Discussion
WLT, neuroinflammation, herpes, psychiatric, HSV-1 infection, psychotic symptoms, schizophrenia, TSPO
SIDE EFFECT, HERPES, CORTEX, INFLAMMATORY RESPONSE
To our knowledge, this is the first study investigating the effect of valaciclovir treatment on neuroinflammation in the hippocampus of patients with schizophrenia. Our main finding is that valaciclovir reduced neuroinflammation in the hippocampus, which could be interpreted as support for the hypothesis that actively replicating herpes viruses are present in the hippocampus and contribute to an inflammatory response. We additionally found significantly reduced neuroinflammation in other included brain regions. Despite the reduction in neuroinflammation, psychotic symptoms and cognitive functioning did not improve in valaciclovir-treated patients. Contrary to what was expected, the score on the 15 WLT decreased over time in valaciclovir-treated patients only, and scores on verbal fluency in both valaciclovir- and placebo-treated patients.We hypothesized the main treatment effects of valaciclovir to be in the hippocampus, because of the affinity of HSV-1 for that region and our earlier finding of neuroinflammation in the hippocampus (Doorduin et al., Following valaciclovir treatment we found reduction in TSPO binding for all brain regions included, which could suggest a global presence of actively replicating herpes viruses, an unknown effect of valaciclovir on TSPO binding or natural variation in neuroinflammation. We found an effect in all tested brain regions, without any clinical effects, which could be an argument for natural variation. TSPO binding was increased in the post-treatment scan, when compared to the pre-treatment scan, in the placebo group. Although this was not statistically significant, it suggests that TSPO binding varies over time. The parietal and occipital cortex that showed a reduced BPA recent meta-analysis reported on the findings of 12 PET imaging studies in schizophrenia (190 schizophrenia patients and 200 healthy controls), using TSPO as a marker of neuroinflammation (Marques et al., There is some discussion on which outcome is the most reliable to determine TSPO binding. The BPWe found a lower performance for the 15 WLT in valaciclovir-treated patients and for the semantic category of the VFT for both treatment groups. This is unusual, as cognitive scores most often improve across a study due to a learning effect. Participation in this study may have been stressful and tiring, affecting concentration in our participants. Impaired concentration could also be a side effect of the high dose valaciclovir, even though we had a wash-out period of 7 days before follow-up measurement. Furthermore, VFT scores decreased in both the valaciclovir and the placebo group. In contrast, the psychiatric condition of patients did not change, as was shown by the pre- and post-treatment PANSS scores.We used [In conclusion, we found a decrease in TSPO binding in the hippocampus of patients with schizophrenia treated with valaciclovir, which was also observed in all other tested brain regions. Although this clearly is not proven by our study, it might suggest that viral activity is responsible for neuroinflammation in patients with schizophrenia. However, other explanations for this association cannot be excluded. Cognitive performance was negatively affected by the treatment, possibly due to study-induced stress. Additional studies are needed to confirm our findings, to find out whether this treatment effect is specific for schizophrenia patients, or for schizophrenia patients that are seropositive for HSV-1 infection, and to understand whether this treatment effect can lead to clinical relevant improvement of symptoms in patients with schizophrenia.