Flavanol Augmentation for Antidepressant Non-Responsive Late Life Depression

The goal of this proposal is to conduct the first pilot study of whether consuming a diet
high in flavanols will augment the cognitive and mood benefits of antidepressant medication
in older adults with Late Life Depression (LLD). LLD affects 3% of community-dwelling adults
over 60 years old, and 15% of older adults living in the community have clinically
significant depressive symptoms. Diagnosis with LLD increases an older adult's risk of
disability by 67-73% over 6 year follow up, causes twice the functional impairment compared
to those without LLD, and is associated with high rates of completed suicide in individuals
over 65. Currently available treatments for LLD (i.e., antidepressant medication) are limited
in efficacy, leading to high rates of recurrence and frequent development of chronicity.
Cognitive impairment, which is commonly associated with LLD, predicts poor acute response to
antidepressants, leads to higher relapse rates during the continuation phase of treatment,
and is associated with the development of adverse age-related health outcomes, including
increased risk of dementia, dependence in activities of daily living (ADL), and driving
cessation.

Novel treatments addressing LLD's underlying neurobiology are critically needed, particularly
therapies that may also have beneficial effects on the cognitive components of LLD. The most
extensively studied brain region to be implicated in both the depressive and cognitive
aspects of LLD has been the hippocampus. Decreased hippocampal volumes are found in depressed
patients compared to controls, and this finding appears to be particularly pronounced in
individuals with recurrent depressive illness. Among the subregions comprising the
hippocampus, evidence suggests that it is decreased neurogenesis within the dentate gyrus
(DG) specifically that may contribute to the development of depression, and it appears that
part of the mechanism of action of antidepressants is to enhance neurogenesis in the DG. As
the DG is also a critical contributor to the cognitive functions of the hippocampus, it
stands out as a highly significant brain region that may be involved with both the mood and
cognitive components of LLD.

Inclusion Criteria

- Men and women aged ≥60 years (Method of ascertainment: clinical interview)

- DSM 5 diagnosis of Major Depressive Disorder (Method of ascertainment: SCID, clinical
interview)

- Subjective report of memory or thinking problems (Method of ascertainment: clinical
interview)

- 24-item Hamilton Rating Scale for Depression ≥16 (Method of ascertainment: HRSD)

- Failure of depressive symptoms to remit following an adequate trial of an
antidepressant (defined as at least 8 weeks of treatment, with 4 weeks of at least
half PDR maximum dose, of an FDA approved antidepressant) (Method of ascertainment:
clinical interview)

- Capable of providing informed consent and complying with the study procedures (Method
of ascertainment: clinical interview)

Exclusion Criteria

- Diagnosis of Substance Use Disorder within the past 12 months (excluding Tobacco)
(Method of ascertainment: SCID, clinical interview)

- History of psychosis, psychotic disorder, mania, or bipolar disorder (Method of
ascertainment: SCID, clinical interview)

- HRSD suicide item > 2 or CGI =7 at baseline (Method of ascertainment: HRSD, CGI)

- Diagnosis of probable or definite dementia (Alzheimer's Disease, Vascular Dementia,
Parkinson's disease, etc.) (Method of ascertainment: SCID, clinical interview, MMSE)

- MMSE ≤24 (Method of ascertainment: MMSE)

- Physical or intellectual disability adversely affecting ability to complete
assessments (Method of ascertainment: clinical interview)

- History of allergy, hypersensitivity, or intolerance to cocoa flavanols (Method of
ascertainment: clinical interview)

- Contraindication to MRI scanning or unable to tolerate scanning procedures (Method of
ascertainment: clinical interview)

- Allergic or adverse reaction to gadolinium, 2 or more prior scans with gadolinium, or
creatinine clearance < 50 (Method of ascertainment: clinical interview, blood draw)

- Daily consumers of dietary or herbal supplements, including Gingko, flavonoid, and
dietary herbal or plant extracts (Method of ascertainment: clinical interview)

- Diabetes or acute, severe, or unstable medical or neurologic condition (Method of
ascertainment: clinical interview, physical exam, EKG)