This is a 12-week, double-blind, placebo-controlled study on the efficacy, tolerability and
safety of oral ziprasidone as monotherapy in patients with (major depressive disorder) MDD.
The study involves the enrollment of a total of 120 patients with MDD over the course of 12
months across two sites. Outpatients suffering from MDD will be treated with either
ziprasidone or with placebo for 12 weeks using the sequential parallel comparison design.
In light of the challenge major depressive disorder (MDD) poses to clinicians and patients
alike, identifying novel treatments is urgently needed to help further refine the standard
of care. Judging by their molecular structure and function, the atypical neuroleptic agents
offer possibilities as effective antidepressants. To date, several studies have been
reported examining the use of atypical neuroleptic agents as adjunctive therapy (used along
with an antidepressant) for MDD. These studies go so far as to suggest that atypical
neuroleptic agents have potential for treating MDD. Until now, atypical neuroleptics have
been strictly viewed as adjuncts, however, it is quite possible that some of the atypical
neuroleptic agents may possess antidepressant properties when used as the lone therapy.
The atypical neuroleptic agent ziprasidone, in particular, is an excellent neuroleptic
candidate for studying antipsychotic effects on MDD for two principal reasons: its structure
makes it favorable for binding to neurotransmitters in the brain and it has fewer
side-effects compared to the other drugs in its class. This study will be the first, double
blind, placebo-controlled trial of ziprasidone as monotherapy for MDD. If safe and effective
as an antidepressant, ziprasidone would represent an additional option for patients with
Potential subjects will be approached during a regularly scheduled clinic visit, upon
referral from another physician, or in response to research advertisements. Interested
individuals will have the opportunity to review the consent form with family, friends, and
other physicians prior to making a final decision regarding study enrollment. Once the
subject has given informed consent, the screening process for the study will commence.
Subjects will have a screening visit to determine eligibility. The screening visit consists
of a medical evaluation, completion of psychological rating scales, physical/neurological
exams, electrocardiogram, and the collection of blood and urine. After subjects pass
screening, they will be randomized into one of 3 study groups. Subjects will receive either
12 weeks of ziprasidone, 12 weeks of placebo, or 6 weeks of placebo followed by 6 weeks of
ziprasidone. Study participants will have a 5 in 8 chance of receiving ziprasidone at some
point in the study.
Subjects will be closely monitored during the study via 2 phone calls weekly from the study
coordinator. The overall safety of the study will also be well scrutinized. The
investigators shall identify an independent physician safety monitor, who will be without
any affiliation to this study. He/she will be provided all the information necessary to
evaluate the study's safety parameters and whether or not they are effective preventative
Various psychological assessments will be completed by research subjects at every study
This research study is designed to test the safety and/or effectiveness of the
investigational use of the drug Ziprasidone that has been approved by the U.S Food and Drug
Administration (FDA). While the drug used in the study is FDA-approved for treating
schizophrenia and Bipolar disorder I, it is not yet approved for alleviating solely the
symptoms of depression.
1. Aged 18-65.
2. Written informed consent.
3. MDD, current according to the fourth version of the Diagnostic and Statistical Manual
for Mental Disorders (DSM-IV) as diagnosed by the Mini International Neuropsychiatric
4. Quick Inventory of Depressive Symptomatology - Self-Rated score of at least 10 at
both screen and baseline visits.
1. Pregnant women.
2. Women of child bearing potential who are not using a medically accepted means of
contraception (to include oral contraceptive or implant, condom, diaphragm,
spermicide, intrauterine device, tubal ligation, or a partner with vasectomy).
3. Treatment with antidepressants for 2 weeks prior to the study.
4. Patients who no longer meet DSM-IV criteria for MDD during the baseline visit, or
patients who demonstrate a 25% or greater reduction in QIDS-SR scores, screening to
5. Serious suicide or homicide risk, as assessed by the evaluating clinician or a score
of 4 on the third item of the HAM-D.
6. Unstable medical illness including cardiovascular, hepatic, renal, respiratory,
endocrine, neurological, or hematological disease.
7. Patients who meet criteria for alcohol or substance dependence, active within the
8. Any bipolar disorder (current or past).
9. Any psychotic disorder (current or past).
10. Psychotic features in the current episode or a history of psychotic features.
11. History of a seizure disorder.
12. Clinical or laboratory evidence of untreated hypothyroidism.
13. Patients requiring excluded medications.
14. Prior course of ziprasidone, or intolerance to ziprasidone at any dose.
15. Any investigational psychotropic drug within the last 3 months.
16. Patients with significant cardiac conduction problems on screening electrocardiogram
such as atrial fibrillation, atrial flutter, atrio-ventricular block, prolonged or
abnormal QTc interval, or prolonged QRS interval.
17. Patients who have suffered a myocardial infarction within the past 12 months, with
uncompensated heart failure, or a history of QTc prolongation.
18. Patients with abnormal serum potassium or magnesium levels upon screening.
19. Patients currently taking other drugs that prolong the QTc including dofetilide,
sotalol, quinidine, class Ia antiarrhythmics, class III antiarrhythmics,
mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin,
gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide,
levomethadyl acetate, dolasetron methylate, probucol or tacrolimus.
20. Patients who have failed to experience significant clinical improvement following 3
or more antidepressant trials of adequate duration (at least 6 weeks) and dose
(minimal effective doses defined as: fluoxetine, paroxetine, citalopram 20mg;
sertraline, fluvoxamine 50mg, escitalopram 10mg, paroxetine CR 25mg, venlafaxine
75mg, duloxetine 60mg, bupropion 150mg, 15mg of mirtazapine, trazodone or nefazodone
21. Patients with a QTc > 450msec at the Baseline visit.