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)