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Keypoint: Improving cognitive function is a primary goal of brain injury rehabilitation and is made possible through the process of neuroplasticity. Brain injury survivors experience a wide range of secondary physical, cognitive, and behavioral consequences that may significantly impact daily life. Ranging from seizures, paralysis, and pain to learning and memory impairment, disorientation, aggression, impulsivity, and noncompliance. Cognitive function postinjury is considered the most impacted and is also cited as the most important predictor for returning to work or prior living status. Improving these symptoms/functions is a primary goal of brain injury rehabilitation and is made possible through the process of neuroplasticity. What Is Neuroplasticity? Neuroplasticity is the science of how the brain changes its structure and function in response to input. These changes include creation of new blood vessels, creation of new synapses, dendritic arborization, and creation of new neurons. These changes may occur in response to positive, as well as negative stimuli (maladaptive vs adaptive plasticity). Examples of maladaptive plasticity include neuronal structure/function changes in response to addictive substances, as well as the strengthening of connections and reinforcement of compensatory mechanisms that impede recovery. Neuroplasticity can occur at multiple levels, from the molecular and synaptic level to higher order levels of cortical maps and large-scale neuronal networks. Data indicates that the brain continuously restructures neural circuitry, in fact, this is the foundation for encoding new experiences and enabling changes in behavior. Channeling this innate ability of the brain to change is essential to maximizing the benefits of rehabilitation.1 Change requires structure, repetition, and consistency by trained and experienced staff. This need for structure, repetition, and consistency is illustrated in a set of principles of neuroplasticity. Principles of Neuroplasticity: Use it or lose it: This principle describes the degradation of neural circuits not actively engaged in task performance for long periods of time. For example, individuals with left side strokes may lose some function on the right side of their bodies. Since tasks with the right side become more difficult, they default to use of the unaffected (left) side. The brain reorganizes and dedicates more “space” to the left motor area, thus limiting recovery potential of the right side. Use it and improve it: Plasticity can be induced through extended training. In other words, training that drives a specific brain function can lead to enhancement of that function. For example, under the guidance of trained staff, a technique known as constraint-induced movement therapy can be used to restrain the arm on the nonaffected side, so that the patient is compelled to use their affected limb as much as possible, thereby improving its function. Specificity: From a treatment standpoint, specificity highlights the importance of tailoring an activity or exercise to produce a result in specific circuitry. Research in this area has shown that specific skill acquisition produces greater changes in the brain than unskilled repetitive movements. While physical exercises aimed at strengthening leg muscles will ultimately help patients improve their sit-to-stand from a chair or bed, more significant changes will occur when that specific sit-to-stand skill is practiced. Repetition matters: Patients may often ask, “how long is this going to take?” While it is difficult to give a precise answer, research shows that thousands and even tens of thousands of repetitions are required to generate change. Utilization of combination therapies can be particularly beneficial for increasing repetitions without necessarily increasing time. For example, physical therapists may increase a patient’s steps outside of their therapy session by having them walk between therapy sessions or stand during their other therapy sessions. Likewise, speech therapists could have patients working on memory or pathfinding activities during their PT session. Intensity matters: This principle can be thought of as the dosage required to induce change. The intensity, or dosage, is highly dependent upon the therapy goals; however, data shows that the more intense a therapy program, the more likely it is that the program will result in substantial change and the more sustainable those changes will be. Time matters: “Plasticity occurs at different times during recovery.” This is particularly relevant in the context of brain injury recovery, as in the acute phase especially, the brain is actively looking for new ways to rewire to regain function (making the training much easier). Without access to the appropriate training during this phase, the brain will instead develop less desirable compensatory mechanisms (like a stroke patient not using their affected limb to do daily tasks). Early access to treatment helps avoid development of maladaptive behaviors. Salience matters: Research suggests that emotions play a role in neuroplasticity. It is easier for us to learn things that we are interested in or that excite us. It is important for therapists to know what really matters to their patients in order to improve skill acquisition by targeting relevant and salient tasks. Age matters: Our brains are much more adaptable when we are younger, which makes change in structure and function easier to achieve. An aging brain is very capable of neuroplasticity, it simply may take more time and be more difficult, requiring more repetitions and higher intensity. Transference or generalization: “Plasticity in response to one training experience can enhance acquisition of similar behaviors.” This principle is best explained in the context of rehabilitation. During therapy, the goal is to get the patient to a level where they can function as independently as possible, meaning that it is important to utilize techniques that can be applied outside of the therapy environment. For example, having a patient reach out to grab an object during PT or OT knowing that they will be able to utilize that same technique to reach for objects at home. Interference: This principle is referencing the development of maladaptive behaviors. When therapy is delayed and maladaptive behaviors surface, therapy is made more challenging by needing to unlearn the maladaptive compensatory mechanisms before real positive change can occur. Methods for Improving Neuroplasticity After Brain Injury Structured Rehabilitation Structured rehabilitation is the most direct way to improve neuroplasticity postinjury, especially multidisciplinary programs. Multidisciplinary programs including all therapeutic disciplines (cognitive, physical, occupational, educational, and counseling) allow for the most efficient use of time and the highest amount of carry over by creating well-balanced and coordinated treatment plans that are supported by each department. Progress can then be reassessed across time, and therapy goals redirected as appropriate. Physical Exercise and Cognitive Activity A large body of evidence tells us that exercise is neuroprotective. Its mechanisms include anti-inflammatory effects, neuro- and angiogenesis, decreasing oxidative stress, promoting long-term strengthening of synapses [long-term potentiation (LTP)], and increasing transcription of genes associated with plasticity. Functionally, this leads to improvements in depressive symptoms, cognitive function, balance, and sleep. By combining the effects of exercise with cognitive training, we are likely to see a substantial impact on neural structure and function. Noninvasive Neurostimulation and Rehabilitation There are a number of different methods of noninvasive neurostimulation (ie, tDCS, TMS, tACS). While these methods of stimulation are not enough to generate action potentials on their own, they produce sub-threshold changes in the firing patterns of already active neurons. By producing these small subthreshold changes, the stimulation may be able to prime the neural circuits so that the brain is more responsive to rehabilitation. Addressing Underrecognized Comorbidities Sleep Sleep-wake disturbances are common after brain injury, impacting up to 80% of brain injury survivors. These disturbances are often multiple and multifaceted ranging from sleep disordered breathing (sleep apnea) to REM sleep behavior disorders, circadian rhythm disorders, and disruptions in sleep architecture. Sleep has long been established as critical for learning and memory and is now also associated with the ability to suppress memories and unlearn, as well as decrease depressive symptoms. Sleep also impacts various aspects of synaptic strength and structure, including stabilization of dendritic spines and spine pruning, and decreases inflammation. By objectively addressing any sleep disturbances, we can weed out the impact of sleep on cognitive and behavioral function, as well as directly improve the capacity for neuroplastic change. Neuroendocrine Function Neuroendocrine dysfunction is not uncommon postinjury and may or may not be associated with sleep disturbances, since sleep impacts hormone function and vice versa. In general, the pituitary gland, which directs neuroendocrine function, is very susceptible to injury due to its size and location. Our neuroendocrine system relies on tightly regulated negative feedback loops to function properly. When the hypothalamus and/or pituitary is injured, these feedback loops breakdown and lead to widespread functional damage. One specific example is the impact of prolonged stress on neuroplasticity. If the brain is not receiving and sending stress signals appropriately, leading to a prolonged response, we can see atrophy and remodeling of neurons, impacts on gene expression, decreases in LTP, and increases in depression and anxiety. Concluding Thoughts Understanding and utilizing neuroplasticity principles is crucial in neurorehabilitation. Early access to multidisciplinary therapy programs with experienced and trained staff will aid in improving a patient’s ability to engage in daily activities and participate in meaningful social roles. In fact, substantial recovery or restoration of function is unlikely in the absence of targeted intervention. In addition to targeted rehabilitation, we can bolster neuroplasticity by using combination therapies, noninvasive neurostimulation, and addressing underrecognized comorbidities such as sleep and neuroendocrine function. Note: This article originally appeared on Psychiatric Times

Keypoint: A poster at the 2024 ASCP Annual Meeting shared data from 3 randomized clinical trials on the safety and tolerability of this treatment combination. CONFERENCE REPORTER A poster at the 2024 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting shared an analysis of safety data from 3 clinical trials exploring the safety and efficacy of a combination therapy of brexpiprazole and sertraline in the treatment of posttraumatic stress disorder (PTSD). The 3 trials aimed to evaluate the safety and efficacy of brexpiprazole combined with sertraline for the treatment of PTSD.1 These trials included Trial 0612 (Phase 2; NCT03033069), Trial 0713 (Phase 3; NCT04124614), and Trial 0724 (Phase 3; NCT04174170). In all of the trials, participants were male and female outpatients aged 18 to 65 years who had received a DSM-5 diagnosis of PTSD and had experienced symptoms for at least 6 months. Each trial involved an 11-week randomized, double-blind phase. Trial 061 randomized patients into 4 groups: brexpiprazole (1 to 3 mg/day) with sertraline (100 to 200 mg/day), brexpiprazole with placebo, sertraline with placebo, and placebo. Trial 071 compared brexpiprazole (2 to 3 mg/day) with sertraline (150 mg/day) against sertraline with placebo. And Trial 072 tested 3 groups: brexpiprazole (2 mg/day) with sertraline (150 mg/day), brexpiprazole (3 mg/day) with sertraline, and sertraline with placebo. The primary endpoint for these studies was the change in the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) total score from baseline to week 10. Safety assessments included treatment-emergent adverse events (TEAEs), changes in body weight, incidence of suicidality, and deaths. Results showed that the incidence of TEAEs varied across the trials. In Trial 061 (n=316), TEAEs were reported in 72.5% of the brexpiprazole plus sertraline group, 70.7% in the brexpiprazole plus placebo group, 69.6% in the sertraline plus placebo group, and 78.0% in the placebo group. In Trial 071 (n=401), 60.0% in the brexpiprazole plus sertraline group experienced TEAEs compared with 58.2% in the sertraline plus placebo group. In Trial 072 (n=537), TEAEs were 51.4% in the brexpiprazole 2 mg/day plus sertraline group, 48.3% in the brexpiprazole 3 mg/day plus sertraline group, and 51.2% in the sertraline plus placebo group. When data from the 3 studies were pooled, the overall incidence of TEAEs was similar between the brexpiprazole plus sertraline group (55.5%) and the sertraline plus placebo group (56.2%). Common TEAEs included nausea, headache, weight gain, and diarrhea. Notably, weight gain was more common in the brexpiprazole plus sertraline group (5.2%) compared with the sertraline plus placebo group (1.3%). The mean change in body weight from baseline to week 12 was an increase of 1.5 kg for the brexpiprazole plus sertraline group, whereas the sertraline plus placebo group saw a slight decrease of 0.2 kg. The incidence of suicidality-related TEAEs was lower in the brexpiprazole plus sertraline group (0.6%) compared with the sertraline plus placebo group (1.1%). Three deaths occurred across the studies, each in different treatment arms, but none were deemed related to the study treatments. The investigators concluded that the combination of brexpiprazole and sertraline appears to be safe and well-tolerated in patients with PTSD, with no new safety concerns emerging from the trials. They added that this combination therapy holds potential as a new treatment option for PTSD, subject to confirmation of its efficacy. Note: This article originally appeared on Psychiatric Times

Keypoint: Clinicians should carefully weigh the risks and benefits of each prescribed medication for an older adult with neuropsychiatric diseases and periodically review all prescribed medications. Learn more here. SPECIAL REPORT: POLYPHARMACY Older adults, defined as individuals older than 65 years, are vulnerable to drug-induced adverse effects due to age-related physiological changes, such as decreased renal and hepatic function, increased body fat, lower total body water, and lower lean body mass, all of which can impact the pharmacodynamics and pharmacokinetics of medications and increase the elimination half-life. Older adults experience a higher prevalence of comorbid chronic conditions, such as diabetes, heart disease, arthritis, and other psychiatric conditions. Nearly 95% of older adults have at least 1 chronic condition, and nearly 80% have 2 or more. Polypharmacy is common given multiple medical comorbidities, but exposure to multiple medications may further lead to harm due to inappropriate medication prescription. The World Health Organization defines polypharmacy as “the administration of many drugs at the same time or administration of an excessive number of drugs.”3 Surprisingly, there is no consensus on the medication threshold and definition of polypharmacy. However, it is commonly described as the concomitant use of 5 or more medications. For older adults, polypharmacy can be associated with increased poor health outcomes due to increased risk of falls, drug-drug or drug-supplement interactions, medication nonadherence, hospitalizations, and death. Findings from a recent meta-analysis examining the prevalence of polypharmacy and factors associated with polypharmacy showed that individuals older than 65 years had a higher prevalence of polypharmacy when compared with data from studies with individuals younger than 65. Additionally, there were lower estimates of polypharmacy in community settings when compared with outpatient and hospital settings, with overall results showing that older age and inpatient settings were associated with a higher prevalence of polypharmacy. Although consensus is unclear on the definition of polypharmacy in psychiatry, one common definition is the use of 2 or more psychiatric medications, further broken down into categories (eg, 2 or more medications of the same class, multiclass, adjunctive, augmentation, and total pharmacy). The estimated prevalence of polypharmacy in older adults hospitalized for psychiatric illness/disorders is as high as 80%.4 Not surprisingly, findings from a recent study examining the rates of polypharmacy in older adults with and without dementia showed that the median number of medications for adults with dementia was 8, compared with 3 in those without dementia. Similarly, data from a meta-analysis examining the association between polypharmacy and depression showed an increased prevalence of polypharmacy in individuals with depression. Older adults with psychiatric comorbidities are particularly vulnerable to polypharmacy and adverse outcomes. In clinical practice, it is often challenging to avoid polypharmacy, particularly in older adults with treatment-resistant diagnoses necessitating augmentation strategies that would require multiple psychotropic medications. However, using the fewest possible medications and the simplest dosing regimen can help reduce the number of drugs prescribed, along with ongoing evaluation of indication, drug-drug interactions, and linking of each medication with a diagnosis. Overall, research findings have indicated that inappropriate polypharmacy can affect up to one-third of the population, with polypharmacy becoming a substantial health care burden associated with an estimated cost of $50 billion in the United States. Therefore, it is imperative to prevent adverse events associated with polypharmacy, identify individuals who are at high risk of receiving inappropriate polypharmacy, and take steps toward deprescribing if possible. Criteria and Screening Tools Explicit criteria and tools have been created to support the deprescribing of inappropriate medications and to reduce the prevalence of polypharmacy in older adults. Mark Beers, MD, and colleagues initially developed the Beers Criteria in the US in 1991 to identify medications for which the potential harm outweighed the expected benefits for nursing home residents. Over time, the criteria have been revised and updated by the American Geriatrics Society (AGS), expanding to include all older adults in ambulatory, acute, and institutionalized settings of care, except hospice and end-of-life care settings. The Beers Criteria is now used widely by clinicians, educators, researchers, health care administrators, and regulators, and although the list can be used internationally, it is specifically designed for use in the US. The updated 2023 Beers Criteria organizes potentially inappropriate medications (PIMs) by organ system and therapeutic category, outlines PIMs that should be used with caution, highlights clinically important drug-drug interactions, and describes medications that require renal dose adjustments. In addition to the Beers Criteria, the Screening Tool of Older Persons’ Prescriptions and Screening Tool to Alert to Right Treatment (STOPP/START) criteria were developed in Ireland by O’Mahony et al in 2008 and are used predominantly in Europe. Data from an earlier study comparing the Beers Criteria with the STOPP/START criteria suggest that the STOPP/START criteria may be more sensitive because they account for therapeutic duplication and potential prescribing omissions, therefore identifying a significantly higher proportion of patients requiring hospitalization as a result of PIM-related adverse events when compared with the Beers Criteria. However, most of the studies conducted in which STOPP/START was applied were specific to an inpatient psychiatric setting compared with the wider application of the Beers Criteria in multiple settings outside the hospital and predominantly used in the US. Deprescribing and Reducing As individuals age, medications that were previously necessary, effective, and safe require reevaluation due to physiological and functional changes (ie, dementia, chronic comorbidities) that may shift the balance of benefits and harms. Additionally, there is increasing evidence that the benefits of many medications, particularly preventive medications, may be more harmful than beneficial with advancing age (eg, strict glycemic or blood pressure control). Therefore, it is imperative to reassess health care goals and priorities, as many older adults may want to shift their focus to comfort and maximizing quality of life. Deprescribing is a suggested intervention to reverse potentially iatrogenic harms of inappropriate polypharmacy and is defined as “the process of withdrawal of inappropriate medication, supervised by a health care professional, with the goal of managing polypharmacy and improving outcomes.” However, results of a meta-analysis showed limited evidence to support deprescribing as an intervention that reduced mortality in randomized studies. Findings from the same study also showed that mortality was significantly reduced when applying patient-specific interventions to deprescribing, suggesting that a more tailored, individual approach may be necessary for more class-specific deprescribing, such as with psychotropic and anxiolytic/hypnotic medications. Many studies have examined the importance of deprescribing certain psychotropic medications in older adults, particularly antipsychotics and anxiolytic/hypnotic medications. In particular, antipsychotic medications are frequently used to treat behavioral and psychological symptoms of dementia (BPSD), especially in long-term residential care settings. Antipsychotics carry an FDA black box warning for increased mortality in older adults and are listed on the Beers Criteria as a medication to be avoided. Data from many studies have shown that deprescribing antipsychotics in older adults with dementia did not result in worsening BPSD or adverse outcomes, suggesting that ongoing reevaluation and gradual dose reduction must be considered in these patient populations. Additionally, findings from another randomized control trial indicated that a systematic review of medications conducted in nursing homes reduced psychotropic drug prescriptions without worsening BPSD symptoms and improved level of functioning. Unfortunately, most studies focus on addressing inappropriate polypharmacy in older adults with dementia in long-term care facilities and have not extensively studied deprescribing in more outpatient-based settings to include the individual and their caregiver. Additionally, it is well known that benzodiazepines (BZDs) and the related hypnotic Z-drugs are harmful for older adults and can result in increased risk of falls, fractures, cognitive impairment, car crashes, and more. Unfortunately, deprescribing BZDs is more challenging than antipsychotics due to complex interactions among patients, physicians, and concerns about distressing but rarely fatal withdrawal syndrome. A recent review of deprescribing BZDs in older adults showed variable success rates in deprescribing, ranging from 27% to 80%, likely attributable to differing approaches that ranged from interventions targeting patient and/or caregivers and providing additional resources to the patient (eg, gradual dose reduction [GDR] with relaxation techniques, sleep hygiene, cognitive behavioral therapy). These interventions can be effective if the patient is motivated to cease taking the medication and does not have significant cognitive impairment, but prescribing interventions that include audits, algorithms, medication review, and supervised GDR may also be helpful additions for physicians to feel more comfortable deprescribing BZDs and related Z-drugs. For example, for patients in more advanced stages of dementia in which they exhibit neuropsychiatric and behavioral symptoms, antipsychotics may be needed to manage behavioral symptoms that have not responded to other interventions despite antipsychotics carrying an FDA black box warning for increased risk of mortality in patients older than 65 years with dementia. For some older adults, it may be impossible to avoid certain medications that may otherwise be contraindicated, and extensive discussion around goals of care, life expectancy, and potential drug-drug interactions and adverse effects are necessary with the patients and family/caregivers when assessing medication indications and their risks and benefits. (See “Strategies for Reducing Polypharmacy in Older Adults” in this article.) Concluding Thoughts Ultimately, more deprescribing intervention studies are needed given the complexity of interventions utilized and the variability of implementation of deprescribing in clinical practice across different health care settings. Deprescribing interventions will need to be tailored to individuals with more target-specific goals to be beneficial, but further studies are needed to determine if there are also unintended consequences to deprescribing. With the recent push discouraging the use of and making it difficult to prescribe antipsychotic and psychotropic medications in long-term care, culminating in the recently passed California law making the prescribers of psychotropic medications (except for antidepressants) legally responsible at the level of misdemeanor for prescribing without documented written consent, many older patients with severe mental illness or behavioral disturbances due to dementia may be left without necessary treatment for severe psychiatric symptoms, which will ultimately lead to greater suffering and caregiver burden. Clinicians should carefully weigh the risks and benefits of each prescribed medication for an older adult with neuropsychiatric diseases and periodically review all prescribed medications and over-the counter supplements and herbal remedies, and discontinue those that are unnecessary and potentially harmful. Note: This article originally appeared on Psychiatric Times

3,4-Methylenedioxymethamphetamine (MDMA) is a psychopharmacological agent with effects that include the enhancement of empathy, prosocial behavior, euphoria, extroversion, feelings of closeness to others, stimulant effects, and mild psychedelic effects. It is a potent releaser and reuptake inhibitor of presynaptic serotonin, dopamine, and norepinephrine. MDMA was synthesized by Merck laboratories in 1912 as a homeostatic agent, though its utility in psychotherapy was not explored until the 1970s. However, its use was banned in 1985 by the Drug Enforcement Agency. After failing to prevent its illegalization, Rick Doblin, PhD, founded the Multidisciplinary Association for Psychedelic Studies (MAPS) in 1986, with the purpose of researching and training in the responsible use of MDMA and other psychedelics. Thanks to the efforts of this institution, there is now a phase 3 clinical study for posttraumatic stress disorder (PTSD). MDMA-assisted psychotherapy has been shown to be beneficial in the management of PTSD, eating disorders, and anxiety disorders. Inspired by this work, Australia legalized MDMA-assisted psychotherapy in June 2023. However, the treatment is not yet covered by Australian Medicare. Nonetheless, there are some private clinics that offer treatment on an out-of-pocket basis. In general, the treatment can last 2 to 8 weeks and involves 2 sessions of MDMA-assisted psychotherapy and 10 to 12 sessions of integration psychotherapy, costing around $20,000. As such, few individuals have had access to this therapy so far. If MDMA gets approved by the FDA in the United States, it will not become a feasible treatment option for most patients until the treatment is covered by Medicare and other insurance companies. As psychedelics other than ketamine (usually prescribed without psychotherapy in most clinics) are still not legal, there is no standardization of the requirements needed to become a psychedelic-assisted psychotherapist. However, there are several websites and institutions offering education psychedelic-assisted psychotherapy, with MAPS as the primary organization providing education on MDMA-assisted-psychotherapy. As a psychiatrist with a clinical and research interest in psychedelics, I had the privilege to attend a 5-day educational event on MDMA-assisted psychotherapy. Our course offered an illustrative example of its effect. On our first evening, the instructors delivered a master class on the most updated scientific and clinical research. In the following days, we reviewed recorded videos of patients treated with MDMA-assisted psychotherapy, many of whom were war veterans. Often, these individuals had trauma prior to enrolling in the army. Others had PTSD from sexual trauma or grief. All of them suffered from severe and debilitating PTSD. Before taking MDMA for the first time, patients had 1 or 2 preparation sessions where they would be interviewed and educated about MDMA and what to expect during the session. The therapy involved administering a lower dose of 50 to 60 mg of MDMA. Two hours later, the patient would be offered a booster. The patient would lie on the bed, covering their eyes while listening to music—preferably without lyrics. The MDMA therapy session lasted about 6 hours, with 2 therapists involved. Vitals and patient safety were consistently monitored. The patient was invited to cover their eyes and allow their “inner healing intelligence” to guide them in their recovery. When ready, they could uncover their eyes and discuss their experience with the therapist. The therapists facilitated, encouraged, and supported the healing experience, using a nonstructured, dynamic therapeutic style. Elements of dynamic, humanistic therapy, and internal family systems were hinted at in the different videos. Under MDMA, patients accessed and processed their traumatic experiences. MDMA created a state of well-being in which a patient could tolerate this process, though it could still be very painful, requiring the therapists to help and moderate this process. Following the first MDMA session, patients returned to their therapists' office for integration therapy, where they talked about their experiences, made sense of them, and explored the impact the therapy had on their lives. As per protocol, patients were scheduled for a second, higher-dose of 100 to 120 mg MDMAsession with the option of receiving a booster later. The work between the patient and the therapist continued, allowing the patients to explore further into their trauma, which would later integrate in the final sessions. Following each session's videos, time was allocated for questions and answers, providing an opportunity for mutual learning. Our teachers were friendly, humble, and inviting. It was beautiful to witness the significant improvement in the patients' PTSD scores and subjective well-being by the end of the MDMA therapy. After this course, it became clear to me that MDMA-assisted psychotherapy can become a powerful, pleasant, and effective way of helping patients with PTSD. Psychotherapy played a key role in their recovery, and the role of the therapists was essential. I cannot conceptualize a safe way of treating patients with MDMA without psychotherapy. Unfortunately, due to MDMA still being illegal, I did not get a chance to have an experiential learning experience with MDMA. Hopefully, this will change soon. However, psychedelic experiences and culture go beyond the ingestion of a psychedelic substance. Research has shown that psychedelic-assisted psychotherapy has the potential to become a third-line treatment for patients with severe and debilitating depression and PTSD who do not improve with more typical psychiatric treatments. In my opinion, psychedelic-assisted psychotherapy could represent an alternative for individuals who are less interested in conventional psychiatric treatments. In addition, psychedelic-assisted psychotherapy can stimulate personal growth in virtually any human willing to explore their inner psyche in a unordinary state of consciousness. I believe that in the right set and setting, psychedelic-assisted psychotherapy can help the breakdown of a person’s narcissistic defenses and enhance compassion towards oneself, other human beings, and our planet. Note: This article originally appeared on Psychiatric Times

Keypoint: A poster presented at the 2024 ASCP Annual Meeting discussed the results of a study analyzing the treatment’s safety and efficacy in this patient population. CONFERENCE REPORTER A poster at the 2024 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting discussed the results of a recent clinical trial exploring the efficacy of lumateperone for the treatment of depressive symptoms in patients with either major depressive disorder (MDD) or bipolar depression with mixed features. According to the study investigators, patients with MDD who are also experiencing a depressive episode of bipolar disorder with mixed features tend to experience more severe symptoms and poorer treatment outcomes.1 The investigators sought to evaluate the effectiveness of lumateperone—which is already approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia and depressive episodes in bipolar 1 and 2 disorders2—in this patient population in a randomized, double-blind, placebo-controlled trial. The trial, known as Study 403, included adults aged 18 to 75 years who had received a DSM-5 diagnosis of either MDD or bipolar 1 or 2 disorder and were experiencing a major depressive episode with mixed features. Participants were randomized to receive either 42 mg of lumateperone or a placebo daily for 6 weeks. The primary measure of efficacy was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) single-item scores, assessed at regular intervals. Safety was monitored through adverse events, Young Mania Rating Scale (YMRS) scores, and incidences of suicidality. The results of the study demonstrated that lumateperone significantly improves symptoms in this patient population, highlighting the efficacy and safety of the treatment compared with placebo. In the combined population of patients with MDD or bipolar depression experiencing a depressive episode with mixed features, 385 patients received treatment, and 383 (191 on placebo and 192 on lumateperone) were included in the modified intent-to-treat (mITT) population. Most patients (89.4%) completed the treatment. Lumateperone significantly improved the MADRS total score compared with placebo on day 43 (least squares mean difference vs placebo [LSMD] = -5.7; P < .0001). Patients treated with lumateperone showed significantly greater improvements in 9 out of 10 MADRS items compared with the placebo group on day 43, including apparent sadness (LSMD = -0.9; P < .0001), reported sadness (LSMD = -0.8; P < .0001), inner tension (LSMD = -0.6; P < .0001), reduced sleep (LSMD = -0.9; P < .0001), reduced appetite (LSMD = -0.5; P < .0001), concentration difficulties (LSMD = -0.4; P < .01), lassitude (LSMD = -0.6; P < .0001), inability to feel (LSMD = -0.7; P < .0001), and pessimistic thoughts (LSMD = -0.4; P < .001). Apparent sadness and reduced sleep showed the largest improvements with lumateperone compared with placebo in change from baseline on day 43 and the earliest significant reductions from baseline on day 8 (P < .05). Five additional items showed significant improvement on day 15 and persisted throughout the study. Lumateperone was generally well tolerated, with most treatment-emergent adverse events (≥99%) being mild or moderate. There was no significant worsening in YMRS total scores, indicating no increase in manic symptoms. The emergence of suicidal ideation was also low and similar between the lumateperone and placebo groups. The investigators concluded that the findings of Study 403 suggest that lumateperone 42 mg is a promising treatment for patients with depressive episodes with mixed features in MDD or bipolar disorder. The drug significantly improved a wide range of depressive symptoms and was well tolerated, offering a potential new therapeutic option for this patient population. They noted that further research may solidify its role in treating mixed-feature depression.

Keypoint: In this CME article, learn more about common clinical conditions, consultation questions, and challenges in the field of critical care psychiatry. CATEGORY 1 CME Premiere Date: May 20, 2024 Expiration Date: November 20, 2025 This activity offers CE credits for: 1. Physicians (CME) 2. Other All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered. ACTIVITY GOAL To describe the field of critical care psychiatry by comparing and contrasting it with general consultation-liaison psychiatry and providing examples of commonly encountered challenges in the psychiatric care of patients in the intensive care unit. LEARNING OBJECTIVES 1. Describe common clinical conditions, consultation questions, and challenges in the field of critical care psychiatry. 2. List the components of the ABCDEF Bundle and describe how they inform a multidisciplinary treatment approach for critically ill patients. TARGET AUDIENCE This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders. ACCREDITATION/CREDIT DESIGNATION/FINANCIAL SUPPORT This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource®, LLC, and Psychiatric Times®. Physicians’ Education Resource, LLC, is accredited by the ACCME to provide continuing medical education for physicians. Physicians’ Education Resource, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity is funded entirely by Physicians’ Education Resource, LLC. No commercial support was received. OFF-LABEL DISCLOSURE/DISCLAIMER This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource, LLC. 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You must have an account to evaluate and request credit for this activity. In the modern history of medicine, some of the most lifesaving advances have come from the field of critical care medicine. Current medical knowledge and technology have transformed it into a field capable of sustaining life despite widespread organ failure, facilitating patient survival through injuries and illnesses that were previously lethal. Given the high proportion of both preexisting and newly emergent psychopathology among critically ill patients, psychiatry has an essential role in the critical care setting. Accordingly, the practice of critical care psychiatry (CCP) continues to grow as patients experience increasingly complex medical illnesses, which commonly affect brain function and quality of life over both short- and long-term time spans. Critical care psychiatrists routinely face specific challenges that general outpatient psychiatrists only rarely see. How do you evaluate a patient who is intubated and/or heavily sedated? What medications are safe for a patient in multi-organ failure who is already on multiple medications? How do you treat symptoms of anxiety or depression in someone who is actively dying? What are the best ways of managing the specific psychopathology of patients who have lived through a course of treatment in the intensive care unit (ICU)? Considering that each of these is a daunting task, and none of the solutions are simple, we advocate for increasing the role of psychiatrists with expertise working in the critical care setting, and with patients who are survivors of critical illness, to help address these difficult clinical challenges. In this CME article, we describe the basic components and common challenges of CCP (Table 1) and dive deeper into a few of these specific clinical scenarios. CCP is practiced by psychiatrists working in consultation-liaison (C-L) roles. C-L psychiatrists care for patients with comorbid medical illness across a variety of settings, both inpatient and outpatient. Over time, specific areas of focus within C-L psychiatry have developed, including psycho-oncology, transplant psychiatry, HIV/AIDS psychiatry, and many others. Using these examples of C-L “sub-subspecialities,” the common features include the following: A clearly defined and specific patient population with illnesses that are prevalent enough to validate and justify an esoteric clinical approach A clinical and research literature specific to this clinical population that is more “granular” and detailed than the general psychiatry literature and representative of a niche within the C-L literature Clinical interventions for the specific patient population that require separate education and clinical mastery A sufficiently large group of practicing physicians active in this area to represent “critical mass” in its formation Although sub-subspecialties do not require formal fellowship training or board certification, per se, past the subspecialty level, they do represent a distinct group of physicians. Viewed in this light, we believe that CCP meets the requirements to be considered the latest C-L psychiatry sub-subspecialty. We hope that a more formal recognition of CCP can accelerate advances in education, research, and patient care in the area. Critical Care Psychiatry Preexisting psychiatric illnesses are present in nearly one-third of patients admitted to the ICU, and many psychiatric conditions require initial general medical stabilization in the ICU, such as suicide attempts, adverse medication reactions, and complex withdrawal states.1,2 Patients with critically illness frequently experience delirium, agitation, anxiety, and demoralization, and survivors of critical illness are at risk for developing depressive disorders, acute stress disorder/posttraumatic stress disorder (PTSD), and neurocognitive disorders. Despite the high prevalence of psychiatric disorders among critically ill patients, development of integrated models of psychiatric care for this population have lagged behind those seen in other care environments. A 2001 study of 56 C-L services across Europe revealed that only 3% of hospital-based psychiatric consultations originated in the ICU, with some health systems reporting as few as 0%. This lack of collaboration is likely 2-sided; intensivists have long managed these conditions independently, without the input of psychiatric consultants who may have limited familiarity with the ICU setting, and psychiatrists have not always embraced opportunities to care for critically ill patients. In fact, some psychiatric consultants may respond to requests to see critically ill patients by asking the team to defer until the patient is either extubated or more medically stable (eg, “medically cleared”). However, given the high degree of psychiatric comorbidity in ICU patients and the need for team-based care, practices are evolving with more psychiatrists now interested in caring for critically ill patients and more intensivists open to integration of psychiatric care. The Society of Critical Care Medicine’s ICU Liberation Campaign has helped transform the field through the introduction of the ABCDEF (sometimes abbreviated as “A to F”) bundle, described in Table 2, which highlights the multifactorial components that can optimize outcomes in critically ill patients.4 In challenging old practices and introducing new strategies, the implementation of the ABCDEF bundle has been proved to significantly improve ICU survivorship and morbidity. From an educational perspective, it provides psychiatrists who are interested in working in the ICU with a clear roadmap for navigating the critical care’s foremost patient priorities and emphasizes using multimodal strategies to optimally manage conditions such as delirium and agitation. Another important finding to emerge from the critical care literature is identification and description of post–intensive care syndrome (PICS). PICS is defined as new or worsening multidimensional impairment in physical, cognitive, other psychiatric, and social domains after a course of ICU care.5 This definition acknowledges the wide range of sequelae patients may experience and informs the multidisciplinary approach needed to address them. Partnerships between intensivists and psychiatrists can help with screening for impairment and referral to psychiatric care, with the shared goal of minimizing the long-term consequences of critical illness and ICU interventions. This conceptualization also highlights the need for ICU survivors to access longitudinal, multidisciplinary follow-up care from teams that include internists, psychiatrists, physical therapists, and other relevant specialists. Many of the problems psychiatrists can help address are not new to the field of critical care, but it is a fast-evolving field that thrives on team-based care. For some of these concerns, there is even a moderate evidence base. However, studies specifically evaluating the impact of collaboration and integration with psychiatric consultants are still minimal, so this is one knowledge gap that practitioners of CCP can work to address, to benefit patients and staff alike. The Critical Care Psychiatrist C-L psychiatrists working with ICU teams may fill a number of roles, largely depending on the structure and culture of their home institution. ICUs vary widely in size, complexity, configuration, staffing, and the types of conditions they treat. For many institutions, traditional reactive consultation remains the default means by which psychiatrists are integrated. However, there is increasing interest in more heavily involved roles for psychiatrists such as embedded, comanaged, and proactive models of care. Conversely, in some ICUs, the role of the psychiatrist may be more removed, providing curbside recommendations or deferring consultation until the patient has transferred out of the ICU. Considering this amount of heterogeneity, there may be benefits to including psychiatrists in the systems-level design and coordination of intensive care. Regardless of the specific role, there are certain fundamental skills and knowledge that can help prepare a consultant for critically ill patients. The expertise of C-L psychiatrists lies at the intersection of general medicine and psychiatry, and nowhere is that expertise more necessary than in the complex, acute environment of an ICU. Nevertheless, some psychiatrists may experience a steep learning curve as they begin to participate in the care of critically ill patients, needing to reacquaint themselves with pathophysiology with which they may not be clinically current. Consultants will always do well to embody humility, curiosity, and flexibility in adapting to new environments and continually improving their knowledge. In fact, this approach often attracts psychiatrists to the field of critical care. To function in any new environment, understanding the language is a must. In deciphering an intensivist’s progress note, the consultant will encounter myriad abbreviations such as TSB, CAM, RASS, ARDS, NGT, CRRT, and many more (respectively, these stand for trial of spontaneous breathing, the confusion assessment method, the Richmond Agitation-Sedation Scale, acute respiratory distress syndrome, nasogastric tube, and continuous renal replacement therapy).6 Basic knowledge of ICU-related pathophysiology and interventions is one way for psychiatrists to be fully prepared to assist in caring for these patients. Respiratory failure and mechanical ventilation are core concepts to understand the care of ICU patients. Many patients require sedation to tolerate mechanical ventilation, so familiarity with common sedative agents (such as propofol, fentanyl, and dexmedetomidine) is another helpful piece of knowledge. Common systemic medical problems treated in the ICU include stroke, myocardial infarction (MI), respiratory failure, shock, trauma, and burns. Many psychiatric consultations are similar to those encountered by C-L psychiatrists elsewhere in the hospital, such as evaluation of safety, agitation, delirium, insomnia, depression, anxiety, psychosis, addictive disorders, and decision-making capacity. However, critical care psychiatrists may be more likely to see pathology such as catatonia, neuroleptic malignant syndrome, serotonin syndrome, and complex withdrawal states. Whether or not the reason for consultation is similar to those seen elsewhere, the numerous challenges specific to critical care (Table 1) will often complicate the care of critically ill patients. In the ICU, even common consultation questions may require a distinct approach to patient evaluation and management. Patients often cannot provide a full history. If they are comatose or noncommunicative, they may not be able to provide any history. Accordingly, the psychiatrist relies more heavily on information gathered from review of the medical records, discussion with the consulting physician and the patient’s nurse, and collateral history from the patient’s friends or family. Similarly, the determination of the plan of care also relies on input from several members of the team through shared decision-making, at minimum with the ICU physician and the patient or surrogate decision-maker. However, the complete multidisciplinary team also includes nurses, pharmacists, respiratory therapists, physical and occupational therapists, speech/language pathologists, and other consulting physicians. Critically ill patients frequently require mechanical ventilation and are thus unable to speak. For many psychiatrists, this negates most, if not all, of their normal approach to psychiatric evaluation. However, by using a systematic approach, the critical care psychiatrist can effectively perform a thorough mental status examination and possibly even gather historical information about the patient. First, adequate consciousness must be established to ensure the patient can participate in the interview. Then, language comprehension can be confirmed with the use of basic commands and “yes/no” questions. Basic cognitive functions such as orientation and attention must be tested to assess if there are any cognitive impairments are present that could affect the rest of the evaluation. If basic cognition is established, then increasingly difficult questions or prompts may be used to understand cognitive function more thoroughly. For a patient with reasonably intact cognition, the psychiatrist may then go on to gather further information about active psychiatric symptoms and other pertinent history. When questions are phrased appropriately, some patients in the ICU can report a surprising amount of history this way. If the patient is unable to reliably participate by nodding, the psychiatrist may attempt another simple proxy for communication, such as squeezing their hand. Given these potential barriers to communication, skills in physical examination are also very important in the evaluation of critically ill patients. A focused neuropsychiatric examination can provide an abundance of diagnostic information. This examination will often evaluate for reflexes, clonus, muscle tone, extrapyramidal symptoms, and catatonia. Ultimately, deficits in cognition and communication need not prevent the psychiatrist from performing an adequate evaluation of a patient in the ICU. Prescribing medications is a core part of the psychiatric consultant’s armamentarium, but working with patients who are critically ill introduces new levels of challenges in prescribing. Considering all the unique physiology of this patient population, critical care psychiatrists are often operating with a limited or absent evidence base due to a lack of prospective, controlled studies in this setting to evaluate the safety and effectiveness of commonly used pharmacologic agents. Many patients are in multi-organ failure, so hepatic and renal function must be accounted for. Cardiac function (especially the QTc interval) and abnormal vital signs may also need to be considered. Gastrointestinal function and access are also important factors because many patients can only take enteral medications when they are crushed and administered via a nasogastric tube, limiting the available options for certain pharmacologic agents. Furthermore, most ICU patients are already being prescribed numerous medications, so drug-drug interactions are another consideration that will affect the choice and dose of additional agents. The liaison aspect of C-L psychiatry is also of paramount importance when working in ICUs, where lives often hang in the balance and each patient’s status can change suddenly and dramatically. This type of environment can be frustrating, frightening, and bewildering for new and seasoned staff alike, so the psychiatrist’s role in staff support and education can have a profound impact. At the core of ICU care is a multidisciplinary team collaborating daily. Psychiatrists can help the team to think of patients as whole, awake, and autonomous individuals with interests and loved ones outside of the hospital walls, so that the patients can experience individualized, compassionate care. ICU staff also benefit from understanding the rationale behind psychiatrists’ recommendations, such as bedside education for nurses about finer details of mental status findings and how they relate to behavioral interventions and choices of medications. Finally, keeping staff engaged while supporting them through the inevitable difficulty of working in a high-stress environment is an important aspect of sustaining a healthy and resilient workforce that is less prone to burnout and attrition. As evidenced by “F for family” in the ABCDEF Bundle, patients’ loved ones can also become integral contributors to the holistic care of critically ill patients. Having a loved one who is suffering from a critical illness can be frightening enough to family members, but the manifestations of delirium, including agitation, combativeness, hallucinations, confusion, and even unresponsiveness, can be especially terrifying. Critical care psychiatrists can offer education to the family about the nature and course of delirium, what symptoms mean, and even how family members can assist the patient with environmental interventions such as reorientation, sleep-wake cycle management, cognitive engagement, exercise and mobility, and promotion of feeling safe and comfortable. Understanding and participating in the care of their loved one can help families feel empowered instead of helpless. Beyond the ICU As a sub-subspecialty, CCP is esoteric and generally confined to a single care setting. Accordingly, as patients heal and transfer out of the ICU or discharge from the hospital, their psychiatric care will need to be transitioned, often to a general outpatient psychiatrist. Given the medical and psychiatric complexity of these patients, it can be helpful to both the patient and the outpatient psychiatrist to appreciate and understand the short- and long-term impacts of critical illness. For example, in recent research involving elderly patients, the resolution of cognitive symptoms from hospital-related delirium was estimated to be only 55% at the time of hospital discharge and 80% at 6 months.7 Given the general understanding of delirium as an acute condition lasting days to weeks, these persisting cognitive deficits are often underrecognized, complicating the evaluation and treatment of patients with both cognitive and other psychiatric symptoms. The general psychiatrist can benefit from basic knowledge about how to approach patients who are survivors of critical care. Considering the many traumatic reasons that individuals end up in the ICU, acute stress disorder and PTSD are important differential diagnoses. Many critically ill patients also face premature confrontations with their mortality, which can induce symptoms of anxiety or depressive disorders. Depressive disorders, specifically in the wake of certain medical conditions (such as stroke or MI) are known to generally respond favorably to antidepressant medication, whereas other types of psychological and existential disruptions with associated depressive symptoms may be better suited for treatment with psychotherapy. The process of evaluating post-ICU psychiatric conditions (either new onset or worsened) can be complex and it can be helpful to include the patient’s medical history and their reaction to their time in the ICU in a thorough biopsychosocial evaluation. This approach can also apply to the care of family members of critical illness survivors, who may often seek treatment related to the stress of having a critically ill loved one. The Way Ahead CCP is an emerging sub-subspecialty of C-L psychiatry with the potential to improve the psychiatric status of many patients. The practice of CCP requires knowledge of internal medicine and psychopharmacology, skills in neuropsychiatric evaluation, and a flexible, team-based approach to properly serve as a consultant in the high-acuity critical care setting. Physicians must understand and tolerate the inherent risks of caring for critically ill patients in a practice setting where there are significant limitations to the available evidence guiding psychiatric care. For those wishing to learn more about CCP, the Academy of Consultation-Liaison Psychiatry website offers many educational materials, including those found on the CCP Special Interest Group page,8 such as previous presentations from experts in the field and a selected bibliography of relevant, high-yield publications. Other online resources, such as the Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center at icudelirium.org, also provide clinicians with helpful educational materials that can be used to build knowledge, inform practice, and educate colleagues, patients, and families. The practice and growth of CCP has much to offer our patients, our colleagues, and our health systems. The field is ripe for scholarship to better inform the safety and efficacy of psychiatric interventions used during and after a patient’s course of critical care. Given the high personal, institutional, and societal costs of critical care, psychiatrists working in the ICU environment to address neuropsychiatric sequelae of critical illness play a fundamental role in improving the care and recovery of survivors of critical illness. As this care environment represents a rapidly changing landscape of clinical innovation and continuous redesign, CCP is well positioned to prioritize care that focuses on patients’ cognitive and psychological recovery, paving the way for substantial short- and long-term benefits to patients, their support networks, and the entire health system. Note: This article originally appeared on Psychiatric Times

Teenagers who use cannabis have a dramatic increased risk for a psychotic disorder compared with their counterparts who don't use the drug, new research showed. Investigators at the University of Toronto, The Centre for Addicti and Mental Health (CAMH), and the Institute for Clinical Evaluative Sciences (ICES), in Canada, linked recent population-based survey data from over 11,000 youngsters to health service use records, including hospitalizations, emergency department (ED) visits, and outpatient visits. "We found a very strong association between cannabis use and risk of psychotic disorder in adolescence [although] surprisingly, we didn't find evidence of association in young adulthood," lead author André J. McDonald, PhD, currently a postdoctoral fellow at the Peter Boris Centre for Addictions Research and the Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, Ontario, Canada, said in a news release. "These findings are consistent with the neurodevelopmental theory that teens are especially vulnerable to the effects of cannabis," said McDonald, who conducted the research. The study was published online on May 22 in Psychological Medicine. Increased Potency "Epidemiologic research suggests that cannabis use may be a significant risk factor for psychotic disorders," the authors wrote. However, methodological limitations of previous studies make it difficult to estimate the strength of association, with the current evidence base relying largely on cannabis use during the twentieth century, when the drug was "significantly less potent." It's plausible that the strength of association has increased due to increased cannabis potency. The researchers believe youth cannabis use and psychotic disorders is "a critical public health issue," especially as more jurisdictions liberalize cannabis use and the perception of harm declines among youth. To estimate the association between cannabis use during youth and the risk for a psychotic disorder diagnosis, using recent population-based data, they used data from the 2009 to 2012 cycles of the Canadian Community Health Survey (CCHS) linked to administrative health data at ICES to study noninstitutionalized Ontario residents, age 12-24 years, who had completed the CCHS during that period. They excluded respondents who used health services for psychotic disorders during the 6 years prior to their CCHS interview date. Respondents (n = 11,363; 51% men; mean age [SD], 18.3 [15.2-21.3] years) were followed for 6-9 years, with days to first hospitalization, ED visit, or outpatient visit related to a psychotic disorder as the primary outcome. The researchers estimated age-specific hazard ratios during adolescence (12-19 years) and young adulthood (20-33 years) and conducted sensitivity analyses to explore alternative model conditions, including restricting the outcome to hospitalizations and ED visits, to increase specificity. Compared with no cannabis use, cannabis use was significantly associated with an 11-fold increased risk for psychotic disorders during adolescence, although not during young adulthood (adjusted hazard ratio [aHR], 11.2; 95% CI, 4.6-27.3 and aHR, 1.3; 95% CI, 0.6-2.6, respectively). Perception of Harm Declining When the researchers restricted the outcome to hospitalizations and ED visits only, the strength of association "increased markedly" during adolescence, with a 26-fold higher association in cannabis users than in nonusers (aHR, 26.7; 95% CI, 7.7-92.8). However, there was no meaningful change during young adulthood (aHR, 1.8; 95% CI, 0.6-5.4). "Many have hypothesized that adolescence is a more sensitive risk period than adulthood for the effect of cannabis use on psychotic disorder development, yet prior to this study, little epidemiologic evidence existed to support this view," the authors wrote. The data also suggest that cannabis use is "more strongly associated with more severe psychotic outcomes, as the strength of association during adolescence increased markedly when we restricted the outcome to hospitalizations and ED visits (the most severe types of health service use)," the investigators noted. The authors noted several limitations. For instance, it's unclear to what extent unmeasured confounders including genetic predisposition, family history of psychotic disorders, and trauma might have biased the results. In addition, they could not assess the potential confounding impact of genetic predisposition to psychotic disorders. The possibility of reverse causality also cannot be ruled out. It's possible, they noted that individuals with "psychotic dispositions" may self-medicate or show greater disposition to cannabis use. Moreover, the dataset neither captured important factors regarding the cannabis itself, including delta-9-tetrahydrocannabinol potency, mode of use, product type, or cannabis dependence, nor captured institutionalized and homeless youth. Nevertheless, they pointed to the findings as supporting a "precautionary principle" — as more jurisdictions move to liberalize cannabis use and perception of harm declines among youth, the findings suggest that evidence-based cannabis prevention strategies for adolescents are warranted. Note: This article originally appeared on Medscape

In the wake of the COVID-19 pandemic, physicians continue to experience burnout at alarmingly high rates. In a recent survey of 2440 physicians, approximately 63% of respondents reported having at least 1 manifestation of burnout in 2021; this was higher than all 4 prior assessment time points since 2011. Because physician burnout is more common in certain specialties, it is crucial to identify trends and offer help to those at higher risk. This article examines the symptoms, causes, and prevalence of burnout among clinicians in various specialties, and outlines strategies physicians can use to address burnout. What Is Physician Burnout? The American Medical Association (AMA) defines physician burnout as a long-term stress reaction that can include the following: Emotional exhaustion; Depersonalization (lack of empathy for or negative attitudes toward patients); and Feeling of decreased personal achievement. For many clinicians, symptoms of burnout were accelerated by the COVID-19 pandemic. During the pandemic, chronic stress due to work overload, exposure to infected patients, lack of protective equipment, and poor efforts to control infection rates increased the risk of burnout. Other factors associated with burnout include system inefficiencies, administrative burdens, and increased regulation and technology requirements. The consequences of physician burnout affect patients as well as clinicians. From a patient’s perspective, physician burnout can result in poor physician/patient rapport, adherence to treatment, and treatment outcomes. For physicians, burnout can lead to declining mental health and subsequent depression, substance abuse, and suicide. Physician Burnout: Which Specialties Are Most Affected? Although burnout affects clinicians in all specialties and practice settings, the rate is higher in certain specialties. The AMA’s Organization Biopsy® is an assessment tool large health care organizations can use to measure and improve the health of their organizations. One of the parameters this tool measures is burnout. The AMA’s 2022 Organizational Biopsy received more than 13,000 responses from physicians and other clinicians from more than 70 organizations in 30 states. The specialties with the highest rates of burnout were as follows: Emergency medicine: 62%; Hospital medicine: 59%; Family medicine: 58%; Pediatrics: 55%; Obstetrics and gynecology: 54%; and Internal medicine: 52%. Medscape conducts an annual survey on physician lifestyle and happiness that includes questions about burnout and depression. In 2023, this 10-minute online survey included input from 9,175 physicians in 29 specialties. Overall for all specialties, 36% of respondents said they felt burned out, 5% said they felt depressed, and 18% said they felt both burned out and depressed. Based on the Medscape 2023 survey results, the following sections summarize the rates of burnout and depression among physicians clinicians working in emergency medicine, family medicine, pediatrics, obstetrics and gynecology, and internal medicine. Burnout in Emergency Medicine In Medscape’s 2023 survey, emergency physicians reported the following8: 42% felt burned out; 4% felt depressed; and 23% felt both burned out and depressed. Burnout was reported by a higher proportion of women (51%) than men (38%). The 3 largest factors contributing to burnout among emergency medicine physicians were having too many bureaucratic tasks (51%), a lack of respect from patients (50%), and a lack of respect from administrators/employers, colleagues, or staff (46%). Burnout in Family Medicine Slightly more than one-half of female family physicians (51%) and one-third of male family physicians (33%) reported experiencing burnout. The overall proportion of respondents who said they felt burned out was 42%. Depression affected 4% of family medicine physicians, while 15% said they felt both burned out and depressed. By far the largest contributor to family physician burnout was having too many bureaucratic tasks; 73% of respondents reported tasks such as paperwork and charting were the main culprit. Working too many hours and a lack of respect from administrators/employers, colleagues, or staff were cited as factors contributing to burnout by 36% and 31% of respondents, respectively. Burnout in Pediatrics Overall, 39% of pediatricians reported feeling burned out. More female pediatricians reported feeling burned out more than their male counterparts (46% vs 26%, respectively). The proportion of respondents who said they felt depressed was 3%, while 19% reported being both burned out and depressed. The 3 largest contributors to burnout were having too many bureaucratic tasks (65%), lack of respect from administrators/employers, colleagues, or staff (40%), and spending too many hours at work (38%). Burnout in Obstetrics and Gynecology In Medscape’s 2023 report, obstetrics and gynecology physicians reported the following11: 38% felt burned out; 5% felt depressed; and 20% felt both burned out and depressed. Obstetrics and gynecology physicians reported that the 3 largest contributors to their burnout were having too many bureaucratic tasks (56%), spending too many hours at work (47%), and a lack of respect from administrators/employers, colleagues, or staff (42%). Burnout in Internal Medicine Nearly half of female internists (49%) reported dealing with burnout, vs 31% of male internists. However, 4% of both male and female internists said they felt depressed, and 21% of both male and female internists said they felt both burned out and depressed. Having too many bureaucratic tasks was the primary contributor to internist burnout (64%). Insufficient compensation/salary was the second-leading factor (40%), followed by a lack of respect from administrators/employers, colleagues, or staff (35%). Physician Stress and Burnout: What Can Be Done? Many of the factors known to contribute to burnout are systemic and need to be addressed by health care organizations. However, physicians can take action to limit their stress and prevent exhaustion. The following strategies may help mitigate burnout: Optimizing physical health by exercising regularly, eating a healthy diet, and developing good sleep habits; Employing stress management techniques, such as meditation and mindfulness exercises; Making time to pursue other interests, hobbies, or relaxing activities that bring joy and satisfaction; Setting healthy boundaries by limiting work hours and saying “no” or delegating tasks to preserve time and energy; and Seeking physician burnout therapy or coaching to build new skills, learn how to properly set boundaries, and recognize additional burnout symptoms. Note: This article originally appeared on Psychiatry Advisor

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

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

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

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