• Reduction in neuropsychological measures of impulsivity [ Time Frame: Measured at Week 8 ] [ Designated as safety issue: No ]
• Reduction in suicidal ideation [ Time Frame: Measured at Week 8 ] [ Designated as safety issue: Yes ]
• Occurrence of suicidal ideation or acts necessitating a change in treatment [ Time Frame: Measured at Month 6 ] [ Designated as safety issue: Yes ]

• Reduction in neuropsychological measures of impulsivity
• Reduction in suicidal ideation
• Occurrence of suicidal ideation or acts necessitating a change in treatment (all measured throughout the study)

This study will compare the effectiveness of two antidepressant medications in treating depression in people who have attempted suicide or are currently experiencing suicidal ideation.

Major depressive disorder (MDD) is a common and serious psychiatric illness. It is among the leading causes of disability and is the psychiatric disorder that is most commonly associated with suicide. The treatment of MDD with antidepressant medication, however, remains a process based largely on trial and error. In particular, little empirical evidence exists to guide the treatment of MDD when suicide is a major factor. Selective serotonin reuptake inhibitors (SSRIs) are a type of antidepressant medication that works by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance. This study will compare the effectiveness of paroxetine, an SSRI antidepressant, versus bupropion, a non-SSRI antidepressant, in treating depression in people who have attempted suicide or are currently experiencing suicidal ideation.

Participants in this double-blind study will be randomly assigned to receive either paroxetine or bupropion for 8 weeks. Weekly study visits will include interviews with a psychologist, self-report scales, and medication monitoring. All participants will then be offered 4 additional months of open label treatment with their assigned medications, and study visits will occur at least monthly. If original medication assignments prove to be ineffective, participants will have the option to switch to another medication, which, in most cases, will be the other study medication. After completing the 6-month study, participants will be referred for ongoing treatment at another clinic, but will continue attending clinical follow up visits at the study site until their new care has been established.

• Drug: Paroxetine CR for major depressive episode
• Drug: Bupropion XL for major depressive episode

• Active Comparator: Participants will receive paroxetine for 8 weeks
• Active Comparator: Participants will receive bupropion for 8 weeks

Inclusion Criteria:

• Currently suffering from a major depressive episode (unipolar only)
• History of a past suicide attempt or score greater than 2 on the Hamilton Depression Rating Scale (HDRS) item #3 (suicide) at in-person screening interview. Patients with suicidal plan or intent will only be enrolled as inpatients if independent inpatient treatment team agrees.

Exclusion Criteria:

• Any of the following conditions: bipolar disorder; current psychotic symptoms; past or current bulimia or anorexia nervosa or purging behavior occurring, on average, at least twice a week for 3 months; already taking selective serotonin reuptake inhibitors (SSRIs) or bupropion for other indications (such as anxiety disorders)
• Primary disorder is an anxiety disorder (e.g., panic disorder, general anxiety disorder, obsessive compulsive disorder, social anxiety disorder), with secondary depression
• Drug or alcohol dependence within 6 months prior to study entry (current drug or alcohol abuse may be permitted if study officials determine that the abuse is of lesser importance than the major depressive episode)
• Systolic blood pressure greater than 150 mm Hg or diastolic blood pressure greater than 90 mm Hg
• Significant active physical illness, particularly those that may affect the brain or serotonergic system (e.g., blood dyscrasias lymphomas, hypersplenism, endocrinopathies, kidney failure, severe chronic obstructive lung disease, autonomic neuropathies, active malignancy)
• Active medical problems
• Requires antipsychotic medication
• History of hypomania or mania while taking antidepressants
• Any condition that may make the use of an SSRI or bupropion medically inadvisable
• Currently using Zyban
• Failure to respond to adequate trials of three SSRIs, paroxetine, or bupropion within 2 years prior to study entry (failure to respond to therapeutic trial defined as at least 2/3 maximal pulsed dose rate [PDR] dose for at least 6 weeks)
• Pregnant, breastfeeding, or plans to become pregnant during the course of study participation
• Currently on effective treatment, requires adjunctive antipsychotic or mood stabilizing medication, or is unlikely to respond to single agent treatment for depression