Response In Late-life Depression Research Articles

Poster Number: EI 42 - Immunological Markers Associated with Brain Health and Treatment Response in Late-Life Depression: Pilot Study

Poster Number: EI 42 - Immunological Markers Associated with Brain Health and Treatment Response in Late-Life Depression: Pilot Study

Genomic predictors of remission to antidepressant treatment in geriatric depression using genome‐wide expression analyses: a pilot study

This first pilot study of genome-wide expression as predictor of antidepressant response in late-life depression examined genome-wide transcriptional profiles in a randomized placebo-controlled trial of combined methylphenidate and citalopram. Genome-wide transcriptional profiles were examined in peripheral blood leukocytes sampled at baseline and 16 weeks from 35 older adults with major depression, who were randomized to methylphenidate + citalopram, citalopram + placebo, or methylphenidate + placebo. Methylphenidate doses ranged between 10 and 40 mg/day, and citalopram doses ranged between 20 and 60 mg/day. Remission was defined as Hamilton Depression Rating Scale score of 6 or below. Early remission was achieved in the first 4 weeks of treatment. We hypothesized that differential gene expression at baseline can predict antidepressant response. We analyzed gene expression in 24 remitters and 11 non-remitters. At baseline, we found three genes showing higher expression in all remitters versus non-remitters that satisfied the established level of significance: a fold change of 2 and p-value of 0.05 that included HLA-DRB5, SELENBP1, and LOC388588. Two gene transcripts showed higher expression in early remitters at baseline compared with non-remitters. The first gene was CA1 carbonic anhydrase gene, on chromosome 8 involved in respiratory function (fold change 2.54; p = 0.03). The second gene was the SNCA-α-synuclein gene, implicated, which binds to dopamine transporter (fold change 2.1; p = 0.03). Remission to antidepressants in geriatric depression may be associated with a particular gene expression profile in monoaminergic and metabolic pathways and needs to be replicated in a larger sample.

A Meta-Analysis of Executive Dysfunction and Antidepressant Treatment Response in Late-Life Depression.

Depressed older adults with executive dysfunction (ED) may respond poorly to antidepressant treatment. ED is a multifaceted construct and different studies have measured different aspects of ED, making it unclear which aspects predict poor response. Meta-analytic methods were used to determine whether ED predicts poor antidepressant treatment response in late-life depression and to determine which domains of executive functioning are responsible for this relationship. A Medline search was conducted to identify regimented treatment trials contrasting executive functioning between elderly responders and nonresponders; only regimented treatment trials for depressed outpatients aged 50 and older were included. Following the most recent PRISMA guidelines, 25 measures of executive functioning were extracted from eight studies. Six domains were identified: cognitive flexibility, planning and organization, response inhibition, selective attention, verbal fluency, and the Dementia Rating Scale Initiation/Perseveration composite score (DRS I/P). Hedge's g was calculated for each measure of executive functioning. A three-level Bayesian hierarchical linear model (HLM) was used to estimate effect sizes for each domain of executive functioning. The effect of planning and organization was significantly different from zero (Bayesian HLM estimate of domain effect size: 0.91; 95% CI: 0.32-1.58), whereas cognitive flexibility, response inhibition, selective attention, verbal fluency, and the DRS I/P composite score were not. The domain of planning and organization is meaningfully associated with poor antidepressant treatment response in late-life depression. These findings suggest that therapies that focus on planning and organization may provide effective augmentation strategies for antidepressant nonresponders with late-life depression.

Emotional Processing Functional Magnetic Resonance Imaging Is Associated with Treatment Response in Late Life Depression

Late-life depression (LLD) is a distinct clinical entity which has been estimated to affect 8-16% of elderly patients. Its disease burden is considerable with effects on mortality, development of dementia, functional status, and healthcare utilization. Research has established functional magnetic resonance imaging (fMRI) markers as reliable predictors of treatment in response in LLD, including differential activity and connectivity between various neural structures and networks. However, an underexplored area of previous fMRI studies is whether neural activity during affective tasks may be associated with treatment response in LLD.

Cingulum bundle white matter lesions influence antidepressant response in late-life depression: A pilot study

BackgroundLate-life depression is associated with white matter hyperintense lesions (WMLs) occurring in specific fiber tracts. In this study, we sought to determine if greater WML severity in the cingulum bundle or uncinate fasciculus was associated with poor short-term antidepressant response. MethodsEleven depressed elders completed a baseline cranial 3T MRI and received antidepressant treatment following a medication algorithm. MRIs were analyzed to measure the fraction of each fiber tract׳s volume occupied by WMLs. Statistical analyses examined the effect of dichotomized fiber tract WML severity on three- and six-month depression severity after controlling for age and baseline depression severity. ResultsGreater WML severity in the left hemispheric cingulum bundle adjacent to the hippocampus was associated with greater post-treatment depression severity at three- (F1,7=6.42, p=0.0390) and six-month assessments (F1,5=9.62, p=0.0268). Other fiber tract WML measures were not significantly associated with outcomes. LimitationsThe study had a small sample size and analyses were limited to only a priori fiber tracts. ConclusionsThis pilot study supports the hypothesis that focal damage to the cingulum bundle may contribute to poor short-term antidepressant response. These findings warrant further investigation with a larger, more definitive study.

Magnetic Resonance Imaging Predictors of Treatment Response in Late-Life Depression

In older adults, depression not only results in more years lived with disability than any other disease but it also carries additional risks of suicide, medical comorbidities, and family caregiving burden. Because it can take many months to identify an effective treatment regimen, it is of utmost importance to shorten the window of time and identify early on what medications and dosages will work effectively for individuals having depression. Late-life depression (LLD) has been associated with greater burden of age-related changes (eg, atrophy, white matter ischemic changes, and functional connectivity). Depression in midlife has been shown to alter affective reactivity and regulation, and functional magnetic resonance imaging (fMRI) studies in LLD have replicated the same abnormalities. Effective treatment can normalize these alterations. This article provides a review of the current literature using structural and functional neuroimaging to identify MRI predictors of treatment response in LLD. The majority of the literature on structural MRI has focused on the vascular depression hypothesis, and studies support the view that loss of brain volume and white matter integrity was associated with poorer treatment outcomes. Studies using fMRI have reported that lower task-based activity in the prefrontal cortex and limbic regions was associated with poorer outcome. These imaging markers may be integrated into clinical decision making to attain better treatment outcomes in the future.

Executive Functioning Complaints and Escitalopram Treatment Response in Late-Life Depression

Executive dysfunction may play a key role in the pathophysiology of late-life depression. Executive dysfunction can be assessed with cognitive tests and subjective report of difficulties with executive skills. The present study investigated the association between subjective report of executive functioning complaints and time to escitalopram treatment response in older adults with major depressive disorder (MDD). 100 older adults with MDD (58 with executive functioning complaints and 42 without executive functioning complaints) completed a 12-week trial of escitalopram. Treatment response over 12 weeks, as measured by repeated Hamilton Depression Rating Scale scores, was compared for adults with and without executive complaints using mixed-effects modeling. Mixed effects analysis revealed a significant group × time interaction, F(1, 523.34) = 6.00, p = 0.01. Depressed older adults who reported executive functioning complaints at baseline demonstrated a slower response to escitalopram treatment than those without executive functioning complaints. Self-report of executive functioning difficulties may be a useful prognostic indicator for subsequent speed of response to antidepressant medication.

Resting state functional connectivity and treatment response in late-life depression

Indices of functional connectivity in the default mode network (DMN) are promising neural markers of treatment response in late-life depression. We examined the differences in DMN functional connectivity between treatment-responsive and treatment-resistant depressed older adults. Forty-seven depressed older adults underwent MRI scanning pre- and post-pharmacotherapy. Forty-six never depressed older adults underwent MR scanning as comparison subjects. Treatment response was defined as achieving a Hamilton Depression Rating Scale of 10 or less post-treatment. We analyzed resting state functional connectivity using the posterior cingulate cortex as the seed region-of-interest. The resulting correlation maps were employed to investigate between-group differences. Additionally we examined the association between white matter hyperintensity burden and functional connectivity results. Comparison of pre- and post-treatment scans of depressed participants revealed greater post-treatment functional connectivity in the frontal precentral gyrus. Relative to treatment-responsive participants, treatment-resistant participants had increased functional connectivity in the left striatum. When adjusting for white matter hyperintensity burden, the observed differences lost significance for the PCC-prefrontal functional connectivity, but not for the PCC-striatum functional connectivity. The post-treatment “frontalization” of the DMN connectivity suggests a normalizing effect of antidepressant treatment. Moreover, our study confirms the central role of white matter lesions in disrupting brain functional connectivity.

Patterns of Reduced Cortical Thickness in Late-Life Depression and Relationship to Psychotherapeutic Response

Cortical atrophy has been associated with late-life depression (LLD) and recent findings suggest that reduced right hemisphere cortical thickness is associated with familial risk for major depressive disorder, but cortical thickness abnormalities in LLD have not been explored. Furthermore, cortical atrophy has been posited as a contributor to poor antidepressant treatment response in LLD, but the impact of cortical thickness on psychotherapy response is unknown. This study was conducted to evaluate patterns of cortical thickness in LLD and in relation to psychotherapy treatment outcomes. Participants included 22 individuals with LLD and 12 age-matched comparison subjects. LLD participants completed 12 weeks of psychotherapy and treatment response was defined as a 50% reduction in depressive symptoms. All participants underwent magnetic resonance imaging of the brain, and cortical mapping of gray matter tissue thickness was calculated. LLD individuals demonstrated thinner cortex than controls prominently in the right frontal, parietal, and temporal brain regions. Eleven participants (50%) exhibited positive psychotherapy response after 12 weeks of treatment. Psychotherapy nonresponders demonstrated thinner cortex in bilateral posterior cingulate and parahippocampal cortices, left paracentral, precuneus, cuneus, and insular cortices, and the right medial orbitofrontal and lateral occipital cortices relative to treatment responders. Our findings suggest more distributed right hemisphere cortical abnormalities in LLD than have been previously reported. In addition, our findings suggest that reduced bilateral cortical thickness may be an important phenotypic marker of individuals at higher risk for poor response to psychotherapy.

Dynamic Prediction of Treatment Response in Late-Life Depression

To identify actionable predictors of remission to antidepressant pharmacotherapy in depressed older adults and to use signal detection theory to develop decision trees to guide clinical decision making. We treated 277 participants with current major depression using open-label venlafaxine XR (up to 300 mg/day) for 12 weeks, in an NIMH-sponsored randomized, placebo-controlled augmentation trial of adjunctive aripiprazole. Multiple logistic regression and signal detection approaches identified predictors of remission in both completer and intent-to-treat samples. Higher baseline depressive symptom severity (odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.80-0.93; p<0.001), smaller symptom improvement during the first two weeks of treatment (OR: 0.96, 95% CI: 0.94-0.97; p<0.001), male sex (OR: 0.41 95% CI: 0.18-0.93; p= 0.03), duration of current episode≥2 years (OR: 0.26, 95% CI: 0.12-0.57; p<0.001) and adequate past depression treatment (ATHF≥3) (OR: 0.34, 95% CI: 0.16-0.74; p= 0.006) predicted lower probability of remission in the completer sample. Subjects with Montgomery Asberg (MADRS) decreasing by greater than 27% in the first 2 weeks and with baseline MADRS scores of less than 27 (percentile rank= 51) had the best chance of remission (89%). Subjects with small symptom decrease in the first 2 weeks with adequate prior treatment and younger than 75 years old had the lowest chance of remission (16%). Our results suggest the clinical utility of measuring pre-treatment illness severity and change during the first 2 weeks of treatment in predicting remission of late-life major depression.

Treatment Course With Antidepressant Therapy in Late-Life Depression

In order to assess the effect of gray matter volumes and cortical thickness on antidepressant treatment response in late-life depression, the authors examined the relationship between brain regions identified a priori and Montgomery-Åsberg Depression Rating Scale (MADRS) scores over the course of an antidepressant treatment trial. In a nonrandomized prospective trial, 168 patients who were at least 60 years of age and met DSM-IV criteria for major depression underwent MRI and were enrolled in a 12-week treatment study. Exclusion criteria included cognitive impairment or severe medical disorders. The volumes or cortical thicknesses of regions of interest that differed between the depressed group and a comparison group (N=50) were determined. These regions of interest were used in analyses of the depressed group to predict antidepressant treatment outcome. Mixed-model analyses adjusting for age, education, age at depression onset, race, baseline MADRS score, scanner, and interaction with time examined predictors of MADRS scores over time. Smaller hippocampal volumes predicted a slower response to treatment. With the inclusion of white matter hyper-intensity severity and neuropsychological factor scores, the best model included hippocampal volume and cognitive processing speed to predict rate of response over time. A secondary analysis showed that hippocampal volume and frontal pole thickness differed between patients who achieved remission and those who did not. These data expand our understanding of the prediction of treatment course in late-life depression. The authors propose that the primary variables of hippocampal volume and cognitive processing speed, subsuming other contributing variables (episodic memory, executive function, language processing) predict antidepressant response.

Late-Life Depression Research: Lessons Learned From the Metabolic Syndrome

Late-Life Depression Research: Lessons Learned From the Metabolic Syndrome

Relationship of endothelial function and atherosclerosis to treatment response in late‐life depression

Treatment response in late-life depression has been linked to cerebrovascular disease notably via the vascular depression hypothesis. This study investigated the relationship between endothelial function and atherosclerosis and treatment response to antidepressant monotherapy. Twenty five patients with late-life depression were compared with 21 non-depressed control subjects in a case control study. Nine of the depressed subjects were responders to antidepressant monotherapy and 16 were not. Vascular measures included assessment of carotid intima media thickness (IMT) representing atherosclerosis and biopsied small artery dilatation to acetylcholine to assess endothelial function in a subset of subjects. There were no group differences in vascular risks or sociodemographic variables. There was a significant group difference (responders versus non-responders versus controls) on both IMT and endothelial function (p < 0.01 and p < 0.05, respectively) with a significant difference between controls and non-responders (p < 0.001) on IMT and between controls and responders (p < 0.05) and control versus non-responders (p < 0.05) on endothelial function but no significant difference between responders and non-responders. On both IMT and endothelial function, there was a gradient across groups, with control subjects having best vascular structure or function, non-responders worse and responders in-between. The results are consistent with a hypothesis that poorer antidepressant response in later life depressive disorder may be linked to an underlying vascular dysfunction and pathology. The study is small, and the results require replication but if confirmed, trials with vasoprotective medication aimed at improving vascular function in order to alter the prognosis of late-life depression would be a rational development.

Predictors of Antidepressant Response in Late-Life Depression

Several biological factors are thought to contribute to late-life depression — for example, gray-matter structural changes and cerebrovascular factors that might cause ischemic white-matter lesions at various cortical and subcortical sites. Some of these factors might also affect response to antidepressant treatment. To identify possible predictors of antidepressant response in late-life depression, investigators in this …

High worry severity is associated with poorer acute and maintenance efficacy of antidepressants in late-life depression

Co-morbid anxiety symptoms are common in late-life depression (LLD) and predict poorer treatment outcomes. No research has delineated the impact of different dimensions of anxiety (such as worry/anxious apprehension and panic/anxious arousal) on treatment response in LLD. We explored the impact of the dimensions of worry and panic on acute and maintenance treatment outcomes in LLD. We measured anxiety symptoms in 170 LLD subjects receiving protocolized treatment. Exploratory principal component analysis was used to delineate dimensions of anxiety symptoms. We defined sub-groups based on factor scores. We used survival analysis to test the association of pretreatment anxiety dimensions with time to response and time to recurrence of LLD. The principal component analysis found two factors: "worry" and "panic." Three sub-groups were defined: low panic-low worry, low panic-high worry, and high panic-high worry. The low panic-high worry and high panic-high worry sub-groups had longer time to response than the low panic-low worry sub-group. Time to recurrence was longer in low panic-low worry subjects randomized to drug. Among subjects with high worry, there was no difference between those with low versus high panic regarding both time to response and time to recurrence of LLD. High levels of worry were associated with longer time to response and earlier recurrence with pharmacotherapy for LLD. There was no additional effect of panic symptoms on treatment outcomes when accounting for the effects of excessive worry. These results suggest that worry symptoms should be a focus of strategies to improve acute and maintenance treatment response in LLD.

Pilot Study of Augmentation With Aripiprazole for Incomplete Response in Late-Life Depression

To determine the feasibility and safety of aripiprazole augmentation for incomplete response to sequential selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) pharmacotherapy in late-life depression. This study was a 12-week, open-label pilot study of 24 patients (recruited from June 1, 2006, to June 1, 2007) aged 65 years and above (mean, 73.9 years) diagnosed with major depressive disorder (MDD) (according to DSM-IV) who responded partially (17-item Hamilton Rating Scale for Depression [HAM-D-17] score of 11 to 15) or not at all (HAM-D score > 15) to a 16-week trial of escitalopram (up to 20 mg/day), followed by either duloxetine (up to 120 mg/day) or venlafaxine (up to 225 mg/day) for 12 weeks. Subjects received 2.5 to 15 mg per day of adjunctive aripiprazole (mean dose, 9.0 mg/day) for 12 weeks. The criterion for remission during treatment with aripiprazole was a HAM-D score < or = 10 for 2 consecutive weeks. Of 24 subjects in the intent-to-treat study group, 19 completed 12 weeks of augmentation with aripiprazole, 12 of 24 (50%) met criteria for remission, and 2 of 24 discontinued due to side effects (sedation, akathisia). The mean (SD) HAM-D score decreased significantly by 6.4 (5.8) points (paired t test for means, p < .01, df = 16). There were no relapses among the 12 subjects who participated in continuation treatment over a median period of 27.6 weeks. In older adults with MDD with incomplete response to SSRI and SNRI pharmacotherapy, aripiprazole was well tolerated, and symptoms of depression improved significantly during treatment with aripiprazole. A randomized, double-blind, placebo-controlled trial of adjunctive aripiprazole for incomplete response in late-life depression is warranted to further evaluate benefit and risk. clinicaltrials.gov Identifier: NCT00177671.

Empirically Derived Decision Trees for the Treatment of Late-Life Depression

Objective:Several predictors of treatment response in late-life depression have been reported in the literature. The aim of this analysis was to develop a clinically useful algorithm that would allow clinicians to predict which patients will likely respond to treatment and thereby guide clinical decision making. Method: A total of 461 patients with late-life depression were treated under structured conditions for up to 12 weeks and assessed weekly with the 17-item Hamilton Rating Scale for Depression (HAM-D-17). The authors developed a hierarchy of predictors of treatment response using signal-detection theory. The authors developed two models, one minimizing false predictions of future response and one minimizing false predictions of future nonresponse, to offer clinicians two clinically useful treatment algorithms. Results: In the first model, early symptom improvement (defined by the relative change in HAM-D-17 total score from baseline to week 4), lower baseline anxiety, and an older age of onset pred...

Incomplete response in late-life depression: getting to remission

Incomplete response in the treatment of late-life depression is a large public health challenge: at least 50% of older people fail to respond adequately to first-line antidepressant pharmacotherapy, even under optimal treatment conditions. Treatment-resistant late-life depression (TRLLD) increases risk for early relapse, undermines adherence to treatment for coexisting medical disorders, amplifies disability and cognitive impairment, imposes greater burden on family caregivers, and increases the risk for early mortality, including suicide. Getting to and sustaining remission is the primary goal of treatment, yet there is a paucity of empirical data on how best to manage TRLLD. A pilot study by our group on aripiprazole augmentation in 24 incomplete responders to sequential SSRI and SRNI pharmacotherapy found that 50% remitted over 12 weeks with the addition of aripiprazole, and that remission was sustained in all participants during 6 months of continuation treatment. In addition to controlled assessment, evidence is needed to support personalized treatment by testing the moderating role of clinical (e.g., comorbid anxiety, medical burden, and executive impairment) and genetic (eg, selected polymorphisms in serotonin, norepinephrine, and dopamine genes) variables, while also controlling for variability in drug exposure. Such studies may advance us toward the goal of personalized treatment in late-life depression.

Neurocognitive Correlates of Response to Treatment in Late-Life Depression

Depression is often associated with neurocognitive deficits in older adults, particularly in the domains of information processing speed, episodic memory, and executive functions. Greater neurocognitive dysfunction while depressed is associated with a less effective treatment response; however, questions remain about the specific variables that characterize patients showing low treatment response and persistent cognitive deficiencies. The authors examined neurocognitive variables that differentiated patients who showed robust versus weak responses to antidepressant therapy. The baseline sample included 110 women and 67 men, with a mean age of 69.1 years (SD = 6.9) and mean education of 14 years (SD = 3.3). Patients enrolled in a treatment study completed both a structured diagnostic assessment for depression and neuropsychological testing at study entry and 1-year follow-up. Clinicians rated patient depression using the Montgomery-Asberg Depression Rating Scale. Neuropsychological assessments consisted of prose recall and percent retention (Wechsler Memory Scale -III Logical Memory), word-list recall, attention and visuomotor processing speed (Trail Making A, Symbol Digit Modalities Test), and mental flexibility (Trail Making B). Patients underwent treatment for depression following the guidelines of the Duke Somatic Treatment Algorithm for Geriatric Depression approach. Individuals who demonstrated the greatest improvement in mood symptoms at follow-up exhibited better prose recall and faster processing speed at baseline than individuals who demonstrated weaker treatment responses. These differences remained after controlling for depression severity at both time-points. The current results suggest that better pretreatment cognitive function, particularly in verbal memory, is associated with a greater treatment response in late-life depression.

Empirically Derived Decision Trees for the Treatment of Late-Life Depression

Several predictors of treatment response in late-life depression have been reported in the literature. The aim of this analysis was to develop a clinically useful algorithm that would allow clinicians to predict which patients will likely respond to treatment and thereby guide clinical decision making. A total of 461 patients with late-life depression were treated under structured conditions for up to 12 weeks and assessed weekly with the 17-item Hamilton Rating Scale for Depression (HAM-D-17). The authors developed a hierarchy of predictors of treatment response using signal-detection theory. The authors developed two models, one minimizing false predictions of future response and one minimizing false predictions of future nonresponse, to offer clinicians two clinically useful treatment algorithms. In the first model, early symptom improvement (defined by the relative change in HAM-D-17 total score from baseline to week 4), lower baseline anxiety, and an older age of onset predict response at 12 weeks. In the second model, early symptom improvement represents the principal guide in tailoring treatment, followed by baseline anxiety level, baseline sleep disturbance, and--for a minority of patients--the adequacy of previous antidepressant treatment. Our two models, developed to help clinicians in different clinical circumstances, illustrate the possibility of tailoring the treatment of late-life depression based on clinical characteristics and confirm the importance of early observed changes in clinical status.