This is a randomized (patients assigned to treatment groups by chance), double-blind (neither the study physician nor the patient will know the identification of treatment assigned), active- and placebo-controlled study to assess the efficacy and safety of JNJ26489112 in adult patients with treatment-resistant major depressive disorder (MDD). The active control used in the study is venlafaxine extended-release \[XR\], an antidepressant drug used to treat patients with MDD. A target of 150 patients will be randomly assigned (like flipping a coin) to 1 of 3 treatment groups with approximately 50 patients planned per treatment group. This study consists of a screening phase of up to 4 weeks, a 6-week double-blind treatment phase, and a safety follow-up period that includes a 1-week taper phase (described below). During the screening phase, patients who meet entry criteria for the study will be tapered off their current psychotropic medications (medications affecting the mind or mood or other mental processes) prior to randomization in the double-blind treatment phase of the study. In the double-blind treatment phase, patients will be randomly assigned to receive either 2 capsules of JNJ26489112, venlafaxine XR (the active comparator), or placebo (a sugar pill) once daily for 6 weeks. Upon completion of the double-blind treatment phase or when patients discontinue study drug at any time point during the double-blind treatment phase, study medication will be tapered and/or discontinued in a blinded manner over a 1-week period. A Data Monitoring Committee (DMC) made up of individuals not involved in the conduct of the study will monitor safety during the study. The primary outcome measure will be the change from baseline to end point (after 6 weeks of treatment or at the time of early withdrawal from the study) in the total score from the Montgomery-Asberg Depression Rating Scale (MADRS, a scale that physicians use to measure the severity of depression in patients and changes in depression due to antidepressant treatment). Patient safety will be monitored during the study by evaluating adverse events (side effects) reported and findings from clinical laboratory test results, 12-lead electrocardiograms (ECGs), vital sign measurements, body weight measurements and physical, neurologic, and ophthalmologic examinations performed. Blood samples for assessing pre- and post dose levels of JNJ26489112 or venlafaxine will be obtained at protocol-specified time points during the study. In addition, a blood sample will be obtained from all enrolled patients at Visit 2 for pharmacogenomics research (research to help identify genetic markers of response, to explain variability in the data, or to address emerging clinical issues). Patients will receive double-blind treatment with 2 capsules of JNJ26489112 (500 mg/day during the first 3 weeks that may be increased up to 1000 mg/day by week 4), venlafaxine XR (75 mg/day during week 1 increased to 150 mg/day during weeks 2-6\]), or placebo orally (by mouth) with food once daily for 6 weeks. After 6 weeks, venlafaxine XR 150 mg/day will be tapered to one 75 mg/day capsule for 1 week and patients receiving JNJ26489112 or placebo will be switched to 1 capsule of placebo for 1 week.