To Rescue Cognition With Valaciclovir

Rationale: Schizophrenia is a chronic and disabling brain disease, with unknown aetiology. Recently, we have shown the presence of an inflammatory process in the hippocampus of schizophrenic patients during psychosis. In addition, we found evidence for the presence of herpes viruses in the temporal lobe of schizophrenic patients during psychosis. Taken together, we hypothesize that the hippocampal inflammation is caused by the presence of herpes viruses, and that this inflammation interferes with the normal involvement of the hippocampus in cognition. Anti-viral treatment, with valaciclovir, that reduces the activity herpes viruses in the hippocampus could reduce the neuroinflammation and thus improve cognition and symptoms in schizophrenia. Objective: The main objective is to find a pre- and post-valaciclovir treatment difference in hippocampal inflammation, as measured with positron emission tomography, in schizophrenic patients exposed to a psychotic episode. The secondary objective is to improve cognition by the supposed anti-inflammatory effect on the hippocampus of valaciclovir. Study design: The study is double-blind randomized placebo-controlled trial. Study population: For this study, 24 male patients compliant with schizophrenia disorder (DSM-IV codes 295.xx) are included that have a psychosis. The age should be above 18 and patients of all ethnic backgrounds can be included. Intervention (if applicable): Of the 24 included patients, 12 patients will receive 8 g (4x2 g per day) of valaciclovir daily for a period of 7 consecutive days and 12 patients will receive 8 g (4x2 g per day) of placebo daily for 7 consecutive days. Main study parameters/endpoints: The main study parameters are the pre-and post-treatment \[11C\]-PK11195 binding potential (an inflammatory marker) in the hippocampus, the pre- and post-treatment performance on the PANSS, the attention, memory and IQ test. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients will be admitted to a psychiatric hospital, if not already admitted as a part of their regular treatment, and treated with valaciclovir for seven consecutive 24-h periods. Patients have to fill in a questionnaire and have to undergo a part of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) interview and a MRI scan once, and have to undergo a PANSS interview, attention, memory and IQ tests, and PET scan twice. A total of 345 ml of blood will be taken for the determination of kidney and liver function, herpes virus antibodies, acyclovir levels in blood and for the PET scan data-analysis. Treatment with valaciclovir may cause nausea and headache but the risk of serious side effects is low (\<1 out of 10.000). For the PET scan, the arterial catheterization can cause discomfort and the patients are exposed to radioactivity with minor to moderate risk. The patients treated with valaciclovir can have direct benefit form the treatment, because it may reduce symptoms. In general, when this study finds evidence for the involvement of herpes viruses in schizophrenia, this can lead to improved treatment of these patients in the near future.