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Current Studies

Mindfulness Based Stress Reduction

This research study is co-sponsored by the National Center for Complementary and Alternative Medicine and the National Institute of Mental Health. Mindfulness-Based Stress Reduction (MBSR) is a promising treatment, for improving clinical outcomes and neurocognitive function in older adults with anxiety disorders or major depressive disorder (MDD) along with cognitive impairment. This project is important because these disorders are very common and cause cognitive impairment in older adults; together, these clinical and neurocognitive impairments are highly disabling and inadequately helped by existing treatments.

Our treatment is based on well-known links in aging between a hyperactive hypothalamic-pituitary-adrenal (HPA) axis stress response and cognitive impairment. HPA axis hyperactivity seems to be dependent on worry severity and is reversible with treatment, improving memory as well as clinical symptoms. Findings suggest that novel treatments that inhibit HPA axis hyperactivity in late-life mental disorders will remediate cognitive impairment.  Mindfulness-based interventions are acceptable, feasible, and reduce anxiety and depression in older adults. MBSR counteracts anxiety and depression by increasing mindfulness and decreasing worry and rumination; it also inhibits HPA axis hyperactivity, generating the hypothesis that MBSR can improve clinical symptoms and cognitive impairment in older adults with anxiety disorders and MDD via increased mindfulness, resulting in reduced worry/rumination and reducing the HPA axis stress response. We are adapting and testing MBSR for older adults with depression or anxiety and mood-related cognitive impairment. We will randomize 100 older adults to the MBSR protocol or a control condition and will examine feasibility.

MBSR is a promising, novel treatment strategy for late-life anxiety disorders and MDD. PUBLIC HEALTH RELEVANCE: Chronic anxiety and depression lead to cognitive decline in older adults through the mechanism of HPA axis hyperactivity. This study proposes to use Mindfulness-Based Stress Reduction, a brief, easily implementable intervention that is also a potent inhibitor of a hyperactive neuroendocrine stress response, to improve anxiety, depression, and cognition in older individuals.

Incomplete Response in Late-Life Depression: Getting to Remission

Treatment resistant late-life depression (TRLLD) is a large public health challenge: at least 50% of older people fail to respond adequately to antidepressant pharmacotherapy. Getting to and sustaining remission is the primary goal of treatment, yet there is a paucity of controlled studies of how best to manage TRLLD.

To address this gap, we are conducting a three-site study at Washington University (PI: E. Lenze, MD), University of Pittsburgh (PI: C. Reynolds, MD), and University of Toronto (PI: B. Mulsant, MD). We hypothesize that aripiprazole augmentation will be superior to placebo for bringing about and sustaining remission in elderly patients who respond incompletely to venlafaxine XR (a commonly used first-line antidepressant).

We will enroll approximately 150 patients at Washington University aged 60 and older with major depressive disorder and treat them openly for approximately 12 to 16 weeks with venlafaxine XR (up to 300mg/d) (phase 1). Participants meeting criteria for incomplete response will be randomly assigned to receive either aripiprazole (2-15 mg/d; target dose: 10 mg/d) or placebo augmentation of venlafaxine for 12 weeks (phase 2), with the goal of achieving remission (MADRS≤10 for two consecutive assessments). Those who remit in phase 2 will receive continuation treatment with the same double-blinded intervention to which they were randomly assigned (phase 3), for 12 weeks to determine the stability of remission. Efficacy and tolerability data will provide a clinically informative estimate of benefits and risks of aripiprazole augmentation for TRLLD.

In addition we will develop evidence relevant to personalized treatment for LLD by testing the roles of clinical (comorbid anxiety, medical burden, and executive impairment) and genetic (selected polymorphisms in serotonin, norepinephrine, and dopamine genes) variables, while controlling for variability in drug exposure for efficacy and tolerability analyses. This approach will allow us to distinguish treatment-specific resistance factors versus general prognostic factor.


Past Studies

Risk Genes for Late-Life Depression After Hip Fracture

Disabling medical events are a major risk factor for late-life depression (LID), which in turn leads to poor functional recovery and increased mortality. Effective prevention of LLD in this setting requires research on its etiology and risk factors. Thus, we will examine genetic polymorphisms in the serotonergic system, and psychological, social, and aging-related factors as risk factors for the onset of LLD after a hip fracture, a severe and disabling event.
In our pilot work, the serotonin transporter promoter polymorphism (5-HTTLPR) s allele and the 5-HT2a (-1438)A/G allele were associated with an increased likelihood of LLD and/or higher levels of depressive symptoms after hip fracture.

This grant integrates clinical research methods for assessing LLD with state of the art genetic methods. We will examine association of five genetic polymorphisms in the serotonin system (5-HTTLPR, 5-HT2a (- 1438)A/G, 5-HT1a (-1019)C/G, TPH-2 (1463)G/A and BDNF dinucleotide repeat) with the onset and course of LLD in 470 elderly persons who have had a hip fracture. We will collect samples for genotyping, and we will follow subjects for one year. We will longitudinally assess LLD as well as variables related to vulnerability to LLD (e.g., cognitive status, disability, medical and psychiatric comorbidity, medication use, and life events). We will collect the same information over one year on a comparison group of 100 elderly persons who have not suffered a hip fracture. We hypothesize that these polymorphisms will be associated with LLD in the hip fracture group.

Beyond the testing of study hypotheses, we will model risk for LLD using both genetic and non-genetic factors (e.g., vulnerability due to personality, disposition, or prior depression; age-related changes; social support). We will replicate genetic results in a second sample of hip fracture subjects. Data and samples from this study will be made available for future genetic studies, by our group as well as other investigators.

The public health relevance is great, as LLD is a devastating and difficult-tc-treat illness. The proposed research will be essential to reducing the burden of LLD by improving our understanding of the etiology of this illness: additionally, findings from this research could lead risk profiling using genetic and other risk factors, a necessary step for prevention.

Enhanced Acute Medical Rehabilitation for Late-Life Depression After Disablement

Elderly persons who have suffered a disabling medical event are likely to develop depression.    Existing acute medical rehabilitation settings – skilled nursing facilities (SNFs) and inpatient rehabilitation facilities (IRFs) – often do not adequately meet the needs of depressed elders, resulting in a missed opportunity for affective and functional recovery. Therefore, this R34 will develop enhanced medical rehabilitation for depressed disabled patients.  The goal of this enhanced rehabilitative care is to reduce depressive symptoms and improve function.  The intervention will consist of: (1) high intensity physical therapy and occupational therapy (2) recommendations by mental health experts for further clinical management of depression as needed.

In this R34 we will develop enhanced medical rehabilitation for depressed disabled patients, in three stages: (1) develop a treatment manual (2) pilot and iteratively modify the intervention (3) carry out a preliminary randomized trial of the intervention in a SNF, with usual care comparison.