The FDA has urged clinicians, family members, and caregivers to carefully monitor patients who are taking certain antidepressant drugs for signs of worsening depression or the emergence of suicidality, particularly at the beginning of therapy or when the dose is changed. This recommendation coincides with the agency’s request for manufacturers of 10 antidepressants to include a warning statement in their labeling that recommends close observation of both adult and pediatric patients for these behaviors.

The drugs included in the warning are Prozac (fluoxetine), Zoloft (sertraline), Paxil (paroxetine), Luvox (fluvoxamine), Celexa (citalopram), Lexapro (escitalopram), Wellbutrin (bupropion), Effexor (venlafaxine), Serzone (nefazodone), and Remeron (mirtazapine). The FDA has not concluded that these drugs cause worsening depression or suicidality, but it wants health care providers to be aware that worsening of symptoms could be due either to the underlying disease or to drug therapy. The FDA’s actions follow recommendations made by two advisory committees in February.

“The message is to watch for these behaviors when patients start on a drug,” said Russell Katz, MD, Director of the FDA’s Division of Neuropharmacological Drug Products, in an interview with NEUROPSYCHIATRY REVIEWS. “We don’t know whether the drugs cause them or not, but you should be aware that they might happen and take them seriously. We are still analyzing the data to see whether we really can say if the drugs cause suicidality. Right now, we cannot say that.”

REASONS FOR CONCERN

The FDA first became aware of a potential increase in suicidality among pediatric patients with depression nearly a year ago after an initial report about Paxil, as well as subsequent studies on other drugs, appeared to suggest an increased risk of suicidal thoughts and actions in children. Overall, more than 20 studies have been conducted in pediatric patients with depression. However, there were no suicides in any of the trials, and it was unclear whether certain behaviors reported in these studies represented actual suicide attempts or other self-injurious behavior that was not suicide related. “On closer scrutiny, companies had described various behaviors in very different, highly idiosyncratic ways,” said Dr. Katz. “For example, in one study one girl slapped herself in the face, so that company, to be conservative, called that self-injurious behavior, or suicidal behavior, which most people would consider that not to be. When we looked at the data from all the companies in the pediatric studies … we couldn’t reliably conclude that what the companies called suicidal behavior was, in fact, suicidal behavior.”

In February, the FDA told two advisory committees that the data from the studies were unreliable and therefore it could not conclude that there was an increased incidence in suicidal behavior, according to Dr. Katz. So the FDA decided to have an outside group of leading researchers in suicidology, which has been coordinated through Columbia University but involves researchers from all over the United States, review blinded descriptions of these various behaviors. The panel will reclassify the cases according to whether it believes there is enough information to determine whether the behaviors are suicidal. At that point, the FDA will finish its analyses of whether any drugs may indeed be linked to an increased incidence of suicidality. “But right now, we cannot tell, and that’s what we told the committees in February,” said Dr. Katz.

At that meeting, about 60 people spoke of family members, often children, who had taken these drugs and committed suicide. “I think what came out of that meeting in general was that it appears as if there is some segment of the treating community, and of the patient community as well, who really weren’t necessarily paying as close attention as they should have been to various changes in the patient’s behavior, particularly after starting these drugs,” said Dr. Katz. For many years, there have been incidents of patients committing suicide after starting treatment. “Nobody knows why that is,” Dr. Katz cautioned. “We’re now trying to see whether it might be related to the drugs in kids, but we don’t know that. Nonetheless, the message that came through was that families would call physicians and say, ‘My child is behaving differently now,’ and there wouldn’t be much response. So the [advisory] committees very clearly wanted us to increase the warnings in labels for all of these drugs, to make it clear that patients should be observed closely for changes in behavior when these drugs are started—particularly with regard to suicidal behavior. The labeling that we’ve asked sponsors to adopt says quite clearly, ‘We don’t know that the drugs do this. But in any event, whether the drugs do it or don’t, watch closely; take seriously reports of changed behaviors.’ The labeling we’ve proposed also says that there are other behaviors that we really do believe are related to treatment—irritability, agitation, panic attacks, motor restlessness. We have no idea if those behaviors are related to increased depression or increased suicidality, but nonetheless you should watch for those closely as well. So the warnings we’re asking sponsors to adopt in their labeling are just an admonition to clinicians and family members to watch patients closely when the drugs are started, and if any serious new behavior emerges, be aware of it, whether the drugs cause it or not.”

TO TREAT OR NOT TO TREAT

The only drug that has been approved by the FDA to treat depression in pediatric patients is Prozac, although physicians can and do prescribe other antidepressants to children. “We’re making no statement about whether physicians should treat patients with these drugs,” stated Dr. Katz. Studies have been conducted for the other nine drugs, but “they have not demonstrated sufficient evidence to be approved, which is not the same thing as saying that we know they don’t work. It’s not that we know they don’t work; we just don’t have evidence that they do work. It’s a subtle difference but an important difference. If we knew that they didn’t work, we would take a very different position on this. We would say, ‘They might be dangerous, they don’t work, there’s no point in taking them.’ So we are not taking a position on whether patients should be treated with these drugs. That really is a decision that the physician and family have to make on their own in each individual case.”

Dr. Katz noted that the warning statement is intended for both adult and pediatric patients. Potential changes in behavior that can occur after treatment is started have been observed in both adults and pediatric patients. “We have explicitly asked sponsors in our proposed labeling to say that this applies to adults and pediatric patients. In fact, if you look at labeling now, there is a statement that says, ‘Watch your patients closely after you start,’ because you have to watch them closely for suicidal behavior. We’re basically just reiterating the same thing. We’re just putting that more prominently in the labeling.”

WILL COMPANIES COMPLY?

Dr. Katz is confident that the drug companies will comply with the FDA’s warning request. To date, the FDA has no data regarding the comparative potential risks among the drugs. “We’re asking all the drugs to adopt essentially identical language,” he pointed out. “There is no particular drug that is being put at a competitive disadvantage by saying, ‘Watch closely after you start my drug,’ because all drugs will have essentially the same language. In addition, we are clearly saying that we don’t know if the drugs do this, at least in regard to suicidal behavior. We think that all drugs are being treated essentially identically. The public knows that we have asked them to do this, and if you read the proposed labeling, it really is just an admonition to practice good medicine.”

The only advice the agency is giving is what is embodied in the proposed language for the labeling, emphasized Dr. Katz. “We’re not recommending any particular course of action on the part of the physician should these behaviors emerge, although we do say that you might give consideration to discontinuing or lowering the dose. But we don’t want to be particularly prescriptive in this regard, because it might just be the natural history of the illness, and the physician in any individual case may decide, ‘Well, this is just the illness. I think the patient still needs to be on the drug.’ So we don’t want to tell physicians what to do. What we’re really saying is watch for the behaviors, take note of it, and then decide in your best judgment what should be done about it.”

WARNING FALLOUT?

Dr. Katz hopes that physicians will not shy away from prescribing the drugs to patients who could benefit from them. “It’s a possibility that people will be frightened away from them, and that’s certainly not our goal,” said Dr. Katz. “We are certainly not saying, ‘Don’t use these drugs.’ The critical point in that regard is to make it clear to people that we do not know if the drugs increase suicidal behavior. We know that they increase to some extent other types of behavior, which the label mentions. But as far as what most people are worried about, which is suicidal behavior, we do not know if the drugs do this. All we know is that sometimes patients—adults and pediatric patients—get worse or become suicidal after treatment is started. We are not saying that the drugs cause them, so we don’t want people to conclude from the label that the drugs cause suicidality. We don’t want people to misread the label or to misread any agency pronouncements on this point.”

If physicians do not feel competent enough to manage patients with depression, Dr. Katz recommends referring them to someone who is better trained and who feels comfortable watching patients as closely as they need to be watched. “We just really want people to do the right thing, which in this case largely is to be aware that these behaviors can occur. So, is it possible that some people will look at the label and say, ‘Well, I’m not going to treat a patient who needs this drug,’ and then the patient is left untreated when he or she should be treated? That would be a bad outcome. But we hope the labeling is clear enough on these critical points, and we hope the agency’s pronouncements about this are clear enough. We hope no one is scared off using them for the wrong reasons.

“One thing we do know is that Prozac is effective, and we don’t know if the other drugs are effective,” Dr. Katz continued. “But that’s not the same thing as saying that we know that they are not effective. We know that many people believe that these drugs work. Many people use them. We’re not saying that’s the wrong thing to do at all. As many people have pointed out, over the past 10 or 15 years, the rate of suicide has gone down, and this is simultaneous with the increase in the use of all these drugs across the board. That doesn’t prove that the drugs are lowering the suicide rate, but it’s possible. In other words, these drugs may be working, and they may be protecting patients. Depression itself in some cases is a lethal disease. It has a high risk of suicide, and many people feel that these patients should be treated with these drugs even though they are not approved for this use. We would like to have data that show they are effective. We don’t have that data for most of the drugs, but that doesn’t mean that they don’t work. That’s really the state of knowledge at the moment.”

THE NEXT STEP?

The FDA hopes to have some answers by September as to whether any of these drugs actually increase the risk of suicide. At that point, the FDA may take additional action, said Dr. Katz. “I know right now people are anxious because we don’t have all the information we would like to have,” he said. “There isn’t much we can do about that until we actually do the analyses. In the meantime, all we can say is to watch your patients closely.… We hope that by September we will have a better answer at least to the question of whether the drugs cause suicidal behavior.”

Complete Warning Information From the FDA’s Public Health Advisory

• Health care providers should carefully monitor patients receiving antidepressants for possible worsening of depression or suicidality, especially at the beginning of therapy or when the dose either increases or decreases. Although the FDA has not concluded that these drugs cause worsening depression or suicidality, health care providers should be aware that worsening of symptoms could be due to the underlying disease or might be a result of drug therapy. • Health care providers should carefully evaluate patients in whom depression persistently worsens, or emergent suicidality is severe, abrupt in onset, or was not part of the presenting symptoms, to determine what intervention, including discontinuing or modifying the current drug therapy, is indicated. • Anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although the FDA has not concluded that these symptoms are a precursor to either worsening of depression or the emergence of suicidal impulses, there is concern that patients who experience one or more of these symptoms may be at increased risk for worsening depression or suicidality. Therefore, therapy should be evaluated, and medications may need to be discontinued when symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. • If a decision is made to discontinue treatment, certain of these medications should be tapered rather than stopped abruptly (see labeling for individual drug products for details). • Because antidepressants are believed to have the potential for inducing manic episodes in patients with bipolar disorder, there is a concern about using antidepressants alone in this population. Therefore, patients should be adequately screened to determine if they are at risk for bipolar disorder before initiating antidepressant treatment so that they can be appropriately monitored during treatment. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. • Health care providers should instruct patients, their families, and their caregivers to be alert for the emergence of agitation, irritability, and the other symptoms previously described, as well as the emergence of suicidality and worsening depression, and to report such symptoms immediately to their health care provider.

—Colby Stong

Suggested Reading
Holden C. Psychopharmacology: FDA weighs suicide risk in children on antidepressants. Science. 2004;303:745.

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