What is treatment resistance in psychiatry? A “difficult to treat” concept

World Psychiatry 18:3 October 2019 neurotransmitters, such as serotonin, can be attached to his­ tones and facilitate gene expression in neurons. In parallel, experimental approaches have become more so­ phisticated and informative. Several laboratory innovations are of particular interest for psychiatric epigenomics. First, single­ cell approaches are redefining the meaning of epigenetic sto­ chasticity and directly address the issues of cell type differences in the brain. Second, easily available somatic cells, such as fibro­ blasts, can be reprogrammed into neurons, partially addressing the need for brain tissue. Third, CRISPR­Cas9 technology can be used not only for editing genomes, but also epigenomes, which is of considerable interest for modeling disease components in tissue culture and animals. Fourth, progress in computational strategies has enabled the integration of epigenomic data with genomics, transcriptomics, and metabolomics. The compre­ hensive trans­omic approaches enable the identification of hub elements and cellular pathways centrally involved in disease. Given the rapid developments in molecular biology and brain imaging technologies, an ideal experiment – a prospective epi­ genomic study in the living brain of psychosis­predisposed individuals – may not be science fiction in the near future. Despite the challenges thus far, epigenetics and epigenomics remain an important part of the psychiatric research agenda. There are still no better ways to explain the numerous dynamic features of complex diseases, which by definition do not con­ form with the stability of DNA sequence. Uncovering the mech­ anisms of discordance in monozygotic twins or the delayed age of psychosis onset would be of major importance for precision psychiatry. The success and progress of psychiatric epigenetics relies on the ever improving experimental and computational tools and, more importantly, on the diligence and creativity of scientists working on this very interesting, but also challenging, part of human biology.