The purpose of this study is to see how certain hormones cause changes in mood, thinking and brain structure in patients with major depression with psychotic features versus patients with non-psychotic depression and healthy controls. The researchers' goals are to understand the clinical, cognitive and biological differences between psychotic and non-psychotic depression. In addition, we will examine the effectiveness of using mifepristone to treat psychotic depression. Furthermore, we aim to understand the mechanisms of action of mifepristone.

The study will recruit 50 subjects diagnosed with psychotic major depression (PMD), 25 subjects with non psychotic major depression (NPMD), and 25 healthy control subjects. Subjects will be 18-85 years of age, male or female, of any ethnic background. We include healthy control subjects so that we have a comparison group of non-symptomatic individuals.

All subjects (PMD's, NPMD's, and healthy controls) will undergo the eligibility screening. If they meet all the study requirements, they will be admitted to the to the General Clinical Research Center (GCRC) at Stanford Hospital for 2 nights and 3 days. We will obtain a waist /hip ratio, vitals, psychiatric ratings, and clinical laboratory tests. Additionally, subjects will undergo neuropsychiatric testing and an MRI scan.

Only the PMD patients will continue on in the study after Day 3. These patients will be randomly assigned to receive mifepristone or placebo under double blind conditions for a total treatment period of 8 days. Patients will be assessed on clinical ratings and adverse events on Treatment Days 15 and 22. On Day 22, patients will be readmitted for two nights to the GCRC where they will have their vitals taken, waist/hip ratio performed, clinical laboratory tests, neuropsychiatric testing and an MRI scan. Patients will be followed up at 1 week, 2 weeks and 1, 3, 6 and 12 months post treatment. Patients who initially received placebo and are still symptomatic will be offered 8 days of open-label mifepristone on an outpatient basis immediately following placebo treatment. These patients will be assessed clinically and for adverse events on Treatment Days 4, 18, 15 and 22 (1-week and 2-week post-treatment follow-up).

Inclusion Criteria:for PMD (psychotic major depression) and NPMDs (non-psychotic major depression) are as follows:

• Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) diagnosis of major depressive disorder with or without psychotic features, bipolar II disorder with psychotic features in a major depressive episode.
• 21-item Hamilton Rating Scale for Depression (HAM-D) score greater than or equal to 21.
• Thase Core Endogenomorphic Scale score greater than or equal to 6 on the items included in the 21-item HDRS (Hamilton Depression Rating Scale).
• Between 18 - 85 years of age.
• Female patients of child bearing capacity with psychotic depression receiving treatment with mifepristone are required to use a double-barrier method of contraception or abstinence for the entire duration of the study as well as for thirty days after the last dose of Mifepristone is taken.
• If currently taking antipsychotic, antidepressant, anticonvulsant, and/or mood-stabilizing medications, must be stable on the medication for at least one-week prior to entering the study.
• Pre-existing (current) primary treating psychiatrist for subjects with psychotic features.
• Any secondary diagnoses from the anxiety disorder spectrum is acceptable, with the exclusion of obsessive-compulsive disorder (OCD).

Inclusion criteria for healthy controls are as follows:

• Between 18 - 85 years of age.
• Have a HAM-D score of less than or equal to 5.


Exclusion Criteria:for PMDs and NPMDs are as follows:

• Electroconvulsive therapy (ECT) in the 6 months prior to the study.
• Abuse of drugs or alcohol in the 6 months prior to study.
• Unstable or untreated hypertension, cardiovascular disease, or endocrine disorders.
• Use of additional prescription medications, street drugs, or alcohol during the week before the study and during the study.
• Previous mifepristone failure or non-response.
• Any Axis II diagnosis or traits which would make participation in the study difficult.
• Current pregnancy or lactation.

Exclusion criteria for healthy controls:

• Personal history of Axis I or Axis II disorders.
• Active medical problems.
• Abuse of drugs or alcohol in the 6 months prior to study.
• Use of additional prescription medications, street drugs, or alcohol during the week before the study and during the study.
• Currently pregnant or lactating.