Psychiatric Pharmacogenetics: Maximizing Benefits While Minimizing Side Effects
By: Zeynep Yilmaz, and James L. Kennedy, MD MSc FRCP(C)
Dr. James L. Kennedy is the Director of the Neuroscience Research Department at the Centre for Addiction and Mental Health and the Co-Director of the Brain and Therapeutics Division in the Department of Psychiatry, University of Toronto. Dr. Kennedy has an extensive, and unique combination of training in psychiatry, genetics, and neuroscience. As a professor and full-member of IMS, he has supervised well over a hundred trainees, including undergraduate and graduate students, postdoctoral fellows, and visiting scientists.
What is pharmacogenetics, and why is it important to study?
Pharmacogenetics is the science of linking a person’s DNA sequence with their response to medication. Because DNA provides its own unique blueprint of the body, we can make specific predictions as to the right drug and its correct dosage for a particular patient. We hope to prevent patients from continuing for weeks on ineffective medication and then having to switch to another medication, going through the entire disappointing sequence of non-response. We need to move beyond trial-and-error prescription of medications. With pharmacogenetics, we can help predict which patients will not respond to a particular medication, and also predict the best choice of medication on the basis of their genotype and psychiatric condition.
How did you become interested in pharmacogenetics?
I became interested in pharmacogenetics when I witnessed many patients suffer while receiving the standard textbook dose of an antidepressant or antipsychotic medication. I saw the answer was in the power of new DNA technology for testing patients to determine their combination of genetic variants and whether a given patient metabolized the medication quickly or slowly. I had also read seminal papers by Prof. Werner Kalow from his work here at the University of Toronto in the late-1950s and 1960s. He was the first to point out that people were genetically predisposed to having different rates for metabolizing medications, essentially coining the term “pharmacogenetics.” Prof. Kalow and I trained students in my laboratory, and before he passed away, he saw the fruits of these labours with the delivery of genetic tests for characterizing drug metabolism. Another Toronto researcher, Dr. Victor Ling, discovered the role of drug transporter proteins, for which there are now DNA-based tests to determine their variation across individuals. Given this powerful history in pharmacogenetics at the University of Toronto, I was inspired to carry the science forward using the developments in the human genome and genetic testing technology.
What are some of the clinical applications of pharmacogenetics in psychiatry?
We have a number of patented genetic discoveries making their way into the clinic, including a test using dopamine system genes to predict risk for tardive dyskinesia (uncontrolled muscle movements) as a result of prolonged use of antipsychotic medications. We also have a genetic test that identifies depressed patients who are at risk for developing mania as a result of their antidepressant treatment. We have just published an important paper showing the role of the melanocortin 4 receptor (MC4R) gene in determining the risk for antipsychotic-induced weight gain. The newer antipsychotic medications have the side effect of substantial weight gain; some patients will gain more than 100 lb during one year of treatment and often go on to develop diabetes and heart disease. After the initial finding of this gene’s effect in the first sample, we replicated the exact same result in three independent samples.
It is now possible for the physician to see a patient in the morning, for the patient to have a quick sampling of their saliva using a swab, and this sample to be shipped off to a specialized lab where the genotyping of the relevant genetic variants for common medications can be done overnight. The results are emailed to the physician the next day, and the physician writes a prescription on the basis of the patient’s genetic profile. There is little delay in starting treatment, and the choice of medication is precise and targeted to avoid side effects and achieve the best response.
On which psychiatric disorders are you conducting pharmacogenetic studies?
I expect that pharmacogenetic information will apply to virtually every psychiatric disorder. Over the 20 years that I have been doing research here at CAMH/UofT, I have overseen the collection of more than 24,000 DNA samples for disorders including schizophrenia, bipolar disorder, obsessive compulsive disorder, attention-deficit/hyperactivity disorder, addictions, eating disorders, suicidality in teenagers treated with antidepressants, as well as severe depression in young children. Unfortunately, not all of these patients have been characterized in terms of medication response. These studies are difficult because they require a patient to be followed over an extended period of time. Nonetheless, we have several thousand DNA samples from psychiatric patients with drug response and side effect information – one of the largest collections in the world.
How do you predict the future of pharmacogenetics?
As we move into the future, I see many benefits arising from pharmacogenetic testing in the population. It is easy to imagine the substantial healthcare savings when we can prevent non-response or debilitating side effects from medication treatment. If patients are prescribed the right drug from the start, they should have fewer doctor visits and stay compliant with their medication. Currently, under our large pharmacogenetic initiative funded by the Ministry of Economic Development and Innovation to test 20,000 patients, Ontario stands to be the leader, as the largest single geographic region offering pharmacogenetic testing in the world. Personalized medicine with pharmacogenetics is estimated to save Ontario at least $88 million in health care costs over the next 5 years. Pharmacogenetics is a very exciting area benefiting from rapid increases in DNA-based information, and computer-based algorithms combining information from multiple gene variants together to create more powerful methods to define an individual’s tailor-made treatment.
One of our recent projects is an innovative treatment for anorexia nervosa. We believe that one of the medications that has a calming effect in schizophrenia patients, but causes weight gain, may be helpful in anorexia nervosa by reducing anxiety associated with eating. It will be interesting to see if MC4R gene variation can predict those individuals that, in this case, gain weight in a helpful way. The fact that MC4R is expressed in the appetite centre of the brain may help demonstrate its value in predicting the patients that would get the most benefit from this medication.