Research Study of Bipolar Mood Symptoms and Cognitive Problems

Background

Herpes Viral Infections and Mental Illness. Recent studies have suggested that chronic,
recurrent infections with the herpes family of viruses may play a role in chronic mental
illnesses such as schizophrenia and bipolar disorder. Several studies have indicated that
individuals with schizophrenia have evidence of increased exposure to Herpes viruses (Buka
et al, 2001; Srikanth et al, 1994; Pelonero et al, 1990; Bartova et al, 1987 ) though this
has not been found in all studies (Fux et al, 1992; DeLisi et al, 1986; King et al, 1985).
Leweke et al (2004) found that untreated individuals with recent first episode schizophrenia
had increased levels of serum and CSF IgG antibodies to CMV and Toxoplasma gondii in
comparison to controls without psychiatric illness. Notably, serum IgM levels were not
increased indicating that infection had not occurred recently. Treated individuals with
schizophrenia had similar antibody levels as controls. Finally, Dickerson et al have
recently shown that previous HSV-1 infection is associated with cognitive impairment in
bipolar disorder, with a relative risk of 22.2 and that this risk was increased in the
presence of the COMT158 Val/Val genotype (Dickerson et al, 2006).

It is well known that active replication of herpes viruses may occur after extended periods
of latency. It has also been shown active replication of the virus in the central nervous
system may be triggered by environmental or psychosocial stressors and cause mood and even
psychotic symptoms (Koehler and Guth 1979; Schlitt et al. 1985; Fisher, 1996). Taken
together with the evidence of increased exposure to Herpes viruses found in individuals with
schizophrenia and bipolar disorder, one hypotheses that remains to be tested is that
episodic reactivation of HSV-1 in the brain triggered by environmental stressors could be a
pathogenic mechanism contributing to symptomatology in a subset of bipolar disorder and
schizophrenic patients.

Cognitive Impairment in Bipolar Disorder

Cognitive, or neuropsychological, functioning is one of the major domains of symptomatology
in major mental illness. While cognitive impairment in schizophrenia has been long
established, neuropsychological functioning in bipolar disorder has been less extensively
studied. Nevertheless, there is evidence that patients with mood disorders frequently
manifest cognitive deficits in attention, executive and memory functions (Hoff et al. 1990;
Goldberg et al. 1993; Seidman et al. 2002). While symptomatic bipolar disorder patients have
been shown to have widespread cognitive abnormalities, evidence from many studies also
supports the hypothesis that there are persistent residual cognitive impairments in patients
in the euthymic phase of illness (van Gorp et al. 1998; Thompson et al. 2005). As noted
above, Dickerson et al have very recently shown an association between HSV-1 seropositivity
and cognitive dysfunction in bipolar disorder (2006).

Valacyclovir in Schizophrenia

Recent studies have shown that herpes viruses may play an etiologic role in the cognitive
impairments that occur in a subset of patients with schizophrenia and bipolar disorder.
Dickerson et al. (2003a) found that serum antibodies to HSV1 were an independent predictor
of cognitive dysfunction in schizophrenia. Similarly, Dickerson et al. (2004) found that
serological evidence of infection with HSV1 was also predictive of cognitive impairment in
bipolar disorder. This association was independent of other factors that could affect
cognition including manic, depressive and psychotic symptoms, age of onset, education, or
medications. A clinical trial using the antiviral medication valacyclovir in schizophrenia
was recently conducted (Dickerson et al. 2003b). This study found a significant improvement
in psychiatric symptoms in individuals with schizophrenia who were seropositive for
cytomegalovirus, another virus in the herpes family. This is the first evidence that an
antiviral medication may be helpful in a psychiatric condition.

The study will be divided into two phases

Screening Phase. Subjects will initially be screened by telephone and, if they meet major
inclusion and exclusion criteria, will then be invited for an in-person screening. After a
consenting process, subjects will first under go RBANS testing. If they meet criteria for
cognitive impairment (total score <85) subjects will then go one to have a rapid HSV1 test
administered (result available in 1-7 days at Hopkins) and will undergo a Structured
Clinical Interview for DSM-IV (SCID) conducted by a research assistant. Subjects who test
positive for HSV-1 and who have a diagnosis of Bipolar I or Bipolar II disorder on the SCID
will be invited back to meet with a team psychiatrist to complete the screening, including a
psychiatric interview and examination, a medical history and physical examination, vital
signs, and baseline laboratory tests including a complete blood count and blood chemistries
as well as any other evaluation the treatment team feels is medically indicated. Subjects
who are appropriate for the study will be invited to join the Active Phase of the study.

Active Phase

A second consenting process will be conducted for entrance into the active phase of the
trial. Subjects will enter this phase within 14 days of the RBANS testing of the screening
visit. During this phase the patients will be randomly assigned to receive either
valacyclovir or placebo in addition to their standard psychiatric medications. The patients
will receive capsules containing valacyclovir or placebo and will be blinded during the
course of the study. Valacyclovir will be started at a initial dose of 1000mg twice daily.
At the baseline visit, mood rating scales including the YMRS, MADRS, and PANSS will be
administered. Please see the Study Schematic (end of Form A) for all scales, history forms,
and questionnaires that will be administered during screening and throughout the study.
Subjects will then meet with the treatment team every 2 weeks for rating scale measurements
and assessments for side effects. At the end of 8 and 16 weeks, subjects will again undergo
RBANS testing. Both subjects and raters will remain blind during the trial