• Change from baseline in the HAMD17 Total Score and HAMD24 Total Score, and all subscales and all individual items [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Change from baseline in 30-item Brief Profile of Mood States (BPOMS) Scale and subscales (Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment). [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Change from baseline in Sheehan Disability Scale (SDS) total score and subscores [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Relative contribution of improvement on the mood states, defined by BPOMS subscales to overall improvement in work and activities, HAMD24 item 7 using path analysis [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Relative contribution of improvement on the mood states, defined by BPOMS subscales to overall improvement in SDS total score using path analysis [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Change from baseline in 16-item Quick Inventory of Depressive Symptomatology Self Report (QIDS16SR) Total Score [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Probability of Remission as measured by the HAMD17 Total Score ≤ 7 and by the QIDS16SR Total Score ≤ 5 [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Response Rates at endpoint as measured by ≥ 50% improvement in the HAMD17 Total Score and ≥ 50% improvement in the QIDS16SR Total Score [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Change from baseline in Pain Numerical Rating Scale (NRS) [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Change from baseline in the Clinical Global Impression-Severity Scale (CGI-S) [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Change from baseline in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Change from baseline on the patient reported quality of life outcomes as measured by the Social Adaptation Self-evaluation Scale (SASS) [ Time Frame: over 3 months ] [ Designated as safety issue: No ]
• Change in vital signs and weight, including baseline to endpoint; abnormal values at any time; and abnormal values at endpoint [ Time Frame: over 3 months ] [ Designated as safety issue: Yes ]
• Change laboratory values, including baseline to endpoint; abnormal values at any time; and abnormal laboratory values at endpoint [ Time Frame: over 3 months ] [ Designated as safety issue: Yes ]
• Summary of Serious Adverse Events and Treatment-emergent adverse events [ Time Frame: over 3 months ] [ Designated as safety issue: Yes ]
• Summary of Adverse Events and Serious Adverse Events leading to discontinuation [ Time Frame: over 3 months ] [ Designated as safety issue: Yes ]
• Summary of Overall discontinuation rates [ Time Frame: over 3 months ] [ Designated as safety issue: Yes ]
• Sustained Remission as measured by the HAMD17 Total Score ≤ 7 and by the QIDS16SR Total Score ≤ 5 in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Sustained Response at endpoint as measured by ≥ 50% improvement in the HAMD17 Total Score and ≥ 50% improvement in the QIDS16SR Total Score in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change from baseline in Hamilton Depression Rating Scale (HAMD 24) Item 7 (Work and Activities)in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change from baseline in the HAMD17 Total Score and HAMD24 Total Score, and all subscales and all individual items in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change from baseline in 30-item Brief Profile of Mood States (BPOMS) Scale and subscales in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change from baseline in Sheehan Disability Scale (SDS) total score and subscores in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Relative contribution of improvement on the mood states, defined by BPOMS subscales to overall improvement in work and activities, HAMD24 item 7 using path analysis in Acute treatment responders [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Relative contribution of improvement on the mood states, defined by BPOMS subscales to overall improvement in SDS total score using path analysis in Acute treatment responders [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change from baseline in 16-item Quick Inventory of Depressive Symptomatology Self Report (QIDS16SR) Total Score in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change from baseline in Pain Numerical Rating Scale (NRS) in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change from baseline in the Clinical Global Impression-Severity Scale (CGI-S) in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change from baseline in the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH-CPFQ) in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change from baseline on the patient reported quality of life outcomes as measured by the Social Adaptation Self-evaluation Scale (SASS) in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
• Change in vital signs and weight, including baseline to endpoint; abnormal values at any time; and abnormal values at endpoint in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
• Change laboratory values, including baseline to endpoint; abnormal values at any time; and abnormal laboratory values at endpoint in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
• Summary of Serious Adverse Events and Treatment-emergent adverse events in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
• Summary of Adverse Events and Serious Adverse Events leading to discontinuation in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
• Summary of Overall discontinuation rates in Acute treatment responders (patients who remain on the treatment dose to which they were originally randomized) [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
• To assess predictors of remission based on early drug vs. placebo response in various MDD symptom domains as defined by total scores, subscale scores, and individual item scores from the efficacy and quality of life measures [ Time Frame: over 3, 9 months ] [ Designated as safety issue: No ]
• To investigate differential patterns of symptom response between duloxetine acute treatment responders (60 mg/day) and nonresponders (dose increase to 120 mg/day) using patient-rated efficacy and quality of life assessments [ Time Frame: over 9 months ] [ Designated as safety issue: No ]

• HAMD-24 Subscales and individual items [ Time Frame: 9 months ]
• MDD Outcomes [ Time Frame: 9 months ]
• Functional Outcomes [ Time Frame: 9 months ]
• Pain Measures [ Time Frame: 9 months ]

Study F1J-US-HMFS comprises two identical multicenter, 9-month, randomized, placebo-controlled, double-blind, trials (HMFSa and HMFSb). The purpose of this study is to compare the efficacy and safety of Duloxetine 60 mg once daily to placebo on depression in patients aged 18-65. Data from the two trials will be reported in both individual and pooled analyses. Pooling the two studies will allow for increased power to detect differences between duloxetine and placebo on secondary and exploratory objectives. Only one data lock is planned for this study, when all patients have completed all study procedures.

• Drug: Duloxetine hydrochloride
• Drug: Placebo

• Experimental: duloxetine 60 mg QD, PO for 3 months, after which may be increased to duloxetine 120 mg QD, PO for 6 months
• Placebo Comparator: placebo QD, PO for up to 9 months, may be increased to duloxetine 60 mg QD, PO during the first 3 months

Inclusion Criteria:

• Male or female outpatients
• Aged 18-65 who meet the DSM-IV-TR diagnostic criteria for MDD
• Have a MADRS total score of at least 22 at visits 1 and 2
• Have a CGI-S score of at least 4 at visits 1 and 2
• Have a degree of understanding such that the patient can provide informed consent, complete protocol required assessments and communicate intelligibly with the investigator and study coordinator.

Exclusion Criteria:

• Patients judged clinically to be at serious suicidal risk in the opinion of the investigator
• Patients who have any prior history of bipolar disorder, psychosis, or schizophrenia
• Patients who have any current (within the past six months) DSM-IV-TR primary Axis I disorder other than MDD
• Patients with uncontrolled narrow-angle glaucoma
• Patients who have a serious medical illness that is in the opinion of the investigator not stabilized or is likely to require intervention, hospitalization, or use of an excluded medication during the course of the study.