To Rescue Cognition With Valaciclovir

Study Overview
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Brief Summary
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This is a one-week, randomized, double blind add-on study of valaciclovir versus placebo in 24 clinical patients with Schizophrenia according to DSM IV, currently experiencing psychosis as is defined by the positive items of the Positive and Negative Syndrome Scale (PANNS) score, being five or higher on one item or four on two items of this scale. Each patient will be randomized to double blind treatment with either valaciclovir or placebo for one week. The main objective is to find a pre- and post-valaciclovir treatment difference in hippocampal inflammation, as measured with positron emission tomography. The secondary objective is to improve cognition by the supposed anti-inflammatory effect on the hippocampus of valaciclovir. This is measured by pre- and post-treatment performance on the PANSS, the attention and memory test. Both the treatment team and the patient will remain blinded during the course of the study. Following the active treatment phase, patients will receive treatment as clinically indicated.

Detailed Description
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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.

Official Title
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A Double Blind Placebo Controlled Study of Valaciclovir in Treatment of Psychosis in Patients With Schizophrenia

Conditions
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Schizophrenia, Psychosis

Intervention / Treatment
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* Drug: Valaciclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age above 18 Written informed consent for participation Diagnosis: schizophrenia, all subtypes (DSM-IV 295.xx) Psychosis, characterised by a total score on the positive scale on the PANSS above 14. In addition, a minimal score of 4 or more on an item of the positive scale. Exclusion Criteria: The use of benzodiazepines. Benzodiazepines have affinity for the peripheral benzodiazepine receptor which is the target receptor for [11C]-PK11195 PET and they can thus interfere with the PET study. The use of a nonsteroidal antiinflammatory drug or paracetamol in week before the PET scans and during the treatment of valaciclovir The use of anticoagulants or having coagulation disorder Use of somatic medication which may affect the immune system (e.g. corticoids, anti-inflammatory drugs, immune suppressive drugs) Use of any investigational drug Current or recent (<1 year) alcohol or substance abuse Disturbed kidney function Disturbed liver function Current or recent (<4 weeks) infectious or inflammatory disease Current systemic disease Major metabolic disease (diabetes, hyper- or hypothyroidism, Cushing disease or Addison disease) Somatic, organic or neurological disorder Participation in a scientific research study (<1 year) involving radiation Claustrophobia Presence of materials in the body that can be magnetized, like: A pacemaker Metal fragments Shunts Artificial heart valves Vascular clips Fixed hearing aid Tattoos containing metal Hair implants Artificial dentures

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valaciclovir<br>The patients in the experimental group will be treated with 4 times 2 grams valaciclovir per day for seven days. | Drug: Valaciclovir<br>* 4 times 2 grams valaciclovir per day, administrated orally, for seven days.<br>* Other names: Anti-viral drugs;|
| Placebo Comparator: Placebo<br>Patient receives placebo four times a day for seven days. | Drug: Valaciclovir<br>* 4 times 2 grams valaciclovir per day, administrated orally, for seven days.<br>* Other names: Anti-viral drugs;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To find a pre- and post-valaciclovir treatment difference in hippocampal inflammation | 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. | 8-15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To find pre- and post-treatment [11C]-PK11195 binding potential in other brain areas than the hippocampus. | Secondary study parameters are the antibodies against common viruses and the pre- and post-treatment [11C]-PK11195 binding potential in other brain areas than the hippocampus. This is also measured by means of PET and MRI | 8-15 days | 
| To find whether the patients hae antibodies against common viruses | Secondary study parameters are the antibodies against common viruses, measured in the blood samples. | 8-15 days | 
| To find a pre- and post-valaciclovir treatment difference in hippocampal inflammation | The secondary objective is to improve cognition by the supposed anti-inflammatory effect on the hippocampus of valaciclovir, this will be measured by means of PANSS, the attention, memory and IQ test. | 8-15 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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schizophrenia, treatment, inflammation, neuroinflammation, hippocampal