Inclusion Criteria:
1. Provision of signed and dated informed consent form
2. Has an established residence and phone
3. Agrees to and is eligible for behavioral testing, magnetic resonance imaging, and blood draws.
4. Stated willingness to comply with all study procedures and lifestyle considerations (see Section 5.3, Lifestyle Considerations) and availability for the duration of the study
5. Males and females; Age 18-55 years
6. DSM-V diagnosis of bipolar disorder
7. Has a current major depressive episode
8. Depression at enrollment of sufficient severity to score \> 11 on the QIDS
9. Be stably medicated for at least 4 weeks (a non-medicated subject may be included in the study if judged to be appropriate in the medical/psychiatric opinion of the investigator)
10. BMI between 18.5 and 35
Exclusion Criteria:
1. Diagnosis of any other major psychiatric disorder such as schizoaffective disorder, schizophrenia, or current psychotic depression
2. A history of bipolar disorder with rapid cycling
3. Concurrent manic symptoms of sufficient severity to pose a substantial risk of the development of a manic episode (\>19 on the YMRS)
4. Current drug or alcohol or substance use disorder moderate or severe, except nicotine (within 6 months for severe use disorder; 2 months for moderate use disorder)
5. Volunteers currently receiving more than 4 mood-relevant psychotropic medications in a daily regimen (since this may signify a more brittle or complex clinical state)
6. Taking any of the following medications: medications with significant interactions with ibuprofen; immune-modulating medications (e.g. oral steroids); regular use of NSAIDs (\> 3 times per week)
7. Current or prior cardiac disease, cardiac arrhythmia (e.g. supraventricular tachycardia, atrial fibrillation, ventricular fibrillation), or history of cardiac ablation therapy
8. Unstable medical condition, including significant respiratory disease (e.g., asthma, reactive airway disease (i.e., exercise induced asthma), or chronic obstructive pulmonary disease (COPD)), liver disease, hypothyroidism (i.e., condition not adequately stabilized for 3 months), or other conditions likely to require hospitalization or with a life expectancy of \< 6 months (e.g., cancer).
9. History of claustrophobia that would prevent participation in imaging scans
10. Actively suicidal, as defined by expressive ideation with a plan and intent for suicide or developing suicidal ideation that requires immediate medical or treatment intervention or a suicide attempt within the previous six months
11. Participants who endorse a history of moderate to severe traumatic brain injury (\>30 min. loss of consciousness or \>24 hours posttraumatic amnesia) or other neurocognitive disorder with evidence of neurological deficits
12. Inadequate understanding of English
13. Currently pregnant or breast-feeding; fecund women not using adequate contraceptive methods; plan to become pregnant within 12 months
14. Metal in the body (e.g. history of working as a sheet metal worker) or pacemaker which is a contra-indication to magnetic resonance imaging
15. Has epilepsy, a neuromuscular disorder, or tardive dyskinesia
16. Has a chronic infectious illness
17. Requires immediate hospitalization for psychiatric disorder
18. Requires medications for a general medical condition that contraindicate any study medication
19. Receiving or have received during the index episode vagus nerve stimulation, electroconvulsive therapy, transcranial magnetic stimulation, or other somatic treatments
20. Allergy to, or other medical contraindication to ibuprofen (e.g. stomach ulcers)
21. Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome or "long-COVID".
22. Current use of medications or dietary supplements for weight or appetite control, whether prescribed or not
23. Ulcerative colitis, Crohn's disease or other autoimmune disorder (except treated hypothyroidism)
24. Activity restrictions that limit the subject's ability to engage in intense physical activity
25. Use of beta-blockers, calcium channel inhibitors, or other heart-modulating medications (e.g., amiodarone)
26. Clinically significant abnormality on EKG
27. Hypertension, hepatitis, renal dysfunction, and/or anemia of sufficient severity to pose a risk to the participant
28. Moderate or heavy smoker based on Fagerstrom
29. Resting heart rate \>100 beats per minute, systolic blood pressure \> 160 mmHg, diastolic blood pressure \> 100 mmHg
30. Clinically significant screening laboratory abnormalities not covered above
31. Any reason not listed herein that would make participation in the study hazardous
