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Long-term potentiation (LTP)-like activity can be induced by stimulation protocols such as paired associative stimulation (PAS). We aimed to determine whether PAS-induced LTP-like activity (PAS-LTP) of the dorsolateral prefrontal cortex (DLPFC) is associated with cortical thickness and other structural measures impaired in Alzheimer's dementia (AD). We also explored longitudinal relationships between these brain structures and PAS-LTP response after a repetitive PAS (rPAS) intervention. Mediation and regression analyses were conducted using data from randomized controlled trials with AD and healthy control participants. PAS-electroencephalography assessed DLPFC PAS-LTP. DLPFC thickness and surface area were acquired from T1-weighted magnetic resonance imaging. Fractional anisotropy and mean diffusivity (MD) of the superior longitudinal fasciculus (SLF)—a tract important to induce PAS-LTP—were measured with diffusion-weighted imaging. AD participants exhibited reduced DLPFC thickness and increased SLF MD. There was also some evidence that reduction in DLPFC thickness mediates DLPFC PAS-LTP impairment. Longitudinal analyses showed preliminary evidence that SLF MD, and to a lesser extent DLPFC thickness, is associated with DLPFC PAS-LTP response to active rPAS. This study expands our understanding of the relationships between brain structural changes and neuroplasticity. It provides promising evidence for a structural predictor to improving neuroplasticity in AD with neurostimulation. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Working memory is associated with gamma oscillations (30-50Hz). Previous studies have demonstrated altered gamma oscillations in the elderly population that may be related to general cognitive decline. However, it is unknown how gamma oscillations change with age or if there is an age when gamma oscillations optimally mediate working memory performance. That is, gamma oscillations may be maximal in middle-aged adults compared to younger and elderly adults. The objective of this study was to evaluate working memory evoked gamma oscillations in adults aged 19-29 years (mean 23.32±2.85 1SD) compared to adults aged 30-60 years (mean 39.10±8.11 1SD). METHODS: Subjects completed the verbal N-back task administered at four working loads (0, 1, 2, 3), while electroencephalography (EEG) was collected. Gamma power was measured during correct responses. RESULTS: Reduced gamma oscillations were observed in the adults aged 19-29 compared to those aged 30-60 years. Age was found to be positively related to the power of gamma oscillations. No differences were found on N-Back accuracy. CONCLUSIONS: Increased working memory evoked gamma oscillatory activity may provide a neurophysiological marker in the healthy aging brain. [ABSTRACT FROM AUTHOR]

Agitation, a common dementia symptom often arising from untreated pain, lacks comprehensive research on its connection with opioids prescribed for long-term pain. This study investigated the relationship between opioid use and agitation in dementia patients. Participants ( n  = 188) were categorized into opioid, acetaminophen PRN, or no-pain medication groups. Despite higher reported pain levels in the opioid group, no significant differences in agitation were observed among the groups. In conclusion, opioid use for pain management in older adults with dementia did not significantly impact agitation, emphasizing the ongoing importance of proper pain management in improving dementia care and addressing agitation in this population., Competing Interests: The authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Objectives: The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project pools archival datasets on older age bipolar disorder (OABD). An initial Wave 1 (W1; n = 1369) analysis found both manic and depressive symptoms reduced among older patients. To replicate this finding, we gathered an independent Wave 2 (W2; n = 1232, mean ± standard deviation age 47.2 ± 13.5, 65% women, 49% aged over 50) dataset., Design/methods: Using mixed models with random effects for cohort, we examined associations between BD symptoms, somatic burden and age and the contribution of these to functioning in W2 and the combined W1 + W2 sample (n = 2601)., Results: Compared to W1, the W2 sample was younger (p < 0.001), less educated (p < 0.001), more symptomatic (p < 0.001), lower functioning (p < 0.001) and had fewer somatic conditions (p < 0.001). In the full W2, older individuals had reduced manic symptom severity, but age was not associated with depression severity. Age was not associated with functioning in W2. More severe BD symptoms (mania p ≤ 0.001, depression p ≤ 0.001) were associated with worse functioning. Older age was significantly associated with higher somatic burden in the W2 and the W1 + W2 samples, but this burden was not associated with poorer functioning., Conclusions: In a large, independent sample, older age was associated with less severe mania and more somatic burden (consistent with previous findings), but there was no association of depression with age (different from previous findings). Similar to previous findings, worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning., (© 2024 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Objective: Sex-specific research in adult bipolar disorder (BD) is sparse and even more so among those with older age bipolar disorder (OABD). Knowledge about sex differences across the bipolar lifespan is urgently needed to target and improve treatment. To address this gap, the current study examined sex differences in the domains of clinical presentation, general functioning, and mood symptoms among individuals with OABD., Methods: This Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) study used data from 19 international studies including BD patients aged ≥50 years (N = 1,185: 645 women, 540 men).A comparison of mood symptoms between women and men was conducted initially using two-tailed t tests and then accounting for systematic differences between the contributing cohorts by performing generalized linear mixed models (GLMMs). Associations between sex and other clinical characteristics were examined using GLMM including: age, BD subtype, rapid cycling, psychiatric hospitalization, lifetime psychiatric comorbidity, and physical health comorbidity, with study cohort as a random intercept., Results: Regarding depressive mood symptoms, women had higher scores on anxiety and hypochondriasis items. Female sex was associated with more psychiatric hospitalizations and male sex with lifetime substance abuse disorders., Conclusion: Our findings show important clinical sex differences and provide support that older age women experience a more severe course of BD, with higher rates of psychiatric hospitalization. The reasons for this may be biological, psychological, or social. These differences as well as underlying mechanisms should be a focus for healthcare professionals and need to be studied further., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Persons with mental illness as their sole underlying medical condition are eligible to access medical assistance in dying (MAiD) in a small number of countries, including Belgium, the Netherlands, Luxemburg and Switzerland. In Canada, it is anticipated that people experiencing mental illness as their sole underlying medical condition (MI-SUMC) will be eligible to request MAiD as of March 17th 2024. To date, few studies have addressed patient and family perspectives on MAiD MI-SUMC care processes. This study aimed to address this gap and qualitatively explore the perspectives of persons with lived experience of mental illness and family members on care considerations during MI-SUMC implementation., Methods: Thirty adults with lived experience of mental illness and 25 adult family members residing in Ontario participated in this study. To facilitate participant engagement, the semi-structured interview used a persona-scenario exercise to discuss perspectives on MAiD MI-SUMC acceptability and care considerations. Framework analysis was used to inductively analyze data using NVivo 12 Pro. Steps, processes, or other care considerations suggested by the participants were charted in a framework matrix after familiarization with the narratives. Key themes were further identified. A lived-experience advisory group participated in every aspect of this study., Results: Six themes were developed from the patient and family narratives: (1) Raising MAiD MI-SUMC awareness; (2) Sensitive Introduction of MAiD MI-SUMC in goals of care discussions; (3) Asking for MAiD MI-SUMC: a person-focused response; (4) A comprehensive circle of MAiD MI-SUMC care; (5) A holistic, person-centered assessment process; and (6) Need for support in the aftermath of the decision. These themes highlighted a congruence of views between patient and family members and described key desired process ingredients, including a person-centred non-judgmental stance by care providers, inter-professional holistic care, shared decision making, and the primacy of patient autonomy in healthcare decision making., Conclusions: Family and patient perspectives on the implementation of MAiD MI-SUMC offer important considerations for service planning that could complement existing and emerging professional practice standards. These stakeholders' perspectives will continue to be essential in MAiD MI-SUMC implementation efforts, to better address the needs of diverse communities and inform improvement efforts., (© 2024. The Author(s).)

Background: Social determinants of health (SDoHs) are nonmedical factors that significantly impact health and longevity. We found no published reviews on the biology of SDoHs in schizophrenia-spectrum psychotic disorders (SSPD)., Study Design: We present an overview of pathophysiological mechanisms and neurobiological processes plausibly involved in the effects of major SDoHs on clinical outcomes in SSPD., Study Results: This review of the biology of SDoHs focuses on early-life adversities, poverty, social disconnection, discrimination including racism, migration, disadvantaged neighborhoods, and food insecurity. These factors interact with psychological and biological factors to increase the risk and worsen the course and prognosis of schizophrenia. Published studies on the topic are limited by cross-sectional design, variable clinical and biomarker assessments, heterogeneous methods, and a lack of control for confounding variables. Drawing on preclinical and clinical studies, we propose a biological framework to consider the likely pathogenesis. Putative systemic pathophysiological processes include epigenetics, allostatic load, accelerated aging with inflammation (inflammaging), and the microbiome. These processes affect neural structures, brain function, neurochemistry, and neuroplasticity, impacting the development of psychosis, quality of life, cognitive impairment, physical comorbidities, and premature mortality. Our model provides a framework for research that could lead to developing specific strategies for prevention and treatment of the risk factors and biological processes, thereby improving the quality of life and increasing the longevity of people with SSPD., Conclusions: Biology of SDoHs in SSPD is an exciting area of research that points to innovative multidisciplinary team science for improving the course and prognosis of these serious psychiatric disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Although lithium is considered the gold-standard treatment for bipolar disorder (BD), it is associated with a variety of major endocrine and metabolic side effects, including parathyroid hormone (PTH) dependent hypercalcemia. Aside from surgery and medication discontinuation, there are limited treatments for hypercalcemia. This paper will assess data from a randomized controlled trial (RCT)., Methods: This is a secondary analysis of an RCT that explored the effects of atorvastatin (n = 27) versus placebo (n = 33) on lithium-induced nephrogenic diabetes insipidus (NDI) in patients with BD and major depressive disorder (MDD) using lithium (n = 60), over a 12-week period. This secondary analysis will explore serum calcium levels and thyroid stimulating hormone (TSH) measured at baseline, week 4, and week 12., Results: At 12-weeks follow-up while adjusting results for baseline, linear regression analyses found that corrected serum calcium levels were significantly lower in the treatment group (mean (M) = 2.30 mmol/L, standard deviation (SD) = 0.07) compared to the placebo group (M = 2.33 mmol/L, SD = 0.07) (β = - 0.03 (95% C.I.; - 0.0662, - 0.0035), p = 0.03) for lithium users. There were no significant changes in TSH., Conclusion: In lithium users with relatively normal calcium levels, receiving atorvastatin was associated with a decrease in serum calcium levels. Although exciting, this is a preliminary finding that needs further investigation with hypercalcemic patients. Future RCTs could examine whether atorvastatin can treat PTH dependent hypercalcemia due to lithium and other causes., (© 2022. The Author(s).)

Objectives: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study., Design: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed., Setting: Community-based multi-centered study based in Toronto across 5 academic sites., Participants: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls., Measurements: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores., Results: A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD., Conclusions: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.

Alzheimer's disease is a major cause of morbidity and mortality. Currently, there are no disease-modifying pharmacotherapies for this condition. Aducanumab, an amyloid beta-directed monoclonal antibody that targets aggregated forms of amyloid-beta in the brains of people with Alzheimer's disease, has raised hopes that such a therapy has been discovered, but its approval by the US Food and Drug Administration has engendered a good deal of controversy. A similar application for approval has been submitted to Health Canada. In response to this, a group of Canadian clinical dementia experts representing a number of organizations, including the Canadian Geriatrics Society, was convened by the Canadian Consortium on Neurodegeneration in Aging (CCNA) to discuss the evidence currently available on this agent and seek consensus on what advice they would offer Health Canada on the application. There was wide-spread agreement that it would be premature for aducanumab to receive approval for the treatment of Alzheimer's disease. It was also noted that the Canadian health-care system is poorly prepared at this time to deal with a disease-modifying therapeutic with targeting, administration, and monitoring characteristics like aducanumab. In this paper, the consensus reached is presented along with its underlying rationale., Competing Interests: CONFLICT OF INTEREST DISCLOSURES Dr. Chertkow has participated as an unpaid advisor in 2020 for establishment of an international database by Biogen. Rockwood is Co-founder of Ardea Outcomes, which (as DGI Clinical) in the last three years has contracts with pharma and device manufacturers (Biogen, Hollister, Novartis, Nutricia, Roche, Takeda) on individualized outcome measurement. In 2019 he accepted an honorarium from Biogen for taking part in an interview. Dr. Black discloses that in the last 5 years (2016–2021) she has received personal fees for ad hoc consulting from Hoffman LaRoche, Biogen, Pfizer, Eli Lilly, Novartis and Merck. She has also received personal fees for speaking from Biogen, Eli Lilly and Novartis. Dr. Black discloses support to her institution for contract research from Eli Lilly, GE Healthcare, Eisai Biogen, Genentech, Optina, Hoffman LaRoche, NovoNordisk, and UCB. Dr. Borrie is principal investigator for Biogen and a sub-investigator for Eisai for two clinical trials and does not personally receive any compensation from Biogen. Dr. Hsiung has received research support as a clinical trials site investigator from Anavax, Biogen, Eli Lilly and Roche. Dr. Kirk has participated in and been recompensed by advisory boards for Biogen, Genzyme and Roche. He has also received compensation for speaking engagements with Biogen. Dr. Masellis reports consulting fees from Biogen Canada relevant to the submitted work. Dr. Nygaard is a paid, independent consultant to Biogen Canada National Advisory Board. Dr. Verret has received funds from Biogen (for the ENGAGE TRIAL). He is a member and has received funds for the advisory boards of Biogen, Roche, Abbvie; and has received funds from Biogen for continuous medical education. David Hogan, Natalie Phillips, Manuel Montero-Odasso, Shabbir Amanullah, Christian Bocti, Howard Feldman, Morris Freedman, and Tarek Rajji report no conflicts of interest relating to this consensus statement., (© 2021 Author(s). Published by the Canadian Geriatrics Society.)

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes., (© 2021 the Alzheimer's Association.)

Objective: Lithium remains an important treatment for mood disorders but is associated with kidney disease. Nephrogenic diabetes insipidus (NDI) is associated with up to 3-fold risk of incident chronic kidney disease among lithium users. There are limited randomized controlled trials (RCT) for treatments of lithium-induced NDI, and existing therapies can be poorly tolerated. Therefore, novel treatments are needed for lithium-induced NDI., Method: We conducted a 12-week double-blind pilot RCT to assess the feasibility and efficacy of 20 mg/d atorvastatin vs placebo in the treatment of NDI in chronic lithium users. Patients, recruited between September 2017 and October 2018, were aged 18 to 85, currently on a stable dose of lithium, and determined to have NDI., Results: Urinary osmolality (UOsm) at 12 weeks adjusted for baseline was not statistically different between groups (+39.6 mOsm/kg [95% CI, -35.3, 114.5] in atorvastatin compared to placebo groups). Secondary outcomes of fluid intake and aquaporin-2 excretions at 12 weeks adjusted for baseline were -0.13 L [95% CI, -0.54, 0.28] and 98.68 [95% CI, -190.34, 387.70], respectively. A moderate effect size was observed for improvements in baseline UOsm by ≥100 mOsm/kg at 12 weeks in patients who received atorvastatin compared to placebo (38.45% (10/26) vs 22.58% (7/31); Cohen's d = 0.66)., Conclusion: Among lithium users with NDI, atorvastatin 20 mg/d did not significantly improve urinary osmolality compared to placebo over a 12-week period. Larger confirmatory trials with longer follow-up periods may help to further assess the effects of statins on NDI, especially within patients with more severe NDI., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Statins have recently been linked to having effects on cognition and mood in mood disorders, though results are mixed. In this paper, we use data from a recent randomized controlled trial (RCT) to examine the effect of statins on cognition and mood in patients with Bipolar Disorder (BD) and Major Depressive Disorder (MDD)., Methods: This is a secondary analysis of a randomized, double-blind, placebo-controlled clinical trial (n = 60) originally designed to examine the effect of atorvastatin (n = 27) versus placebo (n = 33) for lithium-induced diabetes insipidus in BD and MDD patients who were using lithium. For this analysis, the primary outcome was global cognition Z-score at 12-weeks adjusted for baseline. The secondary cognition outcomes were (1) Screen for Cognitive Impairment in Psychiatry (SCIP), and (2) executive function Z-score. The primary mood outcome (secondary outcome of this analysis) was depression relapse during 12-week follow-up (Mongomery Asberg Depression Rating Scale (MADRS) ≥10). The secondary mood outcomes were (1) relapse rate into a manic episode, and (2) relapse rate into any mood episode., Results: After 12 weeks follow-up, atorvastatin and placebo groups did not differ in terms of global cognition Z-score (β = -0.009287 (-0.1698,0.1512), p-value = 0.91). Similarly, composite Z-scores for SCIP and executive functions did not differ significantly. Depression relapse during 12-week follow-up was not significantly different between the groups (χ 2 (1) = 0.148, p-value = 0.70). Similarly, there was no difference between groups regarding relapse into mania., Conclusion: In BD and MDD patients with lithium-induced nephrogenic diabetes insipidus randomized to atorvastatin or placebo, we found no significant differences in cognition and mood outcomes at 12-week follow-up., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Approximately one-third of patients with Alzheimer disease (AD) develop delusions. Delusions have been linked to numerous adverse outcomes, including worsened cognitive and functional decline, increased caregiver burden, and higher mortality rates. Previous studies have indicated that both AD and neuropsychiatric symptoms within AD are associated with abnormal functional connectivity of the resting brain, but no studies have focused on how delusions alter resting-state functional connectivity. The authors' objective was to test for differences in resting brain function between delusional and non-delusional patients with AD. The authors hypothesized that patients with AD with delusions would exhibit reduced connectivity of the default mode network (DMN) compared with patients with AD without delusions., Methods: Resting-state functional magnetic resonance imaging was used to investigate differences in functional connectivity between 15 patients with AD with delusions and 15 comparable patients with AD without delusions. A group-level principal component analysis was used to identify functional networks accounting for greatest variability over all subjects, and the DMN was selected for between-group analysis. Dual regression was used to reconstruct individual subject component maps, and a two-sample t test was used to compare groups with and without delusion, adjusted at a false discovery rate of 0.05., Results: The two cohorts were comparable demographically and cognitively. The patients with delusions showed significantly reduced connectivity of the left inferior parietal lobule (IPL) with the rest of the DMN., Conclusion: Delusions in AD are associated with reduced connectivity within the DMN, specifically the left IPL. The authors' findings provide insight into the underlying neuropathophysiology of delusions in AD., (Copyright © 2019 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) has emerged as a powerful tool to non-invasively probe brain circuits in humans, allowing for the assessment of several cortical properties such as excitability and connectivity. Over the past decade, this technique has been applied to various clinical populations, enabling the characterization and development of potential TMS-EEG predictors and markers of treatments and of the pathophysiology of brain disorders. The objective of this article is to present a comprehensive review of studies that have used TMS-EEG in clinical populations and to discuss potential clinical applications. To provide a technical and theoretical framework, we first give an overview of TMS-EEG methodology and discuss the current state of knowledge regarding the use of TMS-EEG to assess excitability, inhibition, plasticity and connectivity following neuromodulatory techniques in the healthy brain. We then review the insights afforded by TMS-EEG into the pathophysiology and predictors of treatment response in psychiatric and neurological conditions, before presenting recommendations for how to address some of the salient challenges faced in clinical TMS-EEG research. Finally, we conclude by presenting future directions in line with the tremendous potential of TMS-EEG as a clinical tool., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Antipsychotic use in older patients is associated with many adverse effects, including tardive dyskinesia and extrapyramidal symptoms, which, in turn, increase the risk of falling. Antipsychotics are also associated with metabolic syndrome and cognitive impairment in older patients. Integrated care pathways (ICPs) are designed to manage specific conditions using standardized assessments and measurement-based interventions. This study aims to compare the use of recommended tools to monitor for adverse effects associated with antipsychotics in older patients managed within an ICP and those managed under usual care conditions-i.e., treatment as usual (TAU)., Methods: We reviewed and compared the health records of 100 older patients enrolled in an ICP for late-life schizophrenia with those of 100 older patients treated with antipsychotics under TAU conditions., Results: Monitoring rates were significantly higher in the ICP group than in the TAU group for all assessments: extrapyramidal symptoms (94% versus 5%), metabolic disturbances (91% versus 25%), fall risk (82% versus 35%), and cognitive impairment (72% versus 28%). Rates of antipsychotic polypharmacy were also six times higher in the TAU group., Conclusion: Older patients with schizophrenia treated with antipsychotics within an ICP experience higher rates of monitoring and less psychotropic polypharmacy than older patients treated with antipsychotics under TAU conditions. These findings suggest that an ICP can improve the quality of antipsychotic pharmacotherapy in older patients and thus possibly its effectiveness. This needs to be confirmed by a randomized controlled trial., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Cardiovascular risk factors (CVRFs) have been linked to both depression and cognitive decline but their role in neuropsychiatric symptoms (NPS) has yet to be clarified., Objective: Understanding the role of CVRFs in the etiology of NPS for prospective treatments and preventive strategies to minimize these symptoms., Methods: We examined the distribution of NPS using the Neuropsychiatric Inventory (NPI) scores in three cohorts from the Prevention of Alzheimer's Dementia with Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression (PACt-MD) study: older patients with a lifetime history of major depressive disorder (MDD) in remission, patients with mild cognitive impairment (MCI), and patients with combined MCI and MDD. We also examined the link between individual NPS and CVRFs, Framingham risk score, and Hachinski ischemic score in a combined sample., Results: Analyses were based on a sample of 140 subjects, 70 with MCI, 38 with MCI plus MDD, and 32 with MDD. There was no effect of age, gender, education, cognition, or CVRFs on the presence (NPI >1) or absence (NPI = 0) of NPS. Depression was the most prevalent affective NPS domain followed by night-time behaviors and appetite changes across all three diagnostic groups. Agitation and aggression correlated negatively while anxiety, disinhibition, night-time behaviors, and irritability correlated positively with CVRFs (all p-values <0.05). Other NPS domains showed no significant association with CVRFs., Conclusion: CVRFs are significantly associated with individual NPI sub-scores but not with total NPI scores, suggesting that different pathologies may contribute to different NPS domains.

Amnestic mild cognitive impairment (aMCI) is defined as a transitional state between normal aging and Alzheimer's disease (AD). Given the replicated finding of increased microglial activation in AD, we sought to investigate whether microglial activation is also elevated in aMCI and whether it is related to amyloid beta (Aβ) burden in-vivo . Eleven aMCI participants and 14 healthy volunteers completed positron emission tomography (PET) scans with [ 18 F]-FEPPA and [ 11 C]-PIB. Given the known sensitivity in affinity of second-generation TSPO radioligands, participants were genotyped for the TSPO polymorphism and only high-affinity binders were included. Dynamic [ 18 F]-FEPPA PET images were analyzed using the 2-tissue compartment model with arterial plasma input function. Additionally, a supplementary method, the standardized uptake value ratio (SUVR), was explored. [ 11 C]-PIB PET images were analyzed using the Logan graphical method. aMCI participants had significantly higher [ 11 C]-PIB binding in the cortical regions. No significant differences in [ 18 F]-FEPPA binding were observed between aMCI participants and healthy volunteers. In the aMCI group, [ 18 F]-FEPPA and [ 11 C]-PIB bindings were correlated in the hippocampus. There were no correlations between our PET measures and cognition. Our findings demonstrate that while Aβ burden is evident in the aMCI stage, microglial activation may not be present.

Background: Evaluation of telepsychiatry (via videoconference) for older adults is mostly focussed on nursing homes or inpatients. We evaluated the role of a community based program for older adults in rural and remote regions of South Australia., Method: The utilization pattern was studied using retrospective chart review of telepsychiatry assessments over 24 months (2010-2011). Satisfaction was evaluated through prospective post-consultation feedback (using a 5-point Likert scale), from patients, community based clinicians and psychiatrist participating in consecutive assessments from April-November 2012. Descriptive analysis was used for the utilization. Mean scores and proportions were calculated for the feedback. Mann Whitney U test was used to compare patient subgroups based on age, gender, prior exposure to telepsychiatry services and inpatient/ outpatient status. Feedback comments were analysed for emerging themes., Results: On retrospective review of 134 consults, mean age was 75.89 years (SD 7.55), 60.4% (81) were females, and 71.6% (96) lived independently. Patients had a broad range of psychiatric disorders, from mood disorders to delirium and dementia, with co-morbid medical illness in 83.5% (112). On feedback evaluation (N = 98), mean scores ranged from 3.88-4.41 for patients, 4.36-4.73 for clinicians and 3.67-4.45 for psychiatrists. Feedback from inpatients (14 out of 37) was significantly lower compared to outpatients (37 out of 61) (chi sq. = 0.808, p < 0.05), and they were significantly less satisfied with the wait time (U = 163.0, p < 0.05) and visual clarity (U = 160.5, p < 0.05). Audio clarity was the most common aspect of dissatisfaction (mean score less than 3) among patients (6, 11%). Psychiatrists reported a preference for telepsychiatry over face to face in 55.4% (46) assessments. However, they expressed discomfort in situations of cognitive or sensory disabilities in patients., Conclusions: In rural and remote areas, community-based telepsychiatry program can be a useful adjunct for psychiatrist input in the care of older adults. Innovations to overcome sensory deficits and collaboration with community services should be explored to improve its acceptance among the most vulnerable population.

Background: Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15-20% of lithium users and predicts a 2-3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin., Methods: We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18-85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline., Results: Not applicable., Conclusion: The aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk., Trial Registration: ClinicalTrials.gov NCT02967653 . Registered in February 2017.

Background: Nicotinic acetylcholine receptors (nAChR) have been implicated in the pathophysiology of schizophrenia, and deficits in this system may contribute to high rates of cigarette smoking in this population. nAChR stimulation may modulate neuroplasticity, or long-term potentiation (LTP), which is a key mediator of cognitive performance. Varenicline is a nAChR partial agonist that may improve cognitive deficits in both smokers and non-smokers with schizophrenia; however, the mechanism by which varenicline alters cognition in schizophrenia remains unclear. Thus, the aim of this randomized, double-blind, placebo-controlled, crossover study was to determine the effects of varenicline on LTP-like plasticity indexed through transcranial magnetic stimulation (TMS) in non-smokers with schizophrenia., Methods: Varenicline (0.5mg BID × 5 doses) or placebo was administered to 9 non-smokers with schizophrenia and 10 non-smoker healthy subjects. LTP-like plasticity was induced by TMS and paired associative stimulation (PAS) at 0.1Hz to the left motor cortex and measured every 15min for two hours post-PAS., Results: There was a significant diagnosis × medication interaction on peak potentiation (F (3, 34)=6.04, p<0.02) and post-hoc analyses indicated that varenicline significantly increased LTP in schizophrenia and decreased LTP in healthy subjects., Conclusions: These preliminary findings suggest that varenicline may produce differential effects in non-smoking schizophrenia compared to control subjects. Given the role of LTP in learning and memory, these observations may suggest the potential for varenicline in the treatment of cognitive deficits in patients with schizophrenia., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This paper summarizes the existing evidence for integrated care pathways (ICPs) for the treatment of schizophrenia. Scoping review methods following PRISMA guidelines were employed due to the variable nature of the evidence in this area. The review identified 13 papers. Of these papers, 7 focused on describing ICP content and process-related data and 6 examined clinical outcomes. Of the 6 studies providing outcome data, 2 reported improved outcomes associated with ICPs. Conceptually, ICPs hold great promise for improving the quality of schizophrenia care. However, in contrast with other specialty healthcare domains, the schizophrenia ICP evidence base is very limited and has not fulsomely begun to address ICPs for effectiveness.

Background: Deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG) is becoming an effective therapeutic option for treatment resistant depression (TRD)., Objective/hypothesis: Identifying the neurophysiological mechanisms altered by DBS may lead to more tailored treatment parameters and enhanced efficacy., Methods: Twenty TRD patients with implanted DBS in the SCG were recruited. Patients participated in three EEG recording sessions, one with DBS ON, one with DBS randomized to ON or OFF, and one with DBS OFF. During each session, subjects performed N-back working memory tasks, namely the 0-back and 3-back. Fourteen subjects with valid EEG were included in the analysis. Changes in frontal gamma oscillations (30-50 Hz) and coupling between theta (4-7 Hz) and gamma oscillations as a result of DBS stimulation were quantified and correlated with depressive symptoms., Results: DBS stimulation resulted in suppression of frontal oscillations in the ON state relative to the OFF state during the N-back tasks. Greatest suppression was demonstrated in beta and gamma oscillations and most pronounced during the 3-back. Suppression of gamma oscillations in the 3-back correlated with a reduction in depressive symptoms. DBS ON relative to OFF in the 3-back also resulted in an increase in theta-gamma coupling that correlated with a reduction in depressive symptoms., Conclusion: Suppression of gamma oscillations and increased theta-gamma coupling through DBS is likely mediated by both SCG activation of inhibitory circuits and an enhancement of plasticity in the frontal cortex. Activation of both pathways may explain the therapeutic properties of DBS in TRD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Schizophrenia is a severe mental disorder characterised by a complex phenotype including positive, negative, affective and cognitive symptoms. Various theories have been developed to integrate the clinical phenotype into a strong neurobiological framework. One theory describes schizophrenia as a disorder of impaired neural plasticity. Recently, non-invasive brain stimulation techniques have garnered much attention to their ability to modulate plasticity and treat schizophrenia. The aim of this review is to introduce the basic physiological principles of conventional non-invasive brain stimulation techniques and to review the available evidence for schizophrenia. Despite promising evidence for efficacy in a large number of clinical trials, we continue to have a rudimentary understanding of the underlying neurobiology. Additional investigation is required to improve the response rates to non-invasive brain stimulation, to reduce the interindividual variability and to improve the understanding of non-invasive brain stimulation in schizophrenia.

Antipsychotic medications are widely used to manage psychotic and behavioral disorders in older adults, including primary psychotic disorders such as schizophrenia, and psychosis and behavioral disturbances associated with dementia. These two broad diagnostic indications are associated with contrasting recommended treatment durations, with the former requiring indefinite treatment across the life span. Antipsychotic drug dosing for schizophrenia is based primarily on studies of younger patients and thus may not apply to older adults. It is critically important to address the effects of aging on antipsychotic dosing given the recent emergence of data that suggest a critical role for age-related sensitivity to these drugs. Antipsychotic drugs are not only associated with somatic and neurological adverse effects but also increased all-cause mortality and sudden cardiac death in this vulnerable population. This review focuses on the sensitivity of older adults to adverse effects from antipsychotic medications and the current pharmacokinetic and pharmacodynamic explanatory models of susceptibility. Implications of recent research findings for individualized pharmacotherapy are discussed.