Trial to Determine the Maximum Tolerated Dose (MTD) Based on Safety and Tolerability, of Org 26576 in Patients With Major Depressive Disorder (174001)(COMPLETED)(P05704)

Inclusion Criteria:

• provide written informed consent after the scope and nature of the investigation has been explained to them, but before beginning any trial-related activities, including screening evaluations;
• be between 18 and 65 years, inclusive;
• be a male; or a female who is non-pregnant, nonlactating and using an acceptable method of birth control (intrauterine device, double-barrier method, hormonal contraceptives); or a female who is not of childbearing potential (i.e., surgically sterile or postmenopausal for at least 1 year). All females must have a negative urine and serum pregnancy test at Screening;
• be able to speak, read, understand, and possess the ability to respond and follow simple instructions in English or be able to speak, read, understand and possess the ability to respond to questions and follow simple instructions in their native language if the investigator is fluent in that language and any required documents/assessments, including the informed consent and cognitive testing battery, can be translated into that language;
• be diagnosed with current major depressive disorder as defined by the Diagnostic and Statistical Manual, Fourth Edition - Text Revision (DSM-IV-TR) (single episode: 296.21, 296.22, 296.23; recurrent: 296.31, 296.32, 296.33), and confirmed by the Mini International Neuropsychiatric Interview (MINI);
• have mild to severe depression as evidenced by a score of at least 9 but not more than 20 on the Quick Inventory of Depression Symptomatology - Clinician Rated (QIDS-C);
• be anti-depressant naïve (have not been treated with an antidepressant at an adequate dose and duration [as determined by the investigator] within the current episode);
• be able to discontinue use of any psychotropic medications, including antidepressants, prior to admission. The time between last dose of the psychotropic medication and Admission must be at least five half-lives;
• be able to refrain from all use of grapefruit containing products from the time of Admission until the last assessment is performed at Discharge;
• smoke = 10 cigarettes or equivalent daily, and be able to limit use of tobacco products during hospitalization to the requirements specified in Section 3.5.3;
• have a body mass index (BMI) between 18.0 and 32.0 kg•m-2, inclusive

Exclusion Criteria:

• has any current and primary Axis I disorder other than major depressive disorder;
• has any history of bipolar I or II disorder, dysthymia, psychotic depression, psychotic disorders, posttraumatic stress disorder, borderline personality disorder, obsessive compulsive disorder, or eating disorder;
• the duration of the current depressive episode is longer than 2 years at Screening;
• has any history of a significant suicide attempt, or poses a current risk of attempting suicide, in the investigator's opinion, based on clinical interview and responses provided on the Beck Scale for Suicidal Ideation (BSS);
• has history of sensitivity/idiosyncrasy to glutamatergic drugs or chemically related compounds or excipients which may be employed in the trial or to any other unknown drug used in the past;
• is known to be HIV positive;
• has any clinically significant concurrent endocrine, renal, respiratory, cardiovascular, hematological, immunological, cerebrovascular, neurological, malignancy, or any other concurrent medical condition in the judgment of the investigator that has become unstable or may interfere with the interpretation of safety and efficacy evaluations; or has any history of diabetes mellitus;
• has any history of liver disease (e.g., cirrhosis, hepatitis), or liver injury. History of hepatitis A greater than one year prior to Screening is acceptable;
• has a history of seizure disorder or treatment with anticonvulsants to prevent seizures (childhood febrile seizures may be acceptable upon the approval of Organon);
• has a diagnosis of mental retardation or organic brain syndrome;
• has a current diagnosis of substance (excluding nicotine) or alcohol dependence (within the past 6 months), and/or a confirmed positive result on the urine drug/alcohol screen at the screening visit. If the urine drug/alcohol screen is positive at Screening, it may be repeated with prior approval from Organon;
• is taking medications prohibited in Section 3.4 of the protocol, or is unable to wash off of prohibited medications in the period between Screening and Admission;
• positive test result at Screening on hepatitis B surface antigen or hepatitis A IgM antibodies or hepatitis C total antibodies;
• clinically significant ECG, EEG, vital signs, physical examination, or abnormal laboratory findings at Screening that, in the opinion of the investigator, would preclude participation in the trial. Clinically significant findings should be discussed with the Organon CRS;
• any abnormal finding greater than 1.5 times the upper normal limit at Screening on liver laboratory parameters (SGPT, SGOT, GGT, LDH, bilirubin, alkaline phosphatase);;
• QTc values >450 milliseconds at Screening using Bazett's QTc formula;
• participation in an investigational drug trial within 30 days or 5 drug half-lives, whichever is longer, prior to the anticipated first dose of trial medication;
• donation of blood within 60 days prior to the anticipated first dose of trial medication;
• inability/unwillingness to remain supine for extended periods of time (as specified in Section 3.5.3) on CSF sampling days (Block D subjects only) and/or on days in which blood is sampled for hormones (all subjects).
• for Block D subjects who will be undergoing CSF sampling: any sign of increased intracranial pressure (abnormal papillary responses, papilloedema, etc. on fundoscopy); coagulopathy/thrombocytopenia (on Screening laboratory assessment); history of lower spinal malformation, degenerative vertebral joint disease, local infection, or other abnormalities that would exclude lumbar puncture.