N-Acetyl Cysteine and Aspirin as an Adjunctive Treatment for Bipolar Disorder

NCT01797575 | Completed Phase 2 Results FDA Drug

• 3 other identifiers: HSC-MS-12-0046SMRISMRI#11T-009
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Bipolar Disorder

Keywords

Bipolar Disorder; Mood Disorder; Bipolar Depression; Mood Swings

Outcome Measures

Primary Outcomes (4)

• Number of Patients Demonstrating a > 50% Decrease in Depression Scores on the Montgomery-Åsberg Depression Rating Scale (MADRS)

  The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions on the following symptoms: 1. Apparent sadness; 2. Reported sadness; 3. Inner tension; 4. Reduced sleep; 5. Reduced appetite; 6. Concentration difficulties; 7. Lassitude; 8. Inability to feel; 9. Pessimistic thoughts; and 10. Suicidal thoughts.

  Received drug for 8 weeks during week 0 to week 8 of the study

• Number of Patients Demonstrating a > 50% Decrease in Depression Scores on the Montgomery-Åsberg Depression Rating Scale (MADRS)

  The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions on the following symptoms: 1. Apparent sadness; 2. Reported sadness; 3. Inner tension; 4. Reduced sleep; 5. Reduced appetite; 6. Concentration difficulties; 7. Lassitude; 8. Inability to feel; 9. Pessimistic thoughts; and 10. Suicidal thoughts.

  Received drug for 8 weeks during week 9 to week 16 of the study

• Number of Patients Demonstrating a > 30% Decrease in Depression Scores on the Montgomery-Åsberg Depression Rating Scale (MADRS)

  The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions on the following symptoms: 1. Apparent sadness; 2. Reported sadness; 3. Inner tension; 4. Reduced sleep; 5. Reduced appetite; 6. Concentration difficulties; 7. Lassitude; 8. Inability to feel; 9. Pessimistic thoughts; and 10. Suicidal thoughts. This 30% MADRS reduction was analyzed in addition to initial outcome measures of 50% MADRS reduction due to the smaller than expected study sample size.

  Received drug for 8 weeks during week 0 to week 8 of the study

• Number of Patients Demonstrating a > 30% Decrease in Depression Scores on the Montgomery-Åsberg Depression Rating Scale (MADRS)

  The MADRS is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions on the following symptoms: 1. Apparent sadness; 2. Reported sadness; 3. Inner tension; 4. Reduced sleep; 5. Reduced appetite; 6. Concentration difficulties; 7. Lassitude; 8. Inability to feel; 9. Pessimistic thoughts; and 10. Suicidal thoughts. This 30% MADRS reduction was analyzed in addition to initial outcome measures of 50% MADRS reduction due to the smaller than expected study sample size.

  Received drug for 8 weeks during week 9 to week 16 of the study

Secondary Outcomes (7)

• Inflammation as Indicated by C-reactive Protein (CRP) Levels

  baseline, week 8, week 16

• Inflammation as Indicated by Interleukin 6 (IL-6) Levels

  baseline, week 8, week 16

• Inflammation as Indicated by Soluble Interleukin-2 (IL-2) Receptor Levels

  baseline, week 8, week 16

• Inflammation as Indicated by Tumor Necrosis Factor (TNF)-Alpha Levels

  baseline, week 8, week 16

• Oxidative Stress as Indicated by Superoxide Dismutase Activity

  baseline, week 8, week 16

Study Arms (4)

Aspirin

ACTIVE COMPARATOR

research subject will be taking aspirin 1000mg (2 capsules of 500mg) every morning in addition to his/her mood stabilizing drug (lithium, anticonvulsants, any atypical antipsychotics) or combinations

Drug: Aspirin

N-acetyl-cysteine

ACTIVE COMPARATOR

research subject will be taking N-acetyl-cysteine (NAC) 1000mg (2 capsules of 500mg) two times a day in addition to his/her mood stabilizing drug (lithium, anticonvulsants, any atypical antipsychotics) or combinations

Dietary Supplement: N-acetyl-cysteine (NAC)

Aspirin and NAC

ACTIVE COMPARATOR

research subject will be taking aspirin 1000mg (2 capsules of 500mg) every morning and NAC 1000mg (2 capsules of 500mg) two times a day in addition to his/her mood stabilizing drug (lithium, anticonvulsants, any atypical antipsychotics) or combinations.

Drug: Aspirin; Dietary Supplement: N-acetyl-cysteine (NAC)

Sugar Pill

PLACEBO COMPARATOR

research subject will be taking 4 capsules of matching sugar pill( placebo) in the morning and 2 capsules of matching placebo in the evenings in addition to his/her mood stabilizing drug (lithium, anticonvulsants, any atypical antipsychotics) or combinations

Drug: Sugar Pill

Interventions

Aspirin DRUG

aspirin 1000mg (2 capsules of 500mg) every morning in addition to his/her antidepressant and/or mood stabilizer medicine

Also known as: Ecotrin, Bayer Aspirin, Bufferin, Acetylsalicylic Acid

Aspirin; Aspirin and NAC

N-acetyl-cysteine (NAC) DIETARY_SUPPLEMENT

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

Also known as: Acetylcysteine, N-Acetyl Cysteine, NAC

Aspirin and NAC; N-acetyl-cysteine

Sugar Pill DRUG

research subject will be taking placebo in addition to his/her antidepressant and/or mood stabilizer medicine

Sugar Pill

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to 65 years
• A diagnosis of BD type I or II according to SCID-I interview;
• Currently in a depressive or mixed episode, based on DSM-IV/ SCID-I criteria;
• MADRAS \>20 at entry in the study;
• No CURRENT liver, kidney, heart disease or ulcers or bleeding dyscrasia;
• No HYSTORY of kidney dysfunction or cardiac problems;
• ON therapeutic doses of a mood stabilizing drug (lithium, anticonvulsants, any atypical antipsychotics) or combinations for at least ONE month.
• Allowed psychiatric co-morbid conditions, such as anxiety disorders, PTSD and substance use (as long as do NOT meet abuse or dependence criteria according to the SCID-I in the past 2 months).

You may not qualify if:

• CANNOT be on any :
• Anti-inflammatory: NSAIDs: Aspirin (bufferin, bayer aspirin, ecotrin), diflunisal (dolobid, diflunisal),Salsalate (amigesic, salflex), Ibuprofen (motrin, advil), Naproxen (naprosyn,aleve, midol extended relief), Fenoprofen (nalfon), Ketoprofen (actron), dexketoprofen(ketron D), Flurbiprofen (ansaid), Oxaprozin (daypro), Loxoprofen (loxfen, loxonin), Indomethacin (indocin, indocin SR), Sulindac (clinoril), Etodolac (lodine), Ketorolac (toradol), diclofenac (voltaren, cataflam), Nabumetone (Relafen) Piroxicam (feldene), Meloxicam (mobic), Tenoxicam (mobiflex), Lornoxicam (xefo),mefenamic acid (ponstel), meclofenamic acid (meclofenamate sodium), celecoxib (celebrex) Anticoagulants: Coumadin (Warfarin), Heparin Anti-oxidant agents Fish oil NAC ( N-acetyl cysteine)
• Pregnancy
• CANNOT change the dose of the psychotropic medications during the trial
• Women Able to Become Pregnant: Participation in this study may involve risks to an embryo, fetus, or unborn child. If the subject is a female and able to become pregnant, a urine pregnancy test will be performed which must be negative prior to enrolling into the study, and the subject must agree not to become pregnant during the study. Urine pregnancy tests will be performed at Screening visit and week 8. The study staff will review adequate birth control methods with the subject and will remind her that she should not become pregnant during the study. Appropriate methods of birth control include: hormonal contraceptives (such as birth control pills, patches, and implants), barrier methods (such as a condom and diaphragms and spermicidal foam or jelly, surgical (hysterectomy or tubal ligation) or intrauterine device (IUD). The subject will be instructed to notify the study doctor immediately if there is a chance that she has become pregnant.
• Also, if the subject is breast-feeding an infant or plan on breast-feeding an infant, she must notify the study doctor. It is not known if this drug is excreted in human milk; therefore, breast-feeding is not permitted during the study.
• Patients can be on any mood stabilizing agents or combinations, as well as on other psychotropic medications at study entry, and the doses of those medications cannot be changed during the trial. They cannot be on any anti-inflammatory or anti-oxidant agents or anticoagulant at the point they are enrolled. If patients decompensate significantly, and/or become acutely suicidal, participation on the trial will be terminated.

Sponsors & Collaborators

• The University of Texas Health Science Center, Houston: lead
• Stanley Medical Research Institute: collaborator

Study Sites (1)

UT Center of Excellence on Mood Disorders

Houston, Texas, 77054, United States

Location

Related Publications (2)

• Dean RL, Marquardt T, Hurducas C, Spyridi S, Barnes A, Smith R, Cowen PJ, McShane R, Hawton K, Malhi GS, Geddes J, Cipriani A. Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder. Cochrane Database Syst Rev. 2021 Oct 8;10(10):CD011611. doi: 10.1002/14651858.CD011611.pub3.

  PMID: 34623633 DERIVED

• Bauer IE, Green C, Colpo GD, Teixeira AL, Selvaraj S, Durkin K, Zunta-Soares GB, Soares JC. A Double-Blind, Randomized, Placebo-Controlled Study of Aspirin and N-Acetylcysteine as Adjunctive Treatments for Bipolar Depression. J Clin Psychiatry. 2018 Dec 4;80(1):18m12200. doi: 10.4088/JCP.18m12200.

  PMID: 30549489 DERIVED

Related Links

• UT Center of Excellence on Mood Disorders at Houston

MeSH Terms

Conditions

Bipolar Disorder; Mood Disorders

Interventions

Aspirin; Acetylcysteine; Sugars

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Amino Acids; Amino Acids, Peptides, and Proteins; Carbohydrates

Limitations and Caveats

Mild to moderately severe depressive symptoms at baseline (therapeutic effects of NAC and Aspirin would have been different in more depressed sample). Small sample size (findings lack the required precision in estimates of effect).

Results Point of Contact

• Title: Jair C Soares, MD
• Organization: The University of Texas Health Science Center at Houston

jair.c.soares@uth.tmc.edu

713-486-2627

Study Officials

• Jair C Soares, MD

  The University of Texas Health Science Center, Houston

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor & Chairman - PSY-Behavioral Sciences

Study Record Dates

• First Submitted: June 8, 2012
• First Posted: February 22, 2013
• Study Start: January 1, 2013
• Primary Completion: February 1, 2017
• Study Completion: February 1, 2017
• Last Updated: April 30, 2018
• Results First Posted: April 30, 2018

Record last verified: 2018-03

Locations

US (1)