Biological Predictors of Clozapine Response: A Systematic Review

Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.

Background Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1041-x) contains supplementary material, which is available to authorized users.

Treatment-resistant schizophrenia is the object of intense interest because of recent developments in its treatment and aetiology. The actual definition of treatment-resistant schizophrenia is, however, still controversial. It should reflect the legitimate and varied needs and perspectives of people with schizophrenia, their family members, mental health care givers, mental health administrators, public health officials, and those who fund the direct and indirect costs of treating schizophrenia. The most common definition of treatment-resistant schizophrenia denotes patients with schizophrenia who, despite at least two adequate trials of classical neuroleptic drugs, have persistent moderate to severe positive, or disorganisation, or negative symptoms together with poor social and work function over a prolonged period of time. This definition reflects the viewpoint of people with this illness, their family members, and mental health care givers. Approximately 30% (range 10-45%) of schizophrenic patients meet these criteria. While this definition is adequate for many purposes, it should be realised that the remaining 70% of schizophrenic patients, whose positive symptoms respond adequately to neuroleptic treatment, may also have clinically significant negative symptoms, poor social and work function, clinically significant cognitive dysfunction, poor quality of life relative to the normal population, and constitute a significant burden to family and society. The lifetime suicide rate in both treatment-resistant and responsive schizophrenic patients is 9-13%, indicating that conventional definitions of neuroleptic response do not convey lower risk of suicide. However, before defining a patient as treatment resistant, it is important to consider whether the patient has received an inadequate duration of treatment, and/or too low, or possibly too high, doses of neuroleptic drugs. Using these stringent criteria, treatment resistance may be present at the time of initial diagnosis and treatment, but if not present initially, it will usually develop subsequently-sometimes not until after multiple acute exacerbations over a period of years. During the first months and years after the diagnosis of schizophrenia has been made, clinicians should be especially alert in identifying a patient as treatment resistant in order to diminish the severe social disability and suicidality which may ensue if it is not recognised and correctly treated. Once present, treatment resistance is usually permanent. However, some treatment-resistant patients may again become responsive to treatment or undergo spontaneous remission of positive symptoms in later life. The treatment of patients with schizophrenia who are treatment resistant is generally much more expensive that that of neuroleptic-responsive patients because their symptomatology and disturbed behaviour leads to more frequent and longer duration hospitalisations. Patients with treatment-resistant schizophrenia may manifest one or more of the classical subtypes of schizophrenia which may differ biologically in terms of neurochemistry and structural brain abnormalities, e.g. ventricular enlargement. They usually have poorer premorbid function, an earlier age at onset of positive symptoms, are more likely to be male than female, and may have various quantitative types of cortical or ventricular abnormalities evident with computer tomography or magnetic resonance imaging scans. There are no established qualitative differences in cognitive dysfunction between the two groups of patients with schizophrenia, but cognitive impairment is more severe in treatment-resistant patients. Treatment-resistant schizophrenia does not usually respond to increased dosages of neuroleptic drugs, switching to other types of neuroleptics, or adding adjunctive agents such as benzodiazepines, antidepressants, anticonvulsants or lithium carbonate. (ABSTRACT TRUNCATED)