Neurobiology of Treatment Responses in MDD

Inclusion Criteria:

• Meet DSM V criteria for Major Depressive Episode, single episode or recurrent, for atleast a month;
• Unmedicated for at least 10 half-lives of the previous AD used;
• Willing to limit the introduction of any new treatments during the study;
• 18 - 55 years of age;
• Right handed;
• Capable of giving written informed consent;
• Hamilton Depression Rating Scale (17-item HDRS, not including atypical features) >15at screening and randomization;

Exclusion Criteria:

• Major medical illness (e.g., cancer, HIV, Hepatitis C, etc.) or concurrent, untreated,or symptomatic medical illnesses, including acute or ongoing pain, autoimmune orinflammatory disease;
• Use of narcotic analgesics within the last 6 months or regular use of sleeping aids (including benzodiazepines and related compounds), more than twice a week;
• Recent history of substance abuse (within the last 6 months) or history of substancedependence (lifetime);
• Other comorbid psychiatric illnesses, such as Bipolar Disorder, Obsessive CompulsiveDisorder, Panic Disorder, any psychosis, or Axis II diagnoses. Generalized Anxiety andSocial Anxiety Disorders will NOT be considered exclusionary given their commonassociation with MDD
• Concurrent participation in other therapeutic trials;
• Pregnancy/nursing;
• Ongoing treatment with medications with psychotropic properties;
• Contraindications to PET or MRI methods;
• Impairments, activities or situations that would prevent completion of the studyprotocol;
• Prior non-response to duloxetine;
• Active suicidal ideation.
• Urine screens positive for opioids or any substances of abuse.
• Allergy to fentanyl (because of structural similarity to the radiotracer [11C]carfentanil to be employed in the study).