Antiviral treatment in schizophrenia: a randomized pilot PET study on the effects of valaciclovir on neuroinflammation.

BACKGROUND: Patients with schizophrenia experience cognitive impairment, which could be related to neuroinflammation in the hippocampus. The cause for such hippocampal inflammation is still unknown, but it has been suggested that herpes virus infection is involved. This study therefore aimed to determine whether add-on treatment of schizophrenic patients with the anti- viral drug valaciclovir would reduce hippocampal neuroinflammation and consequently improve cognitive symptoms. METHODS: We performed a double-blind monocenter study in 24 male and female patients with schizophrenia, experiencing active psychotic symptoms. Patients were orally treated with the anti-viral drug valaciclovir for seven consecutive days (8 g/day). Neuroinflammation was measured with Positron Emission Tomography using the translocator protein ligand [11C]-PK11195, pre-treatment and at seven days post-treatment, as were psychotic symptoms and cognition. RESULTS: Valaciclovir treatment resulted in reduced TSPO binding (39%) in the hippocampus, as well as in the brainstem, frontal lobe, temporal lobe, parahippocampal gyrus, amygdala, parietal lobe, occipital lobe, insula and cingulate gyri, nucleus accumbens and thalamus (31-40%) when using binding potential (BPND) as an outcome. With total distribution volume (VT) as outcome we found essentially the same results, but associations only approached statistical significance (p = 0.050 for hippocampus). Placebo treatment did not affect neuroinflammation. No effects of valaciclovir on psychotic symptoms or cognitive functioning were found. CONCLUSION: We found a decreased TSPO binding following antiviral treatment, which could suggest a viral underpinning of neuroinflammation in psychotic patients. Whether this reduced neuroinflammation by treatment with valaciclovir has clinical implications and is specific for schizophrenia warrants further research.

Individual Heterogeneity in the Relations Between Sleep, Inflammation, and Somatic Symptoms.

OBJECTIVE: Poor sleep is associated with the experience of more somatic symptoms and a proinflammatory state, whereas a proinflammatory state may also result in the experience of more somatic symptoms. However, existing studies ignore individual differences in these associations. We aimed to study relations between sleep, inflammatory markers, and somatic symptoms at a within-individual level. METHODS: Time series of daily data on sleep, somatic symptoms, and inflammation markers in 10 healthy individuals (age, 19-58 years; three men) for 63 days were analyzed. Bidirectional lagged ( t - 1) and contemporaneous ( t ) relations between sleep duration, inflammatory markers (C-reactive protein, interferon-α, interleukin 1RA), and somatic symptoms were analyzed using 24-hour urine and diary data. Unified structural equation modeling was used to analyze the association between sleep duration, the three inflammatory markers, and the amount of somatic symptoms at the individual level. RESULTS: Associations were found between sleep and at least one of three inflammatory markers in four individuals, both positive (three associations) and negative (five associations) and contemporaneous (four associations) and lagged (four associations). Sleep was related to somatic symptoms in four individuals, both positive ( n = 2) and negative ( n = 2) and contemporaneous ( n = 3) and lagged ( n = 1). Inflammatory markers were associated with somatic symptoms in three individuals, both positive (three associations) and negative (one association) and contemporaneous (three associations) and lagged (one associations). Two individuals showed no associations between sleep, inflammatory markers, and somatic symptoms. CONCLUSIONS: We observed a large variability in presence, strength, and direction of associations between sleep, inflammatory markers, and somatic symptoms.

The association between herpes virus infections and functional somatic symptoms in a general population of adolescents. The TRAILS study.

BACKGROUND: FSS have been suggested to follow activation of the immune system, triggered by herpes virus infections. The aim of this study was to find out whether herpes virus infections were associated with the experience of FSS in adolescents, and whether this association was mediated by hsCRP, as a general marker of immune activation. METHODS: This study was performed in TRAILS, a large prospective population cohort of 2230 adolescents (mean age: 16.1 years, SD = .66, 53.4% girls). FSS were assessed using the somatic complaints subscale of the Youth Self-Report. FSS were analyzed as total scores and divided in two group clusters based on previous studies in this cohort. Levels of hsCRP and antibody levels to the herpes viruses HSV1, HSV2, CMV, EBV and HHV6 were assessed in blood samples at age 16. Also a value for pathogen burden was created adding the number of viruses the adolescents were seropositive for. Multiple regression analysis with bootstrapping was used to analyze the association between viral antibodies and pathogen burden, hsCRP and FSS scores. RESULTS: Antibody levels and pathogen burden were not associated with FSS total scores or FSS scores in both symptom groups. hsCRP was associated with the total FSS score (B = .02, 95% CI: .004 to .028, p = .01) and FSS score in the symptom group of headache and gastrointestinal complaints (B = .02, 95% CI: .001 to .039, p = .04). CONCLUSION: Our study showed no association between herpes virus infections and FSS in general or specific FSS symptom clusters. A role for inflammatory processes in FSS development was supported by the significant association we found between hsCRP levels and FSS, especially in the symptom group of headache and gastrointestinal complaints.

Association between exposure to HSV1 and cognitive functioning in a general population of adolescents. The TRAILS study.

BACKGROUND: Infections with different herpes viruses have been associated with cognitive functioning in psychiatric patients and healthy adults. The aim of this study was to find out whether antibodies to different herpes viruses are prospectively associated with cognitive functioning in a general adolescent population. METHODS: This study was performed in TRAILS, a large prospective general population cohort (N = 1084, 54% female, mean age 16.2 years (SD 0.6)). At age 16, immunoglobulin G antibodies against HSV1, HSV2, CMV and EBV were measured next to high sensitive C-Reactive Protein (hsCRP). Two years later, immediate memory and executive functioning were assessed using the 15 words task and the self ordered pointing task. Multiple linear regression analysis with bootstrapping was performed to study the association between viral infections and cognitive function, adjusting for gender, socioeconomic status, ethnicity, and cannabis use. RESULTS: Presence of HSV1 antibodies was associated with memory function ((B = -0.272, 95% CI = -0.556 to -0.016, p = 0.047)), while the association with executive functioning did not reach statistical significance (B = 0.560, 95% CI is -0.053 to 1.184, p = 0.075). The level of HSV1 antibodies was associated with both memory function (B = -0.160, 95% CI = -0.280 to -0.039, p = 0.014) and executive functioning (B = 0.296, 95% CI = 0.011 to 0.578, p = 0.046). Other herpes viruses and hsCRP were not associated with cognitive functioning. CONCLUSIONS: Both presence and level of HSV1 antibodies are prospectively associated with reduced cognitive performance in a large cohort of adolescents.