**1. Introduction**

The treatment of schizophrenia involves the suppression of hallucinations, delusions, agitation, and an array of behavioral problems that often accompany these symptoms [1]. When acute symptoms start to subside with antipsychotic drug treatment, psychotherapy and rehabilitation interventions can be undertaken. The heterogeneity of schizophrenia may account for concentration of the disease in some families, reduced concordance between monozygotic twins, and patient‐specific causations. The identity of genes and pathways involved in schizophrenia and the mechanisms affecting them are forthcoming. This devel‐ opment has identified important insights including the fact that a relatively large number of genes affected in schizophrenia belong to relatively few critical pathways. This includes the Dopamine pathway that has provided the foundation for the development of primary treatment of the disease. There is an opportunity to focus on additional affected pathways for the treatment of a subset of patients. One of the mechanisms that may affect schizophrenia‐ related pathways is DNA methylation. This chapter will discuss primary molecular studies that support a threshold model for this complex disease, including complete genome sequences of monozygotic twins discordant (MZD). Specifically, we identify patient‐specific genes that may be affected by a variety of mutational mechanisms, including DNA methyla‐ tion. Here, the predisposition for the disease is realized on a threshold scale (**Figure 1**) via mutations involving a variety of mechanisms including sequence variations and copy number variations in nuclear genes as well as changes in genome‐wide DNA methylation [2, 3]. The threshold model can only be tested on monozygotic twins discordant for the disease. Next, we will argue for the direct role of DNA methylation in schizophrenia using two sets of independentresults; methylation differences between MZD twins and tissue‐specific response of olanzapine (antipsychotic) treatment in rats *in vivo* [4, 5]*.*

**Figure 1.** A threshold model for predisposition to schizophrenia in monozygotic twins discordant (MZD) for schizo‐ phrenia [2].

We will also discuss three facets of schizophrenia and their implications in the development of any strategy for amelioration: (i) the role of *de novo* sequence variations (nuclear and mtDNA) in the etiology and treatment of psychiatric disorders, including schizophrenia; (ii) the involvement of DNA methylation in the development of psychiatric disorders, particularly schizophrenia; and (iii) the interplay between DNA sequence variation and DNA methylation. The insights covered will be incorporated into the development of strategies toward person‐ alized medicine for the treatment of psychiatric disorders.

**1. Introduction**

28 Schizophrenia Treatment - The New Facets

phrenia [2].

The treatment of schizophrenia involves the suppression of hallucinations, delusions, agitation, and an array of behavioral problems that often accompany these symptoms [1]. When acute symptoms start to subside with antipsychotic drug treatment, psychotherapy and rehabilitation interventions can be undertaken. The heterogeneity of schizophrenia may account for concentration of the disease in some families, reduced concordance between monozygotic twins, and patient‐specific causations. The identity of genes and pathways involved in schizophrenia and the mechanisms affecting them are forthcoming. This devel‐ opment has identified important insights including the fact that a relatively large number of genes affected in schizophrenia belong to relatively few critical pathways. This includes the Dopamine pathway that has provided the foundation for the development of primary treatment of the disease. There is an opportunity to focus on additional affected pathways for the treatment of a subset of patients. One of the mechanisms that may affect schizophrenia‐ related pathways is DNA methylation. This chapter will discuss primary molecular studies that support a threshold model for this complex disease, including complete genome sequences of monozygotic twins discordant (MZD). Specifically, we identify patient‐specific genes that may be affected by a variety of mutational mechanisms, including DNA methyla‐ tion. Here, the predisposition for the disease is realized on a threshold scale (**Figure 1**) via mutations involving a variety of mechanisms including sequence variations and copy number variations in nuclear genes as well as changes in genome‐wide DNA methylation [2, 3]. The threshold model can only be tested on monozygotic twins discordant for the disease. Next, we will argue for the direct role of DNA methylation in schizophrenia using two sets of independentresults; methylation differences between MZD twins and tissue‐specific response

**Figure 1.** A threshold model for predisposition to schizophrenia in monozygotic twins discordant (MZD) for schizo‐

We will also discuss three facets of schizophrenia and their implications in the development of any strategy for amelioration: (i) the role of *de novo* sequence variations (nuclear and mtDNA)

of olanzapine (antipsychotic) treatment in rats *in vivo* [4, 5]*.*
