Key Point: Tomorrow, August 31, is Overdose Awareness Day. What can you be doing to help prevent overdose deaths? CLINICAL CONVERSATIONS August 31 is Overdose Awareness Day. A recent study shows that about 1 in 3 Americans have lost someone they knew to a drug overdose.1 To help address this issue, Psychiatric Times sat down withJoseph R. Volpicelli, MD, PhD, the executive director of the Institute of Addiction Medicine, to discuss the opioid crisis, best practices for substance use disorder treatment, and more. Psychiatric Times: In your opinion, what should clinicians be doing to help prevent overdose deaths? Joseph R. Volpicelli, MD, PhD: With over 100,000 deaths due to drug overdose this past year, it is important that all clinicians, regardless of specialty, join in the fight to prevent overdose deaths. This includes asking patients about drug and alcohol use as part of each clinical visit. If an issue is present, clear and nonjudgmental advice should be offered so the patient can address the issue. Clinicians should be aware of treatment options, and if they are uncomfortable treating the problem directly, then appropriate referral and follow-up are necessary. Even patients who do not present with a drug issue should be educated that with the advent of synthetic opioids like fentanyl in the drug supply, any illicit drug could have a fatal dose of an opioid with simply 1 accidental use. PT: The theme for this year’s Overdose Awareness Day is “Together we can.” Do you think substance use disorder treatment is best managed by a team? How do you employ this in your own practice? Volpicelli: Yes absolutely, a team is essential to treat substance use disorder. Medications such as methadone and buprenorphine are very effective in reducing craving and illicit opioid use, and the medication naltrexone, or VIVITROL, is effective in reducing relapse to opioid use in someone who has detoxified from opioids. However, while effective, these medications only work when taken. Our program’s team of physicians, nurse practitioners, and counselors/coaches address psychosocial issues that lead to drug use and interfere with sustained treatment. We believe that treatment is more than recovery from drug use; it is discovering new options for individuals to find connections and meaning in life. In addition to the treatment team, we must work together with the community to raise awareness and reduce the stigma associated with addiction. This includes improving access to care and removing barriers to quality, effective treatment. PT: How best can clinicians combine medication and psychosocial treatment when treating patients struggling with addiction, specifically opioid use disorder? Volpicelli: The use of medications and psychosocial support work synergistically to help patients struggling with addiction. Often, patients with opioid addiction have exhausted their finances trying to support their drug habit and fractured or ignored social connections with people because they are preoccupied with getting high. The emotional pain of financial and social isolation is temporarily removed by redosing, but this only serves to perpetuate a vicious cycle of addiction. While medications can be beneficial in reducing withdrawal symptoms and the desire to use drugs, they do not repair broken relationships with family members or give one a sense of purpose. By combining medications and psychosocial support early in treatment, we can improve treatment engagement and medication adherence. Working collaboratively with patients, the clinician can address barriers to care and help motivate patients who are ambivalent about addressing their addiction. Later in treatment, we focus on repairing broken social connections and helping patients find purpose. A part of every clinical visit in our program is to assess a patient’s interest and engagement in enjoyable activities, and how well they get along with friends and family, and enjoy and function in their job. PT: What practice tips would you offer to clinicians who have less experience in managing patients with opioid use disorder? Volpicelli : The most important practice tip I would offer to less experienced clinicians is to remember that people with addictions are your friends, neighbors, and family members. Addressing their issues with the same compassion and understanding as patients with other medical conditions will help you accurately assess and offer treatment. Often, people with opioid use disorder feel stigmatized by the medical community and are reluctant to share information and accept care. Establishing a good therapeutic relationship is the most important first step. PT: Can you speak a little to the challenges of addressing opioid addiction and use in patients with comorbid psychiatric disorders? Volpicelli: Comorbid psychiatric disorders are very common in those with opioid addiction. Individuals with comorbid anxiety and depression will often report that drug use helps them cope and feel better. The idea of stopping opioid use then is fraught with the fear that these symptoms will get worse. To help alleviate these fears and the symptoms, it is critical to recognize and offer alternatives to drug use. Treatment can include the use of medications that specifically address comorbid psychiatric conditions and behavioral counseling. PT: How can clinicians best screen for potential opioid use/abuse in new patients? Volpicelli: Including questions about drug and alcohol abuse should be included in every clinical encounter. When presented without judgment, one will typically get accurate responses. Drug screening from urine or blood samples can confirm the patient’s narrative report. In addition, one can review their medication history. Virtually every state offers a Prescription Drug Monitoring Program to see if there is some anomaly in the patient’s prescription pattern (ie, increasing doses of opioids, several health care professionals writing for opioids). The physical exam can offer clues such as small pupils or tract marks on the limbs. One can also employ questionnaires that screen for drug opioid addiction, such as the Screener and Opioid Assessment for Patients with Pain (SOAPP), Current Opioid Misuse Measure (COMM), or Drug Abuse Screening Test (DAST). PT: Do you think the opioid crisis is getting better or worse? Why? Volpicelli: The number of fatal overdose deaths decreased last year for the first time in several decades. Increased public awareness of the opioid crisis and reductions in limitations for health care professionals are causes for optimism that the crisis has peaked. However, the addition of adulterants to the opioid supply, such as xylazine and stimulants, has made it more challenging to manage patients. Protocols to detoxify patients from opioids or start buprenorphine are more difficult as the additives to the opioid supply do not have any established effective medical treatments. As treatment becomes more accessible and is addressed more aggressively by the medical community, we should make progress in improving the opioid crisis. PT: What would you say are today’s most pressing issues concerning substance use disorder? Volpicelli: We have effective treatments, but they are often not accessible, and once started, it has been a challenge to keep patients engaged in treatment. Structural issues such as limited health care resources in poorly served urban and rural communities, the cost of quality care, and a medical community that does not fully embrace addiction as a medical condition compromise the use of the available effective treatments. PT: Your research led to the discovery of naltrexone to treat alcohol addiction, an FDA-approved medicine intended to reduce alcohol craving and relapse. Can you share a little bit about your research process? Are there any specific findings you think might surprise your fellow clinicians? Are there any efficacy issues? Volpicelli: This year marks the 30th anniversary of the US Food and Drug Administration approval of naltrexone to treat alcohol addiction (and the 40th to treat opioid addiction).Research has convincingly shown that naltrexone is a safe and effective treatment for alcohol addiction. There are over 50 placebo-controlled randomized trials and supporting meta-analysis of these trials to show that naltrexone is effective. There is no other form of alcohol addiction treatment that has such a large empirical basis for its effectiveness. However, only about 10% of those with alcohol addiction receive any treatment for alcohol use disorder, and less than 2% of those in treatment receive a prescription for naltrexone. The biggest disappointment in my research career is the underutilization of naltrexone. Perhaps the most surprising finding among my fellow clinicians is that naltrexone is so versatile in how it can be used. Most clinicians use naltrexone in recently detoxified patients with the goal of complete abstinence. However, we know that reductions in alcohol use can have substantial health benefits, and particularly for individuals who drink alcohol occasionally, naltrexone can be administered in a targeted way to moderate one’s drinking. Naltrexone can be prescribed as a daily pill, targeted to drinking situations, or given as a once-a-month injection. When integrated with psychosocial support, naltrexone is very effective for those with high baseline levels of alcohol craving and those with a positive family history of alcohol addiction. Alcohol addiction is likely a heterogenous disorder, and some people are not naltrexone responders but would respond to other medications. Future research is needed to best match the right medicine for the patient. PT: How best can clinicians integrate harm reduction models into opioid use disorder treatment? Volpicelli: While abstinence from illicit opioids is the preferred goal, for many individuals, it is unrealistic in their current situation. For various reasons, people are either unwilling or unable to abstain completely. In these cases, engaging people in treatment and reducing harm as much as possible is important. It is often stated that we need to meet people where they are at, which is very true if we engage people in treatment. I would add, though, that if people are in a bad place, we have a responsibility to not only meet them where they are at but also help them move from that bad place. So, harm reduction at its best reduces harm and encourages growth to a healthy, productive life. PT: Are there any other substance use disorder treatments in the pipeline that you are excited about? Volpicelli: The introduction of injectable formulations of buprenorphine and naltrexone, like VIVITROL, has been a welcome addition to opioid addiction treatment. The use of a sustained-release version of these medications reduces the risk of medication diversion and nonadherence. In addition, several exciting new medications to treat substance use disorder are in the pipeline. For example, GLP-1 agonists such as semaglutide have interesting preclinical and early reports of effectiveness in treating alcohol addiction. Also, there is renewed interest in psychedelic-assisted therapy, such as low-dose psilocybin, to treat alcohol and opioid addiction. I have also been involved in nonmedical treatment, such as the use of neurostimulation techniques. Finally, to help address issues in access to treatment, there has been increased interest in virtual telemedicine and digital therapeutics to help provide psychosocial support. PT: You designed a treatment modality called the BRENDA Model (B – biopsychosocial evaluation, R – report findings to patient, E – empathize, N – what are the needs of the patient, D– direct advice, A – assess patient's response to advice). How can clinicians employ this in their own practices? Volpicelli: Researching medical treatments for addictions is often compromised by subject nonadherence and dropouts. To address this, I designed the BRENDA approach to improve treatment engagement and retention. This approach borrows from motivational enhancement techniques and is easy to learn and use effectively—even with clinicians without formal training in motivational interviewing. The first step is to conduct a full biopsychosocial evaluation to evaluate how substance use is associated with adverse consequences. The subject is then given feedback on the evaluation to help them make the connections between their substance use and its consequences. This process is conducted with an emphasis on empathy and a nonjudgmental attitude to get a sense of what issues are most relevant to the subject. Next, the collaboration between the clinicians and the subject identifies the needs and goals of the subject (ie, why the subject would want to reduce their drinking or drug use). As the subject feels the clinician has a fair understanding of what matters most to the subject, the clinician offers direct advice, such as starting a new medication, and explains how the intervention will benefit the subject. Finally, the clinician assesses the subject's response to the direct advice and the motivation to follow through. Any ambivalence or reluctance to follow through is explored, and barriers to treatment recommendations are addressed. This approach was successfully used in research studies and is easily applied in clinical settings. Clinicians and their staff can be trained to adopt this approach to improve the therapeutic relationship and approach each patient with the empathy and care they deserve. While it may take a little extra time with the patient, improving patient engagement and adherence is worth the effort. PT: Do you have any final thoughts to share? Volpicelli: Addiction treatment is safe and effective. The main challenge for the medical community is to help reduce social stigma and barriers to care. We all have a responsibility to help inform the public about the advances in medical treatment for addictions and how integrating medical care with psychosocial support can bring freedom to those who suffer from addiction. Note: This article originally appeared on Psychiatric Times .

Brexpiprazole is an atypical antipsychotic that is approved by the FDA as monotherapy treatment for schizophrenia and as an adjunctive treatment to antidepressants for major depressive disorder (MDD). Brexpiprazole is a partial agonist at the serotonin 5-hydroxytryptamine1A and dopamine D2 receptors and an antagonist at serotonin 5-hydroxytryptamine2A; it is also equally potent at 2 norepinephrine receptors – an antagonist at the noradrenergic α1B and α2C receptors. A meta-analysis of efficacy in schizophrenia by Reyad et al that included data from 14 randomized controlled trials (RCTs) found that on the positive and negative syndrome scale (PANSS) the mean difference (MD) among individuals taking brexpiprazole when compared to placebo was -4.48 points. On the clinical global impressions - severity of illness (CGI-S) scale, the MD between the 2 groups was -0.23. On the personal and social performance scale (PSP), the MD was 3.24. All these results favored brexpiprazole when compared with placebo among individuals with schizophrenia. In MDD, those receiving brexpiprazole did better than those receiving placebo on the Montgomery-Åsberg depression rating scale (MADRS, MD=-1.25), the Sheehan disability scale (SDS, MD=-0.37), and the Hamilton depression rating scale (HDRS17, MD=-1.28). The investigators noted that the use of brexpiprazole was associated with greater risk for akathisia [risk ratio (RR)=1.72], weight gain (RR=2.74), and somnolence (RR=1.87) compared with placebo. They also noted that 2 mg/day dosing of brexpiprazole was associated with less risk of akathisia, when compared with the 3 mg/day dosing (7% at 2 mg, 14% at 3 mg, 2% for placebo). In May 2023, the FDA provided supplemental approval for brexpiprazole oral tablets for the treatment of agitation associated with dementia due to Alzheimer disease (AD), making it the first FDA-approved treatment option for this indication. The FDA however retained the Boxed Warning for brexpiprazole that is included for medications in this class indicating that older adults with dementia-related psychosis are at an increased risk of death when treated with antipsychotic medications, with the rewording in the Boxed Warning that it did not apply if the primary diagnosis was agitation associated with dementia due to AD, even if psychosis was present. Significantly, brexpiprazole is not FDA-approved as a prn medication. The goal of this review is to evaluate the data from published randomized controlled trials (RCTs) on the use of brexpiprazole among individuals with behavioral and psychological symptoms of dementia (BPSD) to assist clinicians with making an informed treatment decision. A total of 3 RCTs that evaluated the efficacy, safety, and tolerability of brexpiprazole among individuals with BPSD were included. One article by Grossberg et al included data from 2 RCTs that evaluated the use of brexpiprazole in the treatment of people with BPSD. We also used data from the recently published version of the third study. The quality of the identified studies was assessed using the Jadad scale. Table 1 discusses the characteristics of the included studies, Table 2 describes study results, and Table 3 reviews the quality of included studies. One study evaluated 1 mg versus 2 mg versus placebo; 1 study evaluated 2 mg and 3 mg versus placebo (these 2 studies are described in the FDA-approved product insert); and 1 study evaluated the flexible dose of 0.5 – 2 mg versus placebo. The trials were of good quality and were rated as a 5/5 on the Jadad Scale. Exploring Efficacy Study 1 In this multicenter, randomized, double-blind, placebo-controlled, parallel-arm study, 433 participants were randomized to receive brexpiprazole 2 mg/day (n=140), brexpiprazole 1 mg/day (n=137), brexpiprazole 0.5 mg/day (n=20), or placebo (n=136) for 12 weeks.4 The 0.5 mg/day brexpiprazole arm was removed early in the study when information from other ongoing and completed studies demonstrated that 0.5 mg was a non-efficacious dose. As there were very few patients in the brexpiprazole 0.5 mg/day arm, these patients were not included in the efficacy analyses. Additionally, these individuals were pooled with the 1 mg/day arm in the safety analyses. However, these individuals were included in the analyses of the Sheehan Suicidality Tracking Scale, Mini Mental State Examination (MMSE), and extrapyramidal symptoms scales (EPS; the Simpson-Angus Scale, the Abnormal Involuntary Movement Scale, and Barnes Akathisia Rating Scale). Participants were randomized to receive brexpiprazole doses or placebo in a 1:1:1 fashion. The medication was titrated over a period of 2 to 4 weeks (Days 1-3, 0.25 mg/day; Days 4-14, 0.5 mg/day; Days 15-28, 1 mg/day; Day 29 onwards, assigned dose). Participants who were not able to tolerate their assigned dose of the drug or matching placebo had to discontinue the trial. Baseline characteristics were similar across the brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, and placebo groups. A total of 79.6% of the participants had received treatment for agitation in Alzheimer disease (AAD) and psychosis prior to the study. The most common medications used to treat AAD in this group were risperidone (17.4%), quetiapine (15.5%), lorazepam (14.1%), and haloperidol (11.1%). During the study period, a total of 74.8% of participants used 1 or more medications for AD including memantine (45.1%), donepezil (27.8%), and rivastigmine (11.8%). The study was completed by 122 patients (87.1%) in the brexpiprazole 2 mg/day group, 121 (88.3%) in the brexpiprazole 1 mg/day group, 13 (65.0%) in the small sample brexpiprazole 0.5 mg/day group, and 121 (89.0%) in the placebo group. The brexpiprazole 2 mg/day group showed statistically significant improvements on the primary efficacy endpoint (CMAI Total score), when compared with placebo (P=0.040; Cohen’s d effect size= -0.25). Brexpiprazole 2 mg/day also demonstrated numerical improvements, although not statistically significant results on the key secondary efficacy endpoint [Clinical Global Impression – Severity of illness (CGI-S)] as related to agitation (Cohen’s d effect size= -0.17, P=0.16), as well as on the NPI-Nursing Home (NPI-NH) Agitation/Aggression domain (Cohen’s d effect size= -0.19, P=0.12). No benefits were noted for the brexpiprazole 1 mg/day dosing when compared with placebo on either the primary efficacy endpoint (CMAI Total score; Cohen’s d effect size= 0.02, P=0.90), or key secondary end points [(CGI-S as related to agitation; Cohen’s d effect size= 0.09, P=0.44); (NPI-NH Agitation/Aggression domain; Cohen’s d effect size= -0.03, P=0.78]. Study 2 In this study, which was not used by the FDA for analysis for approval, participants (n=270) were randomized to receive brexpiprazole 0.5-2 mg/day (n=133) or placebo (n=137). Eligible participants were randomly assigned in a 1:1 proportion to receive either flexible doses of brexpiprazole 0.5-2 mg/day or placebo for 12 weeks. Brexpiprazole treatment commenced at 0.25 mg/day (Days 1-3), was raised to 0.5 mg/day (Days 4-14), and subsequently escalated to a targeted dose of 1 mg/day (Days 15-28, with the option to revert to 0.5 mg/day). Starting from Day 29 (Week 4 visit), an additional escalation to 2 mg/day was possible. Beyond Week 4, dose adjustments (increases or decreases) could occur at any point during scheduled or unscheduled visits, guided by the investigator's assessment of the participant's response and tolerability. Participants who were unable to tolerate brexpiprazole 0.5 mg/day or corresponding placebo were discontinued from the trial. Baseline characteristics were similar between the brexpiprazole and the placebo groups. A total of 66.5% of participants had received treatment for AAD and psychosis, with common prior medications being risperidone (14.5%), chlorprothixene (14.1%), haloperidol (11.5%), and quetiapine (10%). During the study, 83.3% of participants used 1 or more medications for AD, with memantine (51.7%) and donepezil (31.2%) being common. The study was completed by 117 participants (88.0%) in the brexpiprazole group and 121 (88.3%) in the placebo group. The brexpiprazole 0.5-2 mg/day group did not achieve statistical superiority on the primary efficacy endpoint (CMAI Total score) when compared with placebo (Cohen’s d effect size= -0.18, P=0.15). However, benefit was noted for brexpiprazole 0.5-2 mg/day on the key secondary endpoints of CGI-S as related to agitation (Cohen’s d effect size= -0.30, P=0.016) and the NPI-NH Agitation/Aggression domain (Cohen’s d effect size= -0.34, P=0.0068). The post hoc analyses showed that the subgroup of individuals who were titrated to the maximum dose of brexpiprazole at 2 mg/day at week 4 demonstrated improvements on the CMAI Total score when compared with individuals who were titrated similarly on placebo (Cohen’s d effect size= -0.41, P=0.012). These individuals also demonstrated improvements on CGI-S as related to agitation (Cohen’s d effect size= −0.59, P<0.001). Study 3 Lee et al conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-arm trial of brexpiprazole among 345 individuals with AAD who were randomized to receive either brexpiprazole (n = 228) or placebo (n = 117) for 12-weeks. Participants in the brexpiprazole group were further randomized 1:2 to receive brexpiprazole fixed doses of 2 or 3 mg/day. The dose titration for brexpiprazole was as follows; first week, 0.5 mg/day; second week, 1 mg/day; third and fourth weeks, 2 mg/day; beyond fourth week, 2 or 3 mg/day (fixed doses). The primary efficacy end point was a change from baseline to week 12 on the CMAI Total score. Secondary efficacy measures were the CGI-S and the Clinical Global Impression Improvement (CGI-I) scales, specifically applied to agitation, and the NPI-NH Agitation/Aggression domain. In contrast to the other 2 trials, the participants in this trial needed to meet the International Psychogeriatric Association definition of agitation to be eligible for participation in the study. The baseline demographic and clinical characteristics between the 2 groups were generally similar. A total of 184 (81.4%) individuals in the brexpiprazole group and 95 (81.9%) individuals in the placebo received standard medications for AD, mainly memantine or donepezil. The study was completed by 198 (86.8%) individuals in the brexpiprazole groups and 104 (88.9%) individuals in the placebo group. On the CMAI Total score, individuals receiving brexpiprazole 2 or 3 mg/day showed statistically significant improvements when compared with placebo (Cohen’s d effect size=0.35, P=0.003). Additionally, benefits were noted for the brexpiprazole 2 or 3 mg/day group on the CGI-S score as related to agitation (Cohen’s d effect size=0.31, P=0.008). Furthermore, benefits were also noted for brexpiprazole 2 or 3 mg/day group on the following exploratory end points: CMAI factor 1: aggressive behavior score (Cohen’s d effect size=0.33, P=0.004); CMAI factor 2: physically nonaggressive behavior score (Cohen’s d effect size=0.25, P=0.03) and the CMAI factor 3: verbally agitated behavior score (Cohen’s d effect size=0.29, P=0.01) and the CGI-I score (P=0.007). Additionally, on the NPI-NH Total score, the brexpiprazole 2 or 3 mg/day group did better than placebo (Cohen’s d effect size=0.39, P=0.001). Safety and Tolerability Study 1 Over 12 weeks, treatment emergent adverse events (TEAE) incidence rates were as follows: 65.0% (brexpiprazole 2 mg/day), 49.0% (brexpiprazole 0.5-1 mg/day), and 45.9% (placebo) groups respectively.4 Most of the TEAEs were rated as being mild or moderate. Serious TEAEs were seen in 9.3% (brexpiprazole 2 mg/day), 10.2% (brexpiprazole 0.5-1 mg/day), and 5.2% (placebo) groups respectively. Agitation in 1 participant on brexpiperazole 0.5 mg/day was the only TEAE that was considered related to the study drug. Discontinuation due to TEAEs was as follows: 4.3% (brexpiprazole 2 mg/day), 8.9% (brexpiprazole 0.5-1 mg/day), and 5.2% (placebo) groups respectively. Agitation (4 vs 1) and QTc interval prolongation (2 vs 0) led to the discontinuation from the study in the brexpiprazole vs placebo groups. The investigators did not find any significant differences between the groups on suicidality, extrapyramidal symptoms (EPS), QTc interval, body weight, metabolic parameters, and cognitive dysfunction. A total of 5 participants in the brexpiprazole groups and 0 in the placebo group died during the study. However, it was determined that none of these deaths were attributable to the study medication. Study 2 TEAE incidence over 12 weeks was similar between brexpiprazole 0.5-2 mg/day (56.8%) and placebo (58.4%) groups.5 Most of the TEAEs were rated as being mild to moderate. Serious TEAEs were as follows: 5.3% for brexpiprazole 0.5-2 mg/day and 4.4% for placebo groups respectively. A total of 6.8% of the individuals in the brexpiprazole group discontinued the study due to TEAEs when compared with 0.7% of the individuals in the placebo group. Post hoc analysis showed no TEAE differences for participants titrated to 2 mg/day brexpiprazole at week 4 vs placebo. No clinically meaningful between-group differences were observed in other safety assessments, including suicidality, EPS, QTc interval, body weight, metabolic parameters, and cognitive dysfunction. Two patients died during the study, with neither of the deaths being considered related to the study drug. Study 3 Approximately 40.7% of the individuals in the brexpiprazole 2 or 3 mg/day reported TEAEs, when compared with 31.0% in the placebo group.5 Headache was noted in 6.6% of individuals in the brexpiprazole group and in 6.9% of individuals in the placebo group. Other TEAEs seen in the brexpiprazole vs placebo groups were as follows: cardiovascular events, 0.9% vs 0.9%; any cerebrovascular events, 0% vs 0%; any extrapyramidal symptoms, 3.5% vs 0%; somnolence/sedation, 4.0% vs 0.9%; accident or injury TEAE, including falls, 2.2% vs 3.4%; and metabolism and nutrition disorder, 1.3% vs 1.7%. The investigators rated the majority of TEAEs as being of mild or moderate severity; 5.3% and 4.3% of the brexpiprazole and placebo groups, respectively, discontinued treatment due to AEs. There was 1 death in the brexpiprazole group, but it was thought to be unrelated to the use of the drug. The mean standard deviation (SD), increase in body weight from baseline to week 12 was 0.3 kg in the brexpiprazole group vs 0.0 kg in the placebo group. Weight gain of ≥7% from baseline to week 12 was experienced by 1.5% of individuals in the brexpiprazole group, and 0% of the individuals in the placebo group. From baseline to week 12 weight loss of ≥7% was noted in 1.0% of participants in both groups. None of the participants in either group reported suicidal ideation or behavior as a TEAE. On the MMSE score, the mean change from baseline to week 12 was 0.7 for the brexpiprazole group and 0.4 in the placebo group. The investigators reported that there were no clinically meaningful differences noted on the laboratory test results, vital signs, or electrocardiograms between the brexpiprazole and placebo groups. In addition, the EPS rating scale score changes were also rated as being minimal. Making Sense of the Data Brexpiprazole titrated to 2 or 3 mg/day over 2 to 4 weeks (3 mg dose only following 28 days of 2 mg) provides statistically significant, although modest benefits among individuals with AD who present with agitation. Additionally, brexpiprazole appears to be well tolerated when compared with placebo. No significant differences were noted between brexpiprazole and placebo on rates of suicidality, EPS, QTc interval, body weight, metabolic parameters, and cognitive dysfunction. There were no cerebrovascular events (CVAEs) noted in the studies, and the deaths in the study population were deemed as not being attributable to brexpiprazole. A previous meta-analysis looked at the use of other atypical antipsychotic medications among individuals with dementia-related psychosis; interestingly, the data for brexpiprazole appears similar (SMD=effect size). Yunusa et al in their meta-analysis found benefits for aripiprazole among individuals with BPSD when compared with placebo on the NPI (SMD= −0.17), the BPRS (SMD= −0.20), and on the CMAI (SMD= −0.30).7 Benefits were noted for quetiapine on the BPRS (SMD= −0.24), and risperidone on the CMAI (SMD= −0.26) when compared with placebo. In another meta-analysis, Yunusa et al found that aripiprazole (SMD= −0.12) and olanzapine (SMD= −0.17) demonstrated small although nonsignificant numerical improvements in NPI-NH psychosis scores, compared with placebo.8 However, quetiapine (SMD=0.04) did not show any benefits among individuals with dementia related psychosis. The tolerability of brexpiprazole in individuals with BPSD appears to be favorable when compared with other atypical antipsychotics. There were no CVAEs noted in the studies and none of the deaths were deemed as being attributable to brexpiprazole. Additionally, there was no cognitive decline noted with the use of brexpiprazole. Sedation is the adverse effect to watch for when using brexpiprazole among individuals BPSD. When looking at other antipsychotics, Yunusa et al noted that the risk for CVAEs were greater with olanzapine (OR=4.28) and risperidone (OR=3.85), when compared with placebo.7 Additionally, the investigators noted that risperidone (OR=2.23) produces greater risk of EPS. Furthermore, somnolence was greater with aripiprazole (OR=3.14), olanzapine (OR=4.08), quetiapine (OR=4.47), and risperidone (OR=2.57). When compared with placebo, quetiapine (OR=2.11) was associated with increased urinary incontinence or urinary tract infections. In their second meta-analysis Yunusa et al found that mortality was noted to be higher for aripiprazole (OR=1.58), olanzapine (OR=2.21), quetiapine (OR=1.68), and risperidone (OR=1.63).8 Additionally, risperidone (OR=3.68) and olanzapine (OR=4.47) appeared to increase the risk of CVAEs. The investigators noted that the odds of mortality were numerically higher in the brexpiprazole group when compared with the placebo group (OR = 2.22, 95% CI, 0.3-16.56). These data differ from the data that we obtained from the 3 brexpiprazole studies that are reviewed in this article. There were no brexpiprazole-related deaths identified in these studies. This difference in data is probably due to pooling of data from the 2 individual studies for the meta-analysis by Yunusa et al. Strengths and Limitations of the Studies The strengths of the included studies are that they are all well conducted, multicenter RCTs (Jadad 5/5) that included ≥1000 participants with AAD. Additionally, they used varying doses of brexpiprazole. The limitations of the studies are that they mainly had Caucasian participants, were only 12 weeks in duration, included more participants who were living in care facilities, included participants who had limited comorbidities, there was a restriction in concomitant therapies, and the functioning on these participants were not assessed. Additional limitations were that these trials were designed primarily to study the efficacy, safety, and tolerability of brexpiprazole for the management of AAD. These issues limit the generalizability of the data obtained from these studies including the use of brexpiprazole among other BPSD symptoms namely apathy, anxiety, psychosis, etc, and among individuals with dementia due to other etiologies including vascular disease, frontotemporal dementia, dementia with Lewy bodies, and Parkinson disease dementia . Brexpiprazole is also not indicated for as needed dosing for treating agitation among individuals with AD. As brexpiprazole is only available in an oral formulation, it cannot be used in situations where intramuscular (IM) or intravenous (IV) dosing is required to manage emergent agitation among individuals with dementia; it is not to be used as prn. In an algorithm from Canada, the authors recommend sequential trials of risperidone, aripiprazole, quetiapine, carbamazepine, citalopram, gabapentin, and prazosin, after completion of a baseline assessment and discontinuation of medications that potentially exacerbate BPSD.9 The second algorithm from the Harvard South Shore program proposes 3 separate algorithms in emergent, urgent, and nonurgent settings. IM olanzapine is recommended as first-line treatment for emergent BPSD. Haloperidol injection is the recommended second choice, followed by a possible consideration for IM benzodiazepine. Oral second-generation antipsychotics (SGAs) aripiprazole and risperidone are recommended as first line treatment in an urgent setting. Prazosin is recommended as a possible next option, and electroconvulsive therapy could be a final treatment option. The authors recommend the following order of medications: trazodone, donepezil and memantine, antidepressants such as escitalopram and sertraline, SGAs, prazosin, and finally carbamazepine for nonemergent agitation. Based on available evidence, where can brexpiprazole be placed in these treatment algorithms for the management of BPSD? Brexpiprazole can possibly be placed along with aripiprazole and risperidone in the Canadian algorithm for sequential medication trials. In the Harvard South Shore algorithm, it can possibly be a first line treatment option in the urgent setting along with aripiprazole and risperidone. We recommend using nonpharmacological management strategies as first line treatment among individuals with BPSD. Additionally, we recommend using pharmacological management strategies including brexpiprazole at the lowest effective doses and for the shortest time-period. Given the consistent lack of efficacy of brexpiprazole doses at 1 mg and below in the clinical trials, time will tell if these lower doses can be effective in a subset of agitated patients with dementia due to AD. We are clearly only beginning to learn about brexpiprazole; the data supports its use in minimizing future episodes of agitation in patients with AD when symptoms of agitation are dangerous and damaging despite the use of non-pharmacological treatments. Furthermore, medications should only be trialed for partially responsive or refractory symptoms of BPSD, and that too in conjunction with nonpharmacological treatments to optimize outcomes among these individuals. Concluding Thoughts Available evidence from 3 high quality, 12-week RCTs indicate that brexpiprazole at 2-3 mg/day, is more efficacious than placebo at reducing agitation among individuals with AD dementia. Some benefits may also be noted with 0.5-1 mg/day dosing of brexpiprazole among these individuals. Additionally, brexpiprazole at these doses is well tolerated among individuals with AD, with no evidence for CVAEs or deaths being attributed to the drug. However, robust data from multiple additional high-quality trials of longer duration using brexpiprazole among individuals with different etiologies for dementia and targeting different BPSD symptoms are needed to cement its place as a definitive first line treatment for the management of BPSD. Otherwise, the use of brexpiprazole will be limited to just the management of agitation among individuals with AD dementia. Note: This article originally appeared on Psychiatric Times .

Key Point: Phase 2 trials suggest extended-release oral ketamine formulations could be alternative to clinic-administered treatment for resistant depression. Phase 2 trials suggest extended-release oral ketamine formulations could provide antidepressant efficacy for patients with treatment-resistant depression (TRD), without the requirement for parenteral administration, or the degree of dissociative adverse effects associated with injectable ketamine and intranasal esketamine. In the phase 2 trial results of R-107 (Douglas Pharmaceuticals) recently published in Nature Medicine1, and of KET01 (Ketabon, collaboration of HMNC Brain Health andDevelco Pharma) presented in May at the American Society of Clinical Psychopharmacology Annual Meeting in Miami,2 both extended-release oral formulations of ketamine were associated with statistically significantly more improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) measure of depressive symptoms than placebo when added to the antidepressant regimens of outpatients whose symptoms were unremitting despite their current, and at least 2 previously tried, antidepressants. In the published randomized placebo-controlled trial with R-107, Paul Glue, MD, of the University of Otago in Dunedin, New Zealand, and colleagues applied a cohort enrichment design; randomizing only the 168 participants who had initially responded to the addition of the investigational agent out of the 231 who had received the agent in the initial open-label, 8-day phase. "We chose this design owing to observations that acute antidepressant clinical trials in non-TRD have high failure rates—inability to separate clinical response between active and placebo arms," Glue et al explained. "Failure rates can be reduced by using an enrichment design, in which nonresponders are excluded, followed by a subsequent relapse-prevention phase in treatment responders," the investigators observed, noting that the design has been found to reduce failure rates to as low as 25%. All participants met criteria for TRD and presented with depressive symptoms that had persisted despite treatment with 2 or more antidepressants. At baseline, all participants had MADRS scores greater than or equal to 20. The cohort included those currently on antidepressants (n=165) and others who had stopped taking, or had their antidepressant discontinued (n=60). Most participants took the R-107 while at home. The trial primary endpoint was statistically significantly greater improvement of MADRS score with drug than placebo at week 13. Secondary outcomes included rates of remission (MADRS total score less than or equal to 10) and response (greater than or equal to 50% reduction MADRS from baseline), and the rates and types of adverse events. In addition to comparing drug effect with placebo, the investigators sought to determine optimal dose of the investigational ketamine formulation, and so participants were randomized to receive double-blind R-107 in doses of 30, 60, 120, or 180 mg or placebo twice weekly for 12 weeks. Glue told Psychiatric Times that the 180 mg dose twice weekly was found to be the closest to a minimum effective dose that could maintain a durable response over 3 months. "This is consistent with trends we have seen in the 6-month pen label safety study and in the compassionate use program, where most patients take 180mg twice a week," he said, adding, "Some patients may benefit from lower doses." The investigators reported that the primary endpoint was met, with a least square mean difference of MADRS score for the 180 mg tablet vs placebo at 13 weeks of -6.1 (05% CI 1.0-11.16). Although the rates of response with R-107 at week 13 were numerically higher, and rates of relapse numerically lower than with placebo, the differences were not statistically significant. Relapse rates during the double-blind phase ranged from 70.6% for placebo to 42.9% with 180 mg of R-107. Glue noted that the primary endpoint of reduction in MADRS with the active agent, and separation from placebo were both statistically and clinically significant. "The minimum clinically important difference in placebo-controlled antidepressant trials using the MADRS varies between 2-4 points, depending on which studies are included in meta-analyses.” "The 6-point difference reported in... (this) study would therefore be clinically significant. The reduction in MADRS at 92 for the 180 mg dose group compared to placebo had a positive P value, which also demonstrates clinical significance. This result informs the dose to be used in phase 3," Glue explained. Glue anticipates that the phase 3 clinical testing will provide sufficient evidence of safety and efficacy to warrant product registration. "In phase 3 we will treat a nonenriched population of patients with TRD, randomized and double-blinded to test or placebo study arms. The primary efficacy endpoint will be MADRS separation between the 2 groups at 5 weeks," he said. The investigators characterized the tolerability of R-107 as "excellent," with no observed changes in blood pressure and minimal reports of sedation. The most common adverse events were headache, dizziness, and anxiety. The occurrences of dissociation were also described as "minimal"; reported by 26 participants (11.6%), with mean dissociation (Clinician-Administered Dissociative States Scale) scores of less than 3. The relatively few reports of dissociation, compared with that associated with ketamine injection, is attributed to a low systemic concentration from the slow-release dosage form. Peter Surman, PhD, Chief Scientific Office, Douglas Pharmaceuticals, and a coauthor of the phase 2 trial report, commented that while he is confident that R-107 will proceed to pivotal registrational clinical studies and ultimately prove safe and effective for home administration, he anticipates that protocols for its use will include specific restrictions and monitoring. "There will likely be restrictions on the quantity of tablets that can be dispensed to a patient. Douglas Pharmaceuticals are anticipating a risk evaluation and mitigation plan for the commercial product focused on mitigation of abuse and diversion of R-107," Surman told Psychiatric Times. "At the same time, we are planning to include elements that will aid treatment adherence such as notification when it is time to take your medication. "We are anticipating that patients who respond to R-107 will self-administer R-107 at home. We expect that many doctors will prefer their patients to come to clinic for their first few doses to determine how they respond, and to monitor safety and tolerability.”

Imagine that you and your traveling companion are touring the ruins of the ancient city of Pompeii. Your historically uninformed companion asks you, “So, what caused the destruction of Pompeii?” You reply that an erupting volcano in 79 AD was the cause, and you go on to describe its features: the expulsion of gases, rock fragments, and molten lava spewing from within the Earth through a vent onto the Earth’s surface. Your companion strenuously objects, “No, no! All you did was describe the observable features of a volcano. I want to know the cause of Pompeii’s destruction!” At that point, you might be puzzled, or a bit annoyed, and reply that you have just identified the cause. Perhaps your friend was trying to pose a deeper question, such as, “What is the cause of volcanoes?” You see the problem: You were answering by invoking 1 level of causal explanation (level 1), whereas your friend was seeking a level 2 causal explanation. The latter is a perfectly legitimate and laudable mode of inquiry—but it remains the case that the destruction of Pompeii was indeed caused by an erupting volcano. There is nothing wrong with the level 1 explanation, incomplete though it is. Often, in science and medicine, that is the best we can do in our present state of knowledge. Now, transposing the argument into the realm of psychiatric diagnosis: We often hear critics argue that psychiatric diagnoses are “purely descriptive” and are “currently defined only by symptoms. That is, they do not refer to any known pathophysiological processes or specific causes.” These critics argue that DSM diagnoses are merely “agreed-upon labels—a kind of shorthand—for describing symptoms…”2 This claim often leads to the charge that psychiatric diagnoses are little more than exercises in circular logic. Why? Because, the argument goes, “a purely descriptive diagnosis cannot be the cause for its symptoms, because it merely describes them: [for example], depression cannot be the cause of depressed mood.” As one critic put it: “Here is the circular logic: How do we know a patient has depression? Because they have certain symptoms. Why are they having these symptoms? Because they have depression.” The argument then expands to allege that “misleading circular causal claims” are potentially harmful, because they may lead the public “to misunderstand the nature of mental health problems.” To be clear: We acknowledge many problems and inadequacies in current DSM-5 psychiatric diagnostic categories, including, but not limited to the DSM’s rejection of diagnostic hierarchies and the problematic heterogeneity of the “mental disorder” construct. Nevertheless, we believe the critics’ circularity argument is ill-founded, misleading, and fallacious. To put it simply, these critics are insisting on a level 2 causal explanation while discounting the (admittedly limited) value of a level 1 causal explanation. We will show presently why diagnoses such as schizophrenia or bipolar disorder, properly made, are neither circular nor uninformative nor lacking in explanatory value, despite the absence of “known pathophysiological processes” as part of their diagnostic criteria. The critical phrase here is “properly made.” First though, we need to clear away some rhetorical underbrush that often obscures the reality of psychiatric diagnosis. Misunderstanding the DSM-5 In our experience, very few US psychiatrists and psychotherapists have taken the time to read the first 25 pages of the DSM-5; ie, the Introduction and Use of the Manual sections. This has led to several mistaken beliefs about the nature, scope, and purpose of the diagnostic categories—and, more important, of the diagnostic process. Firstly, it is simply not the case that the DSM diagnostic categories are defined only by symptoms, understood as the patient’s subjective report of what he or she feels or experiences. On the contrary, many psychiatric diagnostic categories include a variety of signs as part of their criteria set; ie, objective features that can be clinically observed and measured. Examples include significant weight loss (in major depressive episode, anorexia nervosa); psychomotor agitation or retardation; stereotyped movements; distractibility (during evaluation), avoidance of eye-to-eye gaze (in autism); and, of course, numerous objectively measurable deficits in cognitive function, such as impaired recent memory and inability to calculate. We would also classify observable features such as pressured speech, loose associations, and markedly elevated or depressed affect as signs—not symptoms. Secondly, to make a valid DSM-5 diagnosis, the clinician must, yes, must devise a case formulation based on biopsychosocial factors: “…that may have contributed to developing a given mental disorder. Hence it is not sufficient to simply check off the symptoms in the diagnostic criteria to make a mental disorder diagnosis .” In our experience, this DSM-5 requirement is rarely appreciated, much less satisfied, by most US clinicians. This is unfortunate, as the case formulation very clearly provides substantive, explanatory content for the patient’s condition, not merely a recitation of the patient’s symptoms. Finally, the diagnostic process of the DSM-5—apart from its diagnostic criteria—requires a series of rule outs before a final diagnosis can be made. For example, a diagnosis of schizophrenia (criterion E) requires that “…the disturbance is not attributable to the physiological effects of a substance…or another medical condition.” In clinical practice, this requires the psychiatrist to consider and rule out a variety of neurological, endocrine, and infectious conditions, ranging from complex partial seizures to “myxedema madness” (severe hypothyroidism) to tertiary syphilis—causes of so-called “secondary psychosis.” The Circularity Fallacy Critics who claim that psychiatric diagnoses are merely tautologies do not seem to realize that what the patient does not have is just as important, and as informative, as what they do have. As our colleague, Awais Aftab, MD, has pointed out9: “An important thing about diagnoses in medicine is that they don’t just identify something, they also typically exclude other things. For example, to say ‘you have unipolar depression,’ also implies, ‘I don’t think you have bipolar depression.’ To say, ‘you have generalized anxiety disorder’ also means ‘I don’t think your anxiety is secondary to psychotic symptoms.’ In this sense, to say, ‘Your anxiety is caused by generalized anxiety disorder’ can be interpreted as ‘The way I understand your anxiety, it seems to be best described as generalized anxiety disorder rather than major depressive disorder with anxious features, or as panic disorder… We sometimes colloquially use ‘caused by’ with the meaning of ‘this is how it best makes sense’ or ‘this is how it is best described.’” Thus, when we provide the patient with a psychiatric diagnosis , we are simply hypothesizing the existence of a condition that “best makes sense” of the patient’s presenting signs and symptoms. This is very close to what philosophers of science call “inference to the best explanation.” In so doing, we are not making any metaphysical claims, or reifying the condition by positing some essence, substance, or thing residing inside the patient—akin to, say, a burst appendix. Indeed, we recognize that psychiatric (and medical) diagnoses are in large measure socially constructed, but that does not render them in any sense unreal, metaphorical, or tautological. (The concept of health is also socially constructed, but few would argue that health is thereby rendered mythical, metaphorical, or in some sense nonexistent.) Aftab pointed out that there are some diagnoses—perhaps we should call them pseudo-diagnoses—that embody so little descriptive or causal content as to be trivially nonexplanatory. He gives the example of “fever of unknown origin” (FUO). As he put it: “Imagine saying to a patient, ‘Your fever is caused by FUO.’ That makes no sense at all. We know that this specific fever has some unidentified cause, yet that cause is so abstract, so distant, steeped in so much ignorance, that the mere knowledge that there has to be some cause doesn’t make it so that the mere use of the term offers us some causal explanation.” We would argue that the conditions often termed serious mental illnesses do not fit the FUO paradigm. On the contrary, debilitating afflictions such as schizophrenia, bipolar disorder, and melancholic/psychotic forms of major depression have so many external validators—eg, family history, course of illness, characteristic biomarkers, genetic risk factors, and typical response to treatment—that it makes sense to speak of these conditions as causing symptoms. The Substance Abuse and Mental Health Services Administration (SAMHSA) notes: “Bipolar disorder is a brain disorder that causes intense shifts in mood, energy, and activity levels…[and] schizophrenia is a chronic and severe mental disorder that causes people to interpret reality abnormally.” [italics added] There is nothing circular or tautological in SAMHSA’s statements. Essentially, SAMHSA is invoking what we have called level 1 causality, cognizant that we do not know the precise pathophysiological processes that explain bipolar disorder or schizophrenia (level 2 causality). It is just as reasonable to state that “Smith’s command auditory hallucinations and paranoid delusions are caused by his having schizophrenia” as it is to state that “The destruction of Pompeii was caused by an erupting volcano.” The truth of the first claim is not dependent on knowing the etiopathology of schizophrenia. The truth of the second claim is not dependent on any knowledge of shifting tectonic plates in the genesis of volcanoes. Ironically, the paper by Kajanoja and Valtonen demonstrates how the circularity charge collapses under its own weight. They write (footnote 3) that1 “…it is logically circular to say that depression caused the person’s depressed mood, [but] it is not circular to say that depression caused the person to not attend an event.” [italics added] We completely agree. But this is precisely where the circularity charge falls apart. For if the depression itself can cause a person to “not attend an event,” then, ipso facto, depression itself necessarily has causal efficacy; ie, it can itself act on individuals to produce clinical or behavioral effects. Consequently, there is no reason in principle why depression could not also cause the person to sleep poorly, eat poorly, feel guilty or suicidal, or experience psychomotor slowing. And importantly: None of these facts requires us to have a complete or even a partial understanding of the pathophysiology or etiopathology of depression itself. Historical Identification of Disease Critics alleging the circularity of psychiatric diagnosis seem to have limited understanding of the identification of disease states through the ages. Indeed, the history of medicine is replete with examples of diseases first identified long before their underlying physiological mechanisms—their etiopathology—were known. In 1817, when James Parkinson described a well-defined constellation of signs and symptoms he called “the shaking palsy,” he had in fact identified a disease state that caused the patient’s signs and symptoms, and what would later become known as Parkinson disease. Importantly, he did so without knowing anything at all about what caused the disease that would bear his name. It would be absurd, on that basis, to say that Parkinson disease did not exist—or was not the cause of parkinsonian symptoms—until its etiopathology was discovered in the 1950s and 60s. In fact, the French neurologist Jean-Martin Charcot (1825-1893) explicitly referred to the condition as Parkinson disease as early as 1888, decades before its etiopathology was uncovered.13 This fact flatly contradicts the position that just conditions with known and identified pathophysiology count as bona fide diseases. Finally, to be clear: In asserting that some psychiatric diagnoses can legitimately be said to be causative of symptoms, we are not claiming that psychiatric disorders arise solely from constitutional-biological factors. On the contrary: We recognize that powerful psychological and social forces often set in motion a pathological process that results in the manifestation of symptoms. This fact reaffirms the importance of the case formulation and its biopsychosocial orientation. Concluding Thoughts Causality is not a simple, single-layered concept. Aristotle, for example, recognized 4 types or levels of causation, which he called material, formal, efficient, and final. Similarly, in our response to Aftab, we described 3 alternate uses or senses of the term causality. To be sure, our current psychiatric nosology leaves much to be desired. One of us (RP) has quipped that the DSM-5 is “by far the worst diagnostic framework psychiatry could have chosen—except for all the rest.”7 Of course, we all wish that psychiatry were at the point of invoking level 2 causality in our diagnoses, and research continues to yield important knowledge in the realm of pathophysiology. But our incomplete understanding does not mean that our diagnostic categories are merely short-hand labels for a bunch of symptoms—or empty, acausal tautologies. When arrived at carefully, including a biopsychosocial case formulation, a psychiatric diagnosis can explain a great deal about the patient’s presenting problem and remains the royal road to effective treatment. Note: This article originally appeared on Psychiatric Times .

Keypoint: Results from a new study on psychiatric bed supply in the U.S. shows no growth. Psychiatric hospitalization for youth is an important resource for those with serious mental health needs. A new study finds that the number of psychiatric beds for youth varies widely between states. The study also finds no increase in the number of beds recently, despite added need. Increased treatment capacity for acutely suffering children and adolescents is greatly needed. As the number of youth who report significant mental health problems continues to rise, it would be at least somewhat reassuring to know that the capacity to treat these problems is also rising. Unfortunately, when it comes to youth needing psychiatric hospitalization, that does not seem to be the case, particularly if you live in certain states. A recent study published in the journal JAMA Pediatrics used survey data to look at trends in pediatric inpatient psychiatric bed capacity across time and across the country. Psychiatric hospitalization is typically the last resort and highest level of care that can be offered to youth struggling with mental health problems and is usually reserved for those who are in imminent danger to themselves or others due to suicidality, psychosis, aggression, or weight loss (for people with eating disorders). If a hospital bed is not available, some of these youth are compelled to stay for long periods of time in emergency departments to wait for one while others get “discharged” home to their outpatient clinicians (if they have them) to manage as best they can. Can you imagine this kind of system for people who have heart attacks? The study had two main findings. First, there was quite a bit of variability in bed availability by state. The overall number of beds across the country was 15 per 100,000 youth, but this number ranged broadly from a low of 0 (Alaska) to a high of 75 (Arkansas). A color-coded map indicated that some of the lowest rates were in the west, in states such as Oregon, California, and Wyoming, while higher numbers were scattered across states like Alabama, Oklahoma, Missouri, and Maine. Second, looking at the relatively short interval between 2017 and 2020, there were no significant increases or decreases in the total number of hospitals that offered inpatient psychiatric care for youth or the total number of beds. Just 6 percent of U.S. hospitals offered inpatient psychiatric care for youth (including hospitals that do only psychiatric care). For those of us who work daily in pediatric mental health , these numbers confirm impressions we have had for many years—namely that resources for children with severe mental health problems are woefully inadequate and put youth and their families at significant risk. Further, the practice of trying to treat these youth in outpatient and community settings is likely contributing to the burnout and staffing shortages seen across many mental health clinics. Why are there so few hospitals offering inpatient child psychiatry care? It shouldn’t shock folks that one of the main drivers is economics, as these facilities tend to be very labor-intensive and much less profitable than, for example, surgical services or radiological testing. There is also, sadly, a great deal of infighting within the mental health community itself about where to spend the few dollars available. There certainly is an argument to be made that, rather than building more psychiatric units, we should invest more in early intervention and preventative services that can make an impact before a youth develops a severe mental health condition in the first place. This sounds great but, at the same time, we need to accept the reality that serious psychiatric disorders, just like serious medical conditions, are going to develop for some no matter how much prevention we offer, and these youth deserve the same level of accessible care as those who develop major medical conditions like cancer. Hopefully, studies like these will provide some of the hard information we need to advocate for a healthcare system that truly values physical and mental health conditions equally. We sorely need increased mental health resources at all levels: preventative, community, and acute care if we are serious about reversing the troubling trends we are seeing with our youth today. Note: This article originally appeared on Psychology Today .

Life is journey. We all go through ups and downs. Sometimes you feel stuck but you must shake off the dust and think of an alternative of seeking joy, content, and wisdom. Gratitude - The struggles can alter your perspective on life. I always feel grateful because there are so many people that struggle everyday in dire circumstances, no food, water, shelter. I have no never experienced that type of suffering. It’s important to always take a Birds Eye perspective on life and count each and every one of your blessings. Try to uplift your heart and soul as you only have one life!

Keypoint: Cannabis use during adolescence can profoundly impact brain development. SPECIAL REPORT: ADDICTION Case Study “Valerie” is a 17-year-old adolescent girl living in an urban area. She works evenings at a department store and babysits to help her family make rent for the month. She avoids bringing friends home, as her parents are often physically and verbally abusive to each other. Two years ago, a friend introduced her to synthetic cannabis vaping. These products seemed cooler than nicotine, and she felt she was self-medicating her stress. After all, medical cannabis was listed on her state’s compassionate registry to treat posttraumatic stress disorder, so she believed it could not be that risky. To Valerie, vaping was not even real cannabis use . One day after school, her friend raced through the halls and shoved a vape pen in her hand. She was stunned. The school principal found Valerie still holding the vape pen in her hand. Valerie was asked to show the principal the contents of her backpack, which included another cannabis vape pen. Valerie was suspended and transferred to an alternative school. At the new school, she avoided the other students, as she considered them troublemakers. Valerie continued to go on walks by herself late at night while her parents fought and would vape cannabis. Over the course of the school year, Valerie withdrew further and remained in her room, not showering or brushing her teeth consistently. She presents now to psychiatry clinic with her mother after the school notified child protective services (CPS) about school truancy. Valerie’s experience with cannabis is not unusual. Most teenagers do not know the contents of the vape products they consume. Prevalence is also high in Valerie’s age group. The Monitoring the Future survey of 2023 found that the percentage of youth using marijuana in the last year was 29% in 12th grade, 18% in 10th grade, and 8% in 8th grade. Similarly, the percentage of 12th graders vaping marijuana remains at about 20% and has not varied since 2019. Vaping marijuana serves as a way for users to avoid detection by adults, and/or it could be a way for users to supplement their combustible marijuana use. Cannabis Use in Adolescence Cannabis use during adolescence can profoundly impact brain development. The brain develops until age 25, with evolution in gray and white matter. In adolescence, gray matter diminishes while white matter increases, impacting cognitive development. Synaptic pruning takes place, promoting learning and brain efficiency. The prefrontal cortex also develops during adolescence and is responsible for the development of impulse control and appropriate social behavior. Substance use, including cannabis use, may lead to loss of gray matter in areas such as the medial prefrontal cortex, compromising decision-making skills and impulse control. In addition, cannabis may negatively affect other cognitive domains, particularly learning, memory, attention, and working memory. Regular cannabis use is also associated with amotivational syndrome, defined by apathy and decreased goal-directed behavior. These effects may result in decreased occupational achievement, such as college matriculation, among adolescents who use cannabis regularly, leading to significant economic costs to the general population. All of these factors could be pertinent to teenagers like Valerie. Among the risks of cannabis are its detrimental effects on mental health, including the bidirectional link of cannabis use with psychosis and an increased risk of comorbid substance use disorders (SUDs). In patients with preexisting psychosis, cannabis is associated with worse health outcomes and greater disease severity. In adolescents, cannabis is also believed to affect synaptic plasticity and N-methyl-d-aspartate receptor–mediated memory formation. Since adolescence to early adulthood is the time frame associated with the onset of schizophrenia, this can be a particularly fraught period. Psychosis The link between cannabis use and the onset of psychosis has long been an area of interest and speculation. Observational studies have consistently pointed to an association between cannabis use and schizophrenia; however, the nature and mechanisms of this relationship remain poorly understood. One hypothesis is that tetrahydrocannabinol (THC) may augment psychosis via alteration of dopamine and glutamate activity. Of note, unique individuals may respond differently to cannabis, suggesting that genetic and epigenetic factors may impact one’s susceptibility to psychosis. Several plausible genes and risk factors for cannabis-induced psychosis are listed in the Figure. A genome-wide association study of 184,765 participants found 8 unique single nucleotide polymorphisms associated with lifetime cannabis use. The study found genetic overlap in risk for cannabis use and schizophrenia. Another study used a Mendelian genetic analysis to find a causal relationship of cannabis use with increased schizophrenia risk (OR, 1.37). Inconsistencies and Safety The risks of modern cannabis products are exacerbated by inconsistencies in product composition, such as cannabinoid concentrations, and lack of US Food and Drug Administration oversight. Variations in THC content of cannabis products may be influenced by factors including cultivation methods, processing techniques, and storage conditions. Due to lack of consistent regulation, cannabis products may contain incorrect labeling and be of varied potency, contributing to heterogeneous effects and safety problems. Additionally, the increased popularity of synthetic cannabinoids has led to dangerous consequences. Synthetic cannabinoids are artificial compounds that have effects similar to those of THC but with significantly greater potency. Synthetic cannabinoids, sometimes known as Spice or K2, act as full agonists of cannabinoid receptors—unlike THC, which is a partial agonist. These products are difficult to detect due to structural diversity and rapid metabolism and are associated with severe intoxications and even fatalities. Highly potent synthetic cannabis may therefore promote development of psychotic symptoms. Reduced Perception of Harm The public may tend to focus on the medical benefits of cannabis products while underemphasizing its potential harms. The belief that cannabis is a medicine has likely led to increased adoption. Several formulations have been developed as medical cannabis products, with some evidence supporting therapeutic benefits in specific conditions. Medical cannabis products vary in their composition and include dronabinol (THC), nabilone (synthetic cannabinoid similar to THC), cannabidiol (CBD), and nabiximols (cannabis-derived extracts with equal parts THC and CBD). These products collectively have been shown to have benefits in epilepsy, chronic pain, spasticity, appetite, Parkinson disease, sleep, SUDs, and Tourette syndrome. However, these products can have adverse effects that may limit their use. On May 16, 2024, the US Department of Justice proposed transfer of marijuana from Schedule I of the Controlled Substances Act (CSA) to Schedule III of the CSA. While Schedule I drugs are those with no medical use that cannot be prescribed by a physician, Schedule III drugs are those with medical use and low to moderate potential for physical and psychological dependence. A change in scheduling would not legalize medical or recreational use of marijuana under federal law, but it would instead subject marijuana and cannabis-derived products to the Federal Food, Drug, and Cosmetic Act. Rescheduling of cannabis undoubtedly would have an impact on perception of harm posed by cannabis use, as it would then be researched for potential medical properties. Already, cannabis is approved for medical use in at least 38 states. In some states, it is also decriminalized or even legalized. The contradiction between state and federal laws concerning cannabis use can be confusing. Case Study Continued For youth like Valerie, cannabis can be life-changing. By the end of the case study, Valerie begins to demonstrate symptoms of prodromal schizophrenia and/or severe depression, and it is highly possible that these disorders are cannabis induced. With first the transfer to an alternative school and then isolation followed by issues of absenteeism, Valerie faces educational prospects that seem grim. However, linkage to child psychiatry through CPS and addiction-focused care engagement can improve her prognosis. Concluding Thoughts It is unsurprising that the perceived risk of harm from cannabis has decreased over time and that the concept of cannabis as a medicine is gaining traction. Studies suggest that perception of cannabis-related risk decreased among all adult age groups from 2002 to 2019. Interestingly, illicit cannabis use and the prevalence of cannabis use disorders increased significantly more in states that passed medical marijuana legalization laws than in states that did not, illustrating the impact of politics on public health. This is relevant, as adolescents are particularly vulnerable while their brains are undergoing maturation until young adulthood. They may be unaware of both the general harms posed by cannabis and the true composition of the substances they are vaping and consuming. Furthermore, chronic cannabis use is associated with increased schizophrenia risk, and schizophrenia has its onset in early adulthood. Unfortunately, addiction and mental health services are not accessible to all adolescents and young adults. In fact, per the American Academy of Child and Adolescent Psychiatry , only half of children and adolescents with general diagnosable mental health problems, let alone those with SUDs, receive the care they need.14 It is thus even more important that psychiatrists and primary care providers screen for cannabis use and cannabis use disorders and stay abreast of cannabis-related legislation that can impact patient health and safety. The cost is too great not to. Note: This article originally appeared on Psychiatric Times .

Keypoint: Diagnostic criteria are not the same as the disorders they identify. This article is a response to the article “ Descriptive Labels Are Not Causes, No Matter How Hard You Try: A Response to Pies and Ruffalo ” by Jani Kajanoja, MD, PhD, and Jussi Valtonen, PhD. We thank Jani Kajanoja, MD, PhD, and Jussi Valtonen, PhD, for their thoughtful and vigorous rejoinder to our article. While we have many disagreements with their thesis, we know that our Finnish colleagues share with us the wish to provide the best possible care for our patients. We now wish to respond to some of the salient claims and conclusions in their rejoinder, with the caveat that we are providing a severely abbreviated and selective response. We hope that, in due course, we will be able to address their arguments more comprehensively. We believe that at the heart of this debate are at least the following questions: (1) What is meant by the term diagnosis in psychiatry? (2) How do diagnostic criteria (as in DSM-5) relate to clinical conditions? (3) What is the nature of causality in psychiatry? (4) What causal weight and explanatory power does a psychiatric diagnosis carry? (5) What constitutes circularity or tautological reasoning in the way psychiatric diagnoses are formulated? First, however, we would like to clear up a few confusions and misapprehensions arising from our article. Our volcano analogy has been misunderstood by several readers, including Drs Kajanoja and Valtonen (henceforth, Drs K & V). In truth, the vignette could have been presented more clearly. As most readers will recall, analogies are formally stated as “A is to B as C is to D.” In our volcano vignette, the corresponding terms would be: (A) visible, surface manifestations of a volcano are to (B) the deep structure of volcanos (underground movement of tectonic plates) as (C) clinical manifestations of psychiatric illness (hallucinations, delusions, etc) are to (D) the etiopathology/pathophysiology of the illness. Our aim was primarily to show that we do not need to know the deep structure (ie, etiology) of some event, condition, or phenomenon—whether volcano or schizophrenia—to assert that the entity has causal efficacy, (ie, that it can make things happen). We were assuredly not analogizing or likening a psychiatric diagnosis or disorder to a volcanic eruption—though, quite frankly, any clinician who has witnessed a severe, uncontrolled manic episode might beg to differ! In any case, the analogy is not crucial to our central argument, which is essentially this: diagnostic criteria such as those in DSM-5 must not be confused with the clinical condition to which the criteria point. We believe that this confusion permeates nearly all the arguments put forth by Drs K and V, and leads them to draw erroneous conclusions regarding the causal weight and explanatory power of a psychiatric diagnosis. The diagnostic criteria for a given DSM disorder/disease are indeed descriptive—nobody disputes this—but they are not merely descriptive, as Drs K and V seem to believe. The diagnostic criteria are also indicial, defined as “of, pertaining to, or resembling…an index finger.”1 The diagnostic criteria point to something external to themselves; namely, to an actual clinical state of affairs or condition embodied in the patient. It is trivially obvious that it is not the diagnostic criteria that cause the patient’s symptoms—and, of course, nobody in clinical psychiatry would claim that. The criteria are merely inert words in a manual, or concepts in the heads of DSM committee members. Rather, it is the clinical condition to which the diagnostic criteria point that causes the patient’s symptoms. As our colleague, Awais Aftab, MD, has put it in his elegant deconstruction of the issue (in which he specifically critiques the paper by Drs K and V): “The diagnostic criteria in official manuals such as the DSM and ICD are simply indices, as a way of pointing towards and recognizing the existence of a state, a condition, a syndrome, a property cluster, etc. They do not constitute the condition itself (see Kendler 2017). It is not the case that “depression” is nothing more than the symptom criteria in diagnostic manuals. Rather, the criteria are a way for us to recognize the condition of depression.” In more poetic terms, as a Buddhist saying puts it, “A finger pointing at the moon is not the moon.” We believe that Drs K and V repeatedly confuse the indicial function of DSM diagnostic categories with the conditions to which they point. To borrow 2 terms from the linguist Ferdinand de Saussure, they confuse the signifier with that which is signified. Psychiatric Diagnosis Requires More Than Symptom Lists The following is an example of how we see things quite differently from Drs K and V. Our 2 colleagues present the following statement: “Alex is experiencing depressed mood, loss of pleasure, insomnia, weight gain, and psychomotor agitation.” Drs K and V present this as a kind of prototype of psychiatric diagnoses, which they define as, “…labels for situations in which given diagnostic criteria are met.” They contrast the above statement with what they call a “causal claim,” such as “Alex is experiencing depressed mood because their partner wants a divorce.” With all due respect to our Finnish colleagues, we think they have grossly oversimplified—indeed, trivialized—the diagnostic process in psychiatry. To put it bluntly: anybody with keen eyes and ears, and 15 minutes to spare, could easily determine that a friend or family member has depressed mood, loss of pleasure, weight gain, and visible agitation. That is not diagnosis! And it is a far cry from diagnosing, say, the depressed phase of bipolar I disorder, which requires a holistic synthesis of the patient’s developmental history; course of illness; relevant medical history; family history; pertinent medical rule-outs; mental status exam, etc. Once again, in our view, Drs K and V seem confused about the difference between raw diagnostic criteria and the actual clinical conditions to which the criteria point. A psychiatric disorder is a gestalt, and is: “…not identical to a mere itinerary of parts in isolation. This is because a whole also includes the interactions and relationships between parts that often generate novel properties.” Moreover, “An accurate descriptive diagnosis connects an individual person in the clinic with a large body of clinical and scientific information.”2 This includes validators such as “…genetics, family history, personality traits, risk factors, course of illness, [and] treatment response.”2 These supportive data are almost never captured in the formal diagnostic criteria. In sum: Drs K and V minimize or entirely negate the causal weight that inheres in a diagnosis of at least some of the most serious psychiatric disorders, such as bipolar I disorder, schizophrenia, obsessive-compulsive disorder, and others. (To be sure: not all psychiatric diagnoses possess this degree of causal weight or number of validators—a topic for another time). Regarding Circularity and Causal Weight In fairness to Drs K and V, they have now clarified that they did not claim that: “…psychiatric diagnoses, in and of themselves, reflect circular reasoning…There is nothing wrong with descriptive diagnoses as long as their descriptive nature is made clear. Our criticism was directed towards falsely invoking a psychiatric diagnosis as an explanation for the symptoms, which is a logical fallacy.” We appreciate the clarification, but we do not agree that psychiatric diagnoses have no explanatory power or content at all, as Drs K and V imply. Furthermore, we find no basis in logic—or in clinical realities—that would show descriptive and explanatory to be mutually exclusive or disjunctive properties of a set of diagnostic criteria. Thus, the DSM-5 criteria for bipolar I disorder for example are indeed descriptive—no one disputes that—but are not merely descriptive. They also point to a real clinical condition that carries causal implications and explanatory weight. Accordingly, bipolar I disorder is reasonably held to be the causeof a patient’s manic or depressive symptoms. That these symptoms are also part of the diagnostic criteria for bipolar I disorder does not in any way confer circularity on the causal claim. As Dr. Aftab puts it: “There is a perfectly legitimate sense in which depression can be said to affect how people think, feel and act, and in my view, it is misleading and inaccurate to assert otherwise.” Crucially, we would add this: anything that can affect something else has causal efficacy. All this is not to say that the major DSM diagnostic categories fully explainthe patient’s condition. It is very rare that we ever fully understand all the causes of the patient’s clinical condition, which may number in the thousands, often including many psychodynamic, psychosocial, and characterological factors. But the DSM diagnosis is at least the beginning of a causal explanation, as Aftab points out.2 Finally, we agree with Drs K and V (and with Aftab) that there is some risk of reifying a psychiatric diagnosis—as if it were a physical object or material thing sitting inside the patient and mechanically or physiologically causing symptoms. But this risk can be mitigated by using—and discussing with the patient—the biopsychosocial approach embodied in the case formulation, which (to repeat) is a mandatory part of the DSM diagnostic process. Much more could be said in response to Drs K and V, but we will need to defer that for now. We appreciate the opportunity to present our views, and we hope that readers will find this exchange stimulating and useful. Note: This article originally appeared on Psychiatric Times .

Advocacy groups for patients with neurologic disorders have become a common feature in the landscape of drug and device development and federal research funding allocation. On Capitol Hill, advocates have racked up some impressive legislative wins that aim to set a federal agenda for developing new medications. At the US Food and Drug Administration (FDA), advocacy groups played a significant role in several recent high-profile and controversial approvals for drugs for Alzheimer's disease, Duchenne muscular dystrophy (DMD), and amyotrophic lateral sclerosis (ALS). Such gains suggest these groups are growing in power. But with these wins come questions about whether large advocacy organizations — some of which receive significant industry funding — wield too much influence. "You need to think very carefully about how you open these processes up to greater patient involvement," Matthew S. McCoy, PhD, assistant professor of Medical Ethics and Health Policy at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, told Medscape Medical News. It's important not to "end up with a situation where it's the best-connected, the most well-resourced, the most-savvy patient organizations that are able to exercise outsize influence," he added. Just because a group has deep pockets does not mean that its priorities align with the disease burden. And not every patient population is represented by a professionalized patient advocacy organization, McCoy noted. "There is the potential for the rich to get richer," he said. A Seat at the Table Long ago, the FDA and the National Institutes of Health (NIH) began giving patients a seat at the table, in part because of the path blazed by AIDS activists in the late 1980s and early 1990s, said McCoy. Patient advocacy is often visible during FDA advisory committee meetings. The agency usually allows an hour, sometimes more, for members of the public to express support or concerns about the product being reviewed. Patients and caregivers — often aided by advocacy organizations — also submit hundreds, sometimes thousands, of letters before a product review. The Alzheimer's Association spent years advocating for approval of the anti-amyloid agent aducanumab (Aduhelm, Biogen/Eisai). In 2020, the organization urged patients and caregivers to submit written and oral testimony to the FDA advisory panel that was reviewing the drug. Despite patients' pleas, the panel ultimately declined to support the drug's approval, citing safety concerns and limited evidence of efficacy. As controversy swirled around the medication — which had the potential for life-threatening brain swelling — advocates continued to apply pressure. Going against the expert panel's recommendation, in June 2021, the FDA granted accelerated approval prompting three of the panelists to resign in protest. Aducanumab's initial price — $56,000 a year — was seen as a major threat to the viability of Medicare. Still, the Alzheimer's Association stood behind the decision to approve the drug. But by early 2024, Biogen/Eisai said they would stop selling aducanumab, citing other priorities. Once again patient advocates showed up in March 2022 when the FDA advisers were reviewing Amylyx Pharmaceuticals' ALS drug Relyvrio (sodium phenylbutyrate and taurursodiol). Trials had showed limited efficacy, but patients testified they would accept greater risk for a chance to be treated with the drug. As reported by Medscape Medical News, the committee ultimately voted against approval. Six months later, the FDA approved Relyvrio anyway. In April 2024, Amylyx removed Relyvrio from the market following phase 3 trial results that showed no difference between the treatment and placebo. The drug manufacturer Sarepta Therapeutics, which develops treatments for genetic conditions such as DMD, has a history of working with — and funding — patient advocacy groups. The company encourages nonprofits to apply for grants or sponsorship on its website. As previously reported by Medscape Medical News, at a 2016 advisory committee, when Sarepta was seeking approval of its first DMD therapy eteplirsen (Exondys 51), 52 speakers, most from patient advocacy groups, pleaded for the drug's approval. When the panel voted no, Sarepta mobilized families to pressure the agency. Exondys was eventually approved. In June, Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, unilaterally gave final expanded approval to Sarepta Therapeutics' gene therapy Elevidys for DMD. Marks overrode his own FDA reviewers, who said the product lacked substantial evidence of efficacy. He acknowledged the drug had not met its primary endpoint but said he found secondary and exploratory endpoints "compelling" and cited an unmet medical need. In an opinion piece in The Washington Post, Aaron Kesselheim, MD, JD, MPH, the director of the Program on Regulation, Therapeutics, and Law at Brigham and Women's Hospital, Boston, and a former member of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee, questioned the approval stating that it undermined both public trust and manufacturers' incentives to do the hard work of proving effectiveness. Patient Voices the 'Secret Sauce' Drugmakers aren't alone in seeing the value of having patients speak directly to government entities. When The Michael J. Fox Foundation wanted to gather co-sponsors for the National Plan to End Parkinson's Act, which President Joe Biden signed into law in July, it recruited and trained patients and caregivers for congressional meetings, said Ted Thompson, senior vice president of public policy at the foundation. Having those individuals "making the personal case for how this disease affects their families…was really the secret sauce," in garnering a large number of co-sponsors and getting legislation signed into law within 2 years of its introduction, Thompson told Medscape Medical News. ALS advocacy groups launched a similar campaign to secure passage of the Accelerating Access to Critical Therapies for ALS Act in 2021. Both pieces of legislation seek to set a federal agenda for developing new therapies in neurodegenerative diseases, in part by directing the FDA and NIH to fund research, engage patients more directly, and form public-private partnerships and councils to spur innovation. But some said patient advocates are still coming far too late to the party. "By the time you hear from patient groups at the meetings at the FDA, often the best opportunities for their input are long past," Leah Zoe Gibson Rand, DPhil, a research scientist with the Program on Regulation, Therapeutics, and Law at Brigham and Women's Hospital, told Medscape Medical News . There should be more focus on the patient perspective earlier in drug development and trial design, Rand added. "There are some things that the patient voice could uniquely tell the agency," said Holly Fernandez Lynch, JD, associate professor of Medical Ethics and Health Policy at the Perelman School of Medicine, University of Pennsylvania. Patients can give insight on what it means to live with a disease, what symptoms are particularly burdensome, and which endpoints matter, Lynch told Medscape Medical News. But, she said, "listening to the patient voice cannot mean that FDA just steps aside and lets anything on the market that patients are willing to try." She noted that individuals "who lack good treatment options have a very good reason to want to try things that haven't yet been proven." If the FDA allows drugs on the market just because patients are willing to try, "5 or 10 years down the road, it's not at all clear that we would end up with drugs that are better, or drugs that work, or drugs that we know anything more about," said Lynch. Does Taking Industry Money Equal Conflicts of Interest (COIs)? Many patient advocacy organizations receive funding from drug companies, medical device makers, or other industry sources, but they aren't always transparent about how much or from which companies, according to studies. As reported by Medscape Medical News , the Alzheimer's Association continued to push for the approval of aducanumab, even as the group received millions of dollars from the drugmakers. The association was accused of failing to disclose the potential conflict. It still lobbied for approval, even after the FDA advisers in 2020 voted against the drug. It is not uncommon for individuals who speak in favor of a product's approval to receive money for transportation and/or lodging from the drug's manufacturer. In 2018, McCoy and colleagues reported in JAMA Internal Medicine that between 2009 and 2017, a quarter of the speakers at the Anesthetic and Analgesic Drug Products Advisory Committee had COIs, mostly from industry, and that they were not disclosed in approximately 20% of the instances. In a 2017 study of 104 large patient advocacy organizations published in The New England Journal of Medicine, McCoy and colleagues reported that 83% had received funds from industry. At least 39% had a current or former industry executive on the governing board, and 12% had a current or former industry executive in a board leadership position. Of the 104, 38 were focused on cancer and 13 on neurologic conditions. Of these, only 12% had published policies for managing institutional COIs. McCoy emphasized the industry's reliance on partnering with patient groups, particularly during FDA advisory committee meetings. "The sponsors wouldn't be paying for patients to show up and give these testimonies if they didn't think it made a difference," he said. "The audience isn't just panel members; it's also agency officials and maybe elected officials as well," McCoy said. "The Fox Foundation, with a $300 million-plus budget, gets about $5-$6 million a year from industry," said Thompson. The money is earmarked for the organization's Parkinson's Disease Education Consortium; none goes toward advocacy. And, he said, "the foundation has never specifically endorsed a product or device." When organizations that receive industry funding back a particular product, "it does appear to be [a conflict], and whether it is an actual one or not, appearances sometimes are all that matter," said Thompson. Lynch said accepting industry money "is a really significant conflict." While advocates might need that money to fund advocacy efforts or make grants to advance research priorities, the acceptance might hinder willingness to demand evidence or to complain about a product's price tag, she said. "You don't want to bite the hand that feeds you, right?" Both McCoy and Lynch said patient groups — and individual patients — should at a minimum disclose industry funding, especially when speaking at an advisory committee. Federal agencies and members of Congress actively seek patient input when considering legislation and funding priorities. But the individuals testifying at an advisory committee aren't likely to represent all patients, and there's a danger that they are just the loudest voices, said McCoy. "We need to think more carefully about how we actually understand the preferences of a big, diverse patient population," he said. Lynch agreed. Within the ALS community, "a lot of people who take different perspectives than some of those that are the leading voices, get shouted down, and their voices get drowned out, and they get attacked on social media," she said. The group may be at the table, "but they're just one voice at the table," she said. Note: This article originally appeared on Medscape .

Smartwatches, smartphones, and other wearable devices are transforming how we track our physical health and behavior. Researchers are also exploring whether these devices might provide insights into our mental health, with the goal of developing AI tools that can help identify when people need mental health support or professional care. However, research supported by the National Institute of Mental Health suggests that AI tools built on smartphone data may struggle to accurately predict clinical outcomes like depression in large and diverse groups of people. What did the researchers do? Lead author Daniel Adler of Cornell University and colleagues from Northwestern University Feinberg School of Medicine, Weill Cornell Medicine, and Michigan Medicine analyzed behavioral data from 650 people, collected via their smartphones. While the study was larger and more diverse than previous studies, participants were primarily female, White, middle to high income, and between 25 to 54 years old. The smartphone data included behavioral measures related to mobility, phone usage, and sleep. Participants also completed the PHQ-8, a standard self-report measure of depression symptoms. Drawing from recent studies, the researchers developed AI models that analyzed the smartphone data to produce a depression risk score for each participant, indicating the likelihood of clinically significant depression. The researchers then assessed the reliability of the models by identifying age, race, sex, and socioeconomic subgroups for whom the model predictions were less accurate. What did the researchers find? Overall, the best-performing AI model proved to be only moderately accurate in predicting who had clinically significant depression (as measured by the PHQ-8). While the model identified some patterns, it consistently underperformed for specific groups of people. For instance, the researchers found that the model was skewed toward identifying people as having a higher risk of depression if they were older, female, Black or African American, low income, unemployed, or on disability. On the other hand, the model was skewed toward identifying people as having a lower risk of depression if they were younger, male, White, high income, insured, or employed. To better understand these results, the researchers examined how the AI model associated different behaviors with depression risk. For example, the AI model predicted that higher phone usage in the morning was generally associated with lower depression risk. However, when the researchers looked at the data, they found this association did not hold across all age subgroups. While higher morning phone usage was linked with lower depression risk for young adults (ages 18 to 25 years), it was associated with higher risk for older adults (ages 65 to 74 years) The AI tool also predicted that measures of increased mobility, as captured by GPS, were generally associated with lower depression risk . However, the underlying data showed these associations did not hold across all income-related subgroups. For people who came from low-income households, who were on disability, and who were uninsured, greater mobility was associated with higher depression risk. What do the findings mean? The findings highlight the challenges of using AI models built on smartphone data to predict mental health outcomes across a large, diverse group of people. When associations between people’s behavioral patterns and their mental health outcomes vary across demographic groups, AI models may be more likely to make incorrect predictions for some of those groups, leading to skewed results. According to the researchers, the results underscore the importance of developing AI tools using data from people whose behavioral patterns are similar to those of the intended population. One way to increase the effectiveness of AI models may be to develop predictive models that are focused on smaller, more targeted populations. The researchers note that their study focused on associations between behaviors and depression risk across individuals. It is possible that personalized models—models built on behavioral data from one person over time—may be able to predict individual depression risk more accurately. Note: This article originally appeared on Medscape .

New research provides more evidence that inflammation may contribute to the development of psychiatric disorders and suggests that measuring certain inflammatory biomarkers may aid in the early identification of individuals at high risk. Using large-scale datasets, researchers found that elevated levels of certain inflammatory biomarkers, particularly leukocytes, haptoglobin, and C-reactive protein (CRP), and lower levels of anti-inflammatory immunoglobulin G (IgG) were associated with an increased risk for psychiatric disorders. Individuals with psychiatric disorders had persistently higher levels of leukocytes and haptoglobin, as well as persistently lower levels of IgG, than controls during the 30 years before diagnosis, which suggest "long-term processes and may aid in the identification of individuals at high risk," the researchers wrote. In addition, a higher level of leukocytes was consistently associated with increased odds of depression across different methods of mendelian randomization (MR) analysis, "indicating a possible causal relationship between leukocytes and depression," they said. The study, with first author Yu Zeng, MSc, with the Mental Health Center and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China, was published online on August 21 in JAMA Psychiatry . Inflammatory Phenotype Individuals with psychiatric disorders have been found to have elevated levels of inflammatory biomarkers, but prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk. To investigate further, Zeng and colleagues employed a "triangulation" approach consisting of an exploration dataset of 585,279 adults in the Swedish AMORIS cohort with no prior psychiatric diagnoses and a measurement of at least one inflammatory biomarker, a validation dataset of 485,620 UK Biobank participants, and genetic and MR analyses using genome-wide association study summary statistics. In the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11), haptoglobin (HR, 1.13), or CRP (HR, 1.02) had an elevated risk for any psychiatric disorder. In contrast, there was an inverse association for IgG level (HR, 0.92). "The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank," the authors reported. In trajectory analyses, compared with controls, individuals with psychiatric disorders had higher leukocyte and haptoglobin levels and lower IgG up to three decades before being diagnosed. The MR analysis suggested a possible causal relationship between leukocytes and depression. The underlying mechanisms for the associations of serum leukocytes, haptoglobin, CRP, and IgG with psychiatry disorders remain unclear. "Possible explanations mainly include blood-brain barrier disruption, microglia activation, neurotransmission impairment, and other interactions between inflammations and neuropathology," the researchers wrote. A related paper published online on August 21 in JAMA Psychiatry looked at trajectories of inflammation in childhood and risk for mental and cardiometabolic disorders in adulthood. This longitudinal cohort study found that having persistently raised levels of inflammation as measured by CRP throughout childhood and adolescence, peaking at age 9 years, were associated with an increased risk of developing psychosis disorder, severe depression, and higher levels of insulin resistance. Support for Precision Psychiatry This study is "another strong indication that inflammation plays a role in depression," Andrew H. Miller, MD, professor of psychiatry and behavioral sciences and director of the behavioral immunology program, Emory University School of Medicine, Atlanta, Georgia, who wasn't involved in the study, told Medscape Medical News. "The work adds to the mounting data that there exists an inflammatory phenotype of depression that may uniquely respond to treatment and may have a unique trajectory," Miller said. "Eventually the field will want to embrace this novel phenotype and better understand how to recognize it and treat it. This is our entrée into precision psychiatry where we identify the right treatment for the right patient at the right time based on an understanding of the underlying cause of their illness," Miller added. Also weighing in, Alexander B. Niculescu III, MD, PhD, professor of psychiatry and medical neuroscience, Indiana University School of Medicine, Indianapolis, cautioned that these biomarkers are "very nonspecific and are likely related to these subjects that go on to develop psychiatric disorders having more stressful, adverse life trajectories." "There are better, more specific blood biomarkers for psychiatric disorders already available," Niculescu told Medscape Medical News . His group recently reported that a panel of blood-based biomarkers can distinguish between depression and bipolar disorder, predict a person's future risk for these disorders, and inform more tailored medication choices. Notably, they observed a strong circadian clock gene component to mood disorders, which helps explain why some patients' conditions become worse with seasonal changes. It also explains the sleep alterations that occur among patients with mood disorders, they said. Note: This article originally appeared on Medscape .

Note: Some people become upset when reading the list below. Only read it if you feel safe to do so, and stop if it is too upsetting. People with PTSD and substance abuse may be prone to boundary problems, such as the following: Extremes: trusting too much or too little; isolation or enmeshment. Relationships that are brittle (easily damaged, fragile). Tolerating others' flaws too much; doing anything to preserve the relationship. Use of substances as an attempt to connect with others. Avoiding relationships because they are too painful. Overcompliance at times; too much resistance at other times. Always being the one to give. Spending time with unsafe people. Not seeing the hostility in others' words or actions. Being overly angry, with a hair-trigger temper; often ready to "blow up." Difficulty expressing feelings; expressing them in actions rather than words (acting out). May respect men for being "strong" and disrespect women for being "weak." Feeling that one can never get over a loss; not knowing how to mourn; fear of abandonment. Difficulty getting out of bad relationships. Confusion between fear and attraction (i.e., feeling excited when it is really fear). it Relationships with people who use substances. Living for someone else rather than yourself. Manipulation: guilt, threats, or lying. Reenactments: getting involved in repeated destructive relationship patterns (e.g., recreating the trauma roles of abuser, bystander, victim, rescuer, or accomplice). "Stockholm Syndrome": feeling attachment and love for the abuser. Wanting to be rescued; wanting others to take responsibility for the relationship. Confusion about what is appropriate in relationships: What can one rightly expect of others? When should a relationship end? How much should one give in a relationship? Is it okay to say "no" to others? • "Identification with the aggressor": believing the abuser is right. Ideas for a Commitment Commit to one action that will move your life forward! It can be anything you feel will help you, or you can try one of the ideas below. Keeping your commitment is a way of respecting, honoring, and caring for yourself. Option 1: In a real-life situation this week, try setting a boundary with either yourself or someone else. Option 2: Memorize your top three ways to say "no" to substances. Option 3: Pick a role play and write out how you would handle it. Option 4: Fill out the Safe Coping Sheet. (See below for an example applied to this topic.) EXAMPLE OF THE SAFE COPING SHEET APPLIED TO THIS TOPIC Old Way New Way Situation My mother keeps critizing me My mother keeps critizing my decisions * Your Coping * Consequence get overwhelmed and resentful. I just let her talk at me until she's done. Sometimes I go out afterwards and smoke crack so I can get a "holiday" from her. I feel walked over. I know the crack is destroying my body and my bank account. I set a boundary by asking her to stop criticizing meit is hurting my recovery, and I cannot listen to it right now and will leave the room if necessary. I feel better, like I've taken control. She seemed surprised and didn't like hearing it, but it was okay. How safe is your old way of coping? How safe is your new way of coping? Rate from 0 (not at all safe) to 10 (totally safe) Source: Seeking Safety