Treatment Of Late-life Depression Research Articles

Mindfulness-Based Cognitive Therapy Regulates Brain Connectivity in Patients With Late-Life Depression.

Late-life depression (LLD) is an important public health problem among the aging population. Recent studies found that mindfulness-based cognitive therapy (MBCT) can effectively alleviate depressive symptoms in major depressive disorder. The present study explored the clinical effect and potential neuroimaging mechanism of MBCT in the treatment of LLD. We enrolled 60 participants with LLD in an 8-week, randomized, controlled trial (ChiCTR1800017725). Patients were randomized to the treatment-as-usual (TAU) group or a MBCT+TAU group. The Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) were used to evaluate symptoms. Magnetic resonance imaging (MRI) was used to measure changes in resting-state functional connectivity and structural connectivity. We also measured the relationship between changes in brain connectivity and improvements in clinical symptoms. HAMD total scores in the MBCT+TAU group were significantly lower than in the TAU group after 8 weeks of treatment (p < 0.001) and at the end of the 3-month follow-up (p < 0.001). The increase in functional connections between the amygdala and middle frontal gyrus (MFG) correlated with decreases in HAMA and HAMD scores in the MBCT+TAU group. Diffusion tensor imaging analyses showed that fractional anisotropy of the MFG-amygdala significantly increased in the MBCT+TAU group after 8-week treatment compared with the TAU group. Our study suggested that MBCT improves depression and anxiety symptoms that are associated with LLD. MBCT strengthened functional and structural connections between the amygdala and MFG, and this increase in communication correlated with improvements in clinical symptoms.Randomized Controlled Trial; Follow-Up Study; fMRI; Brain Connectivity

Effects of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, on Perceived Stress and Cognitive Function Among Patients With Late-Life Depression: A Randomized, Double-Blind, Sertraline- and Placebo-Controlled Trial.

BackgroundCompared with adults with depression in the general population, elderly depressive patients are prone to poor treatment response, more side effects, and early withdrawal with current antidepressants (which principally modulate monoamines). Whether N-methyl-D-aspartate receptor enhancement can benefit treatment of late-life depression deserves study. This study aims to compare sodium benzoate (a D-amino acid oxidase inhibitor and an indirect N-methyl-D-aspartate receptor enhancer), sertraline (a selective serotonin reuptake inhibitor), and placebo in the treatment of late-life depression.MethodsIn this randomized, double-blind trial, 117 patients with major depressive disorder aged 55 years or older received 8-week treatment of 250–1500 mg/d of sodium benzoate, 25–150 mg/d of sertraline, or placebo in 2 medical centers. The primary outcome measures were Hamilton Depression Rating Scale and Perceived Stress Scale scores.ResultsThree treatments similarly decreased clinicians-rated Hamilton Depression Rating Scale scores. Compared with placebo, sodium benzoate but not sertraline substantially improved Perceived Stress Scale scores and cognitive function. Sertraline, but not benzoate, significantly reduced self-report Geriatric Depression Scale scores. Benzoate and placebo showed similar safety profiles, while sertraline was more likely to raise low-density lipoprotein than benzoate and placebo. Benzoate-treated patients were less likely to drop out than sertraline or placebo recipients.ConclusionsSertraline can reduce subjective depressive symptoms, while benzoate can decrease perceived stress, improve cognitive function, and enhance treatment adherence in late-life depression patients. The results show promise for D-amino acid oxidase inhibition as a novel approach for perceived stress and cognitive decline among patients with late-life depression.Trial RegistrationClinicalTrials.gov Identifier: NCT03414931. Registered January 2016.

Vascular and metabolic risk factors of late-life depression

Late-life depression (LLD) is a common complex mood disorder with high comorbidity of both psychiatric and physical diseases, cognitive decline, and increased mortality. The mechanisms underlying LLD are incompletely understood. The heterogeneity of depression complicates research into the underlying mechanisms, and factors involved in LLD may differ from those involved in early-life depression. This narrative review provides an overview of (micro-)vascular and metabolic factors involved in the development of LLD. Evidence suggests that cerebral small vessel disease, generalized microvascular dysfunction, and metabolic risk factors, including diabetes and inflammation, may contribute to the development of LLD, while the role of neurodegeneration needs further in-depth investigation. Accordingly, vascular and metabolic factors may provide promising targets for the prevention and improvement of treatment of LLD. Guidelines to screen for LLD in cardiovascular care need further implementation, as do integrated care approaches that treat LLD and diabetes jointly. However, intervention studies are needed to assess which interventions are appropriate and most effective in clinical practice.

The associations of late-life depression with all-cause and cardiovascular mortality: The NHANES 2005–2014

IntroductionLate-life depression has been linked to all-cause and cardiovascular mortality; however, results from previous studies showed heterogeneity. We aimed to examine the associations of late-life depression with all-cause and cardiovascular mortality in a representative sample of the US population. MethodsIn this prospective cohort study, participants aged 60 years or older in the National Health and Nutrition Examination Survey from 2005 to 2014 with measurement of depressive symptom and information of vital status were included for analysis. The Patient Health Questionnaire (PHQ-9) was used to measure depressive symptoms, and major depression was defined as PHQ-9 score ≥10. Multivariable proportional hazards models were used to examine the associations of depression and depressive symptoms with all-cause and cardiovascular mortality. ResultsAmong 8,082 participants included in the analysis, 603 (weighted prevalence: 6.1%) had major depression. There were 1,434 deaths from all causes, including 291 deaths from cardiovascular disease during an average follow-up of 63.2 months. After adjustment for covariates, depressive symptoms were associated with higher risk of all-cause and cardiovascular mortality; major depression was associated with increased risk of all-cause (HR=1.52, 95% CI: 1.18, 1.97) and cardiovascular mortality (HR=2.17, 95% CI: 1.36, 3.46). LimitationsThe assessment of depression with self-reported PHQ-9 scale, instead of a clinical diagnosis. Prevalent comorbidities were self-reported, which may raise concerns about misclassification. ConclusionsLate-life depression and its symptoms are associated with increased risk of all-cause and cardiovascular mortality. These findings may inform future studies of late-life depression treatment as a means of reducing mortality.

A randomized controlled trial of cognitive control training (CCT) as an add-on treatment for late-life depression: a study protocol

BackgroundAlready a major health concern, late-life depression (LLD) is expected to form an increasing problem in the aging population. Moreover, despite current treatments, LLD is associated with a poor long-term prognosis and high rate of chronicity. Treatment provision and treatment accordingly warrant improvement, where add-on treatments might contribute to the efficacy of conventional therapies. Although it is known that impaired cognitive control contributes to LDD, it is not targeted sufficiently by current interventions. Research on cognitive control training (CCT) shows promising results on depressive symptoms, cognitive performance, and overall functioning. However, further research is needed to determine the long-term effects of CCT on LLD, its cost-effectiveness, and mechanisms of change.MethodsIn the current multicenter randomized controlled trial (RCT) with a between-subjects design participants aged 60 years and over with a current LLD receiving treatment as usual (TAU) are randomized to add-on CCT or placebo training. Randomization is stratified by depression severity. Participants will receive eight online CCT or placebo sessions spread across four consecutive weeks. They will complete a post-training assessment after 1 month and three follow-up assessments scheduled three, six and 12 months after completing the training. We expect CCT and TAU to be more (cost-)effective in reducing depressive symptoms than placebo training and TAU. Additionally, we will be looking at secondary clinical, cognitive and global functioning outcomes and likely mechanisms of change (e.g., improved cognitive functioning, reduced rumination, and improved inhibition of negative stimuli).DiscussionThe proposed RCT aims to contribute to the clinical and scientific knowledge on the long-term effects of CCT as an add-on treatment for LLD. Cost-effectiveness is particularly relevant considering the expected volume of the target demographic. The study will be a pragmatic trial with few inclusion restrictions, providing information on feasibility of web-based trainings in clinical settings. The outcomes are potentially generalizable to guidelines for treatment of LLD.Trial registrationThis trial is registered in the Netherlands Trial Register (code: NL7639). Registered 3 april 2019.

Transcranial Magnetic Stimulation Indices of Cortical Excitability Enhance the Prediction of Response to Pharmacotherapy in Late-Life Depression

BackgroundOlder adults with late-life depression (LLD) often experience incomplete or lack of response to first-line pharmacotherapy. The treatment of LLD could be improved using objective biological measures to predict response. Transcranial magnetic stimulation (TMS) can be used to measure cortical excitability, inhibition, and plasticity, which have been implicated in LLD pathophysiology and associated with brain stimulation treatment outcomes in younger adults with depression. TMS measures have not yet been investigated as predictors of treatment outcomes in LLD or pharmacotherapy outcomes in adults of any age with depression. MethodsWe assessed whether pretreatment single-pulse and paired-pulse TMS measures, combined with clinical and demographic measures, predict venlafaxine treatment response in 76 outpatients with LLD. We compared the predictive performance of machine learning models including or excluding TMS predictors. ResultsTwo single-pulse TMS measures predicted venlafaxine response: cortical excitability (neuronal membrane excitability) and the variability of cortical excitability (dynamic fluctuations in excitability levels). In cross-validation, models using a combination of these TMS predictors, clinical markers of treatment resistance, and age classified patients with 73% ± 11% balanced accuracy (average correct classification rate of responders and nonresponders; permutation testing, p < .005); these models significantly outperformed (corrected t test, p = .025) models using clinical and demographic predictors alone (60% ± 10% balanced accuracy). ConclusionsThese preliminary findings suggest that single-pulse TMS measures of cortical excitability may be useful predictors of response to pharmacotherapy in LLD. Future studies are needed to confirm these findings and determine whether combining TMS predictors with other biomarkers further improves the accuracy of predicting LLD treatment outcome.

Mechanisms and Treatment of Late-Life Depression.

(Appeared originally in Translational Psychiatry 2019; 9:188).

Beyond ECT – Neuromodulation and Interventional Psychiatry for Treatment Resistant Depression in Later Life

There is a paucity of research, in general, on TRD-LL and on novel approaches and interventional methods for older adults suffering with TRD-LL. Most of the lack of data stems from limited studies on these interventions in older adults since most pharmacotherapy and neuromodulation trials specifically exclude older adults or those with comorbid medical or psychiatric conditions. Broadly, approaches can be divided into those that are FDA approved for depression (but not specifically for TRD-LL) and those that are available and empirically supported but not FDA approved. Among the FDA approved treatments of transcranial magnetic stimulation (all forms of rTMS and dTMS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and now intranasal ketamine, TMS has been most extensively studied for treatment of late life depression. Newer forms of TMS are also being evaluated in older adults. Though there are extensive data on the use of VNS in TRD, there are no studies in older adults specifically, although a multicenter trial supported by the US Center of Medicare and Medicaid Services, which will recruit adults aged 65 and above, will soon be underway. Published studies in DBS have included older adults but not in appreciable numbers for separate analyses. Studies thus far suggest some benefit in TRD but no specific data for TRD-LL. Most of the published studies of IV ketamine, which is not FDA approved for depression, are limited to case reports which tend to support its use and tolerability in TRD-LL when used as monotherapy or in combination with other interventions. Use of intranasal ketamine, which was recently FDA approved earlier in 2019, in TRD-LL remains anecdotal. Among other approaches with empirical support, but not necessarily FDA approved specific indications, are behavioral interventions (exercise, stress reduction activities), bright light therapy, combination pharmacotherapy (lithium, T3/T4, atypical antipsychotics, psychostimulants, D3 agonists, and opioid analogs), and combination pharmacotherapy and psychotherapy. After briefly reviewing the above interventions, discussion will focus on the clinical assessment of TRD-LL and possible treatment algorithms.

A systematic review of ketamine for the treatment of depression among older adults

<h3>Introduction</h3> Depression is the second most prevalent mental health disorder among older adults after anxiety disorders. It effects 7% of the general older population globally 5.6% of US older adults. Suicide rates also increase between ages of 60-90 in both men and women around the world. A large body of literature shows increased association of late life depression with increased morbidity and mortality in this age group. Evidence for depression as a risk factor for physical and cognitive decline that results in lower quality of life and function among older adults underlines the importance of early recognition and prompt treatment of this serious condition. The most common modalities currently used for treatment of late life depression include pharmacotherapy, psychotherapy and electroconvulsive therapy (ECT). Pharmacotherapy mostly consists of antidepressants targeting the monoaminergic system. Ketamine has recently emerged as a novel, rapid acting option for treatment resistant depression in adults. Ketamine is a N-methyl-D-aspartate (NMDA) receptor antagonist, which has been used primarily as an anesthetic since the 1960s. In 1990s preclinical studies demonstrated the role of NMDA receptor antagonists in treatment of depression, which was later confirmed in a pilot clinical study. Berman et al administered subanaesthetic doses of Ketamine (0.5mg/kg) vs. placebo to 7 study participants which resulted in robust decreases in Hamilton Depression Rating Scale scores within 4 hours of the infusion in all participants. The effect was sustained for 3 days followed by diminution of the scores and relapse of symptoms. This rapid onset anti-depressant effect of ketamine compared to conventional antidepressants attracted considerable interest and these findings have since been reliably replicated in multiple different studies, using different protocols and routes of administration of ketamine. This systematic review evaluates randomized controlled trials completed in the older adult population with depression to appraise the efficacy and tolerability of ketamine specifically in this population. <h3>Methods</h3> The authors followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) On November 09, 2019 the authors conducted a comprehensive search of multiple databases: PubMed (through November 09, 2019), MEDLINE (Ovid ALL 1946 to November 08, 2019), Embase (Ovid 1974 to 2019 November 08), PsycINFO (Ovid 1806 to October Week 4 2019), Web of Science Core Collection (through November 09, 2019), and Cochrane Central Register of Controlled Trials (Issue 11 of 12, November 2019). The search strategy was filtered for human studies in PubMed, MEDLINE, and Embase using controlled vocabulary terms in the search strategy. On December 13, 2019 an updated search was completed. The search repeated the controlled vocabulary terms and free text terms. <h3>Results</h3> A total of 1699 citations were deduplicated to 1005 and uploaded to Covidence for screening by two separate screeners. Two studies were found to meet the inclusion criteria for this review. The first study showed a significant reduction in depression symptoms with use of repeated subcutaneous ketamine administration among older adults with depression. The second study failed to achieve significance on its primary outcome measure but did show a decrease in MADRS scores with intranasal ketamine. This study also showed a higher response and remission rates in esketamine group when compared to the placebo group. Both the studies showed relapse in symptoms after a week of last treatment, but the benefits were better sustained with repeated treatments. The adverse effects from ketamine generally lasted only lasted a few hours and abated spontaneously without any additional intervention. No cognitive adverse effects were noted in either trial from the use of ketamine. <h3>Conclusions</h3> The current evidence for use of ketamine among older adults with depression indicates some benefits with one positive and one negative trial. Although one of the trails did not achieve significance on primary outcome measure, it still showed benefit of ketamine in reducing depressive symptoms. Both studies show longer sustenance of antidepressant effects at higher doses and with repeated treatments. One of the studies showed better ketamine efficacy in younger old subjects (65 to 74 years) when compared to older old (³75 years) subjects. Ketamine was well tolerated in both studies with adverse-effects being mild and transient. Additionally, there were no negative cognitive effects of ketamine noted among any of the study participants. Based on the limited current evidence, it is our opinion that ketamine shows some benefit in relieving depressive symptoms in older adults. However, there is dearth of randomized controlled trials and we need more well designed studies to arrive at a reliable conclusion regarding ketamine's benefit in treating depression among older adults. <h3>Funding</h3> None

Metabolomic predictors for late-life depression

<h3>Introduction</h3> Depression is a major public health problem among older adults and among the leading causes of global burden of disease and disability. Yet, current understanding of pathophysiology and optimal prevention and/or treatment of late-life depression (LLD) is limited. Advanced approaches involving methods such as metabolomics present an innovative path to identify novel biomarkers of LLD outcomes. Several known biological pathways involving tryptophan and lipid-inflammatory molecules (eicosanoids) are relevant to depression; however, there have been few systematic investigations of metabolomic predictors of long-term trajectories of LLD. <h3>Methods</h3> This is a convenience sample of ∼7000 Nurses' Health Study (NHS) participants with known metabolites and who completed depression items every four years from 1992-2016. Between 1989 and 1990, blood samples were collected and stored under standard conditions. In NHS, data on known metabolites were generated by merging the data from multiple case-control studies; however, all metabolites were profiled using liquid chromatography mass spectrometry in the same laboratory. Continuous metabolite values were transformed to probit scores to account for batch effects. We used a previously developed harmonized depressive symptom scale that was indexed to the five-item Mental Health Inventory (MHI-5, range=0-100 points). For cross-sectional analysis, we performed multivariable logistic regression models to evaluate the associations of baseline metabolite levels and likelihood of the moderate or severe depressive symptoms (MHI-5 cut-off=60); for longitudinal analysis, we used latent growth-curve analysis to identify group-based trajectories of depressive symptoms and then related baseline metabolite levels to long-term trajectories. <h3>Results</h3> The mean age of female nurses at blood draw was 57.0 (range=42.6-70.2) years. There were ∼6300 NHS participants with available data on tryptophan metabolites and ∼1300 NHS participants with available data on eicosanoids. We observed stronger signals for cross-sectional associations of higher circulating levels of tryptophan, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) with lower risk of moderate or severe depressive symptoms, adjusted for age at blood draw, fasting status, case-control status, physical activity, body mass index, diet index, alcohol use, and cigarette smoking [multivariable odds ratio (95% confidence interval): for tryptophan=0.86 (0.80-0.93), p<0.01; for EPA=0.84 (0.71-1.01), p=0.06; for DHA=0.85 (0.71-1.02), p=0.07]. From 1992-2016, we identified four depressive symptom trajectory groups: minimal depressive symptoms (63%), worsening depressive symptoms (12%), improving depressive symptoms (20%), and persistent severe depressive symptoms (5%). Additional results from multinomial models evaluating the associations between metabolites and long-term LLD trajectories will be presented. <h3>Conclusions</h3> In this sample, tryptophan and omega-3 fatty acid metabolites were significantly related to LLD outcomes; these metabolites may play a role in the pathophysiology of LLD. <h3>Funding</h3> HMS Livingston Fellowship Award

Clinical and Cognitive Predictors of Response to Psychotherapy in Late Life Depression

<h3>Introduction</h3> Late life depression (LLD) is a common and heterogeneous condition that is associated with increased disability, cognitive impairment, and all-cause mortality in older adults. Anti-depressant medication and psychotherapy have been identified as effective treatments for LLD, though as many as 50% of patients do not respond to treatment. Several clinical (age, age of MDD onset, MDE severity, anxiety, perceived stress, social support, sleep quality) and cognitive (executive dysfunction, global cognitive impairment) factors have been identified as predictors of response to anti-depressant treatment. Less is known about predictors of psychotherapy treatment response in LLD, but cognitive dysfunction has been linked to poor treatment outcomes and may negatively impact the effectiveness of behavioral interventions that are subserved by various cognitive processes. <h3>Methods</h3> Participants included 83 individuals with LLD (HAM-D > 17) enrolled in a manualized 12-week psychotherapy with a licensed psychologist. All participants completed diagnostic interviews, comprehensive neuropsychological assessments and clinical evaluations before and after treatment. Separate multiple linear regression models were used to assess independent effects of baseline MDD features (age at onset, severity, treatment history, frequency and chronicity of MDEs), related clinical factors (comorbid anxiety and hoarding behaviors, perceived stress and health, social support, sleep disturbance), and cognitive performance (global cognition, executive functioning, episodic memory, processing speed, language, visuospatial skills, motor speed and dexterity) as predictors of treatment response, with percent change in HAM-D as the outcome variable. Cognitive performance was grouped by domain using composite Z-scores based on group means and standard deviations (all Chronbach's a's > .70). <h3>Results</h3> Forty-five percent (n=38) of participants showed treatment response (>50% reduction in HAM-D post-treatment). Responders were significantly younger (mean age = 69.76) than non-responders (mean age = 73.11, t = 7.10, <i>p</i> = .009). Level of education, gender distribution, and baseline depression characteristics (severity, length of episode, anti-depressant use) were equivalent (all <i>p</i>'s > .05). depression features accounted for 23.9% of the variance in HAM-D change, and showed a trend toward significance for older age of MDD onset associated with increased treatment response (t = 1.85, b = 0.38, <i>p =</i> .06) after accounting for age (t = 2.10, b = 0.31, <i>p = .</i>017). Non-depression clinical features accounted for 31.2% of the variance in HAM-D change, and greater sleep disturbance was associated with worse treatment response after accounting for age (t = 2.53, b = 0.34, <i>p = .</i>015). Cognitive performance accounted for 10.1% of the variance in HAM-D change, with no significant predictors after accounting for age (t = 2.36, b = 0.25, <i>p = .</i>021 <h3>Conclusions</h3> Our findings show that older age and sleep disturbance predict poorer response to treatment with 12 weeks of psychotherapy in a sample of individuals with LLD. Older age may negatively impact treatment response via increased risk for underlying neurodegenerative pathologies that are not affected by treatment with psychotherapy or medication. Similarly, sleep dysfunction in older adults has been implicated in the pathogenesis of Alzheimer's disease and related dementias and may reflect the presence of an underlying neurodegenerative process that is not targeted by psychiatric intervention. A preliminary exploration of cognitive factors suggests that cognitive dysfunction may play a more limited role in response to psychotherapeutic relative to pharmacologic intervention. Future research should assess the effect of neurodegenerative pathology on response to treatment with psychotherapy and medication in LLD. <h3>Funding</h3> This project was supported by the National Institute of Mental Health grant 1R01MH101472.

Molecular imaging of the serotonin transporter availability and occupancy by antidepressant treatment in late-life depression

Patients with late-life depression (LLD) have a more variable response to pharmacotherapy relative to patients with mid-life depression. Degeneration of the serotonergic system and lower occupancy of the initial target for antidepressant medications, the serotonin transporter (5-HTT), may contribute to variability in treatment response. The focus of this study was to test the hypotheses that lower cortical and limbic serotonin transporter (5-HTT) availability in LLD patients relative to controls and less 5-HTT occupancy by antidepressant medications would be associated with less improvement in mood and cognition with treatment in LLD patients. Twenty LLD patients meeting DSM-IV criteria for a current major depressive episode and 20 non-depressed controls underwent clinical and neuropsychological assessments, magnetic resonance imaging to measure gray matter volumes and high-resolution positron emission tomography (PET) scanning to measure 5-HTT before and after 10–12 weeks of treatment with Citalopram or Sertraline (patients only). Prior to treatment, 5-HTT was lower in LLD patients relative to controls in mainly temporal cortical and limbic (amygdala and hippocampus) regions. Gray matter volumes were not significantly different between groups. 5-HTT occupancy was detected throughout cortical, striatal, thalamic and limbic regions. The magnitude of regional 5-HTT occupancy by antidepressants was 70% or greater across cortical and sub-cortical regions, consistent with the magnitude of 5-HTT occupancy observed in mid-life depressed patients. Greater regional 5-HTT occupancy correlated with greater improvement in depressive symptoms and visual-spatial memory performance. These data support the hypothesis that serotonin degeneration and variability in 5-HTT occupancy may contribute to heterogeneity in treatment response in LLD patients.

Impact of vascular risk factors on clinical outcome in elderly patients with depression receiving electroconvulsive therapy

BackgroundAlthough electroconvulsive therapy (ECT) is a highly effective, safe, and well-tolerated antidepressant treatment for late-life depression (LLD), there is large variability in response rates across individuals. We hypothesized that these variations would be in part explained by the level of vascular risk in this population. We therefore compared response rates to ECT in patients with LLD presenting with or without vascular risk factors (VRF). Methods52 patients with LLD (age > 55) who received a course of ECT were separated into 2 groups according to the presence of VRF (n = 20) or not (n = 32). Framingham score (10-year risk for developing a coronary heart disease) was calculated for each patient. Our primary outcome was the number of responders to ECT in each group (defined as at least 50% decrease of the Montgomery–Åsberg Depression Rating Scale score following ECT course). Scores at the self-rated Beck Depression Inventory are also reported. ResultsPatients with VRF presented significant lower response rates to ECT (12 out of 20; 60%) than patients without VRF (30 out of 32; 94%; p = 0.004). A negative correlation was found between Framingham score and changes in depression scores pre/post ECT (r = -0.42; p = 0.0039). LimitationsOur study was limited by sample size and retrospective design. ConclusionPatients with LLD and VRF showed lower response rates to ECT than those without VRF. The more the VRF increased, the less the antidepressant effect of ECT was observed. Results are discussed in light of the role of apathy in clinical response to ECT.

Low corticosterone levels attenuate late life depression and enhance glutamatergic neurotransmission in female rats.

Sustained elevation of corticosterone (CORT) is one of the common causes of aging and major depression disorder. However, the role of elevated CORT in late life depression (LLD) has not been elucidated. In this study, 18-month-old female rats were subjected to bilateral adrenalectomy or sham surgery. Their CORT levels in plasma were adjusted by CORT replacement and the rats were divided into high-level CORT (H-CORT), low-level CORT (L-CORT), and Sham group. We showed that L-CORT rats displayed attenuated depressive symptoms and memory defects in behavioral tests as compared with Sham or H-CORT rats. Furthermore, we showed that glutamatergic transmission was enhanced in L-CORT rats, evidenced by enhanced population spike amplitude (PSA) recorded from the dentate gyrus of hippocampus in vivo and increased glutamate release from hippocampal synaptosomes caused by high frequency stimulation or CORT exposure. Intracerebroventricular injection of an enzymatic glutamate scavenger system, glutamic-pyruvic transmine (GPT, 1 μM), significantly increased the PSA in Sham rats, suggesting that extracelluar accumulation of glutamate might bethe culprit of impaired glutamatergic transmission, which was dependent on the uptake by Glt-1 in astrocytes. We revealed that hippocampal Glt-1 expression level in the L-CORT rats was much higher than in Sham and H-CORT rats. In a gradient neuron-astrocyte coculture, we found that the expression of Glt-1 was decreased with the increase of neural percentage, suggesting that impairment of Glt-1 might result from the high level of CORT contributed neural damage. In sham rats, administration of DHK that inhibited Glt-1 activity induced significant LLD symptoms, whereas administration of RIL that promoted glutamate uptake significantly attenuated LLD. All of these results suggest that glutamatergic transmission impairment is one of important pathogenesis in LLD induced by high level of CORT, which provide promising clues for the treatment of LLD.

110 - Investigations of Risk, Resilience and Novel Therapeutics of Late Life Neuropsychiatric Disease

Converging data from multiple domains of preclinical and human studies has underscored the importance of focusing on genetic, synaptic and neural circuity as critical neurobiological mechanisms of late life neuropsychiatric disease. These complementary research approaches have been applied to identify novel molecular mechanisms that may represent early intervention targets, as well as promising new treatments. The symposium will include four speakers who span the range of studies in animal models, post-mortem brain tissue, molecular imaging and clinical trials combined with biomarkers. Dr Etienne Sibille will present his research on the procognitive, neurotrophic and neurogenic effects of novel compounds augmenting dendritic inhibition and restoring neuronal connectivity, which is affected in aging and in neurodegenerative disorders, such as Alzheimer’s disease. Dr. Robert Sweet will present new GWAS and human postmortem findings regarding risk/resilience to psychosis in Alzheimer's Disease, with an emphasis on synaptic mechanisms of resilience. Dr Helen Lavretsky will present a study of the neuroimaging, genetic and epigenetic effects of memantine and escitalopram treatment in late life depression. The strategy of incorporating biological measures into a clinical trial is an important opportunity to understanding the neurobiological mechanisms. Dr Gwenn Smith will present multi-modality molecular imaging data to understand the synaptic changes associated with Alzheimer’s Disease pathology in late life depression and mild cognitive impairment. Consideration of interdisciplinary research approaches and applications to different neuropsychiatric conditions may have particular relevance to understanding the neurobiological mechanisms underlying neuropsychiatric symptoms as risk factors or complications of neurodegenerative disease.Molecular imaging methods to visualize the neuropathology of Alzheimer’s disease (AD) in vivo provide an unprecedented opportunity to understand the neuropsychiatric (NPS) and cognitive symptoms observed in early stage AD by testing hypotheses informed by human neuropathology and animal models. A fuller understanding of the neurobiology of early AD and its clinical progression is essential to identify individuals at risk and to identify targets for prevention and treatment. Numerous neuroimaging studies have shown that beta-amyloid and tau is necessary but not sufficient to explain cognitive decline and that models to explain cognitive decline must also include measures associated with synaptic dysfunction (eg cerebral glucose metabolism or brain volumes). Human data and animal models support the further investigation of serotonin (5-HT) degeneration. Relative to other molecular targets, there is stronger evidence for 5-HT loss in both cognitive deficits and neuropsychiatric symptoms (NPS) in Alzheimer’s Disease. 5-HT compounds are the only agents with preclinical evidence of multiple therapeutic mechanisms relevant to prevention and symptomatic treatment: blockade of amyloid precursor protein processing or neuroprotection, synaptic plasticity and improvement in both cognitive deficits and NPS. Multi-radiotracer PET studies of beta-amyloid (Aβ), tau and 5-HT have been performed longitudinally in amnestic, multi -domain, MCI (aMCI-MD) and cognitively normal elderly. Cortical and limbic 5-HT degeneration was a more powerful predictor of longitudinal memory decline than Aβ or Tau. Elucidating the role of 5-HT, in relation to Tau and Aβ in cognitive decline in aMCI-MD will have fundamental implications for the design of prevention and intervention studies targeting 5-HT.

Oxidative DNA damage is increased in older adults with a major depressive episode: A preliminary study

BackgroundDNA oxidative damage is a marker of increased oxidative stress activity. Elevated DNA oxidative damage has been associated with major depressive disorder in young adults, but there is no information about DNA oxidative damage in late-life depression. This study aims to evaluate whether older adults with late-life depression (LLD) has increased DNA oxidative damage compared to healthy older adults. MethodsWe included 92 participants (57 with LLD [73.2 ± 7.7 years-old] and 35 non-depressed subjects (Controls) [70.5 ± 7.4 years-old]). We analyzed the plasma 8‑hydroxy-2′-deoxyguanosine (8-oxo-dG), a marker of DNA oxidation, using a commercially-available ELISA assay. ResultsLLD participants had significantly higher 8-oxo-DG levels compared to controls (P<0.001). 8-oxo-dG levels were significantly correlated with depressive symptoms as assessed by the Hamilton Depression Rating Scale (rho=0.34, p<0.001). The plasma levels of 8-OHdG were not significantly correlated with other clinical, neurocognitive, and demographic variables. LimitationsOur current results are limited by the relatively small sample size, cross-sectional design, and the recruitment of participants in tertiary center for assessment and treatment of LLD. ConclusionsOlder adults with LLD have increased DNA oxidative damage. Our findings provide additional evidence for elevated oxidative stress activity in LLD and the possible activation of age-related biological pathways and enhanced biological aging changes in LLD.

Late-Life Depression Treatment: the State of the Art

Purpose:to present an overview of domestic and foreign current research covering the treatment of late-life depression.Materials and method:the keywords “depressive disorder”, “late age”, “psychopharmacotherapy” were used to search for scientific articles in the databases MedLine, PubMed for the period 2000–2020.Discussion and conclusions:the variability of multiple aging factors in depressive patients of late age leads to significant heterogeneity of geriatric depressions and difficulties in selection of therapy. In the current literature on the treatment of late-life depression, there are quite heterogeneous recommendations on the choice of different drugs, recommended dosages, duration of therapy and time to replace drugs if they are ineffective. The global trend of transition to personalized therapy of mental diseases requires identification of predictors of therapeutic response in patients. Significant data has already been accumulated on potential predictors of therapeutic response to antidepressants in young and middle-aged patients using clinical, neurobiological, neurocognitive and genetic parameters. The search for predictors of therapeutic response is especially important in late life, since the selection of adequate antidepressant therapy is associated not only with the effectiveness, but also with the safety of treatment of elderly patients. To date our knowledge of the problem of predicting the therapeutic response in this group of patients remains very limited and requires further study

Exploring Language Learning as a Potential Tool against Cognitive Impairment in Late-Life Depression: Two Meta-Analyses and Suggestions for Future Research.

Late-life depression (LLD) affects about an eighth of community-dwelling seniors. LLD impacts well-being, with loneliness and small social networks being typical. It has also been linked to cognitive dysfunction and an increased risk of developing dementia. Safety and efficacy of pharmacological treatments for LLD have been debated, and cognitive dysfunction often persists even after remission. Various cognitive interventions have been proposed for LLD. Among these, one has received special attention: foreign language learning could serve as a social intervention that simultaneously targets brain structures affected in LLD. Lifelong bilingualism may significantly delay the onset of cognitive impairment symptoms by boosting cognitive reserve. Even late-life foreign language learning without lifelong bilingualism can train cognitive flexibility. It is then counterintuitive that the effects of language learning on LLD have never been examined. In order to create a theoretical basis for further interdisciplinary research, this paper presents a status quo of current work through two meta-analyses investigating cognitive functioning in LLD on the one hand and in senior bilinguals or seniors following a language course on the other hand. While LLD was consistently associated with cognitive dysfunction, inconsistent results were found for bilingualism and language learners. Possible reasons for this and suggestions for future research are subsequently discussed.

Association of Markers of Microvascular Dysfunction With Prevalent and Incident Depressive Symptoms: The Maastricht Study.

The etiology of late-life depression (LLD) is still poorly understood. Microvascular dysfunction (MVD) has been suggested to play a role in the etiology of LLD, but direct evidence of this association is scarce. The aim of this study was to investigate whether direct and indirect markers of early microvascular dysfunction are associated with prevalent and incident LLD in the population-based Maastricht Study cohort. We measured microvascular dysfunction at baseline by use of flicker light-induced retinal vessel dilation response (Dynamic Vessel Analyzer), heat-induced skin hyperemic response (laser- Doppler flowmetry), and plasma markers of endothelial dysfunction (endothelial dysfunction; sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [Von Willebrand Factor]). Depressive symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9) at baseline and annually over 4 years of follow-up (n=3029; mean age 59.6±8.2 years, 49.5% were women, n=132 and n=251 with prevalent and incident depressive symptoms [PHQ-9≥10]). We used logistic, negative binominal and Cox regression analyses, and adjusted for demographic, cardiovascular, and lifestyle factors. Retinal venular dilatation and plasma markers of endothelial dysfunction were associated with the more prevalent depressive symptoms after full adjustment (PHQ-9 score, RR, 1.05 [1.00-1.11] and RR 1.06 [1.01-1.11], respectively). Retinal venular dilatation was also associated with prevalent depressive symptoms (PHQ-9≥10; odds ratio, 1.42 [1.09-1.84]), after full adjustment. Retinal arteriolar dilatation and plasma markers of endothelial dysfunction were associated with incident depressive symptoms (PHQ-9≥10; HR, 1.23 [1.04-1.46] and HR, 1.19 [1.05-1.35]), after full adjustment. These findings support the concept that microvascular dysfunction in the retina, and plasma markers of endothelial dysfunction is involved in the etiology of LLD and might help in finding additional targets for the prevention and treatment of LLD.

Cortical Thickness of the Salience Network and Change in Apathy Following Antidepressant Treatment for Late-Life Depression

ObjectiveApathy is common in late-life depression and is associated with poor response to antidepressant drugs. In depressed older adults, apathy may be characterized by neuroanatomical abnormalities of the salience network. The current study examined whether cortical thickness of select salience network structures predicted change in apathy following a 12-week treatment with escitalopram. MethodsA sample of 46 older adults with major depressive disorder received 12 weeks of escitalopram treatment at a daily target dose of 20 mg. All participants underwent a structural brain MRI scan at baseline, and cortical thickness was estimated in key cortical nodes of the salience network: the caudal anterior cingulate cortex and the insula. We measured baseline and post-treatment symptoms using the Apathy Evaluation Scale and the Hamilton Depression Rating Scale. ResultsA thicker insula at baseline predicted reduction in apathy symptoms following 12 weeks of treatment with escitalopram, even when controlling for age, baseline depression severity and change in depressive symptoms. ConclusionReduced insular thickness predicted residual apathetic symptoms following escitalopram treatment. These results converge with our previous findings of abnormal functional connectivity of the insular cortex in older depressed individuals with apathy. Older depressed adults with apathy may benefit from alternative treatment approaches or augmentative interventions that target abnormalities of the salience network.