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

Inclusion Criteria: Provision of signed and dated informed consent form Has an established residence and phone Agrees to and is eligible for behavioral testing, magnetic resonance imaging, and blood draws. 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 Males and females; Age 18-55 years DSM-V diagnosis of bipolar disorder Has a current major depressive episode Depression at enrollment of sufficient severity to score > 11 on the QIDS 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) BMI between 18.5 and 35 Exclusion Criteria: Diagnosis of any other major psychiatric disorder such as schizoaffective disorder, schizophrenia, or current psychotic depression A history of bipolar disorder with rapid cycling Concurrent manic symptoms of sufficient severity to pose a substantial risk of the development of a manic episode (>19 on the YMRS) 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) 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) 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) Current or prior cardiac disease, cardiac arrhythmia (e.g. supraventricular tachycardia, atrial fibrillation, ventricular fibrillation), or history of cardiac ablation therapy 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). History of claustrophobia that would prevent participation in imaging scans 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 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 Inadequate understanding of English Currently pregnant or breast-feeding; fecund women not using adequate contraceptive methods; plan to become pregnant within 12 months 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 Has epilepsy, a neuromuscular disorder, or tardive dyskinesia Has a chronic infectious illness Requires immediate hospitalization for psychiatric disorder Requires medications for a general medical condition that contraindicate any study medication Receiving or have received during the index episode vagus nerve stimulation, electroconvulsive therapy, transcranial magnetic stimulation, or other somatic treatments Allergy to, or other medical contraindication to ibuprofen (e.g. stomach ulcers) Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome or "long-COVID". Current use of medications or dietary supplements for weight or appetite control, whether prescribed or not Ulcerative colitis, Crohn's disease or other autoimmune disorder (except treated hypothyroidism) Activity restrictions that limit the subject's ability to engage in intense physical activity Use of beta-blockers, calcium channel inhibitors, or other heart-modulating medications (e.g., amiodarone) Clinically significant abnormality on EKG Hypertension, hepatitis, renal dysfunction, and/or anemia of sufficient severity to pose a risk to the participant Moderate or heavy smoker based on Fagerstrom Resting heart rate >100 beats per minute, systolic blood pressure > 160 mmHg, diastolic blood pressure > 100 mmHg Clinically significant screening laboratory abnormalities not covered above Any reason not listed herein that would make participation in the study hazardous