Dementia Risk in MDD Differs Depending on Treatment Resistance or Responsiveness

Older patients with treatment-resistant major depressive disorder (MDD) are more likely to be diagnosed with Alzheimer’s disease and other types of dementia than their peers who respond to treatment, according to a study in the American Journal of Geriatric Psychiatry. However, compared with older patients who do not have MDD, the risk of dementia is higher for those with MDD regardless of how well their depression responds to treatment.

Che-Sheng Chu, M.D., of Kaosiung Veterans General Hospital in Taiwan, and colleagues analyzed data from 54,702 patients in the Taiwan National Health Insurance Research Database, including 30,390 patients who were diagnosed with MDD at a mean age of about 62 and 24,312 controls matched by age, sex, income, and residence. The researchers divided the patients with MDD into two groups based on how effectively they responded to antidepressant treatment in the year following their depression diagnosis: 6,078 were treatment-responsive, meaning they took only one antidepressant, while the remaining 24,312 were treatment-resistant, meaning they had switched antidepressant regimens at least twice. All patients were enrolled between 2002 and 2004 and were followed until December 31, 2011, or death, whichever came first.

Compared with controls, treatment-resistant patients were roughly 13 times more likely to develop any dementia, 25 times more likely to develop Alzheimer’s disease, seven times more likely to develop vascular dementia, and 13 times more likely to develop unspecified dementia during follow-up.

Risk was also elevated in the treatment-responsive group, though to a lesser extent. Compared with controls, patients in this group were roughly eight times more likely to develop any dementia, 13 times more likely to develop Alzheimer’s disease, six times more likely to develop vascular dementia, and seven times more likely to develop unspecified dementia during follow-up.

The researchers did not find any significant differences in risk among treatment-resistant patients who took different classes of antidepressants (i.e., SSRIs vs non-SSRIs).

Chu and colleagues wrote that their findings suggest that treatment resistance in MDD leads to more profound cognitive decline, which is consistent with previous studies.

“Older patients with treatment-resistant depression have several unique risk factors, including chronic physical illness, symptom dimensions (e.g., apathy), structural/functional brain changes, social isolation, and barriers to care, which all contribute to a higher risk of developing subsequent dementia,” they wrote. “This study underscores the importance of adequate depression management in the elderly population.”

For related information, see the American Journal of Psychiatry article “Cognitive Outcomes After Antidepressant Pharmacotherapy for Late-Life Depression: A Systematic Review and Meta-Analysis.”

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Among Teen Girls With Anorexia, Actual Weight Not Associated With Self-Esteem

In adolescent girls with anorexia nervosa (AN), body dissatisfaction and self-esteem are related to negatively biased perceptions about their bodies, not their actual weight, according to a study published this week in the Journal of Eating Disorders.

“Low self-esteem and high body dissatisfaction are pivotal risk factors for eating disorders that are closely linked and mutually reinforce each other in both non-clinical samples and individuals with eating disorders,” wrote Linda Lukas, M.Sc., of University Hospital Ludwig-Maximilians-University in Munich, Germany, and colleagues. “These risk factors might play a particularly important role in adolescents, who are in a critical stage of identity formation and subject to rapidly changing perceptions, thoughts, and feelings about their developing bodies. This leaves them especially vulnerable to constant comparison to the unrealistic images portrayed in the media.”

Lukas and colleagues recruited 40 adolescent girls with AN and 40 without any mental disorders ages 12 to 18 (median age 15). The researchers calculated participants’ BMI, assessed their body dissatisfaction using the Body Shape Questionnaire, and assessed their self-esteem using the Rosenberg Self-Esteem Scale. Participants’ interpretation bias was determined using the Scrambled Sentences Task, in which they were presented with scrambled sentences relating to their bodies (such as “my fat bottom find attractive I”); participants then had to rearrange the sentences using five of the presented words, with each sentence allowing them to choose a positive (“I find my bottom attractive”) or negative (“I find my bottom fat”) solution. The researchers then calculated participants’ interpretation bias based on how often they created negative sentences relative to positive ones.

Among participants with AN, BMI did not predict self-esteem or body dissatisfaction, while body-related interpretation bias was a significant predictor of both. A more negative interpretation of participants’ bodies was associated with higher body dissatisfaction and lower self-esteem, regardless of BMI. In contrast, among those without AN, both BMI and interpretation bias were significant predictors of self-esteem and body dissatisfaction, suggesting that both actual weight and perceptions of their bodies are linked to body dissatisfaction and self-esteem.

“These cognitive biases may distort how adolescents with AN perceive their bodies, preventing them from experiencing their bodies as thin, even when they are underweight, and may reinforce their belief that their bodies are flawed, unattractive, and not thin enough, thereby perpetuating their high body dissatisfaction and low self-esteem,” the authors wrote. “Addressing the dysfunctional cognitions related to one’s body may facilitate interrupting dysfunctional associations between low self-esteem, body dissatisfaction, and disordered eating behaviors.”

For related information, see the Psychiatric News Special Report “Youth With Eating Disorders—Time Is of the Essence in Achieving Remission.”

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Hepatitis C May Help Cause Behavioral Symptoms of Schizophrenia, Bipolar Disease

Hepatitis C virus (HCV) may cross into the lining of the brain and thus help cause behavioral symptoms in schizophrenia and bipolar disorder, according to a study in Translational Psychiatry.

Maree J. Webster, Ph.D., of the Stanley Medical Research Institute, and colleagues performed RNA sequencing on postmortem brain samples from 84 people with schizophrenia, 73 with bipolar disorder, 23 with major depressive disorder (MDD), and 76 controls. The researchers took the samples from each brain’s choroid plexus, a collection of cells that make up the lining of the brain’s fluid-filled cavities and produce the fluid that protects the brain and spinal cord. (Viruses are known to target the choroid plexus.)

The researchers found more viruses overall, including herpesviruses, in samples from people with schizophrenia or bipolar disorder than in controls or samples from people with MDD. But, unlike other viruses, HCV was only present in choroid plexus samples of people who had schizophrenia or bipolar disorder.

The researchers also analyzed the electronic health records of 285 million individuals, finding that the prevalence of chronic HCV was 3.6% and 3.9% in people with schizophrenia and bipolar disorder, respectively, whereas it was 1.8% in people with MDD and .5% in people without psychiatric disorders.

“Our findings provide compelling support for the viral hypothesis of psychiatric disease and identify HCV as a feasible viral pathogen that contributes to the neuropathology of [schizophrenia] and [bipolar disorder],” the researchers wrote. “Given that the worldwide rate of [schizophrenia] and [bipolar disorder] is approximately 1% and 3%, respectively, identifying and immediately treating the small subset of patients infected with HCV has the potential to improve psychiatric symptoms for hundreds of thousands of people.”

For related information, see the Psychiatric News article “A Call to Action: Test Our Patients for Hepatitis C.”

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Several Interventions Can Effectively Address Mental Health Symptoms Among Physicians

Face-to-face, skills-based interventions such as mindfulness and mind-body programs show promise in preventing or reducing common mental health disorder symptoms among physicians, according to a meta-analysis published in Nature Mental Health.

“Physicians have elevated rates of common mental disorder, specifically depression and anxiety, and are at increased risk of death by suicide compared with all other professional groups and the general population,” wrote Katherine Petrie, Ph.D., of the University of New South Wales in Australia, and colleagues. “[T]hese results provide important guidance for workplaces as to some promising interventions that could improve the mental health of this workforce.”

The researchers identified 21 studies that included 2,336 experienced physicians and residents (mean age of 35 years) and analyzed the impact of a variety of interventions to address anxiety, depression, or general psychological distress. The interventions included mindfulness- and mind-body-based approaches, psychoeducational approaches, and cognitive behavioral therapy (CBT), among others. Some were held face-to-face while others were delivered digitally, and they included both group-based and individual interventions.

The authors found that a range of interventions resulted in a moderate reduction in depression, anxiety, or general psychological distress symptoms among physicians. Mindfulness- and mind-body-based interventions were particularly effective in reducing symptoms, as were skills-based approaches such as CBT, stress management, and peer support. By contrast, interventions that used a psychoeducational approach did not significantly reduce symptoms compared with control conditions. Additionally, the authors found that interventions delivered face-to-face were more effective than those delivered digitally.

“[T]hese findings highlight the need for careful consideration and planning around how these programs can be implemented into the ongoing professional education and working environment of physicians,” the authors wrote. “There is a balance to be struck between efficacy and issues of scalability, feasibility and sustainability…. [T]he direct and indirect costs of physician ill health to the health-care system (for example, presenteeism, absenteeism, turnover) should be a key consideration in this decision-making process, and the use of protected time or continuing professional development points may be a means to encourage adherence and ensure program completion.”

For related information, see the Psychiatric News article “Investing in Residents’ Mental Health Vital to Psychiatry’s Own Health.”

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Metformin May Curb Weight Gain in Youth Who Take Antipsychotics

Taking metformin may help overweight or obese adolescents who take antipsychotic medications avoid the weight gain commonly associated with the drugs, according to researchers in the multicenter Metformin for Overweight and Obese Children and Adolescents With Bipolar Spectrum Disorders Treated With Second-Generation Antipsychotics (MOBILITY) study. The results were recently published by the Patient-Centered Outcomes Research Institute.

Melissa P. DelBello, M.D., M.S., of the University of Cincinnati, and colleagues examined data from 1,565 youth ages 8 to 19 years who had a diagnosis of bipolar disorder and had overweight or obesity. All patients had an established history of taking a second-generation antipsychotic medication or had recently begun taking one shortly before enrollment.

The patients and their caregivers viewed a seven-minute educational video and received printed materials about healthy diet and exercise. The researchers then randomized the patients to either lifestyle alone or lifestyle plus metformin. For the metformin group, the researchers recommended starting at a dose of 500 mg daily and increasing to a maximum dose of 1,000 mg twice daily, but dosing was flexible and carried out according to clinical discretion. The researchers collected data about the patients’ height, weight, and BMI at baseline and at a maximum of 10 follow-up visits, which were recommended monthly for the first three months and every three months after that for up to two years. They also assessed the patients’ weight-related quality of life using the Sizing Me Up & Sizing Them Up scale, a 22-item self-report and parent-proxy measure of obesity-specific health-related quality of life for youth that includes subscales for emotional, physical, and school functioning as well as teasing/marginalization, positive social attributes, mealtime challenges, and social distress/avoidance.

At six months and two years, the patients in the metformin/lifestyle group had greater reductions in BMI than those in the lifestyle-only group along with greater improvements in quality of life. However, they also had more adverse events, including 12 serious adverse events necessitating or prolonging hospitalization such as abdominal pain and refractory headache. Eleven percent of patients in the metformin/lifestyle group discontinued metformin because of gastrointestinal side effects.

“Based on our assessment … of the risks and benefits of adding [metformin] to a brief healthy lifestyle intervention among youth with [bipolar disorder] who have overweight or obesity, clinicians should strongly consider prescribing [metformin] in conjunction with [second-generation antipsychotics],” the researchers wrote. “… Although most clinicians regularly assess mood symptoms in this population, the striking prevalence of [quality-of-life] impairments directly related to weight underscores the importance of discussing with patients and their caregivers how weight gain may be adversely affecting their lives.”

For related information, see the Psychiatric News articles “Metformin May Reduce Weight Gain in Youth Taking Antipsychotics” and “New Guideline Calls for Metformin to Prevent Antipsychotic-Induced Weight Gain.”

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Few Mental Health Facilities Offer AUD Medications

Just 10% of mental health treatment facilities offer medications for alcohol use disorder (AUD), according to a research letter published today in JAMA Network Open.

Perhaps more concerning, only about 40% of facilities that provide both mental health and substance use disorder (SUD) services offer medications for AUD—a disorder estimated to affect more than 11 million adults in the United States.

Susan H. Busch, Ph.D., of the Yale School of Public Health, and colleagues compiled data on 6,572 mental health and SUD facilities that provided outpatient care and responded to the 2023 National Substance Use and Mental Health Services Survey (hospitals, federal facilities, and residential treatment centers were excluded). Of these, 2,640 facilities primarily provided mental health services (but could potentially treat co-occurring SUD), while the remaining 3,932 facilities provided both primary mental health and primary SUD services.

Among the facilities specializing in mental health, just 262 (9.9%) reported offering medications for AUD, even though many such facilities offered other SUD services such as individual/group counseling or case management. Among the mental-health-plus-SUD facilities, 1,633 (41.5%) offered medications for AUD.

There were several differences in medication for AUD availability based on facility setting, region, and other characteristics. For example, among primary mental health facilities, medications for AUD were most likely offered at certified community behavioral health clinics (21.2%), whereas among mental-health-plus-SUD facilities, medications for AUD were most common at partial hospitalization/day treatment facilities (51.9%).

Busch and colleagues also found that medications for AUD were more likely to be offered at facilities that accepted insurance, those that had integrated primary care, and those that prescribed antipsychotics (the latter indicating the presence of a prescribing physician onsite).

“When people do not access substance use treatment due to misconceptions, ambivalence, stigma, or uncertainty about how to seek care, mental health facilities are uniquely positioned to help overcome these barriers,” Jennifer D. Ellis, Ph.D., wrote in an invited commentary. However, increasing uptake of evidence-based medications for AUD “requires buy-in of physicians, administrators, and clinic directors.”

Ellis cited multiple approaches to increase engagement with AUD medications, such as incentivizing screening and referral to treatment, increasing insurance coverage of these medications, and possibly leveraging accreditation organizations such as the Joint Commission to improve training and monitoring of staff.

For related information, see the Psychiatric News Alert “Stigma, Unfamiliarity Identified as Patient Barriers to Medications for AUD.”

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Anticholinergic Medications Results in Physical Performance Decline in Older Adults

Medications with strong anticholinergic burden, including some common psychiatric drugs, were tied to accelerated physical decline when used in older adults, suggesting these medications should be avoided in these patients, according to a study published today in JAMA Network Open.

Lower gait speed and grip strength are linked to poor health outcomes, such as new-onset disability and mortality, wrote Shelly L. Gray, Pharm.D., M.S., from the University of Washington in Seattle, and colleagues. “Drugs with anticholinergic and sedative properties are frequently prescribed to older adults, with prevalence ranging from 20% to 40%.... However, it is not known if long-term use has sustained associations with reduced physical function.”

Gray and colleagues looked at data from 4,283 adults 65 years or older without dementia at recruitment who attended at least two visits and had been enrolled for at least 10 years with Kaiser Permanente Washington. Researchers tallied participants’ exposure to medications deemed strong anticholinergics, including certain antipsychotics, sertraline and tricyclic antidepressants, benzodiazepines, and z-drugs. Researchers accounted for varying intensity, duration, and timing of past exposures to the medications to better estimate their cumulative effects and then correlated participants’ exposures to changes in their gait speed and grip strength.

Researchers found that higher cumulative anticholinergic exposure was associated with slightly larger decline rates in gait speed and grip strength beyond aging and comorbidities. Overall, their findings suggested that sustained high use of anticholinergics over several years could result in a gait speed decline that would reach the threshold of clinically meaningful.

Limitations of the study identified by the researchers included its predominantly White study population and the fact that prescribing guidance has recommended limiting anticholinergic use in older adults for several years. As a result, clinicians may have intentionally avoided these medications in older adults with multimorbidity and/or frailty—the group most likely to decline in physical performance—which could have minimized their findings.

“Anticholinergics are associated with numerous adverse outcomes in older adults; therefore, it is essential for clinicians to avoid their use when possible, prescribe the lowest effective dose, and periodically reevaluate patients to identify deprescribing opportunities to minimize potential harms,” researchers concluded.

For related information, see the Psychiatric News article “Anticholinergics Linked to Increased Risk of Dementia.”

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Salt May Increase Risk of Depression and Anxiety

Pass the salt, please … or maybe not? A study published this week in the Journal of Affective Disorders found that frequently adding salt to food is associated with an elevated risk of depression and anxiety.

Luyi Zhu, of the First Affiliated Hospital of Wenzhou Medical University, and colleagues collected data from 276,138 adults enrolled in the UK Biobank who reported not making any significant changes in their diet in the five years prior to enrolling. At baseline, the UK Biobank participants were asked: “Do you add salt to your foods? (Do not include salt used in cooking).” Responses included never/rarely, sometimes, usually, and always.

The researchers followed the individuals from baseline (2006 to 2010) until their first diagnosis of depression or anxiety, death, they left the study, or May 1, 2023—whichever occurred first. The median follow-up period was 14 years; over the follow-up, 10,486 individuals developed depression and 10,786 developed an anxiety disorder.

After adjusting for demographic (age, race, etc.), lifestyle (drinking, smoking, etc.), and clinical (weight, hypertension, etc.) variables, Zhu and colleagues calculated that compared with individuals who never/rarely added salt:

• Individuals who sometimes added salt had a 10% increased risk of depression and an 8% increased risk of anxiety.
• Those who usually added salt had a 19% increased risk of depression and an 8% increased risk of anxiety.
• Those who always added salt had a 45% increased risk of depression and a 24% increased risk of anxiety.

The researchers also found that an adequate intake of fruits and vegetables could mitigate the depression and anxiety risks of copious salt addition. “[I]ndividuals who have a sufficient intake of vegetables and fruits are likely to consume fewer processed foods, partially explaining the observed phenomenon,” they wrote. “Furthermore, numerous studies have affirmed the protective effects of the inherent nutritional components in vegetables and fruits against anxiety and depression.”

For related information, see the Psychiatric News Special Report “Using Nutrition as a Therapeutic Modality.”

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Antidepressant Discontinuation Symptoms Generally Nonserious

People who stopped taking antidepressants experienced one more withdrawal-like symptom on average than those who discontinued a placebo or stayed on the medications, according to a systematic review and meta-analysis issued today by JAMA Psychiatry today. Among the symptoms, however, mood worsening was not associated with discontinuation.

Michail Kalfas, M.Sc., of King’s College in London, and colleagues undertook the study due to the “lack of consensus and clarity on the evidence relating to incidence and duration of antidepressant discontinuation symptoms,” they wrote. “The proposed high incidence of discontinuation symptoms from [clinical trials] and surveys has had significant effects on policy and attitudes toward antidepressant use.”

The researchers identified 50 randomized clinical trials published before November 7, 2023, that assessed adults with various psychiatric disorders who stopped antidepressant treatment and whose discontinuation symptoms were assessed using standardized measures such as the Discontinuation Emergent Signs and Symptoms (DESS) scale. The 50 studies included 17,828 adults whose symptoms were followed for up to 52 weeks after abrupt or tapered discontinuation.

Kalfas and colleagues reported that discontinuation of antidepressants was associated with one additional symptom on the DESS after one week compared with those who continued an antidepressant or discontinued placebo. This falls significantly below the cutoff point of four or more symptoms considered to be a clinically significant discontinuation syndrome. Across antidepressants, dizziness was the most frequent symptom associated with antidepressant cessation, affecting 6% of participants after accounting for placebo effects. Other symptoms positively associated with antidepressant cessation included nausea, vertigo, headache, nervousness, and diarrhea.

Antidepressant discontinuation was not associated with greater depressive symptoms in the first two weeks compared with placebo, despite being measured in studies specifically examining major depressive disorder; this suggests that later presentation of depression symptoms is more likely to represent depression relapse, researchers wrote.

“The lack of evidence of prolonged withdrawal symptoms could reflect shorter duration of antidepressant use, although our findings do cast a degree of doubt on the need for routine use of longer-term tapering regimens…,” the researchers wrote. “Acknowledgment of the burden of discontinuation effects is crucial; nevertheless, it is important that professional practice and media narratives surrounding discontinuation effects are proportionate. Undue emphasis on discontinuation effects may increase the likelihood of real and debilitating symptoms, which arise (or are maintained) via processes distinct from pharmacological mechanisms.”

For related information, see the Psychiatric News article “About 1 in 6 Who Stop Antidepressants Experience Side Effects, but Rarely Severe.”

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Centanafadine May Improve ADHD Symptoms in Adolescents

The investigational drug centanafadine improved symptoms of attention-deficit/hyperactivity disorder (ADHD) in adolescents in a Phase 3 clinical trial. The results of the trial, which was sponsored by Otsuka Pharmaceutical Development & Commercialization, were published in the Journal of the American Academy of Child & Adolescent Psychiatry.

“Neurobiological and pharmacological ADHD research has focused on the roles of norepinephrine and dopamine. However, emerging evidence suggests that serotonin may also contribute to the disorder,” wrote Timothy E. Wilens, M.D., of Harvard Medical School, and colleagues. They noted that serotonin levels have been shown to influence processes related to mood, executive function, sleep, and memory—all of which are linked to core symptoms and associated features of ADHD, such as inattention, impulsivity, deficits in emotional regulation, anxiety, and depression. Centanafadine is a norepinephrine, dopamine, and serotonin reuptake inhibitor.

The researchers (who included investigators from Otsuka) analyzed data from 451 adolescents ages 13 to 17 years who took part the trial. Participants received 164.4 mg or 328.8 mg of centanafadine or placebo once daily for six weeks. The researchers conducted symptom assessments via interviews with a parent/guardian or caregiver of each adolescent (same person throughout the study).

The mean baseline ADHD Rating Scale Version 5 (ADHD-RS-5) total raw score among participants was 37.5. At week six, the mean ADHD-RS-5 total raw score decreased by 15.5, 18.5, and 14.2 points for the centanafadine 164.4-mg, centanafadine 328.8-mg, and placebo groups, respectively. The difference in mean ADHD-RS-5 scores between the centanafadine 328.8 group and placebo at week six was considered statistically significant. The benefits of the 328.8-mg dose over placebo came as early as one week after initiating medication.

Treatment-emergent adverse events occurred in 31.4% of patients in the centanafadine 164.4-mg group, 50.3% in the centanafadine 328.8-mg group, and 23.8% in the placebo group. The most common treatment-emergent adverse events were decreased appetite, nausea, headache, and rash.

For related information, see the Psychiatric Services article “Recent Trends in Medication Treatment for Attention-Deficit Hyperactivity Disorder.”

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VR-Assisted Therapy Can Reduce Severity of Auditory Hallucinations

An immersive, virtual reality (VR)–based psychotherapy can help reduce the frequency and severity of auditory hallucinations in people with schizophrenia, according to a study appearing in Lancet Psychiatry.

Using VR in the treatment of hallucinations allows therapists to digitally embody the heard voice as a three-dimensional avatar, explained Lisa Charlotte Smith, Ph.D., of Copenhagen University Hospital, and colleagues. “This approach facilitates a dialogue between the voice-hearer and the avatar representing a dominant voice, with the therapist assisting the voice-hearer in gaining confidence in standing up to the voice,” they wrote. “The aim is to gradually alter the patient’s response to the avatar, resulting in a more assertive relationship.”

The researchers recruited 271 adults with a schizophrenia spectrum disorder from outpatient clinics across Denmark; all participants had been experiencing auditory hallucinations for at least three months. Participants were randomized to receive either seven sessions of the VR therapy (Challenge-VRT) over 12 weeks or enhanced usual care—which involved flexible assertive community treatment supplemented by seven additional support sessions.

Challenge-VRT is a manualized intervention comprising three phases: reclaiming power over the voice, improving self-worth, and recovery. In the VR sessions, patients engage in dialogues with their avatar, which is voiced by the therapist using a voice transformer; therapists can switch to their natural voice to provide support if needed. The VR dialogues last between two and 20 minutes, with the remainder of each 60-minute session used for preparation and debriefing.

After 12 weeks, participants receiving Challenge-VRT had statistically greater reductions in the severity and frequency of their auditory hallucinations compared with those receiving enhanced usual care. After 24 weeks, hallucination frequency remained lower in the Challenge-VRT group relative to the control group, though there was no longer any difference in hallucination severity.

Smith and colleagues noted that nearly 80% of participants completed the full Challenge-VRT course, and the intervention was generally well tolerated except for a temporary increase in auditory verbal hallucination symptoms during the initial phase. “Few serious adverse events occurred despite the sample consisting of patients who had, on average, experienced voices for 15 years, and for whom hospital admissions and self-harm were not uncommon occurrences,” they wrote.

For related information, see the Psychiatric News article “Virtual Reality Shows Promise in Patients With SMI.”

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Study Derives Optimal Payment Incentives for Contingency Management

Effective contingency management (CM) programs for stimulant and/or opioid use disorder have median inflation-adjusted payment incentives of $128 per week for voucher protocols and $55 per week for prize protocols, according to a report in JAMA Psychiatry.

“These data are intended as starting points or a guide; complex protocols or programs that focus on challenging clinical presentations may need to consider more robust reinforcement schedules,” wrote lead author Carla J. Rash, Ph.D., of the University of Connecticut Health School of Medicine, and colleagues.

CM interventions—such as the California Recovery Incentives Program—make use of monetary incentives (typically gift cards/vouchers or entries for a cash prize drawing) to encourage patient participation in substance abuse treatment. While CM programs have more than 40 years of research support, they are not widely used in the United States.

Rash and colleagues reviewed 112 published CM protocols that involved reinforcement of stimulant- and/or opioid-negative urine drug tests and categorized each protocol as having small, medium, or large effect sizes compared with a non-CM program. They then computed weekly inflation-adjusted incentive payments for voucher- and prize-based protocols.

Of the 112 protocols coded, 49 protocols (44%) reinforced stimulant-negative urine drug tests only, seven protocols (6%) reinforced opioid-negative urine drug tests only, 24 (21%) reinforced both stimulant- and opioid-negative urine drug tests, and 32 protocols (29%) reinforced treatment for additional drugs beyond stimulants and/or opioids (alcohol, benzodiazepines, cannabis, barbiturates, phencyclidine).

Results showed that for the most common protocol length of 12 weeks, the optimal weekly payments in programs that showed moderate to large effect sizes would total about $1,536 ($128/week) for voucher and $660 ($55/week) for prize protocols.

To put these numbers in context, the authors noted that weekly estimated costs for first-line treatments approved by the Food and Drug Administration for opioid use disorder are $126 for methadone treatment, $115 for buprenorphine, and $271 for injectable naltrexone.

“At this time, CM is the treatment with the strongest evidence of efficacy for stimulant use disorders, yet CM remains underused in clinical applications,” they wrote. “In the midst of the continuing opioid and stimulant crisis, our field has the opportunity to invest in evidence-based CM as an effective treatment for substance use disorders.”

For more information, see the Psychiatric News article “Experts Discuss Options for Treating Stimulant Use Disorder.”

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Esketamine Monotherapy Outperforms Placebo for Treatment-Resistant Depression

Esketamine nasal spray monotherapy showed significant and clinically meaningful improvement over placebo in adults with treatment-resistant depression (TRD) starting within 24 hours after initial dosing, according to the results of a study mounted by drugmaker Janssen and published today in JAMA Psychiatry.

Pharmacotherapy for patients with TRD “commonly involves augmentation or combination approaches. However, some of these patients encounter tolerability issues (e.g., weight gain, sexual dysfunction, lethargy, gastrointestinal issues) … which significantly contribute to nonadherence or discontinuation,” wrote Adam Janik, M.D., an investigator with Janssen’s parent company, Johnson & Johnson, and colleagues. “Esketamine monotherapy may expand treatment options for adult patients with TRD by addressing an unmet need of patients experiencing treatment-limiting tolerability concerns and non-response.”

Esketamine was initially approved by the Food and Drug Administration (FDA) in 2019 as an adjunct medication for TRD. Earlier this year, the FDA expanded the indication to allow esketamine as a stand-alone TRD therapy based on the findings of this study.

Janik and colleagues randomized 378 adults with moderate to severe TRD without psychotic features to receive 56 mg esketamine (n= 86), 84 mg esketamine (n = 95), or placebo spray (n = 197) twice weekly. Researchers assessed participants’ changes on the Montgomery-Åsberg Depression Rating Scale (MADRS) over 28 days, after which most participants opted into an open-label study of esketamine (variable dosing) or traditional oral antidepressants for 12 additional weeks.

After 28 days of treatment, the individuals taking either esketamine dose had larger average reductions in their MADRS scores (13 points for the 56 mg group and 14 for the 84 mg group) than those taking placebo (average seven-point reduction). Response and remission rates were also about two to three times as high in the esketamine groups compared with placebo.

In participants who continued esketamine in the 12-week, open-label phase, depressive symptoms remained stable or improved. Adverse events were common among participants given esketamine, most commonly nausea (25%), dissociation (24%), dizziness (22%), and headache (19%).

Limitations of this study include the exclusion of patients with significant psychiatric or medical comorbidities or substance dependence, as well as limited racial and ethnic diversity among participants. Also, the well-known adverse events that are associated with esketamine, such as dissociation and dizziness, led to many participants correctly guessing their treatment, which could have influenced the study results.

For related information, see the Psychiatric News articles “Helping Patients With Treatment-Resistant Depression Reach Remission” and “Disappointing Results for Esketamine as an Add-On After Acute Phase.”

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Intensive Residential Dynamic Psychotherapy Effective for Personality Disorders

A six-month residential program that incorporates intensive short-term dynamic psychotherapy (ISTDP) can produce lasting improvements for individuals with difficult-to-treat personality disorders, according to a study in the American Journal of Psychotherapy.

ISTDP is a therapeutic modality that helps patients understand and confront their inner conflicts, using a strong therapeutic alliance to break down patients’ maladaptive defenses and self-defeating behaviors. This treatment has shown good success in outpatient settings for people with personality disorders, and starting in 1994, the Viersprong hospital in Amsterdam built it into their residential program for treatment-resistant personality disorders, shifting the traditionally individual psychotherapy to a group model—as described in an accompanying article.

Kees L.M. Cornelissen, M.A., a private practice psychotherapist at ISTDP-House in Bergen op Zoom, the Netherlands, and colleagues examined the long-term outcomes of 155 patients who were admitted to the residential ISTDP program between 1995 and 2005. Of these, 107 patients completed questionnaires and interviews in 2006, providing up to 10 years of post-discharge data; for the remaining patients, data previously acquired at discharge and scheduled one- and two-year follow-ups were included.

Personality disorder severity was assessed with the Symptom Checklist-90-Revised, which examines eight domains: agoraphobia, anxiety, hostility, cognitive deficits, depression, interpersonal sensitivity and mistrust, sleeping difficulties, and somatization.

Over the 10-year follow-up, the researchers found that patient symptom scores remained stable after discharge, while overall functioning increased slightly. At residential program admission, 39% of patients had a job, and by year 10 this had increased to 88%. Conversely, the number of patients receiving social welfare benefits dropped from more than 50% at admission to less than 10% at 10 years. The number of patients living with a partner fluctuated during the follow-up but was generally between 30% and 40%.

Residential ISTDP “comes with higher upfront treatment costs than outpatient services,” Cornelissen and colleagues wrote. However, given “the significant costs to both the individual and society associated with personality disorders in terms of functional impairments, disability, and time away from work, administrators should consider the cost-effectiveness of investing in an intensive residential program.”

For related information, see the American Journal of Psychotherapy article “Benefits of Using Intensive Short-Term Dynamic Psychotherapy in Psychiatric Practice.”

(Image: Getty Images/iStock/NoSystem images)

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