Research Study of Bipolar Mood Symptoms and Cognitive Problems
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a sixteen week, randomized, double-blind add-on study of valacyclovir versus placebo
      in approximately 60 outpatients meeting diagnostic criteria according to the Diagnostic and
      Statistical Manual of Mental Disorders (DSM) -IV Bipolar I or II disorder, testing positive
      for HSV-1 and who have demonstrable cognitive impairment defined as a total score of less
      than 85 (one standard deviation from the normal range) on the Repeatable Battery for the
      Assessment of Neuropsychological Status (RBANS). Each patient will be randomized to
      double-blind treatment with either valacyclovir or placebo for sixteen weeks. All subjects
      will be maintained on a stable regimen of psychiatric drugs prescribed by their treating
      psychiatrist. Patients will be evaluated every 2 weeks by the treatment team and mood rating
      scales will be administered at each visit including the Young Mania Rating Scale (YMRS) and
      the Montgomery Asberg Depression Rating Scale (MADRS). The RBANS will be administered again
      at 8 and 16 weeks. 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.

      Primary Hypothesis:

      Valacyclovir will be superior to placebo in reducing cognitive symptoms associated with
      bipolar disorder in subjects who have been previously infected with Herpes Simplex virus I
      (HSV-1).

      Secondary Hypothesis:

      Valacyclovir will be superior to placebo in reducing mood symptoms associated with bipolar
      disorder in subjects who have been previously infected with HSV-1.
    

Detailed description: 
      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 virusesthough
      this has not been found in all studies . Leweke et al found that untreated individuals with
      recent first episode schizophrenia had increased levels of serum and cerebrospinal fluid
      (CSF) immunogloublin G (IgG) antibodies to Cytomegalovirus (CMV) and Toxoplasma gondii in
      comparison to controls without psychiatric illness. Notably, serum immunoglobulin M (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 Herpes Simplex Virus -1 (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 catechol-o-methyltransferase (COMT) 158 Val/Val
      genotype.

      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. 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 Herpes Simplex 1 (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. 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. 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. found that serum antibodies to HSV1 were an independent predictor of
      cognitive dysfunction in schizophrenia. Similarly, Dickerson et al. 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. 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 the Structured
      Clinical Interview for the Diagnostic and Statistical Manual 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. 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
    

Intervention name(s): Valacyclovir; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Subjects take two 500 mg capsules twice daily for 16 weeks.; Subjects take two 500 mg capsules twice daily for 16 weeks.
Other intervention name(s): Valtrex
Intervention MeSH terms: Valacyclovir
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Bipolar; Cognitive; Attention; Memory; Manic Depression; Bi-polar