In 2004, after evaluating 372 randomized clinical trials involving almost 100,000 patients, the Food and Drug Administration issued a black-box warning on antidepressants. The most serious caution of its kind, the warning served to alert patients and medical providers that the drugs were associated with an increased risk of suicidal thinking and behavior in children and adolescents.
Three years later, the FDA expanded the black-box warning to include individuals ages 18 to 24. At the time, the agency also mandated that the warning label state that depression and certain other psychiatric disorders are themselves associated with increased suicide risk. The added language came amid concerns that these black-box warnings, and the attention they had garnered, contributed to decreased treatment of depression.
Those same concerns remain today, leading researchers at Johns Hopkins University to explore new ways of treating children and adolescents suffering from major depression using antidepressants. “We were making great headway into being able to treat depression in kids until the black-box warning,” says Dr. Adam Kaplin, an assistant professor of psychiatry and neurology at Johns Hopkins University School of Medicine in Baltimore. Though the use of antidepressants seems to have increased somewhat since the black-box revision in 2007, evidence shows it remains below pre-label levels.
Kaplin was the senior investigator on a study, published in the journal Translational Psychiatry in May, which used testing in mice and computer simulation to develop new treatment strategies for more safely prescribing antidepressants to young patients.
The FDA’s decision to add a black-box label more than a decade ago followed meta-analyses of research showing that the rate of suicidal thinking or suicidal behavior doubled among those taking antidepressants to 4 percent of patients, up from 2 percent of patients given a placebo. The agency’s analysis of the research found the risk was highest among children and adolescents, and that there was no indication of increased risk for patients older than 24. (In patients age 65 and older, antidepressants have been found to have a protective effect against the risk of suicidal thinking and behavior.)
But in decrying the FDA’s decision to issue a black-box label, many critics have summarily dismissed the findings behind it — noting, among other things, that none of the young patients studied successfully took their own lives and that depression by itself, as noted on the warning label, increases one’s risk of suicide.
While taking into account the research that led to the warning label, Kaplin and his fellow researchers took a different tack. The multidisciplinary group sought to better understand why antidepressants might increase risk of “suicidality,” or suicidal thinking and behavior, in a small percentage of young people who take the drugs, and what health care providers could do about it. “There is a phenomenon that requires explaining,” he says.
The research team included Kristen Rahn, an instructor in the department of psychiatry and neurology, Dr. Craig Hendrix a professor of medicine with a focus in pharmacology and adjunct professor of medicine Dr. Ying J. Cao, now with Deerfield, Illinois-based research and development firm Astellas Pharma Global Development.
In taking a closer look, the team found, for example, that when mice were given SSRIs, or selective serotonin reuptake inhibitors — the most widely prescribed class of antidepressants — they exhibited more anxiety, not less, in the short term, though the drugs tend to decrease anxiety over the long term.
“So the first thing that happens when you give a drug to increase serotonin is you block the release of serotonin, and that period of time where it is blocked is what leads to, in kids, the impulsive aggressiveness,” Kaplin says. In other words, he says, while kids who weren’t suicidal before don’t suddenly become so, those who were at risk may become more inclined toward suicidal thoughts or behaviors in the first few weeks of taking antidepressants, before the drugs’ therapeutic properties take full effect.
However, when mice given SSRIs were also given a drug with a mechanism that blocked the side effect that increases impulsiveness in kids, the mice saw a much more rapid therapeutic effect. The other drug given alongside antidepressants, called a 5HT1 receptor antagonist, was the FDA-approved beta blocker Pindolol. Kaplin hopes drug companies might have other 5HT1 receptor antagonists not yet approved for market that could work for this purpose.
Previous research in people shows Kaplin wasn’t the first to pair Pindolol with SSRIs in the hopes of improving treatment of depression. While a decade-old study published in a BMJ journal, Evidence-Based Mental Health, didn’t find evidence for long-term benefit, it did find the pairing appeared to increase treatment efficacy during the initial two weeks of treatment — precisely when the risk for increased suicidal thinking and behavior is often highest in young people taking antidepressants.
In analyzing the data on which the FDA based its decision to issue a black-box warning for antidepressants, the team from Johns Hopkins found that those medications that take effect most quickly, or have the shortest half-life, also appear to have the biggest impact on increasing risk of suicidal thinking and behavior in children and adolescents. Though that distinction hasn’t been parsed out by regulators — the black-box warning makes no distinction between types of antidepressants — the only SSRI approved for children ages 8 to 12 is the slowest acting SSRI, Prozac, also called fluoxetine.
Taking that into account, researchers performed a computer simulation to find the optimal dosing strategies for faster-acting drugs that might help patients more quickly see the improvement while mitigating side effects.
The result: The computer spit out dosing strategies similar to those already used in adults with anxiety treated with SSRIs, starting at half the full dose and then slowly increasing to the full dose.
Kaplan says when he approached pediatric psychiatry colleagues at Johns Hopkins they told him they were already treating patients with antidepressants using the stepped dosing strategy that matched what computer simulations recommended to ward off increased impulsiveness in young patients. “Kids … get hyped up, they say, if they start them at the regular dose. So they start them at half the dose and titrate up,” he says.
Still, with a shortage of pediatric psychiatrists nationwide and antidepressants more typically prescribed by time-pressed primary care providers, experts like Kaplin say nuanced treatment strategies tend to take a back seat to simply using the black-box labeled drugs less often, as compared with levels before the warning was issued.
Rahn, Hendrix and Kaplin have submitted a patent application for methods they developed to reduce anxiety and impulsivity in patients who are initiating treatment with SSRIs.
“I think it’s a very interesting study, it’s very thought provoking,” says Dr. Mark A. Frye, chair of psychiatry and psychology at Mayo Clinic in Rochester, Minnesota, who was not involved in the research. While noting that all drugs have side effects, he says the study conducted by Johns Hopkins researchers on antidepressants starts to address some of the concerns raised by the FDA’s black-box warning.
“It’s really looking at are there ways to try to further enhance the safety, further enhance the efficacy, further attempt to reduce side-effect burden with drugs that are available to treat life-threatening conditions, and do it in a way with new, novel research,” Frye says.
He cautions, as Kaplin does, that animal studies aren’t enough to dictate clinical practice. Kaplin says his colleagues in pediatric psychiatry are seeking funding to do research to test the novel antidepressant treatment strategies in people next year.
In the meantime, he and Frye say it’s important that patients and parents talk don’t delay seeking treatment for depression in children. For those concerned about the potential side effects of antidepressants, Frye says they should talk with health providers about what they can do to individualize treatment and make sure children are closely monitored for side effects, in addition to discussing treatment alternatives, such as therapy.
For patients with mild to moderate depression, non-pharmaceutical approaches, such as exercise and talk therapy, may be enough. But many clinicians say that antidepressants are needed to treat the most severe symptoms. While there’s robust debate about whether antidepressants are more helpful or harmful in the long term, research tends to show that talk therapy and medication are more effective at treating depression than medication alone.
Whatever the treatment approach, experts say the stakes couldn’t be higher for young people suffering from depression.
In the wake of the FDA-issued black-box warning aimed at lowering suicide risk in those patients taking antidepressants, there’s some evidence indicating, paradoxically, that the risk of suicide may have increased in young people struggling with untreated depression.
“There’s a number of studies to suggest that since the warning label for antidepressants was brought forward that the rates of prescription use in this patient population has gone down and that the rates of suicidal thinking in this patient population has gone up,” Frye says.
A study published in The BMJ last year concluded that safety warnings about antidepressants and the attendant widespread media coverage decreased antidepressant use, and that “there were simultaneous increases in suicide attempts among young people.” Other evidence suggests increases in suicide rates among young people are unrelated to the black-box warning.
Whatever the case, mental health experts say hand-wringing and inaction isn’t an acceptable response to a child suffering from depression — for parents or providers.
“We’re obliged to first do no harm, but we also know that we must treat symptoms of depression which can be debilitating,” Frye says. “We have a limited number of options and the reality is antidepressants can be very helpful and can be lifesaving.”
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New Strategies Aim to More Safely Treat Depression in Young Patients originally appeared on usnews.com
