HOLLYWOOD, FLA. – A 4-month course of the oral antiviral agent valacyclovir boosted cognition in herpes simplex virus-1–seropositive patients with bipolar disorder and cognitive impairment in a randomized, double-blind placebo-controlled clinical trial.
In this 60-patient study, 53% of participants assigned to valacyclovir (Valtrex) exhibited a clinically meaningful improvement in cognitive function, defined as at least a 10-point gain over baseline on the Repeatable Battery for the Assessment of Neurological Status (RBANS), compared with 14% in the placebo arm, Dr. Jennifer L. Payne reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.
The impressive improvement in response to valacyclovir documented in this study lends support to the viral hypothesis of mental illness, she said. This hypothesis posits that infection with one of the herpes viruses can in genetically vulnerable individuals lead to major mental illness, including schizophrenia, bipolar disorder, and perhaps Alzheimer’s disease.
"The idea behind this is that episodic reactivation of the virus in the [central nervous system] by stress or other stimuli could trigger mood, cognitive, or psychotic symptoms. If you treat patients you see this all the time: A patient comes under some kind of stress and becomes psychiatrically ill. One of the thoughts is that [herpes simplex virus] could underlie some of that psychopathology," according to Dr. Payne, a psychiatrist and director of the women’s mood disorders center at Johns Hopkins University, Baltimore.
She credited Faith B. Dickerson, Ph.D., of the Sheppard Pratt Institute in Baltimore with earlier groundbreaking work identifying a link between herpes simplex virus type 1 (HSV-1) and cognitive dysfunction in bipolar disorder. Dr. Dickerson and her colleagues reported a roughly 20-fold increased risk for cognitive impairment on the RBANS in HSV-1–seropositive, compared with seronegative patients with bipolar disorder (Biol. Psychiatry 2004;55:588-93).
The RBANS is a paper and pencil test that takes roughly 25 minutes. The mean score in the general population is 100. One standard deviation below the mean is a score of 85. Upon retaking the test, 16% of the general population are able to improve their score by 10 points or more, a rate close to the placebo group’s performance in Dr. Payne’s bipolar disorder study. The RBANS has individual sections for attention, immediate memory, delayed memory, language, and visuospatial construction.
HSV-1 typically causes oral herpes lesions. It’s an extremely common infection. By middle age, roughly 70% of Americans have serologic antibody titers to HSV-1. The virus infects the CNS and often remains in a latent state for many years, punctuated by symptomatic recurrences.
Dr. Payne screened 106 bipolar disorder patients; 84 proved HSV-1 seropositive. The mean baseline RBANS score in the seropositive patients was 75, compared with 92 in the seronegative cohort. The observed association between HSV-1 serologic status and RBANS score remained significant in a multivariate logistic regression analysis after investigators controlled for education level.
The 60 study participants were bipolar disorder outpatients, with an average age of 43. Thirty-seven percent met diagnostic criteria for bipolar I disorder; the rest, for bipolar II disorder. All were required to have baseline cognitive impairment as reflected by an RBANS score of 85 or less. Their average baseline Montgomery-Asberg Depression Rating Scale (MADRS) score was 24, with a Young Mania Rating Scale (YMRS) score of 8. Patients remained on their usual psychiatric medications during the study.
Participants in the 4-month trial were evaluated every 2 weeks for a change in mood symptoms using the MADRS and YMRS. The results came as a surprise.
"Our hypothesis had been that cognitive improvement with valacyclovir would be associated with improvement in depression, but the MADRS scores didn’t change over time," according to Dr. Payne.
As is typical in months-long clinical trials conducted in patients with bipolar disorder, there was a high dropout rate. Mean RBANS scores in the 19 patients in the valacyclovir group who completed the study improved from a baseline of 67.6 to 77.7 at 4 months. The 22 study completers in the control group showed no significant change in scores over time.
Dr. Payne said that if these results are confirmed in another clinical trial – and she plans to conduct one including seropositive bipolar disorder patients who are not cognitively impaired – it would be practice changing.
"If these findings hold up, it would indicate that as clinicians, we need to be testing for HSV-1 and treating it in our patients," she said.
Her future plans also include studying HSV-1 antibody status, cognition, and the possible impact of antiviral therapy in patients with major depressive disorder.