This study will compare the effectiveness of relatively new antidepressants which have
different mechanisms of action.
Buproprion (Wellbutrin) works on dopamine and the dopaminergic pathway.
Sertraline (Zoloft) works as a selective serotonin reuptake inhibitor (SSRI).
Venlafaxine (Effexor) works as a mixed serotonin, norepinephrine, and dopamine reuptake
Subjects enrolled in this study will be patients diagnosed with a bipolar disorder who are
presently taking medication to prevent the symptoms of the disease (prophylactic treatment),
but have had breakthrough episodes of depression despite taking their medication.
Patients will receive any one of the three antidepressant medications as noted above plus a
placebo inactive sugar pill, in order to mask which antidepressant is being prescribed) in
addition to their regular medication for bipolar disorder. All of the doses will be
calculated as effective for the treatment of a unipolar major depressive disorder. The
patient will continue receiving the medication for ten weeks.
The effectiveness of the drug treatment will be measured by using three different scales;
1. Inventory for Depressive Symptoms - Clinicians form (IDS-C)
2. Clinical Global Impression scale(CGI-BP)
3. Life Charting Methodology (LCM)
Patients who do not respond to their medication within ten weeks from the beginning of the
study will be considered as non-responders and be offered the opportunity to start the study
again, taking one of the two remaining medications. For example, if a patient was assigned
to take Wellbutrin but it was ineffective, he/she could re-enter the study and be given
either Zoloft or Effexor.
Patients that do respond in the first ten weeks of the study will be eligible to continue
taking the medication for one year to assess the long term effectiveness of the drug on
preventing episodes of depression and to assess for any possible differential induction of
This NIMH-Stanley Foundation Bipolar Network (the "Network") study will be the first
systematic assessment in bipolar depression of the comparative efficacy of bupropion
(Wellbutrin), sertraline (Zoloft), and venlafaxine (Effexor), three newer antidepressants
which have very different mechanisms of action. Bupropion is largely dopaminergic while
sertraline is a serotonin selective reuptake inhibitor (SSRI) and venlafaxine is a mixed
serotonin, norepinephrine, and to a lesser extent dopamine reuptake inhibitor. Subjects
enrolled in this study will be bipolar patients on prophylactic treatment who experience a
breakthrough major depressive episode. Subjects will be assigned in a double-blind manner
using a three-arm forced randomization procedure to antidepressant therapy with either
bupropion, sertraline, or venlafaxine for a ten-week acute response trial. The study
medications will be assigned as adjuvant treatment to mood stabilizing medication(s) which
have proven unsatisfactorily effective within therapeutic range(s) or at maximum tolerated
dose(s). All subjects will receive active drug at dosages established as clinically
relevant for unipolar major depressive disorder. Subjects and research personnel conducting
cross-sectional and longitudinal rating assessments of mood and functioning will be blinded
to treatment group assignment. The primary outcome measures will be the Inventory for
Depressive Symptoms - Clinician form (IDS-C), the Clinical Global Impression (CGI-BP) scale,
and the Life Charting Methodology (LCM). Subjects who worsen from baseline to week four of
treatment will be considered non-responders to the initially assigned medication, and will
be offered re-randomization to either of the two drugs to which the subject was not
originally randomized (e.g., for bupropion non-response, to either sertraline or
venlafaxine) for an additional ten-week acute response trial. Responders to the acute trial
enter a 12 month trial of continuation therapy to assess long term effects on prophylaxis of
depression and possible induction of mania or cycle acceleration. We also wish to explore
possible clinical and biological correlates of acute and long term response to these
antidepressants which have received almost no systematic study in bipolar illness. One
hypothesis of this study is that the acute efficacy for the three antidepressants would be
the same. Another hypothesis is that because of the potent noradrenergic (NE) effects,
venlafaxine would have a higher rate of inducing mania compared with bupropion or
Subjects fulfill DSM-IV criteria for Bipolar I disorder (BPI), Bipolar II disorder (BPII),
Bipolar disorder not otherwise specified (BPNOS), or schizoaffective disorder bipolar
Subjects must be competent to comprehend the purpose of the study and provide informed
Subjects must undergo complete psychiatric diagnostic interview (SCID--DSM-IV), medical,
neurological, and Laboratory examinations (including EKG, renal and liver function tests,
serum electrolytes, urinalysis, HIV, hepatitis B, pregnancy testing, and urine drug screen
for the presence of psychoactive drugs and drugs of abuse).
At least 18 years old.
Subjects must have a depression of sufficient severity to rate greater than or equal to 16
on the Inventory of Depressive Symptomatology -Clinician (IDS-C) comparable to greater
than or equal to 12 on the Hamilton Depression Rating Scale) or the clinician must decide
that there is a need to treat with an antidepressant. In addition, patients must be on at
least one mood stabilizer.
Subjects should have no general medical illness that is causing the mood disorder.
Subjects should not have liver, renal, hematological, or neurological disease.
Women participants of childbearing potential must be nongravid, nonnursing, and using an
acceptable method of birth control.
Patients must not have alcohol or substance use or dependence of sufficient magnitude to
require independent, concurrent treatment intervention (excluding self-help groups), i.e.,
hospitalization, day treatment programs, or counselor visits.
No patients taking concomitant medications that would contraindicate the medications under
study, such as chemotherapy.
No history of bulimia or seizure disorder.