Paroxetine/Bupropion in Suicide Attempters/Ideators With Major Depression

Major depressive disorder (MDD) is a common and serious psychiatric illness. It is among the
leading causes of disability and is the psychiatric disorder most often associated with
suicide. The treatment of MDD with antidepressant medication remains largely trial and error.
Little empirical evidence exists to guide the treatment of MDD when suicide risk 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. The study compared the effectiveness of paroxetine, an
SSRI, versus bupropion, a non-SSRI, on suicidal ideation and/or behavior in depressed
patients with a past suicide attempt and/or current suicidal thoughts. Results of the
completed primary study have been published (Grunebaum MF et al. Neuropsychopharmacology.
2012 Feb;37(3):697-706).

In the ongoing secondary neuro-imaging component of the study, Participants are randomly
assigned to either paroxetine or bupropion treatment for 8 weeks with fMRI scans involving a
reward processing task at baseline and Week 8. Weekly study visits include interviews with a
psychologist, self-report scales, and medication monitoring. All participants will then be
offered 4 additional months of open clinical treatment. If original medication assignments
prove to be ineffective, participants will have the option to switch to another medication.
After completing the study, participants will be referred for ongoing treatment.

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.

- Patients 60 years of age and older must score at least 25 on MMSE at screening.

- Patients 60 years of age and older must have a normal ECG within the past year.

Exclusion Criteria:

- Any of the following conditions: bipolar disorder; current psychotic symptoms; bulimia
or anorexia that is current or within the past year, or current purging at least twice
a week for three 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 or equal to 140 mm Hg or diastolic blood pressure
greater than or equal to 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 daily dose [PDR] 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

- Patients with ferrous metal implants in their bodies, or a history of claustrophobia
that precludes MRI, will be excluded.

- Patients assessed as being unlikely to tolerate the maximum 2-week delay to start of
treatment.