09/20/22

The Death of the Chemical Imbalance Theory?

There was an article published recently in the journal Molecular Psychiatry that is getting a lot of attention online. The Hill, Psychology Today, Neuroscience News and other new outlets highlighted an umbrella review by researchers that questioned the serotonin theory of depression and the value treating depression with antidepressants. In an article for The Conversation, two of those researchers wrote, “Our study shows that this view is not supported by scientific evidence. It also calls into question the basis for the use of antidepressants”; and the chemical imbalance theory of depression.

Joanna Moncrieff and Mark Horowitz wrote that the serotonin theory of depression was widely promoted by the pharmaceutical industry in the 1990s with its marketing a then new class of antidepressant medications, selective serotonin-reuptake inhibitors (SSRIs). This strategy became known as the “chemical imbalance theory of depression.” The theory was endorsed by institutions like the American Psychiatric Association. But this has changed, with psychiatrists like Ronald Pies, saying as early as 2011 that, “the chemical imbalance notion was always a kind of urban legend.”

Pies said in another more recent article for Psychiatric Times that he influenced the APA to replace a statement on its public education website that referred to “imbalances in brain chemistry,” with: “While the precise mechanism of action of psychiatric medications is not fully understood, they may beneficially modulate chemical signaling and communication within the brain, which may reduce some symptoms of psychiatric disorders.” The statement quoted by Dr. Pies is in article titled, “What is Psychiatry?”

Moncreiff and Horowitz pointed to another article on the same website, “What is Depression?”, where it said while several factors can play a role in depression—biochemistry, genetics, personality and environment. For biochemistry, it said: “Differences in certain chemicals in the brain may contribute to symptoms of depression.”

Looking at these articles, the chemical imbalance theory may have been weakened, but I don’t think it was defeated. It seems that when medications can “beneficially modulate” and when “differences in certain chemicals” may contribute to symptoms of depression, the imbalance theory is present implicitly. That is why the new study by Moncrieff et al, “The serotonin theory of depression: a systematic review of the evidence,” in Molecular Psychiatry is so important.

Despite the fact that the serotonin theory of depression has been so influential, no comprehensive review has yet synthesised the relevant evidence. We conducted an ‘umbrella’ review of the principal areas of relevant research, following the model of a similar review examining prospective biomarkers of major depressive disorder. We sought to establish whether the current evidence supports a role for serotonin in the aetiology of depression, and specifically whether depression is associated with indications of lowered serotonin concentrations or activity.

Their comprehensive review indicated there is no convincing evidence that depression is related to or caused by lower serotonin concentrations or activity. Yet surveys suggest 80% or more of the general public believe depression is caused by a ‘chemical imbalance.’ This belief shapes how people understand their moods, leading to a pessimistic view on what they can expect from treatment. “The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs.”

Moncrieff and Horowitz said in The Conversation article that it was important for people know the idea that depression as a chemical imbalance is hypothetical. Moreover, we don’t understand what temporarily elevated serotonin or other biochemical changes produced by antidepressants do to the brain. “We conclude that it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe.” And yet, the serotonin theory of depression has formed the basis for a significant amount of research over the past few decades.

Along with Benjamin Ang, Moncrieff and Horowitz explored the serotonin theory of depression in the scientific literature in, “Is the chemical imbalance an ‘urban legend’? They noted where the chemical imbalance theory was first proposed in the 1960s, focusing initially on the neurochemical noradrenaline instead of serotonin. “What came to be known as the ‘monoamine hypothesis’ (noradrenaline and serotonin are both classified as monoamines), was stimulated by the belief that certain prescription drugs targeted the basis of mood, particularly drugs that were named ‘antidepressants’.”

Following the introduction of the selective serotonin reuptake inhibitor (SSRI), the ‘serotonin hypothesis’ became embedded in the popular and professional consciousness. The pharmaceutical industry promoted the idea that depression was a result of an imbalance or deficiency of serotonin in the brain. SSRIs, which were just being brought to the market, were said to be the ‘magic bullets’ that could reverse this abnormality. In an advertisement for Zoloft, Pfizer said “while the cause is not known, depression may be related to an imbalance of natural chemicals between nerve cells in the brain” and that “prescription Zoloft works to correct this imbalance.”

Ang, Moncrieff and Horowitz more fully documented how the American Psychiatric Association (APA) supported the pharmaceutical company rhetoric from a patient leaflet produced in 2005, which said: “antidepressants may be prescribed to correct imbalances in the levels of chemicals in the brain.” Despite what Dr. Pies said, it seems that the APA did not have many psychiatrists who knew this was a kind of urban legend.

The marketing of SSRIs and the serotonin theory led to a dramatic global increase in their use. Prescriptions in England tripled between 1988 and 1998; and then tripled again between 1998 and 2018. Similar increases took place throughout Europe, with some Eastern European countries where use was previously low, increasing 5-6 times since 2000. In the U.S., antidepressant prescriptions quadrupled between the late 1980s and the mid-2000s.

There is evidence that increasing numbers of people are taking antidepressants on a long-term basis. Research has shown that believing depression is caused by a chemical imbalance is widespread among antidepressant users, encourages people to ask for antidepressants and discourages them from trying to stop.

In 2005, Jeffrey Lacasse and Jonathan Leo published a paper in PLOS Medicine that received a lot of attention. It was the first time the media grasped that the serotonin theory might not be supported by the evidence. Their paper provoked a response by the chair of the FDA psychopharmacology committee, who admitted evidence for a neurochemical deficiency in people with depression was elusive. He thought it could be a ‘useful metaphor,’ but one he would not use with his own patients. While an SSRI may work well with an individual, that “doesn’t prove that there is an underlying imbalance, defect or dysfunction in the person’s serotonin system.”

Responding to a report published by the Citizens Commission on Human Rights, a Church of Scientology organization, Ronald Pies called the chemical imbalance theory an urban legend that no well-informed psychiatrist had ever believed. He claimed the theory was spread by the pharmaceutical industry, and opponents of psychiatry attributed the belief to psychiatrists themselves. A few months later, he wrote an article for Psychiatric Times admitting that there were psychiatrists and other physicians who used the term ‘chemical imbalance’ when explaining psychiatric illness to a patient.

My impression is that most psychiatrists who use this expression feel uncomfortable and a little embarrassed when they do so. It’s a kind of bumper-sticker phrase that saves time, and allows the physician to write out that prescription while feeling that the patient has been “educated.” If you are thinking that this is a little lazy on the doctor’s part, you are right. But to be fair, remember that the doctor is often scrambling to see those other twenty depressed patients in her waiting room. I’m not offering this as an excuse–just an observation.

In 2019 Pies said while some prominent psychiatrists have used the term ‘chemical imbalance’ in public comments about antidepressants, and possibly in their clinical practices, “there was never a unified, concerted effort within American psychiatry to promote a chemical imbalance theory of mental illness.” A good bit of psychiatric opinion follows Pies’ lead and says the idea that depression is caused by brain chemical imbalances is an over-simplified explanation that should not be taken seriously. The attempt by leading psychiatrists to deny that the serotonin theory was ever influential seems to be a tactic to deflect criticism, and allow it to continue in some modified form.

Ang, Moncrieff and Horowitz concluded that during the period 1990-2010, there was considerable coverage of, and support for, the serotonin hypothesis of depression in the psychiatric and psychopharmacological literature. Research papers on the serotonin system were widely cited, and most strongly supported the serotonin theory. Textbooks took a more nuanced approach, but at other points were unreservedly supportive of the theory. Critics of the theory were either ignored or marginalized as antipsychiatry. Yet it seems in 1987 at least one critic, the Irish psychiatrist David Healy, astutely described the neurochemical theory of depression as an exhausted Kuhnian paradigm in “The structure of pharmacological revolutions.” He said it was perpetuated because it served the professional purpose of convincing patients that depression is a biological condition.

Healy was referring to the seminal work by Thomas Kuhn on the philosophy and history of science, The Structure of Scientific Revolutions. According to Kuhn, normal science referred to research firmly based on one or more past scientific achievements that a particular scientific community “acknowledges for a time as supplying the foundation for its further practice.” The process of normal science takes place within a paradigm—like the monoamine hypothesis—where research occurs within the context of a scientific community committed to the same rules and standards for scientific practice. “That commitment and the apparent consensus it produces are prerequisites for normal science.”

Any new interpretation of nature, whether a discovery or a theory, emerges first in the mind of one or a few individuals. It is they who first learn to see science and the world differently, and their ability to make the transition is facilitated by two circumstances that are not common to most other members of their profession. Invariably, their attention has been intensely concentrated upon the crisis-provoking problems; usually, in addition, they are men [or women] so young or so new to the crisis-ridden field that practice has committed them less deeply than most of their contemporaries to the world view and rules determined by the old paradigm. How are they able, what must they do, to convert the entire profession or the relevant professional subgroup to their way of seeing science and the world? What causes the group to abandon one tradition of normal research in favor of another?

So in “The serotonin theory of depression: a systematic review of the evidence,” by Moncreiff at al, we may be witnessing the death of the old paradigm for depression.

Kuhn went on to observe that the proponents of competing paradigms are always at least slightly at cross-purposes. “Neither side will grant all the non-empirical assumptions that the other needs in order to make its case.” While each may hope to “convert” the other to his or her way of seeing science and its problems, the dispute is not one “that can be resolved by proofs.” Kuhn quoted the theoretical physicist Max Planck who said: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.”

08/9/22

Energy Drinks Are No More Effective Than Caffeine

Energy drinks have become a common sight almost where ever you go. Your local convenience store will feature a display of two Monsters, Rockstars or Red Bulls at a discounted price next to the cash register and counter. Sitting nest to the cash register will be a display rack with 5 Hour Energy shots. Statistica reported that energy drinks accounted for 31% of packaged beverage drink sales sold at U.S. convenience stores. Overall, energy drink sales in the U.S. neared $14 billion in 2021. Global energy drink sales reached $57.4 billion in 2020.

History of Energy Drinks

Coca-Cola was developed as a nausea and heartburn tonic, but came with an added extract from coca leaves and caffeine-filled kola nuts to boost energy. Succumbing to government pressure, the company modified its recipe to be cocaine-free in 1929. The first modern energy drink was Lipovitan, created by the Japanese company, Taisho in 1962. It looked, smelled and tasted like cough syrup. Not surprisingly, it didn’t catch on.

The modern enthusiasm for energy drinks began in Thailand in 1976, when a pharmacist invented Krating Daeng, which translates as “Red Bull.” In 1984 an Austrian marketing exec drank a bottle of Red Bull to help with his jet lag. Afterwards he contacted the pharmacist in hope of them teaming up to market it. They added more sugar and caffeine, switched from bottles to cans in an effort to appeal to Europeans, and Red Bull energy drink was created in 1987. A decade later, it came to America.

By the beginning of the 2000s, energy drinks are everywhere. Brands start popping up left and right, and everyone has a preference. In 2001, Rockstar is introduced, followed by Monster Energy in 2002, Pimp Juice by Nelly in 2003, Pit It in 2004. The latter two drinks weren’t very popular, so there’s a good chance you haven’t heard of them. The same year Rip It was introduced, a former monk in India decided to throw his hat in the energy drink ring after seeing the potential for a new kind of boost. He took all the things that give you energy in an energy drink but put them into a tiny, more concentrated shot form, calling it 5 Hour Energy. The shot is a huge success with truckers, who don’t want to drink a lot and stop to pee often but need to stay awake.

Red Bull was the bestselling brand of energy drink in 2021, at $3.26 billion. No surprise, Monster was the second leading energy drink that year with $3.24 billion in sales. Bang Energy was third, at $1.20 billion. 5 Hour Energy sales were $824.5 million. Sales of energy drinks have been growing at a rate of around 5% every year since 2013.

Adverse Effects with Energy Drinks

While they are the fastest growing product in the beverage industry, there has been growing concern about the adverse effects of energy drinks. By 2015, there had been several reports showing adverse effects. “Energy Drink Consumption: Beneficial and Adverse Health Effects” concluded while there may be beneficial effects from energy drinks, there was also evidence of detrimental health consequences. The reported adverse effects were with the cardiovascular system, ischemic stroke and contributing to epileptic seizures. High sugar content could increase the risk of obesity and type 2 diabetes with high energy drink intake.

A Swedish study showed a strong relationship between dental erosion and energy drinks. An American study showed similar results in American children. “Energy drink consumption was associated with about a 2.4-fold increase in dental erosion.” Low pH and high sugar levels of energy drinks are the likely causes.

In “Energy Drinks and Their Adverse Health Effects,” Nadeem et al did a systematic review of 32 studies to evaluate the reported adverse effects. “Only clinical studies reporting adverse events after energy drink consumption were included.” Frequent adverse events with children included insomnia (35.4%), stress (35.4%) and depressed mood (23.1%).

With adults, frequently reported adverse events were insomnia (24.7%), jitteriness/shaking hands (29.8%), and gastrointestinal upset (21.6%). The odds of insomnia and jitteriness were significantly increased with energy drink consumption. When alcohol was mixed with energy drinks, it significantly reduced the sedation effects of the alcohol, “but increased the likelihood of stimulatory effects.” See the following chart from the study:

The authors recommended that individuals avoid frequent energy drink consumption (5-7 energy drinks per week) and avoid co-consumption with alcohol. They suggested increased regulatory standards with the sale of energy drinks, particularly with regard to children.

The National Institutes of Health and the CDC reported a number of safety concerns when consuming energy drinks, beginning with the amount of caffeine. This is accomplished with a hidden-in-plain sight ingredient commonly included in energy drinks called guarana, which has one of the highest concentrations of caffeine in any plant. It may contain up to 3.6% to 5.8% caffeine by weight. Coffee only has up to 2%. So, the addition of guarana increases an energy drink’s total caffeine content.

There are a number of concerns when combining energy drinks with alcohol. It worsens your ability to tell how intoxicated you are. Yet your motor coordination and reaction time may be just as impaired. Drinkers who mix alcohol and energy drinks are also more likely to report unwanted or unprotected sex, driving drunk or riding with someone who is intoxicated.

Drinkers aged 15 to 23 who mix alcohol with energy drinks are four times more likely to binge drink at high intensity (i.e., consume six or more drinks per binge episode) than drinkers who do not mix alcohol with energy drinks.

Between 2007 and 2011 the number of energy drink-related emergency department (ED) visits doubled. “In 2011, 1 in 10 of these visits resulted in hospitalization.” Around 25% of college students consume alcohol with energy drinks; and they binge-drink more often than students who don’t mix alcohol with energy drinks. 42% of all ED visits related to energy drinks involved combining them with alcohol or other drugs (i.e., marijuana, prescription or over-the-counter medicines). The bottom line for the NIH was that “a growing body of scientific evidence shows that energy drinks can have serious health effects, particularly in children, teenagers, and young adults.”

Concern that increased energy drink consumption poses a public health danger, led a team of researchers from the World Health Organization Regional Office for Europe to review the literature of published health risks, consequences and policies with energy drinks. They were concerned particularly with the potential adverse effects on young people. “As energy drink sales are rarely regulated by age, unlike alcohol and tobacco, and there is a proven potential negative effect on children, there is the potential for a significant public health problem in the future.” They gave several suggestions to minimize the potential for harm from energy drinks:

Establishing an upper limit for the amount of caffeine allowed in a single serving of this type of drinks in line with available scientific evidence;
Regulations to enforce restriction of labelling and sales of energy drinks to children and adolescents;
Enforcing standards for responsible marketing to young people by the energy drink industry;
Training health care practitioners to be aware of the risks and symptoms of energy drinks consumption;
Patients with a history of diet problems and substance abuse, both alone and combined with alcohol, should be screened for the heavy consumption of energy drinks;
Educating the public about the risks of mixing alcohol with energy drinks consumption;
Further research on the potential adverse effects of energy drinks, particularly on young people.

Calls for FDA Energy Drink Regulation

Despite the growing consensus and concern with the adverse effects of energy drinks, the industry has been successful in blocking FDA regulation. Lawyers and Settlements.com reported that members of Congress, consumer watch dog groups and federal health officials have been calling on the FDA to modify the rules and regulations governing energy drinks without any change. One of the difficulties is with how the manufacturer categorizes their product.

Manufacturers can decide on their own whether to call their energy drinks beverages or dietary supplements. 5-Hour Energy, Monster and Rockstar are marketed as dietary supplements. Red Bull is marketed as a conventional food. They also don’t need to disclose how much caffeine their drinks contain. “There are different sets of rules for what can be added and what must be disclosed on the label.”

Producers of energy drinks are not required under current federal regulations to disclose caffeine amounts. The FDA reports there are no limits on the amount of caffeine that dietary supplements can contain, whereas over-the-counter stimulant medications are regulated by the FDA as to how much caffeine they can contain, and so are soft drink manufacturers.The FDA stipulates that soft drinks contain no more than 71.5 mg of caffeine per 12 oz drink, but it cannot regulate the caffeine content in energy drinks – with the exception of energy drink companies that self- classify their products as a dietary supplement, such as Monster and Rockstar.

Law practices willing to see if they can get energy drink manufacturers to pay out on wrongful death claims, or as Red Bull GmbH, the beverage’s Austrian parent company did, pay $640,000 for making false claims about their products usefulness. Despite the claims of “numerous scientific studies” showing the ability of energy drinks to improve energy and performance, the truth is they are no more effective than caffeine or other caffeine-containing products.

07/19/22

The Vicious Cycle of Antidepressant Use

CDC data reported that 13.2% of adults used antidepressants in the past 30 days, and their use increased with age. A similar increase by age was apparent when antidepressant use was examined in both men and women. “In all age groups, antidepressant use was higher among women compared with men.” However, a new study suggested that antidepressant use has very little effect on patients’ health-related quality of life.

The above information on antidepressant use was taken from the CDC data brief report looking at Antidepressant Use Among Adults in the United States. Antidepressant use in the past thirty days increased among adults aged 18-39 (7.9%), then to 14.4% among adults aged 40-59, and to 19.0% among adults aged 60 and over. Disconcertingly, 20% of women between 40 and 59 almost one quarter of women 60 and over were prescribed antidepressants. Overall, antidepressant use increased from 10.6% in 2009 to 13.8% in 2018. See the following charts from the CDC data brief.

The New York Times cited these statistics in “How Much Do Antidepressants Help, Really?” It observed that clinical drug trials only follow people taking antidepressants for 8 to 12 weeks, missing the vast majority of people who take them longer. The NYT article then referenced a study published in April of 2022, “Antidepressants and health-related quality of life (HRQoL) for patients with depression.” This study compared Americans with a depression diagnosis who took antidepressants, to Americans with a depression diagnosis who did not take the medications over the course of two years.

The data came from the US National Medical Expenditures Panel Survey (MEPS). The study included all types of antidepressants—SSRIs like Prozac, SNRIs like Effexor, and older antidepressants like phenelzine. The researchers found no significant differences in the changes in quality of life reported by the two groups, suggesting “that antidepressant drugs may not improve long-term quality of life.”

A physician and epidemiologist who was not involved in the study said it was difficult to come to a conclusion on this study alone. Individuals who are prescribed antidepressants are likely more depressed than individuals who aren’t prescribed drugs. “People with more severe depression might be less likely to improve their mental quality-of-life scores over time,” for reasons that don’t correspond to the antidepressants they take. When Peter Simons reviewed the study for Mad in America, he said that critique was simply false.

The researchers used a statistical method called the difference-in-difference (D-I-D) analysis that compared each subject’s follow-up levels to their individual baseline levels for their physical and mental component summaries, (PCS and MCS). They acknowledged their study’s inability to control for the effect of the severity of depression. “However, the D-I-D analysis compare each subject’s follow-up levels to his/her individual baseline levels for the PCS and MCS and investigate the overall change for the group which should minimize the impact of this factor on the overall analysis.”

Another perceived issue with the study was that since people were taking antidepressants for an extended time, some quality-of-life improvements could have taken place before the study began following them. Omar Almohammed, a co-author of the study said it was still reasonable to expect continued increases in quality of life long after beginning an antidepressant. “If we don’t expect improvement from the continuous use of these medications, then the correct decision might be to stop the continuous use of these medications.”

But pills are often cheaper. And it can be difficult for some to access therapy because there aren’t enough providers, and mental health treatment aren’t fully covered by all insurance plans. Robert DeRubeis of the University of Pennsylvania said, “It’s not at all clear that even in the short term, pharmacological approaches, on average, are more effective than psychological ones.”

Clinical trials suggest that although antidepressants do improve depression symptoms over the first few months, their benefits are modest and are much less pronounced among people with mild depression compared with those with severe depression. (This is worrying considering that, according to one study, 73 percent of Americans prescribed antidepressants don’t even have a diagnosis of depression.) And experts are divided over whether these small benefits make a noticeable difference to people’s moods or overall functioning.

Much of this improvement is attributed to the placebo effect, rather than the medication itself. Even researchers who argue the benefits from antidepressants admit they “do not work for everybody.” And over time, they will have even less benefits. There are approximately 15.5 million Americans who have been taking antidepressants for at least five years. The longer that people take them, there will likely be increasingly smaller benefits, “in part because patients build up a tolerance to the medications.”

But there is a vicious cycle if you decide to discontinue your use of antidepressants. Too rapid of a taper can lead to antidepressant withdrawal, euphemistically called “discontinuation syndrome.” These withdrawal symptoms are sometimes seen as a depressive relapse, “proving” the need to remain on antidepressants in order to hold off a major depressive episode. They often include physical sensations such as dizziness, nausea, and “brain zaps” (an electric shock sensation in the head). In “Distinguishing relapse from antidepressant withdrawal,” Mark Horowitz and David Taylor said many withdrawal symptoms overlap with symptoms of anxiety or depressions, making it difficult to distinguish.

Their onset soon after dose reduction, the association of psychological with physical symptoms, their prompt response to reinstatement, and their typical ‘wave’ pattern of onset, peak and resolution can help distinguish withdrawal symptoms from relapse.

Giovanni Fava has researched the adverse effects of antidepressants for almost thirty years. In 1994, he said in an editorial for the journal Psychotherapy and Psychosomatics, “The field of psychopharmacology has generally neglected the issue of potential sensitization of psychiatric disease to psychotropic drug use.” In January of 2022 he released Discontinuing Antidepressant Medications, as a guide for clinicians who want to help patients withdraw from antidepressants. Fava was interviewed by James Moore about the release of his book for a Mad in America podcast.

In Discontinuing Antidepressant Medications, Fava introduced the construct of behavioral toxicity of psychotropic drugs, applying it to the field of antidepressant tapering and discontinuation. Fava said it was originally described by Alberto DiMascio and Dick Shader.

A medication that is used at the normal, average doses may become toxic to the patient and this toxicity expresses itself with phenomena such as loss of clinical effect, where the patient is doing well on antidepressant and after a while of taking medication regularly, the antidepressant no longer works. If you try to increase the dosage, it may only help for a little while. So, loss of clinical effect and hypomanic episodes—that is the medication is really working too much and brings the patient to a state of hypomania or mania which is a symptom of bipolar disorder—but also a paradoxical fact that is that the antidepressant makes you more depressed.In the book, I discuss the relationship between venlafaxine and apathy. This is an example of a paradoxical effect and resistance, the fact that these patients become resistant either to the same medication, when it’s prescribed again or to another medication. Withdrawal is part of behavioral toxicity and my view is quite different from that of other investigators in the field because as a clinician I know that all these manifestations of behavioral toxicity are related.

Fava said if you have two, or three or even four of these manifestations together, it is likely an example of behavioral toxicity. He works with the most difficult cases and explained that the longer a patient is on a medication, “The higher the toxicity that you provoke.” In other words, the antidepressant that initially was effective “has become toxic” to the patient and is causing a problem. He said it is difficult to discontinue an antidepressant if you don’t use some additional medications and psychotherapy. Discontinuing antidepressants is not something that can be applied to all patients.

So, when I discuss with a patient, I’ll say that most of the patients, 90% of the patients respond, “Please, get this medication out of my body as soon as you can.” Then, we continue with that, but a basic problem which is not only in this field but in psychiatry and in medicine today is to believe that there is a procedure we should apply to all patients, and that is clinical practice shows that it’s not possible.

Antidepressant withdrawal, discontinuation syndrome, is becoming a greater concern in American psychiatry, but it isn’t where it needs to be. In addition to Giovanni Fava, Peter Breggin has been critical of the over prescription of psychiatric medications and wrote Psychiatric Drug Withdrawal in 2013. In 2020, the Royal College of Psychiatrists published “Stopping Antidepressants,” which contains information for “anyone who wants to know more about stopping antidepressants.” In May of 2018, The All-Party Group for Prescribed Drug Dependence (in the Parliament of the U.K.) published, “Antidepressant Dependency and Withdrawal.”

The Executive Summary of that publication said it was incorrect to view antidepressant withdrawal as largely mild, self-limiting and of short duration. Antidepressants fulfill criteria for being dependency-forming medications. Around one-third of users “report being addicted to AD [antidepressants], according to their own definition of that concept.” The increase of long-term antidepressant use along with with the misdiagnosis of withdrawal reactions warrants serious concern.

The lengthening duration of AD use (which has doubled on average in the last 10 years) has fuelled rising AD prescriptions over the same time period. The evidence suggests that such lengthening duration may be partly rooted in the underestimation of the incidence, severity and duration of AD withdrawal reactions; underestimations which may have led to many withdrawal reactions being misdiagnosed as relapse or as failure to respond to treatment. It warrants serious concern that the misdiagnosis of withdrawal may be contributing to escalating long-term AD use (since drugs are being reinstated rather than withdrawn), given that long-term use is associated with increased severe side-effects, increased risk of weight gain, the impairment of patients’ autonomy and resilience (increasing their dependence on medical help), worsening outcomes for some patients, greater relapse rates, and the development of neurodegenerative diseases, such as dementia.

For more on antidepressants on this website, try: “Withdrawal or Relapse When Tapering Antidepressants?” and “Are Antidepressants Worth the Risks?”

06/28/22

Time for a Fresh Look at Diagnosis

Allen Frances, chair of the DSM-IV Task Force, has been a vocal critic of modern psychiatry and diagnosis. He was selected by fellow psychiatrist Awais Aftab to do the first interview for Conversations in Critical Psychiatry, a series for Psychiatric Times that aimed to engage prominent individuals who have made important and constructive critiques of psychiatry. Dr. Frances said while he considered psychiatry to be one of the noblest of professions, it had drifted away from best practice. Too many psychiatrists, he said, are reduced to pill pushing with too little time to really know their patients well. And psychiatrists have not done enough to educate primary care physicians, who prescribe 80% of psychiatric meds, on “the principles of cautious prescribing, proper indications, full consideration of risks, and the value of watchful waiting and the tincture of time.”

I despair the diagnostic inflation that results from a too loose diagnostic system, aggressive drug company marketing, careless assessment, and insurance company pressure to rush to judgement. Diagnoses should be written in pencil, and under-diagnosis is almost always safer and more accurate than over-diagnosis.

With regard to the philosophy of diagnosis, he saw three approaches that he likened metaphorically to three kinds of baseball umpires. The first kind called balls and strikes as they are. The second called them as he saw them. The third said there were no balls or strikes until he called them. Frances likened Robert Spitzer, the architect of the modern DSM, to Umpire 1, along with most biological psychiatrists (See “The Quest for Psychiatric Dragons” Part 1 and Part 2 and “Where There’s Smoke …” for more on Robert Spitzer). “The credibility of this model has been destroyed as we have learned more about the unfathomable complexity of the human brain and the complete failure of genetics and neuroscience to provide useful answers about what causes psychiatric problems.” He thought most psychiatrists aspired to be like Umpire 2, doing their best to define mental disorders in useful ways without any pretention that it is the only way or that current constructs would withstand the test of time.

Dr. Frances expressed concern with the risks of over-diagnosis and advocated for a narrower system with higher diagnostic thresholds. He thought experts in each diagnostic area sought to expand their pet diagnoses and worried too much about missing patients (false negatives) rather than mislabeling patients (false positives). These experts were given a free rein in DSM-5, allowing mislabeling to dominate the field. This led to a checklist approach to diagnosis, which was not intended by the creators of the DSM.

The diagnostic exuberance of DSM 5 confuses mental disorder with the everyday sadness, anxiety, grief, disappointments, and stress responses that are an inescapable part of the human condition. DSM 5 ambitiously mislabels normal diversity and childhood immaturity as disorder, creating stigma and promoting the excess use of medications.

Frances thought if anything in DSM could be misused, it would be misused. “Data drawn from research studies on highly selected patients in the hothouse environment of a university research clinic generalize very poorly to the hustle and bustle of primary care.” On Twitter he pointed to a study he said “blows to bits any hope that statistical modeling” could eliminate the many inherent limitations of “Evidence Based Medicine.” This study, “Many Analysts, One Data Set” concluded that uncertainty in interpreting research results was not just a function of statistical power or the use of questionable research practices. It was also a function of the many reasonable decisions made by researchers as they conducted their research. This did not mean that analyzing data and drawing research conclusions from the data was subjective. Rather, it meant “that many subjective decisions are part of the research process and can affect the outcomes.”

Frances said “Evidence Based Medicine” often generalized poorly to everyday practice because: 1) patients in controlled studies aren’t like unselected patients; 2) research settings differ from real life; 3) biases influence data analyses. “EBM provides a necessary guide, but shouldn’t be worshipped.”

Returning to the interview for Conversations in Critical Psychiatry, he noted how there was an inherent financial, intellectual and emotional conflict of interest that leads every medical specialty to recommend over-diagnosis. He recommended that specialty groups like the APA, the American Psychiatric Association, should never be permitted sole power to determine the diagnostic guidelines for that specialty. Contributions from primary care, public health, health economics and consumers are important. With regard to psychiatric diagnosis, he thought the APA had a special conflict of interest because the DSMs were such a valuable publishing property. The income is crucial for meeting its budget. “This makes frequent revision too tempting and results in an unseemingly hyping of the product.”

Soon after the publication of the DSM-5 in 2013, Allen Frances published an article in World Psychiatry, “The past, present and future of psychiatric diagnosis.” He said psychiatric diagnosis is facing a serious crisis caused by diagnostic inflation. “The elastic boundaries of psychiatry have been steadily expanding, because there is no bright line separating the worried well from the mildly mentally disordered.” Drug companies have used their marketing muscle to sell psychiatric diagnoses by convincing potential patients and prescribers that life problems were really mental disorders caused by chemical imbalances and curable by pills.

We are now in the midst of several market-driven diagnostic fads: attention-deficit/hyperactivity disorder (ADHD) has tripled in rates in the past twenty years; bipolar disorder has doubled overall, with childhood diagnosis increasing forty-fold; and rates of autistic disorder have increased by more than twenty-fold. In the US, the yearly prevalence of a mental disorder is reported at 20–25%, with a 50% lifetime rate, and Europe is not far behind. A prospective study of young adults in New Zealand has reported much higher rates and another of teenagers in the US found an astounding cumulative 83% rate of mental disorders by age 21.

He said the DSM-5 was prepared without adequate consideration of clinical risk/benefit ratios and did not calculate the large economic cost of expanding the reach of psychiatry. It has been unresponsive to widespread professional, public and media opposition “based on the opinion that its changes lacked sufficient scientific support and often defied clinical common sense.” A petition endorsed by fifty mental health associations, that called for an independent review, “using methods of evidence-based medicine, was ignored.” It was time for a fresh look at diagnosis.

On the podcast The Recommended Dose with Ray Moynihan, Frances said the tendency over the last forty years has been to turn the stuff of life into mental disorder. “The best customer for a drug, is someone who is basically well.” We get advertisements for drugs as frequently as we get advertisements for cars or brands of beer. When it comes to most psychiatric problems, people get better on their own in a few weeks. “My concern is that we’re way overmedicating the problems of everyday life and that parallel to that, we are terrifically neglecting people who are really sick.”

One of the areas he gave as an example of transforming ordinary life into mental illness is with mild forms of depression, that really aren’t depression, but are being diagnosed as major depressive disorder. “The drug companies have convinced the world that major depressive disorder is one entity, and that it is always a chemical imbalance, and that it always requires a chemical solution in the form of a pill.” Eleven percent of Americans are taking an antidepressant. Grief in particular is often over diagnosed and over treated with medication. Then there is anxiety; children who have temper tantrums; and so on. “In general, we have taken every day experiences, that are part of the human condition, and we’re over diagnosing them as mental disorders, and we’re way too often providing a pill, when there’s not really a pill solution for every problem in life.”

Children have been over medicalized with Attention Deficit Disorder, which should be properly diagnosed at around 2 or 3 percent of the U.S. population. In the U.S., by the time a child is 18, they have a 15 percent chance of getting the diagnosis. “This is absolutely ridiculous. We are turning immaturity into a disease.” There are also unwarranted increases in diagnosing childhood Bipolar Disorder. And there is a terrific overuse of antipsychotics in children with behavior problems. “I think we are doing a massive, worldwide experiment on immature brains, bombarding them with very powerful chemicals, with no knowledge whatever about what the long-term outcome will be; and without informed consent.”

He thinks the DSM-5 set off on in the wrong direction. Psychiatrists were worrying about underdiagnosis, when they should have been concerned with overdiagnosis. He said we have gone overboard in the developed world in giving too much treatment to people who can afford it, while neglecting people who can’t.

Then he was asked to comment on the role of good evidence that comes from systematic reviews, from summaries of evidence. Frances said evidence is absolutely crucial in making medical decisions, even though you can’t trust all of it. It takes time to gather enough reliable evidence to be confident. “But without evidence it’s a crapshoot that will be governed by commercial, for profit elements that so determine how people are treated.

I think the biggest role for change will come from the evidence-based guidelines and from a press that is educated to advertise to the people reading the article, not just the possible miracle medical benefit, which is always exaggerated, but also the possible realistic risks of side effects.

The biggest problem for the doctor is too little time. The more time you have to get to know the patient, the less likely you’ll be inaccurate in your diagnosis. “It’s the easiest thing in the world to give a diagnosis and to write a pill prescription. It’s the hardest thing in the world, often, to get rid of a diagnosis once it’s been established. . . A wrong diagnosis made in ten minutes can haunt for life.” Medication, given casually, can do great harm and you should be as careful in taking medication as you would be for a major life decision.

Originally posted on 5/19/2020

05/24/22

The Truth About Gabapentin

Gabapentin has been peddled as a treatment for problems as diverse as hot flashes, itchy skin, postoperative pain, and social phobia. That is in addition to its approved uses for partial seizures, nerve pain following shingles and moderate-to-severe restless leg syndrome. In November of 2021, GoodRx listed gabapentin as the sixth-most prescribed medication in the U.S. Not surprisingly, in a 1999 email the Marketing Director for Pfizer at the time called gabapentin “the snake oil of the twentieth century,” claiming it had been successful with “just about everything they have studied.”

Pfizer has paid $945 million to resolve lawsuits against the off-label marketing of gabapentin. For a number of years, gabapentin has been known as a drug of abuse—alone or in combination with other drugs. A 2017 study in the journal Addiction by Lyndon et al (discussed below) noted combining gabapentin (Neurontin) or pregabalin (Lyrica) with opioids increased the risk of acute overdose death. The researchers referred to concomitant use of gabapentinoids and heroin as an emerging public health problem.

It is important that doctors and their patients are aware that the combination of opioids with gabapentin or pregabalin potentially increases the risk of acute overdose death through either reversing tolerance or by an additive effect of the drugs to depress respiration.

In 2019 the FDA acknowledged the risk of serious breathing problems with gabapentin and pregabalin and added a warning to their prescribing information. The FDA also required manufacturers to conduct clinical trials to further evaluate their abuse potential, particularly in combination with opioids. “Misuse and abuse of these products together is increasing, and co-use may increase the risk of respiratory depression.” Despite these concerns, gabapentin is still not a Scheduled drug by the DEA, while pregabalin, coming to market in 2004, is a Schedule V controlled substance.

However, Campbell et al reported in “Gabapentin controlled substance status” that seven state boards of pharmacy have independently reclassified gabapentin as a Schedule V drug. Twelve states have implemented prescription monitoring programs and three states are deliberating gabapentin’s future controlled/monitored status. The United Kingdom reclassified gabapentin in 2019, placing it in the same controlled substance schedule as barbiturates, buprenorphine, and tramadol. Despite the lawsuits and FDA-limitations, gabapentin prescriptions dispensed from 2011 to 2017 increased two-fold—from 33.4 million to 64.8 million.

Case reports indicate that gabapentin is abused for a variety of reasons, but the most common listed are for euphoria, potentiating the high from opiates, reduction of alcohol cravings, a cocaine-like high, as well and sedation or sleep. Individuals at the highest risk for abusing gabapentin include those with opioid abuse, mental illness, or previous history of prescription drug abuse. Postmortem toxicology analyses have directly linked gabapentin as a cause of death, but most deaths observed occurred with concomitant use with opiates or benzodiazepines. Gabapentin when combined with these agents appears to be lethal at lower serum gabapentin concentrations than gabapentin alone.

Medical Xpress confirmed that most prescriptions for gabapentin were approved for off-label use. A newly published study, “Outpatient Off-Label Gabapentin Use for Psychiatric Indications,” found that more than 99% were for off-label uses. Amie Goodin, a coauthor of the study, said they had anticipated a lot of off-label use, but were surprised at the magnitude of use.

Out of more than 200,000 patient records, just over 5,700 involved a gabapentin prescription. That corresponds to nearly 130 million visits nationally between 2011 and 2016.The vast majority of those prescriptions were off-label, and most patients were also on other prescription drugs. In nearly one-third of cases, those additional medications included a CNS depressant. Antidepressants were the most common type of CNS depressant, followed by opioid painkillers and benzodiazepines. Of all office visits where off-label gabapentin was in the record, about 5% of patients had a depression diagnosis, and 3.5% had an anxiety disorder.

On March 7, 2022, Medscape announced that Public Citizen filed a petition with the FDA and the DEA to make gabapentin a federally controlled substance. The nonprofit group requested that gabapentin come under the DEA’s Schedule V category, where Lyrica is scheduled. The authors argued the risks with gabapentin warranted more safety measures. Classifying gabapentin as a Schedule V drug would make tracking its use and misuse easier and put into place educational and limitation requirements to lessen the risks of addiction, overdose and death.

The Public Citizen petition said there was substantial evidence of widespread misuse of gabapentin, partly because of the extraordinary levels of off-label prescribing. “Both gabapentin and pregabalin have been empirically linked to the opioid overdose epidemic as drugs that potentiate the activity of these oftentimes deadly analgesics.” There were five systematic reviews summarizing evidence of the harms associated with gabapentin abuse, misuse and diversion.

One review by Smith et al, “Gabapentin misuse, abuse, and diversion: A systematic review,” concluded from their review that gabapentin was “primarily misused for recreational purposes, self-medication, or intentional self-harm, and was used alone or in combination with other substances, especially opioids, benzodiazepines, or alcohol.”

In summary, findings from the present review suggest that gabapentin is misused/abused internationally for recreation, self-medication, or self-harm, with an array of subjective experiences. Substance abuse populations, especially individuals with a history of or current opioid misuse, appear to be at particular risk for misuse/abuse. Further studies to identify risk factors for gabapentin misuse and to characterize gabapentin’s abuse liability are recommended.

Another systematic review by Evoy et al in 2021, “Abuse and Misuse of Pregabalin and Gabapentin: A Systematic Review Update,” confirmed the findings of their 2017 systematic review, that gabapentin and pregabalin are increasingly being misused in order to self-medicate and produce rewarding effects, such as euphoria, relaxation, or disassociation. “Most concerning was the finding of increased evidence of associated patient harm, including increased hospital utilization and opioid-related overdose risk.”

Lyndon et al examined trends in drug-related deaths involving gabapentin in England and Wales from 2004 to 2015 in, “Risk to heroin users of poly-drug use of pregabalin or gabapentin.” They found that prescriptions for gabapentin and pregabalin increased around 24% per year during the study period, from 1 million in 2004 to 10.5 million in 2015. There were concurrent increases in drug-related deaths involving gabapentin and pregabalin; 79% of which involved opioids. “For each increase of 100,000 gabapentinoid prescriptions, the number of deaths increased by approximately 5%.” See the following graphs in the Public Citizen petition.

Postmortem studies in some U.S. jurisdictions have noted an increase in gabapentin-related overdoses. In “Prevalence of gabapentin in drug overdose postmortem toxicology testing results,” Slavova et al found 22% of decedents tested positive for gabapentin. “Among the 3,360 drug-overdose decedents who tested positive for opioids, 880 (26%) also tested positive for gabapentin. Conversely, among the 931 decedents who tested positive for gabapentin, 876 (94%) also tested positive for opioids.”

Buttram et al found in “Law Enforcement-derived data on gabapentin diversion and misuse, 2002-2015” that there were 407 cases of gabapentin diversion reported in 41 states from 2002 to 2015. The gabapentin diversion rate rose steadily from zero in the first quarter of 2002 to a rate comparable to the diversion rate of OxyContin in 2015.

The Public Citizen petition concluded by noting the evidence presented in the petition clearly fulfilled the DEA criteria for scheduling gabapentin:

There is evidence that individuals are taking gabapentin in amounts sufficient to create a hazard to their health and to the community.
There is significant diversion of gabapentin from legitimate drug channels.
Individuals are taking gabapentin on their own initiative rather than on the basis of medical advice from a practitioner.

I’m hopeful the FDA and the DEA will respond to the petition by scheduling gabapentin. I’ve been disturbed with what I’ve seen happen with gabapentin since I first read The Truth About Drug Companies. Marsh Angell described how Neurontin (gabapentin) was transformed from an add-on medication when other anti-seizure drugs failed, into a blockbuster, with sales of $2.7 billion in 2003 by getting doctors to prescribe it for unapproved uses. About 80% of the prescriptions that year were for off-label use. “In fact, Neurontin has become a sort of all-purpose restorative for chronic discomfort of almost any type—yet there is almost no good published evidence that it works for most of these conditions.”

For more information on gabapentin and pregabalin, see “Twentieth Century Snake Oil,” “The Evolution of Neurontin Abuse,” “Foolishness with Gabapentin,” “Gabapentinoids Perpetuate Addiction” on this website.

05/3/22

Medicalizing Normal, Human Grief

Well, it’s official. If your bereavement over the death of someone close to you “lasts longer than social norms and causes distress or problems,” it could be a psychiatric disorder. The symptoms of what is called Prolonged Grief Disorder (PGD) include: avoiding reminders that the person is dead; emotional numbness; feeling life is meaningless; feeling intense loneliness, being detached from others; intense emotional pain related to the death. PGD can be diagnosed if someone is experiencing these symptoms within 12 months of the death of a loved one for adults or within 6 months for children or adolescents.

Prolonged Grief Disorder is the newest disorder added to the DSM. After studies suggested that many people were experiencing persistent difficulties with bereavement, PGD was approved by the APA’s Board of Trustees and Assembly in the fall of 2020 and included in the text revision of the DSM-5 (DSM-5-TR) published in March of 2022. The APA CEO and Medical Director said including prolonged grief disorder in the DSM-5-TR will mean that mental health clinicians and family members will “share an understanding of what normal grief looks like and what might indicate a long-term problem.” The President of the APA was quoted as saying:

The circumstances in which we are living, with more than 675,000 deaths due to COVID, may make prolonged grief disorder more prevalent. . . . Grief in these circumstances is normal, but not at certain levels and not most of the day, nearly every day for months. Help is available.

The reaction by mental health professionals has not been all supportive of the APA adding grief to the DSM listing of psychiatric disorders. Debate over this action has been going on for over a decade and it seems the APA has been incrementally moving in this direction. In 2013 when the bereavement exclusion was removed from the DSM-5 diagnosis of major depression, Allen Frances, who was the chair for the DSM-IV, thought it was a dreadful mistake that flew in the face of clinical common sense. He ranked it as the second worst mistake within the DSM-5. In a 2012 NYT article, “Grief Could Join List of Disorders,” he said: “What I worry about most is that the revisions will medicalize normality and that millions of people will get psychiatric labels unnecessarily.”

A recent NYT article about the addition of PGD to the DSM, “How Long Should It Take to Grieve? Psychiatry Has Come Up With an Answer,” said the new diagnosis was meant to apply to a narrow section of the population whose struggles with bereavement and grief kept them from resuming their previous activities. Joanne Cacciatore, who runs a retreat for bereaved people and has written extensively on grief, said she utterly disagreed that grief could be a mental illness. “To me, that is an incredibly dangerous move, and short sighted.”

Ellen Barry, the author of “How Long Should It Take to Grieve?”, predicted the new diagnosis will most likely open a stream of funding for treatments, “and set off a competition for approval of medicines by the Food and Drug Administration.” She noted how Holly Prigerson other researchers are investigating naltrexone in clinical trials as a form of grief therapy. Donna Schuurman, an internationally recognized authority on grief, predicted in “The Grief Pill is Coming!” that it will become “another massive disappointment in a long line of pharmaceutical marketing deceptions.” Their hypothesis is that PGD is a disorder of addiction; and that patients with PGD continue to “crave” their loved ones after they have died, as a result of the positive reinforcement of their memories of loved ones.

The Origins of Prolonged Grief Disorder

The origins of PGD date back to the 1990s and the work of a psychiatric epidemiologist named Holly Prigerson. She was part of a research team examining the effectiveness of depression treatment in older adults. She noticed many individuals responded well to antidepressant medications, but seemed to be unaffected when she looked at the grief measures used in the study. Her observations were dismissed by psychiatrists on the research team. She was told grief was normal, but she didn’t ignore her observations; she did more research.

Her further research showed that for most people, symptoms of grief peaked at six months postloss, six months after the death. In “An Empirical Examination of the Stage Theory of Grief,” she said a depressive mood in normally bereaved individuals tended to peak around six months postloss. Yearning, not depressed mood was the significant psychological response to natural death. She suggested her findings should lead to a revision of the DSM.

The results also offer a point of reference for distinguishing between normal and abnormal reactions to loss. Given that the negative grief indicators all peak within 6 months, those individuals who experience any of the indicators beyond 6 months postloss would appear to deviate from the normal response to loss. These findings also support the duration criterion of 6 months postloss for diagnosing complicated grief disorder, or what is now referred to as prolonged grief disorder. Unlike the term complicated, which is defined as “difficult to analyze, understand, explain,” prolonged grief disorder accurately describes a bereavement-specific mental disorder based on symptoms of grief that persist longer than is normally the case (ie, >6 months postloss based on the results of the present study). Furthermore, prolonged grief disorder permits the recognition of other psychiatric complications of bereavement, such as major depressive disorder and posttraumatic stress disorder. Additional analyses are needed to examine grief trajectories among those meeting criteria for prolonged grief disorder.

So it seems that Prigerson’s work and that of others who built upon it, led ultimately to the recent action by the American Psychiatric Association making PGD a formal diagnosis. Around 5% of the population experience grief feelings which are profoundly different, longer-lasting and more harmful than the typical bereavement after the death of a loved one. And according to some mental health professionals, this grief can be reliably distinguished from other MH conditions such as depression or post-traumatic stress disorder. Maarten Eisma told Gizmodo, “It diverges from normal grief in its duration and intensity as well as in its impact on everyday life.”

Prigerson said the American Psychiatric Association “begged and pleaded” to define the syndrome conservatively as a year after death to avoid a public backlash. The concern was that everyone feels they still feel some grief at six months. “It just seems like you’re pathologizing love.” She estimated the criteria for PGD should apply to around 4% of bereaved people.

Those who oppose the new diagnosis seem to voice concerns similar to that of Allen Frances, that it gives individuals a diagnostic label unnecessarily; it medicalizes normal human grief experience. Joanne Cacciatore told Gizmodo that the diagnostic criteria for PGD unfairly targeted a subset of grieving people to be diagnosed with a mental illness. Her own research with bereaved parents suggested a majority could experience symptoms that could lead to a diagnosis of PGD or other psychiatric diagnoses up to four years after their child’s death. If this many parents can feel this amount of grief, “perhaps it is the measures that are flawed, not the grievers.”

For example, the criteria states that at one year, you can be diagnosed with PGD if you are intensely yearning for the person who died. What parent would not yearn for a child who died? Intense emotional pain? After such traumatic losses, what person would not feel intense emotional pain one year later?

Cacciatore thinks the diagnostic system is “absolutely broken, and we need an ethical change.” Psychological care should not depend soley on a diagnosis. She thinks we need better grief support education. We need more facilitators and facilities to care for people who are grieving.

Sheila Vakharia noted that in a world where thousands of Americans per week are dying in an ongoing pandemic, how can anyone’s grief over the losses they’ve experienced be considered abnormal? “For a diagnosis such as this to be released at this moment, it just feels tone deaf, and it feels decontextualized, both within the broader policy environment and with the fact that we are in a mass disabling and a mass death event—we’re in a global pandemic.”

For more information on diagnosing grief, see “The Death of Grief” and “Pathologizing Grief.”

04/12/22

The Psychedelic Pendulum and Psychiatry, Part 2

On October 12, 1955 psychiatrist Sidney Cohen took LSD for the first time. Expecting to feel catatonic or paranoid because LSD was then thought to produce a temporary psychosis, he instead felt an elevated peacefulness, as if the problems and worries of everyday life had vanished. “I seemed to have finally arrived at the contemplation of eternal truth.” He immediately began his own LSD experiments, even exploring whether it could be helpful in facilitating psychotherapy, curing alcoholism and enhancing creativity. But on July of 1962 in The Journal of The American Medical Association, he warned of the dangers of suicide, prolonged psychotic reactions, and said: “Misuse of the drug alone or in combination with other agents has been encountered.”

The history of psychedelics seems have followed this pendulum swing from hope and promise, to disappointment and warnings, and then back again to hope and promise. In Part 1 of this article, we looked at the current promise of psychedelic therapy and treatment and mentioned its use to supposedly enhance creativity. Here we’ll take a closer look at the present-day concerns and reservations with the proposed use of psychedelics as therapeutic tools. Tellingly, they haven’t change much since Cohen co-authored “Complications Associated with Lysergic Acid Diethylamide (LSD-25).”

In “Psychedelics—The New Psychiatric Craze,” Joanna Moncrieff acknowledged the “increasingly fashionable” interest in psychedelics as a medical treatment, but wondered if they weren’t just “a powerful form of snake oil.” She noted the ever-lengthening list of problems they were recommended to treat, which included PTSD, depression, anxiety, addiction, chronic pain and distress associated with having a terminal illness. The rationale behind the trend was said to be confusing and contradictory.

On the one hand, psychedelics are promoted as assisting the process of psychotherapy through the insights that the ‘trip’ or drug-induced experience can generate – on the other they are claimed to represent a targeted medical treatment for various disorders, through correcting underlying brain deficiencies.

Increasingly, the use of these drugs is portrayed as if they work by targeting underlying dysfunctional brain processes (i.e., resetting brain processes by acting on 5-HT2A receptors). Moncrieff said claims by David Nutt, a psychopharmacologist and psychedelic researcher that psychedelics “turn off parts of the brain that relate to depression” and reset the brain’s thinking processes by their actions on the 5-HT2A receptors were “pure speculation.” She made the same judgment on a John Hopkins website that said researchers hoped to “create precision medicine treatments tailored to the specific needs of individual patients.” The charity, Mind Medicine Australia’s claim that psychedelic treatments were curative and only required 2-3 dosed sessions, that they were “antibiotics for the mind”, Moncrieff thought was a sales pitch for an expensive therapy.

In reality, psychedelics do not produce the miracle cures people are led to expect, as experience with ketamine confirms. Some people may feel a little better after a treatment, and then the effect wears off and they come for another one and another one, and get established on long-term treatment just as people do on antidepressants.

Official research also over-plays the drug’s benefits. A study published in The New England Journal of Medicine, “Trial of Psilocybin versus Escitalopram for Depression,” found no significant difference between groups in their primary outcome. The study’s discussion then pointed out that secondary outcomes had small differences, but did not consider the placebo effect of participants having a drug-induced experience. The participants were also not typical of those with depression, consisting of mainly well-educated men, almost a third of whom had tried psychedelics before. The study’s researchers said:

The patients in the trial were not from diverse ethnic or socioeconomic backgrounds. Strategies to improve recruitment of more diverse study populations are needed in studies of psilocybin for depression. Also, average symptom severity scores at baseline were in the range for moderate depression, thus limiting extrapolations to patients with severe depressive symptoms or treatment-resistant depression.

The current craze for psychedelics means adverse effects are being minimized, according to Moncrieff. Whether or not people find the effects of psychedelics enlightening or not depends on how the drug-induced experience is interpreted. This highlights the importance of staff as support people while clients are under the influence. Yet she worried that when, and if, psychedelics obtain a medical license, psychotherapy would be dropped or minimized. “The tendency of all psychedelic treatment will be towards the provisions of the drug in the cheapest possible way, which means the minimum of supervision and therapy.”

In “When Drugs of Abuse Become Psychiatric Medications,” Sara and Jack Gorman noted that some commentators have been suggesting we’re on the cusp of a new era in psychopharmacology with the potential of ketamine, MDMA and psilocybin as psychiatric treatments for depression, PTSD and other disorders. They noted how we have information about the biological mechanisms of action for all three of them. Ketamine works mainly through interaction with the brain’s glutamate neurotransmission system. MDMD and psilocybin enhance the brain’s serotonin receptors—the same system affected by SSRI antidepressants.

Unfortunately, however, we still have no firm idea if derangements in any of these neurotransmitter systems are actually the cause of any mood or anxiety disorder. There are many theories linking abnormal glutamate neurotransmission to depression, for example, and some solid data from animal studies suggesting such a link, but no definitive proof that any abnormality in glutamate neurotransmission is part of depression yet exists. We cannot say that any of these drugs work by remediating a known abnormality in the brains of people with psychiatric illnesses any more than we can say that about any of the traditional psychiatric medications.

One final issue is that regardless of the fact that currently approved medications for depression and PTSD are only partially effective for many patients, they are not usually abused or addictive. Yet ketamine, psilocybin and MDMA have long histories as recreational street drugs that can be addictive for some people. In the clinical trials done to date adverse side effects have been minimal, and with the doses and manner in which they are given, addiction is unlikely. Moreover, there are widely used, FDA-approved, psychiatric drugs with known histories of misuse—benzodiazepines and ADHD medications.

Then the Gormans asked a telling question: Is psychiatry following solid science, or going in the direction of approving the use of mind-altering street drugs as medications—and I’d add—because they have no other potential medications on the horizon?

In the journal, JAMA Psychiatry, Joshua Phelps and two others expressed concerns with the growth of industry-sponsored drug development and the assessment of psychedelic drug effectiveness. They noted the market for psychedelic substances was projected to grow from $2 billion in 2020 to $10.75 billion by 2027, “a growth rate that may even outpace the legal US cannabis market.” They said the interest in psychedelic medicine seems to hope that psychedelics will be the next blockbuster class of medicines and has led to efforts to decriminalize psychedelics at the local level, as with Oregon (see Part 1) and other locations. Their concern is that these regulatory changes will adversely affect the quality and rigor of biomedical research with psychedelics.

Although popular excitement, policy momentum, and financial investment in psychedelics continue to increase, it is imperative that research maintains scientific rigor and dispassion to outcomes in the pursuit of improved therapeutics and new insights into the mind, brain, and consciousness that this class of molecules may well afford in the coming years. The presence of large-scale, newly established public companies as an unprecedented category of stakeholder may help to further understanding of these molecules and their possible clinical applications, but these firms also have a unique set of self-interests that must be understood and considered. Research enabled by these firms must still meet the same rigorous standards that are expected elsewhere, even if breakthrough status is warranted.

Then there is another concern described by Will Hall on “Ending the Silence Around Psychedelic Therapy Abuse.” He made his decision to write about therapy abuse when he read Michael Pollan’s best-selling book on psychedelics, How to Change Your Mind. Hill thought Pollan was overly enthusiastic and largely uncritical. “All the new hype about miracle psychiatric treatments and the next wave of cures for mental disorders leaves out the risk of therapy abuse.”

He said from his perspective, as far as drugs go, psychedelics were relatively safe—safer than benzodiazepines or SSRIs. He even acknowledged that reported healings from emotional pain with psychedelics did happen. By raising an alarm about therapy abuse he said he wasn’t exaggerating the dangers of psychedelics, rather: “I’m calling for more honesty about the implications of putting psychedelics in the hands of therapists.”

He noted the inherently imbalanced power relationship of therapist and client, where there is already the potential danger of authority being misused. The therapist has too much influence over a client, and the consequences for clients are too severe to see each side as equal, according to Hall. “And so we protect clients from therapists in the same way we protect children from adults, especially from the most exploitive and extreme violation of therapist trust, sex with clients.” The risks are magnified when you add psychedelics.

Drugs affect judgment, drugs can enhance idealization, drugs can promote risk taking, drugs can lower defenses, drugs can amplify suggestibility, drugs can lead to dissociation… all drugs. Imagine if you heard therapists were giving their clients alcohol to get them talkative, lines of cocaine to get them confident, or cannabis to get them relaxed? You would easily recognize that even if some clients do benefit, the client is also put into a heightened and more easily exploited state. Despite their many unique and often positive qualities, this is still true of psychedelics. And the influence is magnified when the therapist is supplier of and expert about the drug, when the drug has a taboo cultural aura of esoteric healing powers, the media are hyping miracle cures, and scientific experts are waving their hands and calling it “medical treatment.” Add that psychedelic therapists are typically also themselves users of and true believers in these substances. The dangers are obvious.

Psychedelics present some of the same risks as any drugs. Hall said we need to name those risks, and be especially vigilant about them. Otherwise, even though some people will be helped, others will be harmed. “And as the history of psychedelic therapy abuse shows, they already have.” Hall then gave specific historical examples and details from past abuse as well as his own personal experiences.

He wasn’t alone in pointing to this safety concern with psychedelic therapy. In her article on Oregon’s experiment with legalizing psychedelics for STAT, Olivia Goldhill noted that sexual abuse has historically been a problem with psychedelic therapy. “All the usual power imbalances of patients and therapists are exacerbated in a setting where drugs can create feelings of sexual arousal.”

Hall also pointed out that with psychedelics or any other drug, “it’s called getting high for a reason—we lose our feet on the ground.” Gaining a new perspective can be illuminating, but avoidance could come instead of insight. Psychedelics also increase suggestibility, a tendency to accept the beliefs of others illustrated in hypnotic trance states and situations where there is social pressure for conformity. Psychedelics can make some people more dependent on outside influence and more reluctant to consider they may have misjudged their safety when using the drugs.

There is more Will Hall has to say about the potential for therapy abuse with psychedelics, but what we’ve reviewed lays out the concerns. I don’t agree entirely with what seems to me to be a “laissez faire” approach to people who want to use psychedelics for healing or illumination. I’d say there is as much of concern with their use as with benzodiazepines or SSRIs. And given the pendulum swing evident in the history of psychedelics as therapeutic agents, there is a swing back to disappointments and concerns ahead. As Hall astutely said,

All medical treatment outcomes are driven in part by expectation and placebo: eventually the hype around new psychiatric products wears off, and then we are on to the next marketing wave—with iatrogenic harm to patients left in the wake.

STAT said that Washington, New York, Colorado and California are all considering some form of legalizing psychedelics. Other states are enacting decriminalization measures. If Oregon-style legislation spreads to other states, the potential market for legalization will get bigger. Field Trip, a company with a series of clinics used for ketamine therapy plans to set up clinics in Oregon. “Oregon is just the first step. But there’s a big wave coming almost certainly.”

03/22/22

Hardwiring Young Brains

The U.S. Department of Health and Human Services published a report in 2009, “Addressing Prescription Drug Abuse in the United States”, that noted a significant milestone was surpassed with prescription drugs. “For the first time in the U.S., drug overdose deaths outnumbered deaths due to motor vehicle crashes.” In 1999, opioids were involved in 30% of drug overdose deaths. By 2010, this had risen to 60%. Prescription opioid-related overdose deaths then outnumbered overdose deaths from all illicit drugs such as heroin and cocaine.

Opioids are getting the most attention as result of their potential to lead to an overdose, but other classes of psychotherapeutic drugs are also misused. The 2020 National Survey on Drug Use and Health (NSDUH), showed that prescription stimulants, tranquilizers or sedatives such as benzodiazepines are also misused. The 2020 NSDUH defined the misuse of prescription drugs as “use in any way not directed by a doctor, including use without a prescription of one’s own; use in greater amounts, more often, or longer than told to take a drug; or use in any other way not directed by a doctor.” Among people 12 and older 5.8% (16.1 million people) misused prescription psychotherapeutic drugs in 2020.

The 16.1 million people in 2020 who misused prescription psychotherapeutic drugs in the past year included 9.3 million people who misused prescription pain relievers, 6.2 million people who misused prescription tranquilizers or sedatives (including 4.8 million past year misusers of benzodiazepines), and 5.1 million people who misused prescription stimulants.

Surprisingly, the most recent information on the top abused prescription drugs was from 2016 by Statistica and 2017 by GEN, Genetic Engineering & Biotechnology News. GEN listed the top 20 abused drugs ranked by sales data, as did Statistica. The rankings according to revenue are almost identical. Not only have Statistica and GEN failed to continue their monitoring of prescription drugs in this way, I could find no other agency or organization that had done so. I wonder if the pharmaceutical companies had anything to do with this failure.

Statistica put their findings in handy chart (see above) but GEN did not. However, there was added information in the GEN article. This included a brief observation that fifteen of the top twenty drugs showed reduced overall sales from the previous year, likely from the lower prices of generics. Gen said that according to GlobalData, sales for ADHD drugs like Adderall and Concerta were projected to more than double by 2024, from $6.1 billion in 2014 to $13.9 billion. See the chart below which is composed of information in the GEN article.Eight of the listed drugs were opioids. All but five were scheduled as Controlled Substances by the DEA, meaning they have an addictive potential. Methylphenidate, an ADHD stimulant found in Ritalin, Concerta and Daytrana, was in three different drugs on the list as well as the generic drug. Zoloft (sertraline), an antidepressant SSRI, made the list in two different drug forms. Celecoxib, an arthritis treatment, was found in three drugs. Ironically, buprenorphine, one of only three drugs approved for the treatment of opioid misuse, was itself on the list of most abused prescription drugs, with only OxyContin listed ahead of it in pain reliever sales.

Reflecting on the implications of this information for drug treatment, a few questions arise. Are individuals (or parents in the case of ADHD medications) cautioned about the potential for developing an addiction when they or their children are first prescribed any of these drugs? Does the presence of medications like sertraline (Zoloft) and celecoxib on these lists point to a conundrum when they demonstrate a misuse potential but were not listed as controlled substances by the DEA? Does the reality of these medications being abused raise concerns for other medications in the same drug class?

According to ClinCalc, Zoloft was the 12^th most prescribed drug, with 7.7 million patients and 37.2 prescriptions. Forbes said it was often a first line medication for depression, anxiety and PTSD. None of the above abused drugs had more total prescriptions. Zoloft and other antidepressants like it are beginning to be viewed as addictive, so we may see more SSRIs on future most abused prescription drug lists. Long-term users seem to go through withdrawal when stopped too abruptly. See “Are Antidepressants Worth the Risk?”

Misuse of Prescription Drugs by Class

Returning to the 2020 NSDUH, the report also gave information on the misuse of prescription stimulants, tranquilizer or sedative misuse, benzodiazepine misuse and pain reliever misuse.

Prescription stimulant misuse included amphetamine (i.e., Adderall XR) and methylphenidate (i.e., Ritalin, Concerta, Daytrana) products. Among people aged 12 and older, 1.8 percent of the population (or 5.1 million people) misused prescription stimulants in the past year. The percentage was highest among young adults aged 18 to 25 at 4.8% (or 1.6 million people). All other age categories hovered between 1 and 2 percent.

For the most part, prescription stimulants to treat ADHD are Schedule II controlled substances. To what extent does their use as the child’s brain develops lead to substance abuse disorders in later years? See the figure below.

Tranquilizer or sedative misuse included benzodiazepine tranquilizers such as alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin) or diazepam (Valium), and muscle relaxants. Among people aged 12 and older, 2.2% (or 6.2 million people) misused tranquilizers or sedatives in the past year. Again, young adults had the highest percentage of misusers with 3.7% (or 1.2 million people).

Benzodiazepines are chemically similar regardless of whether they are prescribed as a sedative or a tranquilizer. Xanax, which is prescribed as a tranquilizer, has an average half-life of 11.2 hours (the length of time for half the dosage to be metabolized). Halcion, a benzodiazepine prescribed as a sedative, has a short half-life of between 1.5 and 5.5 hours. Research had shown that benzodiazepines with a short half-life have a greater dependency potential. Young adults once again had the highest percent of misusers 3.3% (or 1.1 million people).

Digging deeper into pain reliever misuse, the 2020 NSDUH asked respondents to identify specific pain relievers they used over the past year, and then categorized them into subtypes, such as hydrocodone or oxycodone products. Hydrocodone products such as Vicodin, Lortab, Norco, Zohydro ER and generic hydrocodone were the most commonly misused. Among people 12 and older, 1.7% (or 4.7 million people) misused them. There were 1.1% (or 3.2 million people) who misused oxycodone products such as OxyContin, Percocet, Percodan, Roxicodone and generic oxycodone.

No surprise, young adults aged 18 to 25 had the highest percentage of misuse with 4.1% (or 1.4 million people), followed by adults 26 and older with 3.4% (or 7.5 million people). A question arises at this point with regard to young adults. Given the evident pattern with young adults having the greatest potential to develop problems of misuse with stimulants, tranquilizers benzodiazepines and pain relievers, are they cautioned of this potential when they are first prescribed the medications?

Another way of looking at pain reliever misuse noted .1% of people 12 and older misused prescription fentanyl products. This will likely underrepresent people who used and misused illicitly manufactured fentanyl (IMF) from illegal laboratories; and will not include those who used IMF mixed with heroin or sold as heroin (but only contained IMF). The following figure compares past year pain reliever misuse among people 12 and older by the selected pain reliever subtype.

The 2020 NSDUH researchers presented the above data, and then stated that while prescription pain relievers were the second most common form of illicit drug use in 2020, “most past year users of prescription pain relievers did not misuse them in the past year.” They singled out buprenorphine, a Schedule III opioid used as an FDA approved medication for opioid misuse. Then they said the 26.5% of people who reported misusing buprenorphine over the past year meant: “Almost three fourths of past year users of buprenorphine products did not misuse them in that period.”

Another way to present this data is to say that of the .2% of people who go to a doctor for a buprenorphine prescription, supposedly to help them manage or stop their opioid misuse disorder, over 25% reported they misused their buprenorphine in the past year. There is a higher percentage of people admitting they misused buprenorphine than any of the other pain reliever subtypes.

Or you can sort the pain reliever subtypes according to their DEA scheduling as controlled substances. See the chart below. Misuse with Schedule II pain relievers ranges from 8.9% with morphine to 16.6% with hydromorphone. Schedule IV or Schedule V pain relievers, codeine, at 12.2% and tramadol at 9.0% have noticeably lower misuse percentages, while buprenorphine significantly stands above them all with 26.5% misusing it. Remember it was 4^th or 5^th in the above noted lists of the most abused drugs in 2016 and 2017. What’s going on?

Despite buprenorphine being a Controlled Substance, it is a prescription drug used to treat opioid misuse disorder. This means it activates the same opioid receptors in the brain that the other opioid drugs above do. The effects may not be the same as with OxyContin or heroin, but it’s still an opioid. The people using buprenorphine for medication-assisted treatment (MAT) already have a history of abusing opioids. Apparently more than 25% of them can’t resist the temptation to abuse the very drug they’re supposed to be using to stop their addictive use of opioids.

Future NSDUH surveys will need to monitor this conundrum with buprenorphine, but the above review of the 2020 NSDUH revealed a concerning age-related problem with prescription drugs. There was a pattern of young adults having the highest frequency of prescription drug misuse with all categories—stimulants, pain relievers, benzodiazepines and tranquilizers. SAMHSA (Substance Abuse and Mental Health Services Administration) stated that the fastest growing drug-related problem with teenagers was prescription drugs. This has the potential to result in life-long challenges with addiction.

Our brains continue to develop until we reach our early- to mid-twenties. During adolescence, the pre-frontal cortex further develops to enable us to set priorities, formulate strategies, allocate attention, and control impulses. The outer mantle of the brain also experiences a burst of development, helping us to become more sophisticated at processing abstract information and understanding rules, laws, and codes of social conduct. Drug use impacts perception—a skill adolescent brains are actively trying to cultivate—and can fracture developing neural pathways. Additionally, as our brains are becoming hardwired during adolescence, the pathways being reinforced are the ones that stick. If those pathways include addiction, the impact may lead to life-long challenges.

03/1/22

Withdrawal or Relapse When Tapering Antidepressants?

The number of antidepressant prescriptions written in primary care has continued to increase, and patients are remaining on them for longer durations of time. Yet research into maintaining or discontinuing antidepressants (ADs) in this setting has been almost nonexistent. “Maintenance or Discontinuation of Antidepressants in Primary Care,” published in September of 2021 in The New England Medical Journal, examined the relapse rates of primary care patients who expressed a desire to discontinue their antidepressant. The researchers, G. Lewis and L. Marston et al, found that patients who chose to discontinue their antidepressant therapy had a higher risk of relapse than those who maintained their current medication. However, others believed the results were misleading, because the authors misinterpreted withdrawal effects as relapse.

Lewis, Marston et al found that patients assigned to discontinue their antidepressant medication had a higher frequency of depression relapse than those who maintained their medication through the 52 weeks of follow-up done by the study. Eligible patients were between 18 and 74, and had reported at least two prior episodes of depression. All patients had been receiving and adhering to their daily regimens and had been taking their ADs for more than two years. The main exclusion criterion for the study was current depression. They investigated three SSRIs, fluoxetine (Prozac), citalopram (Celexa) and sertraline (Zoloft), which have similar pharmacologic profiles and similar mechanisms of activity, and mirtazapine (Remeron).

Relapse occurred in 39% of the patients in the maintenance group, while 56% of the patients in the discontinuation group relapsed. Quality-of-life measures and symptoms of depression, anxiety, and medication withdrawal were generally worse in patients who discontinued their ADs. “By the end of the trial, 39% of the patients in the discontinuation group had returned to taking an antidepressant prescribed by their clinician.” See the figures below.

In a critique published in The BMJ of Lewis, Marston et al, Mark Horowitz, Joanna Moncrieff and Beth Parkin said their conclusion that continuing antidepressants reduced the chance of relapse was not warranted. “Because the authors neglected to account for the possibility of antidepressant withdrawal effects being mis-classified as relapse, a fundamental problem in discontinuation trials.” Although the antidepressants were discontinued more slowly than in previous studies, the 8 weeks of discontinuation was still a relatively short taper for patients who had been taking the drugs for more than 2 years. While the approach was consistent with recommendations at the time of the trial (half the dose for one month, then half the dose every second day for one month, before stopping), they are no longer in line with the current guidance from the Royal College of Psychiatrists on Stopping antidepressants.

Antidepressant withdrawal symptoms overlap with most domains of the depression scale used to detect relapse in the study. There was also a high correlation between mean differences on the withdrawal scale and means differences on the depression scale and anxiety scale. “Together, with the overlap of withdrawal symptoms with measures of mood and relapse, this suggests that the withdrawal symptoms may account for the increase in symptom scores and relapse rate.” The reverse would be unlikely, since withdrawal symptoms included physical symptoms that were not intrinsically related to depression—dizziness, electric shocks, and headache. “Occam’s razor would suggest one condition causes several symptoms rather than requiring several conditions.”

Confounding withdrawal with relapse is consistent with the finding that most relapses occurred when withdrawal effects were at their peak, “within 6-12 weeks of when the drugs were stopped (at week 8).” Ninety percent of the total difference in relapse rates between the two arms of the study were present 12 weeks after the drugs were stopped, although this accounts for only 27% of the total follow-up time. Additionally, patients stopping fluoxetine had fewer withdrawal effects than other antidepressants, likely because of its longer elimination half-life. These patients relapsed 25% less than people stopping citalopram and sertraline, “again suggesting withdrawal effects.”

Anxiety and depression scores were the same for both groups at the end of the study. While 44% of the discontinued group had returned to their medication by this time, there was no difference in symptom scores—even with twice as many people on antidepressants in the maintenance group. “This suggests that discontinuation of antidepressants did not worsen mood after the period in which withdrawal symptoms had settled.” There were only small differences in DESS scores (Discontinuation-Emergent Signs and Symptoms) by the end of the 52 week study. Lastly, 71% of the patients in the discontinuation group correctly guessed their allocation to placebo; possibly because of experiencing withdrawal symptoms and then expecting they would get worse.

As there was no effort made to manage the potential confounding of relapse by withdrawal the current study suffers the same flaws as previous discontinuation studies and cannot provide evidence of the benefits of long-term treatment, only the difficulties of stopping it. The authors could resolve some of these concerns by analysing the correlation of withdrawal symptoms with mood scores and relapse amongst individual patients to verify if withdrawal symptoms might account for relapse. They could also re-analyse their data by excluding patients who experienced significant withdrawal symptoms (e.g. modified DESS ≥ 2) from qualifying for a diagnosis of relapse. This would provide a more robust measure of relapse, reducing the potential for the misclassification of relapse as withdrawal. They could also test whether unblinding was associated with relapse.Uncritical interpretation of this study may lead to the erroneous conclusion that antidepressants should be continued to prevent relapse, when in reality all they may be doing is preventing withdrawal symptoms. The more accurate conclusion would be that such symptoms are temporary withdrawal symptoms that can be minimised by stopping the drug more gradually, as recognised by the authors in media interviews, although not in the published paper.

Additional responses in The BMJ supported these points. Bryan Shapiro said, “Dr. Horowitz offers a valid critique of this discontinuation trial—that is, the confounding of illness relapse with antidepressant withdrawal symptoms.” Gary Singh Marlowe said, “For many patients who have been on anti-depressants for more than a few years a 2-month tapering period is insufficient.” Singh Marlowe said practitioners like him have “become increasingly aware that many of the symptoms these patients experience on stopping their anti-depressants are due to the drug withdrawal itself rather than a return of the ‘illness.’” See “Withdrawal Symptoms Cloud Findings of Antidepressant ‘Relapse’ Trial” by Peter Simon on the Mad in America website for more discussion of the Horowitz, Moncrieff and Parkin critique.

Concern that antidepressant withdrawal symptoms are being confounded with relapse symptoms of depression are not just coming from Mad in America and Horowitz, Moncrieff and Parkin. The Mental Elf reported on a systematic review done by the Cochrane Common Mental Health Disorders group on studies where antidepressants were taken for 6 months or more and then discontinued. Relapse rather than discontinuation was the primary outcome for 31 of 33 studies. Only one study reported data on withdrawal symptoms.

All included trials were at high risk of bias. The main limitation of the review is bias due to confounding withdrawal symptoms with symptoms of relapse of depression. Withdrawal symptoms (such as low mood, dizziness) may have an effect on almost every outcome including adverse events, quality of life, social functioning, and severity of illness.

Because of this flaw, the Cochrane group was not able to conclude whether any of the discontinuation strategies were safe and effective, also noting none of them employed tapering protocols beyond a few weeks. The Cochrane authors also doubted the validity of the evidence base for antidepressant continuation, as it depended “on the same and similar studies thoroughly confounded by withdrawal, which is probably mistaken for relapse.”

Consequently, it is unclear to what degree misclassified withdrawal symptoms contributed to “relapse” rates. Research suggests this could pertain to most relapses (El-Mallakh 2012; Greenhouse 1991; Hengartner 2020; Recalt 2019; Rosenbaum 1988). Moreover, withdrawal symptoms may have an effect on almost every outcome including adverse events, quality of life, social functioning, severity of illness, and anxiety and depression scores. For example, low mood and other withdrawal symptoms may register on the Hamilton Rating Scale for Depression (HAM-D) – the prioritised measure for depressive symptoms – and may result in people falsely allocated to having “severe” depressive symptoms.

Based on the review, the Cochrane review authors advised clinicians that:

Because of confounds, the evidence is unreliable for either discontinuation approach or risk of relapse after discontinuation.
It is unclear how long antidepressant treatment has to be maintained after remission. Current guidelines are based on consensus rather than evidence.
Evidence is lacking for appropriate discontinuation approaches for those who do not have “recurrent” depression, the elderly, and those taking antidepressants for anxiety.
The effect of short tapering regimens (≤ 4 weeks) was similar to abrupt discontinuation. Clinicians should expect to taper much slower, perhaps using liquid drug forms or tapering strips, while closely monitoring for withdrawal symptoms.
To taper effectively, clinicians will need to recognise withdrawal symptoms. Withdrawal symptoms differ from relapse or recurrence in timing of onset (within days rather than weeks), a rapid reversal after reintroduction of the antidepressant, and the emergence of somatic and psychological symptoms different from the original illness (e.g. shock-like sensations, dizziness, pronounced insomnia). Utilising the Discontinuation-Emergent Signs and Symptoms (DESS) Scale (PDF) may be helpful in monitoring reductions in dosage. When the patient’s DESS score returns to baseline after a reduction, further reduction is appropriate.
Mark Horowitz, who is a researcher and psychiatrist, was quoted in an article discussing the Cochrane review on Mad in America. He said:

For me, this is such a critical issue both from a personal and a professional perspective. I’m one of the hundreds of thousands of people who have had or are having long, difficult, and harrowing battles coming off long-term depressants because of the severity of the withdrawal effects. And yet, rather than being able to find or access any high-quality evidence or clinical guidance in this situation, I could only find useful information on peer support sites where people who had gone through withdrawal from antidepressants themselves have been forced to become lay experts. Since then, the Royal College of Psychiatrists has taken a great step forward in putting out guidance on Stopping Antidepressants in 2020. However, there is still a lack of research and, therefore, evidence in this area on what works for different people. I want other people to have the evidence base to come off without the same trouble I had.

American psychiatry has fallen behind Britain in protecting its citizens from the potential for iatrogenic harm of antidepressants. In May of 2018, the All-Party Parliamentary Group for Prescribed Drug Dependence published “Antidepressant Dependency and Withdrawal.” At the bottom of the first page is a disclaimer that says this is not an official publication of the House of Commons or the House of Lords. Yet it seems to have influenced the Royal College of Psychiatrists to make public the above linked information for anyone who wants to know more about “Stopping Antidepressants in 2020.”

The Executive Summary of “Antidepressant Dependency Withdrawal” said it was incorrect to view antidepressant withdrawal as largely mild, self-limiting (typically resolving between 1-2 weeks) and of short duration. Available research showed that antidepressant withdrawal reactions are widespread, with incidence rates ranging from 27% to 86%. Nearly half of those experiencing withdrawal described it as severe. Approximately 25% of antidepressant users experienced withdrawal reactions for at least 3 months after cessation; many experienced AD withdrawal for longer than 6 months.

Antidepressants fulfill the criteria for dependency-forming medications within the DSM, the ICD, and the WHO’s definition of dependency. “It is more reasonable to classify antidepressants as potentially dependency-forming medications than not.” Not only do they cause withdrawal in a large proportion of users, there is evidence antidepressants generate tolerance in up to 25% of users. About a third of antidepressant users report being “addicted”, according to their own understanding of the concept.

“The escalation of long-term antidepressant use combined with the misdiagnosis of withdrawal reactions warrants serious concern.” The length of AD use has doubled over the past decade, fueling a rise in prescriptions for the drugs. The evidence suggests this lengthening duration may be partly rooted in “the underestimation of the incidence, severity and duration of AD withdrawal reactions.” This underestimation may have led to many withdrawal reactions being misdiagnosed as relapse or as failure to respond to treatment with AD medications.

There is one final observation to make about the Lewis, Marston et al study. “Maintenance or Discontinuation of Antidepressants in Primary Care,” was of 150 general practices in the United Kingdom, and yet it was published in the prestigious American journal, The New England Journal of Medicine. I wonder if the researchers were attempting to reach a more receptive and less critical audience than if they had published in a prestigious British journal like The BMJ, which did publish the critique of Horowitz, Moncrieff and Parkin.

02/8/22

Are Antidepressants Worth the Risks?

Business Insider published an article in 2016 with some startling statistics on the global use of antidepressants by the Organization for Economic Cooperation and Development (OECD). They discovered that in all 25 countries, antidepressant use was increasing. “The increase in antidepressants consumption has spurred an ongoing debate [about] whether antidepressants are overprescribed (medicalization) or underprescribed (poor access to treatment).” The U.S. was not included in the OECD analysis, but if it had been, it would have topped the list, as the following chart indicates.

The chart suggested that 11% of Americans, 110 per 1,000 people, used antidepressants in 2016. But the use of antidepressants is not an accurate indicator of depression rates. In the U.S., for example, only about one third of people with severe depression take an antidepressant. Yet the use of antidepressants is rising.

The CDC reported that 13.2% of American adults used antidepressants in the past 39 days. Antidepressant use increased with age, from 7.9% among adults aged 18 to 39 to 19.0% for those aged 60 and over. Use was higher among women than men. Almost one-quarter of women aged 60 and over (24.3%) took antidepressants. See the follow figure from the CDC data brief.

The History of Antidepressants

Given the increased use of antidepressants globally and within the U.S., it seems some awareness of the history of antidepressants and their potential side effects would be helpful. In an article for Psychology Today, Mark Ruffalo gave a brief history of antidepressants in his discussion of Prozac (fluoxetine). He saw the introduction of that drug in 1987, the first SSRI, as a “game changing” event in the history of psychiatry.

The search for a drug to specifically target depression began in the 1950s and led to the monoamine hypothesis of depression. The monoamine hypothesis suggested depression was associated with a deficiency in the monoamine systems of serotonin, noradrenaline and dopamine. In the 1960s and 1970s, psychiatry believed norepinephrine played a central role with affective disorders. “Serotonin’s role was minimized and seen only as ancillary to norepinephrine.”

Tricyclic antidepressants such as Tofranil (imipramine) and Elavil (amitriptyline) were brought to market. They block the reabsorption (reuptake) of serotonin and norepinephrine, increasing the levels of these two neurotransmitters in the brain. But there are side effects such drowsiness, blurred vision, constipation, dry mouth, light headedness, sexual problems, and others. Given the multiple adverse effects, tricyclics were only prescribed for the more severe cases of depression. But that all changed with Prozac.

In the early 1970s, the pharmaceutical company Eli Lilly began to investigate the possibility of developing an antidepressant drug that avoided the potential cardiovascular risks associated with some of the earlier tricyclic antidepressants (like imipramine and amitriptyline). The Lilly team, which included the Hong Kong-born biochemist David Wong, synthesized several chemicals derived from an antihistamine called diphenhydramine (found in Benadryl and over-the-counter sleeping aids like Tylenol PM). Wong, who was familiar with European research implicating serotonin in mood regulation, encouraged the team to screen their newly synthesized chemicals for any that might selectively inhibit the reuptake of serotonin. On July 24, 1972, they found one [fluoxetine].

A few years later, Eli Lilly filed an application with the FDA to investigate fluoxetine’s potential to treat clinical depression. Ruffalo said initial expectations were modest. In December of 1987, fluoxetine, now branded as Prozac, received FDA approval. “Within a few months, Prozac sales outpaced the market leader Pamelor (a tricyclic), as physicians believed that Prozac was both safer and avoided the weight gain common with the tricyclics.” Prozac became the best-selling antidepressant of all time.

With Prozac’s mass success, a new type of depressed patient emerged: the mildly depressed. For hundreds of years, depression (historically termed melancholia), was considered a rare and serious disease, usually only observed in psychiatric inpatients. Because Prozac was so safe—and the risk of drug-drug interactions minimal—doctors began prescribing it to patients with milder symptoms, those to whom they might have hesitated to prescribe a tricyclic. Patients who would have been treated in psychotherapy instead started on Prozac. A biological revolution was well underway.

More SSRIs (selective serotonin reuptake inhibitors) came to market. Zoloft (1991) and Paxil (1992) were followed by the release of the so-called SNRIs (serotonin-norepinepherine reuptake inhibitors) such as Effexor (venlafaxine, 1993) and Cymbalta (duloxetine, 2004). Pfizer, the manufacturer of Zoloft, spearheaded the claim in drug advertising that a “chemical imbalance” caused depression, which SSRIs like Prozac and Zoloft corrected.

In 1993, Peter Kramer published Listening to Prozac, which became a New York Times bestseller. In addition to lifting depression, he suggested these new drugs could be used as personality enhancers. “Kramer raised the possibility that, in addition to lifting depression, Prozac could also brighten a dull personality, assist an ambitious employee in climbing the corporate ladder, and make a shy person lively and outgoing.” Public interest in the drug piqued, and in 1993 sales increased 15%. At this point in time, SSRIs are the first-line pharmacotherapy for major depression, anxiety disorders, obsessive-compulsive disorder and post traumatic stress disorder.

SSRI antidepressants are now one of the three most commonly used therapeutic classes of drugs in the U.S. And their long-term use has been steadily increasing as well. In 2014 the CDC reported that 68% of persons who used antidepressants had done so for 2 years or more; 19% between 5 and 10 years; and 25.3% had been using antidepressants for 10 years or more. See the figure below.

The Consequences of Overprescribing Antidepressants

The popularity of antidepressants has led to concern that they are being overprescribed. Allen Frances, who is a Professor and Chair Emeritus of the Department of Psychiatry, Duke University, noted that most antidepressants are now off patent and their popularity cannot be attributed to the marketing of pharmaceutical manufacturers. He said general practitioners, not psychiatrists, write most of the prescriptions.

Often they must do so after rushed visits with patients they don’t know very well; who frequently present on one of the worst days of their lives; with nonspecific symptoms of stress, depression, or anxiety. The quickest way to get a worried patient out of the consulting room is to write a prescription.

Research has shown that between one-third and one-half of patients taking antidepressants long-term have no evidence-based reason to be using them. Frances said there are two reasons patients stay on antidepressants who don’t really need them. The first is because of misattribution. Someone who feels better after starting antidepressants will likely assume the pills caused the improvement—not realizing that most mild symptoms are stress-related and are likely to go away on their own. “Stopping pills that never were, or are no longer, necessary is hard to do once the person believes they have worked.”

The second reason people stay on antidepressants long-term is because of the withdrawal symptoms that occur when these medications are stopped too abruptly, after prolonged use and at higher doses. These symptoms can include: lethargy, sadness, anxiety, irritability, trouble concentrating, sleep problems, nightmares, nausea, dizziness, and strange sensations, like brain zaps. They can also continue for a long time. Frances cited a report to the All-Party Parliamentary Group for Prescribed Drug Dependence, which said:

The available research shows that antidepressant withdrawal reactions are widespread, with incidence rates (i.e. the percentage of antidepressant users experiencing withdrawal) ranging from 27% to 86%, and with nearly half of those experiencing withdrawal describing these reactions as severe. Available research also indicates that withdrawal effects are not ‘self-limiting’ (i.e. typically resolving between 1-2 weeks). Rather, between approx. 25% of users experience AD withdrawal reactions (such as raised anxiety) for at least 3 months after cessation, with many experiencing AD withdrawal for longer than 6 months.

Another Psychology Today article titled, “An Epidemic of Antidepressants,” said the beneficial evidence for antidepressants was ambiguous and there is increasing evidence that their risks have been underestimated. The author suggested the fundamental reason why antidepressants are so widely prescribed is that they fit the ‘medical model’ of mental illness, now the standard view in western culture.

This model sees depression as a medical condition which can be “fixed” in the same way as a physical injury or illness. In a more general way, this fits with our culture’s materialistic assumption that the mind is just a product of the brain, and our mental functioning can be entirely explained in terms of neurological factors.

This is a simplistic and dangerous way of viewing depression, which the overuse of antidepressants shows. Noted by the author, there are many other contributing factors to depression, such as: an unsatisfactory social environment, relationship problems, the frustration of basic needs (for self-esteem, belonging, or self-actualization), a lack of meaning and purpose in life, oppression or unfair treatment, negative or self-critical thinking patterns (related to low self-esteem), a lack of contact with nature, poor diet, and more.

Lack of Evidence for Antidepressants

As it turns out, the evidence for the effectiveness of antidepressants seems to have been exaggerated. In 2018 a study published by the University of Oxford reviewed over 500 international trials and found a consistent benefit of antidepressants to placebos. However, the study used the Hamilton Depression Scale on which participants overall score can range from 0 to 52. Antidepressants only reduced the severity of depression an average of less than 2 points, which is not clinically relevant. See “The Lancet Story on Antidepressants, Part 2” for more on this.

A 2008 meta-analysis by Irving Kirsch showed no significant difference between leading antidepressants and placebos. The findings of this study have been reproduced several times, and cannot be easily dismissed. He found that 82% of the response to antidepressants was due to placebo. See “Listening to Antidepressants” and “Dirty Little Secret” for more on Irving Kirsch and his research.

Researchers who analyzed the data for all randomized placebo-controlled depression drug clinical trials submitted to the FDA found that almost half (49%) had no significant improvement over inert placebos. Whether the studies were published and how the results were reported were strongly related to their overall outcomes. Of the 36 studies whose results were negative or questionable, only 3 were published as not positive. Twenty-two were not published and 11 (in the opinion of the researchers) were published as having positive results, when the FDA thought their finding were negative.

The evidence for the benefits of antidepressants is ambiguous, while their risks have been minimized. “It is well known that SSRIs may have some significant side effects, such as fatigue, weight gain, emotional flatness, loss of libido, insomnia, and agitation.” This raises the question of whether the continued use of antidepressants is worth the risks for the vast majority of those who use them.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Category Archives: Counseling Issues