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Fluoxetine (Prozac), received U.S. Food and Drug Administration approval in 1987. Almost a quarter century later, U.S. sales of antidepressants exceed $11.6 billion, but every one of the approximately 50 antidepressants now on the market is still prescribed on the basis of trial and error. There is no objective test to predict who is likely to respond.
It takes about 6 to 8 weeks to determine if an antidepressant is effective in an individual. For patients who need one, trial-and-error prescribing can be excruciating at best — and fatal at worst. It isn’t surprising that someone with depression (a symptom of major depressive disorder, or MDD) might consider suicide after months and months of failed treatment, with no relief in sight.
A search of PubMed using “depression and biomarkers” yields more than 3,500 results. Unfortunately, few if any of these studies are useful in clinical practice.
“There is an urgent need for valid predictors of effective treatment response, but these studies don’t get replicated and sometimes they don’t have robust results. So, how do we translate that to clinicians who are really interested in knowing how they can change their practice?” asks Subhdeep Virk, MD, assistant professor of psychiatry and clinical medical director of inpatient services at Ohio State University Wexner Medical Center, in Columbus.
In 2008, Brain Resource, an international company with offices in San Francisco and Sydney, sought to answer that question, launching the International Study to Predict Optimized Treatment for Depression (iSPOT-D). Virk is principal investigator for this study at Wexner, one of 12 iSPOT-D study sites in the United States. Enrollment in iSPOT-D is ongoing worldwide. The recruitment goal is 2,016 nonpsychotic MDD outpatients ages 18 to 65, making it the largest known study of its kind.
This prospective, open-label trial randomizes participants to one of three antidepressants — escitalopram (Lexapro), sertraline (Zoloft), or venlafaxine-XR (Effexor-XR). Under the protocol, published last year in the online journal Trials, eligible patients are antidepressant-naïve or willing to undergo a 1-week washout of any nonprotocol medication, and cannot have had an inadequate response to one of the drugs in the study. Each treatment arm includes equal numbers of gender-, age-, and education-matched healthy controls.
Clinical trial coordinators gather a great deal of baseline data, with the intent of helping investigators find common threads in treatment response. Initial screenings include the collection of sociodemographic data and psychiatric evaluation using the Mini-International Neuropsychiatric Interview, the Hamilton Rating Scale for Depression, and the Quick Inventory of Depressive Symptomatology–Self Report. Eligible participants undergo a series of baseline assessments, including:
Coordinators collect blood draws for genotyping, gene expression, and a proteomic and metabolomic analysis. Other tests include a drug and pregnancy urinalysis, an electroencephalogram, and various proprietary assessment tools. About 10 percent of participants undergo magnetic resonance imaging (MRI) to assess brain structure and functional MRI to assess brain function. These assessments are repeated after 8 weeks, and participants are followed by telephone at Day 4 and at Weeks 12, 16, 24, and 52.
The iSPOT-D study is designed to achieve four aims:
Although iSPOT-D is a single study, half the participant sample (n=1,008) is used as the “training set” for identifying predictors and modifiers (study aims 1–3). A replication and validation study is then undertaken using subjects from the second half of the trial (study aim 4). Data from the first half are now being analyzed, and the results will be matched with the data from the second half of the sample.
Preliminary findings for response rates and clinical and behavioral predictors from tests of cognition and emotion were presented at the American Society of Clinical Psychophamacology’s New Clinical Drug Evaluation Unit conference this year. Completion of aim 3, integrating analyses of all markers, is expected by the end of 2014.
“This study has generated a lot of information, and a lot of papers will come out looking at different aspects of the data,” says Virk. “Our group here at OSU, for example, will write a paper on the role of comorbid anxiety. Does the patient respond better if they have anxiety versus not?”
By including independent variables (cognition, genetics, brain structure, brain function) that have been the focus of smaller, inconclusive studies, iSPOT-D investigators hope that this statistically high-powered study will identify objective markers that may predict or moderate response to antidepressants. In the words of the Trials article, “Identifying these markers will be an important first step in a ‘personalized medicine’ approach to the management of MDD” (Williams 2011).
Typically, recurrent — and often chronic — MDD affects an estimated 15 percent of Americans. Only about half of patients respond to antidepressants, and only 1 in 3 achieves remission within 8 weeks of treatment. Those who do not attain remission are at high risk for depression, functional impairment, and serious general medical conditions.
Based on disability-adjusted life years, MDD is the fourth most disabling condition worldwide, and it is expected to move up to second by 2020. The economic burden of depression in 2000, the most recent data available, was estimated at $83 billion, 31 percent of which was direct medical costs (Greenberg 2003). Despite its prevalence, the etiology of depression is still ill-defined.
“I think it is multifactorial,” says Virk. “We know it has environmental, biological, and psychological bases. More and more people are seeking help because they know it is treatable, and the prognosis is good once you get treatment.”
Becki (not her real name), a recent enrollee in iSPOT-D at Ohio State University (OSU), is one of those people. A 37-year-old married mother of three, she attributed her mood change to postpartum depression after the birth of her second child in 2005. Two years after her third child was born in 2009, she realized that postpartum depression isn’t supposed to last so long.
“I had no interest in things that I normally enjoyed, like being outdoors, shopping, or going to movies,” recalls Becki, who works at a hospital in Columbus. “Keeping up with housework became a chore. I had very low energy and found it hard to concentrate at work. I would take naps when the kids would take naps — but for hours. It just dominated me.”
The kids were disappointed that their formerly energetic mom was sleeping all the time. Becki’s husband did his best to pinch-hit around the house. Last March, a friend gave her the contact information for the iSPOT-D study at OSU. Just 3 months later, Becki estimated she’s back to 80 percent of her “old self.”
“I’m probably one of the lucky ones,” says Becki, mindful of the fact that the antidepressant she is taking was randomly assigned. “I’m being treated and it’s been wonderful. It’s strengthened my relationship with my husband and my children, which is the most important thing to me.”
She adds that she is exercising regularly and is making better food choices, although weight was never an issue. “I’d say my mental health has improved my physical health,” says Becki, who did not consult her family physician about her depression before enrolling in iSPOT-D.
“We’re excited about this trial,” adds Virk. “Evidence-based markers will help us determine which patient will respond to which medication, which will save time and money.”