To exclude that alcohol or drug abuse may influence the data, we further grouped the patients according to drug or alcohol abuse. In particular ERV9 and HERV-K have been associated with schizophrenia and other neurological diseases; reviewed in. Elevated levels of HERV transcripts and/or proteins detected in brain samples, plasma or cerebrospinal fluid of patients might be etiologic factors or a consequence of the disease. Moreover, they could be indicators for epigenetic changes induced by medication influencing the epigenetic UNC2250 environment. Using a retrovirus-specific microarray as well as qRT-PCR we have investigated the influence of antipsychotic drugs on HERV transcription in five brain derived cell lines including neural stem cells, gliobastoma and neuroblastoma cells. No or only slight effects were Salannal observed for haloperidol, risperidone, and clozapine. In contrast, VPA increased the transcription of many HERVs, including members of groups ERV9 and HERV-W. VPA is a histone deacetylase inhibitor and thus may cause chromatin remodeling around HERV promoters leading to enhanced expression. Previous investigations have shown that VPA induces chromatin modifications and, in combination with other antipsychotics, alteration of DNA methylation patterns in patients with schizophrenia and bipolar disorders. Interestingly, in our study the effects of VPA appear to be cell type-dependent and are predominantly observed in both neuroblastoma cell lines. SKN-SH and SK-N-MC differ in several features, for example in expression levels of dopamine-beta-hydroxylase, suggesting a differential epigenetic background. This might explain that transcription of two different HERV groups, HERV-W and ERV9, is highly increased by VPA in SK-N-SH and SK-N-MC, respectively. Transcription of group HERV-K is not significantly influenced by any drugs in all cell lines investigated. In a previous study, expression profiling of a broad range of HERVs in brain samples from patients with schizophrenia and bipolar disorders using the retrovirus-specific microarray revealed a significant overrepresentation of HERV-K transcripts in both patient groups compared to healthy controls. To verify these data, and to reassess a possible influence of antipsychotic drugs, we used the same patient material for qRT-PCR. Sorting the data according to patient medication we observed a bias to an increased transcriptional activity of ERV9 and HERV-W in brain tissue of schizophrenic patients treated with VPA in comparison to untreated patients. In addition to the effect of VPA, a slight elevation of ERV9 transcripts was observed in both patient groups compared with healthy controls. Independent of the medication, a significant upregulation of HERV-K transcription was found in some patients with bipolar disorders. These data suggest that transcriptional activation of certain retroviral elements might be associated with the disease at least in some cases. However, these data should be interpreted with caution because many confounding factors, demographic and clinical variables, may conceal the outcome of the experiments Such imponderabilities may also explain differential findings of recently published studies. Drug abuse and alcohol, the parameters with the most influence, were therefore analyzed in this study, but did not show relevant differences. Taken together, our data suggest a complex regulation of HERV activity in human brain cells.Differential HERV expression in patients may depend on environmental factors including epigenetic drugs, as well as pathologic conditions.