Aripiprazole as Augmentation for TRD
Condition: Depression
MeSH terms: Depression; Depressive Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      A sizeable minority of patients suffering from major depression do not have their full set of
      depressive symptoms relieved by a single medication. Often times, a second medication is
      added to a patient's first antidepressant to obtain a better response in hopes of getting the
      depressed patient into full remission from symptoms.

      A typical psychiatric approach of recent has been to add one of the newer anti-schizophrenia
      medications to an existing FDA approved antidepressant in order to achieve better serotonin
      levels in the depressed patient's brain. This optimization of brain serotonin helps to
      alleviate more depressive symptoms. The newest antipsychotic medication to be FDA approved is
      Aripiprazole (Abilify). It may be particularly effective as it may safely elevate sertotonin
      through receptor 1a stimulation, receptor 2a blockade. It may also facilitate low levels of
      dopamine transmission which is truly novel for this agent when compared to other
      schizophrenia drugs. Depressed patients also tend to lack dopamine in their brains. This
      makes Aripiprazole and ideal agent to boost both serotonin and dopamine simultaneously. In
      theory, this may be an effective way to alleviate more depressive symptoms.

      The author suggests to enroll 10 subjects initially in open label fashion to take
      Aripiprazole plus their current FDA approved antidepressant to see if further elimination of
      depressive symptoms occurs and to show this pharmacological approach as a tolerable
      combination of medications. If there are no major safety issues, an amendment to allow 10
      additional subjects will be forwarded to provide a better tolerability sample size.
    

Detailed description: 
      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.
    

Intervention name(s): Drug Abilify
Intervention type(s): Drug
Intervention MeSH terms: Aripiprazole
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: depression