Finding the genetic material in personalized medication

By Mahbod Ebrahimi

It is estimated that 1 in 5 Canadians will suffer from a psychiatric disorder in their lifetime. At present, there are 6.7 million Canadians suffering from various mental illnesses, and this is predicted to increase to 8.9 million people within the next generation.1 There has been a myriad of research on the etiology of psychiatric disorders such as schizophrenia, but our limited knowledge of the underlying mechanisms for their development results in the suboptimal treatment of psychiatric patients.

Dr. James L. Kennedy, a clinical psychiatrist, scientist, and the head of the Tanenbaum Centre for Pharmacogenetics at the Centre for Addiction and Mental Health (CAMH) has led pioneering investigations to identify genes involved in psychiatric disorders and personalizing psychiatric treatment. After completing his medical degree at University of Calgary and residency in psychiatry at Yale University, he returned to Canada and started his molecular genetics laboratory in Toronto at CAMH and has been one of the leaders in psychiatric research over the past 30 years. Dr. Kennedy aims to improve our understanding of the genetic mechanisms causing psychiatric disorders, and also predicting and improving patient outcomes to psychiatric medications.

Currently, for the prescription of psychiatric medication, it is common practice to use the trial-and-error approach. This approach could be influenced by many external factors, including the patient’s age, gender, and dietary habits, which can increase response variability and limit drug effectiveness. Another influence is physicians’ personal preference for prescribing drugs. Some physicians might be more familiar with a particular drug, leading to prescribing the drug for a majority of psychiatric patients rather than focusing on the best option for each individual. In Canada, 7.5% of all patients admitted to hospitals have experienced at least one adverse drug effect, of which nearly 37% have been determined to be preventable.2 Overall, the trial-and-error approach leaves a great deal of uncertainty associated with effective patient treatment.

The lack of accurate and effective treatment for psychiatric disorders, particularly schizophrenia, causes patients to suffer many side effects. The reason for this imprecise treatment is the lack of understanding of the underlying mechanisms of psychiatric disorders and how drugs affect the brain. “The brain is the target organ, and it’s so complicated to figure out all the different interactions for someone getting depressed or someone suffering from schizophrenia,” Dr. Kennedy explains. Unlike other medical fields, such as cardiology or oncology, in psychiatry, researchers cannot conduct direct tissue studies on the target organ, adding another layer of complexity to the patient’s treatment plan.

In response to the lack of effective treatment options for psychiatric disorders, Dr. Kennedy launched the ‘Individualized Medicine: Pharmacogenetics Assessment and Clinical Testing’ (IMPACT) study in 2012—a seven-year study utilizing genetic information to guide physicians’ decisions on the best antidepressant or antipsychotic medication for each patient.3 To this day, the IMPACT study is the largest conducted study on pharmacogenetic testing ordered by physicians, which also included follow-up with patients after the test.

At the beginning of the IMPACT study, Dr. Kennedy and his lab innovated an in-house genetic test and tested over 2000 patients. Upon growing interest and demand for pharmacogenetic information, Dr. Kennedy

Dr. James L Kennedy Head, Tanenbaum Centre for Pharmacogenetics, Director, Molecular Brain Science Research Department. Campbell Family Mental Health Research Institute. Centre for Addiction and Mental Health. Professor, Institute of Medical Science, Department of Psychiatry

Imagine if we had Google for our genes!

partnered with the largest psychiatric pharmacogenetic testing company in the US and tested a total of nearly 12,000 patients’ DNA samples. The genetic test, called the “GeneSight test,” was used to analyze six liver enzyme genes and two brain genes from the serotonin pathway. The results of the GeneSight test included recommendations and rank-ordering of antidepressants and antipsychotic medications. The results were delivered to the patient’s physician to help guide their decision on prescribing the best medication for the patient.

In parallel to Dr. Kennedy’s efforts for personalizing psychiatric treatment in the IMPACT study, he has also led research to identify genes that cause psychiatric disorders, especially schizophrenia. “The best way to treat a patient is to know the exact biology of their disorder,” Dr. Kennedy explains. Although this is a very complicated task, Dr. Kennedy is currently applying advanced molecular genetic techniques to study an array of psychiatric disorders, including bipolar disorder, obsessive-compulsive disorder, anxiety disorders, personality disorders, and most extensively, schizophrenia.

Dr. Kennedy has dedicated a large proportion of his research career to furthering our understanding of the etiology and genetics of schizophrenia. He was one of the contributors to finding novel loci that are associated with schizophrenia, which was published in Nature in 2014.4 Complementing his research, Dr. Kennedy routinely examines and aids schizophrenic patients in his clinical practice.

When asked about his interest in schizophrenia, Dr. Kennedy replied, “I’m fascinated by how a healthy young person, who might be a top performer in high school, could stop socializing with their friends, start developing strange ideas about aliens sending them messages, and become paranoid,”. He continued to explain, “It’s a fascinating question of why the brain would go wrong to create what we call schizophrenia.”

Schizophrenia is a severe mental illness characterized by symptoms such as psychosis, social withdrawal, and cognitive impairment. Dr. Kennedy’s current research focus in schizophrenia is related to the C4 gene, which is an immune system gene involved in our complement system. Due to the strong association with schizophrenia in genome-wide studies, and the fit of the C4 gene with the neuroimmune theory of the illness, it has recently been a major interest in this field.

The C4 gene is long known to play an important role in the immune system for identifying pathogenic cells. Surprisingly, the complement C4 gene also has a nonimmune function in the development of the human brain. During adolescence, the complement C4 protein identifies synapses in the brain that are no longer useful. The C4 protein then facilitates the pruning of these synapses to make the brain more efficient and help transition the person from adolescence into adulthood. However, the normal function of complement C4 in directing the healthy pruning of synapses might be defective in young people who start to develop schizophrenia. One of the ongoing projects in Dr. Kennedy’s lab looks at the relationship between the complement C4 gene and schizophrenia symptoms.

With more than 30 years of genetic and psychiatric research and sampling and analyzing over 35,000 patient DNA samples, Dr. Kennedy and his lab continue to generate ground-breaking research that increases our understanding of psychiatric disorders. Dr. Kennedy hopes to generate better pharmacogenetic testing for people to provide more understandable information on how their body reacts to drugs. “There is no downside to having your genetics measured, particularly for your risk of having side effects to medications,” Dr. Kennedy says. “I think the near future [of psychiatric research] will see value in application of measuring more and more genes that play some role in the brain to mediate drug response and generation of side effects.”

References

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4. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7.