A handful of parents, doctors, and advocates for the mentally ill argued just as passionately about the benefits of antidepressants. Dr. David Fassler, distinguished child and adolescent psychiatrist and trustee of the American Psychiatric Association, reminded the audience that “the biggest risk for a child with depression is to be left untreated.” This view was underscored by a board member of the National Alliance for the Mentally Ill (NAMI), who testified, “I, as a mother and a psychiatrist, realize that the evidence linking suicidal behavior to SSRIs is weak and I will not draw conclusions lightly based on anecdotal information and isolated case reports.”
In support of SSRIs, the panel was presented with convincing evidence from Columbia University’s Dr. David Shaffer, who suggested there was a link between the decline in the suicide rate among fifteen-to twenty-four year-olds over the past ten years and a greater reliance on SSRIs during the same time frame. Dr. Shaffer cited a 2003 World Health Organization study, which found a significant reduction rate (an average of thirty-three percent) of youth suicides in fifteen countries during the last decade.6
But these views were drowned out by the anger and bitterness of the families who lost children to suicide (and, in a few cases, to prison, for homicides committed while “under the influence” of SSRIs). Not surprisingly, their voices overwhelmed the FDA proceedings and colored the daylong debate.
The rancorous proceedings, however, underscored what I see as a more serious problem arising from a fundamental breakdown in the government machinery designed to protect the public from a market-driven drug industry and a health care system that pays more attention to the bottom line than the patients it serves.
In the United States, although Prozac is the only antidepressant currently approved by the FDA for use in treating children and adolescents with depression, doctors are permitted to prescribe any drug on the market “off label”—or without specific regulatory approval. Physicians—not necessarily psychiatrists—routinely prescribe drugs such as Effexor, Paxil, Zoloft, Celexa, Serzone, Wellbutrin, and Remeron for a host of ailments they observe in their teen patients, including anxiety disorders and attention deficit disorders, in addition to a wide range of mood disorders—such as major depression.
Sometimes a drug is prescribed after just a brief consultation with a child and parent; doctors whose schedules are constricted by the dictates of managed care cannot allocate time for close patient monitoring or observation.
We know that the first stop for a family with a child in the throes of a mental health crisis is the family physician or pediatrician; and because of managed care’s prohibitive allowances for mental health, pediatric patients, whose diagnoses may be complex, are seldom thoroughly evaluated or referred to specialists. The bottom line for managed care trumps patient care, and HMOs prefer to see a child prescribed medication rather than an extended course of therapy with a trained psychiatrist or psychologist, which is far more expensive.
I did not realize we had gotten so far afield from the practice of responsible medicine. Like most parents of children struggling with a mental illness, I took it on faith that any doctor licensed to prescribe these medications was familiar with the intricacies of brain chemistry; I assumed that most doctors who see children and teens with depression designed drug treatment regimes tailored specifically for their pediatric patients. I believed that doctors matched symptoms to medication based on precise formulae, with predictable outcomes. Not true.
In 2002, an estimated 157 million antidepressant drug prescriptions were dispensed in the United States. Of an estimated 10.8 million antidepressant prescriptions dispensed to patients under the age of eighteen, pediatricians, family practitioners, or neurologists—not psychiatrists—wrote one-third of them.7 And that is a risky approach for both young patients and their doctors.
In early 2004, product labeling or package inserts for all antidepressants carried the following:
Suicide: The possibility of suicide attempt is inherent in major depressive disorder and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for [Drug X] should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
It was evident, however, that few doctors, outside of psychiatric specialties, were familiar with the nuances of the drugs or their range of side effects.
In two instances cited at the February 2004 FDA hearing, teenage patients were handed a one-or two-week course of an antidepressant drug “sample” by a physician (in neither case was the doctor a psychiatrist) and instructed cavalierly to “try this for a week or two and call me back.” In both instances, the children took their own lives before the sample ran out.
We will never know whether it was the result of an adverse drug reaction, lack of drug effect, or an underlying illness that led these young people to such a heartbreaking end. Likewise, I will never know if the combination of drugs or any single antidepressant medication Will was prescribed in the winter of 2001 contributed to or directly resulted in his suicide attempt. It is unlikely we will get a clear answer to this puzzle anytime soon.
Before I was named to the FDA’s advisory panel, I was unaware of the process by which drugs make it onto the market. But after my exposure to the bureaucracy, I concluded that the FDA’s drug approval process was inherently flawed.
With each new drug application, the FDA receives a fee of approximately five hundred thousand dollars from the drug’s maker to help defray the government agency’s costs of conducting the review. But I was surprised to discover that the FDA relies almost entirely upon data about a drug’s safety from a single source—the drug’s manufacturer (or in the FDA’s parlance, the drug’s “sponsor”). So, the FDA does not oversee an unfettered, government-funded drug review process, where, presumably, potential harmful side effects of a drug such as Paxil or Zoloft could be systematically reported, analyzed, and monitored by rigorous and independent analysis; rather, the FDA conducts a drug approval process narrowly based on data the drug company wants the FDA to see. And since the pharmaceutical companies consider all trial data to be “proprietary,” they cherry-pick the studies that support their claims of a drug’s efficacy and bury others in a drawer.
In 2001 Dr. Marcia Angell, former editor in chief of the New England Journal of Medicine and professor at Harvard Medical School told the NIH Record:
Drug companies are exerting influence over the evaluation of their products either directly or indirectly…[the] FDA is beholden for its existence on companies it is supposed to regulate, and that should never be the case with a regulatory agency.”8
In an interview in November 2002 for a documentary about the FDA’s approval process, Dr. Angell asserted, “You see study after study that is really set up, designed by the company, to show what they want to find.”9 So, it is not illegal—immoral, perhaps, but not illegal—for a drug company to suppress or fail to disclose negative results of its clinical trials. Who knew? Not I, and I have spent the past three years scouring the literature on teen depression and antidepressant medication. As Dr. Thomas R. Insel, director of the National Institute of Mental Health, summed up in early 2004, “We have been dependent on the pharmaceutical industry to provide the answers. The questions they want answered are different than the public health questions.”10 That’s putting it mildly.
Spin these observations out to their logical conclusion: drug companies are in the business of making money; the FDA is in the business of protecting the public. The two are incompatible and they have no business being in bed together.
Try to explain the dysfunctional institutional dynamic of the drug approval process to the parents of a gorgeous and vivacious young woman portrayed in cap and gown in a college graduation photo shown at the FDA hearing. Her mother, Sara Bostock, testified that Cecily became agitated and sleepless upon taking Paxil. Three weeks into a course of treatment on the drug,
she stabbed herself to death late at night in the family’s kitchen. Her autopsy revealed abnormally high levels of the drug in her system, suggesting that the Paxil had failed to metabolize properly.
Since we do know that drugs metabolize at significantly different rates in children and young people, and since there are few predictors of a drug’s potential side effects on children, shouldn’t doctors be taking greater precautions when prescribing these medications to children and adolescents than they might for their adult patients? Shouldn’t younger patients—shouldn’t all patients—be monitored more carefully for adverse reactions in the initial days following the introduction of a new medication?
In the midst of this debate, well-regarded author on depression Andrew Solomon wrote in a March 2004 New York Times editorial,
A patient should know the risks from the start. There is a world of difference between simply believing that life has no value, and knowing that feeling that way may be a side effect of medication. Patients must be able to recognize the difference.11
But I argue that children and adolescents are unable to recognize the difference, hence it falls to parents and practitioners to exercise extreme caution, be aware of the potential and adverse effects, and monitor children and teens closely.
Members of the medical establishment fear, however, that by issuing heightened warnings about the risks associated with SSRIs and other antidepressants, physicians and parents will curtail the drugs’ use, or that by sounding an alarm families with depressed children will be frightened away from seeking treatment. Their fear is not unfounded.
After my commentary appeared in the Washington Post, excoriating the FDA, the media, and the medical establishment for failing to provide parents with the necessary guidance, I received a thought-provoking letter from a psychiatrist practicing in a small community in Maryland. In her letter to the editor printed in the Washington Post, Dr. Carol Paris wrote:
As the sole psychiatrist in full-time private practice in my county, I depend on continuing medical education programs, psychiatric journals and consultations with colleagues to keep me up to date on the standard of care for treatment of psychiatric illnesses. I do not turn to newspapers or popular magazines. So when a parent of a teen I was treating with Paxil called to ask if I was aware of the “information” published that day about the increased risk of suicidal behavior in teens treated with this antidepressant, I was alarmed. Had I missed something in the scientific literature? The last thing I wanted was to recommend a treatment that could result in suicidal behavior in a child who hadn’t been suicidal.12
Dr. Paris consulted a colleague who was board certified in child and adolescent psychiatry and was assured that the study widely reported in the media was flawed and inconclusive; she called her teenage patient’s mother to share this information. But, she said,
I made a decision to no longer accept new patients younger than eighteen. Why? Because at this time, there is no right answer. And while I am willing to explain this to concerned parents, I am not willing to defend myself to a jury that lacks the sophistication to understand the difference between anecdotal evidence and sound scientific research.13
What a pity that the only practicing psychiatrist in the county felt compelled to exclude young patients out of fear of being sued, “not because,” as she emphasized, “I practice bad medicine, but because I might prescribe an antidepressant and a patient might attempt suicide anyway.”
At the conclusion of the FDA’s February 2004 hearing, the advisory panel recommended that the FDA submit the clinical data regarding SSRIs’ efficacy and safety to an independent team of researchers at Columbia University for further analysis to determine whether or not the data, once reclassified into standardized categories, would show evidence of a strong signal of suicidal thinking and behavior. Meanwhile the FDA was urged “to go ahead and issue stronger warning indications to clinicians.” “And to parents,” added Dr. Norman Fost, a professor of pediatrics and bioethics and member of the advisory panel. I concurred.
The FDA also alerted the public to watch for specific rare side effects, including agitation, akathesia (psychomotor restlessness), and anxiety and hostility, which may be attributed to antidepressants in a small subset of patients. Reports of these side effects were at the heart of the testimony the FDA’s advisory panel found particularly troubling—children and teens with no prior history of hostility or anxiety suddenly spun out of control and committed horrific acts of violence or self-destruction.
On March 22, 2004, the FDA adopted the advisory panel’s recommendations and issued a new advisory calling on doctors, patients, and families to be supervigilant for worsening depression or suicidal thinking not only when a course of antidepressants is introduced, but whenever the dosage is changed. The drug companies, including the makers of Prozac, Paxil, Zoloft, Effexor, Celexa, Remeron, Lexapro, Luvox, Serzone, and Wellbutrin, were asked to add new warning labels to the packaging stating “patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases.14*
By and large, psychiatric professionals support the use of antidepressants for their pediatric patients. They have witnessed the drugs’ efficacy in their practices and fear that without the option of including SSRIs in a treatment regime, we would see a swift reversal of the downward trend in teen suicides. But why do the drugs’ effects on adolescents vary so from the results we see in adult populations?
As we know, lack of impulse control and a proclivity for “risk-taking” behavior, attributed to an underdeveloped prefrontal cortex, are hallmarks of adolescence. Risk-taking behavior is significantly more commonplace than in either early childhood or adulthood. “[Adolescence] is a time when the brain is most vulnerable,” says Dr. Jay Giedd, of the National Institute of Mental Health.15
It stands to reason that depressed teens may have more varied and radically different reactions to antidepressant medication than adults. But it also may be the case that, if left untreated, adolescents may suffer disproportionate damage to the areas of the brain undergoing rapid growth and change at a critical time in their development. And the propensity to engage in risky behavior during puberty should challenge us to identify every means available to ensure that depressed teens are offered all possible remedies for suicidal thinking in order to stave off suicidal behavior. I am convinced that the data we’ve seen to date demonstrates that antidepressants play a major role in effectively mitigating these risks in a majority of severely depressed adolescents and children.16
In advance of the February 2004 hearing, the FDA’s point person on this issue, Dr. Thomas Laughren, wrote to the advisory panel and framed the debate succinctly:
While the focus of the discussion at the…meeting will be on pediatric suicidality data, it is important to consider the effectiveness data for these drugs as part of the overall context for this discussion. Ultimately, this is a risk benefit assessment, so it is important to know where we stand on the benefit side of the issue.17
So true.
I appreciate that living is a risky business. There are no guarantees. And try as we might to protect our children, horrific tragedies occur. I believe that antidepressants are effective, and I feel certain that in the next few years, the evidence will continue to mount attesting to their efficacy. I am throwing my lot in with the medical experts, such as Dr. Richard Glass, deputy editor of the Journal of the American Medical Association, who asserts that recent investigations demonstrate that psychopharmacology has progressed “from the highly polarized beliefs of the past to assessment of carefully controlled data.” In his editorial analysis of the landmark 2004 Treatment of Adolescents with Depression Study, he concludes, “As in other areas of health care, good empirical data always trumps beliefs and ideology.”18
Knowing what I now know about the potential risks, would I still encourage an aggressive treatm
ent regime including SSRIs to counter adolescent depression? Would I have supported our doctors’ pursuit of the “right” formula for Will prior to and after his suicide attempt? Yes, I would. And I would urge parents of depressed teens to do the same, with the following caveats inspired by recent debate:
Become as informed as possible about the medication prescribed. If you do not understand the reason the antidepressant is being prescribed for your child or if you lack confidence in the doctor’s ability to monitor your child and work with you closely during treatment, pressure the physician for more answers and a greater degree of engagement.
Be alert to any drastic changes in mood or behavior once your child begins a course of antidepressants or changes prescriptions or dosages. It’s a monumental challenge to be one hundred percent vigilant of a child in the midst of a crisis, but err on the side of caution. Doctors and clinicians should monitor their patients routinely during treatment by insisting on seeing the patient frequently, and they should solicit feedback from parents and family about the teenager. Regrettably, the bulk of the burden falls to you, as family, to observe and report accurately any changes in mood or behavior.
I am convinced that for Will and for me, antidepressants represent the life jacket preventing us from being sucked under by depression’s powerful undertow. But I also want to understand how a small number of pediatric patients exposed to these drugs experienced reactions ranging from suicide to homicide. And I want to know why these kids weren’t being monitored more closely by the doctors who prescribed the medication. Were they misdiagnosed to begin with? Using an SSRI to treat a child with bipolar illness may indeed trigger a manic episode and, hence, lead to an uptick in suicidal impulses; psychiatrists know to stay away from SSRIs, or use them with caution when treating anyone but a person with a clear diagnosis of major depressive disorder. Were the dosages administered correctly or were they elevated precipitously when the patient failed to respond positively? And why has the pharmaceutical industry been allowed to go so long without fully disclosing the results of clinical trials—all of them?
Will's Choice Page 24
