Brain Imaging, Genetics and Treatment for Major Depression

Objective:

Major depressive disorder (MDD) is a serious, debilitating, life-shortening illness that
affects many persons of all ages and backgrounds. Although many patients suffering from MDD
can expect improvement with antidepressant treatment, only a minority experience full
remission, and little is known about the basis for individual differences in treatment
outcome. The rationale for this study follows from the findings that treatment response in
major depression is associated with: 1) variation in the genes encoding the serotonin 2A
receptor (HTR2A) and the KA1 subunit of the glutamate-kainate receptor (GRIK4); and 2)
increases in prefrontal glutamate/glutamine (glx) concentration measured by [+H] magnetic
resonance spectroscopy (MRS). The central hypothesis is that genes associated with
citalopram treatment outcome modulate glutamate concentrations in prefrontal brain (PFB) and
thus facilitate response to citalopram treatment. Such information is important because it
would ultimately allow the development of better treatments for MDD.

Study population:

A total of 104 moderate to severe MDD outpatients aged 25-55 with a baseline 17-item
Hamilton Depression Rating Scale (HDRS) score of greater than or equal to18 who meet DSM-IV
criteria for non-psychotic major depressive disorder (MDD) will be enrolled in the course of
the study.

Design:

Subjects will be screened with an on-site research psychiatric evaluation using a structured
interview (MINI plus). After screening, participants will provide a DNA sample, which will
be analyzed to determine the patient's genotype at several relevant loci. All patients will
then complete an eight-week period of citalopram treatment, during which time they will be
evaluated bi-weekly with self-report questionnaires and clinician ratings to determine
change of MDD symptoms. Participants will also undergo pre- and post-treatment MRS scans to
determine glutamate concentration in the prefrontal brain.

Treatment outcome measures:

The Quick Inventory of Depressive Symptomatology - Clinician-Rated (QIDS-C16) will be the
primary clinical outcome measure and will be collected at baseline and at each treatment
visit. Additionally, levels of glutamate in the prefrontal regions of the brain will be
measured by MRS. Clinical response will be defined as a decrease of 50 percent or greater in
QIDS-C16 score from baseline, and remission will be defined as a QIDS-C16 score of less than
6.

This proposal is part of a K99 training grant and has undergone extensive external review
(K99MH085098-01A2).

- INCLUSION CRITERIA:

- Male and female subjects aged between 25 and 55 years

- Score of 18 or higher on the 17-item Hamilton Depression Rating Scale (HDRS17). We
have set the HDRS17 cutoff score to greater than or equal to18 to increase the
contrast signals between remitters and non-remitters, MRS imaging and genotypic
groups.

- Meets DSM-IV criteria for chronic or recurrent non-psychotic MDD

- No more than 3 failed FDA-approved antidepressant treatments within the current
episode

- No alcohol use in the last 7 days

- Fluent in English or Spanish

- Capacity to understand the nature of the study and provide informed consent

EXCLUSION CRITERIA:

- Lifetime history of schizophrenia, schizoaffective disorder or psychosis not
otherwise specified

- Lifetime history of bipolar disorder (I, II, or not otherwise specified)

- Lifetime history of anorexia nervosa or bulimia nervosa

- Current primary obsessive-compulsive disorder (OCD)

- History of intolerability to citalopram

- Lack of response to an adequate trial of citalopram or escitalopram in the current or
previous episodes of MDD

- Have failed to respond to more than three antidepressants during current major
depressive episode

- Lack of response to 7 or more sessions of ECT in the current or previous episodes of
MDD

- Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory,
cardiovascular (including ischemic heart disease), endocrinologic, neurologic,
immunologic, or hematologic disease

- Females who are sexually active and who are not willing to use effective
contraception for 8-weeks while participating in this study or are pregnant or breast
feeding

- Concomitant medication use which contraindicates the use of the study medication

- Requires any of the following exclusionary medications: antipsychotic medications,
anticonvulsant medications, antidepressant medications, mood stabilizers, central
nervous system stimulants

- Patients on thyroid medication for hypothyroidism: stable on thyroid medication for <
2 months

- Current participation in any modality of psychotherapy and the patient is not willing
to forgo it during participation

- Have a history of drug or alcohol dependence or current abuse within the last 3
months

- Past history of significant head injury with loss of consciousness for about 24 hours
or more

- Current or past history of seizure disorder

- Suicidal ideation with plan and/or intent

- Have received any investigational drug within the last 30 days

- Metallic (ferromagnetic) implants, including pacemakers or other implanted electrical
devices, brain stimulators, some types of dental implants, aneurysm clips (metal
clips on the wall of a large artery), metallic prostheses (including metal pins and
rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery
pump, shrapnel fragments, and possible small metal fragments in the eye

- Unable to lie flat on back for up to 2 hours

- Claustrophobia in scanner

- Positive drug screen

- HIV-positive.