ANTIVIRAL TREATMENT OF CYTOMEGALOVIRUS IN DEPRESSION

Inclusion Criteria:

1. Provision of signed and dated informed consent form

2. Stated willingness to comply with all study procedures and availability for theduration of the study

3. Male or female, aged 18-65 years

4. Diagnosis with major depressive disorder (MDD)

5. Current symptoms of depression, that is, a QIDS-SR score ≥14.

6. Unmedicated for at least 4 weeks (8 weeks for fluoxetine).

7. In good general health as evidenced by medical history, physical exam, and safetylabs

8. Ability to take oral medication and be willing to adhere to the VGCV regimen

9. For females of reproductive potential: use of highly effective contraception for atleast 1 month prior to screening and agreement to use such a method during studyparticipation and for an additional 4 weeks after the end of VGCV administration

10. For males of reproductive potential: use of condoms or other methods to ensureeffective contraception with partner during the study and for at least 90 days afterthe study.

11. Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout studyduration

Exclusion Criteria: General Exclusion Criteria:

• Pregnancy

• Breast-feeding

• Unwillingness to avoid pregnancy during the study due to the possibleteratogenic effects of valganciclovir Medical Conditions:

• Moderate to severe traumatic brain injury (>30 min. loss of consciousness or >24 hours posttraumatic amnesia) or other neurocognitive disorder with evidenceof neurological deficits.

• Presence of co-morbid medical conditions not limited to but includingcardiovascular (e.g., history of acute coronary event, stroke) and neurologicaldiseases (e.g., Parkinson's disease), as well as pain disorders.

• Presence of co-morbid inflammatory disorders such as rheumatoid arthritis orother autoimmune disorders.

• Presence of an uncontrolled medical condition that is deemed by theinvestigators to interfere with the proposed study procedures, or to put thestudy participant at undue risk.

• Presence of a chronic infection (e.g. HIV) that may elevate pro-inflammatorycytokines.

• Presence of an acute infectious illness (e.g. SARS CoV-2) or receipt of avaccination in the week prior to enrollment. Psychiatric Disorders:

• Current significant suicidal ideation (intent to commit suicide or makingspecific plans for suicide)

• Suicide attempt within the last 6 months

• Lifetime history of schizophrenia, schizophreniform, schizoaffective disorder,delusional disorder

• History of a manic or hypomanic episode not better accounted for by substanceuse

• Moderate to severe substance use disorder within the last year, excludingcannabis or nicotine use disorder

• Moderate or severe alcohol use disorder

• Positive urine toxicology (except cannabis) Contraindications to Valganciclovir:

• Myelosuppressive chemotherapy or radiation therapy

• Absolute neutrophil count < 500/mm3

• Platelet count < 25,000/mm3

• Hemoglobin < 8g/dL

• Impaired renal function (estimated glomerular filtration rate <60mL/minute/1.73m2)

• Sensitivity to VGCV, ganciclovir or other nucleoside analogues

• Medications that could interact with VGCV (see below): Prohibited Medications Abacavir Lamivudine, 3TC Amikacin AminoglycosidesAmphotericin B cholesteryl sulfate complex (ABCD) Amphotericin B lipid complex (ABLC) Amphotericin B liposomal (LAmB) Amphotericin B Aprotinin BacitracinBictegravir; Emtricitabine; Tenofovir Alafenamide Cisplatin Colchicine; ProbenecidCyclosporine Dapsone Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide Didanosine, ddI: Doravirine; Lamivudine; Tenofovir disoproxil fumarate Doxorubicin Efavirenz;Emtricitabine; Tenofovir Efavirenz; Lamivudine; Tenofovir Disoproxil FumarateElvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide Elvitegravir;Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate EmtricitabineEmtricitabine; Rilpivirine; Tenofovir alafenamide Emtricitabine; Rilpivirine;Tenofovir disoproxil fumarate Emtricitabine; Tenofovir alafenamide Emtricitabine;Tenofovir disoproxil fumarate Entecavir Flucytosine Gentamicin Hyaluronidase,Recombinant; Immune Globulin Hydroxyurea Imipenem; Cilastatin Immune Globulin IV,IVIG, IGIV Kanamycin Lamivudine; Tenofovir Disoproxil Fumarate MycophenolateParomomycin Pentamidine Plazomicin Polymyxin B Streptomycin Sulfamethoxazole;Trimethoprim, SMX-TMP, Cotrimoxazole Tacrolimus Talimogene Laherparepvec TelbivudineTenofovir Alafenamide Tenofovir, PMPA Tobramycin Trimethoprim Vancomycin VinblastineVinca alkaloids Vincristine Liposomal Vincristine Vinorelbine Zidovudine Other Medications:

• Current and/or past regular use of hormone-containing medications (excludingcontraceptives)

• Current use of non-steroid anti-inflammatory drugs that is deemed by theinvestigators to potentially confound the results of the study or the increaserisk of renal impairment (e.g. more than 3 days/week).

• Current and/or past regular use of immune modifying drugs that target specificimmune responses such as TNF antagonists

• Chronic use of antibiotics such as isotretinoin or minocycline because of theirpotential effects on the microbiome and immune function.

• Current and/or past regular use of antiarrhythmic, anti-anginal, andanticoagulant drugs (does not apply where medications are taken for differentpurpose).

• Inclusion of individuals reporting other types of medications or supplementsnot listed or considered thus far will be at the discretion of the PI based ontheir potential to affect immune function, brain function or brain blood flow. Contraindications to MRI:

• Cardiac pacemaker, metal fragments in eyes/skin/body (shrapnel),aortic/aneurysm clips, prosthesis, by-pass surgery/coronary artery clips,hearing aid, heart valve replacement, shunt (ventricular or spinal),electrodes, metal plates/pins/screws/wires, or neuro/bio-stimulators (TENSunit), persons who have ever been a professional metal worker/welder, historyof eye surgery/eyes washed out because of metal, vision problems uncorrectablewith lenses, inability to lie still on one's back for 60 minutes; priorneurosurgery; tattoos or cosmetic makeup with metal dyes, unwillingness toremove body piercings, and pregnancy.

• Claustrophobia severe enough to prevent scanning Health Factors:

• BMI > 38 because of the effects of obesity on pro-inflammatory cytokineactivity

• Clinically significant abnormalities on screening laboratory tests Non-English speaking participants:

• The majority of the assessments proposed for this study have not been translatedfrom English, thus, non-English speaking volunteers will be excluded.