The Genomics of Bipolar Disorder
By genotyping patients with bipolar disorder and using state-of-the-art imaging technology to evaluate drug effects, Mayo Clinic psychiatry researchers are learning more about the genetics of the disorder and how to better treat it.
Getting a handle on bipolar disorder is like riding a roller coaster with both patients and physicians — all hollering for stability. There is no diagnostic test to confirm bipolar disorder, and choosing the optimal drug therapy is a frustrating odyssey of trial and error. Manic episodes of overly excited states can quickly slide into states of deep depression. And some antidepressants, while effective in one individual, can trigger new rounds of uncontrollable mania in another.
Mayo Clinic psychiatry researchers are investigating ways to end the roller coaster ride, or at least to eliminate some of its rushes and surges. Mark Frye, M.D., is using genotyping and brain scans in research to hopefully one day match the genetic profile of newly diagnosed patients with the most effective and least harmful drug to treat bipolar disorder.
Toward accurate diagnosis
Mayo Clinic is participating in an effort to rewrite accepted diagnostic criteria for bipolar disorder. "Diagnosis is currently made by confirming a set of signs and symptoms," says Dr. Frye. "It would be valuable as a clinician, when someone walks into our Mood Clinic here at Mayo, to have additional tools to help confirm diagnosis and guide treatment selection."
About Bipolar Disorder
Nearly 14 million Americans (4.5 percent) experience some form of bipolar disorder, according to the National Institutes of Mental Health. It is linked to premature death and is a leading cause of disability for people ages 15 to 44.
Bipolar Type I disorder involves manic or mixed episodes lasting at least seven days that can be dangerous and require hospital care. Patients may exhibit inflated self-esteem, grandiose thoughts, reduced sleep, racing thoughts, easy distractibility, agitation, focused goal-directed activity, and heightened involvement in pleasurable or high-risk activities. Patients may also experience depression lasting two weeks. Mood swings interfere with daily function.
Bipolar Type II disorder is less severe. There may be some change in function, but people can generally continue their daily routine. Typically, periods of depression last longer than those of mania.
Dr. Frye and colleagues are performing extensive blood tests, molecular testing and brain scans of patients with bipolar disorder to build the Mayo Clinic Individualized Medicine Biobank for Bipolar Disorder. The biological and clinical data collected in the biobank is intended as a resource for the bipolar research community to facilitate research leading to more accurate diagnosis, individualized drug therapies and increased knowledge about risk factors.
The biobank is a collaborative effort with the University of Minnesota, the Lindner Center of Hope in Cincinnati, Ohio, and all Mayo Clinic campuses. The goal is to include data from 2,000 individuals between the ages of 18 and 80. Samples are usually collected by Mayo's Clinical Research Unit and stored in the Biospecimens Accessioning and Processing (BAP) Shared Resource core facility. (See "A Researcher's Unexpected Journey" in this issue.) The initiative was launched in part through philanthropic support.
"Our hope is that biobank data may one day help identify the right treatment for the right patient," says Dr. Frye. "A good example of this is when clinicians struggle as whether or not to use antidepressants in the depressive phase of bipolar disorder. While not a common event, some patients can develop an antidepressant-induced mania. Right now, we're looking at the most commonly prescribed antidepressants — SSRIs like Prozac, Paxil and Zoloft."
Dr. Frye says the biobank can be used in different ways. In the case of antidepressant-induced mania, they are looking for patients who became manic while on Prozac and compare them with patients who were on the drug for the same time and did not become manic. This is called a case-control design. Using someone who had never been on Prozac as a control would be a bad comparison.
The team is also looking for genes that confer risk of developing bipolar disorder. In these studies, the control group will come from the 20,000 participants in the Mayo Clinic Biobank. The scientists who conduct the lab analyses will be "blind" to the patients' diagnosis.
"Our research work is looking at whether a set of genes associated with this adverse outcome can be identified in such a way that future patients, when depressed, can be given alternative medications or psychotherapy."
In a clinical case conference (NEJM 2011), Dr. Frye reviewed a comprehensive analysis of 15 trials comparing short-term treatment with common antidepressant drugs that had no major benefit.
"There is great need to better understand the neurobiology of bipolar depression and develop novel treatments. Some of our earlier work had characterized bipolar depression as having an increase in glutamate in the anterior cingulate, which is a brain region implicated or associated with depression. Furthermore, we saw a change in glutamine that was linked to clinical remission of depressive symptoms in the presence of lamotrigine." This, he thought, warranted further investigation.
Dr. Frye is now recruiting for a five-year clinical trial to evaluate the effectiveness of lamotrigine treatment for bipolar disorder. Lamotrigine is an anticonvulsive drug that appears to improve mood stability. The trial, funded by the National Institutes of Health (NIH), studies glutamate and glutamine concentrations in brain regions implicated in bipolar disorder, to evaluate their effect on clinical remission.
Participants undergo brain imaging with proton magnetic resonance spectroscopy before and after 12 weeks of treatment with lamotrigine. The imaging technology is a noninvasive method of evaluating the biochemical mechanism of drug action.
Fellow psychiatry researcher David Mrazek, M.D., has long been interested in pharmacogenomics — the science of discovering the genetic basis for individual variations in drug response. He was instrumental in developing a DNA test that can reveal whether a patient has one or more genes that interfere with the body's metabolism of commonly prescribed antidepressant drugs.
Dr. Mrazek notes that treatments can vary drastically even for the same diagnosis within the same family. In his book, "Psychiatric Pharmacogenomics," he cites a case study in which both parents and their twin sons were diagnosed with depression. Surprisingly, each reacted differently to the same drug. Subsequent genotyping revealed different enzymatic activity levels that influenced whether the drug stimulated normal, slow or rapid metabolizing of the drug.
"The ultimate goal is determining how to prescribe the right drug for the right patients at the right dose," Dr. Mrazek says.
A new career direction
In 2006, Dr. Frye returned to his hometown, Rochester, Minn., to join Mayo Clinic. He currently chairs the Department of Psychiatry and Psychology, although his medical career was initially directed toward internal medicine. Since transitioning to psychiatry, he has narrowed his focus to bipolar disorder, including a fellowship at the National Institute of Mental Health (NIMH) at the NIH and eight years directing UCLA's Bipolar Disorder Research Program.
"It was interacting with patients with mood disorders, in particular bipolar disorder, that led me into psychiatry," he says. "I got very engaged when I realized how much there was to discover through brain imaging, genomics and clinical trials. It's exciting to contemplate how research will enable us to better understand bipolar disorder so that we can develop more-effective therapies and achieve better quality outcomes for our patients."
Dr. Frye has a particular interest in early-onset bipolar disorder and the impact of delayed treatment in young people. In a collaborative study, he and other researchers found that half of 529 patients (mean age of 42) had their first symptoms before age 13 or in their adolescence years (JClinPsy 2010).
"Our study, with lead author Robert M. Post, M.D. (of George Washington University), showed that individuals who have onset of the illness in adolescence versus in adult life tend to have a more difficult course," Dr. Frye says. "Is this biologically or genetically based or associated with psychosocial stress? We don't know the answers, but we do know they are less likely to respond to medications and we should be vigilant to correctly diagnose young people and indentify the best treatment interventions for them."
Drug therapy for bipolar disorder has come a long way since its beginning, in 1970, when lithium was approved. A second drug, divalproex, or Depakote, an anticonvulsant, became available in 1994. Today, drugs approved for bipolar treatment include mood stabilizers, anticonvulsants and antipsychotics. However, each comes with side effects ranging from mildly inconvenient to serious rare side effects. While there is need to develop new effective treatments that have less side effect burden, there is as much need to individualize the treatment of bipolar disorder by finding the right medication for the right patient at the right time. Dr. Frye is confident that the Individualized Medicine Biobank for Bipolar Disorder will do much to move the field along.
— April 2011