Category Archives: Counseling Issues

09/12/23

Bad Things Could Happen with ADHD and the Adderall Shortage

In case you didn’t know, the U.S. has been in the midst of an Adderall shortage since October of 2022 when the FDA announced a shortage of the immediate release formulation. At the time, the FDA said some manufacturers having intermittent manufacturing delays, while others reported they could not meet the increased demand. The agency said it has posted information on the shortage and a list of current manufacturers that are still available, and will continue monitor supply and assist manufacturers “with anything needed to resolve the shortage.” But the shortage problem was still with us.

Kate Underwood reported in Green Matters that as of June 2023, the FDA’s Drug Shortages still listed Adderall as a current shortage. While manufacturing disruptions are the typical issues leading to drug shortages, other concerns such as increased demand for the drug, and shortages of the active ingredient or supplies can also occur. Additionally, drug manufacturers don’t usually make a single drug. So, increasing the production of a drug in short supply could negatively impact the availability of other drugs made in the same facility.

Writing for Vox, Dylan Scott added another factor to the Adderall shortage—it is a stimulant drug with the potential for misuse or addiction. The DEA lists Adderall and other stimulant-based ADHD medications as Schedule II drugs, meaning they are considered to have the same addictive potential as many opioids. “The fear is that Adderall would follow the same path as opioid painkillers: careless overprescribing would lead to an epidemic of drug addiction — this time, to stimulants.”

One of the active ingredients in Adderall is amphetamine, and therefore the drug is regulated as a controlled substance under federal law. Its potential for abuse has long been recognized, with the cliche example being college students taking the drug to help them study. A 2018 study by federal researchers found that about 5 million Americans misused a prescribed stimulant, of which Adderall is the most common, at least once in the past year; about 400,000 misused stimulant drugs frequently enough to be characterized as having a disorder. (About 2.7 million people in the US report they have an opioid use disorder.)

Medical News Today described the medical uses, side effects and misuse of amphetamines. The opening sentence on the page says, “Amphetamine is a powerful stimulator of the central nervous system. It is used to treat some medical conditions, but is also highly addictive, with a history of abuse.” Amphetamines are used today to treat ADHD. In the past it has been used to treat narcolepsy, but concerns with side effects have led to it being increasingly replaced by modafinil.

Physical side effects can include low or high blood pressure, erectile dysfunction, rapid heart rate, blurred vision, dry mouth, tics, nosebleed, and others. Psychological effects may include apprehension, anxiety, irritability and restlessness, mood swings, insomnia, obsessive behaviors and grandiosity, or an exaggerated sense of one’s own importance. “In rare cases, psychosis may occur.”

When used as a recreational drug it can speed up reaction times, increase muscle strength and reduce fatigue. A methamphetamine called Pervitin was used by Hitler’s forces for these benefits during WW II; see “Repeating Past Mistakes.”

The DEA Drug Fact Sheet said the following about amphetamines:

The effects of amphetamines are similar to cocaine, but their onset is slower and their duration is longer. In contrast to cocaine, which is quickly removed from the brain and is almost completely metabolized, methamphetamine remains in the central nervous system longer, and a larger percentage of the drug remains unchanged in the body, producing prolonged stimulant effects.

Chronic abuse produces a psychosis that resembles schizophrenia and is characterized by paranoia, picking at the skin, preoccupation with one’s own thoughts, and auditory and visual hallucinations. Violent and erratic behavior is frequently seen among chronic users of amphetamines.

In order to mitigate the potential for abuse, the DEA sets production limits for the manufacturers of Adderall and its generic competitors. In 2019 the DEA announced it was permitting more production of Adderall, but we still don’t know exactly how much production has been authorized or what limits have been set for individual companies. “We don’t know which company gets how much.” Some companies say they are short, but the DEA replies they haven’t used all their supply, so there’s back-and-forth finger-pointing going on. Listen to the On Point program, “What’s behind the ADHD drug shortage” to hear more discussion of this issue.

However, there also seems to a problem that stems from the opioid crisis. In 2021 there was a settlement with the three largest drug distributors that “flag and sometimes block” pharmacies’ orders of controlled substances like Adderall when they exceed a certain threshold. Bloomberg reported that pharmacists said it restricts their ability to fill many different types of controlled substances in addition to opioids. The rules force some independent pharmacists to use creative workarounds. “Sometimes, they must send patients on frustrating journeys to find pharmacies that haven’t yet exceeded their caps in order to buy prescribed medicines.”

This was illustrated in an article for STAT, written by a “biopharma supply chain specialist” who can’t find the Adderall she’s prescribed. She said she’s been using Adderall for ten years to help her function. Then in February of 2023, she was unable to fill her prescription at the pharmacy down the street. She finally was able to fill it at the 20th pharmacy she called, although it meant a 50-minute drive. She recommended several steps to increase the transparency in the supply chain of Adderall. “This will foster efficiency, reliability, and the ability to identify potential risks before they spiral out of control, as has happened now with not just Adderall but other ADHD medications.”

Money making considerations are also involved in the Adderall shortage. Vox reported that after Adderall was approved in 1996, it quickly became the most commonly prescribed treatment for ADHD, although Ritalin and other drugs are still used. PsychCentral listed Adderall as the fourth most prescribed psychiatric medications, with 26.24 million prescriptions in 2020. Other medications prescribed to treat ADHD within the top 25 most prescribed drugs included: Concerta (10th), Vyvanse (20th), and Focalin (24th). Three of the most expensive medications, making the most money for their manufacturers were Concerta ($3.28 billion), Vyvanse ($3.01 billion), and Adderall ($2.35 billion). ADHD prescriptions accounted for over a third of the prescriptions in 2020.

Axios reported some different statistics for both generic and branded Adderall prescriptions, according to IQVIA, a health research firm. Since 2017, IQVIA reported Adderall prescriptions rose from 32.2 million to 41.4 million. This was up more than 10% from 2020. See the following graph taken from the Axios article.

Axios said prescriptions skyrocketed as it became significantly easier to get a diagnosis of ADHD and a prescription for Adderall during the pandemic. A wave of telemedicine startups emerged on TikTok and Instagram, suggesting people should look into ADHD medication if they felt distracted. The Wall Street Journal reported some startups diagnosed people with ADHD and prescribed stimulants after 30-minute video calls — “entirely remotely, and much faster than a typical diagnosis from an in-person psychiatrist.” The trouble with rapid diagnoses is it can be difficult to tell whether the problem is actually ADHD. “Anxiety can present as ADHD, and depression can present as ADHD.”

This spike in diagnoses raises questions about whether ADHD is being over-diagnosed, but that’s really a question that predates the pandemic. See (“The Tip of the ADHD Iceberg” and “National ADHD Epidemic”) for more information. If supply can’t keep up with demand, experts are warning we could have a public health crisis. Even worse, we could face another movement of people from the pharmaceutical market to the illicit drug market, as what happened with opioids. Leo Beletsky, an epidemiologist at Northwestern University said, “Lots of bad things can happen. … Conditions are very much ripe for that to happen here.”

Overdiagnosis of ADHD

In “Twenty-Year Trend in Diagnosed Attention-Deficit/Hyperactivity Disorder”, Xu et al estimated the prevalence of diagnosed ADHD among US children and adolescents from 1997 to 2016. They estimated the prevalence of diagnosed ADHD among US children and adolescents was 10.2% in 2016. There was a consistent upward trend across subgroups by age, sex, race/ethnicity, family income, and geographic regions. “These findings indicate a continuous increase in the prevalence of diagnosed ADHD among US children and adolescents.” They said the common perception that ADHD overdiagnosed in the US was not supported by the scientific evidence. But that is not the end of the matter.

A 2021 study by Kazda et al, “Overdiagnosis of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents” said that questioning the appropriateness of ADHD diagnosis has grown along with the diagnosis rates. They acknowledged that disagreement continues about how much of the increased diagnoses can be attributed to true increases in frequency, improved detection or diagnostic inflation because of misdiagnosis and/or overdiagnosis. They systematically reviewed the research literature to identify and appraise any evidence of overdiagnosis of ADHD in children and adolescents. They found evidence of overdiagnosis and overtreatment of ADHD.

Of the 12,267 potentially relevant studies retrieved, 334 (2.7%) were included. Of the 334 studies, 61 (18.3%) were secondary and 273 (81.7%) were primary research articles. Substantial evidence of a reservoir of ADHD was found in 104 studies, providing a potential for diagnoses to increase (question 1). Evidence that actual ADHD diagnosis had increased was found in 45 studies (question 2). Twenty-five studies showed that these additional cases may be on the milder end of the ADHD spectrum (question 3), and 83 studies showed that pharmacological treatment of ADHD was increasing (question 4). A total of 151 studies reported on outcomes of diagnosis and pharmacological treatment (question 5). However, only 5 studies evaluated the critical issue of benefits and harms among the additional, milder cases. These studies supported a hypothesis of diminishing returns in which the harms may outweigh the benefits for youths with milder symptoms.

They recommended that practitioners, parents and teachers carefully weigh the potential benefits and harms that can go along with ADHD diagnosis and treatment, particularly when individuals with milder symptoms are identified. “For this group, the benefits of diagnosis and treatment may be considerably reduced or outweighed by harms.”

In his review of the study for Mad in America, Peter Simons said “Each [of the 334 included studies] provided data on at least one of the five conditions. They found that all five conditions were supported by the research.” There was also significant evidence of harm after diagnosis, including how a biomedical view of difficulties was associated with disempowerment. He said the researchers warned that diagnosis “can also deflect from other underlying individual, social, or systemic problems.”

Because there is no biological test for ADHD, and the diagnosis is applied subjectively across age, gender, race, and socioeconomic status, there is room for the diagnosis to expand. Additionally, as the diagnostic criteria are loosened, rates of ADHD have increased. The researchers confirmed that a large proportion of the new cases are on the “mild” end of the spectrum. Rates of stimulant treatment for ADHD have also increased, including those with “mild” or “subclinical” ADHD.

In his book, Saving Normal, Allen Frances, a psychiatrist and the former chair for the DSM-IV, said in retrospect, he wishes there had been cautions in the DSM-IV about overdiagnosis and tips to avoid it. He thought they missed the boat. “No one dreamed that drug company advertising would explode three years after the publication of the DSM-IV or that there would be the huge epidemics of ADHD, autism, and bipolar disorder—and therefore no one felt any urgency to prevent them.” For more on the DSM and overdiagnosis, see “Guild Interests Behind DSM Diagnosis.”

The Demedicalization of ADHD

Not only does it seem ADHD is overdiagnosed, there are some researchers who question whether the diagnosis of ADHD meets the criteria for a disorder set out in the manual used by the medical and psychiatric fields. Freedman and Honkasilta argued that the definition of ADHD relies on subjective cultural values to define “abnormal” behavior. Reviewing their study for Mad in America, Peter Simons said, “The diagnosis thus fails to meet the criteria, as stated in the DSM, that disorders must not be reducible to behavior that violates social norms.” The researchers argued that ADHD should be demedicalized and removed from the DSM, like homosexuality was in 1980.

The British Child and Adolescent Psychiatrist Sami Timimi said in his 2017 article, “Non-diagnostic based approaches to helping children who could be labeled ADHD and their families” that it required little intellectual effort to conclude that the concept and definition of ADHD “is replete with problems around reliability and validity.” The diagnostic guidelines note how ADHD behaviors may be minimal or absent in several settings. These include when the person in under close supervision, engaged in an activity that is particularly interesting to them or in a new, novel setting. Even if a genetic basis for ADHD were found, we’d still have to ask why such behaviors should be treated as disorder rather than differences. “Deciding where to draw the line between what we consider part of the “ordinary” spectrum of behaviours and what we decide is “pathological” is more dependent on cultural than scientific processes.”

He said if he asked the question, “what is ADHD?”, it is not possible for him to reply by referring to a particular known pathological abnormality. Instead, he would have to provide a description ADHD as the presence behaviors like of hyperactivity, impulsivity and poor attention. This was contrasted with answering the question, “what is diabetes?” “Diagnosis in that context sits in a “technical” explanatory framework. In psychiatry what we are calling diagnosis (such as ADHD) will only describe but is unable to explain.”

Timimi concluded that ADHD is then not a medical diagnosis, but rather a descriptive classification. And since it is not a medical diagnosis, “it is not surprising that there has been a failure to find any specific and/or characteristic biological abnormality such as characteristic neuroanatomical, genetic or neurotransmitter abnormalities.” He thought the idea of ADHD as a medical diagnosis was past its use-by date and should be discarded.

ADHD is a cultural construct. It is often argued that the use of categorical constructs like ADHD enables the study of aetiology, treatment and prognosis. Evidence outlined above demonstrates that far from enabling any advancement of knowledge or clinical practice, it has created an illusion of progress and resulted in exposure of possibly millions of children and young people to unnecessary and potentially harmful medications. It has spurred on liberal use of stimulant medication, despite the lack of evidence for improved long term outcomes resulting from this.

We are not at the cultural crossroads with ADHD today that we were with homosexuality in 1980. ADHD will likely continue to be a diagnosable disorder. Yet serious consideration of the above discussion of its overdiagnosis, its future demedicalization and removal from the DSM as a disorder and the lack of improvement in long-term outcomes of individuals taking ADHD prescribed stimulants should be done. In retrospect, the Adderall shortage may not truly be the serious public health crisis that is getting all the press coverage. But if it leads people from the pharmaceutical market to the illicit drug market in search of their amphetamines to help them function, like the person in the STAT article, “Lots of bad things can happen.”

07/18/23

Repeating Past Mistakes with Esketamine

image by Owensart from Pixabay

Ketamine has been touted as effective treatment for depression. A recent study by Anand et al said ketamine was “noninferior” to ECT as therapy for treatment-resistant depression without psychosis. Commenting for Medpage Today, the lead author said it was surprising that ketamine was at least at least effective as ECT, which he said is the gold standard for treatment resistant depression. Commenting on the study, Robert Freedman, MD, said it was noteworthy that all the patients considered for the study were initially referred to ECT because it was thought that ECT was their best option. But he thought the results were not life-changing: “Ketamine treatment was effective, but by 6 months, a brief period in a lifetime of depression, the quality of life was no better with the agent than with ECT.”

A longer duration of treatment increases the likelihood of both drug dependence and cognitive adverse effects, including dissociation, paranoia, and other psychotic symptoms. ECT clinics have informed consent documents that list the various cognitive and other adverse effects of that treatment. A similar informed consent document for ketamine should caution patients and clinicians that temporary relief may come with longer-term costs.

Ketamine is a psychoactive substance that makes the “gold standard” of a double-blind research methodology (neither the participants nor the researchers know which treatment participants are receiving) difficult to implement. In a new study that has not yet been peer-reviewed, Lii et al gave volunteers with mild to moderate depression ketamine while they were preparing to go under general anesthesia, essentially blinding them to the psychedelic or dissociative effects. 38.6% guessed their assignment correctly—no better than chance—indicating the anesthesia had masked the drug’s dissociative effects.

Reviewing the study for Science, Claudia Lopez Lloreda reported both groups experienced a 15-point drop in their depression scores. About 40% of the participants still had more than a 12-point decrease 3 days after the ketamine infusion, “meaning they are in remission for their depression.” That improvement was similar to the antidepressant effects of ketamine in other studies. But the doses of anesthesia used in Lii et al were much lower than that used in the other antidepression studies.

All of this suggests that neither ketamine nor the anesthesia by themselves may do much to alleviate depression, says Theresa Lii, an anesthesiologist at Stanford and co-author of the study. Instead, simply going through the complex, orderly treatment procedure itself—during which participants receive attention and one-on-one interactions with doctors and psychiatrists—benefits people. By merely participating in this trial, she says, participants in both the ketamine and placebo groups may have created an expectation that they were going to get better—and they did.

Peter Simons, who reviewed the study for Mad in America, pointed out that on the secondary outcome measure of the study, by day 3 of the follow up, both the ketamine treatment group and the placebo group had a 40% remission rate. “By the end of a week, the placebo group had 57.9% of patients in remission, compared to just 31.6% of those who received ketamine.” After two weeks, the placebo group was still doing better. The researchers suggested the placebo effect may be responsible for supposed powerful antidepressant effects of ketamine. Quoting from the Conclusion of the >Lii et al study,

Secondary and exploratory outcomes also found no evidence of benefit for ketamine over placebo. These findings differ from those of prior antidepressant trials with ketamine conducted without adequate masking, where the large effect sizes reported may reflect expectancy bias [placebo effect]. Our results suggest that ketamine may actually be ineffective for the short-term treatment of MDD.

Introducing Ketamine’s Chemical Cousin: Esketamine

Mark Horowitz and Joanna Moncrieff asked, “Are we repeating mistakes of the past?” in their article for The British Journal of Psychiatry. They were primarily concerned with esketamine, a chemical cousin of ketamine, but they began with a summary of what is known about ketamine which has been licensed as an anaesthetic for five decades. They noted patients often report several unusual symptoms when recovering from ketamine anaesthesia, including delusions, hallucinations delirium and confusion; sometimes ‘out of body’ experiences. It commonly elevates blood pressure and heart rate, and has been associated with fatal heart failure and myocardial infarction as well as stroke and cerebral hemorrhage.

Used recreationally since the 1970s, ketamine or ‘special K’ produces a dissociative state characterized by a sense of detachment often referred to as the ‘K-hole.’ See “Falling Down the K-Hole.” It’s also addictive, quickly inducing tolerance. “Stopping regular use causes a withdrawal syndrome characterised by anxiety, dysphoria and depression, shaking, sweating and palpitations, and craving the drug.” The way it produces its psychoactive and addictive effects is not entirely clear.

Intravenous ketamine was shown to have “rapid-onset antidepressant effects” in as little as 2 hours. While some researchers have claimed it leads to a genuine, long-lasting antidepressant effect, this has not been established in randomized trials. Since ketamine was already licensed for use, Janssen applied to license one of its enantiomers, (S)-ketamine or esketamine, which is more potent than ketamine. After their application was approved, Janssen received patent exclusivity on the new drug application for several years; and the profit from that approval. See the following graphic, taken from Bloomberg Businessweek comparing ketamine and esketamine.

The FDA normally requires two positive efficacy trials to license a drug, showing a statistically significant difference between esketamine and placebo. But Janssen only had one trial that was statistically significant. The three efficacy trials lasted 4 weeks, shorter than the 6 to 8-week trials the FDA usually requires for drug licensing. Janssen also defined “treatment resistant depression” in a fuzzy way that included many current antidepressant users. Participants with treatment resistant depression could be those who had “failed” with two different antidepressants.

The only positive study wasn’t really that positive. It found a difference of 4 points on the Montgomery-Asberg Depression Rating Scale (MADRS) that favored esketamine over an inert placebo. This difference corresponded to less than minimal change (a reduction of 7-9 points on the MADRS); and was one-quarter the size of the placebo response. Participants were also unmasked/unblinded by the noticeable psychoactive effects of esketamine inflating the apparent difference between esketamine and placebo.

The FDA then allowed Janssen to submit the results of a discontinuation trial as evidence of efficacy. The study design was problematical as an efficacy trial because withdrawal effects from esketamine can be mistaken for relapse of depression. Ketamine is recognized as having withdrawal effects and both ketamine and esketamine are Schedule III Controlled Substances. Yet the study report suggested there were no evidence of a withdrawal syndrome on the Physician Withdrawal Checklist. It was not clear how items on the checklist were distinguished from identical items in the MADRS.

As half (48.7%) of relapses occurred in the first 4 weeks following esketamine cessation, the time most likely for withdrawal effects to occur, and as the relapse rate in the placebo group became ‘closer to esketamine with each week’, as highlighted by the FDA, confounding of ‘relapse’ by withdrawal seems likely.

The FDA also noted a concern that the positive results were driven by a single site in Poland. There was a 100% relapse rate in the placebo group, compared with a 33% relapse rate in all the other sites. “It has been demonstrated that if this outlier site is excluded there is no difference between esketamine and placebo (the P-value changes from 0.012 to 0.48), leading to the conclusion that the findings are ‘not robust’.”

There was also disturbing evidence with how the FDA rationalized data on six reported deaths during the licensing trials. There were three suicides occurring after the participant’s last dose of esketamine. The FDA attributed these deaths to “the severity of the patients’ underlying illness.” Yet two of the participants had no indication of suicidal ideation during the study, either at entry or the last visit. Data was not available for the third participant.

Others have argued that these cases might fit with a pattern of a severe withdrawal reaction, consistent with other reports of suicide associated with recreational ketamine, and are significant enough in number to constitute a worrying signal.

An increase in depression and suicidality was also observed during esketamine treatment. Six participants in the esketamine group of the short-term trials became more depressed, compared to only one in the placebo group. Five participants expressed increased suicidal ideation in the esketamine group, compared to two in the placebo group. Paradoxically, Janssen sought and received an expansion of the use of esketamine to include acutely suicidal patients. See “Doublethink With Spravato?”

Horowitz and Moncrieff concluded that history is repeating itself: “A known drug of misuse, associated with significant harm, is increasingly promoted despite scant evidence of efficacy and without adequate long-term safety studies.” But they are not the only individuals concerned with the potential problems with esketamine-related adverse events. Gastalon et al analyzed adverse events (AEs) reported in the FDA Adverse Event Reporting system (FAERS) between March 2019 and March 2020. They found 962 registered reports of esketamine-related AEs in one year, reinforcing worries regarding the safety and acceptability of esketamine. Signals (i.e., statistically significant disproportionality) were detected for disassociation, sedation, feeling drunk, suicidal ideation and completed suicide.

When the trials submitted to the FDA are examined, serious questions with regard to the approval process of esketamine can be raised. The post approval assessment of FAERS data seems to indicate that this sloppy process set up a post marketing examination of the real-world safety and acceptability of esketamine. And it seems Horowitz and Moncrieff legitimately asked if we were repeating with esketamine the past mistakes made with ketamine.

This is the latest of several previous articles I’ve written about my concerns with using ketamine and esketamine to treat depression. In addition to the above-linked articles see “Esketamine Craze,” “In Search of a Disorder for Ketamine,” “Hype and Concern with Esketamine,” “Evaluating the Risks with Esketamine,” “Safety Concerns with Esketamine” and more on my website: Faith Seeking Understanding.

06/13/23

Overdiagnosing Depression with the PHQ

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According to PsychCentral, in 2020 there were more than 252 million prescriptions prescribed for mental health conditions. The total cost spent on psychiatric medications was more than $15.6 trillion. Zoloft (sertraline) was the most prescribed psychiatric medication with 38.22 million prescriptions, but only made Pfizer $523 million. This is because Pfizer’s patent on Zoloft expired in June of 2006. In its last full year of patent exclusivity, Pfizer’s sales for Zoloft totaled $3.3 billion. And it seems Zoloft’s popularity as an antidepressant can be credited at least in part to the introduction of the Patient Health Questionnaire (PHQ-9), which was developed by Pfizer shortly after Zoloft came on the market.

Writing for Insider, Hilary Bruek said Pfizer was persuaded to invest in the research necessary to develop what became the PHQ-9 by Howard Kroplick, one of their marketers. Kroplick told STAT: “It wouldn’t have happened if it wasn’t for me.” The PHQ-9 became a quick and easy tool that made many primary care doctors more comfortable prescribing antidepressants. Once Pfizer decided to underwrite the development of the PHQ-9, they contracted with Robert Spitzer and his wife Janet Williams, who were central figures in the revisions of the DSM-III.

In September of 2001, Kurt Kroenke, Robert Spitzer and Janet Williams published “The PHQ-9” in the Journal of General Medicine. The authors thought brief measures like the PHQ-9 were more likely to be used in the busy setting of primary care clinical practice. “Brevity coupled with its construct and criterion validity makes the PHQ-9 an attractive, dual-purpose instrument for making diagnoses and assessing severity of depressive disorders.” Note that the creators of the nine item PHQ-9 thought it could be used to diagnose depression. STAT reported the PHQ-9 has become an omnipresent tool, being cited in more than 11,000 scientific papers and routinely used in primary care and other routine visits.

Prescribing antidepressants in primary care based upon a PHQ-9 score of 10 or greater appears to be a sensible medical decision. There have been multiple studies such as Moriarty et al in General Hospital Psychiatry, that find the cutoff point of 10 on the PHQ-9 to have “acceptable diagnostic properties” for major depression. Studies, such as Negeri et al in the BMJ find the PHQ-9 has a combined sensitivity of 85% at the standard cutoff value of ≥10. A referral to a psychiatrist to confirm a depression diagnosis means a delay in treatment, meaning a delay in prescribing an antidepressant. Why not just recommend to the patient that they try a SSRI if their PHQ-9 score is equal to or greater than 10?

Malpass et al noted their concern that self-administered questionnaires like the PHQ-9 were regularly used in clinical practice to guide prescribing or to measure recovery and response to treatment. They thought when patients were given the PHQ-9, they were not interpreting the question items in the same way. They used a research technique called cognitive interviewing to identify ‘interpretive measurement error’ (IME). They found a wide range of comprehension and answer-mapping difficulties on the PHQ-9 that persisted over time.

Clinicians have expressed uncertainty about the PHQ-9’s validity and utility, and in the management and diagnosis of depression within primary care have a strong preference for clinical judgement over scores on severity measures. In light of the numerous ways the PHQ-9 may be missing the presence and/or intensity of certain symptoms that are meaningful to patients, clinicians should continue to adopt caution when using and interpreting questionnaire scores. The study raises the question that longer assessments may be better in providing opportunities for distinguishing frequency and severity.

Writing for Mad in America, Peter Simons commented on a meta-analysis study by researchers in the Journal of Epidemiology that concluded the PHQ-9 did not accurately estimate the prevalence of depression. The researchers concluded that that the PHQ-9 “substantially overestimates depression prevalence. There is too much heterogeneity to correct statistically in individual studies.” Simons said they found it was twice as likely to diagnose depression as the SCID, a semi-structured interview guide for making diagnoses according to the diagnostic criteria published in the DSM. 24.6% of participants in the study were found to be depressed by the PHQ-9, while only 12.1% met the criteria for depression on the SCID.

In primary care settings doctors will likely consider a positive score of ten or higher (the standard cut-off for depression screening with the PHQ-9) as indicating the presence of depression and consider it good enough to diagnose patients with depression and recommend antidepressant treatment. “This could lead to massive inflation of the estimates of how many people ‘have’ depression in the population.” The PHQ-9 is technically not a diagnostic measure of depression (despite what its creators said), but when it is used that way, the result is overdiagnosis.

Estimates of depression prevalence should be based on validated diagnostic interviews designed for determining case status; users should evaluate published reports of depression prevalence to ensure that they are based on methods intended to classify major depression.

The bottom line is that when screening tools like the PHQ-9 are used alone to assess depression in a person, clinicians are likely to misdiagnose it. And there are additional problems if the misdiagnosed person begins using an antidepressant to “treat” this so-called depression.

The general public widely believes depression is the result of a chemical imbalance, which shapes how people understand their moods. It may also discourage them from discontinuing a prescribed antidepressant medication, potentially leading to lifelong dependence on these drugs. An umbrella study by Moncrieff et al found “there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.” The researchers said most studies did not find evidence of reduced serotonin activity in people with depression when they were compared to people without depression. The chemical imbalance theory of depression is now seen as an urban legend, “never a theory seriously propounded by well-informed psychiatrists,” according to pro-medication psychiatrist Ronald Pies.

Moncrieff and others have also noted there are adverse effects from taking antidepressants. In “Persistent adverse effects of antidepressants, she said we are not clear about the nature of the neurochemical and physiological changes that occur when we take an antidepressant. “We are even less certain about how the body, including the brain, adapts to the long-term presence of these drugs.” We also do not know whether the changes produced by the drugs in the brain return to normal when the drugs are stopped; or if the changes persist.

Moncrieff then pointed to the withdrawal effects with long-term antidepressant use. She said the evidence suggests a picture similar to benzodiazepine withdrawal. There is a range of duration and intensity, where not everyone experiences noticeable or debilitating symptoms, but there are numerous reports of “withdrawal symptoms being severe and protracted.”

Moncrieff also referred to a 2006 article by David Healy and others that associated antidepressants and violence in some individuals. Healy said mechanisms that linked antidepressant treatment (rather than the depression itself) to violent behavior included akathisia, emotional disinhibition, emotional blunting, and manic or psychotic reactions. “There is good evidence that antidepressant treatment can induce problems such as these and a prima facie case that akathisia, emotional blunting, and manic or psychotic reactions might lead to violence.”

A group of researchers from the Nordic Cochrane Center in Denmark, including Peter Gøtzsche, published a meta-analysis in 2016 that confirmed Healy et al’s findings, according to Moncrieff. They found the risk of aggressive behavior doubled with the use of antidepressants. They also said akathisia was under-reported. Although akathisia occurred more often with study participants who used antidepressants, the difference was not significant. While they found no significant differences in mortality or suicidality, “our data confirmed the increased risk of suicide in children and adolescents.”

A 2016 literature review of long-term newer antidepressant use (SSRIs and SNRIs) by Carvalho et al noted over 12 adverse effects from antidepressants, that included weight gain, bleeding, sleep disturbance, diabetes, osteoporosis and others. The findings of this review suggest that long-term treatment with SSRIs and SNRIs “should be avoided if alternative treatments are available.” The authors noted there is a tendency to extend antidepressant treatment for long periods of time, believing that it protects against recurrence. However, that was not true in all cases. “This finding indicates that in patients with chronic recurring MDD, recurrences are difficult to prevent with [antidepressant] use only.”

It seems that the PHQ-9 depression scale has contributed to the overdiagnosis of depression and the overuse of antidepressants. One might even suggest this was exactly what it was developed to do. The PHQ-9 helped Pfizer (and eventually other pharmaceutical drug companies) reach into the untapped market of primary care physicians and gave them a tool they felt comfortable using in order to prescribe antidepressants to their patients. Unfortunately for the PHQ-9, the evidence that antidepressants have limited efficacy and multiple adverse side effects is growing.

04/11/23

Guild Interests Behind DSM Diagnosis

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Now in its 5th edition, the DSM-5-TR, the text revision of the Diagnostic and Statistical Manual, was released in March of 2022. This happened to be the first update in almost ten years and it’s selling very well for the APA, the American Psychiatric Association. The paperback version, as well as the hardback and desk reference editions, are the top four best sellers in psychiatry for Amazon. Saul Levin, the CEO and medical director for the APA told Axios that the public has been dying to know more about mental illness. “I think what really caught the imagination was that we’re sitting at home now and looking to say, ‘Boy, I’m feeling depressed — let me now go and find out more about it.'”

It’s hard to tell from this quote if Dr. Levin’s comment was a reflection of APA sales data for impulse buys for the DSM-5-TR, but I doubt it. A quick look at the Amazon prices DSM-5-TR indicates the paperback edition sells for $110.76 and the hardcover for $174.90. The desk reference editions are more affordable at $49.14 and $59.99. A better explanation for its bestselling sales is the fact that psychiatry in the U.S. and increasingly around the world has been dominated by the DSM for the past 70 years. Wired Magazine said this so-called bible for psychiatry is used in prisons, hospitals, and outpatient clinics to diagnose patients, prescribe medications, dictate future treatment and to justify payment for these services.

Axios reported how mental health has gone mainstream, with younger workers demand it as an employee benefit. Ralph Lewis, a Toronto-based psychiatrist, said in Psychology Today that psychiatry is guilty of having oversold its ability to answer the problems of coping with life and regulating one’s emotions and behaviors. Life can be stressful and complicated, leaving people with a feeling they can’t cope. “Many assume that psychiatry has the answers to problems of coping with life and regulating one’s own emotions and behaviors.” The expectations are particularly intense on psychiatrists as medical specialists “who are designated as the ultimate gatekeepers for diagnosis of mental illnesses and, more broadly, mental disorders.”

Mental disorders are, by their very nature, difficult to define with specificity. Anxiety and depression are the most common reasons for seeking psychiatric help. There is much confusion among the general public, and even often uncertainty among psychiatrists, as to when to consider these experiences mental disorders: the diagnosis depends on severity, number of associated symptoms, degree of functional impairment, and persistence or recurrence. Unfortunately, psychiatric diagnostic classification systems and mental health awareness campaigns have overgeneralized the definition of mental illness.

Dr. Lewis said the tendency now is to pathologize everyday problems, labeling them as mental disorders. Here he referenced Saving Normal, by Allen Frances, a psychiatrist and the former chair for the DSM-IV. Frances said there should have been cautions in the DSM-IV warning about overdiagnosis and providing tips on how to avoid it. Professional and public conferences, and educational campaigns should have been organized to counteract drug company propaganda.

None of this occurred to anyone at the time. No one dreamed that drug company advertising would explode three years after the publication of the DSM-IV or that there would be the huge epidemics of ADHD, autism, and bipolar disorder—and therefore no one felt any urgency to prevent them. . . We missed the boat.

See “Medieval Alchemy” for more on Allen Frances and Saving Normal.

Dr. Lewis said the COVID-19 pandemic drove up the rates of anxiety, depression and several other mental disorders. Ironically, while the data are complicated, there does not appear to have been much of a rise in the actual rate of mental disorders. What seems to have happened is people’s perception they need psychiatric treatment increased. Although some of the increase represents people now seeking help for significant problems, there is also a phenomenon of these diagnoses being sought.

A diagnosis offers a person an explanation for their difficulties. It lets a person feel understood. It simplifies complexity, helping make sense of things and bringing a bit of order to the inexplicable and chaotic. It provides validation and legitimacy to one’s struggles, as well as sympathy, and it might offer justification for one’s shortcomings or behavioral difficulties. It also confers a sense of identity and group-belonging.

A diagnosis may deliver practical benefits such as sick leave, disability benefits, academic accommodations, and insurance coverage for therapy. Other factors include social media, the internet, and celebrity influence—think about the attention paid to Simone Biles when she withdrew from several events at the 2020 Summer Olympics. And don’t forget about pharmaceutical advertising—just ask your doctor. “In many ways, what we are witnessing is the success of, and unintended consequences of, years of mental health education and destigmatization campaigns.”

Not only does overdiagnosis lead to over-prescribing medications, it also trivializes severe mental illness. The CDC said more than 50% of Americans will be diagnosed with a mental disorder in their lifetime. One in five will experience a mental illness in a given year. “If everyone has a mental disorder, then no one does, and the concept of mental disorder becomes meaningless. It becomes harder for the people most in need of psychiatric services to access the already overloaded system.”

The CDC also stated there was no single cause for mental illness. Early adverse life experiences, the use of alcohol or drugs, feelings of loneliness or isolation as well as biological factors or ongoing chronic medical conditions like cancer or diabetes can contribute to the risk of mental illness. But psychiatry continues to press for the medical model of mental illness and it seems defending the legitimacy of DSM diagnosis goes along with it. This debate has continued without any real movement towards a resolution for the last fifty years.

Dr. Daniel Morehead lamented in “The DSM: Diagnostic Manual or Diabolical Manipulation?” that it would be hard to overstate the torrents of criticism because of the DSM. He said, “The DSM has been, and remains, the centerpiece of contemporary critiques of psychiatry.” Critics of the DSM were wrong. Psychiatry is not at odds with other medical specialties. “Psychiatry differs from them only in the sense that more of the diseases behind psychiatric syndromes lack full explication.”

This is not evidence of its inferiority, according to Morehead, rather it is evidence of the complexity of the human brain. The DSM is “simply the place where clinicians match diseases to treatments through the lens of medical syndromes—just like other doctors.” This seems to be the heart of the debate and the reason for the vigor with which psychiatrists like Dr. Morehead defend the medical basis of psychiatry and psychiatric diagnosis. In another article published around the same time, “Let’s End the Destructive Habit of Doubting Psychiatric Illness,” he said it is time to permanently retire the idea that mental illness may not be fully medical. It is a “pernicious and misleading idea” and he challenged all psychiatrists to no longer tolerate it—publicly or privately.

Dr. Morehead and others appear to recognize that psychiatry is facing an institutional crisis unlike anything it faced since David Rosenhan published “Being Sane in Insane Places” in the journal Science in 1973. Rosenhan has eight “pseudopatients” seek admission to twelve different psychiatric hospitals. Once admitted, they stopped simulating any symptoms of abnormality and waited to see how long it took before they were released. Their length of stay ranged from 7 to 52 days, with an average length of stay at 19 days. None of the pseudopatients were identified as such by hospital staff members; but other patients did.

For more on the Rosenhan study, see “A Censored Story of Psychiatry,” Part 1 and Part 2.

In their book, Psychiatry Under the Influence, Robert Whitaker and Lisa Cosgrove said the trustees of the APA called a meeting shortly after Rosenhan’s article was published. They lamented how the public did not view psychiatry as a medical specialty. The trustees recommended the formation of a task force that would define mental illness and become a preamble to publish the DSM-III. And they made Robert Spitzer the chair of the task force in 1974. Whitaker and Cosgrove said from that beginning, the APA trustees saw how creating a new diagnostic manual could also serve a guild interest.

Remaking psychiatric diagnoses could be part of a larger effort by psychiatry to put forth a new image, which, metaphorically speaking, would emphasize that psychiatrists were doctors, and that they treat real “diseases.”

By adopting the disease model and asserting that psychiatric disorders were illnesses, the APA addressed both its critics and its image problem. Whitaker and Cosgrove said this happened when the organization metaphorically put on a white coat and presented itself as a medical specialty. “This was an image that resonated with the public.” With hindsight, they said, it is easy today to see the ethical peril for the APA that arose when the DSM-III was published. While the APA had devised a new diagnostic manual that helped remake its image, “the peril was that the guild interests might now affect the story it told to the public about the nature of mental disorders, and the efficacy of somatic treatments for them.”

In an interview for Medscape in 2020, the now former chair of the department of Psychiatry at Columbia and former president of the APA, Jeffery Liberman discussed “The Future of Psychiatric Diagnosis” and biomarkers with Melissa Arbuckle, also of Columbia University. She is the vice chair for education and training in the Department of Psychiatry at Columbia. Robert Spitzer, the architect of the DSM-III, was a Professor of Psychiatry at Columbia until his retirement in 2003.

Lieberman acknowledged at the start of the interview there have been no biomarkers identified yet in research. “For the entire history of our discipline, as long as physicians have studied mental illness, we have not had a diagnostic test for it. It’s a clinical diagnosis.” Nevertheless, he has faith that someday there will be a diagnostic test for mental illness: “I do believe that certainly within my professional lifetime, and hopefully sooner rather than later, we will see a diagnostic test.”

The APA self-consciously tied its fate to the DSM in the aftermath of the institutional crisis after the Rosenhan study. It seems to have done so at least partially to affirm itself as a legitimate medical specialty, with the power and authority to prescribe medications. As T. M. Luhrmann noted in Of Two Minds, “psychopharmacology is the great silent dominatrix of contemporary psychiatry.” Prescribing medications is what psychiatrists do that other mental health professionals cannot do. “And as mental health jobs become defined more by their professional specificity, more and more psychiatrists spend more of their time prescribing medication.”

The disease model of mental illness has been a tremendous asset in the fight against stigma and the fight for parity in health care coverage. And it is clear that the disease model captures a good measure of the truth. Mental illness often has an organic quality. People can’t just pull themselves back together when they are hearing voices or contemplating suicide, and their illness is rarely caused by bad parenting alone. Yet to stop at that model, to say that mental illness is nothing but disease, is like saying that an opera is nothing but musical notes. It impoverished us. It impoverishes our sense of human possibility. (Of Two Minds, p. 266)

02/7/23

Paradigm Shift Needed with Depression

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There has been a study published in Molecular Psychiatry, “The serotonin theory of depression: a systematic umbrella review of the evidence,” that debunked the chemical imbalance theory of depression. Wonder of wonders, it led to conversations in the general public about depression and the use of antidepressants. Was the theory just an urban legend, or is it just a shorthand explanation of how antidepressants work, “even if it’s not entirely accurate.” It also resulted in what seemed to be as much a personal attack to the lead author of the study, Joanna Moncrieff, by Rolling Stone: “Who Is the Psychiatrist Behind the Antidepressant Study Taking Over Right-Wing Media?”

She and the other researchers were ridiculed for doing an umbrella review of “outdated” studies. One professor of psychiatry was quoted as saying: “Wow, next she’ll tackle the discrediting of the black bile theory of depression.” The term originated in the humoral theory of Hippocratic medicine, where an excess of black bile was thought to result in a melancholic temperament and lead to symptoms of depression. This was the dominant theory for depression, or melancholia, from antiquity through the 19th century.

Responding to the Rolling Stone article on her blog, Moncrieff said ignoring her critique was no longer working. So, “champions of big Pharma and mainstream psychiatry have gone into attack mode.” In what she referred to a “a time-honoured tactic,” she described how Rolling Stone attempted to discredit her by associating her with the right-wing media coverage of their research.

The article accuses me of ‘promoting widely disputed beliefs about the dangers of various mental health interventions such as antidepressants or alternative forms of treatment’. This is not accurate. Most of the adverse effects I have highlighted in my research are widely recognised, and those that are less well-recognised (such as post SSRI sexual dysfunction- which is now recognised officially by the European Medicines Agency) have not been ‘widely disputed,’ or indeed disputed at all.

Psychiatric Times also used the black bile slur asking its physician readers what they would think if they saw the headline: “Depression Probably Not Caused by Excessive Black Bile.” The authors condescendingly said they believed that Moncrieff et al thought they were publishing something “extraordinarily newsworthy or controversial.” They concluded that “depression is a complex, heterogenous disorder with biological, psychological and sociological determinants and risk factors.” Placebo-controlled studies offered “ample evidence that serotonergic agents are safe and effective in the treatment of acute major depressive disorders.” They hoped that patients and clinicians were not deterred from using antidepressants by the review.

These ad hominem attacks were not the only coverage. On Point, a pod cast on NPR radio, featured Daniel Carlat, the chair of psychiatry at Melrose Wakefield Hospital, part of the TuftsMedicine network, Joanna Moncrieff and Anne Harrington, a professor of the history of science at Harvard University. The host for “Behind the new study changing how doctors view depression” noted while antidepressants work for some people, Pfizer and other pharmaceutical companies don’t know how they work to relieve depression symptoms, “especially SSRIs.” Meghna Chakrabarti said some studies show that as many as 85% of the public believe the chemical imbalance theory of depression. “People have been told for three decades now, that depression is due to a chemical imbalance, and that they need to take antidepressant treatment to put that imbalance right.”

The program explored the gap between what the medical community knows about antidepressants, what the public knows, and why that gap exists. Dr. Carlat said many of the studies reviewed by Moncrieff et al were ones he had read before he wrote his 2010 book, Unhinged: The Trouble with Psychiatry – a Doctor’s Revelations about a Profession in Crisis. He thought their study pulled the data together “in a nice way” that made it very clear: “People have been led to believe that there is a chemical imbalance theory of depression.” Listen to the 40-minute program to hear more from Dr. Carlat.

The overall message seems to be yes, the public believed there was a chemical imbalance theory of serotonin deficiency for depression, but that’s old news. Researchers and academic psychiatrists have never believed this urban legend. Nevertheless, antidepressants still work and are safe and effective, so don’t be deterred from using them. However, that effectiveness rate is only slightly better than a placebo in the clinical trials approved by the FDA. And that difference—around two points on the 52-point Hamilton D depression scale—is “clinically imperceptible.”

Marc Stone was the lead author of a new study published in the BMJ, the British Medical Journal, in August of 2022. He is the Deputy Director for Safety with the FDA. Irving Kirsch, the principal investigator, is the Associate Director of the Program in Placebo Studies at Harvard Medical School, noted for his work on placebo effects with antidepressants. See “Dirty Little Secret” and “Do No Harm with Antidepressants” for more on Kirsch’s work on antidepressants and placebos.

Stone et al again replicated the less-than-two-point difference between drug and placebo across all 73,388 participants. “We found a drug effect among adults equivalent to 1.82 points, with a standardized mean difference of .24.” The response distributions did not appear to be unimodal to the researchers. Further analysis of the data found the optimal model for drug and placebo responses was “a combination of three overlapping normal distributions,” which they referred to as Large responses, Minimal responses and Non-specific. About two thirds of participants had a Non-specific response; and about 15% had a substantial antidepressant effect.

Reviewing the BMJ study for Mad in America, Peter Simon said:

The drug and placebo groups both had extremely high rates of symptom improvement: 84.4% of the placebo group found their depression symptoms improved, while 88.5% of the drug group improved. However, in many cases, this “improvement” was small.

More important is the number of people who experienced a large improvement. This improvement is more likely to be clinically relevant. The researchers found that those taking the drug were more likely to experience this level of improvement—24.5% of the antidepressant group experienced large improvement, versus 9.6% of the placebo group.

Based on these numbers, there seems to be a small group—about 15% of people—who experience a large response to the drug who would not otherwise improve to this level.

Unfortunately, the researchers found no way to predict who, exactly, is in this 15%. They write that if everyone with a depression diagnosis is given an antidepressant, about seven people need to be given the drug (and thus be exposed to the harmful effects with no benefit) before one person benefits.

Only one in seven people who use antidepressants will notice a clear improvement and researchers can’t predict who those individuals will be. That means 85% of individuals using antidepressants will not have a clinically noticeable improvement. Stone et al said the effectiveness of all placebo-controlled antidepressant efficacy trials submitted to the FDA between 1979 and 2016 was 1.82 points on the HAMD17, ranging from 1.62 to 2.56. It is generally agreed that drug-placebo differences greater than 3 points are necessary for a clinician to detect a minimal improvement with a patient. See “Fighting or Fueling Suicide with Antidepressants?”

It doesn’t seem that placebo-controlled studies of antidepressants offer ample evidence that they are “safe and effective” in treating acute major depression. The findings and conclusions of “The serotonin theory of depression: a systematic umbrella review of the evidence” cannot be easily ignored or dismissed.

One final research article to consider is by Peter Sterling, a professor of Neuroscience at the Perelman School of Medicine, University of Pennsylvania. He is a self-described “hard core” neuroscientist. His article, “A Neuroscientist Evaluates the Standard Biological Model of Depression,” concluded that current evidence does not support the hypothesis that depression is “a localized, disordered neural circuit.” Neuroimaging cannot identify “the mental disturbance” we call depression; nor can it be predicted in individuals by analyzing their genetic makeup.

“Chemical imbalance” theories of depression have not been supported, thereby removing any scientific rationale for “antidepressant” drugs. The drugs are not specific but rather affect myriad neurotransmitter systems, offering little advantage for most individuals, but commonly causing long-term harm. The brain adapts to antidepressant drugs, just as it adapts to drugs of abuse, and so for both withdrawal can be extremely difficult.

Depression is far better predicted by levels of childhood trauma, life stress, and lack of social supports. Depression in individuals is significantly reduced by physical repairs to their depressed communities and by psychological repairs through shared experience of childhood trauma and chronic domestic abuse.

If researchers and academic psychiatrists never believed the chemical imbalance theory of depression, why weren’t they as assertive challenging this urban legend as they have been at minimizing the significance of “The serotonin theory of depression: a systematic umbrella review of the evidence?” Does an effectiveness rate of 15% with antidepressants justify 85%—6 of 7 who use them—receiving ineffective, marginally better treatment effectiveness than placebo? Supporters of the current paradigm of depression and its treatment dismiss or minimize evidence that challenges it. There needs to be a paradigm shift in how we think about depression and its treatment.

01/17/23

The Eye of the Beholder with Psychedelic Therapy

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Classical psychedelic drugs such as psilocybin, LSD, and mescaline were used and researched regularly in psychiatry before they were placed in Schedule I of the UN Convention in 1967 and in Schedule I of the US Controlled Substances Act in 1970. These actions legally defined these psychedelics as having no accepted medical use and a high potential for abuse. Without a clinical focus and the widespread use of LSD within the 1960s counterculture movement, research rapidly dwindled. But there has been a resurgence of clinical research interest in the use of psychedelics for psychiatric disorders such as major depression, PTSD, anxiety and addiction.

In “Psychiatry & the psychedelic drugs,” Rucker, Iliff and Nutt described clinical trials using psychedelics pre and post prohibition. They also discussed the methodological challenges of preforming good quality clinical trials, and suggested an approach to the existing legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry.

Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called ‘psychoneurotic’ disorders sometimes benefited considerably from their tendency to ‘loosen’ otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low.

The term ‘psychedelic’ was coined by Humphry Osmond in a letter he wrote to Aldous Huxley in 1956. Osmond combined two ancient Greek words, psyché, meaning soul or mind; and delein, meaning to reveal. So psychedelic means ‘soul revealing.’ The earliest direct evidence for the use of psychotropic plants dates to around 3700 BC in the northeastern region of Mexico. Carbon-dated buttons of peyote and red beans containing mescaline were found in caves used by humans for habitation. Arthur Heffter isolated mescaline from the peyote cactus in 1897.

Albert Hofmann first synthesized LSD in 1938. Coming at a time before there were effective medicinal therapies, the discovery of LSD was of interest to psychiatry. Acute LSD intoxication appeared to mimic some of the symptoms of acute psychosis and drew the research interest of Humphry Osmond. There also seemed to be an increased awareness of repressed memories and other elements of the subconscious, which suggested it could be helpful in psychotherapy. Trials in depressive, anxious, obsessive and addictive disorders in conjunction with psychologically supportive contexts reinforced that view. “By the end of the 1960s, hundreds of papers described the use of mescaline, psilocybin and (most frequently) LSD in a wide variety of clinical populations with non-psychotic mental health problems.”

The widespread use of LSD outside of the carefully orchestrated clinical and research settings and the growing reports of adverse effects when under the influence of LSD and other psychedelics led to prohibition. Medical use stopped quickly when doctors could no longer prescribe it. The following graph taken from “Psychiatry & the psychedelic drugs” depicts how the annual number of publications listed in PubMed rapidly decreased after 1968.

Recently, there have been several studies and randomized controlled trials using psychedelics with various nonpsychotic disorders. In “LSD: can psychedelics treat mental illness?,” written by Anya Borrissova for the Mental Elf blog, Borissova reviewed the findings of Fuentes et al, “Therapeutic Use of LSD in Psychiatry.” This was a systematic review of randomized-controlled clinical trials with LSD. The authors identified 11 studies that met their inclusion criteria: randomized controlled trials of LSD that involved patients with a mental illness diagnosis. The qualities of the studies was scored with the Cochrane Collaboration Risk of Bias Assessment tool.

Seven of the 11 trials had recruited individuals diagnosed with what is now referred to as alcohol use disorder (AUD), 1 for AUD or neurotic diagnosis, 1 for heroin use disorder, 1 for anxiety associated with life-threatening diseases, and 1 with a neurotic diagnosis (depression, anxiety). The publication dates ranged from 1966 to 2014, which covered several changes in how mental disorders were labeled by the four different editions of the DSM, the 2nd through the 5th. The majority of the studies had a low risk of selection, attrition detection and reporting bias, as measured by the Cochrane Collaboration Risk of Bias Assessment tool. However, five of the studies had a high risk of bias due to blinding.

With the studies of alcohol use disorder, a significant effect of LSD was observed in four studies. “However, this effect was related to quality of life and general health in some of the studies, with no clear improvements in alcohol abstinence.” While there was a substantial improvement in total abstinence for the LSD group, there were not significant differences in the global adjustment scale. With regard to the two studies of neurotic symptoms, one study showed statistically significant improvement in symptoms at 6-8 weeks in most measurements. But it failed to reach statistical significance in six months, although all groups showed significant differences in a large number of variables. Fuentes et al concluded that LSD was a potential therapeutic agent in psychiatry; with the strongest evidence for its use in treating alcoholism.

Borissova said the heterogeneity of the studies did not allow for a meta-analysis, which made it difficult to draw firm conclusions. The earlier studies had different methodologies than what is used now, which limits the application of the results to modern research. The use of the gold standard of the double-blind methodology with psychedelics is extremely difficult, if not impossible to achieve, and five studies had a high risk of bias for blinding. The psychiatric diagnostic categories were also different in studies done over such a wide range of time. How the studies defined their ‘control group’ varied, with those that failed to use an active placebo having questionable validity.

When discussing the implications of Fuentes et al, she said LSD generally appears to be safe and potentially effective. The lack of consistency between the studies may have limited their ability to find an LSD effect. “On the basis of this review, we cannot conclude that there is strong evidence of positive effects.” She did think change in scheduling the drugs to allow for easier research into LSD was justified. Tellingly, she ended with this caution: “Psychedelic research inspires a lot of excitement; the danger is that this turns into hype.”

There has been a growing interest in psychedelics as an agent for reaching peak experiences, for self-care or wellness, and as an instrument of therapeutic change. Michael Pollan explored this psychedelic ‘renaissance’ in his 2018 best-selling book, How to Change Your Mind. In a New York Times article, he said now when you leave the airport in Quito, Ecuador, there are people with signs that say: ‘ayahuasca ceremony’ instead of ‘taxi.’ “These people became shamans, like last week. People are getting hurt.” He had positive things to say about his experiences with psilocybin, but cautioned against legalization: “Psilocybin has a lot of potential as medicine, but we don’t know enough about it yet to legalize it.”

The promise of pre-prohibition LSD and psychedelic studies and their potential as therapeutic agents has to be replicated within a modern, controlled context. A 2016 paper by Rucker with different researchers than those cited above, “Psychedelics In the Treatment of Unipolar Mood Disorders,” elaborated on some of the difficulties inherent in designing trials with psychedelics. Blinding is largely impossible. Therapeutic doses of psychedelics produce subjective and objective changes in thinking, feeling and behavior that are usually obvious to both the participant in the study and the observer. Because of this, placebo control is problematic because the absence of the psychedelic effect is obvious. The ‘set’ (psychological state) and ‘setting’ (the interpersonal and physical environment) within which the drug is experienced are inextricably linked to the therapeutic effect.

It appears that a particularly careful and well-considered balance between the needs of the participants and the needs of the trial will be required in studies using psychedelics. . . Trial designers will need, similarly, to be detailed and explicit about the environmental and psychotherapeutic milieu in which a study is to be performed. Clinical trials using psychedelics will need to be sufficiently methodologically detailed at the point of publication to allow genuine replication. Scientific mechanism studies will need, ideally, to be pursued alongside clinical trials if this is pragmatic and ethical. Within this multi-pronged approach to evidence gathering, and a sufficient degree of definition, replicable results and common threads of insight into the nature and applicability of psychedelics to medicine in general, and to psychiatry in particular, should emerge with time.

In “Psychedelics In the Treatment of Unipolar Mood Disorders,” Rucker et al referred to and quoted Rick Strassman’s 1984 literature review, “Adverse reactions to psychedelic drugs.” Strassman noted that the description and reporting of adverse reactions to psychedelics was subject to the investigators’ attitudes towards psychedelics.

With the available data, it appears that the incidence of adverse reactions to psychedelic drugs is low when individuals, both normal volunteers and patients, are carefully screened and prepared, supervised and followed up, and given judicious doses of pharmaceutical quality drug. The few prospective studies noting adverse reactions have fairly consistently described characteristics predicting poor response to these drugs. The majority of studies of adverse reactions, retrospective in nature, have described a constellation of premorbid characteristics in individuals seeking treatment for these reactions where drugs of unknown purity were taken in unsupervised settings.

The authors repeated an assessment of the perceived psychotherapeutic mechanism identified by Betty Eisner and Sidney Cohen in their 1958 article, “Psychotherapy with Lysergic Acid Diethylamide.” Eisner and Cohen said their review of the existing literature in 1958 suggested that 1) LSD lessened defensiveness; 2) there was a heightened capacity to relive early experiences with accompanying release of feelings; 3) therapist-patient relationships were enhanced; 4) there was an increased appearance of unconscious material. Eisner and Cohen went on to describe their exploration of the therapeutic possibilities of LSD with 22 patients with diagnoses ranging from neurotic depression, anxiety, character disorder, borderline personality and schizophrenia. Improvement was noted in 16 of 22 cases, where improvement was judged as continued success in behavioral adaptation.

Rucker et al concluded that psychedelic therapy may represent a kind of “catalyzed psychotherapy,” where the psychedelic drug hastens the breakdown of entrenched, maladaptive ways of thinking and behavior in supportive environments. While the evidence from pre-prohibition literature is unsystematic and methodologically inadequate, it suggests further research is worth doing. But there are limitations to the future research of psychedelic psychotherapy that researchers need to be aware.

As discussed above, it is essentially impossible to develop a double-blind methodology with psychedelics because of the unique characteristics of the drugs. This opens investigations into psychedelic therapy to the potential bias of the researchers—one that cannot be eliminated. Strassman raised this warning in Rucker et al, where he was quoted as saying it is important to use caution when discussing the idea of adverse reactions to psychedelic drugs. Whether the researcher views the drug-induced state as a pathological one, or as trying to reach a “higher” level of consciousness, “The description and/or reporting of adverse reactions to psychedelics is, therefore, subject to some degree of investigators’ perspective on the use of these drugs.”

Given the potential bias of researchers into psychedelic therapy and the current inability of medical research to neutralize it, caution when interpreting the conclusions of any research is necessary. As Anya Borissova said, although psychedelic research inspires a lot of excitement; “the danger is that this turns into hype.” This danger cuts both ways, whether a particular researcher sees the drug-induced state as a pathological one, or as an attempt to reach a “higher” level of consciousness. At the very least, it seems researchers should declare any personal bias with regard to psychedelics within any written or published research into psychedelic therapy.

As an illustration, does knowing that Betty Eisner and Sidney Cohen both personally used LSD at least once (and probably more than just once) alter your assessment of their endorsement of psychedelic therapy? It was 1958 and their failure to do so is not an ethical misstep, but that awareness added to the inability to adequately blind their research should lead to some reservations with their conclusions endorsing psychedelics. Michael Pollan acknowledged the concern of potential bias in psychedelic research:

Western science and modern drug testing depend on the ability to isolate a single variable, but it isn’t clear the effects of a psychedelic drug can ever be isolated, whether from the context in which it is administered, the presence of the therapists involved, or the volunteer’s expectations. Any of these factors can muddy the waters of causality. And how is Western medicine to evaluate a psychiatric drug that appears to work not by means of any strictly pharmacological effect but by administering a certain kind of experience in the minds of the people who take it?

It seems impossible for psychedelic psychotherapy to be separated from its set or setting; and for research into its effectiveness to be reliably evaluated by a double blinded research methodology. The effectiveness (or not) of psychedelic therapy will necessarily be in the eye of the researcher and beholder.

For more on Betty Eisner, Sidney Cohen and early LSD research look, see: “Bill W. and His LSD Experiences.”

Originally posted on October 13, 2020.

12/20/22

Business as Usual with Antidepressants

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In “Serotonin or Not, Antidepressants Work” for Psychiatric Times, Drs. Ronald Pies and George Dawson wrote a critique of an article in Molecular Psychiatry by Moncrieff et al, “The serotonin theory of depression: a systematic umbrella review of the evidence.” They were puzzled with the article’s claim, that there was “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.” They said it was like seeing an article in 2022, that said depression was probably not caused by excessive black bile.

Pies and Dawson dismissed the review as nothing more than “old wine in new bottles.” Then they listed 7 ways they thought the review and its conclusions were amiss. The role of serotonin in mood disorders was not settled science and there may be a role for it “in some types of depression, which is almost certainly a heterogeneous group of disorders.” They quoted Dr. Michael Bloomfield who said: “The problem with the review [by Moncrieff et al] is that…it has lumped together depression as if it is a single disorder, which from a biological perspective does not make any sense.”

Yet it does make sense when you do an umbrella review of studies where depression was assessed as the singular disorder of Major Sepressive Disorder, according to the DSM—which is published by the American Psychiatric Association.

Depression is a complex, heterogeneous disorder with biological, psychological, and sociocultural determinants and risk factors. Very few—if any—US psychopharmacologists and academic psychiatrists have ever endorsed a sweeping chemical imbalance theory of mood disorders. Historically, psychiatrists have never explained clinical depression solely in terms of reduced serotonin or any specific neurotransmitter. Many drugs in clinical medicine work through unknown or multiple mechanisms, as SSRIs do, and this does not affect their safety, efficacy, or approval for medical use. Results of placebo-controlled studies offer ample evidence that serotonergic antidepressants are safe and effective in the treatment of acute major depressive episodes. If serotonergic agents are not helpful, antidepressants from other classes (eg, noradrenergic/dopaminergic agents) may be considered.

Their final word was they hoped patients and clinicians would not be deterred from using antidepressants by the review, “or by the fact that SSRIs’ mechanism of action is complex and not completely understood.” So, the bottom line of their critique was whether or not we understand how serotonin influences depression, SSRIs work. In other words, the serotonin theory of depression may be wrong, but there must be a biochemical connection because antidepressants work. The effectiveness of SSRIs and other antidepressants is evidence of such a relationship. We just haven’t discovered what it is yet.

The Moncrieff et al article has received a significant amount of support as well as critique since it was published. The Rolling Stone wrote how the article “went viral,” but then essentially attempted to marginalize Moncrieff and dismiss her research.

In an email to Rolling Stone, Moncrieff said, “I see our research as linked with the way we understand and evaluate antidepressants, and it logically follows from my other work on the nature of drug action.” I think this statement by Moncrieff is the center of the dispute, but that was not where Rolling Stone went. It went off on a tangent, noting how the Church of Scientology organization, CCHR, frequently promoted her work. Also, that ‘far-right’ commentators like Matt Walsh and Tucker Carlson were promoting its findings. They suggested she was dabbling in conspiratorial thinking. If you conclude that antidepressants don’t work after reading her paper, then you got the wrong message.

Joseph Comaty, a Medical Psychologist, thought the paper didn’t undermine the efficacy of antidepressants. “But we just don’t know the biochemical theory of depression.” As we learn more about mental illness, things will change. According to Comaty: “if what we once believed is no longer tenable, then yeah, we’ll move along and come up with a new one.” That is just the process of scientific inquiry.

However, the mythical nature of the serotonin hypothesis of depression doesn’t seem to have been translated into the marketing and public discussion of antidepressants just yet. And why is it psychiatrists are referring to the Moncrieff et al study as old wine in new wine skins, saying it is akin to declaring depression is not caused by an excess of black bile? If they’ve known the chemical imbalance theory of depression was an error for several years, why did they not correct that false impression in the public media that is now discussing the Moncrieff et al review?

In a blog article, Moncrieff responded to some of the inaccuracies and distortions in the Rolling Stone article. She said apparently their finding was so obvious that it was met with yawns by the psychiatric community. “Yet the public were kept in the dark about the lack of evidence for a chemical imbalance for three decades in what an Australian psychiatrist recently called a ‘scourge on our profession’. And the public is very interested.” Their original paper is in the top 500 most shared scientific papers—of the 21 million that have ever been tracked—and their article in The Conversation (the one Pies and Dawson referred to) had over a million hits by August 3rd.

She noted the attempt to discredit her by association to the Scientologists and the ‘right-wing media.’ The article said she promoted the belief that SSRIs were linked to aggressive behavior, which was said to be a fringe view used by right wing media to argue against gun control in the US. She did comment on research published in the British Medical Journal (BMJ) that found a link between antidepressants and aggressive behavior, as well as suicide, in young people. Her comments were published in an invited editorial in the BMJ.

The journalist does present my response to these issues, but bringing them up seems to suggest that because of this we should never have publicised or maybe even done our research. This amounts to the suggestion that millions of people should be denied information about the drugs they put in their body every day because the message might be taken up by the ‘wrong’ people.

The ’right’ people seem to be the ones who have known for thirty years that the chemical imbalance theory was disproved. They’ve known it was an urban myth, yet did not speak up and correct the wrong impression given to the public. Now that the public is paying attention, they say the news about serotonin is old hat. It seems they want you to ignore the conclusions of the Moncrieff et al study and just return to business as usual with antidepressants.

For more information on the Moncrieff et al study its implications, see “The Death of the Chemical Imbalance Theory?” and “The Myth of the Serotonin Theory of Depression.”

11/22/22

Brain Stimulation or Brain Damage? Part 2

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On Valentine’s Day 1974, British doctors destroyed sections of Derek Hutchinson’s hypothalamus without his consent. Surgeons drilled two holes into his forehead and then sent a wire with an electrical tip deep into his brain. Before the right and left sides of the targeted area of his hypothalamus was burned for thirty seconds each, the surgeon test-stimulated his brain with five to ten volts of electricity to see whether the targeted area of his brain actually controlled emotions, and not pathways crucial to motor functions like walking, talking and breathing. They asked him if he was frightened or angry and he yelled, “Stop it, or I’ll kill you.” Then they proceeded to destroy the targeted areas of his hypothalmus.

As Danielle Egan related in her article, Derek had an hypothalomotomy, a psychosurgery procedure first developed in the 1950s to curb aggressive behavior. Over the next two decades he had repeated overdoses and hospital stays during which he received ECT. At some point, he attacked one of his psychiatrists, but no charges were filed against him. After his wife gave birth to twins, he threatened her with a gun. He met his current wife in a pub and they were married in 1982. He’s struggled with bouts of depression, impotence, insomnia, extreme fatigue and rage since the surgery. “He’s had eight heart attacks, two strokes, has battled anorexia (the hypothalamus also regulates hunger, blood pressure and hormones) and has tried to kill himself seven times.”

An MRI revealed extensive damage to his hypothalamus. They told him “Half of your hypothalamus is gone.” He said that was when he finally woke up. These days Hutchinson is an activist against the use of psychosurgeries and deep brain stimulation (DBS). He thinks psychosurgery should be banned outright and believes mental disorders are caused by an individual’s unique life experiences, and are not a product of a dysfunctional brain.

We must put an end to this immoral, unethical activity being conducted in the name of mental health research… These doctors are guinea-pigging innocent people. These surgeries should never have been invented. They kill the person and they don’t even know they’re not the same person anymore.

There are clear differences between the hypothalomotomy done to Derek Hutchinson and DBS, which seeks to electrically stimulate specific areas of the brain, not destroy them. However, the adverse effects are similar. In another article for Mad in America on DBS, Egan noted that numerous studies have documented serious adverse mood behavior and personality effects. “These include suicide, depression, apathy, fatigue, mania and serious impulse control issues, such as hypomania, aggression, addiction (to gambling, shopping, drugs, alcohol) and hypersexuality, sometimes resulting in criminal behaviour, including pedophilia.” See “Deep Brain Problems” for more on the adverse effects with DBS.

Andrew Scull described the results of two double-blind studies of DBS for depression. The first one by Dougherty et al was prompted by encouraging response rates in multiple open-label DBS trials. But there was not a significant difference in response rates between the active and control groups. “Our results … failed to demonstrate a significant difference between the active and sham-controlled groups during the blinded phase of the study.” Even worse, adverse events were more frequent in the active group than in the control group for worsening depression, insomnia, irritability, suicidal ideation, hypomania, disinhibition and mania.

There was even one completed suicide in the active treatment group. However, it occurred after the person stopped treatment because of a failure to improve and was awaiting removal of the electrodes. “The authors decided that that adverse event did not count!” Notice that the second listed author of this study, Ali Rezai, would later emerge as the lead investigator for the first U.S. clinical trial of DBS for heroin described in Part 1 of this article.

The second trial was conducted by Helen Mayberg and Andres Lozano, who are both well known supporters of DBS, and a couple dozen others. Again, there was no statistically significant difference between the stimulation group and the control group. Scull reported the researchers anticipated those receiving active stimulation would improve twice as much. Both the treatment and the placebo groups improved, but the improvement was slight and not statistically significant.

Thus, once put to a controlled test, the claims for deep brain stimulation as a treatment for depression resoundingly failed. The purely speculative and fanciful biological “theory” of depression on which the intervention rested had not produced the anticipated results.

Then in October of 2019, Mayberg published another DBS study, claiming the procedure was generally safe and well tolerated. “The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications.” Oh, and there were no completed suicides. Yet Andrew Scull pointed out five of the small sample of 28 individuals dropped out after 1, 2, 5, 8 and 11 years. There were 56 adverse events. One patient experienced ten of them and had the electrodes removed after two years and dropped out of the study.

What are we talking about here? Nineteen of the events involved the surgery going wrong in a variety of major ways. Six infections resulted from the brain surgery. Six patients had to have the original device “explanted,” as the authors put it, because the wires caused an infection (3 cases), failed to work (2 cases), or the crude targeting of the device needed adjusting (1 case). Another patient experienced hemorrhage of the cortex and a post-operative seizure. The device failed in 15 cases. There is no further discussion of these iatrogenic disasters, or the suffering they entailed. And then, finally, there were the serious psychiatric sequelae. Fourteen of the twenty-eight patients required re-detention in a psychiatric hospital, one on seven occasions, including five admissions occasioned by suicide attempts.

Despite the above reported adverse events, Helen Mayberg’s assessment of DBS is that it appears to be “generally safe and well tolerated.” Although the DBS studies failed to show any real efficacy with treatment-resistant depression, Mayburg concluded most participants had “a robust and sustained antidepressant response.” Andrew Scull pointed out many of the authors were indebted financially to the medical device manufacturer and that Mayburg owned patents covering the devices in question. Further, he said Mayberg et al “cherry-picked data” for their study. Positive outcomes only appeared when researchers self-assessed the results of their interventions. “Ambitious clinicians let loose in such a situation can easily be carried away by their enthusiasms, and the restraints on experimentation, while stronger than they once were, remain inadequate.”

Scull had a different take on the first-in-the-U.S. clinical trial for treatment resistant opioid use disorder described in Part 1. He pointed out the false impression given by saying the DBS device functioned much like a heart pacemaker. The human brain is not a simple pump. And despite all the progress of neuroscience over the past fifty years, our understanding of it is still primitive. “The idea of a ‘brain pacemaker’ is so ludicrous on its face as to disqualify anyone who uses it.” The analogy appears to rely on the now generally disparaged “chemical imbalance” theory of depression, as evident in the following statement:

By sending a pulsed current through the electrodes, doctors believe they can regulate an imbalance in Buckhalter’s reward circuitry.

Ali Rezai, the doctor leading the clinical trial, readily acknowledged they don’t fully understand how this works. However, they hope that by modulating the rewards circuit, which relies on the chemical messenger dopamine, “you’re getting better control, so you’re not craving dopamine as much.” This suggests DBS for opioid misuse is more explorative and experimental than it is a promising type of treatment. Scull commented: “The prattle about dopamine that he proceeds to utter as a substitute for the scientific evidence we do not possess is an embarrassment — just speculation plucked out of thin air.”

In The Science of Addiction, Carleton Erickson said scientists once held that dopamine was the “pleasure transmitter.” He said this is a simplistic explanation of severe SUD—substance use disorder. Addiction is more than seeking of pleasure or avoiding pain or withdrawal. In addition to the nucleus accumbens (part of the brain’s pleasure or reward system), recent neurobiological findings and theories extend to areas of the brain the modulate meaning and emotional and cognitive memory. “Some drugs appear to be capable of affecting these adjunctive brain areas to transition drugs from pure pleasure to habitual use to severe SUD, where pleasure or pain is no longer important in maintaining drug-taking behavior.”

Reflecting on the continuing pursuit of brain stimulation with transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS) and invasive, deep brain stimulation (DBS), I am reminded of a two-hundred-year-old novel that Mary Shelly anonymously published on January 1, 1818, The Modern Prometheus; or Frankenstein. Shelley told her story within a literary technique known as a frame narrative—a story within a story. In the frame story, Captain Robert Walton and his crew set out to explore the North Pole sometime in the 18th century in order to expand scientific knowledge and hopefully achieve fame. They glimpsed a dog sled driven by a gigantic figure, but it disappeared into the snow. A few hours later, they found a frozen and emaciated Victor Frankenstein, who had been in pursuit of the gigantic creature.

Victor recognizes the same obsession in Walton that drove him to modern laboratory experimentation and creation of the “fiend.” As a warning to Walton, he then recounts the story of his life’s miseries that were a consequence of his obsession. With his last words, he told Walton to seek “happiness in tranquility and avoid ambition.” Let us hope that the pursuers of brain stimulation, particularly DBS, heed that counsel. Experimenting on humans by implanting electrodes into their brain to “treat” their depression or addiction seems like a similar pursuit of ambition over first doing no harm. Hopefully Derek Hutchinson’s life story and its miseries will be heard and give pause to some of these researchers.

Originally posted on February 4, 2020

11/15/22

Brain Stimulation or Brain Damage? Part 1

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Nexstim won FDA clearance for its noninvasive brain stimulation system to treat major depression in November 2017. The Nexstim CEO, Martin Jamieson, said the clearance was a critical milestone for the commercialization of their transcranial magnetic stimulation (TMS) device in the U.S. Then in February of 2019 the FDA cleared a drastically reduced 3-minute session protocol to treat major depression with Nexstim’s NBT (Navigated Brain Therapy) System. The previous protocol time was 37 minutes. The Theta Burst Stimulation is a newer form of repetitive TMS that allows for stimulation to specific areas of the patient’s brain. “The company believes that the shorter protocol will increase ease of use for the NBT system.”

The new 3-minute NBT protocol was approved based on results from a study of 414 patients with treatment-resistant depression, which found that intermittent Theta Burst Stimulation was non-inferior to high-frequency transcranial magnetic stimulation.

There is also Humm, a transcranial alternating current stimulation (tACS) device that claims it can improve your cognitive function and memory. “Humm is a wearable patch that gently stimulates the brain’s natural rhythms to strengthen memory.” Neuroskeptic said he was pleasantly surprised with Humm’s reported study, which he said actually looked solid. Although the study was not published, he thought it would pass peer-review. He noted while there is evidence that individually-tailored theta tACS can benefit working memory, other studies show a disruption of working memory. “My point is that, a priori, there is no reason to assume a beneficial effect of this kind of stimulation.”

And most recently, the British government approved Flow, a headset claimed to reduce chronic depression symptoms. The website for Flow Neuroscience claims most users notice a reduction of their symptoms after 3-4 weeks. The device sends a small jolt of electricity through the skull into the prefrontal cortex. Users are instructed to wear the headset for a half-hour every three days over the course of six weeks. Additionally, they are encouraged to use an app, which provides useful tips such as reminders to get enough sleep, eat right and exercise.

The technology, known as transcranial direct current stimulation [tDCS], has been the subject of numerous tests, most of which have found that it provides some degree of relief from depression symptoms. Many have concluded that it is at least as effective as antidepressants, but without the side effects. Thus far, none of the trials have found any adverse effects of such treatment other than reddened skin where the electrodes are placed and the occasional headache. Such treatments have been found to change the potential of neurons—in some cases, making them fire more often, and in others less often. People with chronic depression typically experience less neural activity in the left side of their prefrontal cortex—the mild shocks are meant to increase such activity to match that in the right side. Some of the trial results have even shown that in some cases, mild electrical stimulation can encourage the growth of new neural connections, perhaps reducing depression symptoms permanently.

A study by Clarke et al. reported in the June 2019 issue of the Journal of Affective Disorders investigated the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment resistant depression and comorbid anxiety. Their study included 248 patients with treatment resistant depression. Of these, 172 also had one or more comorbid anxiety disorders. The researchers found that rTMS therapy showed improvement in depression in patients with major depression alone and those with comorbid anxiety. 39.5% of patients with comorbid anxiety disorders met the response criteria defined in the study and 23.3% met the criteria for remission.

Psychiatry Advisor reported the researchers said: “This study showed that rTMS is equally effective for treating depression, regardless of whether there are comorbid anxiety disorders or not. . . [There] is a role for future research into TMS as a treatment for patients with anxiety conditions without major depression.” TMS or rTMS devices are used typically for treatment-resistant depression and can only penetrate a few centimeters into the outer cortex of the brain. The strength of these devices declines rapidly the farther away the machine is positioned from the scalp. See “Better Living Through Brain Stimulation” for more information on rTMS and TMS.

If you want to target deeper regions of the brain, a more direct stimulation method like tDCS or tACS is needed. tDCS devices are inexpensive and easy to use. They are promoted like patent medicines, able to benefit problems such as: migraine, chronic pain, post-stroke paralysis, Parkinson’s disease, depression, tinnitus, fibromyalgia, marijuana craving and the tendency to lie; and they do not require a prescription. tACS is supposed to reverse the decline of working memory related to the aging brain. See “Jump Starting Your Brain” and “Electrical Psychiatry” for more information on tDCS and tACS.

With deep brain stimulation (DBS), we move to a procedure that requires surgery to implant electrodes into a patient’s brain. Wires connect the electrodes to a device implanted underneath the person’s skin. DBS devices are considered to be a last resort treatment method for conditions like Parkinson’s disease and Tourette Syndrome, and they carry risks of adverse side effects such as mood, behavior and personality changes. These can include suicide, depression, mania and serious impulse control issues, such as hypomania, addiction (gambling, shopping, drugs, alcohol) and hypersexuality. See “Deep Brain Jolts” for more information on DBS. See “Deep Brain Problems” for more information on the adverse effects of DBS.

An odd, unanticipated adverse effect has emerged with DBS. According to The New York Times, DBS electronic implants reduced Parkinson’s symptoms, but they also expunged some patients’ proficiency for swimming. “A lifelong swimmer leapt into deep water near his lakeside home and was horrified to find himself completely unable to swim. Had his wife not rescued him, he might have drowned.” Somehow the signals from the DBS device had deleted his ability to coordinate his arms and legs for swimming.

An article in the journal Neurology by a medical team from the University of Zurich documented nine cases among 250 patients. One of the coauthors said he thought the swimming issue was in a minority of patients, because some are still able to swim and they don’t know why. “We have no clue. They are treated in the same region of the brain. But this is life-threatening, and we need to pay more attention in the future.” In 2015 Australian doctors reported one patient who could not even float with the device turned on. With the device off, he could swim laps. Three other patients with DBS stimulators for Parkinson’s have drowned, but “they did not if the deaths were related to the device.”

Now DBS is targeting addiction treatment and China is emerging as the center for this research. AP News noted how scientists in Europe have struggled to recruit patients for their DBS addiction studies (No surprise, given the above brief description of DBS). In the U.S. there are ethical, social and scientific questions (in addition to the cost of around $100,000 to implant), as well as the adverse effects from surgery. China’s anti-drug laws can force people into years of compulsory treatment, including “rehabilitation” through labor. According to ClinicalTrails.gov, there are now 12 registered DBS clinical trials for addiction being conducted globally, 8 are in China; one each in France, Israel, Canada, and Germany. The trials are primarily for opiate/opioid use and misuse, but there are some for methamphetamine, cocaine, alcohol, and morbid obesity. Some critics believe this surgery should not be permitted.

They argue that such human experiments are premature, and will not address the complex biological, social and psychological factors that drive addiction. Scientists don’t fully understand how DBS works and there is still debate about where electrodes should be placed to treat addiction. There is also skepticism in the global scientific community about the general quality and ethical rigor — particularly around issues like informed consent — of clinical trials done in China.

Dr. Nader Pouratain, a neurosurgeon at UCLA, is investigating the use of DBS for chronic pain. He thought it was time to research DBS for drug addiction. However, only “if we can move forward in ethical, well-informed, well-designed studies.” At least two U.S. laboratories dropped clinical trials of DBS treatment for alcoholism over concerns the study design and preliminary results did not seem to justify the risks. Dr. Emad Eskandar, the chairman of neurological surgery at Albert Einstein College of Medicine said: “The lack of scientific clarity, the important but strict regulatory regime, along with the high cost and risk of surgery make clinical trials of DBS for addiction in the U.S. difficult at the present time.” The FDA blocked an application for a Chinese DBS device for a multi-site, opioid addiction.

In February of 2019, the FDA approved a small, separate trial of DBS for opioid use disorder at the West Virginia University Rockefeller Neuroscience Institute. On November 5, 2019 the Rockefeller Neuroscience Institute announced the launch of the first-in-the-U.S. clinical trial of DBS for treatment-resistant opioid use disorder. The first participant is a 33-year-old man with excessive opioid and benzodiazepine use for more than a decade. The first phase will include 3 additional participants.

ScienceAlert (the article was originally published by The Washington Post) reported Dr. Rezai said he wasn’t advocating DBS as a first line or even a second line treatment. “It’s for people who have failed everything, because it is brain surgery.” He acknowledged that doctors and researchers do not fully understand how this (DBS) works. “The exact mechanisms are not known.” By modulating the reward circuit, which relies on dopamine, “you’re getting better control, so you’re not craving dopamine as much.”

The trial is partly funded by the National Institute on Drug Abuse (NIDA). The director of NIDA, Nora Volkow, said she has spoken with a few of the patients who underwent the procedure in China and thought the surgery had promise. She thought the surgery had disrupted the brain’s fixation on opioids. “They reported more of an ability to engage, to feel interest in other things.” She suggested that brain’s fixation on opioids may be disrupted by the surgery. Helen Mayberg, the director of the Center of Advanced Circuit Therapeutics at the Mt. Sinai Medical Center School of Medicine, said the logic of the effort was sound and the circuitry of the targeted area of the brain was well-mapped compared to other regions. “The key question is whether the researchers have found the precise spot for insertion of the electrodes.”

Brain stimulation (magnetic or electric) has been progressively moving from the laboratory to the clinic and even into the privacy of your home. It seems to me that as brain stimulation devices enter the market place, they are being promoted like patent medicines were a hundred or more years ago. Most of the devices are noninvasive, except for DBS devices, which require brain surgery. DBS has been approved and used to treat medical issues such as chronic pain, Parkinson’s and Tourette Syndrome. And now doctors and researchers are trying it with another desperate and vulnerable population—addicts.

There is a growing global opioid crisis and DBS is being researched and promoted as an addiction treatment for individuals who have failed other approaches. But is DBS treatment worth the risk with addiction? DBS supporters like those mentioned here would say yes. The 2019 World Drug Report estimated there were 35 million worldwide who suffer from drug use disorders. More specifically, there were more than 47,000 opioid overdose deaths in the U.S. in 2017, an increase of 13% from the previous year. The number of new psychoactive substances (NPS) that are synthetic opioids rose from 1 substance in 2009 to 15 in 2015 and 46 in 2017, accounting for 29% of the newly identified NPS in 2017.

Currently there are an estimated 180,000 people globally who have DBS devices implanted in their brains. But that would increase exponentially if DBS becomes a more widespread treatment for addiction. Yet Ali Rezai, the executive chairman of the West Virginia Rockefeller Neuroscience Center (where the FDA clinical trial is being conducted) acknowledged they do not fully understand how DBS works. There are serious ethical, social and scientific questions about DBS as well as a variety of adverse effects that result from the surgery. We will examine some of these in part 2.

Originally posted on January 28, 2020.

10/25/22

The Myth of the Serotonin Theory of Depression

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A research article by Joanna Moncrieff, Mark Horowitz and others, “The serotonin theory of depression: a systematic review of the evidence”, published in the journal Molecular Psychiatry in July of 2022, continues to draw media attention to its findings. The researchers did a systematic umbrella review of the principle relevant areas of research and concluded that the main areas of serotonin research provide no consistent evidence of an association between serotonin and depression. “We suggest it is time to acknowledge that the serotonin theory of depression in not empirically substantiated.” In other words, it’s a myth.

The response from many psychiatrists to the article was that the serotonin imbalance theory has not been treated seriously within the field for many years. Neuroscience News & Research quoted several who thought the findings were not surprising. Dr. Michael Bloomfield a consultant psychiatrist and head of the translational psychiatry research group at University College London said he didn’t think he’d met any serious scientists or psychiatrists who thought that “all causes of depression are cause by a simple chemical imbalance in serotonin.” Allan Young, the director of the Centre for Affective Disorders at King’s College London said, “Most psychiatrists adhere to the biopsychosocial model with very few people subscribing to a simple ‘chemical imbalance’ theory.”

According to Ang, Moncrieff and Horowitz in Is the chemical imbalance theory an ‘urban legend’?, historically there was a considerable promotion of the serotonin hypothesis of depression in both the psychiatric and the psychopharmacology literature. Research papers supporting it were widely cited. While some textbooks were more nuanced, others could be seen to unreservedly indorse it. The American Psychiatric Association (APA) published a patient leaflet in 2005 that said, “antidepressants may be prescribed to correct imbalances in the levels of chemicals in the brain.” See, “The Death of the Chemical Imbalance Theory?” on this website.

It is often assumed that the effects of antidepressants demonstrate that depression must be at least partially caused by a brain-based chemical abnormality, and that the apparent efficacy of SSRIs shows that serotonin is implicated. Other explanations for the effects of antidepressants have been put forward, however, including the idea that they work via an amplified placebo effect or through their ability to restrict or blunt emotions in general.

Moncrieff et al said surveys suggest that 80% of the general public now believe depression is caused by a ‘chemical imbalance.’ They said many general practitioners also subscribe to this view and popular website commonly cite the theory.

The chemical imbalance theory of depression is still put forward by professionals, and the serotonin theory, in particular, has formed the basis of a considerable research effort over the last few decades. The general public widely believes that depression has been convincingly demonstrated to be the result of serotonin or other chemical abnormalities, and this belief shapes how people understand their moods, leading to a pessimistic outlook on the outcome of depression and negative expectancies about the possibility of self-regulation of mood. 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.

Writing for The Conversation, Moncrieff and Horowitz said the serotonin theory of depression has been one of the most influential and extensively researched biological theories of depression. Most antidepressants now in use are presumed to work through their effects on serotonin or noradrenaline. Yet their study shows that is not supported by scientific evidence. “It also calls into question the basis for the use of antidepressants.”

It is important that people know that the idea that depression results from a “chemical imbalance” is hypothetical. And we do not understand what temporarily elevating 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.If you’re taking antidepressants, it’s very important you don’t stop doing so without speaking to your doctor first. But people need all this information to make informed decisions about whether or not to take these drugs.

The organization, Inner Compass Initiative, was able to get Joanna Moncrieff, Mark Horowitz and Irving Kirsch together for an online discussion in “Moving Beyond Myth: A Postmortem Analysis of Chemical Imbalances and Antidepressants Efficacy.” On its website Inner Compass Initiative said it is an organization that is “dedicated to helping people make more informed choices about taking and withdrawing from psychiatric medications.”

Irvin Kirsch has published several studies of the placebo effect and antidepressants, demonstrating that most of the efficacy with antidepressants is from the placebo effect. For more information on Irving Kirsch and his research, see, “Dirty Little Secret,” and “Antidepressant Fall From Grace, Part 2” on this website.

The Inner Compass Initiative moderator, Laura Delano, said the use of antidepressants in the West more than doubled between 2000 and 2015. One in seven Americans and one in six in England take an antidepressant. In October of 2004 the FDA issued a black box warning, indicating an increased risk of suicidal ideation and behavior in children and adolescents treated with SSRIs. However, their off-label use with children and adolescents has increased. In “Antidepressants in Children and Adolescents”, Boaden et al said: “From 2005 to 2012, the prevalence of antidepressant use has increased from 1.3% to 1.6% in the USA, from 0.7% to 1.1% in the UK.”

While the overall percentages are low, keep in mind that at least in the U.S. those increases took place after the FDA required a black box warning of an increased risk of suicidality with children and adolescents treated with SSRIs. In the UK, it represents an increase of over 36%; in the USA, by almost 19%.

“Moving Beyond Myth” begins with a description of how serotonin is measured within the body and a review of the history of the chemical imbalance theory. Joanna Moncrieff said it is not the case that there is a set normal level of serotonin against which people’s serotonin can be judged. She went on to say that the chemical imbalance theory of depression was one of a number of chemical imbalance theories of mental disorders that arose in the 1960s, “in the context of thoughts about drugs that are used to treat these disorders. So, they’re always directly related to the use of drug treatments.” Psychiatrists and researchers came to think that the drugs are working by targeting the underlying abnormality.

Initially they thought that noradrenaline might be relevant in depression. They hypothesized that depression might be due to lower levels of noradrenaline. But when the drugs that selectively target serotonin came out, “people started to think that the underlying abnormality was an abnormality of serotonin, rather than noradrenaline. And that is what the pharmaceutical industry took hold of and ran with in the 1990s when they started to market SSRIs.”

Her point is that chemical imbalance theories have always been dreamed up in the context of the use of different drugs to treat mental disorders. “They are based on the assumption that drugs are working by targeting the underlying abnormality, and that you can deduce the abnormality from the opposite of what the drugs do.” Mark Horowitz goes on to describe the findings of “The serotonin theory of depression: a systematic review of the evidence.”

An added bonus in “Moving Beyond Myth” is to hear Irving Kirsch describe his research into antidepressant efficacy and its relationship to the placebo effect. His most recent research was published in August of 2022 in the BMJ (British Medical Journal). Kirsch and the other researchers did a participant level analysis of randomized, placebo-controlled trials of acute monotherapy for the treatment of major depressive disorder submitted to the FDA between 1979 and 2016. The Conclusions section of the article said:

Patients with depression are likely to improve substantially from acute treatment of their depression with drug or placebo. Although the mean effect of antidepressants is only a small improvement over placebo, the effect of active drug seems to increase the probability that any patient will benefit substantially from treatment by about 15%. Further research is needed to identify the subset of patients who are likely to require antidepressants for substantial improvement. The potential for substantial benefit must be weighed against the risks associated with the use of antidepressants, as well as consideration of the risks associated with other treatments that have shown similar benefits. Because the benefits and risks might be categorically different (eg, reduced sadness v anorgasmia), weighting should be done at the individual level, jointly by patients and their care providers.

The belief that a chemical imbalance underlies depression and other mental disorders has begun to unravel. For some time, it has been set aside by researchers and some psychiatrists as an urban legend. The pharmaceutical industry may continue to hold on to the notion that drugs work by targeting an underlying abnormality and that you can identify the abnormality “from the opposite of what the drugs do.” But it is time the public became aware that the chemical imbalance theory of depression is just a myth.