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"Depression is a highly prevalent disorder that affects 1 in 5 women and 1 in 10 men at some time in their lives. At any point in time, 5% to 10% of adults are clinically depressed, and another 10% to 15% experience subclinical levels or milder forms of depression."
Statements like the above, this one from Johnson and Flake (2007) [696], are frequent in the mental health field, and generally, they are taken at face value. No one asks, "Is depression different from unhappiness, because I know a lot of people, maybe most, have unhappy times in their lives?" Or if the question is asked, it will be answered with a reference to the criteria in the official diagnostic manual (American Psychiatric Association, 2000 [44]), as if fulfilling a checklist of items somehow elevates a person from the realm of human unhappiness to major depressive disorder. Few stop to realize that figures like these are concocted and generally promoted in the interest of empowering mental health professionals. And even if the particular professionals are not pushing drugs, and Johnson and Flake are not, the figures were originally generated to promote the market for psychiatric drugs. In an effort to enlarge the market, the concept of subclinical depression was invented to justify prescribing antidepressants to people who do not meet the standard criteria for major depressive disorder.
The market has become huge. In the United States in 2001, an estimated 24.5 million patient visits were made for depression, with 69% of these visits resulting in prescriptions for SSRIs (Fergusson et al., 2005 [429]; Stafford et al., 2001 [1211]). In 2002, about 6% of all boys were taking antidepressants, and the number has continued to grow. By 2004, an estimated 1 in 10 women was taking one of the newer antidepressants (Vedantam, 2004 [1292]).
The antidepressants generate gigantic revenues for the drug companies. In 2006, according to IMS Health (2007) [648], antidepressants were the most prescribed among all classes of drugs, with a total of 227.3 million prescriptions in the United States. They were third in revenue, with a total of $13.5 billion. To give perspective to these figures, the widely prescribed lipid regulators like Lipitor were second as a class, with 203.0 million prescriptions, and first in revenue, at $21.6 billion.
Antidepressants have, however, been taking something of a licking, from the Food and Drug Administration (FDA) and the media in the last few years, culminating in 2004-2005 with a black-box warning about antidepressant-induced suicidality in children and then in 2007 by another black-box warning about increased suicidality in young adults. But in reality, there was little impact on the prescription of these drugs. U.S. sales of antidepressants declined 1.4% in 2004 and 6% in 2005, followed by a 2% recovery in 2006, with industry determining that the black-box warnings were ultimately "unlikely to significantly threaten, sales" (McManus, 2007). And as already mentioned, they are still number one when it comes to sales.
Soon after the introduction of the first SSRI, fluoxetine (Prozac), into the United States marketplace in January 1988, published reports began describing fluoxetine-induced violence against self and others.
In 1990, Teicher et al. [1243] published their classic article "Emergence of Intense Suicidal Preoccupations During Fluoxetine Treatment" in the American Journal of Psychiatry, describing five patients who developed akathisia and became obsessively suicidal on Prozac, who felt relief when the medication was stopped, and then a resumption of their agitation when it was resumed. In May 1990, the FDA required the manufacture of Prozac, Eli Lilly and Company, to add suicidal ideation and violent behaviors to the Postintroduction Reports section of its label. The section that listed violence and suicide as possible adverse drug reactions began with a caveat that the reported reactions "may have no causal relationship with the drug".
On August 11, 1990, an editorial in The Lancet (5-HT Blockers, 1990 [1]) included "the promotion of suicidal thoughts and behaviour" (p. 346) among the adverse effects of fluoxetine. The journal was ahead of its time in its cautions:
"Fluoxetine represents US know-how at its best and has been aired in the media at a time when biological psychiatry has become supreme in North America. However, we do not know whether the drug is better than earlier antidepressants, whether 5-HT is the main neurotransmitter in depression, and whether the 5-HT uptake blockers have acceptable side effects."
The following year, the British National Formulary, a joint publication of the British Medical Association and Royal Pharmaceutical Society of Great Britain (1991) [228], listed suicidal ideation and violent behavior as fluoxetine side effects. Also in 1991, I published Toxic Psychiatry, in which I observed for the first time that Prozac was producing a continuum of overstimulation that included akathisia, agitation, anxiety, insomnia, depression and mania, and, in the extreme, suicide and violence. I drew on previously sequestered FDA premarketing data on Prozac, the scientific literature, and my own clinical and forensic cases.
Subsequently, many books and reports have dealt with the subject of SSRI-induced violence and suicide (e.g., Breggin, 1992b [192], 1997 [198], 2001a [207]; Breggin et al., 1994a [219]; Glenmullen, 2000 [528]; Healy, 2000 [607]; Teicher et al., 1993 [1244]).
Chapter 7 will present an extensive review and analysis of the literature on antidepressant-induced mental and behavior abnormalities. This chapter will look at the evolution and importance of current changes in antidepressant labels.
These selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and, most recently, escitalopram (Lexapro; see the appendix). These drugs block the removal of the neurotransmitter seronin from the synaptic cleft. A number of other antidepressants are potent nonselective serotonin reuptake inhibitors (NSRIs). These include the atypical venlafaxine (Effexor) and the tricyclic clomipramine (Anafranil). Nefazodone (Serzone) has been withdrawn from the market due to liver damage.
When observations are made in clinical practice and in the scientific literature concerning the impact of SSRIs, they are typically treated as a single category or class of pharmacological agents. It is generally recognized that an adverse mental or behavioral reaction, such as agitation or mania, that is observed in regard to one SSRI is likely to be found with all the other SSRIs. When I initially testified about this reality in deposition and trial as a medical expert, drug company lawyers and experts criticized my position, claiming that I could not use data about one SSRI to draw conclusions about other SSRIs. Then, in 2004-2007, the FDA began issuing required class warnings on adverse psychiatric reactions such as suicidality, hostility, irritability, and mania that are identical for the entire class of SSRIs.
While usually examined as separate classes of antidepressants, the SSRIs like Effexor also share many characteristics with the SSRIs, including the capacity to induce stimulation, anxiety, agitation, and mania.
On February 2, 2004, the FDA held an open meeting of the joint Psychopharmacological Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee to hear public testimony and explore the risk of suicidality associated with antidepressants in children. During September 13-14, 2004 [466], the FDA met again to present a re-evaluation of data on 4,582 pediatric patients from 24 antidepressant controlled clinical trials of 4-16 weeks in duration. With one exception, the studies were drawn from 23 industry sponsored trials. The exception was one National Institute of Mental Health (NIMH) study, the Treatment for Adolescents With Depression Study (TADS), a 12-week trial involving 439 children age 12-17, comparing Prozac alone, cognitive therapy alone, combined therapy, and placebo (March et al., 2004 [872]). Thus industry-sponsored studies dominated the data.
Despite the handicap that the studies were largely developed and conducted with the aim of proving the value of industry products, a meta-analysis of the combined data indicated that antidepressants in children and youth increase the suicide attempt rate and that an estimated 1% to 3% of patients would be at risk of antidepressant-induced suicidality (Hammad et al., 2006 [594]). On October 15, 2004, the FDA mandated a black-box warning, and in early 2005, it was finalized (FDA, 2005a) [467]. According to FDA requirements for describing adverse drug reactions, a risk of 1% or more is considered common.
We will find that the psychiatric establishment continues to minimize the FDA findings. Even the FDA recently described the finding as "modest" (see subsequent discussion). Thomas Insel, director of NIMH, weighed in on the side of drugs, describing them as "medications and of known benefit and of questionable risks" (Vedantam, 2005 [1293]), when the scientific research actually shows them to be medications of no benefit and grave risk.
The New England Journal of Medicine asked one of the panel members of the FDA Psychopharmacological Drug Advisory Committee, physician and epidemiologist Thomas B. Newman (2004) [984], to comment on the results of the studies conducted in the controlled clinical trials to determine the risk of suicidality. He wrote,
"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. (The summary risk ratio was 2.19; 95 percent confidence interval.) Although the FDA staff did not provide this information to the committee, according to my own calculations, such a dramatic result could be expected to occur by chance only 1 time in 20,000 (p = 0.00005). ... The fact that an association emerged from a meta-analysis with a P value of 0.00005, for an outcome that the sponsors of the trials were not looking for, and presumably did not wish to find, was quite convincing."
Notice that the FDA itself failed to provide the p value that made the result so stunning! The panel member had to calculate it for himself.
Newman (2004) [984] also made the point that the FDA found that only 3 of the 15 available controlled clinical trials showed efficacy for antidepressants in treating depressed children. He said that several FDA committee members spoke in favor of the antidepressants, citing either their own experience or the TADS conducted by NIMH; "however, others and I found the evidence of efficacy much less convincing than the evidence of harm". According to Newman,
"In reviewing TADS we were struck by the small size of the difference between fluoxetine and placebo as compared with the effect of placebo alone. ... 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% of the benefit they observed would have also occurred with placebo."
"Randomized trials other than TADS have had less favorable results. The FDA indicated that only 3 of 15 trials of antidepressant use in children with depression had found a statistically significant benefit. The agency also provided us with a meta-analysis that showed that the estimated efficacy of antidepressants in children was minimal and likely to have been overestimated, because published studies have much more favorable results than unpublished studies. Thus, both clinical experience and published trials are likely to lead to inflated estimates of the efficacy of these drugs."
The critique provided by the FDA was by Whittington et al. (2004) [1340], described in chapter 7.
Newman (2004) [984] also found many unanswered questions: "The FDA's meta-analysis suggested that the new antidepressants double the risk of suicidality, about 2.5 percent to 5 percent, in trials lasting two or three months. But what happens if you take them for a year?"
Epidemiologist Newman's (2004) [984] comments summarize the essential problem of psychiatric drugs in general: easy to show their serious adverse effects; difficult to show their effectiveness.
Thus, in 2004, the FDA began to catch up with observations I had begun making in 1991 in Toxic Psychiatry [190] and more elaborately documented in the 1997 edition of this book, concerning the risks of antidepressant-induced suicide, at least in children, and later, the FDA would also affirm the risk in adults, at least young ones. However, in some ways more important, and almost entirely ignored in the press and the medical community, the FDA also confirmed my major critique of the newer antidepressants: that they produce a stimulant-like syndrome or activation that causes a whole array of disorders, from agitation, anger, and hostility to outright mania.
Following public hearings in early 2004 [465], the FDA issued a press release for a Public Health Advisory in regard to children and adults, in which it stated, "The agency is also advising that these patients be observed for certain behaviors that are known to be associated with these drugs, such as, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania."
The FDA's description and its final label changes closely parallel what I had been saying for more than a decade and mimicked language from my 2003 [212] report "Suicide, Violence and Mania Caused by Selective Serotonin Reuptake Inhibitors," in which I concluded, "Mania with psychosis is the extreme end of a stimulant continuum that often begins with lesser degrees of insomnia, nervousness, anxiety, hyperactivity and irritability and then progresses toward more severe agitation, aggression, and varying degrees of mania." In that report, I also discussed akathisia and described the antidepressant-induced stimulant syndrome, including "hypomania/mania, insomnia, nervousness, anxiety, agitation, central nervous system stimulation, emotional lability ... as well as paranoid reaction, psychosis, hostility, and euphoria".
The FDA published its final version of the class label for all antidepressants on January 26, 2005 [467]. The FDA applied the new label changes to all 34 antidepressants on the market, including older, more sedating antidepressants such as amoxapine (Asendin), trazodone (Desyrel), amitriptyline (Elavil), doxepin (Sinequan), and imipramine (Tofranil). The last-minute inclusion of the older antidepressant was an act of deference to the manufacturers of the newer antidepressants, in effect tarring all antidepressants with a brush meant only for the newer ones.
However, the agency's conclusions were based on a limited number of new antidepressants, including bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, escitalopram, and venlafaxine, according to an FDA Talk Paper (2004a) [465]. These were the drugs most often cited by the public at the two FDA hearings.
Although the labels are currently being updated by the FDA to include a warning about antidepressant-induced suicidality in young adults, every antidepressant label until recently had a black-box warning at the top titled "Suicidality in Children and Adolescents" that begins with the following statement:
"Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders."
This statement was already a compromise between the FDA's original proposal and drug company feedback. The FDA's original, stronger draft read, "A causal role for antidepressants in inducing suicidality has been established in pediatric patients" (Lenzer, 2005) [828]. The draft statement went beyond the clinical trials themselves to say that suicidality had been established in general. It also used the dread phrase causal role. In every case in which I have testified against the drug companies in deposition, the defendant companies have tried to dismiss any scientific conclusions about drugs inducing suicidality, unless the conclusion used the term causal. In reality, scientific articles and FDA-approved labels rarely use the concept of causation, giving much relief to the drug companies, who can then claim, however falsely, that causality has not been established.
Meanwhile, referring to the decision made by the FDA Psychopharmacological Drugs Advisory Committee, even staunch advocates of antidepressants have to admit that "the committee concluded that a causal link exists between antidepressant treatment and pediatric suicidality and advised that policies be implemented" (Pfeffer, 2007) [1033].
Beneath the black box, a headline reads "WARNINGS-Clinical Worsening and Suicide Risk". Without identifying it as such, this section contains a warning about the stimulant or activation syndrome that I first described in Toxic Psychiatry in 1991 [190]:
"The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor 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."
Note the specific references to "irritability, hostility, aggressivenes, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania," a virtual prescription for violence. This new addition to the label, the implications of which having been largely overlooked, refers to children and adults. By indicating that nonpsychiatric patients can develop these reactions, the FDA class label challenges the commonly held belief that only patients with a bipolar history or vulnerability are at risk for developing antidepressant overstimulation.
The new label addresses information that should be given to patients and their caregivers who take the newer antidepressants:
"Clinical Worsening and Suicide Risk: Patients, their families and caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms."
Most of the symptoms described in my previous publications and by the FDA in its new label are the result of activation or stimulation, a syndrome similar to that caused by stimulants such as amphetamine, methamphetamine, and methylphenidate, especially in high doses. Compared to antidepressant-induced suicidality, activation is bolstered by a much larger scientific literature and poses a far more common, and often disastrous, level of risk (see subsequent discussion).
Activation should be at the top of the differential diagnosis list when a patient's condition deteriorates while taking antidepressants. If the physician misidentifies drug-induced activation as caused by the patient's original psychiatric disorder, the doctor is likely to continue, or even increase, the antidepressant dose, ultimately causing mania and psychosis.
Simultaneously with the new warnings, the FDA required physicians to provide the families of children receiving antidepressants with a sheet of information titled "Medication Guide: About Using Antidepressants in Children and Teenagers" (Food and Drug Administration, 2005e [471]). The label is currently being updated by the FDA to include young adults but otherwise remains largely unchanged.
In a section titled "You Should Watch for Certain Signs If Your Child Is Taking an Antidepressant," the information sheet states, "Contact your child's healthcare provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, worry you, your children, or your child's teacher." It lists the following danger signs:
Except for suicidality, the medication guide does not specifically state that there is a causal link between this list of reactions and the medications but clearly implies that these reactions are associated with taking medication. Each symptom is consistent with the activation or stimulation syndrome. The inclusion of anger, aggression, and violence shows the FDA's well-justified concern about antidepressants posing a serious danger to others.
In March 2006, Hammad et al. [594] from the FDA Division of Neuropharmacological Drug Products Center for Drug Evaluation and Research published a summary of the agency's methods and findings. Their conclusion minimized the importance of their findings: "Use of antidepressant drugs in pediatric patients is associated with a modestly increased risk of suicidality."
Compare this conclusion of a "modestly increased risk of suicidality" to the previously mentioned observations of the epidemiologist on the FDA's Psychopharmacological Drugs Advisory Committee, Thomas Newman (2004) [984], who said, "The results were striking. ... The fact that an association emerged from a meta-analysis with a P value of 0.00005, for an outcome that the sponsors of the trials were not looking for, and presumably did not wish to find, was quite convincing."
In reality, since the short-term, company-run clinical trials were wholly unsuited to detecting suicidality, the risk had to be much more than "modest" to show up at all. In addition, Hammad et al. (2006) [594] admitted to a fact that I had been insisting on for years in publications and testimony: that the drug company's premier measure of suicidality, the Hamilton Depression (Ham-D) Scale, is useless in that regard. The investigator asks the subject questions from the scale, only one of which is related to suicidality. Obviously, the answers will depend on how seriously the question is asked, and rote questions are likely to elicit rote answers. The inventor of the Ham-D Scale did not himself believe that it, could be used as a scientific tool in the manner that the drug companies have utilized it (Hamilton, 1960) [592].
The FDA report also mentioned that no completed suicides were recorded among all the trial subjects. The agency failed to emphasize that the no suicides occurred on placebo either. Leaving depressed children, drug-free did not produce a single suicide. This wholly contradicts the tendency to give drugs to prevent suicides.
The drug companies, and their promoters at the American Psychiatric Association (APA), have tried to emphasize that the clinical trials evaluated by the FDA produced "suicidality" but no actual suicides (Lenzer, 2005) [828]. Although I have never seen this point made before, it is important to realize that in general, depressed people do not commit suicide during clinical trials. Depression is essentially a loss of hope. During clinical trials, the participants are given hope that a new medication may finally relieve their suffering, they are given professional attention on at least a weekly basis, and they are monitored for any deterioration in their condition. Thus clinical trials provide the essential elements of any good therapy for depression: hope, professional attention, and close monitoring. No wonder placebo turns out to be as good as the drug; participating in the trial is itself therapeutic, at least during its brief duration.
In addition, actively suicidal patients are excluded from clinical trials. They are the most vulnerable and therefore the ones that the drugs are most likely to push into committing suicide.
The FDA authors concluded their report with an acknowledgment to "the drug companies that supplied the data needed for this work". At no point do they respond to the massive evidence that some drug companies, including the manufacturers of Prozac and Paxil, purposely provide junk data calculated to mislead, and especially to minimize, the risks associated with their drugs (see chapter 14).
On June 3, 2004, before the FDA issued its formal label changes concerning children, Health Canada (2004) [604] - the Canadian drug regulatory agency-issued "stronger warnings" for SSRIs and other newer antidepressants that were more encompassing than the U.S. version: "These new warnings indicate that patients of all ages taking these drugs may experience behavioural and/or emotional changes that may put them at increased risk of self-harm or harm to others." In dramatic contrast to the FDA, Health Canada applied the warning to children and adults in regard to suicidality, and it further warned about harm to self and to others (violence):
"Patients, their families and caregivers should note that a small number of patients taking drugs of this type may feel worse instead of better, particularly within the first few weeks of treatment or when doses are adjusted. For example, they may experience unusual feelings of agitation, hostility or anxiety, or have impulsive or disturbing thoughts that could involve self-harm or harm to others" (emphasis added).
This is consistent with my testimony and publications, beginning with Toxic Psychiatry in 1991 [190], in which I warned about both suicide and violence caused by SSRIs and with my book Medication Madness (in press), which will present dozens of case histories illustrating harm to self and to others induced by the SSRIs. The FDA continues to lag behind, however, mentioning hostility and aggression in the new labels as problems associated with SSRIs but without giving these dire outcomes sufficient emphasis.
In Great Britain, all SSRI antidepressants, except fluoxetine, have been banned for use in treating depression in children. The main concern surrounded suicidality that was increased with SSRIs in general, including fluoxetine (Committee on Safety of Medicines, 2003).
I warned the public and the health professions about the risk of SSRI antidepressant-induced suicidality in adults in Toxic Psychiatry [190] (1991) and again in 1997 [198] with a lengthy discussion in the first edition of this book. I elaborate in much greater detail on risk in 2003 [212] in my scientific journal article "Suicidality, Violence and Mania Caused by Selective Serotonin Reuptake Inhibitors (SSRIs): A Review and Analysis."
In the meantime, in 2001, Houston, Texas, attorney Andy Vickery won a product liability suit against GlaxoSmithKline in a Paxil murder-suicide suit (Tobin v. SmithKline Beecham, 2001 [1256]). Donald Schell, age 60, had taken two doses of Paxil before shooting his wife, their daughter, and his granddaughter to death. The jury awarded $6.4 million to two surviving family members (Josefson, 2001) [702].
In fighting the case, GlaxoSmithKline claimed that there was no substantial evidence connecting Paxil to suicide. After reviewing evidence presented by both sides, the judge found that there was sufficient scientific evidence for Paxil-induced suicide to proceed with the case. Under intense pressure from the FDA to reevaluate its existing data, it would take the drug company 5 more years to come around to the same conclusion. Growing concern about antidepressant-induced suicidality led the FDA to require the drug companies to revaluate their earlier controlled clinical trials based on FDA standards for categorizing and reanalyzing data. In May GlaxoSmithKline (2006b) [524] published a "Dear Healthcare Provider" announcement concerning Paxil-induced suicidality in depressed adults. The letter emphasized the supposedly slight increase in suicidality among young adults (through age 30) who take Paxil for a variety of conditions, including depression, panic attacks, anxiety, and obsessive-compulsive disorder. Far more important was the drug company's description of a statistically significant increase in suicidality in all ages of adults in the controlled clinical trials for major depression. Depressed patients receiving Paxil were 6.4 times more likely to display suicidal thoughts and behavior than depressed patients taking a sugar pill. In regard to suicide - the most devastating risk associated with antidepressants - it is safer for depressed persons to stay off Paxil.
The FDA allowed the Paxil manufacturer to soft-pedal the findings by claiming, for example, that the results could be compounded by the fact that suicide is an aspect of "psychiatric illnesses". This is nonsense - and every scientist knows it. Since both groups were depressed, and since they differed only in the substances they were given to take in the blinded trials, Paxil, and not depression, was the cause of this astronomical increase in the rate of suicidality.
If depression had caused the increased suicidality, then the placebo patients - who lacked the supposed benefit of an antidepressant effect - would have suffered a much higher rate of suicidality than the Paxil patients. Instead, they had a much lower rate. In other words, because the antidepressants were supposed to be helping the depressed patients, the relative ineffectiveness of the sugar pill should have led to more suicidality than the drug, not less. The FDA, the drug company, and the media ignored this important fact. Conventional assumptions would have predicted increased suicidality on placebo, instead of increased suicidality on Paxil. It is a complete reversal of the expected outcome, underscoring the seriousness of finding increased suicidality on the drug.
Finally, in December 2006, the FDA held hearings concerning the potential addition of an adult suicide warning to all antidepressant labels. The data generated in older controlled clinical trials indicated that not only children but also young adults to age 24 were developing increased suicidal thoughts and actions when taking the newer antidepressants. The FDA's panel ended up recommending a black-box warning about increased suicidality in the 18- to 24-year-old age group. The FDA's committee was rife with conflicts of interest (Pringle, 2007) [1057].
Note that this conclusion concerning antidepressants in general ignored the Paxil data published in May 2006 by GlaxoSmithKline [524] indicating an increase in suicidality in all ages for adults suffering from Major Depressive Disorder.
In May 2007 [475], the FDA gave published notice of its intention to add a warning about increased suicidality aimed at "young adults" taking antidepressants. The FDA's new warnings required at the top of each antidepressant label are contained in a black box with the title "Suicidality and Antidepressant Drugs". The warning begins, "Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders" (GlaxoSmithKline, 2007) [525].
The FDA's parsing of the suicidality warning into various age brackets meets drug company needs to obscure the basic reality that antideperessants cause suicide in children and adults. I don't know of another example in which a signal for a serious effect like suicidality has been divided up by age brackets, including some and excluding others. The distinctions are too fine to be made on the basis of controlled clinical trials that, at best, can provide a gross signal of a problem.
Once again, to dilute its impact on market for the newer antidepressants, the warning will be required for every drug approved for the treatment of depression, when in fact the data were generated entirely from clinical trials using the newer and more stimulating antidepressants. Because every antidepressant will carry the new warning, many doctors will be misled into believing that the older antidepressants have a similar risk to the newer ones. These doctors will conclude that there are no safer choices than the big moneymakers like Prozac, Paxil, Zoloft, Celexa, and Effexor.
The FDA not only limited its suicidality warnings to children, adolescents, and young adults in the new warning but also declared that there was no increase in antidepressant-induced suicidality in adults beyond age 24 and, furthermore, that "there was a reduction in risk with antidepressants compared to placebo in adults age 65 and older" (GlaxoSmithKline, 2007) [525]. The FDA is inviting doctors to believe, based on a small number of elderly patients in short-term clinical trials, that antidepressants might even reduce the suicide rate among older patients.
When insensitive clinical trials signal a suicide risk in both children and younger adults, it is time to admit flat out that antidepressants cause suicidality in all age groups. Besides, the number of patients 65 and older who were tested was very small.
Meanwhile, there is scientific data contradicting the FDA's suggestion that antidepressants might protect older adults against suicidality. A study published a few months before the FDA hearings evaluated coroners' records, prescription data, physician billing claims, and hospitalization data for more than 1.2 million Ontario residents age 66 and older from 1992 to 2000 (Juurlink et al., 2006) [715]. After evaluating more than 1,000 deaths by suicide, they found that "SSRI antidepressants were associated with a nearly fivefold higher risk of completed suicide than other antidepressants" (p. 813). This makes the FDA even more unscrupulous in acting as if antidepressants are safer in the older population.
As already mentioned, the FDA's new warning is actually weaker than the "Dear Healthcare Provider" letter sent out by GlaxoSmithKline earlier in May 2006 [524]. The Paxil trials as disclosed in the letter showed an increased rate of suicidality in all ages of adults with major depressive disorder.
The FDA's own analysis of all the adult controlled clinical trials found that Paxil was the most dangerous in regard to causing suicide attempts (Stone and Jones, 2006, p. 26) [1218]. With the exception of Paxil, the individual antidepressants did not show a statistically significant increase in adult suicidality. The significant result came only after the data were pooled for all antidepressants. But in regard to Paxil, in adults of all ages and in all psychiatric disorders, there was a statistically significant increase in suicidality (OR 2.76, 95% CI 1.16-6.60, p = 0.02).
Paxil stood out from the pack in terms of dangerousness despite GlaxoSmithKline's efforts over many years to hide cases of Paxil-induced suicidality, to misidentify suicide attempts as emotional lability in their computerized coding system, and to manipulate the suicidality data to make it seem less menacing (chapter 14; Breggin 2006a-c [213][214][215]). Despite the company's efforts to thwart the truth, even in short-term controlled clinical trials that were skewed to avoid demonstrating Paxil-induced suicidality, there was a statistically significant increased rate of suicidality in patients taking the drug compared to patients taking the placebo in all ages and all diagnostic categories.
Keep in mind that controlled clinical trials are planned by the drug companies, supervised by the drug companies, and carried out by paid doctors known to cooperate with the drug companies. Keep in mind that all the data analysis is done at drug company headquarters by drug company executives. Independent scientists play no role anywhere along the process. Keep in mind that the trials are constructed to prove the usefulness of the drug and to minimize adverse effects such as suicidality. Keep in mind that the controlled clinical trials are very short, usually 4-6 weeks long, and that prescreening excludes suicidal and psychotic patients from participating in the studies. Given these caveats, it is surprising that the suicidal signal was so strong that it could shine in the context of these trials.
In real-life medical practice, the rate of drug-induced suicidality will be much higher than in the research-oriented, controlled clinical trials. In actual practice, many patients are already suicidal when they are started on the drug, increasing the likelihood that the drug will push them over into self-injurious behavior. Similarly, in real-life clinical practice, compared to controlled clinical trials used for research, busy doctors provide much less supervision or monitoring, the patients are almost never tested or evaluated for suicidality, multiple drugs are often given at once, and the doctors know little about looking for adverse effects on the mind.
Given that Paxil increased the rate of suicidality by more than 6 times in the drug company's controlled clinical trials, it will be considerably increased in actual practice. We cannot determine exactly how much greater the risk will be in clinical practice, but it will be much higher than in the brief, highly selective, and closely monitored controlled clinical trials.
The American College of Neuropsychopharmacology (ACNP) considers itself the premier organization in the world of professionals concerned with research and practice in the field of psychiatric medications. What was its response to the disclosure that antidepressants in children are ineffective in treating depression but that they can worsen the youngsters' overall condition and cause increased suicidality? This organization, bloated with doctors on the payrolls of drug companies, warned that the FDA was causing a potential disaster. In what the Journal Psychiatric Services called a "chilling summary paragraph," the ACNP concluded ("ACNP Releases," 2006 [10]; Mann et al., 2006 [869]),
"The FDA's recent black box warning could serve to initiate a natural public health experiment. The change in labeling may be accompanied by a reduction in antidepressant prescriptions, particularly for youth. An unintended consequence of this policy could be an increase in youth suicide. That is an empirical question to be examined in the near future."
The real chilling experiment has been the drugging of millions of America's children with toxic so-called antidepressants, with no proven efficacy and with proven adverse effects, including mania and suicidality. Of course, it should be hoped that the change in label reduces the number of children exposed to these drugs. As for the empirical question concerning any potential increase in youth suicide from a reduction in antidepressant use, it is hard enough to draw conclusions from placebo-controlled clinical trials, let alone from societal experiments, where the variables are literally infinite, subjectivity can run rampant, and the controls are nonexistent. There is already a plethora of such epidemiological studies, some claiming that suicide has increased, and some claiming that it has decreased (Van Pragg, 2003) [1281], since the advent of antidepressant treatment for adults.
Society-wide epidemiological studies cannot realistically answer empirical questions about drug efficacy and adverse effects; it is hard enough to do so in carefully controlled clinical trials. And besides, the empirical question has already been answered by the clinical trials. Antidepressants increase suicidality in children and youth as well as adults. But it is guaranteed that these same ACNP so-called experts will start producing flimsy and even ridiculous epidemiological studies in an attempt to undermine the far more reliable data generated in controlled clinical trials.
Is it unfair to say that the ACNP represents the drug companies, rather than America's children? At the end of the ACNP report, there is a list of Task Force members (the report authors), with their disclosures concerning potential conflicts of interest (Mann et al., 2006) [869]. The list of industry affiliations fills one and three-fourth pages. Of the 11 authors, only 1, William Beardslee, the fourth name in the list, claims no industry affiliation. Every one of the other 10 authors acknowledges several drug company affiliations, most have many affiliations, and all 10 have connections to the manufacturers of antidepressants. And these are the professionals, the supposedly top experts, who set the standards for the prescription of psychiatric drugs in America and worldwide!
I am familiar with a number of these men as a result of my work as a medical expert in product liability suits against the drug companies. For example, the lead author, J. John Mann, listed affiliations with two of the leading manufacturers of antidepressants, GlaxoSmithKline (Paxil) and Pfizer (Zoloft). He noted that he had been an expert trial witness on behalf of Pfizer, and I have read his prodrug company reports in that context. But he does not include an equally interesting connection under his list of industrial affiliations: the pharmaceutical giant, Janssen, funds his professorship at Columbia. He is the Paul Janssen Professor of Translational Neuroscience in Psychiatry and Radiology. Janssen is now a part of Johnson & Johnson, the second largest pharmaceutical company in the world, with revenues of $50.514 billion in 2006 (CNN Money, 2007) [290].
The Department of Neuroscience (December 2006) Web page for the Columbia University Medical Center describes the Paul Janssen Professorship and the Paul Janssen Scholars program as resulting from a "partnership" between the university and Johnson & Johnson. It is a frightening illustration of how deeply embedded the pharmaceutical industry has become in the nation's leading medical centers.
Why would Mann fail to list his professorship as one of his industry affiliations? I am sure he takes great pride in his professorship, and he lists it as his university credential. I suspect that this kind of hand-in-glove connection to industry is so commonplace and so inherent in the lives of men like Mann that they hardly consider that it might be a conflict of interest to have your job funded by a partnership between your university and the world's second largest pharmaceutical company, even when that job ostensibly involves providing objective, independent evaluations of pharmaceutical products.
As another example of someone familiar to me from my work as a product liability expert, Jan Fawcett has conducted numerous clinical trials for drug companies over the years. He lists himself as a consultant to ten pharmaceutical companies, as a Speaker's Bureau member for eight pharmaceutical companies, and as recipient of grants and research support from eight pharmaceutical companies. Curiously, Fawcett lists a ninth institution, the NIMH, under industry affiliations, confirming my view that NIMH is now a part of the psychopharmaceutical complex and might as well be considered a branch of the pharmaceutical industry.
For readers who want to see all this, and more, for themselves, the article, including the list of industrial affiliations, can be found through the Neurapsychopharmacology Web site (http://www.nature.com/npp).
The APA has also been busy trying to dampen, and even to obliterate, the effects of the FDA black-box warnings. A June 2007 editorial in the association's American Journal of Psychiatry (Pfeffer, 2007) [1033] lamented, "these policy actions may have had the unintended effect of discouraging the prescription of antidepressants for pediatric patients and pediatric utilization of antidepressants without compensatory increases in other specific treatments" (p. 845). What was the purpose of warning about suicidality, if not to discourage the use of antidepressants?
The viewpoint of the editorial is so warped that it does not even mention that the FDA also found that the vast majority of clinical trials showed that antidepressants are ineffective in treating depression in children. As already noted, only 3 of 15 placebo-controlled clinical trials showed any efficacy. (Two of the three positive studies were sponsored by Eli Lilly, with Graham Emslie [407], a close Lilly collaborator, as the first author; see subsequent discussion.) Also remember FDA committee member and epidemiologist Thomas Newman's (2004) [984] observations that the adverse effects of the antidepressants were much better established than their efficacy, which could largely be accounted for by the placebo effect. Dangerous and ineffective - that should discourage the use of a treatment in children.
There was no need to wait for the FDA to conclude that most studies with children fail to display any antidepressant efficacy. The issue had been decided in the scientific literature years earlier, and additional confirmation was unfolding at the same time as the FDA hearings.
I have observed for more than a decade (Breggin, 1991c [190], 1997a [198]) that there is no scientific evidence that antidepressants are helpful for depressed children. But as a headline in Clinical Psychiatry News indicated a dozen years ago, "Though Data Lacking, Antidepressants Used Widely in Children" (Baker, 1995 [87]).
Sommers-Flanagan and Sommers-Flanagan (1996) [1202] reviewed all double-blind, placebo-controlled efficacy trials for tricyclic antidepressants (TCAs) with depressed young people published during the period 1985-1994. They summarized, "Results indicate that neither TCAs nor SSRIs have demonstrated greater efficacy than placebo in alleviating depressive symptoms in children and adolescents, despite the use of research strategies designed to give antidepressants an advantage over placebo" (p. 145). They concluded, "There has never been a double-blind, placebo controlled study published indicating that antidepressant medications are more effective than placebo in treating child or adolescent depression" (p. 151).
Fisher and Fisher (1996) [446] explored the ethical issues surrounding the use of antidepressants in children. They pointed out how published recommendations for the use of antidepressants fly in the face of data within the same publications. They observed, "The prescribing of antidepressants for children clearly illustrates how a significant group of practitioners (child psychiatrists and pediatricians) can persist in using a procedure that is actually contradicted by research data and at the same time muster justifications for doing so" (p. 101).
A meta-analysis study by Whittington et al. (2004) [1340] in The Lancet found that the combination of published and unpublished studies led to the conclusion that with the possible exception of Prozac, there was no indication of efficacy for the antidepressant treatment of children. In addition, not noted in the article is the fact that the two key studies in favor of Prozac were supported by Eli Lilly, one directly and the other indirectly through funds funneled through NIMH14, and that the lead author in both was Graham Emslie (Emslie et al., 2002, 1997 [407][408]). Emslie was task force cochair and second author of the ACNP's infamous defense of antidepressants. Emslie's industry affiliations included "Grants/Research Support: Eli Lilly, Novartis, Organon" and "Consultant/Speaker's Bureau: Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, McNeil, Otsuka, Pfizer, Inc., and Wyeth-Ayerst".
Whittington et al.'s (2004) [1340] meta-analysis led The Lancet to publish an editorial titled "Depressing Research" (2004), in which the world's oldest medical journal described the anguish of families who lose a child to suicide. It went on:
"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. In this week's issue of The Lancet, however, a meta-analysis by Craig Whittington and colleagues suggests that this is what has been happening for research into the use of antidepressants in childhood. Their results illustrate an abuse of the trust patients place in their physicians."
In the same year, the British Medical Journal (BMJ) published another review of studies and an overall critique of antidepressant research in regard to children (Jureidini et al., 2004) [714]. Its summary points stated the following:
This report was followed by yet another editorial, this time in the British Journal of Psychiatry (Tonkin et al., 2005) [1259]. Concerning antidepressants: in children, it summed up the following:
"The evidence for efficacy is weak. At least five unpublished trials using a placebo control have failed to show an advantage of antidepressants over placebo. Among eight published trials, four found no statistically significant advantage for antidepressants over placebo on any primary outcome measure, and only about a third (17/52) of all published measures show an advantage for drug over placebo. Even the statistically significant improvemems are of dubious clinical importance."
This editorial in Britain's major psychiatric journal concluded, "The currently available evidence indicates that the SSRIs should not be recommended as first-line treatment in children with depression."
Given these striking research reports and editorials in major journals in Great Britain, why would an editorial in America's major psychiatric journal, in defiance of the FDA, recommend the use of antidepressants in children? The answer, simply, is that psychiatrists in the United States are much more in the pocket of the drug companies than psychiatrists in Great Britain.
The editorial in the American Journal of Psychiatry is miffed that the FDA warned about antidepressant-induced suicidality without providing another alternative. But the so-called alternatives for treating depression in children-psychosocial and educational interventions-should have already become the only treatments for childhood depression.
As I describe in The Heart of Being Helpful (1997b) [199] and in The Antidepressant Fact Book (2001a) [207], depression ultimately is loss of hope. It is despair over ever having a worthwhile or happy life. A depressed, unhappy child has lost hope and begun to give up trying to handle life successfully.
In children, the causes of this despair and loss of hope are almost always apparent in the first consultation session, providing it involves the family and includes an evaluation of the child's school life. In children, depression almost always revolves around problems at school and in the home, everything from bullying at school and abuse at home to academic school failure, painful peer relationships, and family conflicts over how to raise the child. The treatment of depression in children requires, first, finding out how and why the child became depressed and, second, helping the child, the family, the school, and all the other participants in the child's life restore hope in the child. Children have many needs, including a stable family, rational discipline, unconditional love, stimulating educational environments, physical security, and emotional safety. The object of therapy is to identify the unmet needs and to help adults meet them.
There is nothing in this American Journal of Psychiatry editorial about the child's basic needs and how to meet them. It is all about promoting drugs. There is nothing about children as human beings in the editorial. American psychiatry's dependence on drugs has led to moral bankruptcy and therapeutic nihilism. When it comes to America's children, psychiatry is doing far more harm than good.
Overall, there has been an important movement at the FDA in the direction of warning the public and the medical profession about the risks associated with antidepressants, but it has taken much too long, and the agency remains unable to come to grips with the reality that antidepressants are lethal and ineffective. Meanwhile, organized psychiatry has fought mightily against making any changes or accommodations in response to increased knowledge about the lack of efficacy and extreme hazards associated with antidepressant treatment. Individual health care practitioners too often seem undaunted by the latest negative information about antidepressants. At the least, these drugs should be contraindicated, in the treatment of depressed children, and in a more ideal world, doctors would stop prescribing them for children or adults, instead turning to more effective and less risky psychosocial interventions in the treatment of depressed people of all ages.