Brexpiprazole for Bipolar Depression
Condition: Bipolar Depression
MeSH terms: Depression; Depressive Disorder; Bipolar Disorder
Study type: Interventional
Phase: Phase 4

Summary: 
      The investigators will conduct an 8-week, non-randomized, open-label study of brexpiprazole
      in 20 persons with bipolar I or II disorder, depressed mood state. Primary aim will be to
      assess if brexpiprazole is associated with a reduction in depressive symptom severity using
      the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary aims will include an
      assessment of the following in patients with bipolar disorder taking brexpiprazole: manic
      symptoms, cognition, safety and tolerability of brexpiprazole, and quality of life.

      Subjects will be discontinued from the study if any of the following conditions occurs:
      change in diagnosis to other than bipolar I or II disorder, development of active suicidal or
      homicidal ideation with plan and intent, worsening of mood symptoms, that in the opinion of
      the investigators requires discontinuation, pregnancy, development of severe life-threatening
      medical condition, involuntary psychiatric hospitalization or incarceration.
    

Detailed description: 
      We will conduct an 8-week, non-randomized, open label study of brexpiprazole in 20 persons
      with bipolar disorder. Primary Aim will be to determine if brexpiprazole is associated with a
      reduction in depressive symptom severity using the Montgomery-Asberg Depression Rating Scale
      (MADRS) in outpatients with bipolar disorder, depressed mood state. Secondary Aims will be:
      1) Assess manic symptoms in patients with bipolar disorder receiving brexpiprazole, 2) Assess
      cognition in patients with bipolar disorder receiving brexpiprazole, 3) Assess the safety and
      tolerability of brexpiprazole in patients with bipolar disorder, 4) Assess quality of life in
      patients with bipolar disorder receiving brexpiprazole. Subjects will be discontinued from
      the study if any of the following conditions occurs: change in diagnosis to other than
      bipolar I or II disorder, development of active suicidal or homicidal ideation with plan and
      intent, worsening in mood symptoms, that in the opinion of the investigators requires
      discontinuation, pregnancy, development of severe or life-threatening medical condition,
      involuntary psychiatric hospitalization or incarceration.

      Study Procedures:

      Baseline: This visit will be split into two portions: Baseline 1 and Baseline 2.

      For Baseline 1 (~3 hours), the psychiatric diagnosis will be confirmed by the structured
      clinical interview for DSM-5 (SCID), mood assessed via the Montgomery-Asberg Depression
      Rating Scale (MADRS), depression via the Inventory of Depressive Symptomatology Self-Report
      (IDS-SR30), mania via the Young Mania Rating Scale, and quality of life via the Quality of
      Life in Bipolar Disorder (QOLBD). Blood will be drawn for complete blood count (CBC),
      Comprehensive Metabolic Panel (CMP, includes a liver panel with AST, ALT, as well as lipids),
      and high-sensitivity c-reactive protein (hs-CRP). A urine sample for drug screen and
      pregnancy test (if applicable), psychiatrist assessment, physical exam, collection of weight
      and vitals will be completed.

      For Baseline 2 (~2 hours), recent depressive symptoms will be assessed via the IDS-SR30 and
      MADRS, mania via the YMRS, current mood via Internal State Scale (ISS), suicidal ideation
      will be assessed via the Columbia Suicide Severity Rating Scale (CSSRS), safety and side
      effects will be assessed with the SAFTEE, the Abnormal Involuntary Movement Scale (AIMS),
      Barnes Akathisia Scale (BAS) and Simpson-Angus Scale (SAS). Subjects will also complete the
      The Ray Auditory Verbal Learning Test (RAVLT) to assess word memory, the Stroop test to
      measure attention, speed, and accuracy of thinking, and The Trail Making Test (TMT) to
      measure attention, speed and accuracy. A urine sample for drug screen and pregnancy test (if
      applicable) will also be completed. Brexpiprazole capsules will be initiated at 0.5 mg/day.

      Baseline 2 to Week 1: Subjects will be given the ISS to fill out at home. Subjects will be
      asked to complete the scale at home on 7 consecutive days between Baseline 2 and Week 1
      visits and return the filled out scales to the researcher's office. The scale will take
      approximately 3-5 minutes to fill out.

      Week 1, 2, 3, 6 (~1.5 hours each): Subjects will complete the MADRS, YMRS, IDS-SR30, ISS,
      SAFTEE, CSSRS, AIMS, BAS, SAS, and a urine sample will be collected for a drug screen.
      Subjects will meet with the psychiatrist for weekly assessment and vitals will be collected.

      Week 4 (~2 hours): Subjects will complete the MADRS, IDS-SR, YMRS, SAFTEE, ISS, C-SSRS, AIMS,
      BAS, SAS, RAVLT, Stroop, TMT, vital signs, a urine sample for a drug screen and a urine
      pregnancy test, and visit the doctor for a psychiatric evaluation.

      Week 8 (final visit ~2.5 hours): Subjects will complete the MADRS, IDS-SR, YMRS, SAFTEE, ISS,
      C-SSRS, AIMS, BAS, SAS, RAVLT, Stroop, TMT, QOLBD, vital signs, a urine sample for drug
      screen, take a urine pregnancy test, have blood drawn for clinical testing (CBC, CMP,
      hs-CRP), and visit the doctor for a psychiatric evaluation and physical exam. During this
      visit, participants will also be provided with aftercare referral information and will begin
      their medication taper. The medication taper schedule is described below under "Study
      Medication and Intervention Description".

      Safety Phone Call (~15 min): Participants will receive a phone call from researchers 7-10
      days following their Week 8 study visit (at the end of their tapering schedule). During this
      phone call, the researchers will assess any withdrawal effects or adverse events and check on
      the status of the aftercare referrals.

      Participants will be paid for their time and inconvenience per visit as follows: $60 at
      Baseline 1, Baseline 2, weeks 1, 2, 3, 6; $70 at week 4; $90 for week 8. Participants will
      also be paid for each ISS scale they bring back at the rate of $1 per scale (maximum $7).
      These payments will be processed during Week 1 visit. These payments will be completed via
      the ClinCard system. Bus or rail passes will be provided. After study completion, standard
      psychiatric care will be provided until referral is arranged.

      Study Medication and Intervention Description:

      Participants will be initiated on a 0.5 mg/day brexpiprazole dose (week 0/baseline); after
      one week the dose will be increased to 1 mg/day (week 1), after another week to 2 mg/day
      (week 2). If any dose appears to be poorly tolerated, the dose titration can be slowed or
      stopped based on clinician judgment. If response in weeks 3-6, defined as a 50% reduction in
      the MADRS, has not been achieved, and the current dose is well tolerated, then additional
      dose increases to 3 mg/day and 4 mg/day (maximum allowed dose in protocol) will occur with at
      least a one week interval between dose increases.

      Following the last study visit (Week 8), participants will be gradually tapered off the
      medication every 2 days until they stop taking the medication completely. For example, if a
      participants takes 4 mg of brexpiparzole at Week 8, then he/she will take 3 mg for 2 days,
      then 2 mg for 2 days, then 1 mg for 2 days, and then 0.5 mg for 2 days. At the end of the
      tapering period (7-10 days depending on the highest brexpiprazole dose at the end of the
      study), participants will receive a safety phone call from a research staff member to assess
      any withdrawal symptoms and check on the status of the aftercare referrals.

      Biostatistics:

      Primary Aim: Determine if brexpiprazole is associated with a reduction in depressive symptom
      severity in outpatients with bipolar disorder, depressed mood state.

        1. The MADRS will be the primary outcome measure with the IDS-SR as a secondary outcome
           measure. Weekly scores on the MADRS and IDS-SR will be assessed using one-way repeated
           measures. Analysis of Covariance (rm-ANCOVA), controlling for age and sex as potential
           confounding variables, with time as the main effect. Participants will be included if
           they complete one post-baseline assessment (intent-to-treat sample). In addition, rates
           of depression response (≥ 50% reduction from baseline) and remission (≤10 on the MADRS
           and ≤12 on the IDS-SR) will be assessed. A significance level of 0.05 will be set for
           all analyses, with all tests being two-tailed.

           Secondary Aims:

        2. Assess manic symptoms in patients with bipolar disorder receiving brexpiprazole. YMRS
           scores will be assessed as with the primary aim above.

        3. Assess cognition in patients with bipolar disorder receiving brexpiprazole. Scores on
           the RAVLT, Stroop and TMT will be assessed at baseline compared to weeks 4 and 8
           separately using paired t-tests or paired-sample Wilcoxon Signed Rank test.

        4. Assess the safety and tolerability of brexpiprazole in patients with bipolar disorder.
           Scores on the SAFTEE, C-SSRS, AIMS, BAS and SAS will be assessed as with the primary
           aim.

        5. Assess quality of life in patients with bipolar disorder receiving brexpiprazole. The
           QOLBD will be assessed as above for cognition.

        6. Assess peripheral inflammation in patients with bipolar disorder receiving
           brexpiprazole. Values on hs-CRP will be compared between baseline and exit as with
           cognition above.

        7. Assess relationships between changes in outcomes measures. Correlations between outcome
           measures (e.g. depressive symptoms and cognition, depressive symptoms and inflammation)
           will be assessed using Pearson's or Spearman's correlation coefficients.
    

Intervention name(s): Brexpiprazole
Intervention type(s): Drug
Intervention description(s): Brexpiprazole is an atypical antipsychotic drug that is used to treat mental/mood disorders.
Other intervention name(s): Rexulti
Intervention MeSH terms: Brexpiprazole
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: mood; bipolar; depression