INCLUSION CRITERIA:
For inclusion in the study, patients must fulfill all of the following criteria:
-Provision of written informed consent before initiation of any study related procedures.
-Male and female patients aged 18 to 65 years old, both inclusive. Women must be either of non-childbearing potential or if of childbearing potential, agree to use a highly effective form of birth control as well as double barrier method contraception. Women of child bearing potential must have a negative serum pregnancy test. Highly effective forms of birth control include but are not limited to: true sexual abstinence, a vasectomized sexual partner, Implanon, female sterilization by tubal occlusion, IUD/IUS (copper coils), Depo-Provera injections, low dose combined oral contraceptive only if used in TriCycle regime, and Evra Patch or Nuvaring use in TriCycle regime. Women should be on a stable method of birth control for a minimum of 3 months prior to study entry.
-Documented clinical diagnosis meeting criteria from the DSM-IV for the following:
296.22 Major Depressive Disorder, Single Episode, Moderate or
296.23 Major Depressive Disorder, Single Episode, Severe Without Psychotic Features, duration at least 1 year or
296.32, Major Depressive Disorder, Recurrent, Moderate or
296.33, Major Depressive Disorder, Recurrent, Severe Without Psychotic Features.
-HRSD17 total score greater or equal to 20; HRSD17 (A/S) score greater or equal to 7; HAM-A total score greater or equal to 16; CGI-S score greater or equal to 4 at both screening and randomization (an interval of at least 2 weeks).
-Patient must agree to voluntary hospitalization for a minimum of 7 days.
-Patient must be able to understand and comply with the requirements of the study, as judged by the investigator.
-Patient must be compliant with the self-administration of medication. No structured psychotherapy will be permitted during the study.
EXCLUSION CRITERIA:
Any of the following is regarded as a criterion for exclusion from the study:
-Patients with current DSM-IV Axis II disorder which has a major impact on the patient's current psychiatric status.
-Patients with current DSM-IV Axis I bipolar disorder (I or II), psychotic disorder, or major depressive disorder with psychotic features.
-Patients with symptoms of psychosis within the past 6 months.
-Patients with a current DSM-IV clinical diagnosis of Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81) or have experienced a Panic Disorder within 1 year prior to randomization.
-Patient whose current depressive episode is less than 8 weeks or greater than 24 months.
-Patients with a lifetime history of inadequate response to an adequate course (6 weeks) of treatment with 3 or more classes of antidepressants or a current history of inadequate course of treatment with 2 or more classes of antidepressants. Electroconvulsive Therapy (ECT) also constitutes an adequate course of treatment.
-History of substance or alcohol abuse in the past 6 months or dependence within 1 year of enrollment (except for caffeine or nicotine dependence), as defined in DSM IV criteria. Patients with a positive urine drug screen (UDS) for methamphetamines (including ecstasy), benzodiazepines, cocaine and/or metabolites, amphetamines, tetrahydrocannibinol (THC), opiates, phencyclidine (PCP), and barbiturates will be excluded except for patients testing positive for prescribed medications. Patients can be retested if the initial UDS is positive, but should be excluded if the results are still positive at the second test. Patients with a positive UDS for a drug(s) legally available by prescription must provide evidence of the prescription for the drug(s).
-Any history of seizure including one febrile seizure. Patients with a family history of epilepsy will also be excluded from participation.
-History of head trauma, including closed head injury in which loss of consciousness occurred greater than one minute.
-Treatment with ECT within the past 3 months prior to randomization.
-EEG with evidence of epileptiform activity on initial baseline screening or after medication washout (4-7 days prior to randomization).
-Patients who pose a serious suicidal or homicidal risk in the opinion of the investigator as assessed by clinical evaluation and suicidality measures. Patients with a suicide or homicide attempt within the past 6 months.
-Women that are pregnant or lactating.
-Positive HIV, Hepatitis B or Hepatitis C test or acquired immunodeficiency syndrome (AIDS).
-Serious unstable medical illness (e.g., asthma, hypertension, poorly controlled diabetes, unstable angina) or illness that, in the opinion of the investigator, would be negatively impacted by the study medication. Hypothyroidism permitted if corrected and on stable regimen for a minimum of 3 months.
-History of pancreatitis.
-QT interval corrected by the Fredericia Formula (QTcF) on screening ECG of greater than 450 (msec).
-Systolic blood pressure less than 95 mm Hg or elevated greater than 140 mm Hg on 3 consecutive measurements at screening.
-Heart rate less than 50 beats per minute or greater than 100 beats per minute on 3 consecutive measurements at screening.
-Conditions that could affect metabolism of study medication (e.g., liver disease).
-Current diagnosis of cancer (except basal or squamous cell skin carcinoma), unless in remission for at least 10 years.
-Current or past diagnosis of stroke or Transient Ischemic Attack (TIA).
-Clinically significant deviation from the reference range in clinical laboratory test results as judged by the investigator including: absolute neutrophil count less than or equal to 1.5X 109/L, ALT or AST greater than or equal to 2 times the upper limit of normal for the reference range; creatinine greater than or equal to 1.8 units.
-Known history of intolerance or hypersensitivity to any medication required by this protocol (or 3 or more classes of pharmaceuticals) or current manifestation of any allergic disorder (other than seasonal allergies) as judged by the investigator.
-Use of antidepressant antipsychotic or mood stabilizing drugs within 2 weeks prior to randomization. Use of anxiolytic or hypnotics within 4 days prior to randomization. Patients on chronic benzodiazepine treatment within past 3 months will be excluded. Use of fluoxetine within 28 days before randomization. Use of monoamine oxidase inhibitors within 14 days prior to randomization. Use of depot neuroleptics within 2 months prior to randomization.
-Use of drugs that induce or inhibit the hepatic metabolizing cytochrome P450 3A4 enzymes within 2 weeks prior to randomization: e.g., inducers: carbamazepine, phenytoin, barbiturates, rifampin, rifabutin, glucocorticoids, thioridazine and St. John's Wort; e.g., inhibitors: ketoconazole (except for topical use), itraconazole, fluconazole, erythromycin, clarithromycin, fluoxetine, nefazodone, troleandomycin, indinavir, nelfinavir, ritonavir, and saquinavir.
-Enrollment in a concurrent investigational study or intake of an investigational drug within 30 days of randomization.
-Inability to understand or cooperate with study procedures due to mental function, visual or hearing impairment or lack of fluency in English or Spanish.
-Involvement or involvement of a family member in either the planning or conduct of the study.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 01/13/2009