on SV2A levels, they found a marked difference between the two study groups. Compared with the placebo group, participants taking escitalopram had a marked increase in synaptic density in both the neocortex (rp value, 0.58; P = .003) and the hippocampus (rp value, 0.41; P = .048). In contrast, there were no significant changes in synaptic density in either the neocortex (rp value, -0.01; P = .95) or the hippocampus (rp value, -0.06; P = .62) in the hippocampus. "That is consistent with our clinical observation that it takes time to evolve synaptic density, along with clinical improvement. Does that mean that the increase in synaptic density is a precondition for improvement in symptoms? We don't know," said Knudsen. Exciting but Not Conclusive Session co-chair Oliver Howes, MD, PhD, professor of Molecular Psychiatry, King's College London, London, United Kingdom, agreed that the results do not prove the gradual increase in synaptic density the treatment response lag with SSRIs. "We definitely don't yet have all the data to know one way or the other," he told Medscape Medical News. Another potential hypothesis, he said, is that SSRIs are causing shifts in underlying brain circuits that lead to cognitive changes before there is a discernable improvement in mood. Indeed, Howes suggested increases in synaptic density and cognitive changes related to SSRI use are not necessarily dependent on each other and could even be unrelated. Also commenting on the research, David Nutt, MD, PhD, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, United Kingdom, said that the "delay in therapeutic action of antidepressants has been a puzzle to psychiatrists ever since they were first discerned over 50 years ago." "So, these new data in humans, that use cutting edge brain imaging to demonstrate an increase in brain connections developing over the period that the depression lifts, are very exciting." Nutt added the results provide further evidence that "enhancing serotonin function in the brain can have enduring health benefits." Funding support was provided by the Danish Council for Independent Research, the Lundbeck Foundation, Rigshospitalet, and the Swedish Research Council. Open access funding provided by Royal Library, Copenhagen University Library. Knudsen declares relationships with Sage Biogen, H. Lundbeck, Onsero, Pangea, Gilgamesh, Abbvie, and PureTechHealth. Another author declares relationships with Cambridge Cognition, and PopReach via Cambridge Enterprise. 36th European College of Neuropsychopharmacology (ECNP) Congress. Abstract S14.04 and P.0378. Presented October 8 and 9, 2023.

Disruptions TOPLINE: US adults with psychiatric illness experienced fewer disruptions in receiving psychotherapy following the transition to virtual psychiatric care that accompanied the onset of the COVID-19 pandemic, a large study has shown. METHODOLOGY: Retrospective study using electronic health records and insurance claims data from three large US health systems. Sample included 110,089 patients with mental health conditions who attended at least two psychotherapy visits during the 9 months before and 9 months after the onset of COVID-19, defined in this study as March 14, 2020. Outcome was disruption in psychotherapy, defined as a gap of more than 45 days between visits. TAKEAWAY: Before the pandemic, 96.9% of psychotherapy visits were in person and 35.4% were followed by a gap of more than 45 days. After the onset of the pandemic, more than half of visits (51.8%) were virtual, and only 17.9% were followed by a gap of more than 45 days. Prior to the pandemic, the median time between visits was 27 days and after the pandemic it dropped to 14 days, suggesting individuals were more likely to return for additional psychotherapy after the widespread shift to virtual care. Over the entire study period, individuals with depressive, anxiety, or bipolar disorders were more likely to maintain consistent psychotherapy visits, whereas those with schizophrenia, ADHD, autism, conduct or disruptive disorders, dementia, or personality disorders were more likely to have a disruption in their visits. IN PRACTICE: "These findings support continued use of virtual psychotherapy as an option for care when appropriate infrastructure is in place. In addition, these findings support the continuation of policies that provide access to and coverage for virtual psychotherapy," the authors write. SOURCE: The study, led by Brian K. Ahmedani, PhD, with the Center for Health Policy and Health Services Research, Henry Ford Health, Detroit, Michigan, was published online October 11 in Psychiatric Services. LIMITATIONS: The study was conducted in three large health systems with virtual care infrastructure already in place. Researchers did not examine use of virtual care for medication management or for types of care other than psychotherapy, which may present different challenges. DISCLOSURES: The study was supported by the National Institute of Mental Health. The authors have no relevant disclosures. Related topic: Telehealth What Happens When There Is No Help?

GLP-1 Agonists and Suicide Risk A statement from the European Medicines Agency (EMA) about semaglutide and, more generally, glucagon-like peptide 1 (GLP-1) agonists recently caused a stir. Could these medicines lead to patients taking their own lives? Medical Authorities Alert The EMA published a press release in early July 2023 to announce that a review is underway after reports from the Icelandic Medicines Agency about two cases of patients who developed suicidal thoughts while taking liraglutide (Saxenda) and semaglutide (Ozempic). There was also a report of self-injury in a patient taking liraglutide. Clearly, a few cases aren't enough to call an entire therapeutic class into question or to establish contraindications. Further investigation is needed, and the European authorities who collected the data are analyzing the approximately 150 reports concerning possible cases of self-injury and suicidal thoughts in patients taking these drugs. We should have some results and answers by November 2023. This alert comes at a time when GLP-1 agonists, especially semaglutide, are being misused, particularly in France. The French health authorities (ANSM) have published a press release and reiterated that these medicinal products should be used only as indicated. Despite these warnings, alerts, and suspicions, the risk profile of GLP-1 agonists appears to clinicians to be very good. Although nausea and vomiting occasionally lead patients to stop treatment, there are no obvious major side effects. A risk for acute pancreatitis (though not yet fully confirmed) has been mentioned, as has a risk for thyroid cancer that has not fully been proven in humans. Do we now have to worry about suicide risk? Another Rimonabant Fiasco? This situation is reminiscent of what happened with rimonabant (Acomplia), which was studied and marketed in the early 2000s. Relatively soon after it reached the market, it was withdrawn, mainly because of a risk for depression and suicide. Is this a case of history repeating itself? Have we found ourselves in the same situation? Frankly, as it stands, I don't think so. It's true that with rimonabant, we had some worrying data that had already been observed in randomized clinical trials. There were already signs of mood disturbances in patients taking the drug vs placebo. With GLP-1 agonists, to my knowledge, there have been no reports of this kind in the clinical trials conducted. Of course, this doesn't rule out a rare risk. That's why we need to continue with the investigations. We also know that there are GLP-1 receptors in the central nervous system. We often talk about them as being located in the hypothalamus, which largely explains the effect of these drugs on appetite. But the mechanisms of action of GLP-1 agonists and medicines conventionally used to reduce appetite (anorectics or even rimonabant) are very different. This is why we don't really expect there to be any psychological side effects with GLP-1 agonists. What's the Explanation? Why do we have these suspicious observations of suicidal ideation or self-injury? What are the possible explanations? In my opinion, we must first confirm that the incidence of these psychiatric disturbances is greater in patients taking GLP-1 agonists than in a similar matched general population group. We should also question whether these mood disturbances are not simply linked to patients with obesity who have easy access to GLP-1 agonists. We know that obesity is associated with an increased risk for suicidal ideation and self-injury. There is another little-known observation: Weight loss is associated with a risk for suicide. It has been spoken about in relation to bariatric surgery. We know that after bariatric surgery (bypass or sleeve gastrectomy) the risk for suicidal ideation is double that of the preoperative period in the same population. And this risk is multiplied by close to four when comparing the population with a control group. But be careful because these data come from observational studies. Although the analysis I'm referring to when I'm speaking in relation to a control population is a control group, it isn't from a randomized trial. There is another interesting piece of data, which is that weight loss, regardless of the method used, is associated with an increased risk for suicide. This is what I found in two prospective studies involving this association, and there is no obvious explanation for it at this stage. Of course, there are lots of types of methodologic bias possible, but this poses the question of why there is a greater risk for suicide and self-injury in people taking a certain treatment and losing weight. In Practice Should we change our attitude towards prescribing GLP-1 agonists? For the moment, there are no recommendations in this regard. I don't think that it's reasonable to upend everything. Of course, the important thing is to adhere strictly to the treatment indications, and in a few weeks' time, we'll see the results from the analyses conducted by the French Health Authorities regarding the causal link between suicide risk and taking a GLP-1 agonist. With our current knowledge, I think we can all agree that losing weight is never a walk in the park. It's a change, for which individual physical and psychological consequences must be measured. Related Topic: Study Supports Efficacy of 9-Item Depression Screening in Identifying Patients at Risk for Suicide

Esketamine Bests Quetiapine for Severe Depression in Head-to-Head Trial BARCELONA — Intranasal esketamine (Spravato, Janssen) is superior to extended-release quetiapine (Seroquel, AstraZeneca), an atypical antipsychotic, for treatment-resistant depression (TRD), results of a large, multicenter, head-to-head phase 3 trial show. Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission in comparison with quetiapine. More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates. The findings were presented here at the 36th European College of Neuropsychopharmacology (ECNP) Congress and were published online October 5 in The New England Journal of Medicine. New Hope The results provide "some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer," said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP. "These patients are not resistant, they just have resistance to monoaminergic drugs," he added. Esketamine, he said, is a "new weapon in our armamentarium." Reif said TRD is a serious condition that affects approximately 20% to 30% of those with major depressive disorder and has "substantial impact" on patients' lives, including quality of life and level of functioning. "We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment," Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was "urgently needed." For the trial, patients from 171 sites in 24 countries with TRD, defined as a <25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy. Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery–Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32. Reif said the study population was representative of a typical TRD population. The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30. Key Findings Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8 compared to those treated with quetiapine (27.1% vs 17.6%; P = .003). This equated to an adjusted odds ratio (OR) for remission of 1.74 (P = .003). Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% versus 14.1% with quetiapine; OR, 1.72 (P = .008). At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, vs 37.0% (P < .001). Reif noted that the definition of remission used in the study was a MADRS score of ≤10, but if the "more lenient" definition of ≤12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, vs 46.7%. Reif also presented results on functional remission rates beyond 32 weeks ― data that were not included in the study as published in NEJM. While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs 25.0%; OR, 1.88; P < .001). The safety data revealed no new signals, Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs 11.0% with quetiapine. Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it "greatly improves patients' functional impairment" while achieving "generally lower" adverse event rates. He added that they are currently running a significant number of secondary analyses "to give us a better grasp of which patient benefits most" from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection. "Tremendous Advance" Session co-chair Mark Weiser, MD, chairman at the Department of Psychiatry, Sackler School of Medicine, Tel Aviv University, Israel, told Medscape Medical News the results are "very exciting" and offer "further proof of a tremendous advance in our field." Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key. "It's great to improve symptoms," he said, "but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that's of extreme importance and makes us feel very optimistic about the future." Also commenting, Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, Barcelona, Spain, welcomed the findings. "The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine," he said in a release. "This gives people with treatment-resistant depression more safe treatment options." The study was funded by Janssen EMEA. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry. 36th European College of Neuropsychopharmacology (ECNP) Congress: Abstract S06.04. Presented October 8, 2023.

Editor's note: Find the latest long COVID news and guidance in Medscape's Long COVID Resource Center. As many as 2 out of 3 people with long COVID also have mental health challenges, including high rates of depression and anxiety, new research shows. It's a surprising finding that shows that those with long COVID may experience more mental distress than people with other chronic illnesses, such as Alzheimer's disease, cancer, diabetes, and cardiovascular disease. The study, published in The Lancet, followed 236,379 patients with long COVID. The investigators found that 62% of patients had received either a neurologic or a psychological diagnosis 6 months after being diagnosed with acute COVID. Mental distress associated with long COVID is a complex phenomenon that has biological, psychological, and social components, said Anna Dickerman, MD, a psychiatrist with New York–Presbyterian Hospital/Weill Cornell Medicine and associate professor of clinical psychiatry at Weill Cornell Medical College. This means that biological underpinnings caused by long COVID affect brain chemistry and give rise to psychological changes, putting a patient at higher risk for depression and anxiety, she said. In turn, changes in mental health can affect a person's risk of social effects such as job loss, disability, and isolation, which can affect self-esteem and self-worth, compounding anxiety and depression. Among patients with long COVID, all of these factors come together to cause what Dickerman has called "a perfect storm" that often results in depression, anxiety, and in some cases, suicidal thoughts. Dickerman and her colleagues at New York–Presbyterian Hospital are working to understand the mental health effects of long COVID so that patients are better able to recover from both the physical and mental health effects of this chronic condition. In an interview, Dickerman explained the mental health implications for people with long COVID and for the doctors who treat them. Excerpts of the interview follow. How does long COVID cause changes in the brain that result in depression? Long COVID causes inflammation in the brain that can cause the release of cytokines (proteins that are secreted from certain cells in the immune system) that are known to cause...fatigue, low energy, and low motivation ― symptoms which are also associated with depression and anxiety. What's more, if a patient had a serious case of acute COVID which led them to go on a ventilator, that too can cause changes in the brain. This means they could have had problems with their oxygenation status, and oxygen deprivation can have both acute and long-term effects on the brain. People can become delirious, meaning they have disturbances in their cognitive function, like attention and awareness (deficits). Patients may also have received steroids for treatment, which have been shown to impact mood and cause depression and anxiety. It's difficult to parse out because problems with attention and memory can also be associated with depression. Teasing apart what's from depression and what's from long COVID is tricky, but we do know that there's something unique about long COVID that causes cognitive deficiencies and changes. How do other factors associated with long COVID, such as insomnia, pain, and fatigue, affect the onset of depression and anxiety? Insomnia itself can be a symptom of depression. It may also be a physical symptom of long COVID similar to pain or difficulty breathing. And if you're not sleeping well, you're going to feel worse both physically and mentally. We also know that pain can affect mood and mood can affect pain — it's a bio-directional relationship. For example, if you're in pain, you're going to feel bad, and if you're depressed, that can also make your pain experience worse. Additionally, if you're in pain, it causes a physical limitation that can keep you from work or seeing your friends and family. These can all impact your social life. Limitations at work can also cause financial stress, which has been shown to impact mental health. Basically, it's a snowball effect that can make you more depressed, and the more depressed you become, the less you're able to participate in the activities that bring you happiness. Are rates of suicide higher in those with long COVID? Multiple studies have shown increased rates of suicidal ideation (thoughts) in patients with long COVID — and it's likely correlated with the degree of physical symptom burden, especially pain. This is consistent with what the research shows us of other chronic illnesses. In terms of specifically quantifying rates of completed suicides in the long COVID population, we simply need more epidemiological data. For now, I would say it's important for providers and the general population to know that these patients may be at increased suicide risk and to screen accordingly. Who is most at risk for mental distress associated with long COVID? Certainly anyone who had a preexisting mental health history before they got long COVID would be at a higher risk. There also seems to be disproportionate effects in those who have stressors related to other social determinants of health, like discrimination, poverty, and healthcare access. As a result, Black and Hispanic minority groups would be at a disproportionate risk for bad outcomes related to long COVID. What are the most effective treatments for those who have mental health problems associated with long COVID? This work is ongoing, and in the coming years we're likely to see new interventions. But for now, what we have in our treatment arsenal is the same evidenced-based treatments for anxiety and depression that we have in patients who don't have long COVID. For example, if a patient meets the clinical criteria for a major depressive episode or an anxiety disorder and they have long COVID, treatment would involve things like antidepressants and cognitive-behavioral therapy. Experts may also recommend a grated, gradual increase in physical activity in some patients with long COVID–associated depression. As a result of the number of people who got COVID, is there now an epidemic of mental health problems associated with the condition? In general, we're in the midst of a mental health epidemic as a result of the pandemic and all the effects that it's had on society, whether or not people had COVID. We're definitely seeing higher rates of depression and anxiety than we did before the pandemic. It's a group of patients that need attention. We also need more research over the next few years so that we can figure out better targeted treatments for this patient population. But for now, we know that it's important to work in an interdisciplinary model where we have psychiatrists working in close collaboration with pulmonologists, general practitioners, and cardiologists to holistically address both the physical and mental issues and not treat them in isolation, because we know there's a relationship.

Adults with greater adverse childhood experiences (ACEs) have higher attention deficit hyperactivity disorder (ADHD) symptom reporting than those with fewer ACEs, according to study findings published in the Journal of Attention Disorders. Yet, higher ACEs did not contribute to other psychological symptoms or worse neurocognitive performances. Studies that examine the relationship between objective cognitive performance and ACEs (early life experiences that may influence mental health outcomes) report conflicting results, and few studies have explored the relationship between objective cognitive performance and ACEs among individuals with self-reported ADHD symptoms. Therefore, investigators sought to characterize ADHD symptom reporting, neurocognitive performance, and other psychological symptoms among adults who experienced ACEs. The investigators conducted a cross-sectional study that began with 144 consecutive adults referred to an urban university academic medical center for neurological evaluation. Following the exclusion of 29 participants (primarily for invalid ADHD symptom reporting), a total of 115 individuals were included for analyses. On average, participants were aged 28.42 years (SD, 6.46), completed 16.47 years of education (SD, 1.99), and 65% (n=75) were women. Participants completed the ACE Questionnaire in which they self-reported ACEs, including emotional, physical, and sexual abuse along with neglect, and witnessing violence. Individuals were split into two groups based on these scores: the high ACEs group scored 4 or greater and the low ACEs group scored 3 or less. Participants also completed the Beck Depression Inventory-Second Edition (BDI-II), Beck Anxiety Inventory (BAI), and the Perceived Stress Scale (PSS). These measures were self-reports of depressive symptoms, anxiety, and perceived stress, respectively. In addition, all individuals completed a battery of standardized neuropsychological tests. "[O]ur results and the growing body of literature demonstrating links between ADHD and ACEs highlight the need for clinicians to consider ACEs during ADHD diagnostic assessments and treatment planning." Compared with the low ACEs group, the high ACEs group had higher ADHD symptom reporting for childhood impulsive (F =14.65; P <.001) and inattentive (F =11.31; P <.001) symptoms, and also reported significantly greater ADHD childhood symptom severity (F =11.31; P <.001). Similar results were found for the assessments of current/adulthood symptoms, with the high ACEs group reporting significantly higher levels of impulsive (F =7.24; P <.001) and hyperactive (F =4.62; P <.05) symptoms, along with greater symptom severity (F =5.51; P <.05) than the lower ACEs group. However, despite these group differences in self-reported ADHD symptoms, psychological symptom reporting of depression, anxiety, and perceived stress did not differ between the high ACEs group and the low ACEs group. Further, neurocognitive functioning was similar across all tested domains between the groups. These results demonstrate that a heavier burden of ACEs resulted in higher ADHD symptom reporting, but did not impact other psychological symptoms or neurocognitive performance. The investigators concluded, “[O]ur results and the growing body of literature demonstrating links between ADHD and ACEs highlight the need for clinicians to consider ACEs during ADHD diagnostic assessments and treatment planning.” Study limitations include recall bias during childhood data reporting and the inability to investigate causative factors due to the cross-sectional study design. References: Alfonso D, Basurto K, Guilfoyle J, et al. The effect of adverse childhood experiences on ADHD symptom reporting, psychological symptoms, and cognitive performance among adult neuropsychological referrals. Related Topic: Paying Attention to ADHD Prescriptions in Your Community ADHD Underappreciated in Older Adults

The risk for depression following retirement is higher in individuals who retire later in life, according to study findings published in The American Journal of Geriatric Psychiatry. Women and individuals living in rural areas seem particularly impacted. Thus far, most studies exploring retirement age and depression have been primarily conducted in Northern European countries with social welfare systems that provide significant support for pensions and employment, contributing to better mental health after retirement. Taiwan (with low labor force participation rates, long working hours, stressful working conditions, and the fastest current rate of population aging globally) is trending toward delayed statutory retirement age and prolonged working life, and the impact this environment may have on later-in-life depression has not been thoroughly explored. Therefore, investigators in Taiwan aimed to determine if retirement is associated with depressive disorders and if retirement age is a mitigating factor. The investigators conducted a population-based study using Taiwan’s National Health Insurance (NHI) dataset from January 2000 to December 2019. The NHI program in Taiwan enrolls about 99% of the national population and the dataset includes 2 million citizens determined by randomized sampling. The investigators identified 84,224 individuals who were aged 50 years and older, employed at the baseline, and had records of retirement during the follow-up period. The International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes were used to track the incidence of depressive disorders in the 7 years before and after retirement. "Instead of implying a beneficial mental effect of retirement, our results highlight that retirement represents a major life change and a potential stressor for older adults." The investigators found that age of retirement was oldest among those who had depression incidence before retirement (n=5111; 6.1%) and youngest among those with depression incidence after retirement (n=5222; 6.2%). For the subsequent analyses, participants with diagnosed depressive disorders prior to retirement were excluded. The investigators found the highest incidence of depressive disorders among individuals who retired after 69 years of age (8.15 per 1000 person-years) and those who retired between 65 and 69 years of age (7.6 per 1000 person-years). This risk of developing a depressive disorder was higher among individuals retiring in the 65 to 69 age group compared with the 60 to 64 group (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.02-1.18). Furthermore, the risk for depression was higher among women (aHR, 1.56; 95% CI, 1.47-1.65; P <.001), people living in rural areas (aHR, 1.11; 95% CI, 1.02-1.20; P =.015), and individuals with a Charlson Comorbidity Index of 1 (aHR, 1.40; 95% CI, 1.27-1.54; P <.001) or 2 and greater (aHR, 1.40; 95% CI, 1.28-1.52; P <.001). These study results indicate that retiring at a later age carries a higher risk of developing depression. The investigators concluded, “Instead of implying a beneficial mental effect of retirement, our results highlight that retirement represents a major life change and a potential stressor for older adults.” Study limitations include the use of insurance identities as proxy for retirement information, a lack of some demographic features, and an inability to identify individuals who may have depression but were not seeking medical help. References: Yang HJ, Cheng Y, Yu TS, Cheng WJ. Association between retirement age and incidence of depressive disorders: a 19-year population-based study. Am J Geriatr Psychiatry. Published online September 16, 2023. doi:10.1016/j.jagp.2023.09.010

Ketamine TOPLINE: Ketamine was no more effective than placebo in reducing depressive symptoms in surgical patients with major depressive disorder (MDD), results of a new study, which contradict prior research, suggest. Although symptoms improved in both study groups, investigators say participants' expectations of an improvement from ketamine may be driving that result. METHODOLOGY: The randomized, placebo-controlled trial included 40 patients who had previously been diagnosed with MDD and who were scheduled for elective noncardiac, nonintracranial surgery. Participants completed pre- and post-surgery depression screenings with the Patient Health Questionnaire-8 (inclusion score was ≥ 12) and the Montgomery-Ǻsberg Depression Rating Scale (MADRS). Patients received an infusion of 0.5 mg/kg of saline (placebo group; n = 20) or ketamine (n = 20) during surgery, along with general anesthesia. At the end of a 14-day follow-up, patients were asked to guess whether they had received ketamine or placebo. TAKEAWAY: MADRS scores dropped by around half 1 day after treatment, indicating an improvement in depressive symptoms in both the group that received ketamine (mean decrease from 25 to 12.6 points) and the group that received placebo (mean decrease from 30 to 15.3 points). There was no significant difference between the two. Participants in the ketamine and placebo groups also reported high rates of clinical response (60% and 50%, respectively) and remission (50% and 35%, respectively), again with no significant difference based on treatment with ketamine or placebo. Only 36.8% of participants accurately guessed their treatment group. Those who guessed they had received ketamine had higher MADRS scores than those who guessed they had received placebo or said they didn't know (10.1 vs 19.2 vs 23.0). The ketamine group had a significantly shorter hospital stay (1.9 days) than the placebo group (4 days) (P = .02). IN PRACTICE: "Our primary findings differ from those of previous antidepressant trials with ketamine conducted without adequate masking, which find robust effects of ketamine," the authors write, adding that "regardless of the intervention being tested, participant expectations of a positive outcome — also known as hope — may drive large decreases in depression symptoms seen in antidepressant trials." SOURCE: Heifets led the study, which was published online October 19 in Nature Mental Health. The study was funded by the Society for Neuroscience in Anesthesiology and Critical Care, the National Institutes of Health, and the Stanford School of Medicine Research Office. LIMITATIONS: The investigators did not measure participants' treatment expectations prior to randomization and could not determine what effect participant expectancy bias may have had on the results. In addition, there was no assessment of the blind for anesthesiologists who administered the ketamine or placebo to patients. DISCLOSURES: Heifets is on the scientific advisory boards of Osmind and Journey Clinical and is a consultant to Clairvoyant Therapeutics and Vine Ventures. Other disclosures are noted in the original article. Related Topic: Study Finds Esketamine Nasal Spray More Likely to Induce Remission in Treatment-Resistant MDD Than Quetiapine Extended Release FDA Approves First Oral Selective 5HT1A Receptor Agonist for MDD

The US Food and Drug Administration (FDA) has cleared the first over-the-counter test for the preliminary detection of fentanyl in urine. With the Alltest Fentanyl Urine Test Cassette (Hangzhou AllTest Biotech Co, Ltd), three drops of fresh urine are placed onto a cassette containing a fentanyl test strip. After 5 minutes, the test result appears as colored lines. "Opioid abuse, misuse and addiction is one of the most profound public health crises facing the US today. It is also a very personal issue for many people, impacting individual lives and families," Jeff Shuren, MD, JD, director, the FDA Center for Devices and Radiological Health, said in a statement. Shuren said this test is an example of the FDA's "continued commitment to authorize tools that can reduce deaths associated with overdoses. The agency expedited review of this test, making a decision on the submission in only 16 days from the date it was received." The FDA cautions that the urine test provides only a preliminary result and that a more specific, alternative chemical method (confirmation testing) must be used to confirm the result. The Alltest Fentanyl Urine Test Cassette includes a preaddressed mailing box for shipping samples to the manufacturer's laboratory for confirmation testing. The FDA also notes that the test may provide an incorrect result if the urine sample is contaminated, for example, by adding bleach. The test does not distinguish between drugs of abuse and certain medications. Consuming certain foods or food supplements can lead to a false positive test result. Related Topic: Fentanyl-Laced Stimulants Fuel Opioid Crisis' Fourth Wave

Recently I had the pleasure of speaking with Jonathan DePierro, Ph.D., about his newly updated book Resilience: The Science of Mastering Life's Greatest Challenges. DePierro is associate director of the Center for Stress, Resilience and Personal Growth (CSRPG) at New York's Mount Sinai Icahn School of Medicine. The book provides pragmatic practices based on years of clinical research with Vietnam veterans, 9/11 recovery workers, and others, backed up by inspiring stories of endurance and transformation. What Is Resilience, and How Can I Build It Up? Resilience can be hard to measure, and many longstanding ways to assess resilience, while helpful, have fallen short. For instance, resilience is not simply the absence of post-traumatic stress disorder; it is the presence of health and, often (but by no means exclusively), accompanied by post-traumatic growth. Regardless, resilience serves to buffer PTSD such that people with greater resilience are less likely to develop pathological outcomes following significant trauma. Not only that, but while many aspects of resilience are innate (related to biological factors affecting brain plasticity, for example), many resilience factors are learnable ("modifiable"). It is these modifiable factors people need to target, train, and track. DePierro and colleagues have developed the Mount Sinai Resilience Scale (2023), which enhances the capacity not only to assess resilience but whether its component factors are being applied effectively. At face value, its 24 items serve as an evidence-based framework for self-assessment as well as a means of identifying areas where resilience can be further trained. Increasing resilience correlates with enhanced long-term health outcomes and has been shown, at the organizational level, to be a cost-effective strategy. Investing in resilience now saves organizations significant costs in the future. Nevertheless, relatively few organizations actually implement robust and demonstrably effective resilience training into their key performance indicators and other measures of progress. Mount Sinai Resilience Scale Each item specifies a behavior or mindset likely to increase resilience and is rated on a scale from "Not at all true" (0) to "Almost always true" (4). For each item, the scale asks, "How useful/effective was this strategy?", highlighting the pivotal role of ongoing nonjudgmental self-appraisal. The scale can be used to track progress over time and identify areas where additional training is helpful. I confronted or faced my fears and problems directly. I actively tried to change or challenge negative or critical thoughts about myself or others. I attempted to become a positive example or role model of how to handle challenges. I turned to friends, mentors, family members, spiritual leaders, or teachers for advice on how to handle challenges. I made efforts to stay hopeful about the future. I sought the support of others. My choices and behaviors were consistent with my convictions of what is right and what is wrong. I told myself that the challenges in my life can lead to personal growth. When given the opportunity to choose my food, I chose foods that were nutritious or healthy. I did my best to get enough sleep. I participated in activities that gave me meaning and purpose. I took time to notice and understand my emotional and bodily reactions to stressful situations. I accepted that there are difficult emotions, situations, or people that I cannot change right now. I felt the positive impact of my religious and/or spiritual beliefs in many areas of my life. I took active steps to emotionally recover from stressful situations. I provided emotional, financial, or other types of support or donations to those in need. I offered support to others. I slowed myself down "in the moment" to handle intensely negative emotional reactions. I worked to forgive myself or others for doing something that was not in line with my values. I dedicated time to my hobbies or interests. I took the time to learn new skills or things that interest me. I made an effort to exercise. I held on to my sense of connection with a higher power or deity. I sought solace in spiritual practices such as prayer, meditation, or faith meetings. Conclusions There is certainly more to the story of satisfaction, wellness and health, recovery from trauma, illness and adversity than simply resilience. Resilience is, however, at the heart of the conversation and, while not a panacea, a foundational ingredient in a life well-lived, in hard times and all times. An updated manual of resilience, geared toward action-oriented steps as well as reflecting deep understanding, provides tools people can immediately deploy—tools sorely in need in today's increasingly stressful, crowded, and confusing reality. Over time, incorporating resilience strategies leads to a shift in one's overall approach to adversity and can be part of a plan for pursuing personal development. Small changes add up, but trying to do to all at once is the antithesis of resilience. It's wise to pick a couple of areas, work on small changes, see results, motivate persistence, and create a virtuous cycle. The goal, in a sense, is to cultivate a resilient personality. From sleep and exercise to cognitive flexibility, to finding meaning and/or faith, to being supported by others and supporting others, there are many relatively accessible, high-impact ways to begin to bend rigidity into resilience. Change that starts small and builds strength and flexibility over time also benefits from self-compassion, so that when we falter, we pick ourselves up with firm kindness rather than descend into self-criticism. Related Article: Growing from Adversity: How to Build Resilience

Child psychiatry primarily focuses on behavioral disorders and emotional problems that affect children, often characterized by anxiety reactions. Emotional maladjustment's in children may include habit disorders and conduct disorders. Parent-child relationships, school experiences, and perceptual difficulties can also contribute to personality problems. Child psychiatry is a branch of medicine that focuses on the study and treatment of mental, emotional, and behavioral disorders in children. It has been recognized as a subspecialty of psychiatry and neurology since the mid 1920s, with subdivisions including infant psychiatry and adolescent psychiatry. The approach to diagnosing and treating children's mental and emotional disturbances differs from that used with adults, as they are living through active and critical developmental phases. Child psychiatry primarily focuses on behavioral disorders and emotional problems that affect children, often characterized by anxiety reactions. Emotional maladjustments in children may include habit disorders and conduct disorders. Parent-child relationships, school experiences, and perceptual difficulties can also contribute to personality problems. Child psychiatry often involves family therapy and specialized methods like play therapy, which allows children to express their feelings, thoughts, wishes, and fears more freely and easily than through verbal communication. It would be much better to consult your Psychiatrist.