Depression in Type 2 Diabetes

Diabetes is a major health problem affecting approximately 18 million Americans. It is a
growing crisis that has devastating complications including heart disease, peripheral
neuropathy and renal failure. According to a literature review by Gavard et al, the
prevalence of major depression in a sample diabetic population in controlled studies was 8.5
to 27.3% (mean prevalence of 14.0%). This was estimated to be up to three times the
prevalence of major depression in the general U.S. adult population. Diabetes and major
depression are mutual risk factors, with diabetic patients more likely to develop major
depression with an odds ratio of 2.5 and depressed patients being more likely to develop
type 2 diabetes with an estimated relative risk of 2.2. Depression also has a significant
impact on the course of diabetes, leading to higher rates of hyperglycemia and diabetic
complications. Depression in patients with diabetes is also associated with poor compliance,
decreased quality of life, increased disability and greater health care utilization. A
recent 8-year follow-up study of patients with diabetes and depression concluded that the
coexistence of these illnesses is associated with a significantly increased risk of death
from all causes beyond that due to either depression or diabetes alone. In this study,
patients with diabetes and depression had a 1.3-fold increased risk of death from all causes
when compared with patients with diabetes alone and a 2-fold increased risk of death when
compared with patients with only depression. Reports from a prospective, community-based
study in western Australia suggest that the behavioral consequences of depression, including
non-compliance with medication and exercise regimens, contribute to increased mortality in
these patients.

TRIAL OBJECTIVES AND PURPOSE Specific Aim 1: To study the biophysical properties of the
white and gray matter in critical cortical and subcortical regions using magnetization
transfer in patients with type 2 diabetes and MDD, non-depressed diabetic controls, patients
with unipolar depression without diabetes and nondiabetic healthy controls. The
investigators are interested in the separate and cumulative effects of both diabetes and
depression on Magnetization Transfer Ratios (MTR) in different brain regions.

Hypothesis: The overarching hypothesis is that both diabetes and depression have the effect
of lowering magnetization transfer ratios (MTR) in the anterior cingulate cortex,
subcortical nuclei (head of the caudate nucleus and putamen) and the frontal white matter.
These effects are cumulative and may not be additive in some regions. Our pilot data suggest
that MTR will be lower in these regions in patients with type 2 diabetes (both with and
without depression) when compared with healthy controls. In some regions (eg. head of the
caudate nucleus - see preliminary data) the investigators anticipate that patients with
diabetes and MDD will have the lowest and healthy controls will have the highest MT ratios.
The group with unipolar depression without diabetes and the diabetic controls will have MT
ratios that fall between these two groups. In other regions of interest, both groups with
diabetes will have values significantly different from healthy controls, with patients
diagnosed with unipolar depression falling between the healthy and diabetic groups.

Specific Aim 2: To examine levels of glutamate and aspartate (creatine ratios) in two
regions involved in the regulation of mood and cognition - the bilateral anterior cingulate
cortex and the left subcortical region (the head of the caudate nucleus and the putamen) in
patients with type 2 diabetes and our three comparison groups.

Hypothesis: Levels of glutamate and aspartate (creatine ratios) will be lower in patients
with combined Type 2 Diabetes and MDD when compared with non-depressed diabetic patients and
healthy controls. Our pilot data provide little basis to expect a simple effect of diabetes
alone but do not rule out an interaction such that effects are only seen, or are worsened,
by the combination of diabetes and depression. The inclusion of a depressed non-diabetic
group in the current design will make it possible to evaluate whether the observed effect in
the doubly-diagnosed group is best viewed as an effect of depression alone or as an
interaction in which diabetes plays a role.

Specific Aim 3: To examine the relationship between regional MTRs and specific cognitive
domains in subjects in all four groups.

Hypothesis: There will be direct correlations in all study groups between MT ratios in the
subcortical nuclei, anterior cingulate cortex and the dorsolateral white matter and
performance on specific cognitive domains, including attention, executive functions,
learning and memory and psychomotor processing.

Exploratory Aim 1: In an exploratory manner the investigators will estimate cerebral blood
volume, a measure of the cerebral microvasculature, in critical brain regions involved in
frontal-subcortical circuitry (anterior cingulate, dorsolateral white, head of the caudate
nucleus and the putamen) in subjects in our depressed diabetic group and the three
comparison groups using dynamic susceptibility contrast MR imaging (perfusion-weighted MR
imaging).

Exploratory Aim 2: A comparison of blood samples from healthy controls, diabetic subjects,
depressed subjects and subjects with both depression and diabetes to see if there is
evidence of differences in plasma neurotransmitter levels, hypothalamic-pituitary-adrenals
(HPA) axis, and immune function between these four subject groups

Inclusion Criteria:

- Age: 30 to 80 years old

- Diagnosis of type 2 diabetes

- Diagnosis of major depressive disorder using standard diagnostic and statistical
manual (DSM) criteria

- Score of 15 or greater on the 17-item Hamilton Depression rating scale

- Mini Mental Status Exam score of 24 or greater

- No evidence of clinical dementia or any other clinical brain disorder

- Free of psychotropic/psychoactive medications for at least 2 weeks

- First episode of depression diagnosed either after or around the time type 2 diabetes
was diagnosed since we are interested in the relationship between the cerebrovascular
effect of diabetes and the pathophysiology of major depression

Exclusion Criteria:

- Presence of dementia or any other clinical brain disorder (Parkinson's, Alzheimer's)

- Mini Mental Status Exam score of less than 24

- Unstable medical illness (grade 4 on the Cumulative Illness Rating Scale)

- Presence of any metallic implant that would preclude an MRI scan (pacemaker, etc.)

- Concurrent Axis 1 disorder (schizophrenia, bipolar)

- Use of atypical neuroleptics for the current episode and/or strong clinical suspicion
that the diabetes is secondary to the use of atypical neuroleptics;

- Recurrent major depression, operationally defined as two or more, well-characterized
episodes of depression, prior to the onset/diagnosis of diabetes

- Seizure disorder

- Stroke/Transient Ischemic Attack

- Central nervous system disorder (multiple sclerosis)

- Trauma to head/Loss of Consciousness

- Claustrophobia

- Eating disorder (anorexia, bulimia)

- Weight of over 350 pounds

- Learning disorder (dyslexia, ADHD)

- Psychosis, panic or anxiety disorder outside the context of depression

- Pregnancy