N-Acetyl Cysteine and Aspirin as an Adjunctive Treatment for Bipolar Disorder
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      We propose to conduct a double-blind placebo-controlled trial with a widely available and
      prototypical non-steroidal anti-inflammatory agent, aspirin, and an antioxidant agent, NAC,
      involving symptomatic Bipolar Disorder type I and II patients having a depressive or mixed
      episode currently. This will be the first controlled study to test the hypothesis that
      aspirin and NAC, by themselves or in combination, will be beneficial in treating depression
      in bipolar disorder patients and in promoting mood stabilization.

      Our study has the following Aims:

      Aim I - Examine efficacy of aspirin in treating depression in bipolar patients in a
      double-blind placebo-controlled add-on design; Aim II - Examine efficacy of NAC in treating
      depression in bipolar patients in a double-blind placebo-controlled add-on design; Aim III -
      Examine efficacy of combined treatment with aspirin and NAC looking for synergistic,
      potentiating effects; Aim IV - Examine the role of markers of neuroinflammation, as possible
      mediators or modulators in therapeutic response in the treatment of depression in patients
      with Bipolar Disorder.
    

Detailed description: 
      study design: BD type I or II patients (n=160), on a depressive or mixed episode, who were on
      therapeutic doses of any of the commonly utilized mood stabilizing agents (lithium,
      anticonvulsants, atypical antipsychotics) for at least one month and who were still
      symptomatic (MADRAS >20) will be enrolled. Patients will be randomly assigned to orally
      receive one of 4 conditions: aspirin 1000 mg (2 capsules of 500 mg) qam, NAC 1000 mg (2
      capsules of 500 mg) bid, combined aspirin and NAC at same doses as given individually or
      matched placebo, as an add-on medication to their ongoing treatment regimen, for an 16-week
      double-blind trial. After the first 8 week of the double blind treatment, the responders will
      keep taking the same study drug, whichever it is. And the non-responders will be
      re-randomized for one of the other three groups of study drugs they haven't tried yet.

      Procedures to be used:

      The study will be carried out at the outpatient clinics affiliated with the UT Health Science
      Center at Houston. After signing informed consent, patients will be submitted initially to a
      structure psychiatric diagnostic interview(SCID-I) to confirm the psychiatric diagnosis,
      followed by a physical examination and routine labs (CBC, liver function tests, electrolytes,
      kidney functions tests, thyroid function tests, urinalyses) to rule out relevant medical
      problems. Physically healthy BD patients on psychotropic medications or combinations will be
      enrolled and randomly assigned to receive, orally, aspirin 1000 mg qam, NAC 1000 mg bid,
      combination of aspirin 1000 mg qam and NAC 1000 mg bid, or placebo. The study drugs doses
      will remain the same for the duration of the study.

      If patients qualify for the study initially based on SCID-I interview, physical examination,
      and routine labs (CBC, liver functions tests, electrolytes, kidney function tests, thyroid
      function tests, and urinalyses), but are not currently taking an approved psychotropic
      medication or combinations they are eligible to participate in a lead-in phase. This phase
      would be starting at their screening visit and last approximately 6 to 8 weeks depending on
      the patient's mood. During this lead-in phase, either the PI or Co-PI will evaluate the
      patient and prescribe either Lithium or Depakote. The patient will be monitored during this
      treatment phase by the PI or Co-PI and will return after two weeks for an evaluation. The
      evaluation will include the Columbia-Suicide Severity Rating Scale(CSSR-S) to assess risk of
      suicide, the Montgomery-Asberg Depression Rating Scale(MADRAS) to assess the severity of
      depression and the UKU side effects rating scale. If the patient is prescribed lithium, their
      lithium levels will be tested. The patient will continue to follow up every two weeks. At the
      4 week visit, the patient will also come in for evaluation (CSSR-S MADRAS and UKU side
      effects rating scale).

      At the 6 week visit, the patient will be re-evaluated for the double-blind study trial. If
      the patient has been on an adequate dose of the psychotropic medication for at least 4 weeks
      and score greater than 20 on the Montgomery-Asberg Depression Rating Scale (MADRS), then they
      will be enrolled.

      If they do not meet inclusion criteria at the week 6 lead-in phase visit, they will return at
      Week 8 and be re-evaluated. PI and Co-PI will continue to prescribe the psychotropic
      medication throughout the lead-in phase (up to 8 weeks) and through the trial (up to 16
      weeks).

      During the lead-in phase participants will not be compensated. They will receive a voucher
      for their parking for each visit. They will be responsible for filling and paying for all
      prescriptions in both the lead-in phase and through the trial (up to 16 weeks).

      Upon completion of the first 8-week double-blind trial, patients who responded to the active
      medication will continued on the same study drug for an additional 8 week double-blind
      treatment. The non-responders to one of the study drugs will be re-randomized for one of the
      other three groups of study not received and will remain in treatment for an additional 8
      week double-blind treatment. Treatment response will be defined as improvement in the MADRS
      scores of at least 50%.

      During the first 8-week trial, patients will be seen at weeks 0, 1, 2, 3, 4, 6 and 8 for
      clinical assessment and mood ratings. During the continuation trial, they will be seen at
      weeks 8, 10, 12, 14 and 16.

      Routine labs (CBC, liver function tests, electrolytes, kidney functions tests, thyroid
      function tests, urinalyses) will be repeated at week 8 and week 16.

      The main outcome measure for the study will be the scores on the Montgomery-Asberg Depression
      Rating Scale, MADRAS, which assess the severity of depressive symptoms. All patients will
      also be assessed with the Young Mania Rating Scale, YMRS,which assess the severity of manic
      symptoms. the Clinical Global Impression-Bipolar version,severity of illness, CGI-S,which is
      used to measure the severity of depressive, mania and severity overall. And, the UKU
      side-effects scale, which will assess all the side effects related or not to the study group
      treatments. In all visits, patients will be seen by the study psychiatrist and the research
      staff will complete mood ratings with the MADRAS, YMRS, CGI-BD, and the UKU side-effects
      scale.

      At baseline (before randomization), week 8 and week 16 blood will be sampled for
      proinflammatory markers (C-reactive protein, soluble interleukin (IL)-2 receptor, IL-6 and
      tumor necrosis factor (TNF)-alpha), and oxidative stress markers (superoxide dismutase
      activity and catalase activity, serum thiobarbituric acid reactive substances (TBARS), which
      have been reported to be elevated in BD patients. These blood samples will be stored for
      possible future research on biomarkers or future genetic studies for up to 20 years, for use
      in pharmacogenetic research during this 20 year timeframe. The samples will be stored at the
      Wet Lab, in a double locked -80 degrees freezer, at BBSB, Department of Psychiatry at
      University of Texas Health Science Center at Houston. (1941 East Road, suite# 3170 Houston-TX
      77054) for future use studying factors of Bipolar Disorder. When (or before) the 20 year
      period ends, the blood sample will be destroyed.

      At the screening visit, week 8, and week 16 we will also be testing the Lithium levels in all
      patients that have been prescribed and currently taking the medication for study purposes.
      This extra test will be conducted for the safety of the patient and more Lithium level tests
      can be ordered under the PI's discretion throughout the 16 week trial.

      Risks and potential benefits:

      Aspirin is a safe medication for administration to humans and is approved by the FDA as an
      anti-inflammatory and analgesic agent. The dose proposed for this study is within the safety
      range as per medication package. Its side-effect profile is overall very favorable and it has
      met widespread use worldwide over the past decades. The main safety issues relate to the
      possibility of gastrointestinal complications, which are rare (and will be closely monitored
      in the weekly or biweekly visits that the study requires), and the propensity to interfere
      with coagulation and cause consequent bleeding (which will be prevented by excluding any
      individuals on use of anticoagulants or with active bleeding problems). There were a few case
      reports and small case series with other non-steroidal anti-inflammatory agents suggesting
      worsening of depressive symptoms related to treatment (e.g., indomethacin, ibuprofen,
      naproxen), but those were uncontrolled reports with individuals who suffered from other
      medical illnesses (rheumatologic diseases).

      For our proposed trial, because some patients may be on lithium at the time they start on
      aspirin, we will exclude individuals with pre-existing cardiac and kidney disease. For
      patients on lithium, we will carefully monitor their serum lithium levels every two weeks
      during the course of the trial. Therefore, at the doses that are being proposed we do not
      anticipate any significant problems related to safety of the proposed intervention.

      NAC is a safe compound that is commonly available and utilized over-the-counter. In a recent
      study the tolerability was excellent and main side effects included changes in energy level,
      headaches, heartburn and joint pain

      Blood Draws: When the blood is drawn, there may be some minimal discomfort and/or bruising.
      Infection, excess bleeding, clotting, or fainting is also possible, although unlikely. All
      usual precautions will be taken to prevent these possibilities and these risks will be
      minimized by using trained staff to perform the blood draws

      Subjects will be carefully monitored. If a subject's condition worsen to the point that
      he/she might become suicidal or severely depressed, we will terminate the subject's
      participation in the study and referred to his/her psychiatrist for psychiatric treatment.

      Breach of Confidentiality: Every effort will be made to protect the subject identity and
      information during the study. All lab work and scan reports will be de-identified and the
      medical records will be protected. However, there is a small chance that the subject
      information may be viewed by someone that is not involved in the research study.

      The study drug must be taken only by the person for whom it has been prescribed, and it must
      be kept out of the reach of children or persons of limited capacity to read or understand.

      By sharing your sample with the study doctor, there is a risk of the possible loss of the
      subject privacy. Although no identifiable (name, address, etc.) information will be shared
      with others outside of this research project. The clinical information obtained from subjects
      will be part of their medical records and maintained at UT Center of Excellence on Mood
      Disorders, in the Department of Psychiatry at UTHSC-H, in facilities with adequate safeguards
      for the protection of confidentiality. The research data will be collected and recorded using
      only arbitrary code numbers for identification, in order to safeguard the confidentiality.
      All data will be kept in a secure area. Only the members of the UT Center of Excellence on
      Mood Disorders research group, who will get approval from CPHS, will have access to the data
      files, or to the master list for the codes. For publications purposes, the patients will be
      designated only by their assigned codes.

      These blood samples, for use in pharmacogenetic research during this 15 year timeframe,
      samples will be stored at the Wet Lab, in a double locked -80 degrees freezer, at BBSB,
      Department of Psychiatry at University of Texas Health Science Center at Houston. (1941 East
      Road, suite# 3170 Houston-TX 77054) The possibility exists that the subject information may
      be taken and used for reasons outside of this project. The United States' Genetic Information
      Nondiscrimination, Act (GINA) of 2008, does not allow for employers or health insurance
      companies to discriminate against the research subject based on his/her genetic information.
      This means that health insurance companies or employers are NOT ALLOWED BY LAW to ask or use
      any of the subject genetic information (DNA, RNA, etc.) gained through testing to make
      decisions that affect the subject or hisher family's health coverage or income in a negative
      way

      Importance of knowledge that may reasonably be expected to result:

      The study will examine possible novel mechanism of actions with modulation of inflammatory
      mechanisms and oxidative stress and could result in the development of novel, low cost, safe
      and widely available treatments for BD patients who have not responded to other commonly
      utilized alternatives
    

Intervention name(s): Aspirin; N-acetyl-cysteine (NAC); Sugar Pill
Intervention type(s): Drug; Dietary Supplement; Drug
Intervention description(s): aspirin 1000mg (2 capsules of 500mg) every morning in addition to his/her antidepressant and/or mood stabilizer medicine; taking N-acetyl-cysteine (NAC) 1000mg (2 capsules of 500mg) two times a day in addition to his/her antidepressant and/or mood stabilizer medicine; research subject will be taking placebo in addition to his/her antidepressant and/or mood stabilizer medicine
Other intervention name(s): Ecotrin; Bayer Aspirin; Bufferin; Acetylsalicylic Acid; Acetylcysteine; N-Acetyl Cysteine; NAC
Intervention MeSH terms: Aspirin; Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Bipolar Disorder; Mood Disorder; Bipolar Depression; Mood Swings