Insane Medicine, Chapter 5: The Manufacture of Childhood Depression (Part 2)

Editor’s Note: Over the next several months, Mad in America will publish a serialized version of Sami Timimi’s book, Insane Medicine. In Part 1 of Chapter 5, he explored the “McDonaldisation” of growing up—how changing attitudes toward childhood have led to an epidemic of childhood “depression.” This week, he discusses the evidence base for “antidepressant” medications for children and adolescents. Each Monday, a new section of the book will be published, and all chapters will be archived here.

The selling of a panacea

Modern medicine has had some amazing successes in alleviating unnecessary suffering and reducing morbidity. Some diseases, like smallpox, have been completely eradicated; others that would have quickly killed most people—from bacterial pneumonia to Type 1 diabetes—can now be cured or effectively managed. But such progress awakens deeper, childish desires and fantasies that all suffering or unpleasant experiences have no value and are simply things we could and should eliminate from human experience.

Ivan Illich’s classic 1974 book Medical Nemesis warned us that medicalisation changes our relationship to hardship and pain and in ways that may ultimately hinder our health and wellbeing. With the advent of various types of pain-killing technologies, we start to imagine that pain and suffering can be removed from the long list of inevitable experiences humans have to comprehend and deal with.

The act of suffering had previously been shaped by culture into something with meaning, which can be stated and shared. Medicalisation led to suffering becoming detached from its cultural and social moorings.

For Illich, medical “civilisation” replaces culturally determined competence in suffering with a growing demand by each individual for the institutional management of their pain. Pain then just becomes an item on a list of complaints—things that we should not have to engage with.

As a result, a new kind of horror emerges. While the experience is still pain, the impact on our emotions has been amplified as this is now felt to be something valueless, opaque, and impersonal. By becoming unnecessary and avoidable, pain becomes unbearable. It has become meaningless, question-less torture.

The loss of meaning and value in pain can change your relationship to it and how you feel about that and other types of suffering. There is something even more sinister that lurks in the idea that mental suffering is valueless, meaningless, and something that can be simply expunged and eliminated by technical means. Unhappiness and mental pain are universal experiences. Yes, they can be devastating, cause significant impairment, and many can benefit for a range of supports, professional and non-professional, to help guide them through those darker times. But it’s not meaningless experience. We have to story it in some way.

When we narrate that experience as a chemical imbalance in the brain that erupts out of our biology and over which we have no control, we are not stating a medical fact, we are giving the experience a meaning. The meanings we give have consequences.

What if narrating suffering as an illness, something valueless, impersonal, with nothing to teach us, causes mental suffering to become even worse as it transforms into meaningless torture that keeps returning? What if this story makes our relationship to suffering primarily antagonistic, something to be feared, controlled, and suppressed, rather than engaged with in some way?

As we expand the medicalisation of pain into all mental suffering, so certain brands present themselves as ideal vehicles to culturally McDonaldise the process of wiping away suffering. Depression has become big business for the pharmaceutical industry, psychiatrists, psychologists, therapists, and a whole host of other players. It has been promoted as a lucrative brand for several decades now (although I don’t doubt most who promote it do so out of a genuine desire to help people).

The promotion of branded depression really took off after the selective serotonin reuptake inhibitor (SSRI) Prozac (the generic name is fluoxetine), first introduced in 1988, was marketed by Eli Lilly (the drug company that manufactured it) as a new antidepressant with few side effects, and promoted with the slogan “happiness in a blister pack.”

Eli Lilly first synthesised the drug that eventually became Prozac in 1971 and originally saw an entirely different future for it. It was first tested as a treatment for high blood pressure, which worked in some animals but not in humans. They then tried it as an anti-obesity agent, but this didn’t work either. When tested on psychotic patients and those hospitalised with depression, it had no obvious benefit, with a number of patients getting worse. Finally, Eli Lilly tested it on patients thought to have “mild depression.” Five recruits tried it and all five felt better after taking it. The rest, as they say, is history.

Prozac soon became a blockbuster drug that was elevated to celebrity status by books like Peter Kramer’s Listening to Prozac, where he spoke about how some of his patients became “better than well” after taking it. National campaigns (supported by Eli Lilly) alerted doctors and the public to the dangers of depression and funded the printing of millions of brochures and posters on depression. Prozac was pushed as entirely safe, non-addictive and with few side effects—a panacea.

Other drug companies soon produced their own SSRI drugs, as the potential for enormous profit became apparent. Most of the marketing effort went into promoting “depression” as a clinical condition. The resulting educational campaigns, often supported by and in collaboration with psychiatric institutions, resulted in an extraordinary expansion in the numbers of people receiving a diagnosis of depression and being subsequently prescribed a “safe, non-addictive” SSRI “antidepressant.”

For example, between 1992 and 1996, the Royal College of Psychiatrists and the Royal College of General Practitioners in the UK promoted the “Defeat Depression Campaign.” Using medicalised language, it sought to educate General Practitioners (GPs—this is the title for UK primary care doctors) and the general public to better recognise and manage depression. The campaign included use of surveys that found that the public seemed to be sympathetic to those with depression but reluctant to consult about it.

85% believed counselling to be effective but were against antidepressants and 78% regarded antidepressants as addictive (which, we now know, is in fact the case). At this time, most patients treated with antidepressants in primary care abandoned taking them due to fear of dependence.

One of the main messages that doctors were encouraged to give to patients was to educate them that dependence was not a problem. Prescriptions soon rocketed. In the UK, between 1991 and 2001, antidepressant prescriptions rose from 9 million to 24 million prescriptions a year.

The public were thus brainwashed into believing depression was a disease like any other medical disease, that chemical imbalances caused depression, that GPs were missing and not diagnosing depression frequently enough, and that treatment with medication was safe and effective. The fashion to explain our mental states as being the result of neurochemical goings on took root, opening the way for all types of mental suffering to become targets for a pill.

The culture of an ill for every pill grew, promoting the language of psychiatric disorders and a corruption of psychiatry through collusion with the pharmaceutical industry. This influenced GPs’ prescribing habits and general public beliefs about the nature of mental functioning and how to make sense of all sorts of mental pain and discomfort.

The growth of the popularity of the concept of childhood depression—from a rare to a common diagnosis that is similar to adult depression and amenable to individualised pharmaceutical and psychological treatments—began in the early 1990s and accelerated rapidly over the next decade.

A shift in theory (and consequently, practice) took place as influential academics claimed that childhood depression was more common than previously thought (quoting figures such as 8-20% of children and adolescents), resembled adult depression, was a precursor to adult depression, was amenable to treatment with antidepressants, and that early intervention was needed to prevent future problems.

This happened before any studies that showed benefit of “antidepressants” in the under-18s were published. Thus, prescriptions of drugs marketed as “antidepressants” began to made to youth under the assumption that adolescents experience this disease called “depression” in a similar way to adults and that they respond to the same treatments.

Psychiatrists in the US started to experiment with prescribing SSRIs to children, spurring drug companies to manufacture and promote products targeted at the young, such as a liquid version of Prozac being manufactured to enable lower doses than the standard 20 milligram capsule to be prescribed.

The UK soon caught up with this new trend. Between 1992 and 2001, prescriptions of SSRIs for under-18s increased tenfold, despite the fact that none had a licence for use in children. But potential disaster was about to strike for the reputation of SSRIs and in particular for its use in young people.

Panacea questioned

In the late 1990s and early 2000s, the first studies, all pharmaceutical industry sponsored, of SSRIs in under-18s were published. They appeared to support the new practice of using this medication, with the authors concluding that these drugs were safe and effective in this age group.

A classic example of how results were “spun” to hide the real findings that these studies were uncovering was the study of the SSRI paroxetine (often referred to as Study 329) that was funded by SmithKline Beecham (SKB; subsequently GlaxoSmithKline, GSK) and published in 2001. The original study concluded that “Paroxetine is generally well tolerated and effective for major depression in adolescents.”

In a unique subsequent re-analysis of this trial (unique because it’s so rare to be able to get hold of original trial data held by drug companies), researchers using the data from the original Study 329 found that paroxetine was in fact no better at treating “major depression in adolescents” than placebo, but there were substantially more harms in the group taking paroxetine—the opposite of what the original Study 329 trial had reported.

The false claims of safety and efficacy from the emerging literature on antidepressants in the young added momentum to the increasing rates of prescribing of antidepressants to under-18s that has largely continued to this day, with one important exception.

In 2002 in the UK, the BBC aired a prime-time documentary programme (known as Panorama) about the SSRI antidepressant Seroxat, examining the false marketing, addictive potential, and the evidence suggesting that it caused increased suicidality, particularly in young people. After the programme aired, the BBC received thousands of calls from viewers reporting similar reactions to that described in the programme (agitation, aggression, and suicidal thoughts). The ensuing media coverage forced the UK Committee on Safety in Medicine (CSM) to investigate these alleged dangers.

In December 2003, the UK CSM issued new guidance to UK doctors stating that SSRI anti-depressants (bar one—fluoxetine) should not be prescribed to the under-18 age group, as available evidence suggested they are not effective and run the risk of serious side effects such as increased suicidality. Several reviews around that time found disturbing shortcomings in the methods and reporting of trials of these newer antidepressants in young people and concluded that drug company supported investigators had hidden unfavourable data, exaggerating the benefits and minimising adverse effects, particularly the increased risk of suicidality in young people.

Following the publication of the CSM guidance, there was an initial impact on rates of prescribing of “antidepressants” to young people, which at the time were estimated to be prescribed to about 50,000 youngsters in the UK. For a couple of years there was a decrease in the prescribing of these SSRIs to under-18s, apart from fluoxetine, the only SSRI not to be clearly contraindicated (although on dubious grounds, given there was no real difference in the profile of this SSRI to others), whose rate of prescribing remained stable. However, by 2006, prescribing rates to under-18s for all SSRI antidepressants except paroxetine started recovering and have continued to increase since.

In the US, there was a rapid acceleration of SSRI prescriptions to under-18s from the late 1980s to 2004. Following the events in the UK that culminated in government supported advice to stop prescribing SSRIs to young people, and the publications of several reviews showing a lack of efficacy and increased likelihood of experiencing adverse events such as suicidality on these medications, many other countries, including the US, found themselves pushed into re-examining their practices and guidelines.

In the US, warnings about safety of SSRIs in under-18s came in October 2004 when their Food and Drug Administration (FDA) issued what is known as a “black box warning” for all SSRI antidepressants prescribed to those under the age of 18. A “black box warning” denotes a box or border around the text that appears on the package insert and signifies that medical studies indicate that the drug carries a significant risk of serious or even life-threatening adverse effects.

The FDA carried out its own study of 23 trials from nine drug companies and found an average risk of suicidality of 4% in SSRI treated under-18s, which was twice the 2% risk found in the placebo group. Unlike in the UK, prescribing rates in the US didn’t significantly decrease after their black box advisory, but rather showed a levelling off of the rate of prescription growth in the years immediately after the warning, with rates of prescribing to under-18s increasing rapidly again after 2008.

The evidence showing potential harms outweigh potential benefits in under-18s has not been contradicted since, but rather further supported in subsequent studies. There is yet to be one study that shows that any SSRI is more effective than placebo according to the ratings of young people or their parents. Despite this, the brief period of decline or levelling off of SSRI prescriptions to the young did not persist. In fact, SSRI use in children and adolescents increased substantially between 2005 and 2012 in every Western country where this has been studied.

Another blow to the reputation of SSRIs happened in 2008, when an important paper was published by renowned researcher Irving Kirsch and colleagues that was widely covered in the media. Their research showed that antidepressants are not significantly better than placebo in treating depression in adults, prompting headlines like “Antidepressants Do Not Work, Say Scientists.”

The researchers had pooled all studies submitted, up to 1999, to the FDA, the regulatory body in the US, for the approval of four SSRI drugs. The antidepressants produced a very small overall reduction in depression symptoms compared with placebo, which enabled the manufacturers to claim that there was a statistically significant difference between antidepressants and placebo. However, this 2008 paper concluded that this statistical difference between antidepressants and placebo was so small that they were not clinically meaningful and would not be noticed by nearly all patients or their doctors.

Recently there has also finally been acknowledgement that antidepressants are “addictive,” after years of patients pointing this out. In February 2018, the UK Council for Evidence Based Psychiatry wrote to The Times critiquing a review of antidepressant efficacy that had received significant press coverage. They highlighted “the disabling withdrawal effects that these drugs cause in many patients, which often last for many years.”

Dr Wendy Burn, then President of the Royal College of Psychiatrists, and Dr David Baldwin, then chair of the Royal College’s Psychopharmacology Committee, responded with a letter stating: “We know that in the vast majority of patients, any unpleasant symptoms experienced on discontinuing antidepressants have resolved within two weeks of stopping treatment.”

This dismissive response prompted complaints to the Royal College about this statement and their denial of the documented symptoms and suffering large numbers of patients were reporting when they attempted to withdraw from taking “antidepressants.”

In subsequent months a media debate ensued, with accusations and counter-accusations, until in September 2019 Public Health England published an historic document, Dependence and Withdrawal Associated with some Prescribed Medications: An Evidence Review.

The document meticulously documented the evidence showing the extent of the problem of withdrawing from antidepressants and made a range of important recommendations. These included more availability of services to assist people coming off antidepressants and other psychiatric drugs, better research, and more accurate national guidelines.

In October 2019, the UK National Institute for Health and Care Excellence (NICE) updated its guidelines to note that withdrawal symptoms from antidepressants can be prolonged and severe and this should now be discussed with patients prior to them being prescribed.

This story of exaggerating the benefits and minimising the risks, including the problem of dependence, has been the hallmark of all psychiatric drug promotion for the past few decades.

Yes, it is a panacea

However, you should not let evidence get in your way. There is too much money to be made and those in power know it might be too difficult now for those trained to prescribe to rethink that whole enterprise.

The story so far: Childhood depression was, until three or so decades ago, considered a rare condition, likely to be related to environmental stressors and not amenable to treatment with pharmacology. Over the course of the 1990s, and before evidence about the safety and efficacy was available, the newer SSRI “antidepressants” began to be used, alongside a new narrative that childhood depression was common, a precursor to adult depression, hugely under-diagnosed, and that early intervention with pharmaceutical treatment was often necessary, effective, and safe.

Now that there was a potential for great wealth to be generated by opening up new markets for “antidepressants,” pharmaceutical companies began publishing studies purporting to show that the medications they make were safe and effective in this age group.

A BBC Panorama documentary in 2002, UK CSM guidelines in 2003, and the US FDA black box warning in 2004 all threatened to fatally dent the profiteering that could be made through marketing these drugs to minors. And for a short time, they did. The 2008 study showing SSRIs were just enhanced placebos did further damage to its reputation for all ages.

But where you have money, you have influence. Soon after this marketing crisis, studies started emerging (and have continued to do) that attempted, successfully it seems, to rehabilitate the prescribing of SSRIs to under-18s and to restore trust in them in general.

Saving SSRIs for the under-18s

One year after the UK CSM guidelines, warning against using SSRIs in the under-18s, were published, a large US multi-centre study on adolescent depression was published. I remember listening to the lunchtime news on my car radio following the publication of this study, as I drove between clinical commitments. I heard an “expert” saying that after the guidelines the previous year telling us to be cautious about prescribing these antidepressants to young people, this ground breaking study had shown that the best outcomes come from combining an antidepressant with psychotherapy and this is what we should now offer depressed young people.

The study concluded that “The combination of fluoxetine with cognitive behavioural therapy (CBT) offered the most favourable trade-off between benefit and risk for adolescents with major depressive disorder.” The authors further concluded that despite calls to restrict access to antidepressant medications, medical management of major depressive disorder in young people with fluoxetine should be made widely available, not discouraged. Indeed, it is this study that has been particularly influential in maintaining the idea that fluoxetine is the one SSRI that has been found to be effective.

The study was a large multi-centre trial that randomised the adolescent participants diagnosed with “Major Depressive Disorder” to four treatment arms: 1. SSRI antidepressant (fluoxetine) only, 2. Placebo only, 3. CBT only, and 4. Fluoxetine plus CBT. The first and most obvious problem comes from the study methodology. The study is really two separate randomised studies: a double-blind comparison of fluoxetine with placebo—as these subjects did not know whether or not they were getting the SSRI or not, and an un-blinded comparison between CBT alone and fluoxetine plus CBT, as these subjects knew what they were receiving and had one active treatment in the CBT alone group and two active treatments in the CBT plus fluoxetine group.

In fact, it’s three studies really: A blinded study comparing fluoxetine and placebo, a second study of CBT alone, and a third study of CBT plus fluoxetine. In study 1, we have a classical “randomised controlled trial” (RCT) with an active treatment and placebo where the participants and those assessing them don’t know who is taking the active treatment and who isn’t (this is called “double blind” because both patients and their assessors don’t know who’s taking the drug or placebo).

In study 2 (CBT alone), we have one active treatment and all participants know they are having this. In study 3, participants are accessing two active treatments and know they are having them. Comparing results across all four groups is therefore misleading. At the very least they should have had a CBT plus placebo group so that they could then randomise participants to CBT plus fluoxetine or CBT plus placebo while making sure they didn’t know whether they were having the SSRI or placebo in addition to CBT.

Not mentioned in the abstract is that the researchers found no statistical advantage of fluoxetine alone over placebo on their main measure in what I am referring to above as “study 1.” This is the only legitimate conclusion that can be made from this study as far as efficacy of fluoxetine is concerned.

What about adverse events? Well, significantly more psychiatric adverse events occurred in the fluoxetine group than the placebo group. The study found a trend toward more suicidal behaviour in those taking fluoxetine (15 v 9, taking fluoxetine v not taking fluoxetine), which is consistent with other trials of SSRIs. So, as with other more objective analysis of SSRIs (such as the re-analysis of Study 329 discussed above), the relevant data from this study shows placebo to be as effective as fluoxetine but fluoxetine produces more adverse events, including a greater tendency to suicidal behaviours.

I’m sure readers won’t be surprised to hear that although the study was funded by the US National Institute of Mental Health, many of the authors disclosed ties to the pharmaceutical industry, including Professor Graham Emslie, who had extensive ties to the pharmaceutical industry and was lead investigator in the first two studies for fluoxetine in childhood depression. This seems a likely contributing reason for why the authors designed a study that was very likely to favour the arm that had two active treatments (CBT plus fluoxetine), which then enabled them to recommend this approach as the new “gold standard”—an approach that allows SSRIs to maintain a prominent place in practice.

The case for CBT plus fluoxetine has not therefore been established by this study.

In 2007, another highly publicised paper was published. The authors examined US and Dutch data on prescription rates for SSRIs up to 2005 in children and adolescents and suicide rates for children and adolescents (through 2004 in the United States and through 2005 in the Netherlands) in order to determine whether there was an association between antidepressant prescription rates and suicide rates during the periods preceding and immediately following the 2004 FDA black box warnings.

The mainstream news media reported the authors’ conclusion that SSRI prescriptions for youths had decreased in both the United States and the Netherlands after the FDA warnings were issued and that subsequently, youth suicide rates increased. They further proposed that the FDA black box warning had thus caused “major depressive disorder” to go untreated, causing an increase in suicide rates. This paper is still regularly cited by those who argue that prescribing SSRIs to under-18s doesn’t cause an increase in suicides, it actually saves lives.

This article was a quite straightforward attempt at deception. It beggars belief that it got through the review process of the journal and was published with its message that the FDA warning had led to more suicides in young people. The most glaring deceit is in the presentation of data shown on the graphs depicting prescribing and suicide rates respectively. If you look at the graphs carefully you will see that in the year in which suicide rates rose in the US, there was no significant drop in SSRI prescribing.

Their graphs for US prescribing rates show no significant decrease in antidepressant prescribing for 2004, but a 17% increase in suicides amongst the young that year (compared to 2003). The graphs show the alleged decrease in prescribing took place in 2005 (not 2004). The argument that there were decreasing rates of antidepressant prescription following the FDA warnings, are based on the 2005 prescription levels (compared with 2003); however, figures for 2005 suicides were not available at the time the paper was written and therefore do not appear.

This means the paper’s main conclusion is based on using the decrease in 2005 prescribing rates and linking this to the increased suicide rate found in 2004. In fact, when the 2005 suicide figures became available, they showed a decrease in the suicide rate in 2005 (compared to 2004) and suicide rates hit an all-time low for the US in 2007, a point in time that clearly follows the alleged decrease in prescribing.

Since 2008, both suicides and antidepressant prescribing to the young have been increasing again, but apparently this association is not worth highlighting.

The graphs on the Netherlands are mixed, show no recognisable pattern, and are based on very small numbers. For example, 2002 shows a 25% increase in suicides compared with 2001, yet it was also the year with the highest rates of prescribing of antidepressants for children and adolescents. At least for the Netherlands data the authors do compare the correct year of prescribing rate with numbers of suicide, but it is arbitrary to just pick out the decrease in prescribing rates (between 2003 and 2005) and a smaller increase in suicide rates (than for example in 2002) in 2004 and 2005 compared to 2003.

This article prompted a complaint by psychiatrists from the Netherlands about the misrepresentation of the Dutch data. The use of Dutch data also raises questions as to why, out of all the other countries they could have had access to prescribing and suicide rate data, they chose the Netherlands. Presumably, they needed to search for a country where they could try to extract data that somehow matched their narrative.

Predictably, when you look at the conflicts of interest statement, several of the authors, including the lead author, disclose conflicts of interest related to financial ties with the pharmaceutical industry.

The idea that decreased rates of prescribing SSRIs to the young leads to more suicides is clearly baloney, but it hasn’t stopped those who wish to exonerate antidepressants failings from peddling junk science to justify harmful practice.

Similarly, the finding that SSRIs are barely more effective than a placebo in adults has been resisted by establishment institutions like the UK Royal College of Psychiatrists. The best-known challenge came from a study by Andrea Cipriani and colleagues, published in 2018 and widely reported with headlines like, “Antidepressants are highly effective and should be prescribed to millions more people with mental health problems, researchers declared last night.”

Researchers had claimed to have conducted the largest-ever review of trials of antidepressants, finding that all 21 they included worked better than a placebo. Reaction from a spokesperson for the Royal College of Psychiatrists, said the analysis “finally puts to bed the controversy on antidepressants, clearly showing that these drugs do work in lifting mood and helping most people with depression.”

But what hasn’t hit the headlines were other large studies that came to a similar conclusion to the 2008 Kirsch and colleagues paper mentioned earlier, or reviews that re-analysed the 2018 Cipriani and colleagues paper but drew very different conclusions. These reviews concluded,

 “Antidepressants seem to have minimal beneficial effects on depressive symptoms and increase the risk of both serious and non-serious adverse events… The benefits of antidepressants seem to be minimal and possibly without any importance to the average patient with major depressive disorder. Antidepressants should not be used for adults with major depressive disorder before valid evidence has shown that the potential beneficial effects outweigh the harmful effects.”

And, “Several methodological limitations in the evidence base of antidepressants were either unrecognised or underestimated in the systematic review by Cipriani et al… The certainty of the evidence for the placebo-controlled comparisons should be very low according to GRADE due to a high risk of bias, indirectness of the evidence and publication bias… The evidence does not support definitive conclusions regarding the benefits of antidepressants for depression in adults. It is unclear whether antidepressants are more efficacious than placebo.”

Therefore, according to available evidence, SSRIs have a small statistically significant advantage over placebo in the short-term studies conducted, but it’s unlikely that this small difference is clinically meaningful. In young people this difference is not even statistically significant.

SSRIs have a range of worrying adverse effects including causing an increase in states of agitation that may lead to suicidal impulses, which is noticeable particularly in the young. None of these studies have looked at long-term outcomes or the problems patients have when they try to withdraw from taking these medications.

We should resist the McDonaldisation of growing up

I have been describing the kind irrational delusions we create when we propagate the belief that we have diagnoses in psychiatry that have explanatory capabilities and that lead us towards simple easy to consume soothents. The spread of this type of the psychiatrisation and McDonaldisation of the pain and struggles involved in growing up has caused considerably more harm to young people than good.

The science is on my side in this conclusion. There is plenty of junk pseudo-science scientism propping up the other side of the argument. In time this will be exposed and the paradigm it supports will be fatally undermined.

 

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