Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors.

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. METHODS: Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. RESULTS: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01]. CONCLUSIONS: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.

A holistic approach to integrating patient, family, and lived experience voices in the development of the BrainHealth Databank: a digital learning health system to enable artificial intelligence in the clinic.

Artificial intelligence, machine learning, and digital health innovations have tremendous potential to advance patient-centred, data-driven mental healthcare. To enable the clinical application of such innovations, the Krembil Centre for Neuroinformatics at the Centre for Addiction and Mental Health, Canada's largest mental health hospital, embarked on a journey to co-create a digital learning health system called the BrainHealth Databank (BHDB). Working with clinicians, scientists, and administrators alongside patients, families, and persons with lived experience (PFLE), this hospital-wide team has adopted a systems approach that integrates clinical and research data and practices to improve care and accelerate research. PFLE engagement was intentional and initiated at the conception stage of the BHDB to help ensure the initiative would achieve its goal of understanding the community's needs while improving patient care and experience. The BHDB team implemented an evolving, dynamic strategy to support continuous and active PFLE engagement in all aspects of the BHDB that has and will continue to impact patients and families directly. We describe PFLE consultation, co-design, and partnership in various BHDB activities and projects. In all three examples, we discuss the factors contributing to successful PFLE engagement, share lessons learned, and highlight areas for growth and improvement. By sharing how the BHDB navigated and fostered PFLE engagement, we hope to motivate and inspire the health informatics community to collectively chart their paths in PFLE engagement to support advancements in digital health and artificial intelligence.

Research of the Holiday kind: Tabulating Ingestion of Mocha Solution (TIMS): a longitudinal prospective cohort study.

The annual "Roll Up the Rim to Win" contest at Tim Hortons restaurants provides customers the opportunity to win prizes. This study investigated win ratios, prize types and patterns of coffee consumption.

Feasibility of remotely supervised transcranial direct current stimulation and cognitive remediation: A systematic review.

With technological advancements and an aging population, there is growing interest in delivering interventions at home. Transcranial Direct Current Stimulation (tDCS) and Cognitive Remediation (CR) as well as Cognitive Training (CT) have been widely studied, but mainly in laboratories or hospitals. Thus, the objectives of this review are to examine feasibility and the interventions components to support the domiciliary administration of tDCS and CR. We performed a systematic search of electronic databases, websites and reference lists of included articles from the first date available until October 31, 2018. Articles included had to meet the following criteria: original work published in English using human subjects, majority of tDCS or CR intervention administered remotely. A total of 39 studies were identified (16 tDCS, 23 CR/CT, 5 using both tDCS & CT). Four studies were single case studies and two were multiple case studies. The remaining 33 studies had a range of 9-135 participants. Five tDCS and nine CR/CT studies were double blind randomized controlled trials. Most studies focused on schizophrenia (8/39) and multiple sclerosis (8/39). Literature examined suggests the feasibility of delivering tDCS or CR/CT remotely with the support of information and communication technologies.

Elevated Monoamine Oxidase-A Distribution Volume in Borderline Personality Disorder Is Associated With Severity Across Mood Symptoms, Suicidality, and Cognition.

BACKGROUND: Monoamine oxidase-A (MAO-A) is a treatment target in neurodegenerative illness and mood disorders that increases oxidative stress and predisposition toward apoptosis. Increased MAO-A levels in prefrontal cortex (PFC) and anterior cingulate cortex (ACC) occur in rodent models of depressive behavior and human studies of depressed moods. Extreme dysphoria is common in borderline personality disorder (BPD), especially when severe, and the molecular underpinnings of severe BPD are largely unknown. We hypothesized that MAO-A levels in PFC and ACC would be highest in severe BPD and would correlate with symptom magnitude. METHODS: [(11)C] Harmine positron emission tomography measured MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in severe BPD subjects (n = 14), moderate BPD subjects (n = 14), subjects with a major depressive episode (MDE) only (n = 14), and healthy control subjects (n = 14). All subjects were female. RESULTS: Severe BPD was associated with greater PFC and ACC MAO-A VT compared with moderate BPD, MDE, and healthy control subjects (multivariate analysis of variance group effect: F6,102 = 5.6, p < .001). In BPD, PFC and ACC MAO-A VT were positively correlated with mood symptoms (PFC: r = .52, p = .005; ACC: r = .53, p = .004) and suicidality (PFC: r = .40, p = .037; ACC: r = .38, p = .046), while hippocampus MAO-A VT was negatively correlated with verbal memory (r = -.44, p = .023). CONCLUSIONS: These results suggest that elevated MAO-A VT is associated with multiple indicators of BPD severity, including BPD symptomatology, mood symptoms, suicidality, and neurocognitive impairment.

Elevated monoamine oxidase a binding during major depressive episodes is associated with greater severity and reversed neurovegetative symptoms.

Inadequate treatment response occurs in approximately 40% of major depressive episodes (MDEs), and one approach to solve this is careful matching of treatment to the specific pathologies of MDE. One such biological abnormality is elevated monoamine oxidase A (MAO-A) levels, which occurs in the prefrontal and anterior cingulate cortex (PFC and ACC) during MDE; however, the subtypes for which this abnormality is most prominent are unknown. We hypothesized that MAO-A levels in the PFC and ACC are most elevated in MDE with greater severity and reversed neurovegetative symptoms (hypersomnia and either hyperphagia or weight gain). MAO-A VT (an index of MAO-A density) was measured using [(11)C]harmine positron emission tomography (PET) in 42 subjects with MDEs secondary to major depressive disorder and 37 healthy controls. The effect of severity and reversed neurovegetative symptoms on MAO-A VT in the PFC and ACC was analyzed using a multivariate analysis of variance (MANOVA). Greater severity and reversed neurovegetative symptoms were associated with elevated MAO-A VT in the PFC and ACC (MANOVA, severity: F(2,38)=5.44, p=0.008; reversed neurovegetative symptoms: F(2,38)=5.13, p=0.01). Increased MAO-A level, when greater severity and reversed neurovegetative symptoms are present, may explain the association of these clinical features with a preferential response to MAO inhibitors, which is especially well-evidenced for reversed neurovegetative symptoms in MDE. As MAO-A creates oxidative stress, facilitates apoptosis, and metabolizes monoamines, therapeutics opposing these processes are predicted to best treat MDE with greater severity and reversed neurovegetative symptoms.

Greater monoamine oxidase a binding in perimenopausal age as measured with carbon 11-labeled harmine positron emission tomography.

IMPORTANCE: Perimenopause is a period of high risk for mood disorders, and it has been proposed that perimenopause is also a window of risk for processes linked to later dementia. However, in human perimenopause, the neurobiological changes implicated in the genesis of mood disorders or dementia have not been identified. Monoamine oxidase A (MAO-A) is an important brain enzyme that creates oxidative stress, influences apoptosis, and metabolizes monoamines. After declines in estrogen level, MAO-A density may be elevated for a month or longer, and repeated declines in estrogen level occur with greater magnitude during perimenopause. OBJECTIVE: To investigate whether MAO-A total distribution volume (VT), an index of MAO-A density, is elevated in women of perimenopausal age (41-51 years). DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional study at a tertiary care psychiatric hospital, 58 women underwent carbon 11-labeled harmine positron emission tomography. These included 19 young women of reproductive age (mean [SD], 28.26 [5.05] years), 27 women of perimenopausal age (mean [SD] age, 45.21 [3.41] years; including 14 women with change in menstrual cycle length with a mean [SD] age of 45.50 [4.00] years and 13 women with no change in menstrual cycle length with a mean [SD] age of 44.92 [2.81] years), and 12 women in menopause (mean [SD] age, 56.25 [3.19] years). MAIN OUTCOMES AND MEASURES: Values of MAO-A VT in the prefrontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, thalamus, hippocampus, and midbrain. RESULTS: On average, MAO-A VT in perimenopausal age was elevated by 34% compared with reproductive age and by 16% compared with menopause (multivariate analysis of variance, group effect, F16,94 = 3.03; P < .001). Within the perimenopausal age group, meeting Stages of Reproductive Aging Workshop criteria for perimenopause, which is mainly based on menstrual cycle length, was not associated with MAO-A VT (F8,18 = 0.548; P = .81) but tendency to cry was positively correlated with MAO-A VT in the prefrontal cortex (r = 0.54; P = .008). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first report of a change in a central biomarker during perimenopausal age that is also present during major depressive episodes and high-risk states for major depressive episodes. The functions of MAO-A influence oxidative stress and apoptosis, 2 processes implicated as excessive in both mood disorders and dementia. Hence, greater MAO-A VT during perimenopause may represent a new target for assessing novel interventions to prevent mood disorders and reduce longer-term risk of neurodegenerative disease.

Presentation of smoking-associated cues does not elicit dopamine release after one-hour smoking abstinence: A [11C]-(+)-PHNO PET study.

The presentation of drug-associated cues has been shown to elicit craving and dopamine release in the striatum of drug-dependent individuals. Similarly, exposure to tobacco-associated cues induces craving and increases the propensity to relapse in tobacco- dependent smokers. However, whether exposure to tobacco-associated cues elicits dopamine release in the striatum of smokers remains to be investigated. We hypothesized that presentation of smoking-related cues compared to neutral cues would induce craving and elevation of intrasynaptic dopamine levels in subregions of the striatum and that the magnitude of dopamine release would be correlated with subjective levels of craving in briefly abstinent tobacco smokers. Eighteen participants underwent two [(11)C]-(+)-PHNO positron emission tomography (PET) scans after one-hour abstinence period: one during presentation of smoking-associated images and one during presentation of neutral images. Smoking cues significantly increased craving compared to neutral cues on one, but not all, craving measures; however, this increase in craving was not associated with overall significant differences in [(11)C]-(+)-PHNO binding potential (BPND) (an indirect measure of dopamine release) between the two experimental conditions in any of the brain regions of interest sampled. Our findings suggest that presentation of smoking cues does not elicit detectable (by PET) overall increases in dopamine in humans after one-hour nicotine abstinence. Future research should consider studying smoking cue-induced dopamine release at a longer abstinence period, since recent findings suggest the ability of smoking-related cues to induce craving is associated with a longer duration of smoking abstinence.