Evaluation of Fluoxetine and Cytotoxic Lysosomal Stress in Glioma (FLIRT)

Inclusion Criteria: 1. Age ≥ 24 years of age Note: Fluoxetine has a warning about suicidal thoughts in children, adolescents, and young adults. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24. 2. Patients with recurrent glioma 3. Tumor volume ≥ 1 cm3 4. Clinical indication for craniotomy for biopsy and resection of the lesion 5. Clinical indication for repeat treatment with Temozolomide 6. Karnofsky Performance Status (KPS) \> 70% 7. Adequate organ function: platelets \> 100,000/µL, hemoglobin \>9 gm/dL, ANC \> 1000/µL; creatinine \< 1.5x upper limit of normal (ULN), total bilirubin \< 1.5x ULN, AST/ALT \< 2.5x ULN within 72 hours prior to first administration of Fluoxetine 8. Able to undergo MRI brain with and without contrast 9. If the patient is a sexually active female of childbearing potential, whose partner is male, or if the patient is a sexually active male, whose partner is a female of childbearing potential, the patient must use appropriate contraceptive measures for the duration of the treatment and for 6 months afterwards. Female patients of childbearing potential must have a negative serum pregnancy test at the time of screening and within 48 hours of starting the infusion of the study drug. 10. Signed informed consent approved by the Institutional Review Board Exclusion Criteria: 1. Patients currently taking or who have taken any other anti-depressant medication within the past year 2. Patients currently taking psychotropic agents or who have taken other psychotropic agents within the past 7 days 3. Patients with any history of mood/psychotic/substance use disorders 4. Prior, unrelated malignancy requiring current active treatment except for cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin 5. Patients who are pregnant or breastfeeding 6. Patients with contrast-enhancing tumor crossing the midline, multifocal tumor, infratentorial tumor, tumor in eloquent brain regions, extensive tumor dissemination (subependymal or leptomeningeal), or in unsafe brain regions per the opinion of the treating neurosurgeon 7. Patients with worsening neurologic deficits, clinically significant increased intracranial pressure (e.g., impending herniation), uncontrolled seizures, or requirement for immediate palliative treatment 8. Unstable systemic disease in the opinion of the treating physician 9. Less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation of recurrent tumor 10. Treated with immunotherapeutic agents within 4 weeks, alkylating agents within 4 weeks, nitrosoureas within 6 weeks, or non-alkylating chemotherapy within 2 weeks before enrollment, unless the patient has recovered from the expected toxic effects of such therapy 11. Treated with antiangiogenic agents (i.e., bevacizumab) within 4 weeks before biopsy 12. Patients who have developed disease progression while receiving temozolomide treatment are not eligible 13. Patients with allergy to fluoxetine 14. Patients with known cardiac disease, predisposing to long QT syndrome 15. Patients with diabetes mellitus, epilepsy, history of bleeding disorders, history of mania or susceptibility to angle-closure glaucoma 16. Patients with a history or who develop significant hyponatremia (serum sodium less than 130mmol/L) 17. Patients with a history of bipolar disorder or schizoaffective disorder 18. Patients with a history of seizure disorder prior to onset of their primary glioma 19. Patients who are currently taking or have taken in the past 2 months: Monoamine Oxidase Inhibitors (MAOI), Pimozide, Thioridazine, Drugs metabolized by the CYP2D6 pathway, Tricyclic Antidepressants, Antipsychotics, Serotonergic Drugs, Triptans, Tryptophan, Anticoagulant drugs (e.g., NSAIDs, aspirin, warfarin), Olanzapine 20. Patients who demonstrated thrombocytopenia following prior treatment with TMZ (platelets \< 50,000/µL)