• Score on the depression rating scale [ Time Frame: Measured at Week 12 ] [ Designated as safety issue: No ]
• Brain energy metabolism [ Time Frame: Measured at Weeks 2 and 12 ] [ Designated as safety issue: No ]

• Score on the depression rating scale; measured at Week 12
• Brain energy metabolism; measured at Week 2 and Week 12

This study will evaluate changes in brain energy metabolism due to treatment with escitalopram in people with major depressive disorder.

Major depressive disorder (MDD) is a severe form of depression. MDD can significantly interfere with an individual's thoughts, behavior, mood, and physical health. People who suffer from MDD often experience feelings of worthlessness; they may feel hopeless and may be unable to cope with problems in their life. In addition, they often experience sleep disruption, loss of appetite, and chronic pain.

Antidepressant medications are often prescribed for treating MDD; however, 30% to 40% of individuals fail to respond adequately to medication.

Preliminary research has shown that lower levels of brain energy metabolism are often associated with MDD. No studies have yet shown whether there is a difference in brain energy metabolism between individuals who respond well to antidepressants versus those who do not. Escitalopram is an antidepressant medication often used to treat MDD. It causes a calming effect and reduces anxiety by increasing the amount of serotonin in the brain. This study will compare the changes in brain energy metabolism due to treatment with escitalopram in individuals with MDD. In turn, these findings may aid in understanding the relationship between brain energy metabolism and depression, and may guide future antidepressant trials.

This 12-week study will enroll individuals diagnosed with MDD, as well as healthy individuals. During Weeks 1 through 4, participants with MDD will receive 10 mg of escitalopram on a daily basis. If a participant does not respond well to the medication, as determined by the study clinician, the dose may be increased to 20 mg per day for Weeks 5 through 8. If a participant continues to not respond to the medication after 8 weeks, the dose may be increased to 30 mg per day for Weeks 9 through 12. Study visits will occur every other week throughout the 12 weeks. Laboratory tests, physical examinations, and vital sign measurements will be performed at each study visit. Outcome measurements will include depression levels as assessed by standardized psychological tests and questionnaires, as well as brain energy metabolite levels as assessed by magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) scans. The MRS and MRI scans will occur at baseline, Week 2, and Week 12; the entire scanning procedure will last 70-80 minutes. Following the end of the study, all participants will be offered follow-up medical care for 3 months. Participants who responded well to escitalopram will be offered continued treatment with the drug, while those who did not respond well to escitalopram will be offered treatment with another antidepressant.

Inclusion Criteria:

For depressed subjects:

• Meets DSM-IV diagnostic criteria for major depressive disorder
• Score of greater than 16 on the Hamilton Depression Rating scale (17 items) at study entry
• Agrees to use an effective form of contraception throughout the study

For healthy volunteers:

• Not currently taking any medications
• No lifetime history of major neurological, medical, psychiatric disorder, or head injury
• Agrees to use an effective form of contraception throughout the study

Exclusion Criteria:

• Current suicidal ideation that may make study participation unsafe
• Current serious or unstable medical illness (e.g., cardiovascular, kidney, liver, respiratory, endocrine, neurologic, or blood-related disease)
• History of seizure disorder
• History of or current DSM-IV diagnosis of any of the following psychiatric illnesses within 12 months of study entry: organic mental disorder, schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, bipolar disorder, mood congruent or mood incongruent psychotic features, substance dependence disorders (including alcohol)
• History of or current diagnosis of dementia, or a score of less than 26 on the Mini Mental Status Examination at screening
• History of multiple adverse drug reactions or allergic reaction to the study drugs
• Currently taking psychotropic drugs or antidepressant medications
• Clinical or laboratory evidence of hypothyroidism
• Failure to respond during current major depressive episode to at least one adequate antidepressant trial, defined as 6 weeks or more of treatment with 40 mg of citalopram per day (or its antidepressant equivalent)
• History of electroconvulsive therapy (ECT) within the 6 months prior to study entry
• Pregnant
• Subjects with a CGI score a 6 ("severely depressed") or 7 ("among the most extremely depressed patients")
• A BMI of 39 or greater, for comfort in scanner