This 6-month study will compare the effectiveness of citalopram (Celexa®), hypericum (St. John's Wort), and placebo for the treatment of minor depression.

Minor depression is highly prevalent, causes substantial morbidity and disability, presents a serious risk factor for the development of major depressive disorder, yet is under recognized and under treated. Researchers have determined that patients with minor depression frequently seek treatment from general practitioners and are often treated with prescription antidepressants. There is a need to evaluate the effectiveness of St. John's Wort in the management of minor depression. If the proposed study demonstrates the efficacy of St. John's Wort and/or citalopram, it will suggest treatment paradigms that can be tested and applied in primary care settings.

Patients who meet screening criteria enter a 2-week washout period (or, for fluoxetine, a 4-week washout period) during which no psychotropic medication is permitted. Participants are then randomly assigned to St. John's Wort, citalopram, or placebo for 12 weeks. Participants who respond to treatment by Week 12 continue to take their originally assigned double-blind medication for up to 26 weeks. At Week 12, nonresponders to placebo are crossed over to 1 of the 2 active treatments. Patients who remain nonresponders to that active treatment are crossed over to the alternative active treatment, with the investigator maintaining blind status. Participants have study visits at screening, during the washout period, at baseline, and every 2 weeks thereafter for the course of the study. At the screening visit, Week 12, and Week 20, patients undergo a complete blood count with differential and other routine laboratory tests.

• Drug: Citalopram
• Drug: St. John's Wort

Inclusion Criteria:

• Minor Depression symptoms for at least 6 months
• Endorse one of the DSM-IV "A" criteria for MDD and at least one other symptom of MDD or endorse both of the "A" criteria for MDD
• Global Assessment of Functioning (GAF) score < 70
• Short form health survey (SF-36) social functioning score <= 75% or an emotional role functioning score <= 67%
• HAM-D-17 score 10-17, inclusive
• Minor depression symptoms for at least 6 months

Exclusion Criteria:

• Major depressive disorder (MDD) or dysthymia within the past year or in partial remission of MDD
• At least a 12-week course of either citalopram at a minimum or 40 mg/day or St. John's Wort at a minimum of 900 mg/day during the current episode of depression
• Previous intolerance to either citalopram or St. John's Wort or history of nonresponse to either citalopram at a minimum of 40 mg/day or St. John's Wort at a minimum of 900 mg/day for at least 12 weeks
• Unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine, neurologic, or hematologic disease
• Uncontrolled seizure disorder
• The following DSM-IV diagnoses: organic mental disorders; substance use disorders, including alcohol, active within the last year or patients with a positive urine drug screen; schizophrenia; delusional disorder; psychotic disorders not elsewhere classified; bipolar disorder; bereavement; adjustment disorder; antisocial personality disorder; panic disorder, social phobia, generalized anxiety disorder (GAD), or obsessive compulsive disorder (OCD). Patients may have a lifetime diagnosis of an anxiety disorder as long as it is not current.
• Mood-congruent or mood-incongruent psychotic features
• Psychotropic drugs
• Hypothyroidism
• Investigational psychotropic drugs within the last year
• Positive toxicology screen
• Medications metabolized by the CYP3A4 system, where induction of this system poses a risk to the medical stability of the patient
• Pregnancy or refusal to use a medically accepted method of contraception
• Serious suicide or homicide risk
• Psychotherapy beginning less than 3 months ago

• National Center for Complementary and Alternative Medicine (NCCAM)
• Office of Dietary Supplements (ODS)