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Treating Depression in Teens Should Get TADS Better

News from the Johns Hopkins Department of Psychiatry and Behavioral Sciences

Dr. Walkup
“The FDA did right with the black-box warning,” says Walkup. “There’s enough data to give us suspicions, to make us monitor patients more, even if, at this point, it’s not enough to tell us what we really need to know.”

That child psychiatrist John Walkup is spending longer hours in his Hopkins office is a lingering effect of the 2003-04 storm that swirled around using SSRIs (serotonin reuptake inhibitors) for clinically depressed teens. Like many experts, Walkup and his colleagues are seeing a surge in referred patients.  

After the FDA’s required “black-box” warnings that antidepressant use in children may increase the risk of suicidality, many primary physicians stopped prescribing. Instead, they sent younger patients directly to psychiatrists. “And some psychiatrists, wanting proper caution,” Walkup says, “changed their threshold for prescribing medicine, saving it for the severest cases.”

Is that helpful? In one way, yes, says Walkup. Being cautious with a vulnerable group can’t be bad. But the shifts in practice signal uncertainty, many feel. “We need perspective,” he says, “in deciding how to help mood-troubled adolescents.

“It’s all about risk and benefit,” explains Walkup.

So for now, he’s heeding what he found as co-leader of Hopkins’ part of the Treatment for Adolescents with Depression Study, an NIMH-funded national project. At its start in 2000, TADS was the first head-to-head look at psychotherapy and an antidepressant for clinically depressed teens. It parceled 439 patients into four treatment arms: fluoxetine (Prozac) alone, cognitive behavioral therapy (CBT), a combination of both or a placebo. By 2004, the first report—one of many to come—showed clear benefits of the short-term treatment: Teens on combined fluoxetine and CBT got significantly better. The drug alone also helped, by some measures. Statistically, psychotherapy wasn’t better than placebo.

“Doctors and policy makers need to know that the combined treatment is the best way to go,” says Walkup. “The challenge, though, is that high-quality psychotherapy isn’t always available. And that should change. Training more providers is worth every penny.”

Until that happens, Walkup and TADS colleagues say some ways exist to keep risk low and benefits high. “Because some children did well on fluoxetine, prescribing the drug under careful monitoring, even without psychotherapy, seems reasonable.” And articles are in press that shed clearer light on what works for whom—if, perhaps, certain teens heal with psychotherapy alone.

But risk? That’s a little murkier. Preliminary TADS results mirror earlier FDA data in suggesting no significant appearance or worsening of suicidality. Overall, thoughts of suicide actually decreased. But at the same time, spontaneous reports of suicidal ideas or behavior were more common in the fluoxetine groups. “That looks contradictory,” Walkup says, “but it really isn’t.” The TADS authors explain why in an upcoming paper on fluoxetine’s safety: Only a small number of kids bucked the beneficial trend. Data on how ill they were when suicidal and their drug compliance are part of the report’s insights.

“So I tell families this,” Walkup says. Studies are good enough that we shouldn’t fear antidepressants, especially given the risks of untreated depression.” More than ever, however, parents and teens need to understand the course of depression, its dangers, and the risks and benefits of being treated. “And they shouldn’t be afraid of that either!”

“As for doctors,” Walkup advises: “Do today whatever you were doing five years ago. But take time to educate, to reassure that with proper monitoring, treatment is safe.”

Is it Dosage?
Dr. Kaplin
Dr. Adam Kaplin

Last year, an FDA survey of studies on SSRI antidepressants for children revealed a small but possible risk of things suicidal. Now, warnings have appeared on all antidepressants for children and adults. This troubles the clinician part of Adam Kaplin, who treats adults with mood disorders. At the same time, the neuroscientist in him has pricked up its ears.

Kaplin’s concern is that people are shying away from the drugs, that the decline in suicide rate which began in 1988, the year Prozac (fluoxetine) was introduced, will end. Also, like everyone else, he wonders what underlies the drugs’ suggested risk. But recently, Kaplin has gone beyond wondering. He’s woven others’ solid research into an intriguing, coherent hypothesis: The SSRI problem is dosage.

Here are the threads: Of the SSRIs tested, only Prozac clearly helps depressed children. It’s also least tied to suicide-related thoughts or actions. “Why is Prozac different?” Kaplin asks. Of them all, it increases the most slowly in blood and brain, taking up to a month to reach a steady state. Paxil, by contrast, takes as little as three days.

Another thread: “For adults with anxiety, we’ve known a jillion years that full-dose SSRIs, to start, make things worse before patients improve. You must begin with a half-dose.” Thread three: In animals given SSRIs, serotonin output first drops before it rises. Why? Neurons have “shutoff valves,” axon-based receptors that sense if serotonin floods a synapse. They feed that news back to supplying cells, which accordingly release less.

So Kaplin suspects that an initial rush of serotonin trips the “valves,” damping down release, lowering serotonin. And studies show that low serotonin makes people impulsive, he says, and perhaps suicidal.

“You can’t change the properties of Zoloft,” he says. But you can prescribe a different dose each day, rising slowly to mimic Prozac’s slip into the nervous system. “Then SSRIs would be as fearsome as blood pressure pills—drugs you ease up to potent levels.”

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