A Double-blind, Placebo-controlled, Randomized, Single Ascending, and Multiple Dose Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Dose Isomyosamine Capsules in Healthy Adult Subjects.

BACKGROUND: Aging is tightly linked to chronic disease, frailty, and death. Multi-morbidity, defined as the presence in the same patient of three or more conditions such as neoplastic, cardiovascular, neurodegenerative, metabolic, or autoimmune diseases, becomes more common with age. METHODS: The study was performed in a double-blind fashion. Subjects within each dose cohort (Cohorts 1, 2, 3, and 4) were randomly assigned to receive Isomyosamine doses (between 150 mg to 600 mg or placebo) or placebo in a 3:1 ratio (6 active: 2 placebo). RESULTS: Isomyosamine single daily doses each of 150 mg, 300 mg, and 450 mg for 3 days and multiple daily doses of 600 mg for 6 days were safe and well tolerated in healthy subjects. In one dose group, there was a decrease in TNF-α levels found in Isomyosamine treated subjects, but no change in the levels in subjects given placebo. The increase in Isomyosamine exposure was proportional to dose across the dose range of 300 mg to 600 mg when administered as a single dose. There was minimal accumulation of Isomyosamine following 5 days of once daily dosing of Isomyosamine 600 mg. Isomyosamine half-life ranged from approximately 15 minutes to 45 minutes across all doses in the single ascending dose and multiple ascending dose portion of the study. Elimination of Isomyosamine included the renal pathway as a minor route. CONCLUSION: Isomyosamine will continue to be investigated in phase 2 clinical trials for the treatment of sarcopenia/frailty, hashimoto's thyroiditis and rheumatoid arthritis.

Effects of somatic treatments on suicidal ideation and completed suicides.

OBJECTIVE: This work was undertaken to define and characterize the role of currently available somatic treatments in psychiatry in either increasing or reducing the risk for suicide. METHODS: Members of the Suicide Prevention Task Group of the National Network of Depression Centers performed a literature review of somatic treatments known to increase or reduce the risk for suicide. The reviews ventured to include all relevant information about the risk for both suicide ideation and completed suicides. RESULTS: Lithium and clozapine are the only two somatic treatments that have high-quality data documenting their antisuicide effects in mood disorders and schizophrenia, respectively. Lithium discontinuation is also associated with increased suicide risk. Ketamine and esketamine may have a small, but immediate, antisuicide effect. Despite the recent Food and Drug Administration approval of esketamine use in depressed suicidal patients, the small disproportional overrepresentation of suicide in subjects who had received esketamine versus placebo (3 vs. 0 among > 3500 subjects) requires ongoing evaluation. The purported antisuicide effect of electroconvulsive therapy is based on low-quality data. The effect of antidepressants is not at all clear. There appears to be direct evidence for antidepressants increasing suicidal ideation and the risk for suicide over the short-term in young people, but indirect (low quality) evidence that antidepressants reduce suicide risk over the long term. CONCLUSIONS: Clinicians have an expanding pharmacopeia to address suicide potential in their patients. Some of the agents with documented antisuicide effects may also increase suicidality under specific circumstances.

Addressing the post-acute sequelae of SARS-CoV-2 infection: a multidisciplinary model of care.

As of July 31, 2021, SARS-CoV-2 had infected almost 200 million people worldwide. The growing burden of survivorship is substantial in terms of the complexity of long-term health effects and the number of people affected. Persistent symptoms have been reported in patients with both mild and severe acute COVID-19, including those admitted to the intensive care unit (ICU). Early reports on the post-acute sequelae of SARS-CoV-2 infection (PASC) indicate that fatigue, dyspnoea, cough, headache, loss of taste or smell, and cognitive or mental health impairments are among the most common symptoms. These complex, multifactorial impairments across the domains of physical, cognitive, and mental health require a coordinated, multidisciplinary approach to management. Decades of research on the multifaceted needs of and models of care for patients with post-intensive care syndrome provide a framework for the development of PASC clinics to address the immediate needs of both hospitalised and non-hospitalised survivors of COVID-19. Such clinics could also provide a platform for rigorous research into the natural history of PASC and the potential benefits of therapeutic interventions.

Developing an IV Ketamine Clinic for Treatment-Resistant Depression: a Primer.

The efficacy of subanesthetic intravenous ketamine for treatment resistant depression (TRD) has spurred a growth of clinics nationwide that provide this service. Ketamine is an FDA-approved drug as an anesthetic but remains unapproved for psychiatric indications, and this status raises a number of short- and long-term safety and efficacy concerns that need to be addressed when implementing and developing this type of clinic. Using a framework of systems, provider, and patient domains, we provide a review of the key challenges in providing ketamine infusions and suggest potential approaches. Under systems issues, we highlight broad stakeholder engagement involving cross-departmental and multidisciplinary considerations, business case development, and delineation of administrative standard operating procedures. In the provider domain, we highlight specific roles for different treatment team members as well as suggested training requirements. In the patient domain, we identify a variety of standard operating procedures involving initial patient assessment parameters, ketamine dosing and administration guidelines, and safety monitoring procedures. Together, this review provides key considerations for developing a ketamine clinic for depression, in an effort to meet the pressing demand for this novel treatment option while helping to ensure its safe implementation.

Relapse risk factors for patients with comorbid affective disorders and substance abuse disorders from an intensive treatment unit.

BACKGROUND AND OBJECTIVES: The prevalence of substance use disorders (SUD), particularly involving opiates and benzodiazepines, has increased to the detriment of public health and the economy. Here, we evaluate relapse factors among the high-risk demographic of patients with SUD and comorbid affective disorders. METHODS: A retrospective chart review of 76 patients discharged after detoxification and simultaneous psychiatric care for concomitant affective disorders and SUDs. Relapse was assessed by two independent evaluators via postdischarge chart review, which included state-wide healthcare utilization, by patient, through healthcare information exchange systems. A Cox Hazards analysis was performed to characterize relapse risk factors. RESULTS: Benzodiazepine use, admission through the emergency department (ED) rather than direct admission, frequent ED use in the preceding year, and history of prior attendance at multiple detoxification programs were risk factors for shortened time-to-relapse. Polysubstance use and intravenous drug use prolonged time to relapse. DISCUSSION AND CONCLUSIONS: Notable findings include the significant relapse risk associated with benzodiazepine abuse and frequent prior ED utilization. These risk factors could reflect a number of underlying mediators for relapse, including anxiety, disease burden, and malingering. Additionally, this study recapitulates the observation in other patient populations that the majority of health resource utilization is attributed to a small population of patients. SCIENTIFIC SIGNIFICANCE: This study is the first to identify relapse predictors among dual-diagnosis affective disorder and SUD patients in survival analysis, and replicates the alarming and largely unknown effect that benzodiazepines have on increasing relapse risk.

Perspectives on illness-related stigma and electronically sharing psychiatric health information by people with multiple sclerosis.

BACKGROUND: Electronic medical records (EMRs) facilitate more integrated and comprehensive care. Despite this, EMRs are used less frequently in psychiatry compared to other medical disciplines, in part due to concerns regarding stigma surrounding mental health. This paper explores the willingness to share medical information among patients with multiple sclerosis (MS), who experience higher rates of psychiatric comorbidities compared to the general population, and the role that stigma plays in patient preferences. METHODS: MS patients were surveyed about their co-occurring psychiatric and non-psychiatric diagnoses, willingness to share their health information electronically among their treating doctors, and levels of self and societal stigma associated with their diagnoses. RESULTS: Participants were slightly more willing to share their non-psychiatric medical information vs. psychiatric information. Despite the presence of stigma decreasing patient willingness to share medical records, those with psychiatric co-occurring disorders, compared to those without, endorsed significantly greater willingness to electronically share their health records. The majority of diagnoses for which participants experienced the greatest difference in self vs. societal stigmas were psychiatric ones, including substance use, eating and mood disorders. Societal stigma strongly correlated with decreased non-psychiatric medication sharing, while self stigma was strongly correlated with decreased psychiatric medications sharing. LIMITATIONS: Standardized scales were not used to assess patient stigma and there is a potential lack of generalizability of results beyond patients with MS. CONCLUSIONS: These insights into patient preferences toward sharing their medical information should inform decisions to implement EMRs, particularly for patient populations experiencing higher than average levels of psychiatric comorbidities.

Evidence and magnitude of the effects of meteorological changes on SARS-CoV-2 transmission.

IMPORTANCE: Intensity and duration of the COVID-19 pandemic, and planning required to balance concerns of saving lives and avoiding economic collapse, could depend significantly on whether SARS-CoV-2 transmission is sensitive to seasonal changes. OBJECTIVE: Hypothesis is that increasing temperature results in reduced SARS CoV-2 transmission and may help slow the increase of cases over time. SETTING: Fifty representative Northern Hemisphere countries meeting specific criteria had sufficient COVID-19 case and meteorological data for analysis. METHODS: Regression was used to find the relationship between the log of number of COVID-19 cases and temperature over time in 50 representative countries. To summarize the day-day variability, and reduce dimensionality, we selected a robust measure, Coefficient of Time (CT), for each location. The resulting regression coefficients were then used in a multivariable regression against meteorological, country-level and demographic covariates. RESULTS: Median minimum daily temperature showed the strongest correlation with the reciprocal of CT (which can be considered as a rate associated with doubling time) for confirmed cases (adjusted R2 = 0.610, p = 1.45E-06). A similar correlation was found using median daily dewpoint, which was highly colinear with temperature, and therefore was not used in the analysis. The correlation between minimum median temperature and the rate of increase of the log of confirmed cases was 47% and 45% greater than for cases of death and recovered cases of COVID-19, respectively. This suggests the primary influence of temperature is on SARS-CoV-2 transmission more than COVID-19 morbidity. Based on the correlation between temperature and the rate of increase in COVID-19, it can be estimated that, between the range of 30 to 100 degrees Fahrenheit, a one degree increase is associated with a 1% decrease-and a one degree decrease could be associated with a 3.7% increase-in the rate of increase of the log of daily confirmed cases. This model of the effect of decreasing temperatures can only be verified over time as the pandemic proceeds through colder months. CONCLUSIONS: The results suggest that boreal summer months are associated with slower rates of COVID-19 transmission, consistent with the behavior of a seasonal respiratory virus. Knowledge of COVID-19 seasonality could prove useful in local planning for phased reductions social interventions and help to prepare for the timing of possible pandemic resurgence during cooler months.

Pilot randomized active-placebo-controlled trial of low-dose ketamine for the treatment of multiple sclerosis-related fatigue.

BACKGROUND: Fatigue is the most common symptom of MS and has no effective pharmacotherapy. OBJECTIVE: To determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related fatigue. METHODS: In this double-blind, randomized, active-placebo-controlled trial, 18 subjects with multiple sclerosis (MS) and reported fatigue received a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.05 mg/kg). The primary outcome was change in Daily Fatigue Severity (DFS) for 7 days following the infusion. Secondary outcomes included Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) measured up to day 28 post-infusion. We analyzed changes in all outcomes using mixed-effect models. RESULTS: In total, 18 participants were enrolled; 67% participants received ketamine. Side effects of ketamine were transient. No change in the DFS was observed after 7 days (-0.10 point; 95% confidence interval (CI): -0.32, 0.12; p = 0.40). We observed a trend in reduced FSS scores at 1 week (-5.2 points; 95% CI: -10.4, 0.14; p = 0.06) and a clinically and statistically significant reduction in MFIS score at day 28 (-13.5 point; 95% CI: -25.0, -1.98; p = 0.04). CONCLUSIONS: Ketamine infusions were safe and well-tolerated. While no change in DFS after 7 days was observed, secondary analyses suggest a benefit of ketamine infusion for reduction of longer term fatigue severity in people with MS.

An Automated Mobile Mood Tracking Technology (Mood 24/7): Validation Study.

BACKGROUND: Electronic tracking has been utilized for a variety of health conditions. Previous studies have shown that there is higher adherence to electronic methods vs paper-and-pencil tracking modalities. Electronic tracking also ensures that there are no back-filled entries, where patients have-to appear compliant-entered their responses retrospectively just before their visits with their health care provider. On the basis of the recognition of an unmet need for a Web-based automated platform to track psychiatric outcomes, Johns Hopkins University partnered with Health Central (a subsidiary of Remedy Health Media LLC) to develop Mood 24/7, an electronic, mobile, automated, SMS-based mood tracker. This is a pilot study to validate the use of Mood 24/7 in anticipation of clinical trials to demonstrate the therapeutic benefit on patients' health outcomes of utilizing digital mood-tracking technology. OBJECTIVE: Mood 24/7 is an electronic mood-monitoring platform developed to accurately and efficiently track mood over time through automated daily SMS texts or emails. This study was designed to assess the accuracy and validity of Mood 24/7 in an outpatient psychiatric setting. METHODS: This pilot study involved a retrospective chart review for depressed outpatients (N=9) to compare their self-reported Mood 24/7 daily mood ratings with their psychiatrist's independent clinical mood assessment at the time of the patient's visit. Their mood ratings via Mood 24/7 were collected over 36 weeks. In addition, a mixed model analysis was applied to compare the weekly Montgomery-Åsberg Depression Rating Scale (MADRS) scores with Mood 24/7 scores over an average of 3 months. RESULTS: A 97.2% (315/324) digital mood reporting adherence was found over 36 weeks, and a significant correlation (r=0.86, P<.001) was observed between patients' Mood 24/7 scores and their psychiatrist's blinded clinical assessment of the patient's mood when seen in the clinic. In addition, a significant concordance (intraclass correlation of 0.69, 95% CI 0.33-0.91, P<.001) was observed in the mixed model analysis of the clinician-administered MADRS vs Mood 24/7 scores over time. CONCLUSIONS: Our chart review and mixed model analyses demonstrate that Mood 24/7 is a valid instrument for convenient, simple, noninvasive, and accurate longitudinal mood assessment in the outpatient clinical setting.

The NAAG'ing Concerns of Modeling Human Alzheimer's Disease in Mice.

Studies over the past two decades report significant reductions in brain N-acetylaspartyl glutamate (NAAG) levels in neurodegenerative diseases with associated cognitive impairment, including Alzheimer's disease (AD). Because NAAG is cleaved by glutamate carboxypeptidase II (GCPII), restoration of brain NAAG levels via GCPII inhibition is a potential therapeutic strategy for AD. Herein, studies were conducted to identify an appropriate murine model of AD that recapitulates human brain NAAG changes in order to preclinically evaluate the therapeutic benefit of GCPII inhibition. Our opposing findings of brain NAAG changes in human and mouse AD highlights the limited predictive value of AD mouse models.

Effects of Sleep, Physical Activity, and Shift Work on Daily Mood: a Prospective Mobile Monitoring Study of Medical Interns.

BACKGROUND: Although short sleep, shift work, and physical inactivity are endemic to residency, a lack of objective, real-time information has limited our understanding of how these problems impact physician mental health. OBJECTIVE: To understand how the residency experience affects sleep, physical activity, and mood, and to understand the directional relationships among these variables. DESIGN: A prospective longitudinal study. SUBJECTS: Thirty-three first-year residents (interns) provided data from 2 months pre-internship through the first 6 months of internship. MAIN MEASURES: Objective real-time assessment of daily sleep and physical activity was assessed through accelerometry-based wearable devices. Mood scaled from 1 to 10 was recorded daily using SMS technology. Average compliance rates prior to internship for mood, sleep, and physical activity were 77.4, 80.2, and 93.7%, and were 78.8, 53.0, and 79.9% during internship. KEY RESULTS: After beginning residency, interns lost an average of 2 h and 48 min of sleep per week (t = - 3.04, p < .01). Mood and physical activity decreased by 7.5% (t = - 3.67, p < .01) and 11.5% (t = - 3.15, p < .01), respectively. A bidirectional relationship emerged between sleep and mood during internship wherein short sleep augured worse mood the next day (b = .12, p < .001), which, in turn, presaged shorter sleep the next night (b = .06, p = .03). Importantly, the effect of short sleep on mood was twice as large as mood's effect on sleep. Lastly, substantial shifts in sleep timing during internship (sleeping ≥ 3 h earlier or later than pre-internship patterns) led to shorter sleep (earlier: b = - .36, p < .01; later: b = - 1.75, p < .001) and poorer mood (earlier: b = - .41, p < .001; later: b = - .41, p < .001). CONCLUSIONS: Shift work, short sleep, and physical inactivity confer a challenging environment for physician mental health. Efforts to increase sleep opportunity through designing shift schedules to allow for adequate opportunity to resynchronize the circadian system and improving exercise compatibility of the work environment may improve mood in this depression-vulnerable population.

Defense Automated Neurobehavioral Assessment Accurately Measures Cognition in Patients Undergoing Electroconvulsive Therapy for Major Depressive Disorder.

OBJECTIVES: The Defense Automated Neurobehavioral Assessment (DANA) is an electronic cognitive test battery. The present study compares DANA to the standard Mini-Mental State Examination (MMSE) in subjects undergoing electroconvulsive therapy for the treatment of major depressive disorder. METHODS: Seventeen inpatient subjects in the Johns Hopkins Hospital Department of Psychiatry were administered longitudinal paired DANA and MMSE tests (7.6 ± 4.1 per patient) from January 10, 2014 to September 26, 2014. Regression analyses were conducted (with or without MMSE scores of 30) to study the impact of the MMSE upper limit, and within-subject regression analyses were conducted to compare MMSE and DANA scores over time. RESULTS: Statistically significant relationships were measured between DANA and MMSE scores. Relationships strengthened when MMSE scores of 30 were omitted from analyses, demonstrating a ceiling effect of the MMSE. Within-subject analyses revealed relationships between MMSE and DANA scores over the duration of the inpatient stay. CONCLUSIONS: Defense Automated Neurobehavioral Assessment is an electronic, mobile, repeatable, sensitive, and valid method of measuring cognition over time in depressed patients undergoing electroconvulsive therapy treatment. Automation of the DANA allows for more frequent cognitive testing in a busy clinical setting and enhances cognitive assessment sensitivity with a timed component to each test.

Exploring the Mechanism of the Clinical Encounter on Depressive Symptoms in Young Adults: A Path Analysis.

Elucidating mechanisms of how high quality clinical encounters with providers may alleviate depressive symptoms in young adults are critical to reduce psychological morbidity and disability. Guided by Street's Model of Health Communication (SMHC), this study explores the predictive relationships of the clinical encounter, which includes communication functions (patient-provider communication and patient self-appraisal of communication skills with provider) and proximal outcomes (patient activation; PA) to improve health outcomes (depressive symptoms) in young adults. This study of young adults (n = 60) employed path analysis to examine the overall model fit and direct and indirect effects of each variable on depressive symptoms. The final SMHC had excellent model fit (X2 = 2.26, p =.32, TLI =.99, CFI = 1.00, RMSEA =.05). Patient-provider communication and self-appraised communication skills with providers had indirect effects on depressive symptoms and a direct effect on PA; PA had a direct effect on depressive symptoms (R2 =.30, p <.01). Findings elucidate potential novel targets, amenable to behavioral intervention, to improve depressive symptoms within the clinical encounter, and provide a foundation for hypothesis-driven model testing among young adults with depressive symptoms.

Neuropsychiatric syndromes of multiple sclerosis.

Neuropsychiatric signs and symptoms occur frequently in individuals with multiple sclerosis (MS), either as the initial presenting complaint prior to a definitive neurological diagnosis or more commonly with disease progression. However, the pathogenesis of these comorbid conditions remains unclear and it remains difficult to accurately elucidate if neuropsychiatric symptoms or conditions are indicators of MS illness severity. Furthermore, both the disease process and the treatments of MS can adversely impact an individual's mental health. In this review, we discuss the common neuropsychiatric syndromes that occur in MS and describe the clinical symptoms, aetiology, neuroimaging findings and management strategies for these conditions.

Dose-dependent inhibition of GCPII to prevent and treat cognitive impairment in the EAE model of multiple sclerosis.

There are no treatments for cognitive impairment in multiple sclerosis (MS). Novel treatments can be evaluated in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS that displays both physical and cognitive impairments. Inhibition of the neuropeptidase glutamate carboxypeptidase II (GCPII) has previously been shown to ameliorate cognitive impairment in EAE, but dosing has not yet been optimized and only a prevention treatment paradigm has been explored. In the study described herein, the dose response of the GCPII inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) was evaluated for preventing cognitive impairment in EAE mice. Mice were immunized and received daily injections of vehicle or 2-PMPA (10, 30, 100, or 300 mg/kg) from the time of immunization (i.e. day 0). Although no doses of the drug altered physical disease severity, the 100mg/kg dose was most efficacious at preventing cognitive impairments in Barnes maze performance. Dose-related increases in brain NAAG levels were observed in post-mortem analysis, confirming target engagement. Using the 100mg/kg dose, we subsequently evaluated 2-PMPA׳s ability to treat EAE-induced symptoms by commencing treatment after the onset of physical signs of EAE (i.e. day 14). Mice were immunized for EAE and received daily injections of vehicle or 100mg/kg 2-PMPA starting two weeks post-immunization. Significant improvements in both cognitive performance and increases in brain NAAG levels were observed. GCPII inhibition is a promising treatment for cognitive impairment in MS, and doses providing equivalent exposures to 100mg/kg 2-PMPA in mice should be evaluated in clinical studies for the prevention and/or treatment of MS-related cognitive impairment.