Due to limited study staff and the COVID-19 pandemic, enrollment has been paused as staff hours for this project have been reduced and reallocated to other projects.

The purpose of the Pilot Study Investigating the Efficacy of Minocycline and n-acetylcysteine for Bipolar Depression is to test the effectiveness of minocycline, n-acetylcysteine, and combined minocycline and n-acetylcysteine pharmacotherapy in order to fill the gap in treatments for bipolar depression. The treatment of bipolar depression remains the greatest unmet need in the management of this lifelong and chronic psychiatric disorder.

The investigators are doing this research study to find out if minocycline alone, N-acetyl cysteine (NAC) alone, or the combination of minocycline and NAC can help people with bipolar depression when added to lithium. The investigators also want to find out if minocycline, NAC, and the combination of minocycline and NAC are safe to take without causing too many side effects.

While the U.S. Food and Drug Administration (FDA) has approved minocycline to treat infections and acne and has approved NAC as a mucolytic, the FDA has not approved minocycline, n-acetylcysteine, or the combination of minocycline and n-acetylcysteine to treat bipolar depression.

This research study will compare minocycline, n-acetylcysteine, and the combination of n-acetylcysteine and minocycline to placebo. The placebo looks exactly like the other study drugs, but contains neither minocycline nor NAC. During this study participants may get a placebo instead of minocycline, n-acetylcysteine, or the combination of minocycline and n-acetylcysteine. Placebos are used in research studies to see if the results are due to the study drug or due to other reasons.

Inclusion Criteria:

1. Able to give written informed consent and follow study procedures
2. Age > or = 18 years and < or = 65 years
3. Meets Diagnostic and Statistical Manual of Mental Disorders V (DSM-V) criteria for Bipolar Disorder Type I, which is the primary focus of treatment
4. Currently depressed, as defined by a Montgomery-Asberg Depression Rating Scale (MADRS) score of > or = 18 at screen and baseline (randomization)
5. Participants will remain on baseline mood stabilizer pharmacotherapy with lithium during the study. They will need to have been on lithium with stable therapeutic blood levels for at least two weeks prior to randomization and agree not to change medications during the study.
6. Women of child bearing potential must agree to use adequate contraception (e.g. oral contraceptives, intrauterine device, double barrier methods), if sexually active. Depo Provera is acceptable if it is started 3 months prior to enrollment. If hormonal contraceptives are used, participants must also agree to use a backup method of birth control. They will also need to understand the risks of lithium and other study treatments to the fetus and infant.

Exclusion Criteria:

1. Unwilling or unable to comply with study requirements
2. Patients who are a serious suicide or homicide risk, or currently in crisis such that inpatient hospitalization or other crisis management should take priority
3. DSM-V diagnosis of Bipolar Disorder not otherwise specified, cyclothymia, schizoaffective bipolar type
4. Primary anxiety disorders (e.g. Panic disorder, generalized anxiety disorder, post-traumatic stress disorder) or patients where the anxiety disorder is the primary focus of treatment
5. Any history of obsessive compulsive disorder (OCD) or OCD-spectrum disorders
6. Clinical or laboratory evidence of hypothyroidism; if maintained on thyroid medication must be euthyroid for at least 1 month before Visit 1
7. Subjects having failed two or more trials of somatic therapy (i.e. medications for bipolar depression or Food and Drug Administration-approved devices) during the current bipolar depressive episode
8. Drug/alcohol abuse or dependence active within the past 3 months, or current substance use disorder that requires detoxification
9. Pregnancy (as determined by urine pregnancy test)
10. Suspected or known clinically unstable systemic medical disorder including epilepsy, untreated endocrine disease, unstable angina, recent ulcers or significant esophagitis
11. Conditions which may be negatively affected by minocycline treatment, such as inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease)
12. History of significant treatment non-adherence or situations where the subject is unlikely to adhere to treatment, in the opinion of the investigator
13. Current use of minocycline or history of anaphylactic reaction or intolerance to minocycline or any component of the preparation
14. Current use of greater than 500mg of NAC/day, 200ug of selenium/day or 500 IU of Vitamin E/day
15. History of anaphylactic reaction or intolerance to NAC or any component of the preparation
16. A primary clinical diagnosis of a personality disorder, or comorbid diagnosis of antisocial or borderline personality disorder
17. A history of C. difficile colitis
18. A history of tetracycline allergy
19. Liver enzymes above the upper limit of normal