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HealthDay News — The U.S. Food and Drug Administration is warning consumers about risks of using compounded versions of the drug ketamine, often taken for psychiatric disorders. Compounded products are not evaluated by the FDA for safety and effectiveness. They are also not regulated like approved drugs, so they present a greater risk. “Although compounded drugs can serve an important medical need for certain patients when an FDA-approved drug is not medically appropriate, they also present a risk to patients and should only be used under the care of a health care provider,” the FDA said in a news release. The agency offered an example of a concerning case reported about a patient in April. That person had taken compounded oral ketamine outside of a health care setting for the treatment of posttraumatic stress disorder (PTSD). The result was slowed breathing and a ketamine blood level that appeared to be twice what a person would typically receive as anesthesia, the FDA said. Patients are increasingly interested in taking compounded ketamine products, including oral formulations, for mental health disorders, such as depression, anxiety, PTSD, and obsessive-compulsive disorder, according to the FDA. Known safety concerns associated with the drug are abuse and misuse, psychiatric events, increases in blood pressure, slowed breathing, and lower urinary tract and bladder symptoms. In the FDA-approved version of ketamine, the expected benefit outweighs these risks when used at appropriate doses. “Despite increased interest in the use of compounded ketamine, we are not aware of evidence to suggest that it is safer, is more effective, or works faster than medications that are FDA-approved for the treatment of certain psychiatric disorders,” the FDA said. The FDA said it understands that getting compounded products through telemedicine platforms and compounders for at-home use may be attractive to some patients, but it reiterated the risk. At-home administration of these products is especially risky because of the lack of monitoring for adverse outcomes, the FDA said. Using compounded products outside a health care setting means there is no monitoring of sleepiness; dissociation or disconnection between a person’s thoughts, feelings, and sense of time, space, and self; as well as changes in vital signs, including blood pressure and heart rate. Related Topic: Study Finds Esketamine Nasal Spray More Likely to Induce Remission in Treatment-Resistant MDD Than Quetiapine Extended Release FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders What Patients and Health Care Providers Should Know There is increased interest in compounded ketamine products (including oral formulations) for the treatment of psychiatric disorders. When considering use of compounded ketamine products, patients and health care providers should know: Ketamine is not FDA approved for the treatment of any psychiatric disorder. FDA is aware that compounded ketamine products have been marketed for a wide variety of psychiatric disorders (e.g., depression, anxiety, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder); however, FDA has not determined that ketamine is safe and effective for such uses. Compounded drugs, including compounded ketamine products, are not FDA approved, which means FDA has not evaluated their safety, effectiveness, or quality prior to marketing. Therefore, compounded drugs do not have any FDA-approved indications or routes of administration. Although compounded drugs can serve an important medical need for certain patients when an FDA-approved drug is not medically appropriate, they also present a risk to patients and should only be used under the care of a health care provider. Use of compounded ketamine products without monitoring by a health care provider for sedation (sleepiness), dissociation (disconnection between a person’s thoughts, feelings, and sense of space, time, and self), and changes in vital signs (such as blood pressure and heart rate) may put patients at risk for serious adverse events. Known safety concerns associated with the use of ketamine products include abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression (slowed breathing), and lower urinary tract and bladder symptoms. For FDA-approved ketamine (see Ketalar prescribing information), the expected benefit outweighs these risks when used at appropriate doses for FDA-approved indications and routes of administration. Despite increased interest in the use of compounded ketamine, we are not aware of evidence to suggest that it is safer, is more effective, or works faster than medications that are FDA approved for the treatment of certain psychiatric disorders. Background Ketamine hydrochloride (referred to here as “ketamine” interchangeably) is a Schedule III controlled substance that is FDA approved as an intravenous or intramuscular injection solution for induction and maintenance of general anesthesia. Ketamine, like many drug products, is a mixture of two mirror-image molecules, R-ketamine and S-ketamine (arketamine and esketamine, respectively). Spravato (which includes only the esketamine molecule), is approved as a nasal spray for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior (in conjunction with an oral antidepressant). On February 16, 2022, FDA published a compounding risk alert describing the potential risks associated with at-home use of compounded ketamine nasal spray and several adverse event reports. The February 2022 compounding risk alert also provided information about Spravato, which is subject to a Risk Evaluation and Mitigation Strategy (REMS) as part of its FDA approval. A REMS is a drug safety program that FDA can require for certain approved medications with serious safety concerns to ensure the benefits of the medication outweigh its risks. The Spravato REMS requires esketamine to be dispensed and administered in medically supervised health care settings that are certified in the REMS and agree to monitor patients for a minimum of two hours following administration because of possible sedation and dissociation and the potential for misuse and abuse. Compounded ketamine products are not FDA approved for any indication, including psychiatric disorders, and are, therefore, not part of a REMS program. This does not mean compounded ketamine products are safer for patients. In fact, because compounded ketamine products are not subject to monitoring requirements under a REMS, they may be less safe. Since the publication of the February 2022 compounding risk alert, FDA has become aware of increasing public interest in the use of sublingual and oral dosage forms of compounded ketamine for the treatment of psychiatric disorders. FDA understands that the ability to obtain such products through telemedicine platforms and compounders for at-home use may be attractive to some patients. However, the lack of monitoring for adverse events, such as sedation and dissociation, by an onsite health care provider may put patients at risk. Additionally, FDA has identified safety concerns associated with compounded ketamine products as discussed below. Furthermore, FDA has not established safe or effective dosing of ketamine for any psychiatric indication because ketamine has not been approved for these uses. These factors may place the patient at risk for serious adverse events, misuse, and abuse. Potential Safety Risks Associated with Compounded Ketamine Products Patients who receive compounded ketamine products from compounders and telemedicine platforms for the treatment of psychiatric disorders may not receive important information about the potential risks associated with the product. As previously noted, safety concerns that may be associated with ketamine products include, but are not limited to, risks of sedation, dissociation, psychiatric events or worsening of psychiatric disorders, abuse and misuse, increases in blood pressure, respiratory depression (breathing becomes slower and shallower and the lungs fail to exchange carbon dioxide and oxygen efficiently), and lower urinary tract and bladder symptoms. At-home administration of compounded ketamine presents additional risks because a health care provider is not available onsite to monitor for serious adverse outcomes resulting from sedation and dissociation. In April 2023, FDA received an adverse event report of a patient who experienced respiratory depression after taking compounded oral ketamine outside of a health care setting for the treatment of PTSD. The patient’s ketamine blood level appeared to be twice the blood level typically obtained for anesthesia. In addition to the potential risks associated with compounded ketamine products, patients and health care providers should be aware that information about use of these products is lacking. For example, FDA has not established safe or effective dosing of ketamine for any psychiatric indication. Furthermore, the dosages of the sublingual and oral compounded ketamine products marketed by compounders and telemedicine platforms may vary, which makes it challenging to predict which potential risks may be associated with these products. In addition to the concerns regarding the short-term use of compounded ketamine, the overall benefit-risk profile of ketamine for treatment of psychiatric disorders is unknown. Conclusions FDA is aware of increased interest in the at-home use of compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. Patients and health care providers should be aware that FDA has identified potential safety concerns associated with the use of compounded ketamine products from compounders and telemedicine platforms, including abuse and misuse, psychiatric events, increases in blood pressure, respiratory depression, and lower urinary tract and bladder symptoms. Home use of compounded ketamine products presents additional risk because onsite monitoring by a health care provider is not available. Ketamine is not FDA approved for the treatment of any psychiatric disorder, and additional clinical studies are needed to adequately investigate ketamine’s benefit-risk profile and safe-use conditions in the treatment of psychiatric disorders. FDA encourages compounders, patients, and health care providers to report adverse events associated with compounded ketamine products to FDA’s MedWatch Adverse Event Reporting program.

Concurrent treatments targeting eating disorders and PTSD are needed to help these patients with complex conditions. Research shows an undeniable connection between posttraumatic stress disorder (PTSD) and eating disorders (EDs). Individuals with significant traumatic histories and/or PTSD have more severe ED symptoms, more suicidality, and more anxiety and depressive symptoms. Studying the intersection between these 2 mental health illnesses helps us understand how to treat them together moving forward, specifically in higher levels of care, including residential ED treatment programs. Groundbreaking research published in the Journal of Eating Disorders shows the effectiveness of integrating trauma treatment with evidenced-based ED treatment in residential programs. The conventional thinking in psychiatry had been that it was best to refrain from trauma work while in intensive treatment settings, deferring this to later outpatient treatment. These research results demonstrate that multimodal, integrated treatment approaches based on principles of cognitive processing therapy (CPT) that address trauma and PTSD can be successfully delivered in residential treatment to patients with PTSD and associated comorbidity. PTSD in Higher Levels of ED Treatment Research from the past few years indicates that PTSD is common in patients receiving higher levels of care. In 2020, we reported that nearly half (49%) of adults admitted to residential ED treatment met the criteria for PTSD,2 whereas results from an additional study from 2021 found that of 613 adults in residential treatment, 53% were reported to likely have PTSD based on PCL-5 >33.3 Furthermore, 35% of women in ED residential treatment also had PTSD, according to results from a 2021 study (Figure 1). Individuals with EDs and comorbid PTSD experience more severe anxiety, depression, ED symptoms, and poorer quality of life compared with those without PTSD. Adults with EDs and PTSD had significantly higher scores than patients without PTSD on all measures, including total number of traumas on the Life Events Checklist (P < .001), global and all subscale scores on the Eating Disorder Examination Questionnaire (P < .001), depression scores on the Patient Health Questionnaire (P < .001), and scores on the Spielberger State-Trait Anxiety Inventory (state P < .001; trait P < .001). Additionally, research shows that PTSD is common among adolescents who are admitted to ED residential programs. Adolescents with EDs and PTSD experienced more severe ED symptoms and poorer quality of life compared with those without PTSD in ED treatment. Our research reported that of the 647 adolescents with EDs admitted to residential treatment, 38% met criteria for PTSD and 75% endorsed at least 1 type of childhood trauma. Those who experienced ED onset from the age of 5 to 10 years had higher rates of PTSD (76%) compared with those who experienced ED onset from the age of 11 to 17 years (45%) and those who experienced ED onset as adults (31%; P < .001). Childhood onset of an ED is associated with more traumatic experiences and current PTSD diagnosis, increased severity of ED and comorbid psychopathology, higher body mass index, and more prior inpatient and residential admissions for ED treatment. Sexual and gender minority individuals in ED treatment have significantly higher rates of PTSD compared with those who do not identify as LGBTQ+. Individuals with EDs and PTSD who identify as LGBTQ+ experience more severe ED symptoms and poorer quality of life. Of the 24% of participants in our study who identified as LGBTQ+, 63% met criteria for PTSD compared with 45% of cisgender heterosexual individuals. Outcomes With Concurrent Treatment Using an integrated clinical approach based on principles of CPT and other evidence-based treatments, we studied outcomes at discharge and 6 months following discharge in 609 patients (96% female; mean age [+/- SD], 26.0 years [+/- 8.8 years]; 22% LGBTQ+) with and without PTSD. All patients improved significantly and retained improvements at follow-up compared with admission. However, all measured symptoms, including those of EDs, major depression, state and trait anxiety, and quality of life, were higher in patients with PTSD at every time point (admission, discharge, and follow-up). Going beyond trauma-informed care by providing evidence-based trauma treatment results in better outcomes. We integrated CPT, 1 of 3 gold-standard PTSD treatment options, into comprehensive ED treatment based on cognitive behavioral therapy and dialectical behavior therapy. Results from the study showed that 81% of patients with PTSD at admission had significant reductions in trauma symptom scores from admission to discharge and 73% of patients with PTSD at admission had significant reductions in scores from admission to follow-up 6 months later. Not only did patients achieve sustained improvements in ED symptoms, but they also gained significant, long-term relief from trauma symptoms after completing programming using an integrated, multimodal clinical approach. Postdischarge outcomes data show that not only treating patients’ mental health illnesses but also providing them with tools and coping skills to self-manage symptoms and maintain recovery can help patients get well and stay well longer. Concluding Thoughts There is growing consensus in the ED field that integrated, concurrent treatments targeting EDs and PTSD are needed to help these patients with complex conditions.2,4,7-10 The findings of this study conclude that concurrent, parallel, and interwoven approaches to treatment, one for the ED and one for PTSD, can be delivered during the same treatment course by the same providers and therapists. Integrated therapy techniques for PTSD and related disorders can be delivered successfully in residential treatment and are associated with lasting improvements 6 months after discharge (Figure 2). The hope for this research and these findings is that they may help others in the ED field develop more effective and integrated treatment approaches for patients with PTSD admitted to higher levels of care for ED treatment. Dr Perlman is chief medical officer at Monte Nido & Affiliates. She is double–board certified in psychiatry and addiction medicine and has trained in psychoanalytic psychotherapy. She is on the board of directors of the Eating Disorders Coalition, has served as vice president of the board from 2018 through 2022, and advocates in the US Congress regularly for increasing eating disorder education and access to treatment. Additionally, she oversees Monte Nido & Affiliates’ institutional review board–approved research study on clinical outcomes as coprincipal investigator and has coauthored several papers in peer-reviewed research journals on PTSD and EDs. Related Topic: Boundary Problems Associated with PTSD and Substance Abuse References 1. Brewerton TD, Gavidia I, Suro G, Perlman MM. Eating disorder patients with and without PTSD treated in residential care: discharge and 6-month follow-up results. J Eat Disord. 2023;11(1):48. 2. Brewerton TD, Perlman MM, Gavidia I, et al. The association of traumatic events and posttraumatic stress disorder with greater eating disorder and comorbid symptom severity in residential eating disorder treatment centers. Int J Eat Disord. 2020;53(12):2061-2066. 3. Scharff A, Ortiz SN, Forrest LN, Smith AR. Comparing the clinical presentation of eating disorder patients with and without trauma history and/or comorbid PTSD. Eat Disord. 2021;29(1):88-102. 4. Rienecke RD, Blalock DV, Duffy A, et al. Posttraumatic stress disorder symptoms and trauma-informed care in higher levels of care for eating disorders. Int J Eat Disord. 2021;54(4):627-632. 5. Brewerton TD, Gavidia I, Suro G, Perlman MM. Eating disorder onset during childhood is associated with higher trauma dose, provisional PTSD, and severity of illness in residential treatment. Eur Eat Disord Rev. 2022;30(3):267-277. 6. Brewerton TD, Suro G, Gavidia I, Perlman MM. Sexual and gender minority individuals report higher rates of lifetime traumas and current PTSD than cisgender heterosexual individuals admitted to residential eating disorder treatment. Eat Weight Disord. 2022;27(2):813-820. 7. Claudat K, Reilly EE, Convertino AD, et al. Integrating evidence-based PTSD treatment into intensive eating disorders treatment: a preliminary investigation. Eat Weight Disord. 2022;27(8):3599-3607. 8. Mitchell KS, Singh S, Hardin S, Thompson-Brenner H. The impact of comorbid posttraumatic stress disorder on eating disorder treatment outcomes: investigating the unified treatment model. Int J Eat Disord. 2021;54(7):1260-1269. 9. Trottier K, Monson CM. Integrating cognitive processing therapy for posttraumatic stress disorder with cognitive behavioral therapy for eating disorders in PROJECT RECOVER. Eat Disord. 2021;29(3):307-325. 10. Scharff A, Ortiz SN, Forrest LN, et al. Post-traumatic stress disorder as a moderator of transdiagnostic, residential eating disorder treatment outcome trajectory. J Clin Psychol. 2021;77(4):986-1003.

The NCE’s developer has announced that it is now initiating phase 3 studies. A study of a new chemical entity (NCE) for treatment-resistant schizophrenia (TRS) found that 40% of patients improved to the point of no longer meeting TRS severity criteria after 6 months of treatment. Study 014/015—a 6-week, randomized, rater-blinded study by Newron Pharmaceuticals—evaluated the safety, tolerability, and efficacy of evenamide, an investigational NCE for the management of TRS. For study 014, investigators recruited a total of 161 patients with TRS who were consistently administered a therapeutic dose of a single antipsychotic medication, excluding clozapine, with the primary aim of assessing the safety and tolerability of orally administered evenamide at 3 predefined doses: 7.5 mg, 15 mg, and 30 mg twice a day. Preliminary efficacy was evaluated by observing changes in Positive and Negative Syndrome Scale (PANSS) scores from baseline. Secondary objectives involved the evaluation of alterations from baseline in Clinical Global Impression of Change (CGI-C), Severity of Illness (CGI-S), and Strauss-Carpenter Level of Functioning (LOF) scale scores. Study 015 served as an extension of study 014 to investigate the long-term advantages of inhibiting glutamate release, continuing with 77 patients successfully completing 1 year of treatment with evenamide. Results from study 014/015 showed a statistically significant improvement in PANSS, CGI-S, and LOF scores at 6 months (p-value < 0.001: paired t-test, LOCF). A considerable proportion of participants who experienced a > 20% reduction in symptoms compared to baseline on PANSS total score at week 6 had maintained their response upon reevaluation at month 6. No participants experienced a worsening of psychosis, and no participants relapsed. And approximately 40% of participants no longer met the protocol severity criteria used to diagnose treatment resistance upon reevaluation at 6 months. These results were recently presented at the 36th European Clinical Neuropsychopharmacology Congress (ECNP) in Barcelona, Spain. “These highly encouraging results from study 014/015…demonstrate the potential benefits of evenamide and its unique glutamatergic mechanism of action,” said Ravi Anand, Newron chief medical officer, in a press release. “The findings show that the addition of this glutamate modulation to first- and second-generation antipsychotics in patients with TRS potentiates their effects on dopamine dysfunction and can potentially produce a beneficial antipsychotic response. “What is remarkable about the effect of evenamide in this study is that treatment benefits continue to accrue overtime, and many patients who do not respond early achieve clinically important benefits later. Importantly, over the course of the study period, we found that no patients relapsed or experienced worsened psychosis, and a significant portion of patients improved to the point that they no longer met the criteria to enroll in the study to begin with.” Given these results, Newron has announced that it is moving into phase 3 studies of evenamide for the same indication. According to Anand, “Following these encouraging results, which have been assessed by our international advisory committee, we are preparing to initiate a potentially pivotal, phase 3, multinational, randomized, double-blind, placebo-controlled trial in patients with TRS and are confident that the results from that study will endorse the use of evenamide as an adjunct treatment to any other antipsychotic as a new therapeutic strategy for TRS.” Related Topic: Schizophrenia Still Linked to Early Mortality Reference 1. Newron TRS study 6 months’ results: evenamide substantially improves patients to an extent that they no longer meet protocol entry criteria. BusinessWire. October 9, 2023. Accessed October 9, 2023.

The newest class of medications to treat insomnia have many advantages. CONFERENCE REPORTER Dual orexin receptor antagonists (DORAs), the newest kid on the insomnia treatment block, do not adversely effect sleep architecture, explained Paul P. Doghramji, MD, at the 2023 Annual Psychiatric Times™ World CME Conference. He also explained DORAs do not have rebound insomnia, tolerance issues, or withdrawal symptoms. Doghramji, Senior Family Physician at Collegeville Family Practice, told attendees how orexins work, and then reviewed the currently available DORAs. Suvorexant was the first DORA on the market, approved in 2014 for difficulties with sleep onset and/or maintenance, he said. Available in 5, 10, 15, and 20 mg doses, Doghramji finds most patients do best at the 20 mg dose but suggested starting with the 10 mg dose. It has a half-life of 15 hours and a Tmax of 2 hours. The most common adverse effects in trials were somnolence, headache, abnormal dreams, dry mouth, cough, and upper respiratory infection. Interestingly, the adverse events rate were in a 2 to 1 ratio of women to men, Doghramji explained. There were no differences in psychomotor or morning driving performance when compared with placebo. Doghramji shared highlights of an interesting study, in which there were significant improvements in both total sleep time and wake after sleep for patients with insomnia and mild to moderate Alzheimer in the suvorexant group as compared with the placebo group. Next on the scene was lemborexant, Doghramji said, which was approved for difficulties with sleep onset and/or maintenance. It is available in 5 mg and 10 mg doses; Doghramji noted it is better to start with the 5 mg dose, and if the desired effect is not realized, move to the higher dose. Lemborexant has more effect on orexin 2 than orexin 1, he explained, with a Tmax of 1-3 hours and a half-life of 17-19 hours. Doghramji noted that because it induces CYP2B6, which impacts the area under the curve for bupropion, patients on both drugs will need a higher dose of bupropion. The most common adverse effects in trials were somnolence/fatigue, he said. Doghramji noted research indicates it is safe in mild obstructive sleep apnea, and no difference in middle of the night auditory awakening threshold or morning cognitive performance, body sway, and driving performance when compared with placebo. In one study, lemborexant showed an improvement in sleep latency to persistent sleep almost as good if not better than zolpidem.2 In addition to sustained efficacy, he also explained patients reported improved fatigue during the day, which he said is an important indicator of treatment success. Approved in 2022, daridorexant is the most recent DORA approved for difficulties with sleep onset and/or maintenance, Doghramji said. Daridorexant is available in 25 mg and 50 mg doses. It has a Tmax of 1-2 hours and a half-life of 8h, which he noted is about half that of the other DORAs. Compared to placebo after 4 days of treatment there was no morning driving impairment, and he said safety as been demonstrated in mild obstructive sleep apnea and moderate chronic obstructive pulmonary disease. Interestingly, the most common adverse effects are nasopharyngitis and headache, he said, but somnolence and fatigue were also reported. In addition to improving latency to persistent sleep and wake after sleep onset, Deradoorian was found to improve daytime function, Doghramji told attendees. He explained the Insomnia Daytime Symptoms and Impacts Questionnaire was created and validated according to FDA guidelines to assess and evaluate daytime functioning in individuals with insomnia disorder. At the 50 mg dose daridorexant improved the IDSIQ sleepiness domain at months 1 and 3, with clinically meaningful at month 3. Doghramji told attendees there are 2 emerging DORAs: seltorexant and vornorexant. Seltorexant is a selective orexin-2 receptor antagonist and is currently in phase 3 trials as an adjunctive therapy to antidepressants for patients with major depressive disorder and insomnia symptoms, he said. On the other hand, vornorexant is a balanced dual orexin antagonist that showed significant improvement in sleep latency to persistent sleep and wake after sleep onset. Related Topic: Orexin Receptor 2 Agonist Improves Sleepiness in Narcolepsy References 1. Herring WJ, Ceesay P, Snyder E, et al. Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial. Alzheimers Dement. 2020;16(3):541-551. 2. Rosenberg R, Murphy P, Zammit G, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial JAMA Netw Open. 2019;2(12):e1918254. Published 2019 Dec 2. 3. Kärppä M, Yardley J, Pinner K, et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep. 2020;43(9):zsaa123. 4. Chepke C, Jain R, Rosenberg R, et al. Improvement in fatigue and sleep measures with the dual orexin receptor antagonist lemborexant in adults with insomnia disorder. Postgrad Med. 2022;134(3):316-325. 5. Mignot E, Mayleben D, Fietze I, et al. Safety and efficacy of daridorexant in patients with insomnia disorder: results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials .Lancet Neurol. 2022;21(2):125-139. 6. Hudgens S, Phillips-Beyer A, Newton L, Seboek Kinter D, Benes H. Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Patient. 2021;14(2):249-268.

Does early improvement in insomnia predict response to pharmacotherapy in psychotic depression? Authors performed a secondary analysis of a randomized clinical trial. CASE VIGNETTE “Mr Penn” is a 34-year-old Caucasian male with a history of recurrent, severe major depressive disorder (MDD) with psychotic features. His most recent psychiatric hospitalization was preceded by a period of significant insomnia with subsequent worsening depression, suicidal ideation with a plan, and an increase in paranoia. During the hospitalization, Mr Penn was started on mirtazapine 15 mg at bedtime. Over the next 7 days, he noted significant improvement in insomnia, with resolution of his suicidal ideation and some improvements in depressive symptoms. At his hospital discharge visit, he asks about whether his dose of mirtazapine should be increased. As his psychiatrist, how would you respond? Insomnia is a common symptom and part of the diagnostic criteria for MDD. A systematic review found that treatment of insomnia improves mood symptoms in MDD. There is some evidence that early insomnia improvement (EII) within the initial weeks of treatment predicts response to antidepressants. However, the clinical utility of EII as a predictor of outcomes of antidepressant treatment remains unclear. There is evidence that psychotic depression (ie, MDD with psychotic features) has a higher severity of insomnia and depressive symptoms and a lower response to antidepressants than nonpsychotic MDD. The Current Study Vos and colleagues6 investigated whether EII predicts response and remission of psychotic depression. The authors performed a secondary analysis of the Dutch University Depression Group (DUDG),7 a double-blind randomized controlled trial of venlafaxine, imipramine, and venlafaxine plus quetiapine in psychotic depression. Participants were aged 18 to 65 years and had a DSM-IV-TR diagnosis of psychotic depression. They had a Hamilton Rating Scale for Depression (HAM-D-17) score of ≥18. Exclusion criteria were no insomnia symptoms at baseline, acute indication for ECT, IA <80, alcohol or substance use disorder in the past 3 months, serious somatic illness, somatic medication affecting mood symptoms, and contraindications for or previous treatment with venlafaxine or imipramine during the current depressive episode. Patients were randomized to 7 weeks of double-blind treatment with venlafaxine, imipramine, or venlafaxine plus quetiapine. A maximum of 3 mg lorazepam per day was also permitted. Depressive symptoms were rated weekly using the HAM-D-17. EII was defined as a ≥20% reduction of insomnia severity (sum of the 3 sleep-related HAM-D-17 items) from baseline after 2 weeks of treatment. Early response for depression was defined as ≥20% reduction in HAM-D-17 score after 2 weeks. The primary outcome measure was response for depression, defined as ≥50% reduction in HAM-D-17 score after 7 weeks (excluding the 3 sleep-related outcomes for the association with EII). Remission of depression was defined as a HAM-D-17 score <8 and the absence of hallucinations and delusions after 7 weeks. Associations between EII and outcomes were analyzed using logistic regression models controlled for age, sex, medication, benzodiazepine use, and pre-treatment insomnia and depression scores. The authors used a last observation carried forward approach for study dropouts. Approximately 114 participants (out of 122 in the original study) met the inclusion/exclusion criteria and were analyzed. Thirty-seven received venlafaxine, 38 imipramine, and 39 venlafaxine plus quetiapine. There were no significant differences in clinical or demographic factors based on the treatment group. The mean participant age was 51 years, and 48% of participants were male. Over the first 2 weeks, the average reduction in insomnia symptoms was significantly greater than other depressive symptoms. EII was achieved in 74% and early response on overall depression in 67% of patients. After 7 weeks, depression response was achieved in 57% and remission in 32%, as well as remission of psychotic symptoms in 67%. EII was a significant predictor of response on overall depression (OR=7.9, 95% CI 2.7-23.4) and depression excluding the 3 insomnia items (OR=6.3m 95% I 2.2-18.3). EII was also a significant predictor of remission of depression (OR=6.1, 95% CI 1.6-23.3) and remission of psychotic symptoms (OR=4.1, 95% CI 1.6-10.9). There were no significant interactions between EII and medications. EII had a higher sensitivity and negative predictive value than early depression response for all outcome measures. Study Conclusions The authors performed the first study of EII as a predictor of treatment outcome in psychotic depression. They found evidence that EII was associated with depression response and remission and remission of psychosis. Insomnia symptoms improved within the first weeks of pharmacotherapy, whereas depressive symptoms improved more gradually. Study strengths include a more homogeneous sample of patients with psychotic depression, and the fact that patients were free of other psychotropics (except possibly low-dose benzodiazepines). Limitations include the lack of data on pre-study benzodiazepines and the lack of a specific insomnia scale. The Bottom Line Early improvement in insomnia was associated with a higher response to depressive and psychotic symptoms in psychotic depression. Further studies are needed to investigate the generalizability of EII as a predictor of treatment response in depression. Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute. Related topic: What are Sleep/Wake Disorders? References 1. Gebara MA, Siripong N, DiNapoli EA, et al. Effect of insomnia treatments on depression: a systematic review and meta-analysis. Depress Anxiety. 2018;35(8):717-731. 2. Cao B, Park C, Rosenblat JD, et al. Changes in sleep predict changes in depressive symptoms in depressed subjects receiving vortioxetine: an open-label clinical trial. J Psychopharmacol. 2019;33(11):1388-1394. 3. Wang M, Zhang B, Zhou Y, et al. Sleep improvement is associated with the antidepressant efficacy of repeated-dose ketamine and serum BDNF levels: a post-hoc analysis. Pharmacol Rep. 2021;73(2):594-603. 4. Manber R, Buysse DJ, Edinger J, et al. Efficacy of cognitive-behavioral therapy for insomnia combined with antidepressant pharmacotherapy in patients with comorbid depression and insomnia: a randomized controlled trial. J Clin Psychiatry. 2016;77(10):e1316-e1323. 5. Jääskeläinen E, Juola T, Korpela H, et al. Epidemiology of psychotic depression - systematic review and meta-analysis. Psychol Med. 2018;48(6):905-918. 6. Vos CF, Birkenhäger TK, Nolen WA, et al. The relationship of early sleep improvement with response to pharmacotherapy in unipolar psychotic depression [published online ahead of print, 2023 Aug 31]. J Clin Psychopharmacol. 2023;10.1097/JCP.0000000000001756. 7. Wijkstra J, Burger H, van den Broek WW, et al. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatr Scand. 2010;121(3):190-200.

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.

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

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?

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