INTRODUCTION

Pharmacogenomics is the study of how genetic factors influence individual responses to drugs and offers a potentially powerful method for implementing personalized medicine. At the Mental Health Research Institute (MHRI) we address the pharmacogenomics of antipsychotic drug medication with emphasis on the treatment of schizophrenia.

Present methods of drug treatment for mental disorders are based on empirical trial and error. This carries major disadvantages for patients who, as a consequence of genetic and other factors, may not respond to the drug and/or can suffer from drug-induced adverse side effects. Poor or adverse responses to therapeutic drugs can have a deleterious impact on carers, society and the economy, as well as causing problems for the individual patient.

Pharmacogenomics has been greatly enhanced by knowledge of the human genome sequence, first published in 2000, and the exponential development of genomic technology. Although still in its infancy, pharmacogenomics seems likely to have a positive impact on the development of personalized and effective treatment of mental disorders and the development of new and beneficial psychotropic drugs.

Pharmacogenomics may facilitate the correct choice of drug at the outset, thereby resulting in personalized medicine that could ensure maximal possible benefit with minimum adverse effect to the patient.

BACKGROUND

Schizophrenia and its treatment

Schizophrenia affects approximately 1% of the Australian population and is among the top 10 causes of burden of disease in young Australian men and women aged 15-24 and in the prime of life. Studies with monozygotic twins show that schizophrenia is due to an interaction, in equal part, between the environment and the inherited genetic makeup of the individual.

Treatment of schizophrenia was revolutionised in the 1950s by the introduction of chlorpromazine (prototype of ‘typical antipsychotics’) and related phenothazine drugs. Patients were not cured, but many were able to engage in relatively normal day-to-day interactions. Unfortunately, typical antipsychotics commonly resulted in stigmatizing and serious extrapyramidal side effects characterized by disabling involuntary movements such as grimacing, rapid eye blinking and tremors. Furthermore, these agents provided little or no relief for some of what are termed the ‘negative’ symptoms of schizophrenia (e.g. disorganised thoughts, inappropriate behaviour).

The introduction of ‘atypical’ or ‘second generation’ antipsychotic medications significantly enhanced the capacity to provide relief from the severity of the symptoms associated with schizophrenia including the ‘positive’ (e.g. hallucinations, delusions) and the ‘negative’. These benefits were achieved without some of the serious movement disorder side effects experienced with the earlier ‘typical’ antipsychotics.

Clozapine, the prototype of the atypical antipsychotics, is the most powerful atypical antipsychotic and is therefore commonly prescribed for patients with schizophrenia who are resistant to treatment with other antipsychotic drugs.

Adverse effects of clozapine

Although regarded as the gold standard medication for ‘treatment resistant’ schizophrenia, clozapine is not without side effects. Thus, clozapine induces agranulocytosis (reduction in blood white cell count to dangerously low levels) in about 1% of patients - an adverse effect that requires frequent blood monitoring of patients on clozapine treatment – and myocarditis (a potentially deadly inflammation of the heart) in 1/1000 patients.

However, the most common adverse effect of clozapine is drug-induced weight gain. More than 50% of patients on clozapine treatment develop obesity and its consequent disorder, the ‘metabolic syndrome’. The metabolic syndrome, characterized by insulin resistant (Type II) diabetes, high blood pressure and increased blood glucose and cholesterol levels, predisposes individuals to heart attacks and stroke. Increases in body weight also have an adverse impact on personal body image and can result in failure to adhere to the prescribed drug regimen.

HIGHLIGHTS

The MHRI Pharmacogenomics Project

MHRI is investigating genetic variations across the human genome with the purpose of discovering associations between clozapine-induced weight gain and gene variations that may serve as a predictive marker of susceptibility to clozapine–induced obesity. We also plan to investigate the relationship between weight gain and drug response in order to determine whether there is a correlation between the genes involved in drug response and those involved in weight gain.

Individual variations or ‘polymorphisms’ in the genetic code are most commonly characterized by single changes in the coding ‘alphabet’ or nucleotide bases of which DNA (the molecular substrate of genes and the genetic code) is comprised. These variations in the genetic code are termed ‘single nucleotide polymorphisms’, or ‘SNPs’ (pronounced ‘snips’ for short). We aim to correlate genetic information derived from the use of the new SNP array technology with changes in the Body Mass Index (an index of weight and obesity) associated with clozapine treatment. In addition, we aim to determine whether there is an association between weight gain and treatment effi cacy.

Methodology: Genome-wide scan of associations

Major international gene screening projects have demonstrated that there are several million SNPs across the human genome. While this scale of project remains diffi cult to achieve outside large genome centres, the fact that gene polymorphisms in close proximity exhibit association with each other means that using a GeneChip microarray to genotype 500,000 SNPs is effective in capturing information from 80-86% of common SNPs.

Genes and regions positive in the analyses will be subject to individual analyses using special mathematical programs such as GeneCounting. DNA from a small blood sample taken from each individual will be genotyped on the GeneChip array and then analysed statistically for association with individual clinical characteristics (phenotypes) - such as obesity. In addition to SNP analysis, modern technology will also enable us to detect large genomic variations commonly called Copy Number Polymorphisms exemplifi ed by deletions or multiple copies of gene segments.

The information gained will allow us to make inferences regarding the functional significance of our findings with respect to individual differences in gene expression. This approach has already yielded clinically important results. Thus, for example, it recently led to the finding that age-related macular degeneration - a major cause of blindness in the elderly - is linked to a mutation in a gene that is functionally relevant to this type of degeneration.

Outcome and implications

Identification of the gene polymorphisms responsible for the weight gain currently seen in patients taking clozapine would have a significant impact on the treatment of patients with schizophrenia. This discovery could provide the basis for a diagnostic test for ‘at risk’ individuals that could be performed before initiation of medication, and inform both the patient and the doctor of the probability of clozapine-induced obesity. This would allow an informed choice as to whether another agent should be used, or if clozapine is to be prescribed, allow the forward planning and implementation of treatment strategies to reduce the likelihood of problematic weight gain and its attendant risks of diabetes and cardiovascular disorders.

In addition to establishing the possible genetic associations of efficacy and adverse side effects of the atypical antipsychotics, this research may help to identify the genetic variants or mutations that underpin schizophrenia. Identifying the genetic origins of schizophrenia would likely lead to a much better understanding of the disorder and improved strategies for its early diagnosis and treatment.

Our data are also likely to be relevant for understanding the genetic basis for predisposition to obesity and the metabolic syndrome. Such findings would likely have important spin-off benefits for more effective management of the current ‘epidemic’ of obesity, the metabolic syndrome and its main complications (type II diabetes and cardiovascular disease) in the wider community.

Our findings are also likely to point to more relevant and refined therapeutic targets for schizophrenia treatment, leading the way to the development of third generation antipsychotics that are more effective and less harmful than the present second (‘atypical’) generation of antipsychotic drugs.

This research program is also likely to provide the template for similar pharmacogenomic studies with respect to other adverse effects of drugs used in the treatment of mental disorders. Thus, for example, sexual dysfunction is commonly associated with some antipsychotic drugs, such as risperidone, as well as antidepressants such as Prozac. The identification of patients at risk before starting therapy would help in the choice of alternative therapies and the pre-emptive implementation of measures that could prevent or ameliorate drug-induced adverse effects.