Zoloft is not approved for the treatment of children or adolescents with major depressive disorder (MDD).
December 10, 2003 UK regulators (the MHRA) all but banned the use of most of the SSRIs, including Zoloft, in children and adolescents. The MHRA explained, with respect to Zoloft:
Clinical trials involving 373 6-17 year olds “did not demonstrate efficacy.”
“Agitation, anorexia and insomnia were among the adverse events that were reported more often by [Zoloft] treated patients than by placebo treated patients.”
“The commonest reasons for discontinuation of treatment were: aggressive reaction (sertraline [Zoloft] 3), agitation (sertraline [Zoloft] 3), hyperkinesia [akathisia] (sertraline [Zoloft] 2), suicidal thoughts (sertraline [Zoloft] 3) and suicide attempt (sertraline [Zoloft] 2, placebo 1).”
February 2, 2004 FDA Advisory Committee meeting held to review the risk of suicide in children and adolescents taking antidepressants.
The day before the hearing, the San Francisco Chronicle revealed that a senior FDA epidemiologist, Dr. Andrew Mosholder, had conducted an analysis of the clinical trial data and found an up to 3 times higher risk of suicidal behavior in children and adolescents taking antidepressants compared to placebo.
The analysis was squelched by senior FDA officials who would not allow Mosholder to present his findings. The circumstances and events surrounding the FDA=s suppression of Mosholder=s report would later result in two separate congressional investigations and congressional hearings in September 2004.
In the course of the February 2004 advisory committee meeting, the FDA announced that it was in the process of negotiating a contract with a group from Columbia University, which group would be assigned the task of re-analyzing the clinical trial data that had already been reviewed by Dr. Mosholder.
The advisory panelists agreed to the re-analysis, but urged the FDA to strengthen the warnings about the risk of suicidal behavior immediately.
March 22, 2004 FDA Public Health Advisory announced that FDA has asked antidepressant manufacturers, including Pfizer, to place, in the Warnings section of their drug’s label, a warning that both children and adults should be monitored closely at the beginning of drug therapy, or when a patient’s dosage is increased or decreased, for signs of “worsening depression,” or “emergent suicidality [that] is severe, abrupt in onset, or was not part of the presenting symptoms.”
In this advisory, the FDA also stated that “health care providers should be aware that worsening of symptoms ... might be a result of drug therapy.” The symptoms listed are: “anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (extreme restlessness), hypomania, and mania.”
May 26, 2004 Pfizer issued a Warning in Canada concerning the “increased risk of suicidal ideation and behavior over that of placebo” for those under 18 taking Zoloft; and that for both adults and children, patients should be monitored for suicidality, “emotional changes” and “agitation-type”events such as: “akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization.”
September 13 and 14, 2004 FDA Advisory Committee meeting held to discuss the “Columbia Review.” 25 of the experts voted “Yes,” that the data presented demonstrated a causal relationship between the antidepressants, including Zoloft, and increased suicidality, 1 voted against and 1 abstained. The FDA panel recommended a black box warning for all antidepressants.
According to Dr. Thomas B. Newman, an expert who sat on the advisory panel, stated that the data analyses from the antidepressant clinical trials were “striking” and “such a dramatic result would be expected to occur by chance only 1 time in 20,000.”
Dr. Newman concluded: “The fact that an association emerged from the meta-analysis ... for an outcome that the sponsors of the trials were not looking for, and presumably did not wish to find, was quite convincing.”
October 15, 2004 FDA issued a Public Health Advisory announcing that it had directed antidepressant drug manufacturers to revise the labeling of their respective antidepressants to include a black box warning that alerts health care providers to an increased risk of suicidality caused by antidepressants in children and adolescents under 18.
The FDA also announced that it had requested that a Patient Medication Guide (MedGuide) be provided to patients with each prescription that will advise patients of the risk. Significantly, the FDA stated: “A causal role for antidepressants in inducing suicidality has been established in pediatric patients.”
January 2005 The new warnings include the statement: “Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the does is adjusted up or down.”
Zoloft Effectiveness
Only 3 out of 15 trials examined by UK regulators and the FDA, which led to the stronger warnings, demonstrated any efficacy in children and adolescents. Both regulatory agencies acknowledged that the drugs have not been proven to be effective in treating childhood depression.
The UK ban on antidepressants for use in children and adolescents in 2003 was due in part (in addition to the suicide risk) to the fact that the drugs had not been shown to be effective. FDA has also stated that “effectiveness has not been demonstrated.”
One of the FDA advisory committee experts from the September 13 and 14, 2004 panel pointed out during the meeting:
I think we have to come back to the issue of efficacy. We have I think very strong evidence of harm and really not very good evidence of efficacy, and although I know many practitioners are convinced that these drugs work, if you look very closely at the [Prozac] trial, just as an example, at the Childhood Depression Rating Scale, the improvement with placebo was 19 points, and the improvement with the drug was 23.4 points. You bring people in, you start a medication, and you see an improvement, you are very, very likely to believe that the drug is effective, and the reason why we do randomized, double-blind trials is because personal experience, however compelling, is not a reliable way to tell whether drugs work. In the study where they worked, in the [Prozac study], the improvement over placebo was really very, very small, and I would say not detectable by a clinician treating individual patients. ...
The expert stated in an article he later wrote for the October 14, 2004 edition of the New England Journal of Medicine: “It is easy to see why the personal experience of clinicians and patients would lead them to believe the drug to be effective, since they would have no way of knowing that more than 85 percent of the benefit they observed would also have occurred with placebo.”
The issue of “lack of efficacy” or “effectiveness” related to Zoloft was recognized by some within the FDA as early as 1991 with respect to adults. For instance, according to an internal FDA memo dated August 26, 1991, Dr. Paul Leber, formerly of the FDA, stated: “In recommending [approval], I have considered the fact that the evidence marshaled to support [Zoloft’s] efficacy as an antidepressant is not as consistent or robust as one might prefer it to be.”
A later FDA memo, dated December 24, 1991, also from Dr. Paul Leber states: “[S]everal foreign national drug regulatory authorities ... presumably provided with the same body of information [as the FDA], have not yet been willing to allow [Zoloft’s] marketing in their respective countries ... [because of] what may be considered the ‘lack of robustness’ of the clinical evidence supporting efficacy in the treatment of depression.”
Dr. Leber concluded: “Approval [of Zoloft] may ... for the reasons enumerated above, come under attack by constituencies that do not believe the agency is as demanding as it ought to be in regard to its standards for establishing the efficacy of antidepressant drug products.”
A number of internal Pfizer memoranda provide additional evidence of Pfizer’s difficulty in proving efficacy to foreign regulators. These documents show, for instance, that Pfizer was surprised in 1991 that the FDA had not questioned it about efficacy. The memo states: “I find it odd that FDA did not at all questioning [sic] efficacy and there are significant questions raised by several European companies.” Another memo states “we have serious concerns regarding the approval of sertaline in key European countries.”
Yet another 1991 memo states that Zoloft had “received an unfavorable review in a number of countries. The common key issue is that regulators are not convinced of sertraline efficacy versus placebo.” The memo states that what Pfizer needed to respond to these issues was a “strongly positive, placebo controlled study ... to ensure regulatory success.” The memo concluded: “To enhance the probability of success in a timely manner, we recommend that the study: ... be designed to enhance the probability of success. ...”
Pharmaceutical influenced medical literature
September 1, 2003 -- Pfizer published a study conducted by Dr. Karen Dineen Wagner, et al., which proclaimed that “Zoloft appears to work for children, with no major side effects.” The study was highly publicized; however, its conclusions received considerable criticism through letters from doctors to the journal editor (see excerpts of some of these letters below):
“The relative benefit increase of sertraline [Zoloft] over placebo . . . suggests that there might in fact be no benefit from sertraline for these patients.”
“[Zoloft] barely achieved a statistically significant improvement over placebo . . . I would appreciate more information about the degree of influence the sponsor [Pfizer] had over the presentation of the data and interpretation of the results. . . . Given the safety and efficacy precautions recently raised about [Paxil], another selective serotonin reuptake inhibitor with a similar mechanism of action (at least in adults), I believe that more convincing data are needed before [Zoloft] can be recommended as first-line treatment for major depression in children and adolescents.”
Dr. Wagner’s claims about the study “reach[] well beyond the trial’s results” and concluded “this trial suggests that [Zoloft] shows little to no perceptible benefit compared with placebo in the treatment of depressed youths.”
It was recently learned that the Wagner study was, in fact, ghostwritten by a Pfizer employee.
According to the editors of The Lancet : “The story of research into selective reuptake inhibitor (SSRI) use in childhood depression is one of confusion, manipulation, and institutional failure.” The editors concluded that “these failings are a disaster” and suggested that “[c]hanges are required at every level of the global health-care infrastructure.” (See The Lancet, April 2004 edition.)
The underlying study that sparked the editorial, also published in the April 2004 edition of The Lancet, found that, after a systematic review of published versus unpublished antidepressant clinical trial data involving children and adolescents, the published data alone show a favorable profile, while hidden and unpublished data show the risk/benefit profile as unfavorable.
Another article, also published in April 2004, in the British Medical Journal, similarly concluded: “[Clinical] investigators’ conclusions on the efficacy of newer antidepressants in childhood depression have exaggerated their benefits”; “Adverse effects have been downplayed”; “Antidepressant drugs cannot confidently be recommended as a treatment option for childhood depression,” and; “A more critical approach to ensuring the validity of published data is needed.”