This study will evaluate the effectiveness of mifepristone to treat adults with psychotic major depression.

Psychotic major depression (PMD) is a severe and often debilitating form of depression. Approximately 25% of people who are admitted to hospitals for depression suffer from PMD. People with PMD experience not only the standard symptoms of depression, but also hallucinations and delusions, causing them to become paranoid, believe their thoughts are not their own, or think that others can hear what they are thinking. Current research has shown that people with PMD secrete increased amounts of cortisol, a hormone released within the body in response to stress. The purpose of this study is to gain a better understanding of why people with PMD tend to have increased levels of cortisol, the effect of increased cortisol on the brain, and whether mifepristone can restore normal cortisol levels as a way to treat PMD. Thus, in this study we will include the PMD group with two comparison groups, a Non-Psychotic Major Depression group and a Healthy Control group with no psychiatric history.

PMD participants in this double-blind study will first be admitted to the General Clinical Research Center (GCRC) at Stanford Hospital for 2 nights and 3 days. This hospital stay will include waist/hip ratio and vital sign measurements, psychiatric and neuropsychiatric ratings, and a magnetic resonance imaging (MRI) scan. After the third day, only patients with PMD will continue on in the study. Participants with PMD will be randomly assigned to receive either mifepristone or a placebo for 8 days. Participants with PMD will be evaluated on Days 15, 22, and 23 to determine whether any improvement in symptoms has been maintained or if changes or negative side effects have occurred after treatment completion. Participants will then be readmitted for 2 nights to the GCRC to undergo the same tests and procedures done at the beginning of the study. PMD participants who received a placebo will be offered mifepristone for 8 days of treatment and will be assessed over a period of 22 days to measure any changes or improvements in symptoms.

Inclusion Criteria for Participants With PMD (psychotic major depression) and NPMD (non-psychotic major depression):

• Meets DSM-IV criteria for major depressive disorder with or without psychotic features, or bipolar II disorder with psychotic features in a major depressive episode
• Hamilton Rating Scale for Depression (HAM-D) score of at least 21
• Thase Core Endogenomorphic Scale score of at least 6
• Use of effective forms of contraception if sexually active
• Must be stable for at least 1 week prior to study entry if taking antipsychotic, antidepressant, anticonvulsant, and/or mood-stabilizing medications
• Currently receiving care from a psychiatrist, if experiencing psychotic symptoms

Inclusion Criteria for Healthy Controls:

• HAM-D score of 5 or lower

Exclusion Criteria for Participants With PMD and NPMD:

• Received electroconvulsive therapy (ECT) within 6 months of study entry
• Abuse of drugs or alcohol within 6 months of study entry
• Unstable or untreated hypertension, cardiovascular disease, or endocrine disorder
• Use of additional prescription medications, street drugs, or alcohol within 1 week of study entry
• Previous reaction or non-response to mifepristone
• Any Axis II diagnosis or traits that would make participation in the study difficult
• Pregnant or breastfeeding

Exclusion Criteria for Healthy Controls:

• History of Axis I or Axis II disorders
• Any active medical problems
• Abuse of drugs or alcohol within 6 months of study entry
• Use of prescription medications, street drugs, or alcohol within 1 week of study entry
• Pregnant or breastfeeding