Effectiveness of Methylphenidate in Improving Cognition and Function in Older Adults With Depression

Less than 50% of older adults with depression achieve remission and functional recovery in
response to first-line antidepressant treatment. Most are left with significant residual
symptoms, putting them at risk for illness relapse, frailty, and suicide. Improved
understanding of the neurobiology of depression in older adults and mechanisms of treatment
response may lead to better clinical management of depression. Methylphenidate (MPH) has long
been used in the elderly and the medically ill to provide rapid improvement in depression,
apathy, and fatigue. However, its potential beneficial effects on cognitive and functional
outcomes in older adults with depression have not been studied. Combining MPH with the
serotonergic antidepressant citalopram may result in better clinical outcomes than would
using citalopram alone. This study will compare the safety and effectiveness of MPH combined
with citalopram, MPH combined with placebo, and citalopram combined with placebo in improving
thinking, memory, and speed of recovery in older adults with depression. The study will also
evaluate selected dopamine- and serotonin-related gene relationships with mood, cognitive
symptoms, and treatment response to MPH and citalopram.

Participation in this double-blind study will last 16 weeks. All potential participants will
initially undergo comprehensive medical, neuropsychiatric, and cognitive assessments and
genetic testing. These initial assessments will include questionnaires about depressive
symptoms, a medical history, an electrocardiogram (ECG), and a blood draw for the genetic
testing. Eligible participants will then be randomly assigned to one of three groups: MPH and
citalopram, MPH and placebo, or citalopram and placebo. All participants will receive 16
weeks of treatment with their assigned medications. Study visits will occur weekly for the
first 6 weeks of treatment and bi-weekly for the remainder of the study. During study visits,
participants will undergo vital sign and weight measurements, answer questionnaires, and
report any medication side effects. Blood will again be drawn at Visits 4 and 10, and the ECG
will be repeated at Visit 10 if any cardiac symptoms occur. Most initial assessments will be
repeated on Visit 13, the last study visit. Participants will also be contacted weekly by
phone throughout the study to answer questions on how they are feeling and any possible side
effects.

Inclusion Criteria:

- Meets Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for
major depressive disorder (recurrent and nonrecurrent course will be identified)

- Score of 16 or higher on the 24-item Hamilton Depression Rating Scale (HDRS) at study
entry

- Score of 26 or higher on the Mini-Mental State Exam (MMSE)

Exclusion Criteria:

- History of psychiatric illness or a substance abuse disorder other than unipolar
depression, diagnosed prior to the onset of the first depressive episode

- Presence of psychotic symptoms

- Severe or acute medical illness (e.g., major surgery, metastatic cancer, stroke, heart
attack) 6 months prior to study entry

- Acute suicidal or violent behavior or history of suicide attempt within the year prior
to study entry

- Presence of delirium, neurodegenerative dementia, Parkinson's disease, or any other
central nervous system (CNS) diseases

- Toxic or metabolic abnormalities on laboratory examination

- Medications taken or medical illnesses present that could account for depression

- Active heart failure categorized as Class III or greater according to New York Heart
Association criteria

- Heart attack or crescendo angina within the 3 months prior to study entry

- Symptomatic cardiac arrhythmias or symptomatic, hemodynamically significant mitral or
aortic valvular disease

- Resting heart rate less than 50 beats per minute and a corrected QT (QTc) interval
greater than 0.45 seconds

- Second or third degree atrioventricular block

- Systolic blood pressure greater than 180 mmHg or less than 90 mmHg and diastolic blood
pressure greater than 105 mmHg or less than 50 mmHg at study entry

- Treated with depot neuroleptic therapy within 6 months prior to study entry

- Treated with any neuroleptic, antidepressant, anxiolytic medication (other than
lorazepam), or over-the-counter CNS-active medications used for treatment of
depression (e.g, St. John's Wort, kava-kava, melatonin) within 2 weeks (4 weeks for
fluoxetine or monoamine-oxidase inhibitors (MAOIs)) prior to the first administration
of study medication

- Known allergy to citalopram or MPH or history of ineffective treatment with citalopram
or MPH for current depressive episode

- Requires concomitant therapy with any prescription or over-the-counter medications
that have potentially dangerous interactions with either citalopram or MPH

- Requires electroconvulsive therapy (ECT) or received ECT within 3 months prior to
study entry

- Initiated psychotherapy within 3 months prior to study entry or will be initiating or
terminating psychotherapy during the study