Alcohol and substance use in older adults with treatment-resistant depression.

INTRODUCTION: Alcohol and substance use are increasing in older adults, many of whom have depression, and treatment in this context may be more hazardous. We assessed alcohol and other substance use patterns in older adults with treatment-resistant depression (TRD). We examined patient characteristics associated with higher alcohol consumption and examined the moderating effect of alcohol on the association between clinical variables and falls during antidepressant treatment. METHODS: This secondary and exploratory analysis used baseline clinical data and data on falls during treatment from a large randomized antidepressant trial in older adults with TRD (the OPTIMUM trial). Multivariable ordinal logistic regression was used to identify variables associated with higher alcohol use. An interaction model was used to evaluate the moderating effect of alcohol on falls during treatment. RESULTS: Of 687 participants, 51% acknowledged using alcohol: 10% were hazardous drinkers (AUDIT-10 score ≥5) and 41% were low-risk drinkers (score 1-4). Benzodiazepine use was seen in 24% of all participants and in 21% of drinkers. Use of other substances (mostly cannabis) was associated with alcohol consumption: it was seen in 5%, 9%, and 15% of abstainers, low-risk drinkers, and hazardous drinkers, respectively. Unexpectedly, use of other substances predicted increased risk of falls during antidepressant treatment only in abstainers. CONCLUSIONS: One-half of older adults with TRD in this study acknowledged using alcohol. Use of alcohol concurrent with benzodiazepine and other substances was common. Risks-such as falls-of using alcohol and other substances during antidepressant treatment needs further study.

Propofol enhancement of slow wave sleep to target the nexus of geriatric depression and cognitive dysfunction: protocol for a phase I open label trial.

INTRODUCTION: Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series. METHODS AND ANALYSIS: SWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2-6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion. ETHICS AND DISSEMINATION: The study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial. TRIAL REGISTRATION NUMBER: NCT04680910.

Perioperative mental health intervention for depression and anxiety symptoms in older adults study protocol: design and methods for three linked randomised controlled trials.

INTRODUCTION: Preoperative anxiety and depression symptoms among older surgical patients are associated with poor postoperative outcomes, yet evidence-based interventions for anxiety and depression have not been applied within this setting. We present a protocol for randomised controlled trials (RCTs) in three surgical cohorts: cardiac, oncological and orthopaedic, investigating whether a perioperative mental health intervention, with psychological and pharmacological components, reduces perioperative symptoms of depression and anxiety in older surgical patients. METHODS AND ANALYSIS: Adults ≥60 years undergoing cardiac, orthopaedic or oncological surgery will be enrolled in one of three-linked type 1 hybrid effectiveness/implementation RCTs that will be conducted in tandem with similar methods. In each trial, 100 participants will be randomised to a remotely delivered perioperative behavioural treatment incorporating principles of behavioural activation, compassion and care coordination, and medication optimisation, or enhanced usual care with mental health-related resources for this population. The primary outcome is change in depression and anxiety symptoms assessed with the Patient Health Questionnaire-Anxiety Depression Scale from baseline to 3 months post surgery. Other outcomes include quality of life, delirium, length of stay, falls, rehospitalisation, pain and implementation outcomes, including study and intervention reach, acceptability, feasibility and appropriateness, and patient experience with the intervention. ETHICS AND DISSEMINATION: The trials have received ethics approval from the Washington University School of Medicine Institutional Review Board. Informed consent is required for participation in the trials. The results will be submitted for publication in peer-reviewed journals, presented at clinical research conferences and disseminated via the Center for Perioperative Mental Health website. TRIAL REGISTRATION NUMBERS: NCT05575128, NCT05685511, NCT05697835, pre-results.

Brain-Hazardous Medications and Potential Subadequate Antidepressant Dosing in Older Surgical Patients Receiving Home Antidepressants: An Observational Study of a Large US Health System.

BACKGROUND: Older surgical patients with depression often experience poor postoperative outcomes. Poor outcomes may stem from brain-hazardous medications and subadequate antidepressant dosing. METHODS: This was a retrospective, observational cohort study covering the period between January 1, 2021 and December 31, 2021. Patients ≥60 years of age who underwent inpatient surgery and had an overnight stay at an integrated academic health care system comprising 14 hospitals were eligible. We analyzed the prevalence of home central nervous system (CNS)-active potentially inappropriate medication (PIM) and potential subadequate antidepressant dosing in older surgical patients receiving home antidepressants. Univariable and multivariable regression models were used to identify factors associated with home CNS-active PIM prescribing and potential subadequate antidepressant dosing. Additionally, outcomes were compared among patients receiving and not receiving CNS-active PIMs and patients receiving and not receiving subadequate antidepressant dosing. RESULTS: A total of 8031 patients were included in this study (47% female, mean age = 70 years) of whom 2087 (26%) were prescribed antidepressants. Roughly one-half (49%, 95% confidence interval [CI], 46.5-50.1) of patients receiving home antidepressants were also receiving ≥1 CNS-active PIM and 29% (95% CI, 27.0-29.3) were receiving a potential subadequate dose. Factors associated with an increased likelihood of receiving a home CNS-active PIM included female sex (adjusted odds ratio [aOR], 1.46), anxiety (aOR, 2.43), asthma or chronic obstructive pulmonary disease (aOR, 1.39), and serotonin-norepinephrine reuptake inhibitor use (aOR, 1.54). Patients aged ≥75 years (aOR, 1.57), black race (aOR, 1.48) and those with congestive heart failure (aOR, 1.33) were more likely to be prescribed a potential subadequate antidepressant dose. Patients receiving potential subadequate antidepressant doses were discharged home less often (64% vs 73%), had a longer hospital length of stay (9 days vs 7 days), and a higher mortality rate (18% vs 10%) compared to patients receiving adequate home antidepressant doses (P-value for all <0.01). No differences in these outcomes were found among patients receiving home antidepressants with or without CNS-active PIMs. CONCLUSIONS: Older surgical patients receiving antidepressants are frequently prescribed brain-hazardous medications and potentially subadequate antidepressant doses. Those receiving subadequate antidepressant doses may be at risk for worse postoperative outcomes compared to patients receiving adequate doses. The role of preoperative medication optimization to improve outcomes for older surgical patients should be evaluated.

Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion.

Bupropion is used for treating depression, obesity, and seasonal affective disorder, and for smoking cessation. Bupropion is commonly prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability, and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in cytochrome P450 (CYP) 2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. SIGNIFICANCE STATEMENT: Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated cytochrome P450 (CYP) 2B6, CYP2C19 and P450 oxidoreductase genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in CYP2B6*6 and CYP2B6 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. CYP2C19 polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4'-hydroxylation of bupropion and primary metabolites. CYP2B6 variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes.

Sertraline modulates hippocampal plasticity and learning via sigma 1 receptors, cellular stress and neurosteroids.

In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other effects that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. We recently observed that the SSRIs fluvoxamine and fluoxetine prevent the acute adverse effects of pro-inflammatory stimulation on long-term potentiation (LTP) in the CA1 hippocampal region. Sertraline showed markedly different effects, acutely inhibiting LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs). In the present studies, we pursued mechanisms contributing to sertraline modulation of LTP in rat hippocampal slices. We found that sertraline partially inhibits synaptic responses mediated by N-methyl-D-aspartate receptors (NMDARs) via effects on NMDARs that express GluN2B subunits. A selective S1R antagonist (NE-100), but not an S1R agonist (PRE-084) blocked effects on NMDARs, despite the fact that both S1R ligands were previously shown to prevent LTP inhibition. Both NE-100 and PRE-084, however, prevented adverse effects of sertraline on one-trial learning. Because of the important role that S1Rs play in modulating endoplasmic reticulum stress, we examined whether inhibitors of cellular stress alter effects of sertraline. We found that two stress inhibitors, ISRIB and quercetin, prevented LTP inhibition, as did inhibitors of the synthesis of endogenous neurosteroids, which are homeostatic regulators of cellular stress. These studies highlight complex effects of sertraline, S1Rs and neurosteroids on hippocampal function and have relevance for understanding therapeutic and adverse drug actions.

Sex differences in plasma proteomic markers in late-life depression.

Previous studies have shown significant sex-specific differences in major depressive disorder (MDD) in multiple biological parameters. Most studies focused on young and middle-aged adults, and there is a paucity of information about sex-specific biological differences in older adults with depression (aka, late-life depression (LLD)). To address this gap, this study aimed to evaluate sex-specific biological abnormalities in a large group of individuals with LLD using an untargeted proteomic analysis. We quantified 344 plasma proteins using a multiplex assay in 430 individuals with LLD and 140 healthy comparisons (HC) (age range between 60 and 85 years old for both groups). Sixty-six signaling proteins were differentially expressed in LLD (both sexes). Thirty-three proteins were uniquely associated with LLD in females, while six proteins were uniquely associated with LLD in males. The main biological processes affected by these proteins in females were related to immunoinflammatory control. In contrast, despite the smaller number of associated proteins, males showed dysregulations in a broader range of biological pathways, including immune regulation pathways, cell cycle control, and metabolic control. Sex has a significant impact on biomarker changes in LLD. Despite some overlap in differentially expressed biomarkers, males and females show different patterns of biomarkers changes, and males with LLD exhibit abnormalities in a larger set of biological processes compared to females. Our findings can provide novel targets for sex-specific interventions in LLD.

Intraindividual variability in post-stroke cognition and its relationship with activities of daily living and social functioning: an ecological momentary assessment approach.

INTRODUCTION: Ecological momentary assessment (EMA) is a methodological approach to studying intraindividual variation over time. This study aimed to use EMA to determine the variability of cognition in individuals with chronic stroke, identify the latent classes of cognitive variability, and examine any differences in daily activities, social functioning, and neuropsychological performance between these latent classes. METHODS: Participants (N = 202) with mild-to-moderate stroke and over 3-month post-stroke completed a study protocol, including smartphone-based EMA and two lab visits. Participants responded to five EMA surveys daily for 14 days to assess cognition. They completed patient-reported measures and neuropsychological assessments during lab visits. Using latent class analysis, we derived four indicators to quantify cognitive variability and identified latent classes among participants. We used ANOVA and Chi-square to test differences between these latent classes in daily activities, social functioning, and neuropsychological performance. RESULTS: The latent class analysis converged on a three-class model. The moderate and high variability classes demonstrated significantly greater problems in daily activities and social functioning than the low class. They had significantly higher proportions of participants with problems in daily activities and social functioning than the low class. Neuropsychological performance was not statistically different between the three classes, although a trend approaching statistically significant difference was observed in working memory and executive function domains. DISCUSSION: EMA could capture intraindividual cognitive variability in stroke survivors. It offers a new approach to understanding the impact and mechanism of post-stroke cognitive problems in daily life and identifying individuals benefiting from self-regulation interventions.

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression.

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine.

Fatness but Not Fitness Linked to BrainAge: Longitudinal Changes in Brain Aging during an Exercise Intervention.

PURPOSE: Fitness, physical activity, body composition, and sleep have all been proposed to explain differences in brain health. We hypothesized that an exercise intervention would result in improved fitness and body composition and would be associated with improved structural brain health. METHODS: In a randomized controlled trial, we studied 485 older adults who engaged in an exercise intervention ( n = 225) or a nonexercise comparison condition ( n = 260). Using magnetic resonance imaging, we estimated the physiological age of the brain (BrainAge) and derived a predicted age difference compared with chronological age (brain-predicted age difference (BrainPAD)). Aerobic capacity, physical activity, sleep, and body composition were assessed and their impact on BrainPAD explored. RESULTS: There were no significant differences between experimental groups for any variable at any time point. The intervention group gained fitness, improved body composition, and increased total sleep time but did not have significant changes in BrainPAD. Analyses of changes in BrainPAD independent of group assignment indicated significant associations with changes in body fat percentage ( r (479) = 0.154, P = 0.001), and visceral adipose tissue (VAT) ( r (478) = 0.141, P = 0.002), but not fitness ( r (406) = -0.075, P = 0.129), sleep ( r (467) range, -0.017 to 0.063; P range, 0.171 to 0.710), or physical activity ( r (471) = -0.035, P = 0.444). With linear regression, changes in body fat percentage and VAT significantly predicted changes in BrainPAD ( ß = 0.948, P = 0.003) with 1-kg change in VAT predicting 0.948 yr of change in BrainPAD. CONCLUSIONS: In cognitively normal older adults, exercise did not appear to impact BrainPAD, although it was effective in improving fitness and body composition. Changes in body composition, but not fitness, physical activity, or sleep impacted BrainPAD. These findings suggest that focus on weight control, particularly reduction of central obesity, could be an interventional target to promote healthier brains.

A Perioperative Mental Health Intervention for Depressed and Anxious Older Surgical Patients: Results From a Feasibility Study.

OBJECTIVES: The perioperative period is challenging and stressful for older adults. Those with depression and/or anxiety have an increased risk of adverse surgical outcomes. We assessed the feasibility of a perioperative mental health intervention composed of medication optimization and a wellness program following principles of behavioral activation and care coordination for older surgical patients. METHODS: We included orthopedic, oncologic, and cardiac surgical patients aged 60 and older. Feasibility outcomes included study reach, the number of patients who agreed to participate out of the total eligible; and intervention reach, the number of patients who completed the intervention out of patients who agreed to participate. Intervention efficacy was assessed using the Patient Health Questionnaire for Anxiety and Depression (PHQ-ADS). Implementation potential and experiences were collected using patient surveys and qualitative interviews. Complementary caregiver feedback was also collected. RESULTS: Twenty-three out of 28 eligible older adults participated in this study (mean age 68.0 years, 65% women), achieving study reach of 82% and intervention reach of 83%. In qualitative interviews, patients (n = 15) and caregivers (complementary data, n = 5) described overwhelmingly positive experiences with both the intervention components and the interventionist, and reported improvement in managing depression and/or anxiety. Preliminary efficacy analysis indicated improvement in PHQ-ADS scores (F = 12.13, p <0.001). CONCLUSIONS: The study procedures were reported by participants as feasible and the perioperative mental health intervention to reduce anxiety and depression in older surgical patients showed strong implementation potential. Preliminary data suggest its efficacy for improving depression and/or anxiety symptoms. A randomized controlled trial assessing the intervention and implementation effectiveness is currently ongoing.

Towards Outcome-Driven Patient Subgroups: A Machine Learning Analysis Across Six Depression Treatment Studies.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous condition; multiple underlying neurobiological and behavioral substrates are associated with treatment response variability. Understanding the sources of this variability and predicting outcomes has been elusive. Machine learning (ML) shows promise in predicting treatment response in MDD, but its application is limited by challenges to the clinical interpretability of ML models, and clinicians often lack confidence in model results. In order to improve the interpretability of ML models in clinical practice, our goal was to demonstrate the derivation of treatment-relevant patient profiles comprised of clinical and demographic information using a novel ML approach. METHODS: We analyzed data from six clinical trials of pharmacological treatment for depression (total n = 5438) using the Differential Prototypes Neural Network (DPNN), a ML model that derives patient prototypes which can be used to derive treatment-relevant patient clusters while learning to generate probabilities for differential treatment response. A model classifying remission and outputting individual remission probabilities for five first-line monotherapies and three combination treatments was trained using clinical and demographic data. Prototypes were evaluated for interpretability by assessing differences in feature distributions (e.g. age, sex, symptom severity) and treatment-specific outcomes. RESULTS: A 3-prototype model achieved an area under the receiver operating curve of 0.66 and an expected absolute improvement in remission rate for those receiving the best predicted treatment of 6.5% (relative improvement of 15.6%) compared to the population remission rate. We identified three treatment-relevant patient clusters. Cluster A patients tended to be younger, to have increased levels of fatigue, and more severe symptoms. Cluster B patients tended to be older, female, have less severe symptoms, and the highest remission rates. Cluster C patients had more severe symptoms, lower remission rates, more psychomotor agitation, more intense suicidal ideation, and more somatic genital symptoms. CONCLUSION: It is possible to produce novel treatment-relevant patient profiles using ML models; doing so may improve interpretability of ML models and the quality of precision medicine treatments for MDD.

Digital and precision clinical trials: innovations for testing mental health medications, devices, and psychosocial treatments.

Mental health treatment advances - including neuropsychiatric medications and devices, psychotherapies, and cognitive treatments - lag behind other fields of clinical medicine such as cardiovascular care. One reason for this gap is the traditional techniques used in mental health clinical trials, which slow the pace of progress, produce inequities in care, and undermine precision medicine goals. Newer techniques and methodologies, which we term digital and precision trials, offer solutions. These techniques consist of (1) decentralized (i.e., fully-remote) trials which improve the speed and quality of clinical trials and increase equity of access to research, (2) precision measurement which improves success rate and is essential for precision medicine, and (3) digital interventions, which offer increased reach of, and equity of access to, evidence-based treatments. These techniques and their rationales are described in detail, along with challenges and solutions for their utilization. We conclude with a vignette of a depression clinical trial using these techniques.

Geroscience-Centric Perspective for Geriatric Psychiatry: Integrating Aging Biology With Geriatric Mental Health Research.

The geroscience hypothesis asserts that physiological aging is caused by a small number of biological pathways. Despite the explosion of geroscience research over the past couple of decades, the research on how serious mental illnesses (SMI) affects the biological aging processes is still in its infancy. In this review, we aim to provide a critical appraisal of the emerging literature focusing on how we measure biological aging systematically, and in the brain and how SMIs affect biological aging measures in older adults. We will also review recent developments in the field of cellular senescence and potential targets for interventions for SMIs in older adults, based on the geroscience hypothesis.

Relationship between baseline plasma p-tau181 and longitudinal changes in cognition and structural brain measures in a cohort of cognitively unimpaired older adults.

INTRODUCTION: Preclinical Alzheimer's disease (AD) affects a significant proportion of cognitively unimpaired (CU) older adults. Currently, blood-based biomarkers detect very early changes in the AD continuum with great accuracy. METHODS: We measured baseline plasma phosphorylated tau (p-tau)181 using electrochemiluminescence (ECL)-based assay (MesoScale Discovery) in 533 CU older adults. Follow-up lasted up to 18 months. Cognitive performance assessment included memory and cognitive control. Structural brain measures included cortical thickness, which includes the AD magnetic resonance imaging (AD MRI) signature, and hippocampal volume. RESULTS: In this cohort of CU older adults, baseline plasma p-tau181 levels were not associated with short-term changes in cognition and structural brain measures. Also, baseline plasma p-tau levels did not influence the effects of behavioral interventions (exercise or mindfulness) on cognitive and structural brain changes. DISCUSSION: The short follow-up and healthy status of this CU cohort might have limited the sensitivity of plasma p-tau181 in detecting changes associated with AD pathology.

Optimizing treatment for older adults with depression.

This review presents a comprehensive guide for optimizing medication management in older adults with depression within an outpatient setting. Medication optimization involves tailoring the antidepressant strategy to the individual, ensuring the administration of appropriate medications at optimal dosages. In the case of older adults, this process necessitates not only adjusting or changing antidepressants but also addressing the concurrent use of inappropriate medications, many of which have cognitive side effects. This review outlines various strategies for medication optimization in late-life depression: (1) Utilizing the full dose range of a medication to maximize therapeutic benefits and strive for remission. (2) Transitioning to alternative classes (such as a serotonin and norepinephrine reuptake inhibitor [SNRI], bupropion, or mirtazapine) when first-line treatment with selective serotonin reuptake inhibitors [SSRIs] proves inadequate. (3) Exploring augmentation strategies like aripiprazole for treatment-resistant depression. (4) Implementing measurement-based care to help adjust treatment. (5) Sustaining an effective antidepressant strategy for at least 1 year following depression remission, with longer durations for recurrent episodes or severe presentations. (6) Safely discontinuing anticholinergic medications and benzodiazepines by employing a tapering method when necessary, coupled with counseling about the benefits of stopping them. Additionally, this article explores favorable medications for depression, as well as alternatives for managing anxiety, insomnia, allergy, overactive bladder, psychosis, and muscle spasm in order to avoid potent anticholinergics and benzodiazepines.

Post-stroke Depressive Symptoms and Cognitive Performances: A Network Analysis.

OBJECTIVE: To examine the relationships between post-stroke depression and cognition using network analysis. In particular, we identified central depressive symptoms, central cognitive performances, and bridge components that connect these 2 constructs. DESIGN: An observational study. We applied network analysis to analyze baseline data to visualize and quantify the relationships between depression and cognition. SETTING: Home and Community. PARTICIPANTS: 202 participants with mild-to-moderate stroke (N=202; mean age: 59.7 years; 55% men; 55% Whites; 90% ischemic stroke). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Patient Health Questionnaire (PHQ-8) for depressive symptoms and the NIH Toolbox Cognitive Battery for cognitive performances. RESULTS: Depressive symptoms were positively intercorrelated with the network, with symptoms from similar domains clustered together. Mood (expected influence=1.58), concentration (expected influence=0.67), and guilt (expected influence=0.63) were the top 3 central depressive symptoms. Cognitive performances also showed similar network patterns, with executive function (expected influence=0.89), expressive language (expected influence=0.68), and processing speed (expected influence=0.48) identified as the top 3 central cognitive performances. Psychomotor functioning (bridge expected influence=2.49) and attention (bridge expected influence=1.10) were the components connecting depression and cognition. CONCLUSIONS: The central and bridge components identified in this study might serve as targets for interventions against these deficits. Future trials are needed to compare the effectiveness of interventions targeting the central and bridge components vs general interventions treating depression and cognitive impairment as a homogenous clinical syndrome.