Incomplete Response in Late Life Depression: Getting to Remission (IRL GREY)

Incomplete response in the treatment of late-life depression (LLD) is a large public health
challenge: at least 50% of older people fail to respond adequately to antidepressant
pharmacotherapy, even under optimal treatment conditions. Treatment resistant late-life
depression (TRLLD) increases risk for early relapse, undermines adherence to treatment for
coexisting medical disorders, amplifies disability and cognitive impairment, imposes greater
burden on family caregivers, and increases the risk for early mortality, including suicide.
Getting to and sustaining remission is the primary goal of treatment, yet there is a paucity
of controlled studies of how best to manage TRLLD.

This is a multi-site study being conducted by 3 sites: University of Pittsburgh, University
of Toronto, and Washington University. We propose to enroll 500 subjects aged 60 and older
with major depressive disorder at this site and treat them openly for 12 weeks with
venlafaxine XR (up to 300mg/d) (phase 1). Participants meeting criteria for incomplete
response will be randomly assigned to receive either aripiprazole (2-15 mg/d; target dose:
10 mg/d) or placebo augmentation (adding a pill without active medicine) of venlafaxine for
12 weeks (phase 2), with the goal of achieving remission (MADRS≤10 for two consecutive
assessments). Those who remit in phase 2 will receive continuation treatment, with the same
double-blinded intervention to which they were randomly assigned (phase 3), for 12 weeks to
determine the stability of remission. Efficacy and tolerability data will provide a
clinically informative estimate of benefits and risks of aripiprazole augmentation for
TRLLD.

In addition to the primary goal of assessing these benefits and risks, we will develop
evidence relevant to personalized treatment for LLD by testing the roles of clinical
(comorbid anxiety, medical burden, and executive impairment) and genetic (selected
polymorphisms in serotonin, norepinephrine, and dopamine genes) variables, while controlling
for variability in drug exposure for efficacy and tolerability analyses. This approach will
allow us to distinguish treatment-specific resistance factors versus general prognostic
factors.

Inclusion Criteria:

1. Age > 60 years.

2. Major depressive disorder (MDD), single or recurrent, as diagnosed by the SCID-IV.

3. MADRS ≥ 15.

Exclusion Criteria:

1. Inability to provide informed consent.

2. Depressive symptoms not severe enough (i.e., MADRS < 15) at the baseline assessments.

3. Dementia based upon DSM-IV criteria as well as a Folstein MMSE score of less than 24.
Patients screened out due to dementia will be referred to a memory clinic or to the
UPMC Alzheimer's Disease Research Center for evaluation to clarify the presence or
absence of a dementia.

4. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective
disorder, schizophreniform disorder, delusional disorder, or current psychotic
symptoms, as diagnosed by the SCID. A recommendation for psychiatric referral will be
made in these cases.

5. Abuse of or dependence on alcohol or other substances within the past 3 months as
determined by SCID, and confirmed by study physician interview.

6. High risk for suicide (e.g., active SI and/or current/recent intent or plan) AND
unable to be managed safely in the clinical trial (e.g., unwilling to be
hospitalized). Urgent psychiatric referral will be made in these cases.

7. Contraindication to venlafaxine XR or aripiprazole as determined by study physician
including history of intolerance of either venlafaxine XR or aripiprazole in the
study target dosage range (venlafaxine XR at up to 225 mg/day; aripiprazole at up to
15mg/day).

8. Failure to respond to at least 6 weeks of venlafaxine (>225 mg/d) plus aripiprazole
(>10 mg/d).

9. Inability to communicate in English (i.e., interview cannot be conducted without an
interpreter; subject largely unable to understand questions and cannot respond in
English).

10. Non-correctable clinically significant sensory impairment (i.e., cannot hear well
enough to cooperate with interview)

11. Unstable medical illness, including delirium, uncontrolled diabetes mellitus,
hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that
are not under medical management. This will be determined based on information from
the patient's personal physician's and study physician clinical judgment. Referral to
the patient's personal physician or to a general practitioner will be made in these
cases.

12. Subjects taking psychotropic medications that cannot be safely tapered or
discontinued prior to study initiation: this would include patients on Monoamine
Oxidase Inhibitors (MAOI) who would need to be off the MAOI for 14 days to be
eligible for the study to avoid adverse drug interactions. Patients will not be
allowed to take antidepressant or atypical antipsychotic medication other than the
study medication, unless it is a low dose antidepressant prescribed for chronic pain
that would not be medically advisable to stop (e.g., amitryptyline 50mg). If a
patient's depression is adequately treated on his/her psychotropic medication, he/she
would not be eligible for the study. If a patient failed a trial of venlafaxine (12
weeks of treatment with venlafaxine including at least 6 weeks on 300mg/day), he/she
would not be eligible. The following are allowed: benzodiazepines up to 2mg/d
lorazepam equivalent; other sedative-hypnotics (e.g., zolpidem, zaleplon,
eszopiclone); gabapentin if prescribed for non-psychiatric indication (e.g.,
neuropathy). Except for MAOIs, there is really no clinical rationale to exclude
patients on specific concomitant medications unless they are medically unstable (in
which case they are excluded from participation). As noted, patients on an MAOI would
need to be off the MAOI for 14 days to protect from adverse drug interactions.