10/3/24

The Medication Merry-Go-Round with Depression

Photo by michaelangelo ramos on Unsplash

There seems to be a paradigm shift brewing for how we explain depression. “Beyond the serotonin deficit hypothesis,” an article that appeared in Molecular Psychiatry, noted how the serotonin deficit hypothesis of depression has persisted among clinicians and the general public alike “despite insufficient supporting evidence.” The next month the journal Psychopathology published a study, “A Descriptive Diagnosis or a Causal Explanation?” that concluded leading professional medical and psychiatric organizations commonly confound a descriptive diagnostic label for depression with a causal explanation. Then there was a third study that explored whether the DSM adequately identified DSM disorders when someone was decreasing, switching, or discontinuing SSRIs/SNRIs following their long-term use.

The End of the Serotonin Theory of Depression

In 2022 an article in Molecular Psychiatry, “The serotonin theory of depression: a systematic umbrella review of the evidence,” concluded the serotonin theory has not produced convincing evidence of a biochemical basis for depression. The researchers suggested it was time to acknowledge that the serotonin theory of depression was not empirically substantiated. The flurry of criticism the article generated didn’t seem to stifle its message. “Beyond the serotonin deficit hypothesis” said in order to combat the eroding public trust in science and medicine (and also combat the rising mental health crisis), “researchers and clinicians must to be able to communicate to patients and the [general] public an updated framework of major depressive disorder (MDD).” These authors suggested that framework should be:

(1) accessible to a general audience, (2) [it should] accurately integrate current evidence about the efficacy of conventional serotonergic antidepressants with broader and deeper understandings of pathophysiology and treatment, and (3) [be] capable of accommodating new evidence.

They discussed how MDD could be understood as inflexibility in cognitive and emotional brain circuits that involved a persistent negative bias. Secondly, they reviewed how effective treatments for MDD enhanced mechanisms of neuroplasticity in ways that facilitated adaptive and emotional processing. Lastly, they considered how researchers, clinicians and other professional could present this framework when discussing MDD with patients or the general public. They also suggested language and metaphors they thought could be useful for effective communication about MDD. For a further discussion of “The serotonin theory of depression,” see: “Paradigm Shift Needed with Depression.”

Is MDD a Description or a Causal Explanation?

In “A Descriptive Diagnosis or a Causal Explanation?” two Finnish researchers observed: “Psychiatric diagnoses are descriptive in nature, but the lay public commonly misconceives them as causal explanations.” Kajanoja and Valtonen said it was not known to what extent this form of diagnostic circular reasoning—diagnoses being discussed as if they describe the causes of symptoms—was mistakenly reinforced by the health authorities themselves. They investigated the prevalence of misleading causal descriptions of depression in the information on the websites of authoritative mental health organizations. Most websites used language “that inaccurately described depression as a causal explanation to depressive symptoms.”

Most psychiatric diagnoses are descriptive: They describe states of mental distress and dysfunction but do not in themselves contain causal explanations. Nonetheless, diagnoses in psychiatry are commonly talked about as if they are concrete entities that explain the symptoms they describe. In this study, we examined whether health organizations themselves contribute to this logical fallacy. We searched for popular websites managed by leading mental health organizations, and evaluated whether they discussed the diagnosis of depression accurately as a description, or inaccurately as a cause for depressive symptoms. We found that the majority of websites presented depression as a cause, instead of a description of symptoms. We discuss the potential harmful consequences of inaccurately presenting descriptive psychiatric diagnoses as causes.

In “Depression Diagnoses Debunked,” SciTechDaily said Kajanoja and Valtonen selected the websites of English-language organizations that seemed to be the most influential ones providing information on depression. These organizations included the World Health Organisation (WHO), the American Psychiatric Association (APA), National Health Service (NHS) in the UK, Harvard and Johns Hopkins Universities, among others. They found most of the organizations portrayed depression as a disorder that caused symptoms and/or explained what caused the symptoms. None of the organizations presented the diagnosis of MDD as a pure description of symptoms. They said:

Presenting depression as a uniform disorder that causes depressive symptoms is circular reasoning that blurs our understanding of the nature of mental health problems and makes it harder for people to understand their distress. . . People seem to have a tendency to think that a diagnosis is an explanation even when it is not. It is important for professionals not to reinforce this misconception with their communication, and instead help people to understand their condition.

Misdiagnosing Antidepressant Withdrawal

A third study by Cosci, Chouinard and Chouinard published in Psychotherapy and Psychosomatics explored whether the DSM alone was adequate to identify psychiatric disorders when an individual was switching, decreasing or discontinuing a SSRI/SNRI. The researchers found that withdrawal/discontinuation symptoms were mis-formulated (misdiagnosed) as DSM-5 psychiatric disorders like a current panic disorder or recurrent major depressive disorder. They noted how existing diagnostic methods with the DSM do not take withdrawal/discontinuation phenomenon into account. The researchers used a new nosographic system, the Diagnostic Clinical Interview for Drug Withdrawal 1-New Symptoms of Serotonin Reuptake Inhibitors or Serotonin-Norephinephrine Reuptake Inhibitors (DID-W1), and found that: “In 58 cases (77.3%), the DSM-5 diagnosis of current mental disorder was not confirmed when the DID-W1 diagnosis of current withdrawal syndrome was established.”

Reviewing the Cosci, Chouinard and Chouinard article for Mad in America, “Antidepressant Withdrawal Commonly Misdiagnosed as ‘Mental Illness’,” Peter Simons said the researchers thought the fact that the DSM does not include criteria for withdrawal symptoms was a barrier to the accurate diagnosis and treatment of depression. “While the DSM asks clinicians to differentiate ‘mental disorders’ from drug-induced symptoms, it does not include drug withdrawal symptoms—from either recreational or prescribed drugs.” Therefore, Cosci, Chouinard and Chouinard suggested the DID-W1 be used to detect withdrawal induced by SSRI/SNRI discontinuation, decrease or switching all psychiatric medications. Limitations of the study included the small sample size, and that study participants were volunteers who were already seeking help for withdrawal reactions.

It seems that when switching, decreasing or discontinuing antidepressants (or antipsychotics) leads to circular reasoning—withdrawal symptoms that can be misdiagnosed as an emerging anxiety disorder, some other psychiatric disorder, or seen as the re-emergence of major depression. Without a tool like the DID-W1, what can a person do to better understand their problems and get off the medication merry-go-round for depression?

The Model of Drug Action May Be the Answer

Joanna Moncrieff, one of the researchers who wrote “The serotonin theory of depression: a systematic umbrella review of the evidence”, has promoted what she calls “the drug-centered model of drug action.” She has written about it multiple times and her discussion can be found in The Myth of the Chemical Cure, on her blog in “Models of Drug Action,” and in “Research on a ‘drug-centred’ approach to psychiatric drug treatment” published in the peer-reviewed journal, Epidemiology and Psychiatric Sciences. In “Models of Drug Action,” she said she formulated two different models of drug action, the disease-centered model, and the drug-centered model. Also see “A Drug is a Drug is a Drug.”

The disease-centered model suggests that psychiatric drugs can reverse, or partially reverse, “the disease or abnormality that gives rise to the symptoms of a particular psychiatric disorder.” This model is borrowed from general medicine and describes drugs through the prism of disease or the collective pattern of symptoms the drugs are thought to treat. The important effects of the drugs—like with serotonin reuptake inhibitors— “are the ones they exert on the disease process.” All other effects are considered to be ‘side effects.’ And the therapeutic effects are believed to only be evident in people with the ‘disease.’

The drug-centered model suggests that psychiatric drugs induce an abnormal or altered state, but do not correct it. Psychiatric drugs like antidepressants are psychoactive substances like alcohol or heroin, and they modify the way the brain functions, producing changes in thinking, feeling and behavior. They exert their effects on the individual regardless of whether or not they have a mental condition (a drug is a drug). The drug-centered model suggests that some drugs may be useful therapeutically in some situations, but not by normalizing brain function. “They do it by creating an abnormal or altered brain state that suppresses or replaces the manifestations of mental and behavioural problems.” See also “Never Enough and No Free Lunch” and “Never Enough and Adaptation.”

See the following table for a comparison of the two models, taken from “Research on a ‘drug-centered’ approach to psychiatric drug treatment.”

When modern psychiatric drugs were introduced in the 1950s, they were understood according to a drug-centred model. Antipsychotics, for example, which were then known as ‘major tranquilisers,’ were regarded as a special sort of sedative. They were thought to have properties that made them uniquely useful in situations like an acute psychotic episode, because they could slow up thought and dampen emotion without simply inducing sleep, but they were not regarded as a disease-targeting treatment. By the 1970s, however, this view was eclipsed and the disease-centred model of drug action became dominant. Accordingly psychiatric drugs were regarded as specific treatments that worked by targeting an underlying disease or abnormality. The change is demonstrated most clearly in the way drugs have come to be named and classified. Prior to the 1950s drugs were classified according to the nature of the psychoactive effects they produce. Existing drugs were crudely classified as having either sedative or stimulant effects on the nervous system. After the 1950s, however, drugs came to be named and classified according to the disease or disorder they are thought to treat; antidepressants, antipsychotics and anxiolytics, for example.

The ascendance of the disease-centred model of drug action did not occur because of overwhelming evidence of the superiority and truth of the disease-centred model. There was not then, and is not now, convincing evidence that any class of psychiatric drugs has a disease centred or disease-specific action. There was not even any real debate about alternative theories of drug action. The disease centred model just took over and the drug-centred view simply faded away. People forgot there had ever been another way of understanding how psychiatric drugs might work.

In summary, we should set aside the serotonin theory of depression because it has not produced convincing evidence of a biochemical basis for depression. Psychiatric diagnosis appears to be circular reasoning that describes states of mental distress, but does not provide a causal explanation of that distress. The withdrawal symptoms when tapering, discontinuing or changing antidepressant medications leads to a misdiagnosis of recurrent major depression or another psychiatric disorder. We need to return to a drug-centered model of drug action to get off of the medication merry-go-round.

It seems we are beginning to pay attention to a question asked by psychiatrist Peter Breggin 25 years ago in Your Drug May Be Your Problem: “Do we know what we are doing to our brains and minds when we take psychiatric drugs?” Doctor Breggin said: “We simply do not understand the overall impact of drugs on the brain.”

Consider this extraordinary reality. The human brain has more individual cells (neurons) than there are stars in the sky. Billions! And each neuron may have 10,000 or more connections (synapses) to other brain cells, creating a network with trillions of interconnections. In fact, the brain is considered to be the most complex organ in the entire universe. With its billions of neurons and trillions of synapses, it is more complex than the entire physical universe of planets, stars, and galaxies . . .

Those trillions of interconnections between brain cells … are mediated by hundreds of chemical messengers (neurotransmitters), as well as hormones, proteins, tiny ions, such as sodium and potassium, and other substances. We have limited knowledge about how a few of these chemical messengers work but little or no idea as to how they combine to produce brain function.

01/16/24

Doubling Down on STAR*D Outcomes

In January of 2006, the NIMH announced the results of Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study, the largest and longest study ever done to evaluate depression treatment. Its purpose was to determine the effectiveness of different treatments for people with Major Depression Disorder (MDD) who did not respond initial treatment with an antidepressant. The startling STAR*D results reported that almost 70 percent of those who did not withdraw from the study became symptom-free. “For the first time, doctors and people with depression now have extensive data on antidepressant treatments from a federally funded, large-scale, long-term study directly comparing treatment strategies.” However, the true remission rate turned out to be 35%, around half of what was reported.

In August of 2023 Ed Pigott and other researchers reanalyzed and published the patient-level data set from the STAR*D study in the British Medical Journal (BMJ), keeping their analysis to the original research protocol. They discovered the STAR*D investigators did not use did not use the STAR*D protocol-stipulated HRSD (Hamilton Rating Scale for Depression), but instead used a non-blinded clinic-administrated assessment, known as the QIDS-C, the Quick Inventory of Depressive Symptomatology. They also included 99 patients who scored as remitted on the HRSD at the outset of the study as well as 125 who scored as remitted when initiating their next-level treatment. “This inflated their report of outcomes.”

Unfortunately, the STAR*D investigators’ assertion of a 67% cumulative remission rate had already become accepted clinical wisdom. The NIMH’s director at the time, Thomas Insel, and an editorial in the American Journal of Psychiatry both claimed STAR*D participants achieved a 70% remission rate. “Our reanalysis found that in step 1, STAR*D’s remission and extent of improvement rates were substantially less than those reported in other open-label antidepressant comparator trials and then grew worse in steps 2-4.” The remission rate in step 1 was 25.5%; by step 4, it was only 10.4%.

Robert Whitaker further reported that Pigott and others discovered only 3% of the participants who entered the trial remitted and stayed well in the trial to its end in one year. One of the STAR*D investigators thought Pigott’s analysis was “reasonable and not incompatible with what we had reported.” That was 13 years ago and as of yet, there hasn’t been a public acknowledgement that these protocol violations were a form of scientific misconduct.

Yet, there has been no public acknowledgement by the American Psychiatric Association (APA) of this scientific misconduct. There has been no call by the APA—or academic psychiatrists in the United States—to retract the studies that reported the inflated remission rates. There has been no censure of the STAR*D investigators for their scientific misconduct. Instead, they have, for the most part, retained their status as leaders in the field.

Thus, given the documented record of scientific misconduct, in the largest and most important trial of antidepressants ever conducted, there is only one conclusion to draw: In American psychiatry, scientific misconduct is an accepted practice.

Whitaker said this presented a challenge to American citizens. If the American Psychiatric Association would not police its own research, it was up to the public to demand the STAR*D paper be withdrawn from the American Journal of Psychiatry. “As STAR*D was designed to guide clinical care, it is of great public health importance that this be done.”

He persuasively argued that there had been an intent to deceive. He said once Pigott and colleagues identified the deviations from the STAR*D protocol (which they did initially in 2010), “the STAR*D investigators’ ‘intent to deceive’ was evident.” After Pigott made the protocol and other key documents available in 2011 on two blogs for the Mad in America website, the scientific community could see the deception.

Their recent RIAT publication [in August of 2023] makes it possible to put together a precise numerical accounting of how the STAR*D investigators’ research misconduct, which unfolded step by step as they published three articles in 2006, served to inflate the reported remission rate. This MIA Report lays out that chronology of deceit. Indeed, readers might think of this MIA Report as a presentation to a jury. Does the evidence show that the STAR*D’s summary finding of a 67% cumulative remission rate was a fabrication, with this research misconduct born from a desire to preserve societal belief in the effectiveness of antidepressants?

In Psychiatry Under the Influence Whitaker and his coauthor Lisa Cosgrove wrote about how the STAR*D trial was an example of institutional corruption. They said there were two forms of institutional corruption, or economies of influence, driving that corruption: psychiatry’s guild interests and the extensive financial ties the STAR*D investigators had with the pharmaceutical industry. They said:

Although this was a NIMH-funded trial, industry influence was indirectly present during the trial. Rush and at least seven other STAR*D investigators had financial ties to Forest Laboratories, the manufacturer of Celexa. The investigators’ collective disclosure statement revealed hundreds of ties to pharmaceutical companies, with many investigators reporting that they had served as both consultants and speakers. Yet, given that this was a NIMH-funded trial, STAR*D couldn’t be blamed on the drug companies, and it could be argued that the “corruption” seen here far outstripped anything seen in a commercial trial of the SSRI antidepressants. (p. 129)

Whitaker said the American Psychiatric Association is best understood as a trade association that promotes the financial and professional interests of its members. The APA has long touted antidepressants as effective and safe treatment. He thought if the STAR*D results has been accurately reported, they would have derailed society’s belief in the safety and efficacy of antidepressants. The STAR*D investigators were, in a business sense, protecting one of their primary “products.” And they were safeguarding the public image of their profession.

This research misconduct has done extraordinary harm to the American public, and, it can be argued, to the global public. As this was the study designed to assess outcomes in real-world patients and guide future clinical care, if the outcomes had been honestly reported, consistent with accepted scientific standards, the public would have had reason to question the effectiveness of antidepressants and thus, at the very least, been cautious about their use. But the fraud created a soundbite—a 67% remission rate in real-world patients—that provided reason for the public to believe in their effectiveness, and a soundbite for media to trot out when new questions were raised about this class of drugs.

This, of course, is fraud that violates informed consent principles in medicine. The NIMH and the STAR*D investigators, with their promotion of a false remission rate, were committing an act that, if a doctor knowingly misled his or her patient in this way, would constitute medical battery.

This cataloging of harm done extends to those who prescribe antidepressants. Primary care physicians, psychiatrists, and others in the mental health field who want to do right by their patients have been misled about their effectiveness in real-world patients by this fraud.

The harm also extends to psychiatry’s reputation with the public. The STAR*D scandal, as it becomes known, fuels the public criticism of psychiatry that the field so resents.

Believing this to be a matter of great importance to public health, Mad in America put up a petition on change.org urging the American Journal of Psychiatry to retract the November 2006 article on the STAR*D results. Their hope is that the petition will circulate widely on social media and produce a public call for retraction that will grow too loud for the American Journal of Psychiatry to ignore. Whitaker hoped the publication of the August 2023 article by Pigott and others linked above in the prestigious journal British Medical Journal will lead the American Journal of Psychiatry to retract a paper that told a fabricated story about the outcome of the STAR*D study.

On December 1, 2023 the American Journal of Psychiatry published a letter from John Rush and four other STAR*D researchers, “The STAR*D Data Remain Strong: Reply to Pigott et al.” The researchers claimed the analytic approach by Pigott et al. had significant methodological flaws and stood by their results and methodology in STAR*D. They further said the effectiveness trials of their study were designed “to be more inclusive and representative of the real world than efficacy trials.” Pigott et al failed to recognize this rationale for the inclusion of the 941 patients in the original analyses that were eliminated from their reanalyses by Pigott et al.

The rationale for removing these participants from the longitudinal analysis appears to reflect a studious misunderstanding of the aims of the Rush et al. paper, with the resulting large difference in remission rates most likely the result of exclusion by Pigott et al. of hundreds of patients with low symptoms scores at the time of study exit.

Robert Whitaker responded to the letter in “After MIA Calls for Retraction of STAR*D Article, Study Authors Double Down.” He said the STAR*D investigators had inflated the “cumulative remission rate” in four principal ways. First by including ineligible patients in their tally of remitted patients. Second, by switching outcome measures. Third, by categorizing early dropouts as non-evaluable patients. Fourth, by calculating a “theoretical” remission rate.

By the end of their letter, they again affirmed the 67% cumulative remission rate. Whitaker thought they had “doubled-down on the fraud they committed in their 2006 summary report of STAR*D outcomes.”

Now that the STAR*D authors have “defended” their work, all the public really needs to know is this: The STAR*D investigators, by including 931 patients who weren’t eligible for the study in their final tally of cumulative remissions, greatly inflated that bottom-line outcome. That is research fraud, and in their letter to the editor, rather than admit that these patients weren’t eligible for the study, they instead falsely accused Pigott and colleagues of “creating” their own “post-hoc” criteria to remove those with “large improvements” in symptom scores from their re-analysis.

Whitaker said the STAR*D scandal evolved into a litmus test for psychiatry. Would they acknowledge the research misconduct and inform the public of how the STAR*S study had been compromised? Was it okay to deceive the public in this way? “And now, with this letter to the editor, we know the answer to that litmus test.”

07/18/23

Repeating Past Mistakes with Esketamine

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.

11/22/22

Brain Stimulation or Brain Damage? Part 2

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 18^th 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

10/25/22

The Myth of the Serotonin Theory of Depression

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.

09/20/22

The Death of the Chemical Imbalance Theory?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

02/19/19

The Death of Melancholia, Part 2

Dr. Bernard Carroll died of lung cancer on September 10, 2018. The New York Times heralded him as the “conscience of psychiatry,” but the work that brought him that label happened later in his professional career. At the youthful age of 28, he published a paper, “Resistance to Suppression by Dexmathasone of Plasma 11-O.H.C.S. Levels in Severe Depressive Illness,” that essentially argued there was a “blood test” for severe depression. The dexamethasone suppression test (DST) measures the body’s ability to suppress cortisol, a stress hormone. But it was too late. Melancholia had already died at the hands of Emil Kraepelin.

In a 1968 article in the British Medical Journal, Dr. Carroll announced that when the test was administered to people with the severest species of depression — a paralyzing gloom then called melancholia, or endogenous depression — their bodies were shown to have trouble suppressing the hormone. People with other kinds of mood disorders had normal scores.

He thought it could be a confirmatory test for a diagnosis of depression—not as a way to actually make a diagnosis in the first place. But nothing happened. The DSM was in the midst of an extreme makeover as psychiatry fought for survival (See “The Quest for Psychiatric Dragons” Part 1 and Part 2 for more on this). Its architects weren’t interested in two distinct kinds of depression. Melancholia was lumped into “major depression” with several other mild and moderate disorders. Edward Shorter said:

Barney’s application of the DST to serious depressive illness was a huge step forward in establishing a biological base for serious depression. . . . It identified a biologically homogeneous group of serious depressives that could then be studied with the tools of molecular biology . . . . [But] the DST was pushed aside before anyone had a chance to do this, and one of the few biological tests in psychiatry has since then lain fallow.

Melancholia had successfully separated from the Hippocratic theory of humors by the late nineteenth century, and was gathering credibility as a distinct mood disorder. However, “Emil Kraepelin … killed off melancholia and prompted its replacement with depression.” In How Everyone Became Depressed, Edward Shorter carefully documented how this took place between the fourth and eighth editions of Kraepelin’s book, Psychiatry: A Textbook for Students and Physicians. By 1913 Kraepelin had convinced himself that what were presented as separate illnesses were instead “a single disease process.” He said: “It is, as far as I know, entirely impossible to discern any particular boundaries among these individuals clinical pictures, that until now have been separate.”

Shorter said Kraepelin’s influence in renaming melancholia “depression” was enormous. But alone, it was not enough to explain how “everybody became depressed.” Freud and the influence of psychoanalysis upon American psychiatry would also play a crucial role. Ironically, Freud had little interest in depression and only wrote about it within one paper, “Mourning and Melancholia” in 1916. It was one of his disciples, Karl Abraham, who wrote about depression as a neurosis, rather than about melancholia or manic-depression. Abraham thought depressive affect to be as widespread as anxious affect, with both conditions often occurring in the same person. “This was the beginning of neurotic depression as a diagnosis separate from the other big depressive illnesses.”

Otto Fenichel then became a central figure in the acceptance of neurotic depression among psychoanalysts. In his book Outline of Clinical Psychoanalysis, written in 1933, he commented how all varieties of neuroses could develop depression. After moving to Los Angeles in 1938, his revised and expanded edition said: “Neurotic depressions are desperate attempts to force an object to give the vitally necessary [narcissistic] supplies, whereas in the psychotic depressions the actual complete loss has really taken place and regulatory attempts are aimed exclusively at the superego.”

To understand why depression became such a huge diagnosis, we thus have the role of psychoanalysis, the thread that begins with Karl Abraham and passes through the émigré analysts, to make depth psychology such a popular conveyor belt for neurotic depression. It is almost unimaginable to us today that psychoanalysis once represented the very heart and soul of psychiatry.

Meticulously, Shorter then traced the wanderings of neurotic depression through the maze of psychoanalysis and its importance to American psychiatry. Depression had become a significant diagnosis by the time of World War II. “By World War II depression had become the standard term for any accumulation of symptoms involving fatigue, anxiety, and so forth. But this was a depression that was far from melancholia.” Many of the patients who received the diagnosis did not appear depressed. A psychiatrist at the University of Toronto said in 1952: “An outstanding feature of mild depression is that the patient rarely complains of feeling depressed and often does not appear particularly despondent.”

Then in 1974 the American Psychiatric Association chose Robert Spitzer to chair the Task Force to revise the DSM-II. He was a junior figure who at the time had developed an interest in the classification of psychiatric disorders. Shorter said he had little exposure to clinical psychiatry “and did not have that deep intuitive understanding of psychological illness that many senior clinicians acquire.” His strong will and determination to impose his own ideas infuriated other Task Force members and made him difficult to work with. Melvin Sabshin said:

Dr. Spitzer had had an immense degree of effort and dedication to the process of developing a new nomenclature. The problem in that, however, has been that Dr. Spitzer has not necessarily thought through how one goes about educating psychiatrists or other mental health professionals and is so exceedingly sensitive to any negative input (to which he responds as if there were an attack on his knowledge, integrity, etc.) that it is difficult to deal with him.

Shorter said Spitzer saw himself in a political, not a scientific battle in formulating the DSM-III. The goal was to win, not necessarily to establish scientific exactness. Above all he wanted to triumph over the despised psychoanalysts. He was determined to exterminate the diagnosis neurotic depression, which had become a favorite of the analysts. “He negotiated a number of political concessions that made little scientific sense.”

Spitzer had collapsed the two depressions of melancholia and nonmelancholia, in use in psychiatry for over two centuries, into a single depression, called major depression, and ensured that it was the only diagnosis you could get into unless you were seeing a psychoanalyst and could qualify for neurotic depression. Major depression, often simply called “depression,” went on to become the diagnosis of one-tenth of the United States population.

Max Fink, one of the pioneers of biological psychiatry commented on the paradigm shift from manic-depression to major depression: “When it was manic depressive illness, it was a small number of people. When it became major depression . . . 50 percent of the people are depressed. That’s absurd. That means there’s something wrong with the label.”

02/12/19

The Death of Melancholia, Part 1

Being depressed is experiencing five or more of nine diagnostic criteria within a two-week period of time. And despite other mood disorders like bipolar disorder, dysthymic disorder, cyclothymic disorder or depressive disorder NOS, (not otherwise specified), there is not a clear distinction between these kinds of depression. The older conceptualization suggested we had a problem of nerves—that it was an illness of the entire body. But according to Edward Shorter, “The current classification is a jumble of nondisease entities, created by political infighting within psychiatry, by competitive struggles in the pharmaceutical industry, and by the whimsy of the regulators.”

Today, with the ubiquity of the diagnosis of depression, we have the idea that low mood and an inability to experience pleasure are our main problem; we see ourselves as having a mood disorder situated in the brain and in the mind that antidepressants can correct. But this is not science; it is pharmaceutical advertising.

Depression is conceptualized and presented as if it exists on an interval scale, ignoring the possibility it may be two or more disorders overlapping one another. In How Everyone Became Depressed, Edward Shorter persuasively advocated that there are two kinds of depression, “as different as tuberculosis and mumps.” He said it made no sense to lump them together under the general term of “depression.” The first kind of depression was nonmelancholic and nonpsychotic, “heavily admixed with anxiety and fatigue.” It is laced with obsessive thinking and often overcome by somatic complaints. The second kind of depressive disorder was melancholia:

It is an independent and unmistakable disease entity, often not combined with anything, and fearsome in a far different way than nervousness, for it may lead to despair, hopelessness, a complete lack of pleasure in one’s life, and suicide. By the late nineteenth century, the difference between these two depressions lay clear in view and observers often distinguished between them. Subsequently, both swim out of focus; nervous disease is broken up, and what we have emerged with today as “depression” bears little resemblance to these historic ancestors.

According to Shorter melancholia is a disease of the whole body. “The endocrine system is intimately involved, and the blackness of affect reaches into the adrenal gland.” Affect is profoundly flattened. Stupor and dejection can alternate with periods of agitation. Oswald Bumke said in 1908, “The essential characteristic of melancholia is a sadness of mood that is not founded in external circumstances, a strongly depressive affect, from which a gloomy assessment of one’s own situation arises, as well as ideas of having sinned in the past and anxious fears about the future.”

Melancholia appears to be sadness, but is often described by patients as pain. A Florida psychiatrist said, “Most of my patients suffering from major depression have described their malady as the worst pain they have had to beat.” Melancholics often look dejected. They have empty eyes and frozen features. They also have slowed thought and movement—psychomotor retardation. “All movements are conducted slowly, any change of bodily position is avoided; the speech is soft, halting and limited to what is absolutely necessary.”

Melancholics at risk of suicide can be difficult to assess because they complain of everything but their mental pain. Shorter suggested it could be that admitting depression in these circumstances “would cause others to thwart your desire for suicide.” In 1911 The New York Times described a doctor at St. Francis Hospital in Pittsburgh who was suffering from a complete nervous breakdown. After shaving under supervision, he asked a male nurse to accompany him to a bathroom and when there, sent the man on an errand. The man had concealed a razor in his pajamas. A few minutes later a doctor saw a stream of blood running from under the door. “Dr. Miller was found with his throat cut from ear to ear.”

What emerges from the stories of melancholic patients is how different they are from patients with nervous disease. This is not a continuum of gravity that begins with the mildly nervous and ends with patients curled into a fetal ball, but a discontinuity as two different kinds of illness somehow end up with depression as their name. Melancholia was not neurotic depression.

Shorter said from the seventeenth century medical writers have described melancholia similar to what was said here. This suggests that we are dealing here with a relatively unchanging biological type, according to Shorter. Other psychiatric illnesses seem to be influenced by personal beliefs and social attitudes. However, in medical writing what changes historically is the distinction of melancholic depression from other kinds. “But the basic melancholic prototype has been visible from the beginning.”

Shorter reserves a distinct, biological niche for melancholia and it seems to fit within a modern dispute over the effectiveness of antidepressants with more severe cases of depression. The melding of melancholia into depression brought about confusion with diagnosis and generated the “jumble of nondisease entities,” which we will examine in the second part of this article. I suggest first that we should look back to the origins of the term and how it too has changed its meaning over time.

Melancholia stems from the Greek melan (black, dark) and chole (bile). Medical practitioners once thought the human body had a system of humors—bodily fluids that included black bile, yellow bile, blood and phlegm. An imbalance of the humors was thought to result in sickness of the body and mind. An excess of black bile (thought to be secreted by the kidneys or spleen) meant the person could become unsociable, liable to anger, irritable, brooding and depressed.

Telles-Correia and Gama Marques said in “Melancholia before the twentieth century” that Richard Burton commented in his 1621 book, The Anatomy of Melancholy, on the confused state of melancholia: “The tower of Babel never yielded such confusion of tongues as the chaos of melancholy doth variety of symptoms.” The authors went on to note Hippocrates (460-379 BC) attributed melancholy to the excess of black bile, which was characterized by several symptoms, including fear and sadness. Galen (129-216 AD) followed Hippocrates in his theory of the four humors, but saw melancholics also having what we would call delusions. Aretaeus of Cappadocia (1^st century AD) also saw melancholy as having a delusional element. Andreas Laurentius (1560-1609) followed Galen and Hippocrates in seeing it was caused by an excess of black bile and saw melancholics having “a disturbed imagination.”

Richard Burton (1577-1640) began to move away from the humor theory of depression and likened the task of gathering the meanings of melancholia to “capturing [a] many-headed beast.” While people suffering from melancholia present with multiple symptoms, the most frequent are fear and sorrow. He defined melancholy as follows:

Melancholy, the subject of our present discourse, is either in disposition or in habit. In disposition, is that transitory Melancholy which goes and comes upon every small occasion of sorrow, need, sickness, trouble, fear, grief, passion, or perturbation of the mind, any manner of care, discontent, or thought, which causes anguish, dulness, heaviness and vexation of spirit, any ways opposite to pleasure, mirth, joy, delight, causing forwardness in us, or a dislike. In which equivocal and improper sense, we call him melancholy, that is dull, sad, sour, lumpish, ill-disposed, solitary, any way moved, or displeased. And from these melancholy dispositions no man living is free, no Stoic, none so wise, none so happy, none so patient, so generous, so godly, so divine, that can vindicate himself; so well-composed, but more or less, some time or other, he feels the smart of it. Melancholy in this sense is the character of Mortality… This Melancholy of which we are to treat, is a habit, a serious ailment, a settled humour, as Aurelianus and others call it, not errant, but fixed: and as it was long increasing, so, now being (pleasant or painful) grown to a habit, it will hardly be removed.

Phillipe Pinel (1745-1826) abandoned the humoral theory entirely and favored a more descriptive psychopathology. He narrowed the field of mental disorders into four groups: Melancholia, Mania, Idiocy and Dementia. For Pinel, melancholia had two opposite forms, seemingly describing what we now call bipolar disorder. The first sense was “a heightening of pride and the chimeric idea of possessing infinite richness and power without limits.” And the second form was “the most fearful despondency, a profound dejection or even despair, therefore considering two forms of melancholia: depressive and expansive.”

In the beginning of the twentieth century the term melancholia was replaced by the term depression, largely under the influence of Emil Kraepelin. Today it carries some significance with certain cases of severe depression, but is known as endogenous depression—not a distinct kind of depression. Melancholia (endogenous depression) is characterized by profound sadness, anhedonia, a loss of emotional resonance, insomnia, anorexia, motor retardation, circadian variability in mood, and the presence of delusions and/or hallucinations. In Part 2 we will look at how Emil Kraepelin and Robert Spitzer finally “killed off” melancholia as a separate disease from depression.

02/16/16

Nearsighted Drug Development

I was encouraged to hear that ALKS 5461 failed in two late-stage clinical trial studies. This isn’t because I have something against Alkermes, the pharmaceutical company developing the drug. I don’t own stock in a competing company trying to bring their new fast-acting antidepressant drug to market ahead of Alkermes. I do think antidepressants are overprescribed and have potentially harmful side effects for some people, but that’s not why I was happy to hear that ALKS 5461 is in trouble. I just don’t think that putting an antidepressant drug on the market that uses a potentially addictive opioid as its active ingredient is a good idea.

Reporting for Reuters, Amrutha Penumudi said that when news of the failed clinical trails for ALKS 5461 were made public by Alkermes, the company saw its shares fall in value by 42.8%, a $3.88 billion loss for the company. ALKS 5461 is the company’s main product, so the bad news about the clinical trials was a major financial blow. William Tanner, an analyst for Guggenheim Partners was widely quoted by Reuters and others as saying that “We believe trial failures present a major setback in the evolution of the company.” Even if ALKS 5461 succeeds in a third as-yet not completed clinical trial, more studies may be required, according to Ken Cacciatore.

ALKS 5461 is a new molecular entity (NME) that has been fast tracked by the FDA for approval as a treatment of Major Depressive Disorder (MDD) with patients who didn’t respond to standard antidepressant therapies. It is a combination of buprenorphine, a Schedule IV Controlled Substance and samidorphan, a naloxone-like substance. Suboxone, which is a combination of buprenorphine and naloxone, is commonly used as an opioid substitution medication for heroin and prescription opioid addicts. The major difference between ALKS 5461 and Suboxone as far as buprenorphine is concerned is that ALKS 5461 is currently being tested in 2 mg and .5 mg doses, where standard protocols for Suboxone as an opioid substitution drug could reach 16 mg or higher. You will find more information on ALKS 5461 and my concerns about its use to treat depression in: “The Coming Depression Apocalypse,” an article I published here a few months ago.

But it doesn’t seem Alkermes is going to give up the fight. In their press release, Richard Pops, the CEO of Alkermes said:

We are steadfast in our commitment to developing new medicines for serious CNS conditions where there is a clear and compelling need for new treatment options for patients and their families. . . . Major depressive disorder is one of these conditions. We are building a large body of evidence supporting our belief in the clinical utility and the novel mechanism of action of ALKS 5461. We await the results of FORWARD-5 and will determine our next steps along the regulatory path with those results in hand.

In one of the failed trials, Alkermes did post-hoc analyses (reanalysis of the data after the fact) that indicated the 2 mg dose was more effective than a placebo. Given the results of the two failed studies, Alkermes said they plan to increase the number of patients in the ongoing trial and “update” the planned statistical analysis for FORWARD-5, the third efficacy study in the FORWARD program. The updated analysis sounds like it means they plan to use the same analysis process applied to the 2mg dose group for FORWARD-4 after the fact. This is bit like cheating if the researchers went p-hacking or data-dredging in their post-hoc analysis. See “How to Lie About Research” for more information on p-hacking.

Another factor regarding Alkermes and ALKS 5461 that concerns me is how the company describes the drug. In their above-linked press release, Alkermes said that ALKS 5461 acted “as a balanced neuromodulator in the brain;” and was “designed to rebalance brain function that is dysregulated in the state of depression.” This sounds eerily similar to the chemical imbalance theory of depression that even psychiatrists such as Ronald Pies have said was always a kind of urban legend. In an article in Psychiatric Times, he said: “To my knowledge, no professional psychiatric organization has ever publicly promoted a ‘chemical imbalance theory’ of mental illness in general.” Look at Robert Whitaker’s response to that article by Pies and the reams of additional evidence to show how Pies’ claim was clearly wrong.

But there is now another concern with the use of opioids to treat depression. A study by Scherrer et al., published in the Annals of Family Medicine, found that people who used prescription opioids for longer than a month may have an increased risk of developing depression. Scherrer was quoted by Agata Blaszczak-Boxe for Live Science as saying the researchers rigorously controlled for pain, “and we feel strongly that these results are independent of the known contribution of pain to depression.” The longer individuals were taking opioids, the greater was their risk of depression.

Citing a 2014 study by Howe and Sullivan in General Hospital Psychiatry, Scherrer et al. said that research on the efficacy of opioids in treating depression was limited by small sample sizes, short follow-up time and lack of control groups. So they do not support opioids as effective long-term treatments for depression. “This evidence, combined with the finding from the present study, supports the conclusion that opioids may cause short-term improvement in mood, but long-term use is associated with risk of new-onset depression.”

Buprenorphine was not one of the opioids studied, but the findings of the Scherrer et al. study does give me increased concern with the fast-track status the FDA has given ALKS 5461. Recent findings do suggest the risk of new onset of depression increases with a longer duration of opioid use. A replication attempt of Scherrer’s study with buprenorphine seems needed before approving ALKS 5461. The short-term projected improvements could lead to long-term problems with depression. “Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression.”

Hopefully the FDA will have the foresight to weigh all the potential adverse effects with ALKS 5461 before approving it. There is a very real potential for physical dependency to develop with ALKS 5461 given that its active ingredient is a Schedule IV controlled substance. Heroin addicts have told me buprenorphine was more difficult for them to come off of than heroin or methadone. And to top it all off, there seems to be evidence that using opioids longer than 30 days carries a risk of new-onset depression. This is not a very promising profile for a future treatment for depression.

Additionally, the initial statistical analysis done on the first two clinical trials failed to demonstrate that it was more effective than a placebo. Only after a post hoc analysis was there evidence of any statistically significant results. And then it was only with the higher, 2mg, dose. Will that lead to even higher doses of buprenorphine to increase its effectiveness? Read more on the concerns with outcome switching in clinical trials here.

Revising the statistical analysis (outcome switching) of the remaining clinical trial may produce statistically significant results, and if it does, it seems Alkermes intends to argue with the FDA to approve ALKS 5461. On the one hand, I can see where Alkermes would attempt to salvage their “lead product.” But I’m hoping their nearsighted focus on profits and the company’s market value will not blind the FDA to the long-term consequences of using opioids like buprenorphine to treat depression.

06/17/15

The Coming Depression Apocalypse

According to the Motley Fool, the pharmaceutical company Alkermes has a potential blockbuster drug for treating major depression in its pipeline. Currently in Phase 3 clinical trials, ALKS-5461 is one step away from Alkermes filing for approval by the FDA. Mental Health Daily reported that ALKS-5461 was given fast track approval by the FDA and is expected to be available in 2016. Its projected use is as a supplementary treatment to current antidepressant drugs. But once approved, the “supplementary” element will likely stop because it’s new and fast acting. The problem is, the drug in ALKS-5461 that is supposed to treat depression is an opioid with addictive potential.

Before going further on this issue, we need to take a short trip into pharmacology and neurotransmitter function in order to understand what’s going on. There are proteins embedded within the membrane of a cell called receptors. These receptors receive chemical signals from outside the cell, and in turn produce a biochemical reaction inside the cell. The chemicals that bind and activate a specific receptor are called agonists. While an agonist causes a reaction, an antagonist blocks that reaction from occurring within the cell. It turns the cell off from the influence of the agonist.

Receptors are activated by either endogenous agonists (hormones or neurotransmitters), or exogenous agonists (drugs). Endogenous agonists are produced by the body. The endogenous opioid agonists include dynorphins, and the more widely known endorphins. If you want more information on biochemistry and neurotransmitter activity, try these Wikipedia pages for starters: opioid receptor, mu-opioid receptor, and agonist.

Opioids are known to have energizing and mood enhancing effects with some users. This effect seems to be associated with dynorphin, which is elevated in depression. Dynorphin is a full agonist for the kappa opioid receptor (KOR). Studies like that done by Knoll and Carlezon, “Dynorphin, Stress and Depression,” suggest that KOR antagonists may have a potential therapeutic potential in treating anxiety and depression. While this biochemical hypothesis makes sense to psychiatrist Daniel Carlat, in The Carlat Psychiatry Report, he was more reserved on the treatment potential of ALKS-5461 than Mental Health Daily and the Motley Fool.

The efficacy of ALKS-5461 for depression remains to be seen. Some trials of ALKS-33 alone have already been performed, particularly in the areas of alcohol dependence and binge-eating disorder. These have been negative.

Now let’s look at my concern with ALKS-5461. First, it is a combination of buprenorphine, and samidorphan, or ALKS-33. Buprenorphine is used in addiction treatment as a detoxification drug and in opioid maintenance therapy, where its brand names are Suboxone (buprenorphine with naloxone) and Subutex (buprenorphine without naloxone). Suboxone and Subutex are classified as Schedule III controlled substances, meaning they have a moderate to low potential for physical and psychological withdrawal. Other Schedule III drugs include ketamine and anabolic steroids.

Buprenorphine is a partial mu opioid agonist, meaning it displaces morphine, methadone, and other full opioid agonists from activating the mu opioid receptor (MOR). But it does not provide the same degree of receptor activation as the full agonists (It doesn’t get you as high), resulting in a net decrease of agonist effect and the onset of withdrawal if it used soon after a full agonist like heroin. Patients planning to begin Suboxone maintenance therapy are told to abstain from opioids for twenty-four hours before their first dose of Suboxone.

At lower doses and with individuals who are not dependent on opioids, both full agonists like heroin and partial agonists like buprenorphine will produce identical euphoric effects. Partial agonists like buprenorphine also have a ceiling effect, meaning that past a certain point, typically 12 to 16 mg, no difference in analgesia, euphoria and respiratory depression will be felt.

Buprenorphine does produce physical dependence. Reportedly, this is to a lesser degree than full opioid agonists; and it is supposed to be easier to discontinue at the end of medication treatment. While this is the received wisdom on websites like NAABT, The National Alliance of Advocates for Buprenorphine Treatment, that has not been the case for what I’ve observed clinically with individuals who have tried buprenorphine. Generally I’ve heard that buprenorphine is harder to kick than heroin. So ALKS-5461 will be treating depression with a drug that may be harder to kick than heroin.

Buprenorphine is also a full antagonist of the kappa opioid receptor (KOR), which underlies its use in ALKS-5461 as an antidepressant. If the production of dynorphine by KOR receptors increases with depression, theoretically then buprenorphine would block these receptors and limit the release of dynorphine—elevating the individual’s mood. Peter Tenore, in “Psychotherapeutic Benefits of Opioid Agonist Therapy,” said that opioids like buprenorphine could be “effective, durable and rapid therapeutic agents for anxiety and depression.” The problem is with the partial agonist effect that buprenorphine has on mu opioid receptors (MOR) you can still use buprenorphine to get high.

That was the rationale for combining naloxone with buprenorphine in Suboxone. Naloxone is an opioid antagonist that counters the effects of opioids at the mu receptor, but doesn’t trigger a euphoric effect. Marketed under the brand name of Narcan, naloxone is used to counter the effects of opioids in overdose situations. The death of Phillip Seymour Hoffman led to calls for greater availability of naloxone (see “The Opioid-Heroin Cycle”) for individuals to use in overdose situations.

While naloxone is still the standard medication for emergency reversal of opioid overdose, its clinical use in long-term opioid addiction treatment is being superseded by naltrexone. Naltrexone (C20H23NO4) is structurally similar to naloxone (C19H21NO4), and samidorphan (C21H26N2O4). But it has a slightly increased affinity for κ-opioid receptors (KOR) and has a longer duration of action than naloxone. Naltrexone is used as a preventative medication for opioid use disorder in Vivitrol, whose marketing rights are owned by Askemet.

Samidorphan (ALKS-33) is also a full opioid antagonist, acting on the MOR receptor with mixed agonist-antagonist activity at the KOR receptor. Combining samidorphan with buprenorphine is supposed to block the agonist effect of buprenorphine on the MOR receptor, while not inhibiting the buprenorphine antagonist effect on the KOR receptor. A study by Shram et al. comparing samidorphan to naltrexone was published online ahead of the June 2015 issue of the Journal of Clinical Psychopharmacology. Samidorphin was found to have greater binding affinity than naltrexone to mu receptors and a longer half-life. This was suggestive of prolonged opioid receptor antagonism at lower doses of samidorphin. The study, though, was funded by Askemet.

Suboxone (buprenorphine and naloxone) and ALKS-5461 (buprenorphine and samidorphin) appear to be biochemical twins. And it does not seem to me that the addictive potential of buprenorphine has been entirely neutralized by its combination with samidorphin as claimed. The history of abuse and diversion with Suboxone supports this concern. If my fear is true, then in the name of treating depression, ALKS-5461 will create a huge population of individuals who become dependent upon buprenorphine.

Coming off of buprenorphine is not fun. Here is a personal testimony of someone tapering off of buprenorphine. Oh, and mood swings with bouts of anxiety or depression are common side effects with buprenorphine withdrawal.

Buprenorphine withdrawal symptoms last longer for those who use buprenorphine for longer periods of time or at higher doses. Additionally, those who use buprenorphine other than prescribed (snort, inject, chew) may experience more severe symptoms than someone taking buprenorphine as prescribed. In these cases, physical buprenorphine withdrawal symptoms can last weeks after stopping.However, psychological withdrawal symptoms can last for many months after cessation. It is recommended that you join a support group or see a psychologist who can help see you through the protracted or post acute withdrawal symptoms (PAWS). Many heavy buprenorphine users experience PAWS. With continued use of buprenorphine, there comes a point where the brain produces in an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS manifest long lasting changes in the brain as a result of long term use.

The Substance Abuse and Mental Health Services Administration (SAMHSA) estimated that in 2013, 1.8 million people had an opioid use disorder; 517,000 of which had one related to heroin use. SAMHSA also estimated that each year, 9.1% of the adult population experience symptoms consistent with major depression. One 2012 study suggested that 10% to 30% of individuals with major depression suffer from treatment resistant depression. Using a U.S. population estimate of 320.94 million, with a median 20% for individuals with treatment resistant depression, that leaves a target population of over 5.84 million Americans with treatment resistant depression. God help us.

I don’t think it is too strong rhetorically to speak of a pending depression apocalypse. I hope I’m wrong. But widespread use of ALKS-5461 could instigate a huge population of individuals dependent upon buprenorphine. And the problems coming off of ALKS-5461 would eclipse what we now know happens with SSRI withdrawal. Within the biochemical worldview, these symptoms will be reinterpreted as evidence of the underlying depression and proof the individual needs to remain on ALKS-5461. Sound familiar?

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: depression