This is a prospective, open-label study that will examine the clinical utility and safety of adding the atypical antipsychotic aripiprazole as an augmenting agent to antidepressant therapy in treatment-resistant depressed patients. The author's a priori hypothesis is that aripiprazole plus a current FDA approved antidepressant will result in significant reductions in depressive symptoms over 6 weeks. Responders (>50% improvement in baseline HAM-D score) will be asked to voluntarily continue in a 6 week open-label extension in order to show that antidepressant effects of aripiprazole are longstanding in nature.

After screening and consenting and liaison with a primary prescriber, 10 eligible subjects will receive aripiprazole 10-30 mg per day as an augmentation agent in combination with their current FDA approved antidepressant medication. The dose of the subject's original antidepressant will remain unchanged during the study unless subject notes intolerable newly emergent antidepressant-related side effects. Based on tolerability and response, aripiprazole will be started at 5 mg per day and augmented as follows (baseline, end of week 1, end of week 2, end of week 4, and termination visit end of week 6) at 5 mg per day increments, the maximum dose being 30 mg per day for patients who are taking antidepressants that have no pre-existing significant inhibitory effect on CYP450 2D6 enzyme system. However, if the patient is taking any antidepressant that has significant CYP450 2D6 enzyme inhibitory properties, that may affect the metabolism of aripiprazole (e.g. paroxetine, fluoxetine), the maximum dose will be 15 mg per day (50% less than the maximum recommended dose). These dose ranges have been chosen because they capture the mean effective dose for ameliorating depressive symptoms in schizophrenia. The dose will be titrated upward or downward based on clinical response. Other psychotropic medications will be permitted during the study if deemed necessary to control side effects (hypnotics, anxiolytics, antimuscarinics, beta blockers, etc.). Subjects who have been on a stable dose of hypnotic or anxiolytic (GABA or Histamine-based) for at least 4 weeks prior to study entry may opt to continue these at current dose or be washed out prior to study start. Aripiprazole will be dispensed biweekly and the participants will be followed for 6-weeks. Participants will be monitored every other week by the HAMD (blinded), CGI, and SAFTEE. Vital signs and weight will also be taken at each visit. After 6 weeks, there will be a two-week taper of aripiprazole (50% reduction in dose per week). Compliance will be measured by pill count All subjects will be voluntarily offered to stay in the study for an additional six weeks where they will meet one final time at the end of week 12 to re-evaluate safety and effectiveness of longer term aripiprazole augmentation. Subjects would then go through a two week taper as above. Subjects who do not wish to continue an additional six weeks may opt out of the study at the original 6 week termination mark. If interim safety analysis (by independent psychiatrist TBD) suggests good safety profile and amendment will be sent to the IRB asking for 10 additional subjects to be enrolled.

Primary and secondary measures and safety evaluations: The primary measures of the study will be changes in HAMD scores over time (we will monitor this to make sure depression scores do not worsen with aripiprazole); the secondary efficacy measure will be changes in CGI scores over time. Safety evaluations will be determined by the SAFTEE rating scale and patient AE reports. An Expectancy Scale will be given to determine if subjects' level of perceived confidence in the drug correlates to the outcomes noted above. This is a superficial way to look at placebo-like rates when placebo is not used in the study.