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
T0 – a) Epidemiologic observations regarding increased prevalence of
depression in a variety of common illnesses/conditions compared to agematched non-ill population. Depression is a prevalent sequela of cardiovascular
and cerebrovascular disease, estimated to affect roughly 33% of stroke survivors at
early, middle or late stages of recovery. Post-stroke depression (PSD) has been
shown to significantly and adversely influence stroke outcome and functional
health in both clinical and community samples. Patients with PSD, compared to
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 example, Seligman’s studies of learned
helplessness.
b) Laboratory, human and animals studies re serotonin and other amines in
post-stroke depression. Epidemiologic data suggest that there may be strong
biologic antecedents and consequences of depression that interact with the
pathophysiologic states that produce ischemic heart and brain disease. However
the occurrence of depression 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 by reduced serotonin-mediated prolactin response. Further, elevations in
serotonin receptor density is 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 in the gene-environment investigations in the biology of depression. In
recent years the 5-HTTLPR polymorphism of the serotonin transporter (SERT) has
been identified as a modulator of depression risk and of therapeutic response to
serotonin reuptake inhibitor (SSRI) antidepressant therapy. The short allele(s) of 5HTTLPR has not 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
CTRI interaction
Clinicians-clinician
investigators prompted to
link these two
components. Might come
to Portal looking for
collaborators for
systematic investigation
Could involve a
preclinical core’s process
for behavioral studies
using RSB, BMI and
CBS’s assistance in
setting up a clinical
development plan and
databases to follow and
track the data.
CRCN, TTRC develop
cost estimates for
services
Developing genotyping
for specific genes related
to depression, etc. would
be appropriate for
Technology Access
Grant.
Could involve interaction
(cardiovascular reactivity) to such stressors. Both can be postulated to interact with
genetic predisposition to depression and perhaps latent vascular lesions underlying
PSD.
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 alleles.
with the TTRC for SNP
genome wide association
studies.
Also potential to interact
with the 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, dementias. Teri and colleagues developed
specific psychosocial-behavioral protocols for treating depression in communitydwelling people with dementia, based on a large basic science of cognitive and
behavioral therapy for depression (Seattle Protocols). This approach challenges
negative cognitions, reduces distortions and enables more adaptive ways of
viewing specific situations or events. A behavioral intervention, used with more
moderately or severely demented adults, increases the level of positive activities
and decreases negative ones. These could be considered similar to phase one and
two drug studies. As one example of these studies, we have recently adapted the
Seattle Protocols for post-stroke depression (PSD), demonstrating that a pleasant
event/problem-solving brief psychosocial-behavioral therapy delivered by
psychosocial nurse practitioners is efficacious in reducing major depression and
promoting remission in ischemic stroke survivors, extending up to two years. This
brief counseling therapy appears to operate independent of antidepressant
treatment. 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 Hamilton
Depression Rating Scale (HDRS). This latter association remains to be confirmed
with a larger sample.
The next step for this program of research would be to conduct the comparative
efficacy studies regarding the mode of delivery of the intervention (for example,
comparing in-person weekly sessions to telephone weekly sessions). This would
enable refinement of the research protocols prior to testing in the real world of T3T4 phases.
Addition of genotyping (e.g. serotonin transporter polymorphisms) with larger
samples is needed to determine if this will help target this psychosocial treatment
to those who benefit most.
T3- Dissemination and implementation of protocols into community practice
If the comparative efficacy studies point the way to the most efficient protocol and
IND submission support
(Pre-clinical core) and
IRB submission,
Regulatory consultation
(RSB) about DNA
storage for future genetic
analysis as mechanisms
are better understood,
protocol development
and database systems
(CBS/BMI), potential
pilot funding (CSR),
conducting the study
(CRCN) and using
research coordinators for
implementation (RSB).
The development of
more refined Phase 3
protocols will require
multiple cores, RSB for
IRB applications, IND
and regulatory issues and
bioethics issues that may
arise, CBS/BMI for
protocol development,
CRCN for study conduct,
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.
CORT for work through
the practice-based
to whom it should be targeted, the next step is to test the most effective strategies
for dissemination into community practice – e.g. with primary care providers,
stroke clinics and neurologists who are seeing people with PSD in their practices.
These studies might evaluate the process of uptake, ahderence to guidelines, and
refinement of guidelines and protocols based on the findings. Guidelines and
training manuals would be outcomes of these studies.
Ideas for these studies might include:
• 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,
This phase would likely be concurrent with T3 research projects, and would
evaluate the effectiveness of these protocols in community-based practices as well
as the impact of health policy changes (e.g., payment for services) on depression
outcomes. This research (as well as T3 research ) could benefit from
collaboration with non-profit organizations serving the target population
(American Heart/American Stroke Association for 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.
networks to study
utilization of therapy
working with CBS/BMI.
Regulatory Support and
Bioethics,
Education & career
development projects for
trainees, scholars, Center
for Scientific Review
(pilot funding)
CORT, BMI, CBS
Education & career
development projects for
trainees, scholars,
Center of Scientific
Review (pilot funding)