Effects of Acute Exercise and Ibuprofen on Symptoms, Immunity, and Neural Circuits in Bipolar Depression

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, andblood 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 thestudy

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 inthe study if judged to be appropriate in the medical/psychiatric opinion of theinvestigator)

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 thedevelopment of a manic episode (>19 on the YMRS)

4. Current drug or alcohol or substance use disorder moderate or severe, exceptnicotine (within 6 months for severe use disorder; 2 months for moderate usedisorder)

5. Volunteers currently receiving more than 4 mood-relevant psychotropic medications ina daily regimen (since this may signify a more brittle or complex clinical state)

6. Taking any of the following medications: medications with significant interactionswith ibuprofen; immune-modulating medications (e.g. oral steroids); regular use ofNSAIDs (> 3 times per week)

7. Current or prior cardiac disease, cardiac arrhythmia (e.g. supraventriculartachycardia, atrial fibrillation, ventricular fibrillation), or history of cardiacablation therapy

8. Unstable medical condition, including significant respiratory disease (e.g., asthma,reactive airway disease (i.e., exercise induced asthma), or chronic obstructivepulmonary disease (COPD)), liver disease, hypothyroidism (i.e., condition notadequately stabilized for 3 months), or other conditions likely to requirehospitalization 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 forsuicide or developing suicidal ideation that requires immediate medical or treatmentintervention or a suicide attempt within the previous six months

11. Participants who endorse a history of moderate to severe traumatic brain injury (>30min. loss of consciousness or >24 hours posttraumatic amnesia) or otherneurocognitive disorder with evidence of neurological deficits

12. Inadequate understanding of English

13. Currently pregnant or breast-feeding; fecund women not using adequate contraceptivemethods; plan to become pregnant within 12 months

14. Metal in the body (e.g. history of working as a sheet metal worker) or pacemakerwhich 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 studymedication

19. Receiving or have received during the index episode vagus nerve stimulation,electroconvulsive therapy, transcranial magnetic stimulation, or other somatictreatments

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 treatedhypothyroidism)

24. Activity restrictions that limit the subject's ability to engage in intense physicalactivity

25. Use of beta-blockers, calcium channel inhibitors, or other heart-modulatingmedications (e.g., amiodarone)

26. Clinically significant abnormality on EKG

27. Hypertension, hepatitis, renal dysfunction, and/or anemia of sufficient severity topose 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