Neurobiology of Treatment Responses in MDD

Volunteers will be randomized to receive placebo pills or a commercially available SNRI for
10 weeks. Volunteers will undergo imaging with structural and functional MRI and PET with
[11C]carfentanil to determine baseline μOR BPND and changes in BPND measures during acute
i.v. medication administration at the time of scanning before and after the 10-week treatment
period.

To elicit the activation of µ-opioid-mediated neurotransmission in the scanner, we utilize
the introduction of medication (active or inactive) 1mL into an intravenous port every 4
minutes, 15 sec per infusion, starting 45 minutes after radiotracer administration, until
scan completion. Participants are made aware that the study drug will be administered at the
time a computer-generated human voice recording reads a second-by-second count of the
infusion timing (15 sec).

Inclusion Criteria:

- Meet DSM V criteria for Major Depressive Episode, single episode or recurrent, for at
least 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) >15
at 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 or
inflammatory 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 substance
dependence (lifetime);

- Other comorbid psychiatric illnesses, such as Bipolar Disorder, Obsessive Compulsive
Disorder, Panic Disorder, any psychosis, or Axis II diagnoses. Generalized Anxiety and
Social Anxiety Disorders will NOT be considered exclusionary given their common
association 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 study
protocol;

- 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).