This Viewpoint explores the effectiveness of various interventions for individuals experiencing grief disorders, particularly prolonged grief disorder, following the death of a loved one.

PURPOSE:Decision trees can use clinical predictors to determine whether to continue the same antidepressant or switch to a different treatment in older patients with major depressive disorder (MDD). We examined whether pharmacogenetic and pharmacokinetic variables could improve their performance. PROCEDURES:We analyzed 191 participants from the Incomplete Response in Late-Life Depression: Getting to Remission (IRL-Grey) trial who had not responded fully after 4 weeks of venlafaxine XR (150 mg/d) and for whom venlafaxine up to 300 mg/d was continued for 8 additional weeks. CYP2D6 genotypes were determined; venlafaxine, o-desmethylvenlafaxine (ODV), and active moiety (AM) exposures at week 4 were calculated using population pharmacokinetic modeling. Decision tree analysis was performed using 5 early clinical predictors of eventual nonresponse identified in previous research and 4 pharmacogenetic and pharmacokinetic potential predictors. One decision tree was designed to optimize specificity (k=0.3), and another to optimize sensitivity (k=0.7). RESULTS:Longer episode duration and lack of partial response at week 4 were retained as clinical predictors, and lower AM and ODV exposures were identified as additional predictors. Negative predictive values (NPVs) of the high-specificity and high-sensitivity trees (77.7% and 73.0%, respectively) were similar to NPVs in trees based solely on clinical predictors. IMPLICATIONS:Our methods can guide future studies combining clinical and biomarker data to address applied pharmacological questions relevant to day-to-day practice.

OBJECTIVES:Nursing home residents are at high-risk for preventable harm and medication errors. This study aimed to identify clinician-reported medication safety failure modes in U.S. nursing homes and prioritize those most suitable for informatics-enabled active monitoring interventions. METHODS:We conducted a mixed-methods failure mode and effects analysis. Semi-structured interviews and field observations were conducted with 23 nursing home clinicians (duration 60-90 min). Interview anecdotes were translated into stepwise failure modes and represented as Unified Modeling Language (UML) workflow diagrams. Respondents rated each scenario's perceived seriousness, detectability, and frequency of routine monitoring; these ratings were combined to identify high-priority targets for intervention. RESULTS:Fourteen failure modes were refined into 10 generalizable clinical scenarios and evaluated via a survey of 61 nursing home healthcare providers from a wide range of sites and roles. Across clinical roles, survey respondents consistently prioritized meclizine/psychotropic co-exposure and diuretic/mobility impairment co-exposure as high-priority scenarios for active monitoring. Scenarios involving psychotropic/CNS-active medications and potential drug-drug interactions were also frequently rated as important and not routinely monitored. CONCLUSIONS:Clinician-derived medication nursing home safety failure modes have been prioritized using multi-stakeholder survey input, yielding a focused set of targets for medication-safety monitoring in nursing homes. IMPLICATIONS:The identified high-priority scenarios can inform the design of automated monitoring tools and pharmacist/nursing workflows. Future work should validate these targets against resident outcomes and evaluate the effectiveness of monitoring interventions.

Abstract Introduction Adults with treatment-resistant late-life depression (TRLLD) have high rates of sleep problems. However, little is known about the occurrence and change in sleep during pharmacotherapy of TRLLD or how sleep affects treatment response. We investigated the bidirectional relationship between sleep and treatment outcomes in the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) study, the largest comparative effectiveness trial of pharmacotherapy for TRLLD to date. Methods This analysis examined: (1) occurrence of reduced sleep in 634 participants in the OPTIMUM randomized controlled trial; (2) how their sleep changed during pharmacotherapy; and (3) whether treatment outcomes differed among participants with consistent insufficient sleep [n = 164], worsened sleep [n = 62], or with improved sleep [n = 158]). We used item #4 (scale 0 – 6) from the Montgomery-Asberg Depression Rating Scale (MADRS) to assess insufficient sleep, representing reduced sleep duration or depth compared to usual sleep pattern. Scores >2 indicate a meaningful reduction in duration or sleep depth. Patients who scored >2 on item #4 throughout the trial were classified as having consistent insufficient sleep; patients who reported an increased score (and >2 at trial end) were classified as having worsened sleep; and patients who reported a decreased scores (and ≤2 at trial end) were classified as having improved sleep. Treatment response was defined as a > 50% reduction in the total MADRS score (minus item #4 ) at trial end. Results About half (51%, n= 323) of participants with TRLLD reported reduced or insufficient sleep before treatment. At trial end, consistent insufficient sleep and worsened sleep were each associated with treatment non-response. Improve sleep was not a significant predictor of treatment response, however participants with consistent sufficient sleep or improved sleep were three times more likely to experience treatment response compared to patients with insufficient sleep and worsened sleep. Conclusion Insufficient or reduced sleep are modifiable factors that may improve treatment outcomes in TRLLD. Given that sleep complaints including insomnia are associated with greater risk of depressive relapse and treatment non-response, a tailored treatment plan for those at greatest risk of sleep disturbance with concomitant depression may facilitate better outcomes. Support (if any)

BackgroundVenlafaxine is commonly prescribed for older adults with depression, yet the relationship between venlafaxine-related exposure and treatment outcomes remains unclear. We aimed to assess the association of exposure to venlafaxine, its active metabolite O-desmethylvenlafaxine (ODV) and its active moiety (i.e., venlafaxine + ODV) with treatment response and adverse effects in late-life depression.MethodWe analyzed data from 325 participants from the Incomplete Response in Late-Life Depression: Getting to Remission (IRL-GRey) study. Participants were ≥ 60 years old, treated openly with venlafaxine (up to 300 mg/day) for 12 weeks. Treatment response was assessed with the Montgomery-Asberg Depression Rating Scale and adverse effects were evaluated with the Udvalg for Kliniske Undersøgelser (UKU) rating scale. Venlafaxine-related exposures were derived from a published population pharmacokinetic model based on the IRL-GRey study, and their associations with treatment outcomes were assessed using regression analyses.ResultAt week 4, the primary endpoint, higher venlafaxine-related exposures were not associated with greater symptom improvement. While at the end of treatment (week 12), we did not observe additional antidepressant benefit with increased venlafaxine-related exposures, higher ODV and active moiety exposures were associated with the occurrence of at least one adverse effect (odds ratio [OR] = 1.6 [1.1, 2.3], p = 0.02 and 1.8 [1.2, 2.6], p = 0.003, respectively). Also, higher venlafaxine and active moiety exposures were associated with nausea/vomiting (OR = 1.1 [1.0, 1.2], p = 0.02 and 2.3 [1.3, 4.0], p = 0.006); while higher active moiety exposure was associated with orthostatic dizziness (OR = 1.9 [1.1, 3.2], p = 0.02).ConclusionOur findings suggest a potential threshold effect, where venlafaxine-related exposure past a certain level did not enhance antidepressant response but increased adverse-effect burden. These results support incorporating exposure measures from therapeutic drug monitoring in antidepressant studies to address the heterogeneity of safety and tolerability outcomes.

Antidepressant augmentation with bupropion was recently demonstrated to increase fall risk in older adults, though specific subpopulations that may have increased risk have not yet been identified. To determine risk factors for falls in older adults with Major Depressive Disorder (MDD) receiving bupropion augmentation. Older adults with major depression were followed for approximately ten weeks during a randomized controlled trial (RCT) with three treatment arms, including bupropion augmentation. Data from the bupropion augmentation arm, which had higher fall rates, were analyzed. 194 older adults with MDD randomized to bupropion augmentation. Participants’ report of falls during biweekly study visits. The following baseline characteristics were significantly correlated (p < 0.05) with total number of falls: number of falls during the previous 6 months (r = 0.42), burden of physical illness measured with the Cumulative Illness Rating Scale-Geriatric (r = 0.26), physical function score on the Patient-Reported Outcomes Measurement Information System (r = -0.23), and baseline Patient Health Questionnaire-9 Score (r = 0.16). There were significant main effects of bupropion dosage level (low, medium, or high) (p = 0.04) and number of falls during the six months prior to study entry (p < 0.001). Study fall rates extrapolated out to the number of falls per year of treatment for subgroups distinguished by dosage level and prior falls ranged from 1.39 falls/year (no history of falls, low dosage bupropion) to 12.32 falls/year (3 + falls during the 6 months prior to study entry, high dosage bupropion). The risk of falls during bupropion augmentation is a function of the patient’s personal history of falls and the dosage of bupropion. Careful patient selection and personalization of dosing strategy might reduce the risk of falls in older depressed patients treated with bupropion.

BACKGROUND:Prolonged Grief Disorder (PGD) in later life may involve volumetric patterns indicative of accelerated brain aging. This study examined whether structural brain age differs between individuals with PGD and those with integrated grief (IG), and whether it is associated with clinical severity. METHODS:Chronically grieving older adults with PGD (n = 36) and IG (n = 56), equated on demographics and time since loss, underwent structural MRI. Machine learning-derived indices were computed for each participant: Brain Age Gap (SPARE-BAG), Alzheimer's disease-like atrophy (SPARE-AD), and five dominant brain aging patterns. Group differences and associations with symptom severity were assessed, along with moderation by age, cognitive status, medical burden, and current and past depression. RESULTS:Compared to IG, the PGD group showed significantly higher SPARE-BAG (t = 2.61, pcorrected = 0.021), SPARE-AD (t = 2.04, pcorrected = 0.045), and medial temporal lobe atrophy pattern (t = 3.44, pcorrected = 0.005). However, these findings were attenuated and no longer significant after accounting for comorbid depressive symptoms. In the PGD group, both SPARE scores positively correlated with grief and depressive symptom severity (pcorrected < 0.03). The SPARE-BAG-grief symptom association was moderated by younger age (z = -2.92, pFDR = 0.018) and higher depressive symptoms (z = 1.88, p = 0.061); SPARE-AD-depressive symptom correlation was moderated by past depression history (z = 2.64, pcorrected = 0.041). CONCLUSION:Adults with PGD exhibit structural brain patterns consistent with accelerated and AD-like aging. However, these findings were largely driven by comorbid depressive symptoms. The brain aging indices were associated with both grief and depressive symptom severity, highlighting the cumulative neurobiological burden associated with PGD and co-occurring depression and underscoring the need for integrative clinical approaches addressing both conditions.

Bereavement is a near-universal experience in late life, yet only some older adults develop prolonged grief disorder (PGD). While most transition from acute grief (AG) to integrated (adaptive) grief, the neurobiological substrates underlying divergent trajectories are unclear. Emotion regulation dysfunction is hypothesized to play a central role in PGD pathogenesis, but longitudinal neuroimaging data in bereaved adults are lacking. This study aims to identify functional brain circuit measures of emotional regulation that predict pathological versus adaptive grief trajectories, aligning with the Research Domain Criteria (RDoc) framework for the Negative Valence System (Loss) construct. This single-site, 1-year longitudinal study aims to enroll 170 adults aged 50-89 years: 115 with AG and 55 age- and gender-equated non-bereaved participants. Participants will complete comprehensive psychiatric, neuropsychological, and psychosocial assessments, alongside neuroimaging both at study baseline and after 12 months. Functional neuroimaging includes resting-state fMRI, a face-shape matching task probing emotion processing, and a stop-signal task probing inhibitory control. Functional neuroimaging data are acquired using a harmonized Human Connectome Project protocol on a GE Signa Premier 3T MRI scanner. We present a comprehensive overview of the eligibility criteria, clinical study procedures, and neuroimaging protocol. Baseline findings from 103 AG and 40 non-bereaved participants thus far enrolled show that the groups are demographically matched and provide high-quality neuroimaging data and robust task performance. This study is among the first longitudinal neuroimaging investigations of AG in older adults and may identify early biomarkers of PGD risk, potentially guiding precision prevention and intervention strategies for bereaved older adults.

Rationale: Individuals acting as surrogate decision-makers for critically ill patients frequently struggle in this role and experience high levels of long-term psychological distress. Prior interventions that were designed solely to improve information sharing between clinicians and family members have been ineffective. Objectives: We sought to examine the impact of a multicomponent family support intervention on patient and family outcomes. Methods: We conducted a patient-level randomized clinical trial at six ICUs in a healthcare system in Pennsylvania. An external interventionist interacted daily with surrogate decision-makers for incapacitated, critically ill patients at high risk of death or severe long-term functional impairment to deliver four types of protocolized support during the ICU stay: emotional support; communication support; decisional support; and, if indicated, anticipatory grief support. The control condition involved usual care plus two brief education sessions about critical illness. Measurements and Main Results: Primary outcome was the surrogates' scores on the Hospital Anxiety and Depression Scale at 6 months (range = 0-42). A total of 444 surrogates of 291 patients were enrolled (233 surrogates in intervention and 211 in control). The Four Supports intervention was delivered with high fidelity (frequency of per protocol delivery of key intervention elements, 97.1%; quality rating of intervention delivery, 2.9 ± 0.2 on a scale ranging from 1 to 3, with higher scores indicating higher quality of intervention delivery). There was no intervention effect on the primary outcome, surrogates' Hospital Anxiety and Depression Scale total scores at 6-month follow-up (β = 0.06; 95% confidence interval, -0.07 to 0.19; P = 0.35), or the prespecified secondary outcomes. Conclusions: Among critically ill patients at high risk of death or functional impairment, a family support intervention delivered by an external interventionist did not reduce surrogates' long-term psychological symptom burden.Clinical trial registered with www.clinicaltrials.gov (NCT01982877).

BACKGROUND:The triglyceride-glucose index (TyG) has been proposed as a promising and clinically relevant biological marker of insulin resistance, which is thought to be prevalent among individuals at risk for depression. To date, there have been no longitudinal studies investigating the relationship between an elevated triglyceride-glucose index and subsequent depressive symptoms. METHODS:Health measures of 19,114 community-dwelling adults living in Australia and the United States of America, with a mean age of 75 years, were followed up for up to 11 years. Fasting triglyceride levels and fasting glucose levels were used to calculate the triglyceride-glucose index (TyG - the logarithmised product of fasting triglyceride level and fasting glucose divided by two), a marker of insulin resistance and risk for atherosclerotic cardiovascular disease. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression 10-item scale (CES-D-10), with a score ≥ 8 used to indicate a diagnosis of depression. The association between TyG and depression one year later was assessed using generalized estimating equations (GEE), with robust variance estimation to handle repeated measures clustered data. The main model was adjusted for age, gender, ethnicity, living arrangements, education, smoking status, alcohol consumption, body mass index, hypertension, type 2 diabetes, chronic kidney disease, a history of cancer, modified mini-mental state examination score, aspirin use, antidepressant use, diabetic medication use, and lipid-lowering medication use. In a secondary analysis, a Cox proportional hazards model was used to compare the incidence of depression up to 11 years between individuals with the highest baseline TyG group and the lowest baseline TyG. RESULTS:After adjustments for confounders, the GEE analysis showed no significant relationship between the highest quartile of TyG (compared to the lowest quartile of TyG) and depression one year later. The Cox proportional hazards model showed no significant difference between the highest and lowest TyG and depressive symptoms, when adjusted for the above covariates. CONCLUSIONS:An elevated triglyceride-glucose index was not associated with the later development of depression in fully adjusted models.

OBJECTIVES:To describe demographic and professional characteristics of the American Association for Geriatric Psychiatry (AAGP) membership based on the 2016 and 2023 surveys. METHODS:Surveys for 2016 and 2023 were created by the AAGP Diversity Caucus and the AAGP Inclusion, Diversity, Equity in Action (IDEA) committee, respectively, and administered to the AAGP membership. The 2023 survey also queried about attitudes towards diversity, equity, and inclusion (DEI). RESULTS:118 of 1,453 AAGP members responded to the 2016 survey, representing an 8.1% response rate. 195 of 1,232 members responded to the 2023 survey, for a response rate of 15.8%. The majority of survey respondents were comprised of academic psychiatrists who hold teaching and administrative roles alongside clinical work and who were predominantly Caucasian, heterosexual, and middle-aged. A comparison of survey responses in 2016 and 2023 revealed slight shifts towards greater diversity, with an increase in the proportion of nonpsychiatry professionals, racialized minorities in Black and Asian groups, and a higher proportion of female respondents. The number of respondents aged 65 and older nearly doubled between 2016 and 2023. Although the majority of respondents favored an increase in focus on DEI at the annual meeting and within the AAGP, 58 of 195 respondents (30%) did not. Respondents below the age of 55 years and who were female were disproportionately in favor of increasing a focus on DEI. CONCLUSION:A limitation of the current findings is the low response rate. Future surveys should implement strategies to increase response rates and longitudinal tracking of survey respondents to identify DEI-related needs of the AAGP's membership. Periodic surveying of the demographic and professional diversity of the AAGP membership is an essential tool that will allow monitoring of DEI efforts in the organization.

Objective: The aim of this study was to identify sleep/wake characteristics associated with suicidal ideation (SI) severity among older adults who are at risk for suicide. Methods: This 6-week observational study examined associations between weekly actigraphy-derived sleep/wake measures and SI severity (Beck Scale for Suicidal Ideation [SSI]). The sample (n = 30; 83% female; average age = 62 years), enrolled April 2021 through March 2023, self reported a physician diagnosis of DSM-5 major depressive disorder with an episode in the last 6 months and also had either recent active SI or a past suicide attempt. Weekly sleep/wake measures included sleep duration, fragmentation, and 2 rhythm variables (interdaily stability and relative amplitude). Primary analyses used age- and sex-adjusted repeated-measure linear mixed models, 1 model per sleep/wake variable, to assess associations between weekly sleep/ wake and SI reported at week's end. We examined if associations of sleep/wake factors with SI were independent of depression severity (Patient Health Questionnaire-8 scores). Results: Longer sleep duration, greater interdaily stability, and higher relative amplitude were associated with lower SI (eg, for each standard deviation higher interdaily stability, SSI scores were an estimated 1.4 points lower [P = .005]). After adjusting for depression severity, both sleep/wake rhythm variables remained significantly associated with SI, whereas the association between sleep duration and SI severity was attenuated by >80%. Conclusion: In this sample, sleep/wake rhythm disruption (but not sleep duration or fragmentation) related to SI independent of depression severity. Targeting disruptions in sleep/wake rhythms may be an important avenue for future trials of sleep medicine approaches to reduce SI in older adults.

BACKGROUND:It remains unclear which individuals with subthreshold depression benefit most from psychological intervention, and what long-term effects this has on symptom deterioration, response and remission. AIMS:To synthesise psychological intervention benefits in adults with subthreshold depression up to 2 years, and explore participant-level effect-modifiers. METHOD:Randomised trials comparing psychological intervention with inactive control were identified via systematic search. Authors were contacted to obtain individual participant data (IPD), analysed using Bayesian one-stage meta-analysis. Treatment-covariate interactions were added to examine moderators. Hierarchical-additive models were used to explore treatment benefits conditional on baseline Patient Health Questionnaire 9 (PHQ-9) values. RESULTS:IPD of 10 671 individuals (50 studies) could be included. We found significant effects on depressive symptom severity up to 12 months (standardised mean-difference [s.m.d.] = -0.48 to -0.27). Effects could not be ascertained up to 24 months (s.m.d. = -0.18). Similar findings emerged for 50% symptom reduction (relative risk = 1.27-2.79), reliable improvement (relative risk = 1.38-3.17), deterioration (relative risk = 0.67-0.54) and close-to-symptom-free status (relative risk = 1.41-2.80). Among participant-level moderators, only initial depression and anxiety severity were highly credible (P > 0.99). Predicted treatment benefits decreased with lower symptom severity but remained minimally important even for very mild symptoms (s.m.d. = -0.33 for PHQ-9 = 5). CONCLUSIONS:Psychological intervention reduces the symptom burden in individuals with subthreshold depression up to 1 year, and protects against symptom deterioration. Benefits up to 2 years are less certain. We find strong support for intervention in subthreshold depression, particularly with PHQ-9 scores ≥ 10. For very mild symptoms, scalable treatments could be an attractive option.

The arc of my career has focused on the integration of clinical care, mentoring, and research, leading to meaningful research questions and intervention trials advancing the field. In this Special Communication, I first offer a brief synopsis of my work as an academic psychiatrist, highlighting mission, themes and publications, sponsors, and collaborators. I then discuss activities as a mentor, focusing on 2 National Institute of Mental Health (NIMH)-funded research career development programs. As the past recipient of K01, K02, and K05 awards from the NIMH (1980-2000), I have taken to heart the obligation to pay it forward: to support, advise, instruct, and guide younger colleagues, challenging them academically and professionally. For 20 years, my P30 infrastructure center grant provided a platform for institutional training grants (T32s) and psychiatric research education grants (R25s) to serve as a foundation for training the next generation of clinical scientists in late life mood disorders, as well as a nidus for interdisciplinary collaboration. I have benefitted greatly from having had mentors and wise friends, particularly David Kupfer, MD; Ellen Frank, PhD; and Thomas Detre, MD, of the University of Pittsburgh School of Medicine; colleagues in the Aging Branch of NIMH throughout my 40-year career as a physician scientist; Dilip Jeste, MD, University of California at San Diego; Daniel Blazer, MD, PhD, Duke University School of Medicine; George Alexopoulos, MD, Weill Cornell School of Medicine; John Rush, MD, University of Texas Southwestern School of Medicine; Alan Schatzberg, MD, Stanford University School of Medicine; M. Katherine Shear, MD, Columbia University Schools of Social Work and of Medicine; Helena Kraemer, PhD, Stanford University School of Medicine; and Edmund Ricci, PhD, University of Pittsburgh Graduate School of Public Health. These colleagues are good listeners, flexible, diverse in perspectives, knowledgeable, nonjudgmental, and able to give constructive feedback, network, and help find resources. I have sought to do likewise with many younger colleagues, both men and women, physicians and PhDs, and persons of different professional, racial, and ethnic backgrounds-totaling about 25 K awardees. I conclude with recommendations for future clinical practice and research in late-life depression, describing a broad spectrum of approaches aiming both to reduce its public health burden and to enhance wisdom, resilience, and well-being in later life.

Abstract Background Aging makes older adults more susceptible to antidepressant-induced side effects due to homeostatic reserve, comorbidity, poly-pharmacy, and age-related pharmacokinetic (PK) changes. Depression in older adults is often treated with venlafaxine, a serotonin-norepinephrine reuptake inhibitor metabolized by the enzyme CYP2D6. CYP2D6 is highly genetically polymorphic and thus might affect venlafaxine treatment outcomes by affecting venlafaxine PK. Aims and Objectives The study aims to investigate whether CYP2D6 metabolizers have different VEN- related PK parameters and examine the impact of these parameters on treatment outcomes in late-life depression. Method Data from participants from the Incomplete Response in Late-Life Depression: Getting to Remission study (IRL-GRey, NCT00892047) were analyzed in this study (N = 325) [1]. We used the software NONMEM to adapt a population PK analyses of VEN and its main metabolite O- desmethylvenlafaxine (ODV) [2]. The PK model was adjusted for CYP2D6 metabolizer status and age. The ANOVA was performed to identify differences in PK model-estimated PK parameters between CYP2D6 metabolizer groups. Treatment efficacy (measured using MADRS) and adverse effects (measured using UKU) were analyzed using regression models to see if they were associated with PK model-estimated drug exposure, followed by sex-stratified analyses for each outcome. Results CYP2D6 metabolizers had significantly different PK model-estimated VEN clearance, VEN exposure, and active moiety (venlafaxine plus ODV) exposure. None of the exposure was associated with treatment efficacy in either whole sample or sex-stratified analyses. The overall presence of adverse effects was associated with higher ODV exposure (OR = 1.5 [1.0, 2.2], p = 0.04) and higher AM exposure (OR = 1.7 [1.2, 2.5], p = 0.003). Only females showed a significant association between overall adverse effects and higher active moiety exposure (OR = 2.0 [1.3, 3.2], p = 0.004). Specifically, higher risk of nausea/vomiting was associated with higher venlafaxine exposure and higher active moiety exposure in both the whole sample (venlafaxine, OR = 1.1 [1.0, 1.2], p = 0.04; active moiety, OR = 2.0 [1.2, 3.4], p = 0.01) and females (venlafaxine, OR = 1.1 [1.0, 1.2], p = 0.02; active moiety, OR = 2.2 [1.2, 4.0], p = 0.01), but not in males. In the whole sample, orthostatic dizziness is associated with higher venlafaxine exposure (OR = 1.1 [1.0, 1.2], p = 0.02) and higher active moiety exposure (OR = 2.0 [1.2, 3.4], p = 0.01). For this adverse effect, females showed had association only with higher venlafaxine (OR = 1.1 [1.0, 1.2], p = 0.02), while males showed significant associations in higher ODV (OR = 5.2 [1.2, 23.0], p = 0.03) and higher active moiety exposure (OR = 5.5 [1.1, 26.8], p = 0.03). Discussion & Conclusions Our study indicated that CYP2D6 metabolizer groups had a significant impact on PK model-estimated VEN-related PK parameters. Higher venlafaxine-related exposure is associated with a higher risk of active effects, especially nausea/vomiting and orthostatic dizziness. Sex might also be an important factor in venlafaxine treatment outcomes. Overall, our study highlights the importance of personalized medicine and its clinical implications in older adults with depression. References 1.Lenze, E. J. et al. Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo- controlled trial. The Lancet 386, 2404–2412 (2015). 2.Lindauer, A. et al. Pharmacokinetic/pharmacodynamic modelling of venlafaxine: pupillary light reflex as a test system for noradrenergic effects. Clin. Pharmacokinet. 47, 721–731 (2008).