01/8/19

Antidepressant Fall From Grace, Part 2

In 1995 Irving Kirsch and Guy Sapirstein set out to assess the placebo effect in the treatment of depression. Like most people, Kirsch used to think that antidepressants worked—the active ingredient in the antidepressant helped people “cope with their psychological condition.” They weren’t surprised to find a strong placebo effect in treating depression; that was their hypothesis and the reason to do the study. What did surprise them was how small the drug effect was—the difference between the response to the drug and the response to the placebo. “The placebo effect was twice as large as the drug effect.”

Along with Thomas Moore and others, Kirsch then did an analysis of data submitted to the FDA for approval of the six most widely prescribed antidepressants approved between 1987 and 1999: fluoxetine (Prozac), paroxetine (Paxil), sertaline (Zoloft), venafaxine (Effexor), nefadozone (Serzone) and citalopram (Celexa). The researchers found that 80% of the response to medication was duplicated in placebo control groups. The mean difference between drug and placebo was clinically negligible. You can read more about this study in Prevention & Treatment, “The Emperor’s New Drugs.”

When they published their findings, Kirsch sad he was pleasantly surprised by the consensus about their findings. “Some commentators argued that our analysis had actually overestimated the real effect of antidepressants.” One group of researchers said the minimal difference between antidepressant treatment and controls was a “dirty little secret” that had been known all along. “The companies that produce the drugs knew it, and so did the regulatory agencies that approve them for marketing. But most of the doctors who prescribe these medications did not know it, let alone their patients.”

According to Irving Kirsch, pharmaceutical companies have used several devices to present their products as better than they actually are. First they will withhold negative studies from publication. While publication bias effects all areas of research, it is acutely problematic with drug trials. “Most of the clinical trials evaluating new medications are sponsored financially by the companies that produce and stand to profit from them.”

The companies own the data that come out of the trials they sponsor, and they can choose how to present them to the public — or withhold them and not present them to the public at all. With widely prescribed medications, billions of dollars are at stake.

Positive studies may be published multiple times, a practice known as “salami slicing.” Often this is done in ways that makes it difficult for reviewers to recognize the studies were done on the same data. The authors may be different. References to the previous publication of the data are often missing. Sometimes there are minor differences in the date used between one publication and another. Sometimes positive data is cherry-picked from a clinical trial and published, giving the impression that the drug seemed more effective than it really was. For more information on this issue, see: The Emperor’s New Drugs: Exploding the Antidepressant Myth by Irving Kirsch.

Published in 2004, the STAR*D study (Sequenced Treatment Alternatives to Relieve Depression) was a multisite, multistep clinical trial of outpatients with nonpsychotic major depression. It was designed to be more representative of the real world use of antidepressants than typical clinical trials; and to show the effectiveness of antidepressants in the best of circumstances. STAR*D was funded by the NIMH at a cost of $35 million dollars and took six years to complete. It was hailed as the “largest antidepressant effectiveness trial ever conducted.” Robert Whitaker described it as follows:

The STAR*D trial was designed to test whether a multistep, flexible use of medications could produce remission in a high percentage of depressed outpatients. Those who didn’t get better with three months of initial treatment with an SSRI (citalopram) then entered a second stage of treatment, in which they were either put on a different antidepressant or given a second drug to augment an antidepressant. Those who failed to remit in step two could go on to a step three, and so on; in total, there were four treatment steps.

According to the NIMH, in level 1, about one-third of participants became symptom-free. In level 2, about 25% of participants became symptom-free. So a half of the participants in the STAR*D study became symptom-free after two treatment levels. “Over the course of all four treatment levels, almost 70 percent of those who did not withdraw from the study became symptom-free.” However, there was a progressive dropout rate: 21% withdrew after level 1; 30% after level 2; and 42% after level 3.

An overall analysis of the STAR*D results indicates that patients with difficult-to-treat depression can get well after trying several treatment strategies, but the odds of beating the depression diminish with every additional treatment strategy needed. In addition, those who become symptom-free have a better chance of remaining well than those who experience only symptom improvement. And those who need to undergo several treatment steps before they become symptom-free are more likely to relapse during the follow-up period. Those who required more treatment levels tended to have more severe depressive symptoms and more co-existing psychiatric and general medical problems at the beginning of the study than those who became well after just one treatment level.

The message communicated to doctors and the public was that STAR*D showed that antidepressants enabled 67% of depressed patients to recover. Robert Whitaker said an article in The New Yorker commented this “effectiveness rate” was “far better than the rate achieved by a placebo.” But this “cumulative” remission rate of 67% was in fact a theoretical rate that assumed those who dropped out of the study would have the same remission rates as those who remained. “They [also] included remission numbers for patients who weren’t depressed enough at baseline to meet study criteria, and thus weren’t eligible for analysis.” Irving Kirsch said the STAR*D symptom remission was temporary for most: “Approximately 93 percent of the patients who recovered relapsed or dropped out of the trial within a year.”

Recently, Kirsch and others acquired the STAR*D raw data through the MIMH and reanalyzed the HRSD (Hamilton Rating Scale for Depression) results. The HRSD was identified by the original as the primary outcome measure for STAR*D. “Yet the outcome that was presented in almost all the study papers was the QIDS (Quick Inventory of Depressive Symptomatology), a measure made up especially for the STAR-D study, with no prior or subsequent credentials.” The QIDS was devised as a way of tracking symptoms during the course of treatment NOT as an outcome measure. And the original study protocol stated it should not be used as an outcome measure.

Analysis of the HRSD data in STAR*D failed to reach the threshold required for a minimal improvement. “It is also below average placebo improvement in placebo-controlled trials of antidepressants.” The STAR*D results were about “half the magnitude of those obtained in standard comparative drug trials.” Commenting on STAR*D in his book, The Emperor’s New Drugs, Irving Krisch said:

This is a rather bleak picture of the effects of antidepressant treatment. In the best of circumstances—which is what the trial was designed to evaluate—only one out of three depressed patients showed a lasting recovery from depression, and since there was no evaluation of what the recovery rate might have been with placebo treatment, there was no way of knowing whether their recovery was actually due to the medication they had been given.

In her review of the Kirsch reanalysis of the STAR*D study, Joanna Moncrieff said STAR*D suggests that in real life situations, people who take antidepressants do not do very well. “In fact, given that for the vast majority of people depression is a naturally remitting condition, it is difficult to believe that people treated with antidepressants do any better than people who are offered no treatment at all.” She thought this might be the reason the results of the main outcome measure (the HRSD) remained unpublished for so long—and also an explanation for the substitution of the QIDS as an outcome measure. In the original STAR*D analysis:

Whether this was deliberate on the part of the original STAR-D authors or not, it was certainly not made explicit. There should surely be uproar about the withholding of information about one of the world’s most widely prescribed class of drugs. We must be grateful to Kirsch and his co-authors for finally putting this data in the public domain.

According to data gathered by the CDC, 10.7% of all U.S. adults in 2011-2014 reported using an antidepressant in the past 30 days. This is 5.9 times the reported usage for 1988-1994. Demographically, the percentages of U.S. adults who used antidepressants increased with age. The percentages of women using antidepressants were also consistently higher then men for all age groups. Yet their effectiveness in treating depression has been shown to be little better than a placebo. And given that they have a multitude of adverse effects—even the SSRIs—in most cases, no medication may be better than an antidepressant.

See “Dirty Little Secret” and “Do No Harm with Antidepressants” on this website for more information on the antidepressant research of Irving Kirsch. See “The Lancet Story on Antidepressants,” Part 1 and Part 2 for more on the ongoing debate over the effectiveness of antidepressants. See “Antidepressant Fall From Grace, Part 1” for a brief history of antidepressants.

01/1/19

Antidepressant Fall From Grace, Part 1

The so-called antidepressants are not a single class of drugs; nor are they just used to treat depression. There has also been a long-running debate over their adverse effects and treatment effectiveness. After Prozac was approved as the first SSRI (selective serotonin reuptake inhibitor) in 1987, the SSRI class of antidepressants became a kind of patent medicine for treating various mood-related conditions, and was even used as a character or personality enhancement. Yet there has been an accumulation of evidence over the past twenty years that questioned whether SSRIs were more effective than placebo. Are antidepressants effective treatments for depression and are they worth the risk?

Currently, the main classes of antidepressants are SSRIs such as Prozac (fluoxetine), Zoloft (sertaline) and Celexa (citalopram); SNRIs (serotonin norepinephine reuptake inhibitors such as Effexor (venafaxine), Cymbalta (duloxetine) and Pristiq (desvenlafaxine); and NDRIs (norepinephrine-dopamine reuptake inhibitors) such as Welbutrin or Zyban (bupropion). Methylphenidate (as Ritalin, Concerta and others) is also chemically a NDRI, but is used primarily as a medication for ADHD and will not be included in the following discussion. Older classes of antidepressants include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and tetracyclic antidepressants (TeCAs). Antidepressants are used to treat major depression, anxiety, obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), eating disorders, chronic and neuropathic pain, bed-wetting, fibromyalgia and menopause, smoking cessation and others.

The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine).It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis.

In 1952 psychiatrists Max Lurie and Harry Salzer coined the term “antidepressant” to describe the action of isoniazid, a medication originally developed as a treatment for tuberculosis. Seeikoff and Robitzek experimented with another ant-tuberculosis drug, iproniazid, which had a greater psychostimulant effect, but also greater toxicity. Serious adverse effects, including liver inflammation, led to its recall as an antidepressant in 1961. These drugs are MAOIs.

A tricyclic antidepressant, Tofranil (imipramine), was also first used to treat depression in the 1950s. Another TCA, Elavil (amitriptyline), was approved in 1961. Dozens of additional TCAs were developed over time. Similar to TCAs, tetracyclic antidepressants (TeCAs) like Remeron (mirtazapine) were introduced in the 1970s. But there were problems with TCAs, including a higher risk of serious cardiovascular side effects. They also had a relatively low toxicity level, making them a suicide risk—not an attractive adverse effect for an antidepressant.

While they are biochemically similar to TCAs and have no real differences in therapeutic effectiveness, SSRIs only affect the reuptake of serotonin, not the reuptake of dopamine and norepinephrine. SSRIs also have a higher toxicity level than TCAs and a lower risk of serious cardiovascular side effects. So an argument was made for SSRIs having fewer and milder side effects than TCAs. Initially persuasive, this claim has become less credible over time.

The SSRI antidepressant craze began with the introduction of Prozac in 1987. Zoloft (sertaline) came to market in 1992, Luvox (fluvoxamine) in 1994, Paxil (paroxetine) in 1996, Celexa (citalopram) in 1998, and Lexapro (escitalopram) in 2002. All the above SSRIs are now off patent and available as generics. Yet they are among the three most commonly used classes of prescription medications in the U.S. 12.7% of persons over the age of 12 reported they took an antidepressant in the previous month, according to data from the National Center for Health Statistics. Antidepressant use is highest among females in two age groups: 40 to 59 (21.2%), and 60 and over (24.4%). The same trend was seen with males from 40 to 59 (11.6%), 60 and over (12.6%). See the linked CDC article for more information on antidepressant use among Americans.

Prozac use swept over the U.S. like a pharmaceutical wave after it was approved. It even became a drug that people took for “cosmetic psychopharmacology,” according to psychiatrist Peter Kramer, the author of the best-selling book: Listening to Prozac. Kramer said: “If I am right, we are entering an era in which medication can be used to enhance the functioning of the normal mind. The complexities of that era await us.”

The complexities of antidepressant use from the early days included evidence of violence and suicide. Toxic Psychiatry by another psychiatrist named Peter Breggin, was published in 1991. Breggin documented reports of suicidal behavior with Prozac in both the popular press and the professional literature. “Suicidal Behavior Tied to Drug,” was published on February 7, 1991 in The New York Times. The article said two cases of suicidal behavior and fantasies (with no prior history) were reported in The New England Journal of Medicine that same day. Eli Lilly (the manufacturer of Prozac) was facing more than 50 lawsuits at the time, but denied that there was any scientific merit to the claim Prozac could prompt suicidal or violent acts.

Dr. Breggin also predicted the rise of what is now called “treatment resistant depression” with SSRIs. He said: “If Prozac can indeed alleviate depression by making more serotonin available in the brain, then with time it may produce incurable depression by making the brain relatively unresponsive to any amount of serotonin.” In 2004 the FDA finally required black box warnings to be placed on the newer antidepressants, warning of the potential for the increased risk of suicidal thoughts and behavior in children and adolescents. Despite the age qualification, the danger for adults is also present.

In an article, Breggin described “How FDA Avoided Finding Adult Antidepressant Suicidality.” Quoting the FDA report of the 2006 hearings, he noted where the FDA permitted the drug companies to search their own data for “various suicide-related text strings.” Because of the large number of subjects in the adult analysis, the FDA did not—repeat, DID NOT—oversee or otherwise verify the process. “This is in contrast to the pediatric suicidality analysis in which the FDA was actively involved in the adjudication.” He added that the FDA did not require a uniform method of analysis by each drug company and an independent evaluator as required with the pediatric sample.

Peter Gøtzsche, a Danish physician and medical researcher who co-founded the Cochrane Collaboration, wrote an article describing how “Antidepressants Increase the Risk of Suicide and Violence at All Ages.” He said that while drug companies warn that antidepressants can increase the risk of suicide in children and adolescents, it is more difficult to know what that risk is for adults. This is because there has been repeated underreporting and even fraud with reporting suicides, suicide attempts and suicidal thoughts in placebo-controlled antidepressant trials. He added the FDA has contributed to the problem by downplaying the concerns, choosing to trust the drug companies and suppressing important information.

Gøtzsche drew attention to a meta-analysis of placebo-controlled trials from 2006 where the FDA reported five suicides in 52,960 patients (one per 10,000). See Table 9 of the 2006 report. However the individual responsible for the FDA’s 2006 meta-analysis had published a paper five years earlier using FDA data where he reported 22 suicides in 22,062 patients (which is 10 per 10,000). Additionally, Gøtzsche found there were four times as many suicides on antidepressants as on placebo in a 2001 study.

Additional adverse side effects from antidepressant use include: weight gain and metabolic disturbances; sexual dysfunction; bleeding; sleep disturbances; emotional blunting; agitation and activation; discontinuation syndrome (withdrawal); violence; and others. New research published in the journal Psychotherapeutics and Psychosomatics concluded that SNRIs should be added to the list of drugs that induce withdrawal symptoms upon discontinuation. Even a gradual withdrawal did not prevent the onset of “withdrawal phenomena” with SNRIs.

The results of this systematic review indicate that withdrawal symptoms may occur after discontinuation of any type of SNRI (venlafaxine, desvenlafaxine, duloxetine, milnacipran, or levomilnacipran). However, the prevalence of withdrawal symptoms was variable and appeared to be higher after discontinuation of venlafaxine.

See a literature review of long-term use of newer generation antidepressants (i.e., SSRIs and SNRIs and others) by Carvalho et al. You can also look at “In the Dark About Antidepressants,” Antidepressant Misuse Disorder” and “Listening to Antidepressants” on this website for more information on antidepressants and their adverse effects. For more information on the association of antidepressants and violence, see Medication Madness by Peter Breggin and “Violence and the Brain” or “Iatrogenic Gun Violence” on this website.

While not everyone will experience these adverse events, they are present for many individuals who have used or are using antidepressants. But if your depression is debilitating, are antidepressants effective enough to be worth risking their potential adverse effects? In Part 2 of “Antidepressant Fall From Grace” we will look at the debate over the efficacy of antidepressants.

04/10/18

The Lancet Story on Antidepressants, Part 1

The Lancet recently published a new paper reporting on a large-meta-analysis of studies on antidepressants done by Cipriani et al., “Comparative efficacy and acceptability of 21 antidepressant drugs.” All 21 antidepressants reviewed in the study were found to be more effective than placebo. Various news agencies, referred to it as “a groundbreaking study;” or as confirming “that antidepressants are effective for major depressive disorder (MDD);” and, “New study: It’s not quackery—antidepressants work. Period.” But the excitement and conclusions noted here seem to have been overdone and a bit premature.

Let’s start with the articles quoted in the first paragraph. The author of an article for The Guardian thought the “groundbreaking” Lancet study showed antidepressants were effective; and “we should get on with taking and prescribing them.” The upshot for him was that the millions of people taking antidepressants (including him) “can continue to do so without feeling guilt, shame or doubt about the course of treatment.” Doctors should feel no compunction about prescribing these drugs. “It’s official: antidepressants work.”

An article for bigthink, “New study: It’s not quackery—antidepressants work. Period,” also thought the Cipriani et al. study was helping to put some of the debate about the effectiveness of antidepressants to bed. Again the reported result was that all antidepressants performed better than placebos. The bigthink author related that in order for a drug to be considered “effective, it had to reduce depression symptoms by at least 50 percent,” which would be an astounding discovery for even one antidepressant, let alone all 21. But that was no quite how the Cipriani et al. study authors defined drug efficacy for their study. The authors said efficacy was the “response rate measured by the total number of patients who had a reduction of ≥50% of the total score on a standardised observer-rating scale for depression,” not a 50% or greater reduction in depressive symptoms. Cipriani was then quoted as saying: “We were open to any result. This is why we can say this is the final answer to the controversy.”

The opening sentence of an article on the Medscape website, “Confirmed: Antidepressants Work for Major Depression,” said: “A large meta-analysis confirms that antidepressants are effective for major depressive disorder (MDD).” Here we find the correct description of efficacy in the study: “Results showed that each studied antidepressant was significantly more efficacious, defined as yielding a reduction of at least 50% in the total score of a standardized scale for depression, than placebo after 8 weeks.” Two additional quotations of Cipriani from a press release about the study are given, suggesting while antidepressants can be an effective tool, they shouldn’t necessarily be the first line of treatment. “Medications should always be considered alongside other options, such as psychological therapies, where these are available.”

Reflecting on these three articles, I thought the Guardian and bigthink articles weren’t as careful as they could have been in their rhetoric about the results of the Cipriani et al. study. Although the Medscape article was more nuanced, it also seemed to lead to the same conclusions as the Guardian article, namely: “The demonstration of the extent of antidepressant superiority over placebo reassures patients and health-care professionals of the efficacy of [this] treatment despite high placebo response rates.” But is this conclusion by the Medscape article accurate? In the discussion section of the Cipriani et al. study, the authors said: “We found that all antidepressants included in the meta-analysis were more efficacious than placebo in adults with major depressive disorder and the summary effect sizes were mostly modest.” Further on was the following:

It should also be noted that some of the adverse effects of antidepressants occur over a prolonged period, meaning that positive results need to be taken with great caution, because the trials in this network meta-analysis were of short duration. The current report summarises evidence of differences between antidepressants when prescribed as an initial treatment. Given the modest effect sizes, non-response to antidepressants will occur.

It does not seem the study conclusively found that antidepressants work for major depression. The authors even said in some individuals antidepressants won’t be effective. Now look at the following two assessments of the Cipriani et al. study from an individual (Neuroskeptic) and an organization (The Mental Elf) that I have found to be fair, nuanced and helpful in their assessments of research into psychiatric and medication-related issues.

The Mental Elf article does have a positive title: “Antidepressants can help adults with major depression” and an overall positive assessment, but there were some clear limitations noted as well. First, gleaning results from the study, it reported the most effective antidepressants studied were: agomelatine (Valdoxan, Melitor, Thymanax), amitriptyline (Elavil), escitalopram (Lexapro), mirtazapine (Remeron), paroxetine (Paxil), venlafaxine (Effexor) and vortioxetine (Brintellix). And it noted the least effective ones studied were: fluoxetine (Prozac), fluvoxamine (Luvox), reboxetine (Edronax) and trazodone (many different brand names). The most tolerable antidepressants were: agomelatine, citalopram (Celexa), escitalopram, fluoxetine, sertraline (Zoloft) and vortioxetine. And the least tolerable were: amitriptyline, clomipramine (Anafranil), duloxetine (Cymbalta), fluvoxamine (Luvox or Faverin), reboxetine (Edronax and others), trazodone and venlafaxine.

The included data only covered a short time period—8-weeks of treatment. So the results may not apply to longer-term antidepressant use. “And some antidepressant side effects occur over a prolonged period, so positive results should be interpreted with caution.” Another concern the author noted was that seventy-eight percent of the trials included in the study were funded by pharmaceutical companies. While industry funding was not associated with substantial differences in response or dropout rates, non-industry funded trials were limited and many trials did not report or disclose their funding.

Another 73% of the included trials were rated as having a moderate risk of bias, with 9% rated as a high risk of bias and only 18% as having a low risk of bias. Significantly, the review pointed out the study did not address specific adverse events, withdrawal symptoms, or when antidepressants were used in combination with other non-drug treatments—information most patients would have found useful. Nevertheless, the Mental Elf reviewer thought the study struck a nice balance between “strong evidence that antidepressants work for adult depression” while “accepting the limitations and potential biases” in the study.

Neuroskeptic who wrote “About that New Antidepressant Study,” thought that while it was a nice piece of work, it told very little new information and had a number of limitations. He thought the media reaction to the paper was “frankly bananas.” He put the effectiveness ratings into perspective by pointing out the “mostly moderate” effect size was .30 on the Standardized Mean Difference (SMD) measure, where .2 was ‘small’ and .5 was ‘medium.’ “The thing is, ‘effective but only modestly’ has been the established view on antidepressants for at least 10 years.” He then cited a previous meta-analysis that found the overall effect size to be almost identical—.31! He then turned to the findings of Irving Kirsch’s research with antidepressants, saying:

Cipriani et al.’s estimate of the benefit of antidepressants is also very similar to the estimate found in the notorious Kirsch et al. (2008) “antidepressants don’t work” paper! Almost exactly a decade ago, Irving Kirsch et al. found the effect of antidepressants over placebo to be SMD=0.32, a finding which was, inaccurately, greeted by headlines such as “Anti-depressants ‘no better than dummy pills.”The very same newspapers are now heralding Cipriani et al. as the savior of antidepressants for finding a smaller effect…

The media hype has been “frankly bananas” about the Cipriani et al. study. More balanced reviews by Neuroskeptic and The Mental Elf thought it was “a nice piece of work” and “a nice balance” between the evidence that antidepressants work for adults with depression while accepting “the limitations and potential biases” in the data. The hype is claiming clear effectiveness for a measure that only shows modest effectiveness over the short-term of 8 weeks. Ironically, the trumpeted findings of Cipriani et al are actually lower than those of Irving Kisrch (.32), who pointed out that the SMD criterion suggested by NICE (National Institute for Health and Care Excellence) was .50. Kirsch et al. said: Thus, the mean change exhibited in trials provides a poor description of results.”

Be sure to read Part 2 of “The Lancet Story on Antidepressants” to see what anti-antidepressant voices have to say about the Cipriani et al. study. For more information on the antidepressant research by Irving Kirsch, see: “Dirty Little Secret” and “Do No Harm with Antidepressants.”

12/23/16

Listening to Antidepressants

Prozac took the U.S. by storm when the FDA approved it in 1987. It also had a similarly radical effect on the thinking of a forty year-old psychiatrist named Peter Kramer. In the Introduction of his now classic book, Listening to Prozac, Kramer described how people became “better than well” with Prozac and how they and he began to “listen” to what Prozac told them. Kramer said it “transformed my views about what makes people the way they are.” But even by 1993, when Listening to Prozac was published, the stories of violence and suicide after taking the first SSRI antidepressant were circulating as well.

Toxic Psychiatry by another psychiatrist named Peter Breggin, was published two years earlier and documented reports of suicidal behavior in both the popular press and the professional literature. “Suicidal Behavior Tied to Drug,” was published on February 7, 1991 in The New York Times. The article said two cases of suicidal behavior and fantasies (with no prior history) were reported in The New England Journal of Medicine that same day. Eli Lilly was facing more than 50 lawsuits at the time and of course denied that there was any scientific merit to the claim the medication could prompt suicidal or violent acts. The year before, “Emergence of Intense Suicidal Preoccupation During Fluoxetine Treatment,” was published in the February 1990 issue of The American Journal of Psychiatry. Its abstract read:

Six depressed patients free of recent serious suicidal ideation developed intense, violent suicidal preoccupation after 2-7 weeks of fluoxetine treatment. This state persisted for as little as 3 days to as long as 3 months after discontinuation of fluoxetine. None of these patients had ever experienced a similar state during treatment with any other psychotropic drug.

Breggin also seems to have predicted the rise of what is now called “treatment resistant depression” with SSRIs. He said: “If Prozac can indeed alleviate depression by making more serotonin available in the brain, then with time it may produce incurable depression by making the brain relatively unresponsive to any amount of serotonin.” In Talking Back to Prozac in 1995, Breggin “blew the whistle” on the newer antidepressants and antidepressant-induced violence, suicide and mania. Finally in 2004 the FDA finally required black box warnings to be placed on the newer antidepressants, warning of the potential for the increased risk of suicidal thoughts and behavior in children and adolescents.

Yes, Dr. Kramer did say as far back as Listening to Prozac that the chemical imbalance theory (the amine hypothesis) was at least incomplete and perhaps false. But then Kramer published Against Depression in 2005, arguing that the socio-economic costs of depression were so large, that modern societies should strive to eradicate it as they did with smallpox. On his blog in 2008 he argued that the chemical imbalance theory was prematurely declared dead, even though “the neurotransmitter theory is incomplete and not fully proven.” He asserted that since 1993 the evidence for it had been steadily growing.

Jonathan Leo and Jeffrey Lacasse did an in depth critique of the evidence Dr. Kramer used to support the chemical imbalance theory. They noted several qualifications used when scientists discuss the biological basis of mood with other scientists. “Yet, in the popular press all these qualifications disappear and instead the public is inundated with declarations about ‘chemical imbalances causing mental illness.’” They said there were two different discussions going on about the theory—a simple, straightforward one in the media and advertisements, but a tenuous nuanced one in scientific circles. In scientific circles, the discussion was about the appropriateness of using the chemical imbalance theory with patients and not so much about the strength of the theory.

In the late 1990s, Irving Kirsch decided to research the placebo effect with the newer (SSRIs and SNRIs) antidepressants. He began with the assumption that there actually was a therapeutic effect with antidepressants, but he wanted to assess the placebo effect: “I was not particularly interested in the drug effect. I assumed that antidepressants were effective.” He was surprised to discover how small the drug effect was. Seventy-five percent of the improvement in the drug group also occurred with people who were given placebo pills with no active ingredient in them.

Critics of his findings said the meta-analysis he and his co-author had done was biased; that they had an unrepresentative sample of clinical trials. So Kirsch and three others replicated the original study with the identical data set used by the pharmaceutical companies for the FDA approval of six of the new generation antidepressants at the time. These six accounted for the bulk of antidepressant prescriptions being written at the time, 2002. “In the data sent to us by the FDA, only 43% of the trials showed a statistically significant benefit of drug over placebo. The remaining 57% were failed or negative trials.” The results here were that 82% of the response to antidepressants was due to the placebo effect.

Kirsch again did a replication in 2008 with a larger number of clinical trials and again found the 82% placebo effect. In both analyses, the mean difference between drug and placebo was less than two points (1.8) on the HAM-D depression scale, used in all the FDA clinical trials for antidepressants at the time. The difference was clinically insignificant. In other words, these miniscule differences were too small to be observable in a normal clinical setting with someone who was depressed. Others, including the FDA, have repeatedly replicated their results. The above history can be found in a 2014 article by Irving Kirsch, “Antidepressants and the Placebo Effect,” or in his 2010 book, The Emperor’s New Drugs. There he speculated:

Antidepressants may be nothing more than active placebos, producing side effects through chemical means and therapeutic effects through psychological means.

Twenty-three years after Listening to Prozac, Peter Kramer published his latest book, Ordinarily Well: The Case for Antidepressants. According to Jonathan Rosen, who wrote “The Assault on Antidepressants” for The Atlantic, Kramer said he believed in the utility of antidepressants, despite their flaws. He not only sought to make a case for antidepressants, he also tried to make a case for psychiatry as “a humanistic science that bridges the impersonal ideals of the laboratory and the pragmatic exigencies of clinical intervention.”

In a book review of Ordinarily Well for The New York Times, Jennifer Senior referred to the original Kirsch research and said Kramer was wary of these studies because they flew in the face of his clinical experience. Indicating that when his own patients asked if their improved mood could be due to a placebo effect, “Dr. Kramer’s answer is an unequivocal no.” And Ordinarily Well attempted to prove his belief. Senior indicated Kramer argued that Kirsch deliberately “’seemed to cull studies in which antidepressants underperformed,’ and treated some drugs as placebos even though they may have had antidepressant effects.” Either Senior or Kramer was unaware of, or failed to mention the above-described replications done by Kirsch and others. She did point out how Kramer used meta-analyses to make his own points, but failed to acknowledge that fact. Another area of concern for Kramer was the mechanism for recruiting subjects for clinical trials.

He is particularly devastating on the subject of recruiting test subjects. One of the most damning chapters features an unnamed facility where antidepressant trials are frequently conducted. Many of the participants are unemployed or underemployed — lonely, dispossessed and eager for the money. Suddenly, they’re getting paid, interacting with others and receiving the careful attention of doctors and nurses. “Even on placebo,” Dr. Kramer writes, “these patients ought to get better.”

There is an indication that evidence-based medicine has some flaws; and that the gold standard of meta-analysis can be undermined by flawed analysis, especially in psychiatric drug research. And there really is a problem with recruiting clinical trials subjects; and sometimes with the methodologies used by researchers in those clinical trials. But remember that if Kramer’s concerns are accepted (and I think they should be), then the newer antidepressants were approved using questionable scientific methods and an unreliable approval process. See “Evidence-Based Treatment … Lacks Evidence.”

If that is the case, where is the protection that FDA approval of pharmaceuticals is supposed to provide? And why aren’t more people pressing for regulatory reform of the FDA clinical trial process? If we accept Kramer’s arguments, we should also acknowledge that the clinical trials used for FDA approval of SSRIs were invalid. Kramer’s rationale for dismissing the evidence for the placebo effect with antidepressants also calls into question the methods used for their approval—and many of the studies afterwards touting their continued effectiveness.

A recent review article by Andrews et al., “Is Serotonin a Downer or an Upper?” challenged the assumptions of the therapeutic effects of SSRIs. “Although the idea that a single neurochemical is the cause of depression is now considered simplistic, the low serotonin hypothesis still lies at the foundation of most research on depression.” The authors noted how many types of depression seem to correspond to higher levels of serotonin, not lower ones. They proposed a radical new way of understanding the role of serotonin in the brain, according to Shannon Peters in, “How Do Antidepressant Really ‘Work’?” They suggest that serotonin coordinates metabolic processes with the storage, mobilization, distribution, production and utilization of energy resources.

Under this theory, there are higher levels of serotonin when there is a need to redistribute limited energy resources. “Serotonin cannot be simply described as an ‘upper’ or a ‘downer’; its symptomatic effects depend on the organism’s state,” write the authors.

When listening to antidepressants, we hear a history of effectiveness that can’t be clearly attributed to the therapeutic effect of the drugs. Expectation or placebo plays a significant role in whether or not these drugs will help an individual “overcome” their depression. Peter Kramer continues to hold on to a narrative that the chemical properties of SSRIs actually do help some depressed individuals, with “little of the benefit coming from the classical placebo effect.” But in debunking the science used to affirm the antidepressant placebo effect, he also calls into question the methods used to approve those same SSRIs in the first place.

What about Peter Breggin? He’s still around and critiquing the use of other classes of psychiatric drugs as well as antidepressants. He was recently the expert witness in a 2016 court case, awarding $11.9 million in a Paxil suicide malpractice case. He has a video series on YouTube, “Simple Truths About Psychiatry,” which is also linked on his website: breggin.com. There is plenty of additional material there to support the ineffectiveness and danger of antidepressants. In 2011, Dr. Breggin was the expert witness in a court case where Prozac was found to be a contributing factor to the murder of a teenager by his friend. “This was the first criminal case in North America where a judge has specifically found that an antidepressant was the cause of a murder.”

There’s more discussion of Irving Kirsch and the placebo effect here on my website. Start with: “Dirty Little Secret” or do a search of the website for his name.

10/21/15

Dirty Little Secret

Quoting Steven Hollon, in his book The Emperor’s New Drugs, Irving Kirsch said it was a “dirty little secret” that there was only a small difference between the experimental and control groups for the patients who participated in the randomized clinical trials (RCTs) used to approve SSRIs. Be sure to get this: the pharmaceutical companies that produced the drugs AND the regulatory agencies that approved them, knew there was essentially no difference between the effects of the drug and the placebo. Yet the drugs were approved for use with humans. “Many have long been unimpressed by the magnitude of the differences observed between treatments and controls, what some of our colleagues refer to as the ‘dirty little secret’ in the pharmaceutical literature.”

Kirsch was originally interested in studying the placebo effect, and not the antidepressant drug effect. “How is it, I wondered, that the belief that one has taken a medication can produce some of the effects of that medication?” He was not surprised to find a substantial placebo effect of the medications on depression. But he was surprised to see how small the drug effect was. “Seventy-five percent of the improvement in the drug group also occurred when people were give dummy pills with no active ingredient in them.”

You can read an article by Kirsch describing the research process described here in: “Antidepressants and the Placebo Effect.”

He replicated the findings in another study published in 2002, using the data submitted to the FDA by the pharmaceutical companies in their process of obtaining approval for six new generation antidepressants. There were some advantages to using the FDA data set. First, they received data on the published and unpublished clinical trials conducted by the pharmaceutical companies. What was particularly important here was that: “The results of the unpublished trials were known only to the drug companies and the FDA, and most of them failed to find a significant benefit of drug over placebo.”

A second advantage was that the FDA trials all used the same primary measure of depression—the Hamilton depression scale (HAM-D). The third advantage was that the FDA data was the same data used for the approval of the medications. So if there had been anything wrong with the trials, one would think, the medications would not have been approved.

In the data sent to us by the FDA, only 43% of the trials showed a statistically significant benefit of drug over placebo. The remaining 57% were failed or negative trials. . . . The results of our analysis indicated that the placebo response was 82% of the response to these antidepressants.

One explanation for Kirsch’s results could be that the replication done in 2002 contained both the published and unpublished clinical trials. The inclusion of failed and negative trials would have lowered the positive results required by the FDA for approval of a medication. So the placebo response was greater in this replication than it was in their original study because of including the unpublished trials. Nevertheless, the majority of the trials failed to show positive results. Remember that the pharmaceutical companies themselves conducted these studies; and that they were the trials done in the process of gaining approval for their medications.

Getting approval of a drug by the FDA requires the submission of two studies showing the new drug is better than a placebo. It doesn’t matter if it takes you ten studies to get those two; only the two positive ones count for approval. The requirement is that two trials have to demonstrate the drug is more effective than a placebo, and that measurement has to be statistically significant. Kirsch’s analysis found just a 1.8-point difference on the HAM-D scale between drug and placebo—a difference that is not clinically significant, even though it may be statistically significant. The National Institute for Health and Clinical Excellence (NICE) has set the criterion for a clinically significant difference between drug and placebo to be at least three points on the HAM-D scale.

A criticism of Kirsch’s 2002 study was that the results were based on clinical trials conducted on subjects who were not very depressed. So Kirsch et al. (2008) reanalyzed the data in: “Initial Severity and Antidepressant Benefits.” They found that “the overall effect of new-generation antidepressant medications is below recommended criteria for clinical significance.” Only for the most extremely depressed patients was there evidence for clinical significance, according to the HAM-D scale. Yet they also concluded this difference was “due to a decrease in the response to placebo rather than an increase in the response to medication.”

So the question becomes, what do all these drugs have in common that gives them a slight, but statistically significant effect on depression over placebo? The answer is that they all produce side effects.

Clinical trials are all double-blind studies, meaning that neither the patient nor the doctor is supposed to know whether the patient is given the active drug or the placebo. Yet in one study, 80% of patients guessed correctly whether or not they were on the drug or placebo; and 87% of doctors also guessed correctly. So most patients and most doctors could break the blind by guessing according to the presence or absence of side effects to the medications. Additionally, “89% of the patients in the drug group correctly ‘guessed’ that they had been given the real antidepressant, a result that is very unlikely to be due to chance.”

So clinical trials are not really double blind studies if most patients can guess whether or not they have been given the real drug rather than the placebo. This ability to “break blind” has been known in the research literature since 1986 when Rabkin et al. published their study, “How Blind is Blind” in the September issue of Psychiatry Research. Yet drug trials continue to use inert placebos.

But what would happen if an active placebo were used in clinical trials? Active placebos have been used with antidepressants in other studies. See “Active Placebos Versus Antidepressants for Depression.” Moncrieff et al. reported that: “differences between antidepressants and active placebos were small.” Kirsch noted that in the nine clinical trials discussed by Moncrieff et al. where an active placebo (atropine) was used, there was only a significant difference in two of the studies.

In the vast majority (78 percent) of the clinical trials in which active placebos were used, no significant differences were found between the drug and the placebo. So comparisons with inactive placebos are much more likely to show drug-placebo differences than comparisons with active placebos. This suggests that at least part of the difference that has been found between antidepressant and placebo may be due to the experience of more side effects on the active drug than on the placebo.

It’s good this dirty little secret is becoming more widely known. But unfortunately the horse has already left the barn. Too bad it wasn’t getting press fifteen years ago before the SSRIs started going off-patent. The pharmaceutical companies have already gouged the public with their SSRI profits and their drugs have gone generic.

Eli Liliy’s Prozac went off patent in 2001. GlaxoSmithKline’s Paxil has been off-patent since 2003. Forest Labs’ Celexa patent expired in 2003. Pfizer’s Zoloft patent expired in 2006. Wyeth’s Effexor (now marketed by Pfizer) went off-patent in 2006. Wellbutrin, developed by Burroughs Wellcome and later acquired by GlaxoSmithKline, lost its patent in 2006. Lexapro was developed by Forest Laboratories in conjunction with Lundbeck and they won two patent extensions. But it lost exclusivity in 2012.

09/2/15

Do No Harm with Antidepressants

In April of 2006, I first read Irving Kirsch’s 2002 article, “The Emperor’s New Drugs.” In that article, Kirsch described how 80% of the response to antidepressant medications was duplicated in placebo control groups. Kirsch’s analysis was of the very same clinical data submitted to the FDA between 1987 and 1999 for the approval of 6 widely prescribed antidepressants. The allusion to Hans Christian Andersen’s tale, “The Emperor’s New Clothes” was fitting. Kirsch played the role of the little boy in Andersen’s tale to my understanding of how antidepressants work. He pointed to antidepressants and said: “But they have little or no therapeutic effect at all!”

Since 2006 I’ve become familiar with the work of several individuals questioning the received wisdom of psychotropic medications, including Joanna Moncrieff. Her book, The Myth of the Chemical Cure, had its own “aha!” moment in the development of my thinking on the clinical use of psychiatric medications. A search of “Faith Seeking Understanding” by their names will pull up other articles where I have referenced them.

Not too long ago, I saw a link to a new article by Joanna Moncrieff and Irving Kirsch, “Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences.” I’ve read previous articles written by Moncrieff and Kirsch, “Efficacy of antidepressants in adults” and “Clinical trials and the response rate illusion.” But still looked forward to reading their latest. It seems to have hammered home the final nail in the coffin of the ineffectiveness of antidepressants for me.

In “The Emperor’s New Drugs,” Kirsch found that the drug/placebo difference was less than 2 points on the Hamilton-D (HAM-D) scale, a scale often used in studies for assessing the effects of antidepressants. Even then, Kirsch et al. were saying that: “the clinical significance of these differences is questionable.” The spin put on his conclusions was that this was only to hold true only for individuals with mild cases of depression. Moderate to severe depression should still have antidepressants as a first-line treatment.

However, in “Efficacy of antidepressants in adults,” Moncrieff and Kirsch pointed out that the studies included in “The Emperor’s New Drugs,” were mainly with patients suffering with severe to very severe depression. They cited additional studies questioning the efficacy of antidepressants and concluded: “Recent meta-analyses show selective serotonin reuptake inhibitors have no clinically meaningful advantage over placebo;” and that “Claims that antidepressants are more effective in more severe conditions have little evidence to support them.”

In their most recent article, Moncrieff and Kirsch tackled the issue of how antidepressants have been shown to be statistically superior to placebo. This statistical significance has been true from the time of Kirsch’s work on “The Emperor’s New Drugs, ” where the authors said that: “Although mean differences were small, most of them favored the active drug, and overall, the difference was statistically significant.” Moncrieff and Kirsch commented that a three-point difference on the HAM-D scale could not be detected by clinicians. Clinically relevant drug-placebo differences would have to be 7 points or greater on the HAM-D scale. “Currently, drug effects associated with antidepressants fall far short of these criteria.”

These conclusions were built upon the work of German psychiatrist Stefan Leucht and his colleagues. You can read a less technical discussion of the importance of this research in Dr. Moncrieff’s blog, here. She said that a reduction of 2 points on the 52 point HAM-D scale, while statistically significant, seemed to be an insignificant amount. “Leucht et al. provide some empirical evidence to support that hunch.”

Given that there was little if any difference in clinically relevant effects between one treatment and another, Moncrieff and Kirsch suggested that patients and healthcare providers should be aware that all treatments, including placebo, produce some positive effect on symptom scales, “while none outperforms a pill placebo to a meaningful degree.”

The small differences detected between antidepressants and placebo may represent drug-induced mental alterations (such as sedation or emotional blunting) or amplified placebo effects rather than specific ‘antidepressant’ effects. At a minimum, therefore, it is important to ascertain whether differences correlate with clinically detectable and meaningful levels of improvement.

So where does this discussion lead us? Treating depressive symptoms with antidepressants should not be a first option. “Given the choice, most depressed patients prefer psychotherapy over medication.” Moncrieff and Kirsch suggest that decisions about treatment should include patient preference, safety and cost. With regard to safety, antidepressants should be a last choice for treatment alternatives.

Their article referenced a study by Andrews et al., “Primum non nocere” (first, do no harm), which noted a series of harmful effects from SSRIs. Serotonin has wide reaching effects on adaptive processes throughout the body and could have many adverse health effects. They described how antidepressants effect the proper functioning of homeostatic mechanisms in the body. Long-term use is associated with a loss of symptom reducing effectiveness with SSRIs. This suggests that the brain is pushing back against the effects of SSRIs and trying to regain the homeostasis present before the use of antidepressants began. “Because of the complex role that serotonin plays in shaping the brain, antidepressants could have complex effects on neuronal functioning.”

Additional negative side effects included attention problems, driving performance, falling and bone fractures in the elderly, gastrointestinal problems such as diarrhea, constipation and irritable bowel syndrome. SSRIs may increase the risk of abnormal bleeding. They can related to an increase risk of cardiovascular events. There is concern that SSRIs can effect neonatal development. One study suggested SSRI use during pregnancy, especially the first trimester, led to an increased risk of Autism Spectrum Disorders. Andrews et al. summarized their findings here:

We have reviewed a great deal of evidence of the effects of antidepressants on serotonergic processes throughout the body. Some of the effects are widely known, but they have been largely ignored in debates about the utility of antidepressants. Indeed, it is widely believed that antidepressant medications are both safe and effective; however, this belief was formed in the absence of adequate scientific verification. The weight of current evidence suggests that, in general, antidepressants are neither safe nor effective; they appear to do more harm than good.

03/18/15

Modern Alchemy with Antidepressants

A study published in the open access journal, PLOS One by Sugarman et al. once again replicated previous studies showing that there was very little clinical difference between an antidepressant and placebo. In a way this is old news. One of the study’s authors, Irving Kirsch previously reported these findings. You can read more on this antidepressant research here and here. I’ve also looked at a 60 Minutes broadcast that interviewed him in “Thor’s Psychiatric Hammer: Antidepressants.” Kirsch has also published a book on the topic: The Emperor’s New Drugs: Exploding the Antidepressant Myth. But here is the significance of the Sugarman et al. study. It was the first evaluation to use “a complete database of published and unpublished trials sponsored by the drug’s manufacturer.”

In 2004, GlaxoSmithKline (GSK) was required as part of a lawsuit settlement to post online the results of all clinical trials involving its drugs. The 2004 lawsuit was because the company had withheld data on the ineffectiveness and potential danger of Paxil (paroxetine) when given to adolescents and children. But it doesn’t seem GSK learned their lesson. In 2014 the company agreed to plead guilty to criminal charges and pay $3 billion in fines for promoting its antidepressant drugs, Paxil and Wellbutrin for unapproved uses and failing to report safety data about Avandia. So Sugarman et al. were able to use the data GSK made available to do the research reported here.

The current analysis is the first evaluation of the efficacy of an SSRI medication in the treatment of multiple anxiety disorders, and the first to utilize a complete database of published and unpublished trials sponsored by the drug’s manufacturer. Our results indicated that paroxetine presented a modest benefit over placebo in the treatment of anxiety and depression, with mean change score differences of 2.3 and 2.5 points on the HRSA [Hamilton Rating Scale for Anxiety] and HRSD [Hamilton Rating Scale for Depression], respectively.

The study’s results found that individuals receiving placebo reported 79% of the magnitude of change with the individuals receiving paroxetine. This was consistent to previously reported magnitudes of 76% for placebo compared to paroxetine. Replicating this previous finding, namely greater than 75% of the drug response, suggested that: “the magnitude of the placebo effect is especially large in the treatment of anxiety and depression.” Given the similarities between paroxetine and other SSRIs, it is possible that similar magnitudes of placebo effects will be found with them. Further research is required to support this proposition. Nevertheless, “the current analysis indicates that the published literature represents an overestimate of the true efficacy of paroxetine in the treatment of anxiety.”

The glass-half-full reporting of the differences between drug and placebo have emphasized that statistically significant differences were found. The problem is, those differences were so small, that their clinical significance was questionable. According to the criteria of NICE, the National Institute of Health and Clinical Excellence, “the mean difference between paroxetine and placebo in the current analyses fell short of clinical significance for the treatment of both anxiety and depression.” Sugarman et al. reviewed these concerns and concluded that changes of three points or less on the HRSD did not correspond to a clinically detectable change and appeared to be “of marginal clinical significance.”

So paroxetine has only a slight benefit over placebo in treating symptoms of anxiety and supports previous work indicating that it has just a modest benefit over placebo when treating depression. Given the known side effects with standard medications used to treat anxiety and depression, their use as a first-line treatment for these problems seems questionable. “The obvious alternative for the treatment of both anxiety and depression is psychotherapy intervention.” But direct comparisons have not generally shown a significant difference between depression treatment modalities (medication or psychotherapy). Similarly inconclusive findings were noted for anxiety treatment.

Allen Frances said there were two differences between medieval alchemy and the pharmaceutical industry today. First is the well-oiled, massively financed, worldwide, and devastatingly effective marketing machine. Second is the requirement for a DSM diagnosis.

A significant portion of the $12 billion spent each year on antidepressants in the United States rewards the drug companies for promoting the overly widespread use of what to many patients are no more than highly advertised, oversold, and very expensive placebos prescribed for a fake diagnosis. (Allen Frances, Saving Normal)

In 2010, there was a study published a Scandinavian psychiatric journal with the provocative title: “Antidepressant Medication Prevents Suicide in Depression.” It concluded from studying 18,922 suicides in Sweden between 1992 and 2003, “that a substantial number of depressed individuals were saved from suicide by postdischarge treatment with antidepressant medication.” Sixteen months after publication, it was formally retracted by the authors for “… unintentional errors in the analysis of the data.”

Psychologist Phillip Hickey reported that after a five month legal battle, he was able to get access to the correct data. The original study found that among completed suicides treated for depression in psychiatric care in the last five years before their suicide, 164 (15.2%) had antidepressants in their blood when they committed suicide. The corrected data indicated that 603 (56%) had antidepressants in them when they committed suicide. The “unintentional error” was huge—an increase of 439 people (268%).

And yet, the study’s author said that no conclusion from the study could be drawn “regarding antidepressants’ effects on suicide risk in any direction.” In other words, you couldn’t conclude that antidepressants prevented or facilitated suicide risk. Hickey reported that at the time of writing the original article, its author has financial ties to Lundback, Eli Lily and GSK (GlaxoSmithKline).

In another study, found in The British Journal of Psychiatry, a team of UCLA researchers randomized 88 participants into double-blind groups for 8 weeks of treatment (placebo or medication) with supportive care; and a separate group receiving supportive care alone. Expectations of medication effectiveness, general treatment effectiveness and therapeutic alliance were also measured. The groups receiving medication or placebo plus supportive care were not significantly different. However, both had significantly better outcomes than the supportive care alone group. Expectations of medication effectiveness were predictive of only the placebo response. Therapeutic alliance predicted participant response to both medication and placebo.

The lead author of the study, Andrew Lechter, said that the results indicated that if you think a pill is going to work, it probably will work. He noted that belief in the effectiveness of the medication was not related to the likelihood of benefitting from it. “Our study indicates that belief in ‘the power of the pill’ uniquely drives the placebo response, while medications are likely to work regardless of patients’ belief in their effectiveness.” He speculated that factors like direct-to-the-consumer advertising could be shaping peoples’ attitudes about medication. “It may not be an accident that placebo response rates have soared at the same time the pharmaceutical companies are spending $10 billion a year on consumer advertising.”

It seems that Lechter is saying that the drug response was independent of the expectations of medication effectiveness, while the placebo response was driven be the prior expectations of the participants, as they were influenced by factors like direct-to-the-consumer advertisings. If true, this would seem to challenge, to a certain extent, the results noted above and in Kirsch’s previous research. Replication of the results is needed before Lechter’s conclusions from his research are accepted. It should be pointed out that paroxetine (Paxil) was approved by the FDA in May of 1996, while direct-to-the-consumer advertising of medications did not begin until 1997. Therefore, it would not have had an effect upon the paroxetine data reported above. I would also feel more comfortable with Lechter’s interpretations of his data if he didn’t have as extensive an association with the pharmaceutical industry. See the “Declaration of interest” in the linked abstract from The British Journal of Psychiatry.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: Irving Kirsch