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.

04/20/18

The Lancet Story on Antidepressants, Part 2

While introducing his review on The Mental Elf of a Lancet study by Cipriani et al., “Comparative efficacy and acceptability of 21 antidepressant drugs,” Andre Tomlin commented how it had been a rough few months where “anti-antidepressant voices” really hit the mainstream. Neuroskeptic thought the study was a nice piece or work, but had very little new information. He also thought the media hype over it was “frankly bananas.” In Part 1 of this article, I looked at the more positive responses to the Cipriani et al. study. Here we will look at the rest of the story from the “anti-antidepressant voices.”

Turn to Part 1 if you want to hear what The Mental Elf and Neuroskeptic had to say about the Cipriani et al. study first. Here we’ll look at the thoughts of Peter Gøtzsche, Joanna Moncrieff and the Council for Evidence-Based Psychiatry.

Tomlin seems to question Gøtzsche’s ‘evidence,’ that antidepressants actually kill people who take them. But turn to “In the Dark About Antidepressants” or “Psychiatry Needs a Revolution” for more on Gøtzsche’s ‘evidence’ on the harm from antidepressants before you dismiss his claims. Remember that Peter Gøtzsche is a careful medical researcher and the Director of the Nordic Cochrane Center. Along with 80 others, he helped start the Cochrane Collaboration in 1993, which is “a global independent network of researchers, professionals, patients, carers, and people interested in health.”

In “Rewarding the Companies that Cheated the Most in Antidepressant Trials, “ Dr. Gøtzsche’s opening comment was: “It is well known that we cannot trust the data the drug companies publish, and it seems that, in psychiatric drug trials, the manipulations with the data are particularly pronounced.” He described, with supporting citations, how half the deaths and suicides that occur in randomised drug trials are not published. When independent researchers have the opportunity to analyze trial data themselves, “the results are often markedly different to those the companies have published.” He then said:

Fraud and selective reporting are of course not limited to the most serious outcomes but also affect other trial outcomes. Several of the authors of a 2018 network meta-analysis in the Lancet are well aware that published trial reports of depression pills cannot be trusted. I therefore do not understand why they are authors on this paper.

He noted how most of the data analyzed by the Cipriani et al. study came from published trials reports, “which we know are seriously unreliable for depression trials.” Gøtzsche pointed out where one of the coauthors for the study had previously coauthored a study showing that “the effect of depression pills was 32% larger in published trials than in all trials in FDA’s possession.” In his opinion, the meta-analytic analysis of the Cipriani et al. study had no clinical value and was “so complicated that it is impossible to know what all this leads to. But we do know that statistical maneuvers cannot make unreliable trials reliable.”

In addition to the doubtful effect of antidepressants noted in the study (see Part 1), Gøtzsche thought ranking the drugs according to their effect and acceptability was a futile exercise. “My thought was that the authors had rewarded those companies that had cheated the most with their trials.” He said it was highly unlikely that some depression pills were both more effective and better tolerated than others.

One doesn’t need to be a clinical pharmacologist to know that this seems too good to be true. Drugs that are more effective than others (which is often a matter of giving them in higher, non-equipotent doses), will usually also be more poorly tolerated.

The reality is that despite serious flaws in depression drug trials, “the average effect is considerably below what is clinically relevant.” That was demonstrated in the Cipriani et al. study and has been shown in several other studies. Examples of the serious flaws noted by Gøtzsche included: “[a] lack of blinding because of the conspicuous adverse effects of the pills, cold turkey in the placebo group because people were already on depression pills before they were randomised, industry-funding, selective reporting and data massage.” He concluded the benefits to harm of depression pills meant that placebo was better than the drug.

Joanna Moncrieff was appalled at the almost universally uncritical coverage given to the Cipriani et al. study. In her article, “Challenging the new hype about antidepressants,” she noted where John Geddes, one of the study’s coauthors, said only one in six people with depression receive effective treatment; and he wanted to make that six out of six. By her calculations, if 9% of the UK population is already taking antidepressants, “and they only represent 1 in 6 of those who need them, then 54% of the population should be taking them. I make that another 27 million people!” Dr. Moncrieff went on and noted once again, that despite the hype, there was nothing groundbreaking in this latest meta-analysis. “It simply repeats the errors of previous analyses.”

The analysis consists of comparing ‘response’ rates between people on antidepressants and those on placebo. But ‘response’ is an artificial category that has been arbitrarily constructed out of the data actually collected, which consists of scores on depression rating scales, like the commonly used Hamilton rating Scale for Depression (HRSD). Analysing categories inflates differences (3). When the actual scores are compared, differences are trivial, amounting to around 2 points on the HRSD, which has a maximum score of 54. These differences are unlikely to be clinically relevant, as I have explained before. Research comparing HRSD scores with scores on a global rating of improvement suggest that such a difference would not even be noticed, and you would need a difference of at least 8 points to register ‘mild improvement’. [See her article for the noted citations and a link to her previous discussion on the HRSD]

Participants in a clinical trial can deduce whether or not they are in the experimental group with the antidepressant medication by recognizing the side effects with antidepressant medication “(e.g. nausea, dry mouth, drowsiness and emotional blunting) irrespective of whether or not they treat depression.” If that happens, these participants may then receive an amplified placebo effect by knowing they are taking an active drug rather than an inactive placebo. “This may explain why antidepressants that cause the most noticeable alterations, such as amitriptyline, appeared to be the most effective in the recent analysis.”

She also pointed out ‘real world’ studies showing the long-term effects of people treated with antidepressants. “The proportion of people who stick to recommended treatment, recover and don’t relapse within a year is staggeringly low (108 out of the 3110 people who enrolled in the STAR-D study and satisfied the inclusion criteria).” Several studies have found that the outcomes for people treated with antidepressants “are worse than the outcomes of people with depression who are not treated with antidepressants.” Moncrieff said calling to increase the use of antidepressants, as Geddes did, will not address the problem of depression and will only “increase the harms these drugs produce.”

As the debate around the [media] coverage highlighted, many people feel they have been helped by antidepressants, and some are happy to consider themselves as having some sort of brain disease that antidepressants put right. These ideas can be reassuring. If people have had access to balanced information and decided this view suits them, then that is fine. But in order for people to make up their own minds about the value or otherwise of antidepressants and the understanding of depression that comes in their wake, they need to be aware that the story the doctor might have told them about the chemical imbalance in their brain and the pills that put it right, is not backed up by science [see her article for a link to this topic], and that the evidence these pills are more effective than dummy tablets is pretty slim.

The Council for Evidence-Based Psychiatry also pointed out “the new research proves nothing new.” Further, they cited where the Royal College of Psychiatrists (RCP) represented the Cipriani et al. study as “finally putting to bed the controversy on anti-depressants.”

This statement is irresponsible and unsubstantiated, as the study actually supports what has been known for a long time, that various drugs can, unsurprisingly, have an impact on our mood, thoughts and motivation, but also differences between placebo and antidepressants are so minor that they are clinically insignificant, hardly registering at all in a person’s actual experience.

Then on February 24^th, the President of the Royal Collage of Psychiatry and the Chair of its Psychopharmacology Committee stated in a letter to The London Times that: “the vast majority of patients, any unpleasant symptoms experienced on discontinuing antidepressants have resolved within two weeks of stopping treatment.” This led to a “Formal Complaint to the UK Royal College of Psychiatrists” when Professor John Read and others wrote to the RCP disputing that claim. The formal complaint stated:

To mislead the public on this issue has grave consequences. People may be misled by the false statement into thinking that it is easy to withdraw and may therefore try to do so too quickly or without support from the prescriber, other professionals or loved ones. Other people, when weighing up the pros and cons of starting antidepressants may make their decision based partly on this wrong information. Of secondary concern is the fact that such irresponsible statements bring the College, the profession of Psychiatry (to which some of us belong), and – vicariously – all mental health professionals, into disrepute.

The complaint cited several research papers documenting how withdrawal effects from antidepressants “often last far longer than two weeks.” The cited research included a study done by the Royal Collage of Psychiatry (RCP) itself, “which found that withdrawal symptoms were experienced by the majority (63%), generally lasted for up to 6 weeks and that a quarter reported anxiety lasting more than 12 weeks. Within 48 hours of the misleading statement in The Times, the survey results were removed from the RCP website, as was a leaflet by the RCP on antidepressant withdrawal. You can listen to a podcast interview with Professor John Read here. There is a link to the RCP leaflet and The Times article there as well.

Stay tuned; this controversy isn’t over yet. In conclusion, to paraphrase Paul Harvey, “Now you know the rest of the Lancet story on antidepressants.”

03/9/18

Psychiatry Needs a Revolution

Peter Gøtzsche wrote a January 2018 editorial in the British Medical Journal, where he elaborated on why he thinks, “Psychiatry is a disaster area in healthcare that we need to focus on.” In his editorial, Gøtzsche said the prevailing paradigm in psychiatry was to say psychiatric drugs have specific effects against specific disorders; and that their actions do more good than harm. However, he asserted that as a consequence of its liberal use of psychiatric drugs, psychiatry actually does more harm than good. Gøtzsche and other so-called “antipsychiatry,” critics are often dismissed by psychiatry. But there was a study that surveyed the attitudes of medical teaching faculty towards psychiatry and psychiatrists; and the results had more in common with the antipsychiatrists than you might think.

Stuart, Sartorius and Linamaa published “Images of Psychiatry and Psychiatrists” in the open access journal, Acta Psychiatra Scandinavica. They surveyed 1,057 teaching medical faculty members from 15 academic teaching centers in the United Kingdom, Europe and Asia. The overwhelming majority of respondents held negative views towards psychiatry as a discipline, psychiatrists and psychiatric patients. Some of their findings were startling: 90% thought psychiatrists were not good role models for medical students; 84% thought psychiatric patients should be treated only within specialized facilities.

When the survey asked about the perception of psychiatry as a profession, 8.9% thought psychiatry was unscientific; 7.7% thought it was not evidenced-based; and 8.0% thought psychiatry was not a genuine, valid branch of medicine. Perceptions of psychiatric treatment thought psychiatrists had too much power over their patients (25.0%); treatments were not as effective as in other branches of medicine (22.6%); and most who receive treatments do not find them helpful (20.4%). Then 28.6% said they would not encourage a bright student to enter psychiatry; and 75.4% said many students at their medical school were not interested in pursuing psychiatry as a career.

Results highlight the extent to which non-psychiatrist medical faculty hold negative opinions of psychiatry as a discipline, psychiatric treatments, psychiatrists as role models for medical students, psychiatry as a career choice, psychiatric patients, and psychiatric training. The most outstanding findings were that psychiatrists were not considered to be good role models for medical students, and psychiatric patients were considered to be emotionally draining and unsuitable to be treated outside of specialized facilities or in general hospitals.

“In Search of an Evidence-Based Role for Psychiatry,” by Read, Runciman and Dillon noted this was not the only study indicating negative views of psychiatry by other medical professionals. They cited a study by Curtis-Barton and Eagles that found medical students were discouraged from choosing psychiatry as a career either a lot or a little because of a perceived lack of evidence base (51%); and the scientific basis of psychiatry (53%). Only 4-7% of UK medical students saw it as a ‘probable/definite’ career because of its poor evidence base. Commenting further on “Images of Psychiatry and Psychiatrists,” Read, Runciman and Dillon said:

Even more revealing than the survey findings was psychiatry’s response to it. The researchers themselves, including a former President of the World Psychiatric Association, wondered whether their colleagues’ opinions are ‘well founded in facts’ or ‘may reflect stigmatizing views toward psychiatry and psychiatrists’. Their own answer to that question becomes abundantly clear when, instead of proposing efforts to address the problems identified by the medical community, such as having little scientific basis, they recommend only ‘enhancing the perception of psychiatrists’ so as to ‘improve the perception of psychiatry as a career.’

The responses to the survey, all written by psychiatrists, dismissed each concern “and blamed everyone but their own profession, including their supposedly ignorant, prejudiced medical colleagues and the biased media.” Read, Runciman and Dillon then described problems with how mental health issues are conceptualized, what causes them and how to treat them. “Despite all this, biological psychiatry is trying to expand the reach of what others consider to be an unscientific, reductionistic, simplistic and pessimistic ‘medical model’.” A truly evidence-based psychiatry would recommend psychiatric medications at a last resort (and for a short time period). The adverse effects of medications should be fully disclosed and “no medical treatment should be forced on anyone against their will.”

Read, Runciman and Dillon said there were three core research areas that psychiatry should be demonstrating progress in, if it is a legitimate scientific, medical discipline. They are: conceptualization, causation and treatment of the disorders.

With regard to the conceptualization of psychiatric disorders, “psychiatry’s primary contribution is an ever expanding list of labels.” Many do not reach even minimal scientific reliability levels and calling them ‘diagnoses’ is often a misnomer. Significantly, the NIMH announced when the DSM-5 was about to be published that it was abandoning the DSM diagnostic approach to classifying mental health problems for its research to develop scientifically robust ‘research domains.’ See “Patients Deserve Better Than the DSM” for more information on this.

“In terms of causation, psychiatry has focused predominantly on chemical imbalances, brain abnormalities and genetics.” But has repeatedly failed findings of any substance in support of that premise. Genetics has an important role, if the research is done on constructs that actually exist. There is also “the role of epigenetic processes whereby genes are activated and deactivated by the environment.”

Research suggests that the safety and efficacy of psychiatric drugs has been grossly exaggerated. Documentation in support of this claim is overwhelming. See the websites for Mad in America, Peter Breggin, and David Healy and RxISK for starters. You can also search this website or start with: “In the Dark About Antidepressants,” “Blind Spots With Antipsychotics.”

Peter Gøtzsche similarly noted concerns with the “liberal use of psychiatric drugs.” He identified four concerns with the prevailing paradigm in psychiatry and gave supporting evidence for each.

First, the effects of the drugs are not specific. “They impair higher brain functions and cause similar effects in patients, healthy people and animals.” For instance, not only does serotonin (SSRI antidepressants influence serotonin levels) seem to have a role in maintaining mood balance, it can effect social behavior, appetite and digestion, sleep memory and sexual desire and function.
Second, research in support of the paradigm that psychiatric drug have specific effects against specific disorder is flawed.
Third, the widespread use of psychiatric drugs has been harmful for patients. In every country where the relationship has been examined, an increased use of psychiatric medications has accompanied an increase in the number of chronically ill people and the number of people on disability pensions.
Fourthly, all attempts to use brain scans to show that psychiatric disorders cause brain damage have failed. “This research area is intensely flawed and very often, the researchers have not even considered the possibility that any brain changes they observe could have been caused by the psychiatric drugs their patients have taken for years” Yet this has been shown repeatedly in many reliable studies, especially for neuroleptic drugs.

Peter Gøtzsche said the prevailing paradigm in psychiatry, that its drugs have specific effects against specific disorders, is unsustainable when the research in support of it is critically appraised. He said psychiatry needed a revolution; reforms were not enough. “We need to focus on psychotherapy and to hardly use any psychiatric drugs at all.” Dr. Gøtzsche is a medical researcher and the Director of the Nordic Cochrane Center. Along with 80 others, he helped start the Cochrane Collaboration in 1993, which is “a global independent network of researchers, professionals, patients, carers, and people interested in health.” The work of the Cochrane Collaboration is recognized as an international gold standard for high quality, trusted information.

01/5/18

In the Dark About Antidepressants

In 2011, antidepressants were the third most commonly prescribed medication class in the U.S. Mojtabai and Olfson noted in their 2011 article for the journal Health Affairs that much of the growth in the use of antidepressants was driven by a “substantial increase in antidepressant prescriptions by nonpsychiatric providers without an accompanying psychiatric diagnosis.” They added how the growing use of antidepressants in primary care raised questions “about the appropriateness of their use.” Despite this concern, antidepressant prescriptions continued to rise. By 2016, they were the second most prescribed class of medications, according to data from IMS Health.

A CDC Data Brief from August of 2017 reported on the National Health and Nutrition Examination Survey. The Data Brief provided the most recent estimates of antidepressant use in the U.S. for noninstitutionalized individuals over the age of 12. As indicated above, there was clear evidence of increased antidepressants use from 1999 to 2014. 12.7% of persons 12 and over (one out of eight) reported using antidepressant medication in the past month. “One-fourth of persons who took antidepressant medication had done so for 10 years or more.”

Women were twice as likely to take antidepressants. And use increased with age, from 3.4% among persons aged 12-19 to 19.1% among persons 60 and over. See the following figures from the CDC Data Brief. The first figure notes the increased use of antidepressants among persons aged 12 and over between 1999 and 2014. You can see where women were twice as likely to take antidepressants as men.

The second figure shows the percent of individuals aged 12 and over who took antidepressant medication in the past month between 2011 and 2014. Note how the percentages increase by age groups for both men and women, with the highest percentages of past month use for adults 60 and over for both men and women.

The third figure shows the length of antidepressant use among persons aged 12 and over. Note that while 27.2% reported using them 10 years or more, 68% reported using antidepressants for 2 years or more. “Long-term antidepressant use was common.” Over the fifteen-year time frame of the data, antidepressant use increased 65%.

The widespread use of antidepressants documented above is troubling when additional information about antidepressants is considered. A February 2017 meta-analysis done by Jakobsen et al., and published in the journal BMC Psychiatry, found all 131 randomised placebo-controlled trials “had a high risk of bias.” There was a statistically significant decrease of depressive symptoms as measured by the Hamilton Depression Rating Scale (HDRS), but the effect was below the predefined threshold for clinical significance of 3 HDRS points. Other studies have indicated that differences of less than 3 points on the HDRS are not clinically observable. See “Antidepressant Scapegoat” for more information on the HDRS. Jakobsen et al. concluded:

SSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.

In his review of the Jakobsen et al. study for Mad in America, Peter Simons noted where these results add to a growing body of literature “questioning the efficacy of antidepressant medications.” He pointed to additional studies noting the minimal or nonexistent benefit in patients with mild or moderate depression; the adverse effects of antidepressant medications; the potential for antidepressant treatment to potentially worsen outcomes. He concluded:

Even in the best-case scenario, the evidence suggests that improvements in depression due to SSRI use are not detectable in the real world. Given the high risk of biased study design, publication bias, and concerns about the validity of the rating scales, the evidence suggests that the effects of SSRIs are even more limited. According to this growing body of research, antidepressant medications may be no better than sugar pills—and they have far more dangerous side effects.

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. That is because there has been repeated underreporting and even fraud in reporting suicides, suicide attempts and suicidal thoughts in placebo-controlled trials. He added that the FDA has contributed to the problem by downplaying the concerns, choosing to trust the drug companies and suppressing important information.

He pointed out 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. Yet the individual responsible for the FDA’s 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 the 2001 study.

In “Precursors to Suicidality and Violence in Antidepressants” Gøtzsche co-authored a systematic review of placebo-controlled trials in healthy adults. The study showed that “antidepressants double the occurrence of events that can lead to suicide and violence.” Maund et al. (where he was again a co-author) demonstrated that the risk of suicide and violence was 4 to 5 times greater in women with stress incontinence who were treated with duloxetine (Cymbalta).

Although the drug industry, our drug regulators and leading psychiatrists have done what they could to obscure these facts, it can no longer be doubted that antidepressants are dangerous and can cause suicide and homicide at any age. Antidepressants have many other important harms and their clinical benefit is doubtful. Therefore, my conclusion is that they shouldn’t be used at all. It is particularly absurd to use drugs for depression that increase the risk of suicide when we know that psychotherapy decreases the risk of suicide. . . . We should do our utmost to avoid putting people on antidepressant drugs and to help those who are already on them to stop by slowly tapering them off under close supervision. People with depression should get psychotherapy and psychosocial support, not drugs.

Peter 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.” Breggin 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.

Vera Sharav, “a fierce critic of medical establishment,” the founder and president of the Alliance for Human Research Protection (AHRP), testified at the 2006 hearing. She reminded the Advisory Committee that the FDA was repeating a mistake they had made in the past. She said in the past the FDA withheld evidence of suicides from the Advisory Committee. German documents and the FDA’s own safety review showed an increased risk of suicides in Prozac. “Confirmatory evidence from Pfizer and Glaxo were withheld from the Committee.” Agency officials “obscured the scientific evidence with assurances.”

What the FDA presented to you is a reassuring interpretation of selected data by the very officials who have dodged the issue for 15 years claiming it is the condition, not the drugs. What the FDA did not show you is evidence to support that SSRI safety for any age group or any indication. They are all at risk. They failed to provide you a complete SSRI data analysis. They failed to provide you peer-reviewed critical analyses by independent scientists who have been proven right. FDA was wrong then; it is wrong now. Don’t collaborate in this. [But they eventually did]

Breggin commented that the FDA controlled and monitored the original pediatric studies because the drug companies did not do so on their own and failed to find a risk of antidepressant-induced suicidality in any age group. “Why would the FDA assume these same self-serving drug companies, left on their own again, would spontaneously begin for the first time to conduct honest studies on the capacity of their products to cause adult suicidality?”

In a linked document of two memos written by an Eli Lilly employee in 1990, Dr. Breggin noted where the individual questioned the wisdom of recommendations from the Lilly Drug Epidemiology Unit to “change the identification of events as they are reported by the physicians.” The person went on to say: “I do not think I could explain to the RSA, to a judge, to a reporter or even to my family why we would do this especially to the sensitive issue of suicide and suicide ideation. At least not with the explanations that have been given to our staff so far.” Those suggestions included listing an overdose in a suicide attempt as an overdose, even though (here he seems to be quoting from a policy or procedural statement) “when tracking suicides, we always look at all overdose and suicide attempts.” Eli Lilly brought the first SSRI, Prozac, to market in 1986.

Next time you hear someone say that the FDA studies only showed increased suicidality in children and young adults as opposed to adults, remember that the adult studies, unlike the pediatric studies, were not controlled, monitored or validated by the FDA. This is one more example of the extremes the FDA will go to in order to protect drug companies and their often lethal products.

The problems with antidepressants, most of which are SSRIs—selective serotonin reuptake inhibitors—were at least partially known as Prozac and its cousins were being developed and brought to market in the early 1990s. As the above discussion indicated, there seems to have been a disregard of the potential for multiple negative side effects from their use, up to and including the various forms of suicidality. The sleight-of-hand done by the drug companies, and apparently the FDA, means that many individuals are in the dark about the adverse side effects stemming from their SSRI medications.

06/24/15

Debating the Harm from Psychotropics

In mid-May of 2015, there was a public debate on whether the long-term use of psychiatric medications causes more harm than good. Before saying “Boring” and moving on to something else, realize that prescriptions for antidepressants are on the rise —increasing by 7.5% in Britain since 2013 and over 500% since 1992. Recent research has shown that more people are taking antidepressants for longer periods of time, “often because they become dependent upon them and cannot stop.” Yet there is no good research into the safe long-term use of these drugs.

It seems that the challenge for the debate grew out of several prominent British psychiatrists publically criticizing the launch of the Council for Evidence-Based Psychiatry, an organization aimed at starting a dialogue about the use of psychiatric drugs and treatments. The two sides of the debate jointly published a paper in the British Medical Journal (BMJ). The original BMJ press release, now removed from the site, inexplicably did not include a declaration of interests for one of the speakers against the motion, Alan H. Young. So what?

Young was initially in print as saying he had no interests to declare, while in fact he had several. This was important information to reveal, not only because it is a BMJ policy, but also because Young was planning to challenge the premise of whether long-term use of psychiatric medication causes more harm than good. In other words, his financial and professional ties to the pharmaceutical industry were initially not reported in a debate where he was defending the use of psychiatric medications. You can view the original press release here; the revised one here. Look at the bottom right column on page 2 for both.

This mistake was caught by one of the speakers for the motion, Peter Gøtzsche, who also reported a series of actions that appeared to be aimed at undercutting Gøtzsche’s credibility and the information he presented. You can read his description of these “bizarre events” related to the Maudsley debate here. You can review the debate here. Gøtzsche opened his time to speak during the debate by estimating that psychiatric drugs were the 3rd leading cause of death among people aged 65 and over.

I have estimated, based on randomised trials and cohort studies, that psychiatric drugs kill more than half a million people every year among those aged 65 and above in the USA and Europe. This makes psychiatric drugs the third leading cause of death, after heart disease and cancer. The drugs furthermore cripple tens of millions. There are no benefits that can justify so much harm.

Gøtzsche also described how clinical trials include patients already taking other psychiatric medications. These participants are then rapidly withdrawn for their medication. If they are randomly placed in a placebo group, they often experienced withdrawal symptoms. “This design exaggerates the benefits of treatment and increases the harms in the placebo group, and it has driven patients taking placebo to suicide in trials in schizophrenia.”

He called for the establishment of withdrawal clinics to help patients slowly and safely taper off of psychiatric drugs. He estimated that 98% of all psychotropic drugs could be stopped without causing harm. In the revised BMJ press release, it says “we could stop almost all psychotropic drugs without causing harm.” Gøtzsche said this replaced his original statement. This could be accomplished by dropping all antidepressants, ADHD medications, and dementia drugs. Only a small percentage of the antipsychotics and benzodiazepines currently used should be continued.

This would lead to healthier and more long-lived populations. Because psychotropic drugs are immensely harmful when used long term, they should almost exclusively be used in acute situations and always with a firm plan for tapering off, which can be difficult for many patients.

The Council for Evidence-Based Psychiatry (CEP) began on April 30th of 2014 with an event at the House of Lords and the release of a publication entitled: Unrecognized Facts about Modern Psychiatric Practice. This is linked on the CEP website. You can get a quick introduction to some of the CEP members and what they believe by viewing some short videos linked on their homepage. One of the innovative ways they have attempted to provide a bridge between the public, policy makers and legislators, and the research community that investigates the areas where psychiatry has caused harm, although the intention has been to help.

Unrecognized Facts is a nifty slide show that presents various facts about modern psychiatric practice, with links on each slide to further available information. Here are a few of examples of what you can find there.

Myth of the Chemical Imbalance

Psychiatric drugs have often been prescribed to patients on the basis that they cure a ‘chemical imbalance.’ However, no chemical imbalances have been proven to exist in relation to any mental health disorder. There is also no method available to test for the presence or absence of these chemical imbalances.

Worse Long-Term Outcomes

There has been little research on the long-term outcomes of people taking psychiatric drugs. The available studies suggest that all the major classes of psychiatric drugs add little additional long-term benefit, and for some patients they may lead to significantly worse long-term outcomes.

Long-Lasting Negative Effects

Psychiatric drugs can have long-lasting negative effects on the brain and central nervous system, particularly when taken long term, which can lead to physical, emotional and cognitive difficulties.

Negative Effects Are Often Misdiagnosed

Psychiatric drugs can have effects that include mental disturbance, including suicide, violence, and withdrawal syndromes. These can be misdiagnosed as new psychiatric presentations, for which additional drugs may be prescribed, sometimes leading to long-term use of multiple different psychiatric drugs in the same person.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: Peter Gøtzsche

Antidepressant Fall From Grace, Part 1

The Lancet Story on Antidepressants, Part 2

Psychiatry Needs a Revolution

In the Dark About Antidepressants

Debating the Harm from Psychotropics