Carmen Andreescu

Gray Matter Changes in Late Life Depression—a Structural MRI Analysis

Multiple brain morphometric changes have been reported in late-life depression (LLD), mostly in studies comparing volumes of circumscribed brain areas. The aim of our study is to characterize the volumetric changes of multiple gray matter regions in relation to age of onset/duration of illness. We predicted that the association of gray matter volumes with total duration of illness and age of onset would differ depending on whether the region was susceptible to the toxic effects of chronic exposure to cortisol or to the vascular/neurodegenerative changes accompanying prodromal dementia. Seventy-one elderly depressed subjects were studied along with thirty-two comparison subjects. High-resolution T1-weighted brain MRIs were processed using an automated labeling pathway technique. To protect against type-I error, we combined the right and left hemisphere volume data. We sampled 24 regions of interest (ROIs). We used the primary visual cortex volume to normalize for individual variations in brain size. LLD Subjects had smaller volumes than non-depressed subjects in 17 of the 24 examined ROIs. Shorter duration of illness and later age of onset was correlated with smaller volumes of parahippocampal area and parietal inferior area. A later age of onset was also correlated with smaller volumes of several frontal and temporal areas, cingulum, and putamen. Our findings support a dementia prodrome model more strongly than a toxic stress model in this group of subjects. However, it remains likely that both processes as well as other factors contribute to the heterogeneity of volumetric brain changes in LLD.

Default-mode network connectivity and white matter burden in late-life depression

The brains default-mode network has been the focus of intense research. This study characterizes the default-mode network activity in late-life depression and the correlation of the default-mode network activity changes with the white-matter hyperintensities burden. We hypothesized that elderly depressed subjects would have altered default-mode network activity, which would correlate with the increased white-matter hyperintensities burden. Twelve depressed subjects (mean Hamilton Depression Rating Scale 19.8±4.1, mean age 70.5±4.9) and 12 non-depressed, comparison subjects (mean age 69±6.5) were included. Functional magnetic resonance imaging (fMRI) data were collected while subjects performed a low cognitive load, event-related task. We compared the default-mode network activity in these groups (including depressed subjects pre- and post-antidepressant treatment). We analyzed the resting connectivity patterns of the posterior cingulate cortex. Deconvolution was used to evaluate the correlation of resting-state connectivity scores with the white-matter hyperintensities burden. Compared with non-depressed elderly, depressed subjects pretreatment had decreased connectivity in the subgenual anterior cingulate cortex and increased connectivity in the dorsomedial prefrontal cortex and the orbito-frontal cortex. The abnormal connectivity was significantly correlated with the white-matter hyperintensities burden. Remitted elderly depressed subjects had improved functional connectivity compared to pretreatment, although alterations persisted in the anterior cingulate and the prefrontal cortex when remitted elderly depressed subjects were compared with non-depressed elderly. Our study provides evidence for altered default-mode network connectivity in late-life depression. The correlation between white-matter hyperintensities burden and default-mode network connectivity emphasizes the role of vascular changes in late-life depression etiopathogenesis.

Elevated cortisol in older adults with generalized anxiety disorder is reduced by treatment: a placebo-controlled evaluation of escitalopram.

BACKGROUND Generalized anxiety disorder (GAD) is a common disorder in older adults, which has been linked to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in this age group. The authors examined whether treatment of GAD in older adults with a selective serotonin reuptake inhibitor (SSRI) corrects this HPA axis hyperactivity. METHODS The authors examined adults aged 60 years and older with GAD in a 12-week randomized controlled trial comparing the SSRI escitalopram with placebo. The authors collected salivary cortisol at six daily time points for 2 consecutive days to assess peak and total (area under the curve) cortisol, both at baseline and posttreatment. RESULTS Compared with placebo-treated patients, SSRI-treated patients had a significantly greater reduction in both peak and total cortisol. This reduction in cortisol was limited to patients with elevated (above the median) baseline cortisol, in whom SSRI-treated patients showed substantially greater reduction in cortisol than did placebo-treated patients. Reductions in cortisol were associated with improvements in anxiety. Additionally, genetic variability at the serotonin transporter promoter predicted cortisol changes. CONCLUSIONS SSRI treatment of GAD in older adults reduces HPA axis hyperactivity. Further research should determine whether these treatment-attributable changes are sustained and beneficial.

Which symptoms predict recurrence of depression in women treated with maintenance interpersonal psychotherapy

Background: Even low levels of residual symptoms are known to increase the risk of relapse and early recurrence of major depression. It is not known if ongoing psychotherapy lessens this risk. We therefore examined the impact of persistent symptoms, including mood, insomnia, and anxiety symptoms, on time to recurrence in women receiving maintenance interpersonal psychotherapy (IPT‐M) for recurrent depression. Methods: We analyzed data on 131 women aged 20–60 from a 2‐year randomized trial of weekly versus twice‐monthly versus monthly IPT‐M. Participants achieved remission with IPT alone (n=99) or IPT plus sequential antidepressant medication (n=32). Medications were tapered before starting maintenance treatment. Residual symptoms were assessed with the Hamilton Rating Scale for Depression (HRSD; total score and subscales); insomnia was also assessed in 76 women with the Pittsburgh Sleep Quality Index (PSQI). Data analyses used Cox proportional hazards regression models. Results: Neither overall burden of residual symptoms (HRSD total score), nor HRSD mood and anxiety subscale scores predicted recurrence during ongoing IPT‐M. In contrast, persistent insomnia measured both by the HRSD‐17 insomnia subscale and the PSQI predicted recurrence. Women with persistent insomnia who required sequential pharamacotherapy had the highest recurrence rate (65%) compared to women requiring sequential treatment without insomnia (13%), or women who had recovered with IPT alone but had persistent insomnia (21%) or no insomnia (18%). Conclusions: Persistent insomnia following the recovery from an episode of recurrent major depression is associated with increased risk of recurrence despite maintenance psychotherapy, particularly for those withdrawn from antidepressant medication. Depression and Anxiety, 2008.

fMRI Correlates of White Matter Hyperintensities in Late-Life Depression

OBJECTIVE This study tests whether or not the structural white matter lesions that are characteristic of late-life depression are associated with alterations in the functional affective circuits of late-life depression. This study used an emotional faces paradigm that has been shown to engage the affective limbic brain regions. METHOD Thirty-three elderly depressed patients and 27 nondepressed comparison subjects participated in this study. The patients were recruited through the NIMH-sponsored Advanced Center for Interventions and Services Research for the Study of Late-Life Mood Disorders at the University of Pittsburgh Center for Bioethics and Health Law. Structural and functional MRI was used to assess white matter hyperintensity (WMH) burden and functional magnetic resonance imaging (fMRI) blood-oxygen-level-dependent (BOLD) response on a facial expression affective-reactivity task in both elderly participants with nonpsychotic and nonbipolar major depression (unmedicated) and nondepressed elderly comparison subjects. RESULTS As expected, greater subgenual cingulate activity was observed in the depressed patients relative to the nondepressed comparison subjects. This same region showed greater task-related activity associated with a greater burden of cerebrovascular white matter change in the depressed group. Moreover, the depressed group showed a significantly greater interaction of WMH by fMRI activity effect than the nondepressed group. CONCLUSIONS The observation that high WMH burden in late-life depression is associated with greater BOLD response on the affective-reactivity task supports the model that white matter ischemia in elderly depressed patients disrupts brain mechanisms of affective regulation and leads to limbic hyperactivation.

Escitalopram for Older Adults With Generalized Anxiety Disorder: A Randomized Controlled Trial

CONTEXT Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders in older adults; however, few data exist to guide clinicians in efficacious and safe treatment. Selective serotonin reuptake inhibitors (SSRIs) are efficacious for younger adults with GAD, but benefits and risks may be different in older adults. OBJECTIVE To examine the efficacy, safety, and tolerability of the SSRI escitalopram in older adults with GAD. DESIGN, SETTING, AND PARTICIPANTS A randomized controlled trial in primary care practices and related specialty clinics in Pittsburgh, Pennsylvania, of 177 participants aged 60 years or older with a principal diagnosis of GAD randomized to receive either escitalopram or placebo and conducted between January 2005 and January 2008. INTERVENTIONS Twelve weeks of 10 to 20 mg/d of escitalopram (n = 85) or matching placebo (n = 92). MAIN OUTCOME MEASURES Cumulative response defined by Clinical Global Impressions-Improvement score of much or very much improved; time to response; and anxiety and role functioning changes measured by the Clinical Global Impressions-Improvement scale, Hamilton Anxiety Rating Scale, Penn State Worry Questionnaire, Late-Life Function and Disability Instrument activity limitations subscale, and the role-emotional impairment and social function subscales of the Medical Outcome Survey 36-item Short Form. RESULTS In the primary analytic strategy in which participants (n = 33) were censored at the time of dropout, mean cumulative response rate for escitalopram was 69% (95% confidence interval [CI], 58%-80%) vs 51% (95% CI, 40%-62%) for placebo (P = .03). A conservative intention-to-treat analysis showed no difference in mean cumulative response rate between escitalopram and placebo (57%; 95% CI, 46%-67%; vs 45%; 95% CI, 35%-55%; P = .11). Participants treated with escitalopram showed greater improvement than with placebo in anxiety symptoms and role functioning (Clinical Global Impressions-Improvement scale: effect size, 0.93; 95% CI, 0.50-1.36; P < .001; Penn State Worry Questionnaire: 0.30; 95% CI, 0.23-0.48; P = .01; activity limitations: 0.32; 95% CI, 0.01-0.63; P = .04; and the role-emotional impairment and social function: 0.96; 95% CI, 0.03-1.90; P = .04). Adverse effects of escitalopram (P < .05 vs placebo) were fatigue or somnolence (35 patients [41.1%]), sleep disturbance (12 [14.1%]), and urinary symptoms (8 [9.4%]). CONCLUSIONS Older adults with GAD randomized to escitalopram had a higher cumulative response rate for improvement vs placebo over 12 weeks; however, response rates were not significantly different using an intention-to-treat analysis. Further study is required to assess efficacy and safety over longer treatment durations. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00105586.

Twelve-year depressive symptom trajectories and their predictors in a community sample of older adults.

INTRODUCTION The aim of this study is to understand the long-term course and outcomes of depressive symptoms among older adults in the community by examining trajectories of depressive symptoms over time and identifying profiles of depressive symptoms predicting different trajectories. METHOD We measured depressive symptoms biennially for up to 12 years, using the modified Center for Epidemiological Studies-Depression (mCES-D) scale, in 1260 community-based adults aged 65+ years. We determined latent trajectories of total mCES-D scores over time. We identified symptom profiles based on subgroups of baseline depressive symptoms derived from factor analysis, and examined their associations with the different trajectories. RESULTS Six trajectories were identified. Two had one or no depressive symptoms at baseline and flat trajectories during follow-up. Two began with low baseline symptom scores and then diverged; female sex and functional disability were associated with future increases in depressive symptoms. Two trajectories began with high baseline scores but had different slopes: the higher trajectory was associated with medical burden, higher overall baseline score, and higher baseline scores on symptom profiles including low self-esteem, interpersonal difficulties, neurovegetative symptoms, and anhedonia. Mortality was higher among those in the higher trajectories. CONCLUSIONS In the community at large, those with minimal depressive symptoms are more likely to experience future increases in symptoms if they are women and have functional disability. Among those with higher current symptom levels, depression is more likely to persist over time in individuals who have greater medical burden and specific depressive symptoms.

Complementary and alternative medicine in the treatment of bipolar disorder — A review of the evidence

A growing number of patients with mood disorders are using complementary and alternative medicine (CAM) interventions. In this paper, we review the published scientific evidence on the benefits and risks of CAM for the treatment of patients with bipolar disorder. Since very few studies of CAM have involved patients with bipolar disorder, most available evidence is derived from trials conducted in patients with major depressive disorder. The use of omega-3 fatty acids has been studied in two controlled studies in bipolar disorder while St. Johns wort (Hypericum perforatum), S-adenosyl-l-methionine (SAMe), and acupuncture have been studied in a series of randomized controlled trials in patients with major depression. Overall, the best evidence supports the use of St. Johns wort for the treatment of mild to moderate depression. SAMe may also be effective for depression. However, both of these products have the potential to induce mania; the extent of this risk needs to be quantified. St. Johns wort can also interact with a variety of medications. Evidence regarding the benefits of omega-3 fatty acids or acupuncture is inconsistent. Data regarding other CAM interventions (e.g., aromatherapy massage, massage therapy, yoga) are almost entirely lacking. In conclusion, better studies are needed before CAM interventions can be recommended to patients with bipolar disorder. In the meantime, patients need to be informed about the possible risks associated with the use of these interventions.

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 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. CONCLUSIONS 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.

What is the optimal duration of a short-term antidepressant trial when treating geriatric depression?

Background: To determine the optimal duration of an antidepressant trial in elderly patients, the authors examined the probability of eventually responding to treatment based on early improvement. Methods: Four hundred seventy-two elderly patients with major depression (nonpsychotic, nonbipolar) were treated under protocolized conditions for up to 12 weeks and assessed weekly with the Hamilton Rating Scale for Depression. The probability of full response after 12 weeks of treatment was calculated in patients who had not fully responded after periods of treatment that lasted for 4 to 10 weeks. Results: Most of the patients who had shown a partial improvement after 4 weeks of treatment became full responders after 4 or more additional weeks of treatment. By contrast, only a few of those who were nonresponders became full responders even after up to 8 additional weeks of treatment. Conclusions: After 4 weeks of treatment, it is possible to reliably identify a subgroup of elderly patients with depression who are more likely to benefit from a change in their treatment than from a few additional weeks of treatment with the same agent.