Optimizing Outcomes of Treatment-Resistant Depression in Older Adults

Older adult participants with treatment-resistant depression will be randomly assigned to a
Step 1 medication strategy.

- Adding aripiprazole to current antidepressant medication

- Adding bupropion to current antidepressant medication

- Replacing current antidepressant medication with bupropion

If depression is not relieved at the end of 10 weeks, or if participants do not qualify for
Step 1, participants will be randomly assigned to a Step 2 medication strategy:

- Adding lithium to current antidepressant medication

- Replacing current antidepressant medication with nortriptyline

All medication strategies will be offered in collaboration with participants' own physicians
with the the research team providing support and guidance.

After treatment in Step 1 and/or Step 2, participants will enter the Continuation Phase to
assess long term follow-up outcomes for 12 months.

Participants in this clinical trial will also be asked to participate in an additional study
to gather imaging and biomarker data.

Inclusion Criteria:

- Men and women aged 60 and older

- Current Major Depressive Disorder (MDD)

- Failure to respond adequately to two or more antidepressant treatment trials of
recommended dose and length

- Patient Health Questionnaire-9 (PHQ-9) score of 6 or higher

Exclusion Criteria:

- Inability to provide informed consent

- Dementia

- Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective
disorder, schizophreniform disorder, delusional disorder, or current psychotic
symptoms

- High risk for suicide and unable to be managed safely in the clinical trial

- Contraindication to proposed study medications, as determined by study physician
including history of intolerance or non-response to proposed medications.

- Non-correctable, clinically significant sensory impairment interfering with
participation

- Unstable medical illness, including delirium, uncontrolled diabetes mellitus,
hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that
are not under medical management.

- Moderate to severe substance or alcohol use disorder