Rethinking Pharmaceutical Treatments for Adolescent Depression

Marie A. Audain

Abstract

Depressive disorders have been directly correlated to increases in suicide and school dropout rates, and have been linked to major co-morbidities in adulthood, making a national health crisis (Rushton). In the United States, nearly one-fifth of the population report at least one bout of depression before the age of nineteen (Thompson et al.). Teens or parents seeking treatment for adolescent depression are most likely to contact their pediatrician or family care provider for help. At this point, many of these patients are placed on antidepressants, often without psychiatric consultation. However, the lack of published peer reviewed information regarding the use of psychotropic medications in children leads to these teens being placed on pharmaceuticals regardless of their adverse reactions (American Psychological Association or APA).

The drugs that are currently used for the treatment of adolescent depression were originally created for adult patients. Therefore, all the testing to deem the medication safe for human use was done using adult participants. However, children are not scaled down versions of adults, and how a drug reacts in the body of an adult is not always analogous to how it will react in the body of a child or an adolescent. Given these facts, it is crucial to examine whether the pharmaceutical approach is a viable treatment option for adolescent depression. To fully explore this issue, this paper will discuss the following questions:

  1. Under the United States Food and Drug Administration’s (FDA) current conditions, how is a drug deemed safe for use by a minor?
  2. What are the problems with the FDA’s current policies regarding drug testing for minors?
  3. Has the use of psychotropic medications by depressed adolescents led to an increase in suicidal ideation within this demographic?
  4. Is the pharmaceutical approach a viable treatment option for adolescent depression?

Under the United States Food and Drug Administration’s Current Conditions, How is a Drug Deemed Safe for Use by a Minor?

In order for a drug to be placed on the market, it must first pass rigorous testing guidelines set up by the FDA. The textbook, Paramedic Care: Principles and Practice by Bryan E. Bledsoe, Robert S. Porter and Richard A. Cherry, outlines the FDA’s testing procedures for a new medication as follows: after a medication has successfully completed the non-human phase of research, a period that can take as long as thirty-six months to complete, it is ready for human trials. The human trials are broken down into four phases (Bledsoe, Porter and Cherry 1: 282-284).

Phase one, done with a small pool of healthy volunteers, tests for how the medication reacts in the body and the levels at which the medication is therapeutic or deadly. In phase two, the drug is introduced to a limited population with the target illness; the purpose here is to evaluate the medication’s efficacy. Because neither the pharmacokinetics nor pharmacodynamics of the new drug is known, in both phase I and phase II, written proof of informed permission must be obtained from all test subjects prior to participation (Yaffe et al.). Because minors cannot give informed consent, using children in these phases of testing is impossible. However, consent is not needed after phase two (Bledsoe, Porter and Cherry 1: 282-284).

Phase three testing has the largest group of participants. Testing is usually done with at least two control groups. One group is given the new drug and another is prescribed either a sugar pill or another drug that has already received FDA approval to treat the same illness. Neither the participants nor the doctors know which group is receiving the new drug or the placebo. This is done to further fine tune the correct dosing regimen for the new drug and to catch any adverse reactions not found in the prior phases. If a new drug has made it successfully past the third round of testing, then it is conditionally approved by the FDA and enters phase four, when it is marketed to the public (Bledsoe, Porter and Cherry 1: 282-284).

In the fourth phase, any previously excluded population such as minors, the elderly, and expectant mothers can now take the drug. Because it is only conditionally approved, the pharmaceutical company must closely monitor the new drug for adverse reactions while waiting for complete approval by the FDA. The time period from creation to full approval for a new drug can be as long as twenty years (Bledsoe, Porter and Cherry 1: 282-284). The approval given by the FDA is limited to the scope that the clinical trials covered, and the new drug is labeled for this use only. The process of obtaining FDA approval for a new drug is not only time consuming for the pharmaceutical company, but very expensive as well.

In an interview for the article, “Why FDA Is Encouraging Drug Testing in Children,” Paula Botstein, M.D., deputy director of the FDA’s Office of Drug Evaluation I, states that because economic returns are likely to be small and because there are added difficulties associated with using children as test subjects, there is little impetus for drug companies to research medication use in children (Bachorik). In order to overcome this lack of available information concerning a drug’s therapeutic effects on pediatric patients, the FDA issued two new proposals: the first changed the pediatric testing guideline regulations, and the second allowed for the FDA approval of off-label use for a drug if the use was published in a peer-reviewed medical journal.

The first proposal, issued in 1994 by the FDA and entitled, “Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients — OMB Control No. 0910-0392,” stated that drugs that had passed rigorous, well-documented adult trials and were currently on the market could be used in pediatric patients if they treated similar illnesses, and if the disease followed a similar pathology in children. Basically, a drug no longer needed to be tested in the pediatric population in order to be cleared for use in children.

This new regulation overrode an FDA regulation in place since 1979 stating that a medication could only be labeled for use in children if all clinical trials were carried out with pediatric volunteers (Yaffe et al.). This policy created “therapeutic orphans,” a term first used by Dr. Harry Shirkey to identify pre-pubescent children who were suffering from diseases for which no drug company could label any medication as safe for use because of the FDA restrictions (Yaffe et al.). However, the FDA has always allowed physicians, based on their medical evaluation of a patient, to use any approved medication that is currently on the market that they feel would appropriately treat the illness (Bachorik). A physician prescribing a drug to a minor, even though there are no pediatric safety guidelines or dosage regimes associated with the medication, can issue that prescription without the written consent of the minors or their guardians. Since the parents bring the child or adolescent for medical treatment, consent is implied, and no further written permission is required.

This provision in the FDA’s regulations sets up an abbreviated phase of testing for an Investigational New Drug (IND), or for a medication that is currently on the market, but is being used in a way that is not FDA approved, a practice referred to as off-label drug use. Just like a pharmaceutical company applying to test an IND, the physician must submit a plan and the appropriate documentation to the FDA. However, unlike the corporation, the physician can begin the treatment plan immediately and does not need to wait for formal written approval from the FDA (Yaffe et al.). The reasoning behind the relaxing of the FDA’s regulation was threefold. First, it allows a doctor to administer the right drug to the right patient without being bogged down in the red tape that a pharmaceutical corporation has to wade through. Second, no time is lost, and the suffering of the patient is hopefully curtailed with the administration of a drug that would normally take years to become eligible to be considered for FDA approval. Third, physician-run IND provides a means to gather documentation on pediatric usage of a medication that can be presented for peer review in a medical journal (Yaffe et al.).

Once the results of the physician’s treatment are published, the drug corporations can make use of the second FDA proposal. Enacted by Congress in 1997, the FDA Modernization Act included a provision that allows pharmaceutical companies to promote the off-label uses of a drug already approved by the FDA as long as those off-label uses were published in peer-reviewed medical journals (Mitka). This created back door access for the pharmaceutical industry. The Modernization Act permits a company to use physician-run IND to extend the scope of the uses for an FDA approved medication or an IND. Without incurring the expense of an added or prolonged testing phase, the drug corporation can now delve into pediatric research. However, these FDA policies do present several inherent problems.

What are the Problems with the FDA’s Current Policies Regarding Drug Testing for Minors?

Under the FDA’s current policy, an IND is not introduced to a pediatric population until the fourth phase of testing, and even then, it can be used only if the IND treats an illness with a similar pathology in children. However, there is no direct correlation between a similar pathophysiology in an adult and similar pharmacokinetics in a minor. This point is further emphasized by Yaffe et al.:

It is recognized that the effects of many drugs on children may vary considerably from the effects on adults even when careful calculation is made to arrive at a dosage proportional to the body weight or the estimated body surface area… In view of these circumstances, there is need for special caution in prescribing medication in the treatment of childhood disorders, particularly when the medication is used for an extended period of time or when a newly marketed drug is employed. (463)

Plainly speaking, just because an illness, i.e. depression, appears to manifest the same way in both adults and teens, does not mean that the medication-whose effectiveness and side effects were tested only in an adult population-will also be metabolized the same way in the body of the adolescent. The elementary considerations of age, efficacy, and the mechanism of action of the drug would seem inherent to a physician’s prescribing practices. Surprisingly, for many doctors, this is not the case.

Once a new medication has been approved for use by the FDA, there are no restrictions placed on off-label uses by doctors (Psaty and Ray). A study performed by David C. Radley and colleagues reviewed the prescribing practices of more than fourteen thousand arbitrarily selected doctors for the year 2001. The research criteria called for the quarterly review of the selected physicians’ patient evaluations over a two-day period. Information was then gathered about one hundred and sixty of the most commonly prescribed drugs and cross-referenced with each patient’s medical evaluation and the FDA-approved label use of that particular medication. Medications prescribed for off-label usage were then further screened and categorized by the depth of evidence-based information available to support the use of a particular medication for a particular patient. The study found that approximately one out of every five drugs given to the patient was for off-label use, and that three out of every four off-label prescriptions issued had no efficacy for the condition they were being used for. The study also found that psychotropic medications were among the drug classes most likely to be issued for off-label use with either very little or a complete lack of clinical evidence to support that use (“Off-label”).

Although there are no limitations placed on the physician, protocols are in place for corporations trying to push the off-label use of their own drugs. The 1997 Modernization Act allows a company to send out copies of peer-reviewed medical journal articles which chronicle the off-label uses of a particular medication while they were waiting for FDA approval of those uses (Psaty and Ray). However, it has been revealed that some drug manufacturing companies are writing these medical articles themselves. “F.D.A. Plan on Medical Articles Takes More Heat,” a New York Times article written by Stephanie Saul, exposed the fact that Merck, a prominent pharmaceutical corporation, had written several research reports chronicling the use of their drug Vioxx. Though well-known doctors were paid to sign onto the reports as authors prior to printing in a medical journal, these “peer-reviewed” journal pieces were in fact ghost-written and misleading in their presentation of critical test results. As so eloquently stated by Dr. Joseph Ross, the primary writer of a JAMA article that first revealed Merck’s duplicity: “What does it mean to be peer-reviewed if the company has essentially conceived the article, composed the draft and written the paper?” (qtd. in Saul). One of the most alarming and debated side effects of psychotropic use in minors is the possibility that it may lead to an increased risk of suicide in teens--a detail that can be easily withheld from a ghost-written corporate article.

Has the Use of Psychotropic Medications by Depressed Adolescents Led to an Increase in Suicidal Ideation Within this Demographic?

According to the evidence-based case review, “Identifying and Treating Adolescent Depression,” the class of drugs most commonly used to treat adolescent depression is selective serotonin reuptake inhibitors (SSRIs). This class of drugs has a higher percentage of compliance than tricyclic antidepressants and monoamine oxidase inhibitors because they only need to be taken once every twenty-four hours. SSRIs are also considered the safer medication since they will not result in a fatality when taken in large amounts (Tompson et al. 175). Although SSRIs will not cause death directly if taken in excess, there is the possibility that adolescents taking these medications at the therapeutic dosage may exhibit suicidal ideation and may have an increased likelihood of suicide. In 2004, teens taking SSRIs and their guardians were sent letters about this possible adverse reaction by the FDA (Ford-Martin, Odle, and Davidson). In 1999, two control groups were developed to test the ability of the SSRI Sertraline to treat acute symptoms of depression in pre-pubescent and adolescent patients. The participation requirements for the study were: an age of at least six and no greater then seventeen, a diagnosis of Major Depressive Disorder (MDD)—defined as “moderate to severe depression lasting two or more weeks” (Ford-Martin, Odle, and Davidson). This diagnosed bout of MDD had to have an onset time of at least a month and a half. Participants were disqualified if they had any other co-morbidity, either of a psychiatric or physical nature with the MDD, if they had a prior history of suicide attempts, or if they were seeing a therapist secondary to the MDD. The trials were double blind and ran concurrently for forty-two days with an initial total of three hundred and seventy-six patients. The results of the trials revealed that the Sertraline group showed greater incidence of reduction or reversal of the symptoms of MDD. No real disparity between the placebo and the Sertraline groups existed when it came to suicidal ideation or attempt, which was less than one percent for both groups (Wagner et al. 1039). The data in the report shows that out of the three hundred and seventy-six patients in the study, one hundred and eighty-nine were on the SSRI and that the rest were on the placebo. Out of both groups two patients from each attempted suicide. However, out of the Sertraline group, three patients also admitted to suicidal ideation. No one in the placebo group displayed this symptom. Suicidal ideation is generally a significant precursor to the suicide attempt. Therefore, for the researchers to fail to note the relationship between the two is, in fact, an attempt to skew the data in their favor. Unfortunately, for some drug corporations, research has become synonymous with marketing.

Psaty and Ray describe this bias of the drug companies in the following excerpt:

The systematic effort to control and shape multiple steps in the research, analysis, and dissemination of articles by pharmaceutical companies or their agents has been aptly called “ghost management.” Ghost authorship, one element of ghost management, is common in the literature published by sponsors. … Medical education and communication companies frequently help sponsors develop publication plans, compose drafts of manuscripts, and manage their submission to journals. Sismondo cites the example of 85 publications planned by one vendor for Sertraline and estimates that up to 40% of the published literature on Sertraline between 1998 and 2000 had been managed by the sponsor through a single medical education and communication company. (1950)

In these tailor-made clinical trials where only the company’s bottom line is considered, the results become suspect.

Issues with the practice of prescribing SSRIs to adolescents led Craig Whittington and Tim Kendal from the National Collaborating Centre for Mental Health in the United Kingdom to review several randomized controlled trials that compared a SSRI with a placebo in children from the ages of five to eighteen (“Most”). All the trials they examined were published in peer-reviewed medical journals and almost all of the published trials led to the conclusion that the SSRI under evaluation showed greater efficacy than the placebo, with few severe adverse reactions. However, when these results were cross-referenced with the suppressed data from their respective trials, the SSRIs were shown to have greater adverse to safe reactions proportionally than the placebo (“Most”).

For an accurate representation of psychotropic medication use in the pediatric population to emerge, drug companies need to make public all the data obtained in their trials stated Whittington and Kendal. “The fact that the drugs reviewed here have previously been recommended for use in children on the basis of a very restricted published evidence base can only serve to increase that sense of urgency” ( qtd.in “Most”). The need for an efficacious treatment of depression exists within the pediatric population. However, the unethical representation of the data from the clinical trials means that the medical community must rethink the use of pharmaceutical treatments for adolescent depression.

Is the Pharmaceutical Approach a Viable Treatment Option for Adolescent Depression?

After reviewing the sources, it becomes clear that when it comes to adolescent depression and psychotropic medications, greater efforts need to be taken by the FDA to regulate the pharmaceutical industry as a whole. The company GlaxoSmithKline grossed nearly five billion dollars for the sale of the SSRI Paroxetine in 2003 (“Most”). The antidepressant is commonly prescribed to adolescents because published trials in medical journals showed it to be efficacious. However, when both the published and unpublished data from the clinical evaluations were evaluated, Paroxetine was revealed to have a higher incidence of suicidal ideation and attempt than the placebo (“Most”). When the drug companies misrepresent or simply refuse to publish unfavorable drug trials, they not only take away consumers’ rights to be patient advocates for themselves, they also remove the consumers’ abilities to make clear, balanced, and informed decisions regarding appropriate health care decisions for themselves and their loved ones.

The FDA is a federal organization whose job, simply put, is to protect the people by policing the pharmaceutical corporations. It is not to bow down to the high priced lobbyists the companies send to swarm Washington D.C. Companies found to be deliberately defrauding the public should face criminal penalties for their actions. Simply paying civil settlements in class action suits is analogous to a slap on the wrist for some of these corporations.

The FDA must also address the abuse of off-label prescriptions. The practice of off-label use can be a highly effective medical tool when used ethically and with the patient’s best care in mind. “There are occasions where physicians should use their best judgment, like in treating extremely rare diseases or pediatric illness. But there are many more cases in which off-label use is encouraged by manufacturers, if not explicitly promoted… ,” states Aaron S. Kesselheim, MD (qtd. in Mitka 1759). Medical doctors who sell their signatures and credibility to the highest bidding drug firm should face the same stiff penalties as the corporations and have their medical licenses stripped. When they took the Hippocratic Oath, doctors pledged “to do no harm”; unfortunately, for some this also meant starting the bidding process. As the FDA regulations stand right now, the only possible answer to the question of whether the pharmaceutical approach is a viable option for adolescent depression is an emphatic no.

Works Cited

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Rushton, Jerry. “Depressive Disorders in Adolescents: Challenges in Diagnosis.” Psychiatric Times 19.9 (2002): 21. Infotrac Health and Wellness Resource Center. Web. 7 Mar. 2008.

Saul, Stephanie. “F.D.A. Plan on Medical Articles Takes More Heat.” New York Times. 19 Apr. 2008. Print.

Tompson, Martha C., et al. “Evidence-Based Case Review Identifying and Treating Adolescent Depression.” Western Journal of Medicine 172 (2000): 172-76. Print.

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Yaffe, Sumner J., et al. “Drug Testing In Children: FDA Regulation.” American Academy of Pediatrics 43.3 (1969): 463-65. Print.

Wagner, Karen Dineen, et al. “Efficacy of Sertraline in the treatment of Children and Adolescents with Major Depressive Disorder: Two Randomized Controlled Trials.” Journal of the American Medical Association 290.8 (2003): 1033-41. Web. 9 Mar. 2008 <http://jama.ama-assn.org>.

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