The purpose of this study is to determine whether olanzapine and fluoxetine combination (OFC) if used for a long time (47 weeks) makes patients suffering from Treatment Resistant Depression stable, determine if OFC is safe when used to treat patients with Treatment Resistant Depression for a long time (up to 47 weeks), to determine whether olanzapine and fluoxetine combination or fluoxetine alone is better to treat Treatment Resistant Depression when treated for a long time ( up to 47 weeks) and to assess the quality of life during treatment.

This is a multicenter, randomized, double-blind, active comparator-controlled, parallel study of patients with Treatment Resistant Depression (TRD), comparing the efficacy and safety of olanzapine and fluoxetine Combination (OFC) versus fluoxetine in relapse prevention of stabilized patients with TRD. The study will consist of 4 phases: a screening phase; a 6- to 8-week open-label acute treatment phase; a 10- to 12-week open-label stabilization phase; and a 27- to 29-week double-blind relapse prevention treatment phase. Patients who demonstrate response to open-label OFC during the acute treatment phase will continue into the stabilization phase. Patients who remain stable while receiving open-label OFC during this phase will be randomized to receive either OFC or fluoxetine during the double-blind relapse prevention phase. Investigators and patients will be blinded to the precise duration of the stabilization period, the definition of remission, and the criteria for entry into the relapse prevention phase; this information is described in a supplement given to Ethical Review Boards (ERBs) and regulatory authorities.

• Drug: Olanzapine and Fluoxetine combination

  Open label acute phase: introductory dose for 4 days then 3/25, 6/25, 12/25, 6/50, 12/50 or 18/50mg, oral, daily, for 6-8 weeks.

  Open label stabilization phase: 6/25, 12/25, 6/50, 12/50 or 18/50 mg, oral, daily for 16-20 weeks.

  Double blind relapse prevention phase: dose determined during stabilization phase at week 17, oral, daily, for 27 weeks.

  Other Names:

  • Symbyax
  • LY900000
• Drug: Fluoxetine
  25 or 50mg/day fixed dosing for 27 weeks
  Other Names:

  • Prozac
  • LY1101440

• Olanzapine and Fluoxetine combination: Experimental
  Intervention: Drug: Olanzapine and Fluoxetine combination
• Fluoxetine: Active Comparator
  Intervention: Drug: Fluoxetine

Inclusion Criteria:

• Have recurrent unipolar MDD, without psychotic features by DSMIV- TR clinical assessment, confirmed by the structured clinician Interview for DSM-IV Axis 1 disorders
• If female and of childbearing potential, test negative for pregnancy and agree to abstain from sexual activity or use a medically accepted means of contraception during the study. Use of any oral or injectable contraception must be initiated prior to receiving treatment.
• Have 17-item HAM-D score greater than or equal to 18 at screening and the day treatment is due to be received for the first time.
• Have treatment-resistant depression, as defined by having demonstrated failure to achieve satisfactory antidepressant response to adequate separate treatment courses of at least 2 different antidepressants within the current episode of MDD.

Exclusion Criteria:

• Have a diagnosis of Parkinson's disease or related disorders.
• Have a current or lifetime diagnosis of any of the following according to DSM-IV criteria: Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Psychotic Disorder Not Otherwise Specified, Bipolar Disorder I or II, Delirium of any type, Dementia of any type, Amnestic Disorder, any Substance-Induced Disorder, or any Psychotic Disorder due to a General Medical Condition.
• Have current diagnosis of post-partum depression, MDD with atypical features, or MDD with a seasonal pattern as defined in the DSM-IV.
• Have paranoid, schizoid, schizotypal, antisocial, and borderline personality disorders (Axis II) as a comorbid or primary diagnosis, based on DSM-IV criteria.
• Have had psychotic symptoms within 1 month prior to Screening or demonstrate psychotic features at screening and on the day treatment is due to be assigned for the first time as determined by the investigator.
• Have DSM-IV substance dependence/abuse or not willing to avoid use of the substance (not including dependence on nicotine or caffeine), as defined by the SCID-I, within the past 30 days.
• Are actively suicidal in the judgment of the investigator.
• Have had one or more seizures without a clear and resolved etiology.
• Have leukopenia or history of leukopenia without a clear and resolved etiology, or known history of agranulocytosis during the patient's lifetime.
• Have ALT/SGPT values greater than or equal to 2 times the upper limit of normal of the performing laboratory (ULN) or AST/SGOT values greater than or equal to 2 times the ULN or total bilirubin values greater than or equal to 1.5 times the ULN at screening.
• Have acute, serious, or unstable medical conditions
• Have any illness such that death is anticipated within 1 year or intensive care unit hospitalization for the illness is anticipated within 6 months.
• Have elevated prolactin levels at screening.
• Have QTc Bazett's >450 milliseconds (male) or >470 milliseconds (female) at screening and when treatment is due to be received for the first time.
• Have received electroconvulsive therapy (ECT) or vagus nerve stimulation (VNS) treatment within the current episode; have a history of failure to adequate treatment courses of ECT or VNS; or will require ECT or VNS at any time during study participation.
• If receiving psychotherapy, light therapy, or both, are anticipated to require changes in frequency/intensity of treatment regimen or to cease treatment regimen over the duration of the study. Patients who are not receiving any of these therapies upon study entry may not begin any of these therapies during screening, or during any treatment phases of the study.
• Have received previous treatment with clozapine.
• Have used a monoamine oxidase inhibitor (MAOI) within 14 days prior to screening or are expected to need MAOI treatment at any time during this study through 5 weeks after the patient discontinues from the study.