Objective: To assess the efficacy of tolcapone to improve cognition in schizophrenia, as a genotype-based targeted treatment of cognitive and negative symptoms of schizophrenia considering the polymorphism rs4680.

Methodology: 20 patients with chronic and stabilized schizophrenia (10 patients with genotype Val/Val and 10 patients with genotype Met/Met according to polymorphism rs4680) will receive treatment with tolcapone during 7 days. The cognitive function and clinical status will be evaluated with a neuropsychological battery and appropriate clinical scales before and after treatment. The efficiency of the activation of the prefrontal cortex will be measured using functional magnetic resonance imaging (fMRI) before and after treatment.

Hypothesis: Only patients with genotype Val/Val treated with tolcapone would show a cognitive improvement, a higher efficiency of the activation of the prefrontal cortex and an amelioration of some negative symptoms.

Inclusion Criteria:

• Ability to give informed consent and express the wish to fulfill all the requirements of the protocol during the study period.
• The patient must be capable of fulfillment of all the requirements of the clinical trial, at the investigator's discretion.
• Patients diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Only chronic patients will be recruited, and they must be clinically compensated in order to consent to participate. The determination of clinical compensation will be conducted according with these criteria: i) outpatients, with absence of hospitalization due to acute psychiatric decompensation in the previous year, and ii) maintained GAF score equal or higher than 60 during the previous month. The recruitment process will include a clinical interview to verify the diagnosis.
• Caucasic ethnicity
• Negative pregnancy test for women of childbearing age.

Exclusion Criteria:

• Severe infections or diseases or hepatic failure (or increased liver enzymes), renal failure or bone marrow failure that advise against participation in the study at the investigator's discretion
• Positive pregnancy test, or breastfeeding women.
• Carriers of pacemaker or any kind of metallic prosthesis incompatible with magnetic resonance imaging.
• History of hypersensitivity to Tasmar® (tolcapone) or to any of its components
• Active (in the last 12 months) substance abuse, or other disease that causes psychiatric symptoms
• Cardiovascular disease and electrocardiogram alterations
• Patients receiving treatment with monoamine oxidase inhibitors during the study or up to 15 days prior to the beginning of the study.
• Patients receiving treatment with a catechol-O-methyltransferase (COMT) inhibitor
• Participation in another clinical trial in the previous 30 days.
• Other circumstances which involve Tasmar® (tolcapone) contraindications: history of Neuroleptic Malignant Syndrome and/or non-traumatic rhabdomyolysis or hyperthermia. Severe dyskinesia. Phaeochromocytoma. Hereditary galactose intolerance. Lapp lactase deficiency or glucose or galactose malabsorption.