On Feb. 2, 2004, Mark Miller of Overland, Kan., spoke at a public forum in the nation's capital, uttering words that no parent should ever have to speak:
"This is important for you to know," he told an FDA advisory committee. "Matt hung himself from a bedroom closet hook, barely higher than he was tall. To commit this unthinkable act, something he had never attempted before, never threatened to any family member, never talked about, he was actually able to pull his legs up off the floor and hold himself that way until he lost consciousness and forced himself to leave us."
Matt Miller was 13 when he took his own life in the summer of 1997.
"He died after a psychiatrist we did not know gave him three sample bottles of a pill we had never heard of, for a perceived illness that his doctor could only guess at," his father testified. "We were advised with great authority that Matt was suffering from a chemical imbalance that could be helped by a new, wonderful medication called Zoloft. It was safe, effective, only two minor side effects were cautioned with us: insomnia, indigestion."
In March 2004, the FDA issued a public health advisory about the potential for increased suicidal thoughts and actions among people who take antidepressants, particularly drugs in the relatively new subclass of agents known as "selective serotonin reuptake inhibitors," or "SSRIs" for short. They work by allowing the body to make more effective use of the brain chemical serotonin, which is a messenger involved in the regulation of mood, emotion, appetite, and sleep. Widely prescribed brand-name drugs in this class include Celexa, Lexapro, Paxil, Prozac, and Zoloft.
In October 2004, the FDA, following recommendations of the advisory committee, ordered makers of all antidepressant medications - not just SSRIs -- to include a "black box" warning and cautionary statements on drug labeling that will "alert health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents."
Britain's Medicines and Healthcare Products Regulatory Agency issued similar warnings in early December, urging doctors to consider alternative therapies and, when prescribing an antidepressant, to prescribe only low doses and monitor patients carefully.
Warning Signs
In the pharmaceutical industry, a black box on a product's label is a stark reminder that for every benefit, every "miracle drug," there is a risk. In the case of widely prescribed and heavily marketed antidepressants, the benefits of relief from symptoms of major clinical depression must be weighed against the relatively infrequent but potentially devastating risks of worsening of depression or suicide.
There is little dispute that antidepressants have helped millions of adults with major depression and other debilitating mental disorders. There is also, however, growing concern among doctors, child safety advocates, and parents that these heavily marketed mind-altering agents are being used too freely and with too little research into their effects in children and adolescents.
In a statement praising the FDA's action in March, Martha Hellander, JD, executive director of the Child and Adolescent Bipolar Foundation, called it "a wake-up call that these powerful and lifesaving drugs used to heal depression may trigger a paradoxical response in some children that parents need to know about."
Watch Out for Bipolar
The risks are higher in depressed children with a family history of bipolar disorder (formerly called manic depression) or who have existing symptoms of mania.
A doctor who served on the FDA Pediatric Advisory Committee tells WebMD that the risk of increased suicidality with antidepressants is incontrovertible. The unanswered question, says Thomas Newman MD, MPH, is whether the drugs work well enough in adolescents to justify taking the risk.
"There's no question that in the short term the drugs increase suicidality, but that doesn't really answer the question about benefits vs. risk. I think that we do need more data to know how effective they are ... whether there is some way of predicting in whom they will have favorable vs. adverse effects, and the whole area of what happens after you've been taking them for a long time or how you should stop them. Anything beyond the short-term trials that have been done we need more data on."
In an article in the Oct. 14 issue of The New England Journal of Medicine, Newman wrote that when FDA staff members analyzed results from randomized trials of antidepressants, "the results were striking. When all the pediatric trials were pooled, the rate of definite or possible suicidality among children assigned to receive antidepressants was twice that in the placebo group."
Psychotherapy Suicide Risk
Miriam Kaufman, MD, associate professor in the department of pediatrics at the University of Toronto and author of a book on helping teens overcome depression, agrees that there is evidence to show an increased risk of suicidality among teens who are started on therapy for depression. She notes, however, that increased suicidality is also seen among adolescents who have just started psychotherapy.
"The risk of suicidality is highest at the beginning of a depressive episode, regardless of treatment," agrees David. A. Brent, MD, professor of psychiatry, pediatrics, and epidemiology at the University of Pittsburgh School of Medicine. "We have data in press now showing that the incidence rate of suicidality in a psychotherapy trial we did is comparable to what has been reported in people treated with medication."
Fudge Factor?
According to an article in the journal Pediatrics, about half a million children and adolescents in the United States each year receive prescriptions for SSRIs. From 1993 to 1997, the number of prescriptions for preschool and school-age children of three drugs, Prozac, Paxil, and Zoloft, grew threefold.
This phenomenon isn't limited to the United States, a Toronto-based child psychiatrist tells WebMD.
"In Canada, just under 2% of the pediatric population is prescribed antidepressants. Sounds small, but it's actually quite large, and the rate of prescribing psychotropic medications has risen dramatically over the last 10 years, even though rates of depression have not. So in other words, the rate of prescribing has gone up much more quickly than the prevalence rate of the disorder, so we have to ask why," says Marshall Korenblum, MD, associate professor in the department of psychiatry at the University of Toronto.
Korenblum tells WebMD that aggressive marketing by drug companies, including direct-to-consumer advertising (banned for prescription drugs in Canada, but not in the U.S.) may account in part for the explosion in sales of antidepressants for kids. But for doctors who prescribe them, the relative safety of newer generation antidepressants like SSRIs compared with older antidepressants known as tricyclic agents was a big selling point.
"If you take the SSRIs in overdose, they're safe. Teenagers would die if they took tricyclics because they have effects on heart, basically heart rhythm, whereas large, large amounts of SSRIs are quite safe. So physicians heard that and said, 'OK, these drugs are safe in the sense that if you overdose on them you're not going to die, and they were showing equal efficacy to the older generation. That's what the early [clinical] studies showed, and I think as a result, prescribing rates kind of took off."
Half Truths, Concealed Evidence
But as Craig J. Whittington, PhD, and colleagues from University College London in England reported in the April 24, 2004, issue of The Lancet, the benign view of newer antidepressants appears to have been based in part on half truths and concealed evidence.
While the researchers found that there was evidence to support the use of one drug, Prozac, in children and teens, the evidence -- both published and unpublished -- was weaker or negative in terms of risk-to-benefit ratio for Paxil, Zoloft, Effexor, and Celexa.
"Moreover, a possible increased risk of suicidal ideation, serious adverse events, or both, although small, cannot be ignored," they write.
In an accompanying editorial, Lancet editors decried the practice of withholding apparently unfavorable or questionable clinical evidence from consideration.
"It is hard to imagine the anguish experienced by the parents, relatives, and friends of a child who has taken his or her own life. That such an event could be precipitated by a supposedly beneficial drug is a catastrophe. The idea of that drug's use being based on the selective reporting of favourable research should be unimaginable," they write.
Risks Yes, but Benefits Too
Lost in the furor over increased suicidality and fudged trial results, however, is the evidence to suggest that newer antidepressants can offer significant clinical benefits to many young patients with depression, says Brent, who served on the FDA advisory committee and reviewed the evidence on antidepressants but was unable to attend the public meeting.
Brent tells WebMD that the growing evidence of increased suicidality has not caused significant changes in his practice.
"You have to explain to people the benefits and the risks, you have to monitor people for suicidality closely at the beginning of a depressive episode, the beginning of treatment anyway, and the only difference is that before you start an antidepressant, you need to explain to the family that there is a slightly increased risk of this happening," he says. "But at least for Prozac, where there's the most data, you're going to help many more people than are going to run into a problem with this. But in my opinion it is an acceptable risk-benefit."
What About Psychotherapy?
Brent is a pioneer of a form of psychotherapy known as cognitive behavioral therapy (CBT), which is based on the idea, backed by clinical evidence, that helping people to change the way they think can also help them change the way they feel. The technique has been shown to be effective in the treatment of depression and anxiety disorders.
But even he acknowledges that at least one SSRI, Prozac, appears to work well both in concert with psychotherapy and when used alone. He points to the recently published Treatment for Adolescents with Depression study (TADS) in which the investigators found that a combination of Prozac and CBT was most effective at treating teens with depression. In the study, however, CBT proved to offer only modest additional benefit, Brent says.
"[Prozac] alone produced almost as good results as the combination of [Prozac] and cognitive behavioral therapy. CBT alone was 10% better than placebo, and you got another 8% response when you added it to the medication. There wasn't an interaction -- the medication didn't work better because they were also getting CBT," he says. "The part that worries us is that there are not a lot of people that can do CBT, and now you're going to be telling people that the standard of care is something that most people can't get."
Not All Evidence Points to Antidepressant, Suicide Link
Other researchers have questioned whether antidepressants are even really at fault.
As reported by WebMD on Dec. 15, researchers at the University of Colorado Health Science Center analyzed insurance claims on more than 24,000 teens with depression and found that when the data were broken down by severity of depression and other risk factors for suicidality, the use of antidepressants did not account for the increase.
The researchers, led by Robert J. Valuck, PhD, RPh, director of pharmaceutical outcomes research at the UCHSC, found that teens who were on antidepressants for six months were less likely to attempt suicide than their nonmedicated counterparts. They reported their findings in the December 2004 issue of the journal CNS Drugs.
"People see that crude relationship between antidepressants and suicide attempts and say antidepressants are bad," Valuck told WebMD. "But what if we adjust for all these factors that may contribute to the person's likelihood of attempting suicide? When we do that, the relationship goes away. There are a lot of things going on in teens who attempt suicide. It is not just the antidepressant drugs."
Brent, writing in the Oct. 14 New England Journal of Medicine, argues that banning or severely curtailing the use of antidepressants in children "would turn the clock back 25 years to a time when the only thing we could offer the families of suicide victims was the hope that someday we would have effective treatments. Ideally, the FDA, families, and clinicians will find the right balance between the risk of suicidality and another, greater risk: the risk that lies in doing nothing."
