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This randomized clinical trial assesses the efficacy of cognitive remediation plus transcranial direct current stimulation targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to dementia in older adults with remitted major depressive disorder, mild cognitive impairment, or both. Key Points: Question: Does cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) slow cognitive decline in older adults with remitted major depressive disorder (rMDD) or mild cognitive impairment (MCI)? Findings: In this randomized clinical trial including 375 participants with rMDD or MCI, those randomized to receive active CR plus active tDCS experienced a slower cognitive decline over a median follow-up of 4 years than those randomized to receive sham-plus-sham treatments. The effects were more prominent in the rMDD (with or without MCI) than in the MCI without rMDD group. Meaning: The treatment of CR plus tDCS is effective in slowing cognitive decline in older adults with rMDD. Importance: Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline. Objective: To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both. Design, Setting, and Participants: This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years. Interventions: CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. Main Outcomes and Measures: The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time. Results: Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active − sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P =.006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active − sham] at month 2, 0.06, 95% CI, −0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P =.10). Preplanned analyses showed treatment effects for executive function (LRT P =.04) and verbal memory (LRT P =.02) and interactions with diagnosis (P =.01) and APOE ε4 (P <.001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4. Conclusions and Relevance: The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease. Trial Registration: ClinicalTrials.gov Identifier: NCT02386670 [ABSTRACT FROM AUTHOR]

Background: Apathy and depression are common neuropsychiatric symptoms across neurodegenerative disorders and are associated with impairment in several cognitive domains, yet little is known about the influence of sex on these relationships. Objectives: We examined the relationship between these symptoms with neuropsychological performance across a combined cohort with mild or major neurodegenerative disorders, then evaluated the impact of sex. Design, Setting and Participants: We conducted a cohort analysis of participants in the COMPASS‐ND study with mild cognitive impairment (MCI), vascular MCI, Alzheimer's disease, mixed dementia, Parkinson's disease, frontotemporal dementia, and cognitively unimpaired (CU) controls. Measurements: Participants with neurodegenerative disease and CU controls were stratified by the presence (severity ≥1 on Neuropsychiatric Inventory Questionnaire) of either depressive symptoms alone, apathy symptoms alone, both symptoms, or neither. A neuropsychological battery evaluated executive function, verbal fluency, verbal learning, working memory, and visuospatial reasoning. Analysis of covariance was used to assess group differences with age, sex, and education as covariates. Results: Groups included depressive symptoms only (n = 70), apathy symptoms only (n = 52), both (n = 68), or neither (n = 262). The apathy and depression + apathy groups performed worse than the neither group on tests of working memory (t(312) = −2.4, p = 0.02 and t(328) = −3.8, p = 0.001, respectively) and visuospatial reasoning (t(301) = −2.3, p = 0.02 and t(321) = −2.6, p = 0.01, respectively). The depression, apathy, and depression + apathy groups demonstrated a similar degree of impairment on tests of executive function, processing speed, verbal fluency, and verbal learning when compared to participants without apathy or depression. Sex‐stratified analyses revealed that compared to the male neither group, the male apathy and depression + apathy groups were impaired broadly across all cognitive domains except for working memory. Females with depression alone showed deficits on tests of executive function (t(166) = 2.4, p = 0.01) and verbal learning (t(167) = −4.3, p = 0.001) compared to the female neither group. Conclusions: This study demonstrated that in neurodegenerative diseases, apathy with or without depression in males was associated with broad cognitive impairments. In females, depression was associated with deficits in executive function and verbal learning. These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes. Key points: Apathy and depression are common symptoms that patients with dementia face during the course of illness, and these symptoms are associated with impairments in several cognitive domains.We examined differences in cognitive performance between patients with either apathy alone, depression alone, both, or neither across a combined cohort with mild or major neurodegenerative disorders. Further, we evaluated this relationship within each sex.Among males, apathy with or without depression was associated with broad cognitive deficits. In females, depression was associated with deficits in executive function and verbal learning.These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a risk factor for Alzheimer's disease (AD). Cerebrovascular disease (CVD) is implicated in MDD and AD. Our study compared participants with AD positive and negative cerebrospinal fluid (CSF) biomarkers on neuropsychological performance, remitted MDD status, and CVD burden. Next, we compared AD-CSF biomarkers and white matter hyperintensities (WMH) burden among three groups: mild cognitive impairment (MCI) (n = 12), MCI with remitted MDD (MDD+MCI) (n = 12), and remitted MDD alone (MDD) (n = 7). Few participants (18%) with MCI+MDD exhibited AD(+) biomarkers. Nearly all participants had moderate-severe WMH. WMH may contribute to cognitive impairment or depression in MCI patients with AD(-) biomarkers. [ABSTRACT FROM AUTHOR]

Background: Recent work suggests that APOEɛ4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS).Objective: To examine the interaction of sex and APOEɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261).Methods: Regression models examined the interactive effects of sex and APOEɛ4 on the number of NPS experienced and NPS Severity. APOEɛ3/4 and APOEɛ4/4 were pooled in the at-risk cohort due to the sample size.Results: In the at-risk cohort, there was a significant sex*APOEɛ4 interaction (p = 0.007) such that the association of APOEɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOEɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOEɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOEɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males.Conclusion: Our study suggests that sex modifies the association of APOEɛ4 on NPS burden. APOEɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: The biological mechanisms linking mild cognitive impairment (MCI) and major depressive disorder are not well understood. We investigated whether molecular senescence changes in older adults are associated with a history of major depressive disorder (MDD) or MCI. Methods: We included 371 participants: 167 with MCI; 62 cognitively normal with a history of MDD; 97 with MDD+MCI; and 45 cognitively unimpaired (CU) without a history of MDD. The candidate Senescence-Associated Secretory Phenotype (SASP) biomarkers were measured in the plasma using a customized LUMINEX assay. Results: The MDD+MCI group had a higher SASP index than the other groups (P < .001). A higher SASP index was significantly associated with worse global cognitive performance, executive dysfunction, slower processing speed, and episodic memory deficits. Discussion: Our study suggests that increased molecular changes are associated with cognitive impairment in older adults with MDD and indicate that accelerated biological aging is an underlying feature of MDD. [ABSTRACT FROM AUTHOR]

Background: By the time Alzheimer's disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed.Objective: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups.Methods: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI.Results: PACt-MD (Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants.Conclusion: PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Exercise interventions have been shown to successfully improve depression in patients with major depressive disorder (MDD), but like other forms of antidepressant treatment, exercise is not effective in all patients and its mechanisms of action have not been fully elucidated. Brain-derived neurotrophic factor (BDNF), a key mediator of neurogenesis and neuronal survival, has been shown to be decreased in individuals with MDD. One potential mechanism by which exercise alleviates depression is through an increase in BDNF. In order to evaluate this hypothesis, we conducted a meta-analysis of studies that assessed the effects of a chronic (multi-week) exercise intervention on BDNF concentrations in MDD patients. MEDLINE, Embase, PsycINFO, SPORTDiscus, Rehabilitation & Sports Medicine Source, and CINAHL databases were searched for original, peer-reviewed reports of peripheral blood BDNF concentrations before and after a chronic exercise intervention in MDD patients. Standardized mean differences (SMDs) were generated from random effects models. Potential sources of heterogeneity were explored in meta-regression analyses. In six studies that met inclusion criteria, resting blood concentrations of BDNF were not significantly higher after a chronic exercise intervention (SMD = 0.43, 95% CI: −0.06–0.92, p = 0.09) in MDD patients. This meta-analysis did not find evidence that a chronic aerobic exercise intervention increases resting concentrations of BDNF in the blood of MDD patients; however, there is a lack of studies in this area making it difficult to reach a definitive conclusion. Future studies on this topic with larger sample sizes and longer durations are needed to draw more robust conclusions. [ABSTRACT FROM AUTHOR]

Objective: To explore the effect of exercise on cognition in depression as well as the impact of potential moderators and intervention type.Method: Controlled and uncontrolled interventional studies that described an exercise intervention and cognitive outcomes in participants with major depressive disorder (MDD) were included following a search of Pubmed, Ovid Medline, PsycInfo and Embase from inception to January 2017. Meta-analyses were conducted to calculate Hedges' g using a random-effects model. Meta-regression explored the relationships among age, baseline cognition, frequency and duration of exercise, and cognitive outcomes. Subgroup analyses were also conducted according to type and intensity of exercise interventions.Results: Of 12 controlled studies and 3 uncontrolled studies that met inclusion criteria, 9 (642 patients) were included in the meta-analysis. No significant effect of exercise was found on global cognition (Hedges' g = 0.08, P = 0.33, I2 = 0%) or on individual cognitive domains. Meta-regression analyses failed to find significant relationships among participant age, baseline cognition, number of exercise sessions per wk, duration of exercise per wk, total duration of exercise during the intervention, or improvement in global cognition. Interventions combining physical with cognitive activity significantly improved global cognition ( P = 0.048), whereas low-intensity interventions were also positive ( P = 0.048).Conclusions: No impact of physical exercise was found on cognition in MDD overall. However, we found that interventions combining physical and cognitive activities had a positive impact, and that lower-intensity interventions, where adherence was improved, also impacted positively. There remains a lack of high-quality data in this population. [ABSTRACT FROM AUTHOR]

Objective: It has been proposed that inflammation may be causally related to depression. If this is the case, it may be possible to distinguish an inflammatory depressive subtype according to illness course, pattern of co-morbidity and symptom profile.Methods: Eight hundred and eleven community dwelling older adults with depression (8 item Center for Epidemiologic Studies scale ≥ 4) from the English Longitudinal study of Ageing (ELSA) were followed for a median of 47 months. Participants with depression and inflammation (C Reactive Protein > 3 mg/l) were compared to those with depression alone.Results: In a longitudinal analysis, depression with associated inflammation was more likely to persist over time. This association was independent of baseline depression severity and medical co-morbidity (OR 1.47 95% CI 1.03 - 2.10, p = 0.034) but was no longer significant following further adjustment for body mass index (OR 1.37 95% CI 0.94 - 2.01, p = 0.106). Inflammation either partially or completely mediated the association between medical co-morbidity, body mass index and depression at follow-up. Depression with inflammation was associated with more amotivation, less sadness, greater medical co-morbidity and higher body mass index.Conclusions: Our findings provide some support for an inflammatory contribution to depression. This subgroup has a worse prognosis and may benefit from interventions targeting co-morbidity, body mass index and associated inflammation. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder is a significant contributor to global disability and mortality. The mechanisms of depression are vast and not fully understood, and as a result current treatment of depression is suboptimal. Aberrant sphingolipid metabolism has been observed in some cases of depression, specifically alterations in ceramide concentrations. The role of ceramides and other sphingolipids in depression is a novel concept. This review summarizes and evaluates the current state of evidence for a role of ceramides in depression pathophysiology and the potential for novel depression pharmacotherapies targeting ceramide metabolism.Methods: Medline, Embase, and PsycINFO databases were searched through October 2016 for English-language studies using combinations of the search terms: ceramide, depression, sphingolipid, and depressive symptoms.Results: Of the 489 articles screened, 14 were included in the qualitative synthesis of this review article. Pre-clinical and clinical evidence suggest that ceramide species may contribute to depression pathophysiology. In human studies, ceramides C18:0 and C20:0 are the species most strongly linked to depression. Evidence for altered ceramide metabolism in depression is present, but data for a causal role of ceramides in depression are lacking.Limitations: This review was limited by potential reporting bias. Furthermore, a lack of specificity of which ceramides were altered in depression was common.Conclusions: Pharmacotherapy targeting ceramide metabolism may be a novel treatment option for depression. A number of pharmacological targets exists for ceramide reduction and a number of currently approved medications inhibit ceramide production. More evidence, pre-clinical and clinical, is warranted to determine the extent and consistency of the role of ceramides in depression. [ABSTRACT FROM AUTHOR]

Background Antidepressant efficacy of omega-3 polyunsaturated fatty acid (n-3 PUFA) treatment in coronary artery disease (CAD) patients remains unpredictable. N-3 PUFA can mitigate oxidative stress, which is common in CAD and may contribute to depressive symptoms. This study investigated whether greater pre-treatment oxidative stress, measured by the ratios of late-stage lipid peroxidation markers (malondialdehyde [MDA], 4-hydroxy-2-nonenal [4-HNE], and 8-isoprostane [8-ISO]) to an early-stage marker (lipid hydroperoxides [LPH]), predicted n-3 PUFA antidepressant benefits in CAD. Methods This was a secondary analysis of CAROTID (CAD Randomized Omega-3 Trial in Depression, NCT00981383). Patient demographics and medical characteristics were collected. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAM-D). Patients were then randomized to receive either 1.9 g/day n-3 PUFA or placebo for 12 weeks, after which HAM-D scores were reassessed. Baseline LPH, 4-HNE, 8-ISO, MDA and n-3 PUFA concentrations were analysed from fasting blood. Results Seventy-nine patients (age = 61.1 ± 8.5, 76% male, HAM-D = 7.5 ± 6.1) were included (n = 45 placebo, n = 34 n-3 PUFA). In the n-3 PUFA group, higher baseline ratios of MDA/LPH (primary analysis: F 1,33 = 6.20, beta = −0.35, p = 0.018), 4-HNE/LPH (exploratory analysis: F 1,33 = 5.35, beta = −0.32, p = 0.027), and 8-ISO/LPH (exploratory analysis: F 1,33 = 6.10, beta = −0.33, p = 0.019), indicating higher oxidative stress, were associated with greater depressive symptom improvement. In each model, higher baseline EPA + DHA concentrations independently predicted depressive symptom improvement with n-3 PUFA (MDA/LPH: F 1,33 = 11.05, p = 0.002; 4-HNE/LPH: F 1,33 = 11.36, p = 0.002; 8-ISO/LPH: F 1,33 = 13.15, p = 0.001). No associations were observed in the placebo group. Conclusions n-3 PUFA may be more likely to improve depressive symptoms in CAD patients with pre-treatment evidence of oxidative stress. [ABSTRACT FROM AUTHOR]

Background: In a recent report, 76 weeks' treatment with a gamma-secretase inhibitor (semagacestat) was associated with poorer cognitive outcomes in Alzheimer's disease (AD).Objective: We sought to examine the effect of semagacestat treatment on neuropsychiatric symptoms (NPS).Methods: 1,537 participants with mild to moderate AD were randomized to 76 weeks' treatment with placebo versus two doses of semagacestat. NPS were assessed with the Neuropsychiatric Inventory (NPI-Total and subdomains). Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive (first 11 items, ADAS11). Mixed-Model Repeated Measures was used to compare the effects of treatment assignment on change in NPI-total and subdomains over time. Survival analysis was used to assess the treatment effect on time to first worsening of NPS (NPI-Total ≥10 or NPI subdomain ≥4) for subjects with no or minor NPS at baseline.Results: Participants on high dose semagecestat (140 mg) had greater increase in NPI-Total and greater risk of incident first worsening in NPI-Total and in subdomains of aberrant motor behavior, appetite, depression/dysphoria, and sleep. ADAS11 increased more in participants whose NPI-Total increased.Conclusion: In participants with mild to moderate AD, high dose semagacestat treatment was associated with greater severity and faster worsening of NPS in a pattern resembling an agitated depression. Increased NPS was associated with cognitive decline regardless of treatment assignment. These findings suggest that greater NPS may be the result of gamma-secretase treatment and emphasize the importance of monitoring NPS as potential adverse events in trials of novel treatments for AD. [ABSTRACT FROM AUTHOR]

Background: Zinc is an essential micronutrient with diverse biological roles in cell growth, apoptosis and metabolism, and in the regulation of endocrine, immune, and neuronal functions implicated in the pathophysiology of depression. This study sought to quantitatively summarize the clinical data comparing peripheral blood zinc concentrations between depressed and nondepressed subjects. Methods: PubMed, Cumulated Index to Nursing and Allied Health Literature, and PsycINFO were searched for original peer-reviewed studies (to June 2012) measuring zinc concentrations in serum or plasma from depressed subjects (identified by either screening or clinical criteria) and nondepressed control subjects. Mean (±SD) zinc concentrations were extracted, combined quantitatively in random-effects meta-analysis, and summarized as a weighted mean difference (WMD). Results: Seventeen studies, measuring peripheral blood zinc concentrations in 1643 depressed and 804 control subjects, were included. Zinc concentrations were approximately −1.85 µmol/L lower in depressed subjects than control subjects (95% confidence interval: [CI]: −2.51 to −1.19 µmol/L, Z 17 = 5.45, p < .00001). Heterogeneity was detected (χ2 17 = 142.81, p < .00001, I2 = 88%) and explored; in studies that quantified depressive symptoms, greater depression severity was associated with greater relative zinc deficiency (B = −1.503, t 9 = −2.82, p = .026). Effect sizes were numerically larger in studies of inpatients (WMD −2.543, 95% CI: −3.522 to −1.564, Z 9 = 5.09, p < .0001) versus community samples (WMD −.943, 95% CI: −1.563 to −.323, Z 7 = 2.98, p = .003) and in studies of higher methodological quality (WMD −2.354, 95% CI: −2.901 to −1.807, Z 7 = 8.43, p < .0001). Conclusions: Depression is associated with a lower concentration of zinc in peripheral blood. The pathophysiological relationships between zinc status and depression, and the potential benefits of zinc supplementation in depressed patients, warrant further investigation. [ABSTRACT FROM AUTHOR]

This paper reviews the discovery and history of the use of irreversible monoamine oxidase (MAO) inhibitors (MAOIs) such as phenelzine, tranylcypromine and isocarboxazid, as well as the second generation selective and reversible MAOIs such as the MAO-A inhibitor, moclobemide and the MAO-B inhibitor, selegiline. Data for review were identified from a literature search of OvidSP Medline and PsycInfo performed in July 2012, using the subject terms and keywords of ‘monoamine oxidase inhibitors’, ‘major depression’, ‘depressive disorder’ and ‘depression (emotion)’. The search was limited to papers published in the English language and from 2007 onward only. Irreversible MAOIs have the potential to treat the most challenging mood disorder patients including those with treatment-resistant depression, atypical depression and bipolar depression. Unfortunately, the use of irreversible MAOIs has been declining sharply due to lack of marketing and the excessive fears of clinicians. Moreover, few clinicians now have any experience, let alone comfort, in prescribing this class of antidepressants. The newer MAOIs are available as another option for the treatment of major depression but have not replaced the irreversible MAOIs for the specific sub-types of depression for which they are now recommended in most consensus guidelines and treatment algorithms. The pharmacology, drug interactions and dietary recommendations associated with the use of MAOIs are reviewed. With the appropriate dietary restrictions and attention to potential drug interactions with serotonin and noradrenaline agents this class of drugs can be used effectively and safely. The MAOIs still represent an important element in our therapeutic armamentarium. Despite recommendations by opinion leaders and consensus guidelines for the use of MAOIs in specific sub-types of depression, the prescription rate of MAOIs is far less than expected and is decreasing. The “bad reputation” and the lack of industry support for this class of agents (especially the irreversible MAOIs) must be overcome in order to continue to provide a potentially useful treatment for a very vulnerable yet substantial sub-population of mood disorder patients. [ABSTRACT FROM AUTHOR]

Highlights: [•] Plasma zinc concentrations are lower in major depression. [•] Zinc deficiency induces depression-like behaviors in animals. [•] Zinc interacts with multiple endocrine and immune functions. [•] Synaptic zinc modulates neural networks that regulate mood and cognition. [Copyright &y& Elsevier]

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Objective: Vascular risk factors (VRFs) have been associated with stroke and cognitive impairment, however, the role of VRFs in predicting post-stroke depression (PSD) has not been assessed. The objective of the current study was to determine whether VRFs are associated with the risk of PSD in an acute stroke population. Methods: In this observational study, patients meeting World Health Organization MONICA Project and National Institute of Neurological Disorders and Stroke criteria for stroke were eligible. Patients were assessed for depression, cognition, and stroke severity, and VRF and demographic information were obtained. Results: A total of 102 patients were recruited within 4 months post-stroke. Using a score of ≥16 on the Center for Epidemiological Studies Depression scale to determine depressive symptoms, 38 patients (age 72.1 ± 15.6, 44.7% male) screened positive for depressive symptoms and 64 (age 70.1 ± 13.6, 51.6% male) screened negative. Analysis of VRFs showed that only hypertension (P = .044) independently predicted the presence of depressive symptoms (χ2 = 4.742, P = .029, Nagelkerke R2 = .062). Conclusions: Hypertension was associated with post-stroke depressive symptoms, while there was no relationship between PSD and other VRFs. Hypertension may have a greater impact than other VRFs on mood following stroke and may have a role in prevention and treatment of PSD. [ABSTRACT FROM PUBLISHER]

The article discusses a study on the effects of major depressive disorder (MDD) on completion, adherence and outcomes in cardiac rehabilitation (CR). The study involved 195 patients with coronary artery disease (CAD) at the Cardiac Program of the Toronto Rehabilitation Institute in Ontario. Patients with MDD showed higher CR noncompletion and nonadherence rates compared to those without MDD. Poorer cardiopulmonary fitness increases were also observed in patients with MDD.

This analysis assessed 3 subscales derived from the nursing home Minimum Data Set (MDS), the Cognitive Performance Scale (CPS), Depression Rating Scale (DRS), and Aggressive Behavior Scale (ABS), as outcome measures in clinical trials of long-term care residents with Alzheimer disease (AD). A total of 26 patients with moderate-to-severe AD and agitation/aggression enrolled in a trial of memantine were assessed using the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory Nursing Home Version (NPI-NH), and the Cohen-Mansfield Agitation Inventory (CMAI) administered by trained researchers. MDS data were collected as part of their standard clinical care. The MDS subscales correlated significantly with their corresponding research scales: CPS and MMSE (r = -0.57, P = .003); DRS and NPI-NH total (r = 0.42, P = .038); DRS and NPI-NH depression (r = 0.41, P = .04), and ABS and CMAI (r = 0.54, P = .004). DRS and ABS scores did not change significantly from baseline to 3 months though the NPI-NH and CMAI did, indicating limited sensitivity to change. This suggests that the MDS subscales measure comparable aspects of cognitive function and depressive and agitated/aggressive behavior as the MMSE, NPI-NH, and CMAI. However, this analysis also suggests that sensitivity to change of the DRS and ABS may be limited compared to the NPI-NH and CMAI. As these findings are preliminary, further research is needed to determine the utility of MDS scales in outcomes research. [ABSTRACT FROM AUTHOR]

Background: Activation of indoleamine 2,3-dioxygenase (IDO) and higher concentrations of several kynurenine metabolites have been observed post-stroke, where they have been associated with increased mortality. While lower tryptophan or a higher ratio of kynurenine/tryptophan (K/T) in peripheral blood have been associated with dementia and the severity of cognitive symptoms in Alzheimer's disease, the association between K/T ratios and post-stroke cognitive impairment (PSCI) has not been investigated. Methods: Patients were recruited from the acute stroke unit of a general hospital within 1 month post-stroke. Assessments included the Standardized Mini-Mental State Examination (sMMSE) for cognition, the National Institutes of Health Stroke Scale (NIHSS) for stroke severity, and the Center for Epidemiological Studies-Depression Scale (CES-D) for depressive symptoms. Tryptophan and kynurenine concentrations were determined by highperformance liquid chromatography. Results: A total of 41 patients with ischemic stroke ([mean ± SD] age 72.3 ± 12.2 years, 53.7% male, sMMSE 25.6 ± 4.1, NIHSS 7.27 ± 5.55) were recruited. Higher K/T ratios were associated with lower post-stroke global cognition (i. e. sMMSE scores; β = -.327, P = .037). A backward stepwise elimination linear regression (F1,40 =6.15, P=.005, adjusted R2=.205) showed that the highest K/T ratio tertile (β = -.412, P = .006) predicted lower sMMSE scores, controlling for age (β = -.253, p = .081), with NIHSS (β = -.027, P = 0.859), and lesion volume (β = -.066, P = 0.659) removed from the model. In receiver operating characteristic analysis, a K/T ratio of 78.3 μmol/mmol (top tertile) predicted significant cognitive impairment (sMMSE score≦ 24) with 67% sensitivity and 86% specificity (area under the curve = 0.730, p = .022). Conclusions: These data suggest an inflammatory response characterized by IDO activation may be relevant to the development of PSCI. Since the neuroactivity of kynurenine metabolites may be amenable to pharmacotherapeutic intervention, the K/T ratio may be a clinically important biomarker. [ABSTRACT FROM AUTHOR]

Objectives: To determine which serotonergic system-related single nucleotide polymorphisms (SNPs) predicted variation in treatment response to citalopram in depression following a traumatic brain injury (TBI). Methods: Ninety (50 M/40 F, aged 39.9, SD = 18.0 years) post-TBI patients with a major depressive episode (MDE) were recruited into a 6-week open-label study of citalopram (20 mg/day). Six functional SNPs in genes related to the serotonergic system were examined: serotonin transporter (5HTTLPR including rs25531), 5HT1A C-(1019)G and 5HT2A T-(102)C, methylene tetrahydrofolate reductase (MTHFR) C-(677)T, brain-derived neurotrophic factor (BDNF) val66met and tryptophan hydroxylase-2 (TPH2) G-(703)T. Regression analyses were performed using the six SNPs as independent variables: Model 1 with response (percentage Hamilton Depression (HAMD) change from baseline to endpoint) as the dependent variable and Model 2 with adverse event index as the dependent variable (Bonferroni corrected p-value < 0.025). Results: MTHFR and BDNF SNPs predicted greater treatment response ( R2= 0.098, F = 4.65, p = 0.013). The 5HTTLPR predicted greater occurrence of adverse events ( R2= 0.069, F = 5.72, p = 0.020). Conclusion: Results suggest that polymorphisms in genes related to the serotonergic system may help predict short-term response to citalopram and tolerability to the medication in patients with MDE following a TBI. [ABSTRACT FROM AUTHOR]

Objective: Depression occurs in 18% to 45% of patients with coronary artery disease (CAD) where it is associated with an increased risk of acute coronary events and mortality. Our objective was to quantitatively summarize the data on the efficacy and tolerability of antidepressant (AD) treatment for depression in CAD. Methods: We performed a meta-analysis of randomized, placebo-controlled, double-blind trials with a database search of the English literature (to March 2008) and manual search of references. Results: Four clinical trials with ADs (mirtazapine, citalopram, fluoxetine, and sertraline) of a 9- to 24-week duration involving 798 subjects (402 ADs, 396 placebo) with documented CAD and meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for depression were included. ADs were superior to placebo for decreasing Hamilton Depression Rating Scale (HDRS) scores (402 ADs, 396 placebo; weighted mean difference 1.41, 95% CI 0.53 to 2.29, P = 0.002) and Beck Depression Inventory (BDI) scores (373 ADs, 369 placebo; weighted mean difference 2.27, 95% CI 0.60 to 3.94, P = 0.008). The proportion of patients (216 ADs, 213 placebo) who responded (a 50% or more reduction in HDRS scores, OR 1.72, 95% CI 1.17 to 2.54) and remitted (HDRS of 8 or less at final assessment, OR 1.80, 95% CI 1.18 to 2.74), were also significantly higher with AD, compared with placebo, with no significant differences between the 2 groups for overall dropouts (OR 0.84, 95% CI 0.42 to 1.68) or dropout owing to adverse events (OR 1.30, 95% CI 0.75 to 2.25). The combined studies were homogeneous except for overall dropout rate (P = 0.01). Conclusion: Treatment with ADs for depression in CAD results in significant therapeutic effects without substantially increased rates of discontinuation. [ABSTRACT FROM AUTHOR]

The article discusses a study which identified the prescription pattern and safety profile for irreversible monoamine oxidase inhibitors (MAOI) in older adults in Canada. The study explored the prevalence and incidence of irreversible MAOI use and the frequency of coprescribing MAOI with contraindicated medications between January 1, 1997 and April 14, 2007. It found that MAOI are underprescribed and underutilized in patients with atypical depression and treatment-refractory depression.

Summary: An increase in immune-stimulated synthesis of kynurenine from tryptophan by indoleamine 2,3-dioxygenase (IDO) has been observed in patients with coronary artery disease (CAD). However, neuropsychiatric correlates of IDO activation remain unexplored. We hypothesize that IDO activation, as measured by the kynurenine to tryptophan (K/T) ratio, is associated with depressive symptoms in those with CAD. This cross-sectional study recruited subjects with CAD (n =95) from a cardiac rehabilitation facility. Demographic, anthropometric and cardiac data were obtained by chart review. Patients using an antidepressant were excluded. The presence of a major depressive episode or minor depression was assessed using a structured clinical interview for depression based on Diagnostic and Statistical Manual 4th edition criteria. The Center for Epidemiological Studies-Depression Scale (CES-D) was used to quantify depressive symptoms. A standardized exercise stress test was used to assess cardiopulmonary fitness as summarized using the peak volume of oxygen consumption (Peak VO2). Kynurenine and tryptophan were assayed from fasting plasma samples to obtain the K/T ratio. Higher K/T ratios were significantly associated with higher CES-D scores (β =.322, p =.002) in a linear regression controlling for time since most recent acute coronary syndrome (tACS), age and sex. Twenty-four patients met criteria for depression (16 major depression; 8 minor depression). There was a trend towards higher K/T ratios in depressed vs. non-depressed patients (45.6±20.0μmol/mmol vs. 38.5±15.7μmol/mmol, F =3.778, p =.055) when controlling for age, sex and tACS. Activation of IDO is associated with the severity of depressive symptoms among patients with CAD. [Copyright &y& Elsevier]

Objectives To delineate the differences between older persons with and without a diagnosis of major depression. Methods Participants were recruited from three outpatient clinics serving older patients at St Michael's Hospital. To be included in the study, participants had to speak English and have no evidence of significant sensory deficits that would interfere with neuropsychological testing. Participants were excluded if they had active delirium, active CNS disease (including dementia), active substance abuse, unstable medical disease, recent ECT treatment and a current/past diagnosis of a psychotic disorder. The diagnosis of major depression was made by qualified professionals in accordance with established guidelines. Participants were administered structured measures assessing global cognition, medical co-morbidity, subjective memory complaints, mood and detailed neurocognitive testing evaluating working memory, attention and speed of processing. Differences between depressed and non-depressed subjects with respect to these measures were analyzed using analysis of variance (ANOVA). Results Thirty-six participants were included in this study. The depressed (n = 17) and non-depressed (n = 19) groups were well matched in terms of age, education, medical co-morbidity and mini-mental state exam (MMSE) score. While the depressed subgroup had significantly higher subjective memory, language and cognitive complaints, there were no significant differences observed between the two subgroups on measures of memory and learning, attention and speed of information processing, fine motor dexterity and verbal fluency. Conclusion This study suggests that while significant depressive symptoms are strongly associated with increased cognitive complaints, they are not associated necessarily with objective cognitive impairment. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine the role of the serotonin transporter gene polymorphisms on the risk of major depression following traumatic brain injury (TBI). Methods: Seventy-five patients who had sustained a TBI and who met the Diagnostic and Statistical Manual of Mental Disorders (4th ed) (DSM-IV) criteria for mood disorder due to TBI were compared to 99 controls with TBI but no mood disorder. The severity of depression was rated using the Hamilton Depression Rating Scale (HAMD) for the depressed patients. All patients were genotyped for the serotonin transporter gene-linked polymorphic region (5-HTTLPR) with the assay for the rs25531 allelic variant. Results: The distribution of genotype frequencies was not different between the depressed and control groups (χ2 = 1.43, df = 2, p = 0.488) and for the depressed patients there was no association between HAMD scores and the polymorphisms (t-test = 1.71, df = 68, p = 0.092). Conclusion: There was no evidence of association between the serotonin transporter gene polymorphisms and depression post-TBI. Future research is indicated into the possible role of other candidate genes as risk factors for depression in this population. [ABSTRACT FROM AUTHOR]

Objective: Depression in patients with Alzheimer's disease (AD) is common (15% to 63%) and is associated with significant morbidity and increased mortality. Our objective was to quantitatively summarize the data on the efficacy and safety of antidepressant treatment for depression complicating AD.Method: We performed a metaanalysis of randomized, double-blind, placebo-controlled trials of antidepressants with a database search of the English literature (up to 2006) and a manual search of references in the retrieved articles. We extracted the proportion of subjects who responded and remitted, experienced adverse events (AEs), discontinued treatment due to AEs, or discontinued treatment for any reason. Cognition scores were also extracted.Results: We included 5 studies, which involved 82 subjects treated with antidepressants and 83 subjects who received placebo treatment. Antidepressants were superior to placebo for both treatment response (odds ratio [OR] 2.32; 95% confidence interval [CI], 1.04 to 5.16) and remission of depression (OR 2.75; 95% CI, 1.13 to 6.65). There were no significant differences between the 2 groups for change in cognition (weighted mean difference -0.71, 95% CI, -3.20 to 1.79), overall dropouts (OR 0.70; 95% CI, 0.29 to 1.66) or dropout due to AEs (OR 1.41; 95% CI 0.36 to 5.54). The numbers needed to treat for one additional AD patient to respond to antidepressant treatment were 5 (95% CI, 3 to 59) and 5 (95% CI, 2 to 24) for remission of depression.Conclusions: Antidepressant treatment for depression in AD is efficacious, with rates of discontinuation that are comparable to placebo. Nonetheless, clinicians must be vigilant regarding the potential side effects of antidepressants in this population. [ABSTRACT FROM AUTHOR]

Objectives: To examine temporal trends in electroconvulsive therapy (ECT) use among all 12 million Ontario residents between January 1992 and December 2004 and to examine the differential trends in older adults, compared with younger ones.Methods: We undertook a time-series analysis to examine annual trends in the use and prevalence of ECT, using linked provincial datasets. Descriptive data were presented for the population as a whole, and then trends were described separately by age groups (younger and older). As a comparator, we similarly examined antidepressant prevalence for older adults over the same time period.Results: Overall rates of ECT prevalence were stable. Annual population rates of individuals receiving ECT increased by about 27%, from 12.3 per 100 000 population in 1992 to 15.6 per 100 000 in 1997, and then decreased to 12.5 per 100 000 by 2004. The population rates of ECT were about threefold higher among older adults, relative to the younger population. Antidepressant prevalence increased by 90.1% among older adults over the same time period. The female-to-male ratio was relatively stable over time.Conclusions: The rate of ECT has been relatively stable since the early 1990s. Older adults were much more likely to be prescribed a course of ECT than younger adults. ECT remains a commonly prescribed treatment, particularly in old age. [ABSTRACT FROM AUTHOR]

Context The pathophysiology of major depressive disorder (MDD) includes disturbances in several neuroanatomical substrates and neurotransmitter systems. The challenge is to elucidate the brain mechanisms of MDD behavioral symptoms, chiefly those of anhedonia. Objectives To visualize the neuroanatomical substrates implicated in altered reward processing in MDD, using functional magnetic resonance imaging in combination with a dopaminergic probe (a 30-mg dose of oral dextroamphetamine sulfate) to stimulate the brain reward system; and to test the hypothesis that a hypersensitive response to dextroamphetamine in MDD involves the prefrontal cortex and the striatum. Design and Interventions Among subjects with MDD and healthy control subjects, functional magnetic resonance imaging data were collected before and after single-blind administration of dextroamphetamine. Setting Subjects were recruited through local newspaper advertisements and by word of mouth. Participants Twelve depressed subjects (mean age, 34.83 years; male-female ratio, 6:6) met criteria for MDD according to the DSM-IV, were not taking antidepressants, and had no comorbid Axis I disorders. Twelve control subjects (mean age, 29.33 years; male-female ratio, 5:7) were healthy volunteers without a history of Axis I disorders. Main Outcome Measures Functional magnetic resonance imaging blood oxygen level–dependent activation was measured during a controlled task, and dextroamphetamine-induced subjective effects were assessed using the Addiction Research Center Inventory. Results Subjects with MDD had a hypersensitive response to the rewarding effects of dextroamphetamine (2-fold increase; t21 = 2.74, P = .01), with altered brain activation in the ventrolateral prefrontal cortex and the orbitofrontal cortex and the caudate and putamen (F1,44 = 11.93, P = .001). Conclusion Dopamine-related neuroanatomical substrates are involved in altered reward processing in MDD, shedding light on the neurobiology of the anhedonic symptoms in MDD and suggesting these substrates as future therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: The state of the brain reward system in major depressive disorder was assessed with dextroamphetamine, which probes the release of dopamine within the mesocorticolimbic system, a major component of the brain reward system, and produces measurable behavioral changes, including rewarding effects (eg, euphoria). We hypothesized that depressed individuals would exhibit an altered response to dextroamphetamine due to an underlying brain reward system dysfunction reflected by anhedonic symptoms. Methods: In a double-blind, placebo-controlled, randomized, parallel study, the behavioral and physiological effects of a single 30-mg dose of oral dextroamphetamine sulfate were measured. Forty patients with a diagnosis of DSM-IV major depressive disorder who were not taking antidepressant medications (22 assigned to dextroamphetamine and 18 to placebo) were compared with 36 control subjects (18 assigned to dextroamphetamine and 18 to placebo) using validated self-report drug effect measurement tools (eg, the Addiction Research Center Inventory), heart rate, and blood pressure. Results: Multiple regression analysis showed that severity of depression as measured by the Hamilton Rating Scale for Depression correlated highly with the rewarding effects of dextroamphetamine in the depressed group (model R[sup 2] = 0.63; interaction P = .04). A subsequent analysis categorizing the depressed group into patients with severe symptoms (Hamilton score >23) and those with moderate symptoms revealed a significant interaction between drug and depression (P = .02). Patients with severe symptoms reported rewarding effects 3.4-fold greater than controls. Conclusions: The results suggest the presence of a hypersensitive response is present in the brain reward system of depressed patients, which may reflect a hypofunctional state and may provide a novel pathophysiologic and therapeutic target for future studies. [ABSTRACT FROM AUTHOR]

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Lithium augmentation of antidepressant therapy in elderly outpatients has not been systematically assessed. A prospective, practice-based observational study of 44 patients comparing an antidepressant monotherapy group (N = 23) with a lithium augmentation group (N =21) was conducted in a geriatric psychiatry, outpatient clinic. The severity of depression was evaluated with the Montgomery-Asberg Depression Rating Scale (MADRS), the DSM-III-R Global Assessment of Functioning (GAF), a treatment effectiveness rating (ER) and the Geriatric Depression Scale (GDS). Patient-reported adverse events were systematically collected. The mean age for the group was 76.5 ± 6.0 years, 81.8% were female and the most common principal diagnosis was major depression (88.6%). Doxepin was the most commonly prescribed antidepressant (29.5%), followed by nortriptyline (27.2%) and phenelzine (15.9%). Patients receiving lithium augmentation were less depressed and functioning better than those in the antidepressant alone treatment group--MADRS: 8.5 ± 8.8 vs 13.9 ± 9.0 (p < 0.05); GAF: 77.9 ± 8.3 vs 68.5 ± 10.5 (p < 0.01); ER: χ[sup2] = 4.5 (p < 0.05); GDS: 4.0 ± 2.7 vs 5.9 ± 4.3 (NS). Patients in the lithium group tended to report fewer adverse events (3.7 ± 2.1 vs 5.0 ± 3.0 (NS)). Results suggest that lithium augmented patients are less depressed and report fewer adverse events than those on antidepressants alone. Lithium appears to be a safe and effective addition to antidepressant pharmacotherapy in the elderly. [ABSTRACT FROM AUTHOR]

Almost half of older patients with major depressive disorder (MDD) present with cognitive impairment, and one-third meet diagnostic criteria for mild cognitive impairment (MCI). However, mechanisms linking MDD and MCI remain unclear. We investigated multivariate associations between brain structural alterations and cognition in 3 groups of older patients at risk for dementia, remitted MDD (rMDD), MCI, and rMDD+MCI, as well as cognitively healthy nondepressed control participants. We analyzed magnetic resonance imaging data and cognitive domain scores in participants from the PACt-MD (Prevention of Alzheimer's Disease With Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression) study. Following quality control, we measured cortical thickness and subcortical volumes of selected regions from 283 T1-weighted scans and fractional anisotropy of white matter tracts from 226 diffusion-weighted scans. We assessed brain-cognition associations using partial least squares regressions in the whole sample and in each subgroup. In the entire sample, atrophy in the medial temporal lobe and subregions of the motor and prefrontal cortex was associated with deficits in verbal and visuospatial memory, language skills, and, to a lesser extent, processing speed (p <.0001; multivariate r = 0.30, 0.34, 0.26, and 0.18, respectively). Widespread reduced white matter integrity was associated with deficits in executive functioning, working memory, and processing speed (p =.008; multivariate r = 0.21, 0.26, 0.35, respectively). Overall, associations remained significant in the MCI and rMDD+MCI groups, but not the rMDD or healthy control groups. We confirm findings of brain-cognition associations previously reported in MCI and extend them to rMDD+MCI, but similar associations in rMDD are not supported. Early-onset and treated MDD might not contribute to structural alterations associated with cognitive impairment. [ABSTRACT FROM AUTHOR]

A letter to the editor "Combined Drug Therapy for an Elderly Depressed Patient" is presented.

This article presents a study which reports that some psychosocial therapies may reduce depression, aggression, or apathy in people with dementia. Behaviour therapy administered by a trained caregiver reduced depression in people with Alzheimer's disease and a major or minor depressive disorder. Psychomotor therapy reduced aggression compared with activity therapy in people with Alzheimer's disease. Multisensory stimulation/snoezelen therapy reduced apathy compared with activity therapy or no therapy in people with moderate to severe dementia. The neuropsychiatric symptoms of dementia, also known as behavioural and psychological symptoms of dementia are common, serious problems that effect the quality of life for both the patient and their caregivers.

Objective: Depressive symptoms are common among people with Type 2 diabetes mellitus (T2DM). This study aimed to validate the 3-factor structure of the 14-item Center for Epidemiological Studies Depression (CES-D) scale proposed by Carleton et al. (2013) in a T2DM population.Methods: The CES-D was administered to consecutive patients with T2DM entering a rehabilitation program. Construct validity was assessed using confirmatory factor analysis. Subscale viability, differential item functioning, and associations with clinical characteristics were tested in bifactor models.Results: Among adults with T2DM (n=305, age 56.9±11.1, 44.9% male, duration of diabetes 7.8±7.9years, HbA1c 0.076±0.014%), the construct validity of Carleton's 3-factor solution (negative affective, positive affective and somatic symptoms) was confirmed, although negative affective and somatic symptoms were highly correlated (r=0.926). The CES-D items can be summed to arrive at a total score (ωH=0.869), but not subscale scores (ωS>0.7). Differential item functioning was not found based on age or body mass index (BMI), but Item 1 ("I was bothered by things that don't usually bother me") was inflated in women and Item 7 ("I felt that everything I did was an effort") was inflated in those with higher glycosylated haemoglobin (HbA1c). The general depression factor decreased with age (β=-0.247, p<0.001) and increased with BMI (β=0.102, p=0.041) but not HbA1c (β=0.065, p=0.461). Negative affective symptoms (β=0.743, p=0.001), but not other depressive symptoms, were higher in women.Conclusions: The 14-item CES-D retained construct validity in adults with T2DM. Depressive symptoms were associated with younger age, female gender and BMI, but not with glycemic control. [ABSTRACT FROM AUTHOR]

Abstract: Stroke is a leading cause of physical disability with neurodegenerative sequelae such as dementia and depression causing significant excess morbidity. Stroke severity can be exacerbated by apoptotic cell death in ischemic tissue, of which inflammatory activity is a key determinant. Studies have identified harmful and beneficial sets of T lymphocytes that infiltrate the brain post-stroke and their activation signals, suggesting that they might be targeted for therapeutic benefit. Animal models and human studies implicate interleukin(IL)-17 and its congeners (e.g. IL-23, IL-21) as mediators of tissue damage in the delayed phase of the inflammatory cascade and the involvement of T lymphocytes in propagating IL-17 release. In this review, we highlight the current understanding of IL-17 secreting cells, including sets of CD4+ αβ and CD4− γδ T lymphocytes, as potentially important mediators of brain pathology post-stroke. Interactions between the IL-17 axis and innate pathways, positive feedback mechanisms that prolong or amplify IL-17, and IL-17 regulatory pathways may offer intervention targets to enhance recovery, prevent long-term decline, and improve quality of life. [Copyright &y& Elsevier]

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 (χ2 (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. [ABSTRACT FROM AUTHOR]

Objective We aimed to characterize self-poisoning deaths in people with cardiovascular disease (CVD) and compare to other suicide decedent groups. Methods Suicide deaths by self-poisoning in people with CVD (n = 151) were compared to suicide deaths by other methods in people with CVD (n = 260) and suicide deaths by self-poisoning in people without CVD (n = 509). Sub-analysis of the CVD self-poisoning group compared people with depression and without depression. Toxicology reports were compared between intentional self-poisoning groups. Results A higher proportion of suicide deaths were due to self-poisoning in the CVD group compared to the non-CVD group. People with CVD were less likely to have any identified stressor (excluding medical stressor) prior to dying from self-poisoning compared to those without CVD. Female sex, past suicide attempts, living circumstances, and comorbid substance abuse were each significantly associated with self-poisoning as the method of suicide in people with CVD. Opioid, any antidepressants, benzodiazepines, and tricyclic antidepressants (TCAs) were commonly identified as lethal in people with CVD. Compared to people in the CVD self-poisoning without depression group, people in the CVD self-poisoning with depression group were more likely to have lethal levels of TCAs. Conclusions Our findings characterize suicide deaths in people with CVD, and identified notable differences based on method of death and presence of depression. [ABSTRACT FROM AUTHOR]

Allostatic load (AL) indicates the cumulative impact of stress on homeostatic mechanisms. Depression and AL have been associated with cognitive deficits, but it is unclear if they do so independently. Using data from middle-aged participants in the observational longitudinal Midlife in the United States (MIDUS) study (n=708, 57.5% female, 63.8±10.6 years old in 2014), we assessed whether the effect of prior depression (Composite International Diagnostic Interview Short-Form in 1995) on cognitive decline between 2004 and 2013 (composite Z-scores derived from the Brief Test of Adult Cognition by Telephone and the Stop & Go Switch Task) was moderated by AL Z-scores in 2004 (calculated from biomarkers in blood, urine, and electrocardiography). A significant depression × AL interaction predicted a decline in a composite cognitive score (β=-0.066, SE=0.029, p=0.024) and executive function (β=-0.068, SE=0.025, p=0.007). Depression predicted a decline in composite cognition among those with AL Z-scores above -0.055. AL subdomains of lipid metabolism, glucose metabolism, cardiovascular function, and inflammation showed evidence of moderation. Middle-aged adults with depression who had higher allostatic load were at greater risk of cognitive decline. Future studies should evaluate whether the interaction predicts dementia and whether midlife interventions targeting depression and AL attenuate cognitive decline. [ABSTRACT FROM AUTHOR]

Background: Myocardial infarction (MI) has been associated with an increased risk of suicide, further increased among individuals with a comorbid psychiatric illness. A paucity of studies have examined details of suicide among individuals with cardiovascular disease (CVD) and comorbid depression. We aimed to compare demographic, clinical and suicide-specific characteristics between suicide victims with CVD with depression (CVD+D) and without comorbid depression (CVD-D).Methods: Coroner data on suicide decedents with CVD (n=413) occurring in Toronto, Canada from 1998 to 2012 were collected. Characteristics were compared between the CVD+D and CVD-D groups. Regression analysis examined for gender differences in these groups.Results: CVD+D subjects compared to CVD-D were more likely to have had a past suicide attempt (p=0.008), and to have experienced a bereavement (p=0.008) or financial stressor (p=0.005) in the past year. Each of these variables remained significantly associated with the presence of depression after the regression analysis. Within the CVD+D group, females were more likely to die from suicide by self-poisoning (p<0.0001) and males by shooting (p=0.001).Limitations: Psychological autopsies were not available. The definition of CVD was broad and the accuracy of its diagnosis could not be confirmed.Conclusion: Individuals with CVD+D who died from suicide had significant differences in clinical characteristics and specific stressors compared to those without depression. These data may help to better characterize suicide risk and prevention in this vulnerable population. [ABSTRACT FROM AUTHOR]

Background: Depressive symptoms have been associated with increased risk of cognitive decline in later life. There are no interventions proven to reduce risk of cognitive decline in older adults with depression, and it is unclear how these effects are mediated. We aim to determine what mediates the relationship between depressive symptoms and cognitive decline in later life.Methods: Seven thousand six hundred and sixty six community dwelling older adults (age ≥ 50) from the English Longitudinal study of Ageing (ELSA) underwent clinical assessment. Inflammation was assessed with C Reactive Protein and depressive symptoms were assessed with the 8-item version of the Center for Epidemiologic Studies (CESD) scale.Results: Five thousand, five hundred and ninety (73.5%) had a follow-up cognitive assessment after a median of 47 months. Depressive symptoms were independently associated with cognitive decline (B=0.09, p<0.001). Low physical activity, inflammation, metabolic syndrome and vascular risk factors were associated with elevated depressive symptoms. Low physical activity (z=2.16, p=0.03) and inflammation (z=2.3, p=0.02) mediated the relationship between depressive symptoms and cognitive decline while hypertension, diabetes and smoking also contributed.Limitations: This is an observational study with a limited duration of follow up. Not all variables related to cognitive decline were accounted for in this analysis.Conclusions: The relationship between depressive symptoms and cognitive decline in later life appears to be mediated by low physical activity, increased inflammation and vascular risk factors that may be amenable to modification. [ABSTRACT FROM AUTHOR]

The prevalence of depression is higher among people with type 2 diabetes (T2DM). Individually, both conditions are associated with systemic inflammation. This study aimed to summarize the clinical data comparing peripheral inflammatory markers in blood between people with T2DM, with and without comorbid depression. From 2187 records, we identified 20 original peer-reviewed articles from which blood inflammatory marker concentrations could be combined and compared between people with T2DM and comorbid depression (D) vs. no depression (ND) as standardized mean differences (SMD) in random effects meta-analysis. Concentrations of C-reactive protein (CRP; N D /N ND = 1742/15244, SMD = 0.31 95% confidence interval [0.16, 0.45], Z 16 = 4.03, p < 0.01; I2 = 84.0%) and interleukin-6 (IL-6; N D /N ND = 677/4349, SMD = 0.17 [0.04, 0.30], Z 4 = 2.58, p = 0.01; I2 = 48.1%), were higher, and concentrations of brain derived neurotrophic factor (BDNF; N D /N ND = 358/1512, SMD = −0.37 95% confidence interval [−0.64,−0.10], Z 2 = −2.68, p = 0.01; I2 = 61.2%) were lower, among those with depression. Depression in T2DM was associated with systemic inflammation and lower peripheral blood BDNF concentrations. Inconsistency between studies suggests the need to explore further population heterogeneity and pathophysiological elements. PROSPERO (CRD42020188509). • Comorbid depression in type 2 diabetes (T2DM) presents a clinical challenge. • In T2DM, depression was associated with higher interleukin-6 and C-reactive protein. • Higher C-reactive protein may reveal links with vascular comorbidity burden. • Lower brain-derived neurotrophic factor was found in depression in T2DM. [ABSTRACT FROM AUTHOR]

People with type 2 diabetes mellitus (T2DM) are at increased risk for depression. Both conditions are associated with disturbances in polyunsaturated fatty acids. Omega-3 and omega-6 fatty acids can be converted into bioactive epoxides by cytochrome P450s (CYP450), which play pro-resolving roles in the inflammatory response; however, soluble epoxide hydrolase (sEH) metabolizes epoxides into diols, which lack pro-resolving functions and can be cytotoxic. Here, we survey serum CYP450- and sEH-derived metabolite concentrations in people with T2DM with and without a major depressive episode. Sunnybrook Type 2 Diabetes Study (NCT04455867) participants experiencing a major depressive episode (research version of the Structured Clinical Interview for DSM-5 criteria) were matched 1:1 for gender, glycosylated hemoglobin A1c and body mass index to participants without a current depressive episode. Depression severity was assessed using the Beck Depression Inventory 2nd Edition (BDI-II). From fasting morning blood, unesterified serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry following solid phase extraction, and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay. Between 20 depressed and 20 non-depressed participants (mean age 58.9 ± 8.5 years, 65% women) with T2DM, several sEH-derived fatty acid diols, but not IL-6, were higher among those with a depressive episode (effect sizes up to d = 0.796 for 17,18-DiHETE, a metabolite of eicosapentaenoic acid [EPA]; t = 2.516, p = 0.016). Among people with a depressive episode, two epoxides were correlated with lower BDI-II scores: 12(13)-EpOME (ρ = −0.541, p = 0.014) and 10(11)-EpDPE (ρ = −0.444, p = 0.049), metabolites of linoleic acid and docosahexaenoic acid (DHA), respectively, while the ratio of 12,13-DiHOME/12(13)-EpOME was correlated with higher BDI-II scores (ρ = 0.513, p = 0.021). In people with T2DM, major depressive episodes and depressive symptom severity were associated with an oxylipin profile consistent with elimination of pro-resolving lipid mediators by sEH. • Oxylipin mediators are perturbed in type 2 diabetes mellitus (T2DM). • Soluble epoxide hydrolase (sEH)-derived diols were elevated in depressed T2DM patients. • Lower cytochrome P450 (CYP450)-derived epoxides were linked to greater depression severity. • Disruptions in the CYP450-sEH pathway were related to depressive episodes in people with T2DM. [ABSTRACT FROM AUTHOR]