A Double-Blind Trial of Adjunctive Valacyclovir to Improve Cognition in Early Phase Schizophrenia

One hundred and seventy-five participants (N=70 HSV-1 seropositive and N=105 HSV-1
seronegative) will be randomized 1:1 to receive adjunctive valacyclovir or adjunctive placebo
for a 16 week period. The primary outcome that will be assessed is improvement in changes in
visual and working memory scores in HSV-1 positive and negative participants over the course
of the study. We will also measure the overall cognitive functioning and the severity of
psychiatric symptoms over the course of the study and will evaluate the tolerability and
safety of valacyclovir treatment in this population. In addition, we will explore the
relationship between changes in the levels of inflammatory markers (HSV2, CMV, EBV, CRP, and
Toxoplasmosis) and treatment response over the course of the study.

Inclusion Criteria:

- 18 to 40 years of age at study entry.

- Able to give written informed consent.

- DSM IV-TR Diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder as
confirmed by Structured Clinical Interview for DSM-IV-TR (SCID)

- Onset of schizophreniform disorder, schizophrenia, or schizoaffective disorder within
the past eight years as defined by first medical records documentation of these
conditions

- Outpatient or inpatient.

- Clinical stability as defined by:

1. CGI-S score of less than or equal to 4 (moderately ill) at randomization AND

2. Participants must not have experienced an exacerbation of their illness within 4
weeks prior to randomization leading to an intensification of psychiatric care in
the opinion of the investigator. Examples of intensification of care include, but
are not limited to: inpatient hospitalization, day/partial hospitalization,
outpatient crisis management, or psychiatric treatment in an emergency room AND

3. Antipsychotic treatment stability for at least 4 weeks prior to randomization (no
change in antipsychotic dosing, addition of any new antipsychotic medication, or
discontinuing an antipsychotic medication)

- Fluent in English.

- Female participants of childbearing potential must test negative for pregnancy at
screening visit and agree to use a single, effective, medically acceptable method of
birth control for the duration of the study.

Exclusion Criteria:

- Known IQ less than 70 as determined by medical history.

- IV drug use within previous three month prior to study entry.

- Any serious active medical condition that affects brain or cognitive functioning
(e.g., epilepsy, serious head injury, brain tumor or other neurological disorder) in
the investigator's opinion.

- Known medical history of Human Immunodeficiency Virus (HIV)

- Receipt of valacyclovir or chemically-related medication within 2 weeks prior to
randomization.

- History of hypersensitivity to valacyclovir or acyclovir as determined by self-report
and medical history.

- DSM-IV diagnosis of substance dependence within 3 months of study entry (with the
exception of nicotine or caffeine dependence).

- Participants who have participated in a clinical trial with any pharmacological
treatment intervention for which they received study-related medication in the 4 weeks
prior to screening AND participants currently receiving treatment (within 1 dosing
interval plus 4 weeks) with an investigational depot formulation of an antipsychotic
medication.

- Females who are pregnant or planning to become pregnant or breastfeeding or planning
to do so during the study period.

- Participants with current acute, serious, or unstable medical conditions, including,
but not limited to: inadequately controlled diabetes, asthma, COPD, recent
cerebrovascular accidents, acute systemic infection or immunologic disease, unstable
cardiovascular disorders, malnutrition, or hepatic or renal disease, renal including
renal failure, gastroenterologic, respiratory, endocrinologic, neurologic, hematologic
including thrombotic thrombocytopenia purpura/hemolytic uremic syndrome, or infectious
diseases

- Participants who require concomitant treatment with any other medication other than
those allowed as specified in Attachment 2, or with any other medication specifically
excluded in Attachment 2.

- Clinically significant electrocardiogram (ECG) abnormality prior to randomization as
defined by: participants with a corrected QT interval (Bazett's; QTcB) >450 msec
(male) or >470 msec (female) prior to randomization. Repeat ECGs will be conducted at
the discretion of the principal investigator or medical designee.

- Test positive for (1) Hepatitis C virus antibody, (2) Hepatitis B surface antigen
(HBsAg) with or without positive Hepatitis B core total antibody.

- Participants with moderate to severe renal impairment as defined by creatinine
clearance (CrCl) < 60 ml/min (measured by the Cockcroft-Gault equation) at screening.

- Participants with hepatic impairment as defined by liver transaminases or total
bilirubin > 3 × upper limit of normal (ULN).

- Participants considered a high risk for suicidal acts - active suicidal ideation as
determined by clinical interview OR any suicide attempt in 90 days prior to screening.

- Participants who demonstrate overtly aggressive behavior or who are deemed to pose a
homicidal risk in the investigator's opinion.

- Participants currently receiving cognitive remediation therapy at time of study entry

- Participants who have had electroconvulsive therapy (ECT) within 12 months of study
entry or who will have ECT at any time during the study.