The Translational Research Cycle – Example in Infectious ...



The Translational Research Cycle and CTRI interactions – Example of Biobehavioral interaction in Chronic Conditions

Topic: Depression complicating recovery in a variety of chronic illnesses, conditions

Clinical depression is more common in people recovering from or living with a variety of chronic conditions such as coronary artery disease, stroke, COPD, arthritis and so on. Recent epidemiologic studies suggest that there are genetic markers for predisposition to clinical depression that may interact with life stressors (including acute illness as a major stressor) and mediate both onset and recovery from depression in chronic illness.

|Translational research cycle |CTRI interaction |

|T0 – a) Epidemiologic observations regarding increased prevalence of depression in a variety of common |Clinicians-clinician investigators |

|illnesses/conditions compared to age-matched non-ill population. Depression is a prevalent sequela of |prompted to link these two |

|cardiovascular and cerebrovascular disease, estimated to affect roughly 33% of stroke survivors at early, middle|components. Might come to Portal |

|or late stages of recovery. Post-stroke depression (PSD) has been shown to significantly and adversely influence|looking for collaborators for |

|stroke outcome and functional health in both clinical and community samples. Patients with PSD, compared to |systematic investigation |

|non-depressed post-stroke patients, have more functional dependence, poorer cognitive status, greater | |

|self-perceived impairment, increased health care utilization and costs, impaired rehabilitation response, | |

|delayed return to social function, and delayed return to work. These negative outcomes are evident in the acute| |

|phase and as much as two years post-stroke. Further, depression in the first few months post-stroke is | |

|associated with increased short-term and long-term mortality from all causes. | |

|b) Epidemiologic observations of frequency of specific serotonin transporter polymorphisms in interactions with | |

|environment | |

|T1 –a) Basic science studies of behavioral interventions and mechanisms for behavioral of depression. For |Could involve a preclinical core’s |

|example, Seligman’s studies of learned helplessness. |process for behavioral studies using|

| |RSB, BMI and CBS’s assistance in |

|b) Laboratory, human and animals studies re serotonin and other amines in post-stroke depression. Epidemiologic |setting up a clinical development |

|data suggest that there may be strong biologic antecedents and consequences of depression that interact with the|plan and databases to follow and |

|pathophysiologic states that produce ischemic heart and brain disease. However the occurrence of depression |track the data. |

|across a wide range of chronic illness with acute exacerbation suggests the mechanisms must be broader than | |

|direct effects of brain damage. Serotonin pathways appear affected in the acute post-stroke phase, as evidenced |CRCN, TTRC develop cost estimates |

|by reduced serotonin-mediated prolactin response. Further, elevations in serotonin receptor density is |for services |

|correlated with the alleviation of symptoms of depressed mood in patients with PSD, consistent with the | |

|serotonin and amine hypotheses of depression. Interaction of biological and psychosocial stressors is suggested |Developing genotyping for specific |

|in the gene-environment investigations in the biology of depression. In recent years the 5-HTTLPR polymorphism |genes related to depression, etc. |

|of the serotonin transporter (SERT) has been identified as a modulator of depression risk and of therapeutic |would be appropriate for Technology |

|response to serotonin reuptake inhibitor (SSRI) antidepressant therapy. The short allele(s) of 5-HTTLPR has not |Access Grant. |

|only been associated with a heightened risk for depression and poorer treatment response in general depression, | |

|but also with higher sensitivity to environmental stress and sustained blood pressure and pulse increases |Could involve interaction with the |

|(cardiovascular reactivity) to such stressors. Both can be postulated to interact with genetic predisposition to|TTRC for SNP genome wide association|

|depression and perhaps latent vascular lesions underlying PSD. |studies. |

|c) Large scale SNP genotyping to identify additional potential markers/genes associated with PSD |  |

|d) If a new gene/marker is discovered, perhaps targeted re-sequencing of large populations to identify all |Also potential to interact with the |

|alleles.    |TTRC for targeted re-sequencing of |

| |SERT and/or new genes to identify |

| |all alleles |

|T2 -  Clinical investigations of psychosocial-behavioral interventions to treat depression following stroke, MI,|IND submission support (Pre-clinical|

|dementias. Teri and colleagues developed specific psychosocial-behavioral protocols for treating depression in |core) and IRB submission, Regulatory|

|community-dwelling people with dementia, based on a large basic science of cognitive and behavioral therapy for |consultation (RSB) about DNA storage|

|depression (Seattle Protocols). This approach challenges negative cognitions, reduces distortions and enables |for future genetic analysis as |

|more adaptive ways of viewing specific situations or events. A behavioral intervention, used with more |mechanisms are better understood, |

|moderately or severely demented adults, increases the level of positive activities and decreases negative ones. |protocol development and database |

|These could be considered similar to phase one and two drug studies. As one example of these studies, we have |systems (CBS/BMI), potential pilot |

|recently adapted the Seattle Protocols for post-stroke depression (PSD), demonstrating that a pleasant |funding (CSR), conducting the study |

|event/problem-solving brief psychosocial-behavioral therapy delivered by psychosocial nurse practitioners is |(CRCN) and using research |

|efficacious in reducing major depression and promoting remission in ischemic stroke survivors, extending up to |coordinators for implementation |

|two years. This brief counseling therapy appears to operate independent of antidepressant treatment.  |(RSB). |

|Furthermore, carrying one or more 5-HTTLPR s-alleles was associated not only with a higher risk of depression, | |

|but also with the strongest reduction in depressive symptoms through therapy, as measured by the 17 item |The development of more refined |

|Hamilton Depression Rating Scale (HDRS). This latter association remains to be confirmed with a larger sample. |Phase 3 protocols will require |

|The next step for this program of research would be to conduct the comparative efficacy studies regarding the |multiple cores, RSB for IRB |

|mode of delivery of the intervention (for example, comparing in-person weekly sessions to telephone weekly |applications, IND and regulatory |

|sessions). This would enable refinement of the research protocols prior to testing in the real world of T3-T4 |issues and bioethics issues that may|

|phases. |arise, CBS/BMI for protocol |

|Addition of  genotyping (e.g. serotonin transporter polymorphisms) with larger samples is needed to determine if|development, CRCN for study conduct,|

|this will help target this psychosocial treatment to those who benefit most. |CORT for use of practice based |

| |networks to expand study conduct, |

| |TTRC for potential novel |

| |genetotyping assay development. |

| |Education & career development with |

| |potential projects to involve TL and|

| |KL trainees and scholars. |

|T3- Dissemination and implementation of protocols into community practice |CORT for work through the |

|If the comparative efficacy studies point the way to the most efficient protocol and to whom it should be |practice-based networks to study |

|targeted, the next step is to test the most effective strategies for dissemination into community practice – |utilization of therapy working with |

|e.g. with primary care providers, stroke clinics and neurologists who are seeing people with PSD in their |CBS/BMI. Regulatory Support and |

|practices.  These studies might evaluate the process of uptake, ahderence to guidelines, and refinement of |Bioethics, |

|guidelines and protocols based on the findings.  Guidelines and training manuals would be outcomes of these |Education & career development |

|studies.   |projects for trainees, scholars, |

| |Center for Scientific Review (pilot |

|Ideas for these studies might include: |funding) |

|• Determining whether primary care providers can incorporate the short intervention into their practices. | |

|• Identifying optimal practice models for dissemination – mental health/primary care collaborations versus | |

|referral to mental health providers | |

|• Will primary care providers, neurologists, and stroke clinics incorporate genotyping into their care to target| |

|the delivery of the brief psychosocial intervention? | |

|• Incorporation of the brief psychosocial intervention as a component of stroke support groups. | |

|T4 – Evaluation of the uptake of protocols, clinical guidelines, |CORT, BMI, CBS |

|This phase would likely be concurrent with T3 research projects, and would evaluate the effectiveness of these |Education & career development |

|protocols in community-based practices as well as the impact of health policy changes (e.g., payment for |projects for trainees, scholars, |

|services) on depression outcomes.   This research (as well as T3 research ) could benefit from collaboration |Center of Scientific Review (pilot |

|with non-profit organizations serving the target population (American Heart/American Stroke Association for |funding) |

|example).   | |

| | |

|Examples of  T4 research might include: | |

|• A comparison of depression severity scores among stroke patients in general medical clinics implementing the | |

|short intervention compared to those with usual care.  Other outcomes could also be measured – functional stroke| |

|outcomes, quality of relationships with spouses, control of comorbid conditions (e.g., diabetes). | |

|• Cost-effectiveness analysis of the implementation of the intervention protocol using different practice models| |

|for dissemination in primary care settings. | |

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