Brain Imaging, Genetics and Treatment for Major Depression
Brain Imaging, Genetics and Treatment for Major Depression
Background:

 - Antidepressants help many people with depression, however, some do not seem to benefit as
 much. Currently, it is not possible to determine who will improve with certain
 antidepressants. Studies have shown that genes may influence whether an antidepressant works
 for an individual. Other studies have shown that depressed people tend to have lower levels
 of a chemical called glutamate in parts of their brain, and that glutamate levels increase
 after recovering from depression. Researchers want to study the antidepressant citalopram
 (Celexa) to see how it affects glutamate levels in the brain. They also want to study how a
 person s genes affect their response to this treatment.

 Objectives:

 - To see whether glutamate levels and certain genes affect how a person responds to a
 particular antidepressant medication.

 Eligibility:

 - Individuals between 25 and 55 years of age who have been diagnosed with major depression
 (without psychotic features). Participants may not have tried more than three antidepressant
 treatments.

 Design:

 -  Participants will be screened with a physical exam and medical history. They will answer
 questions about mood and current feelings of depression, as well as family history of
 depression. Blood and urine samples will be collected.

 -  This study will have two phases. The first phase may last up to 7 weeks depending on
 current antidepressant use and involves one to seven outpatient visits. The second phase
 lasts 8 weeks and involves five outpatient visits, one every 2 weeks.

 -  In the first phase, participants will stop taking their current antidepressant
 medications for at least 2 weeks before the next phase of the study. Participants who
 are on fluoxetine (Prozac) will need to be off it for 6 weeks.

 -  At the end of this phase, participants will have brain imaging studies to look at brain
 function and chemistry.

 -  In the second phase, participants will take citalopram at the standard dose. They will
 answer questions about mood and response to the medication. They will also provide blood
 and saliva samples for tests.

 -  At the end of this phase, participants will have brain imaging studies to look at brain
 function and chemistry.
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.