Desperate Remedies

History shows us that the mentally ill are extraordinarily vulnerable to therapeutic experimentation.  Their situation is not unique of course.  Others suffering from chronic illnesses for which there are no obvious remedies have often been subjected to dangerous and mutilating therapies later shown to be of little or no therapeutic value.  Sometimes this has occurred at the hands of mainstream medics.   Others have found themselves preyed upon by charlatans and quacks.  The history of the treatment of syphilis or of cancer provides many examples of this phenomenon.  But those afflicted with serious mental illness seem singularly prone to such a fate, and the interventions directed at them have been particularly brutal and extreme.¹

In the period between the 1920s and the 1940s, for example, the belief that chronic infections were poisoning the brain and causing people to go mad licensed an orgy of “surgical bacteriology” — the removal of thousands of teeth and tonsils and then, when that failed to produce cures, the surgical excision of stomachs, spleens, colons and uteruses.  Horse serum was injected into spinal canals to produce meningitis, on the forlorn hope that this would stimulate the immune system to combat whatever was throwing the brain off track.  Barbiturates were administered to put patients into deep sleep to reduce the over-stimulation of the nervous system, and subsequently one of the major medical advances of the early twentieth century, insulin, was used to put mental patients into prolonged comas, life-threatening episodes that were often accompanied by seizures and that sometimes proved irreversible.  Based on the false notion that schizophrenia and epilepsy could not co-exist, patients were injected with metrazol, a chemical that produced the sensation that one was on the brink of death before it provoked a grand mal seizure that all-too-often led to fractured hips and vertebrae, but allegedly restored those so treated to sanity.  Metrazol’s brutal and fearsome effects led two Italian neurologists to invent a better way to induce seizures, the passage of electricity through the brain, and ECT soon replaced the injections — used as a treatment for depression, not schizophrenia, but also widely employed to subdue and discipline unruly patients.  (ECT remains the only one of these interventions to still have a place in contemporary psychiatry.)  And then there is the most notorious of these experimental treatments, the decision to operate directly on the brain, excising portions of patients’ frontal lobes, the most distinctive and developed portion of the human brain.  Tens of thousands of these operations were performed, and lobotomies were still being performed into the 1970s, the procedure having won for its inventor, Egas Moniz, the 1949 Nobel Prize in medicine.

How to account for this dubious history? One major factor, I think, is the unique vulnerability of the mentally ill.  That vulnerability continues even now, but it was particularly acute for much of the last century.  Then, as now, psychotic patients were deemed to be (and often were) incapable of making rational choices about their fate, and stigmatized as biologically inferior specimens, it was easy to treat them as objects, not sentient beings.  What made them even more defenseless was the fact that they were shut up in another sense of that term, locked away in mammoth asylums where they were stripped of all civil rights and had scant ability to resist whatever measures psychiatrists proposed to employ.

Families were often not consulted about patients’ treatments, but even when they were, they were often desperate for some intervention that might alleviate the disturbance and distress that serious mental illness brings in its train.  With no other obvious treatments available, the temptation to agree to a high-risk intervention, even if the prospects for improvement were low, proved to be extraordinarily powerful.  That remains the case even now.

We have a recent example of this phenomenon in the FDA’s decision to approve Biogen’s Aduhelm (aducanumab) as a treatment for Alzheimer’s disease.  In laboratory studies, the drug appeared to reduce the amyloid plaques that are characteristically present in the brains of these patients, but clinical trials showed scant evidence of clinical benefit, and exposed the risk of potentially fatal side-effects from bleeding and swelling of the brain.  The FDA’s outside panel of neurologists were scathing about Adulhelm’s value and strongly recommended against its release into the marketplace, only to be overruled — a decision that led at least three of them to resign in protest.  Families clamoring for anything that might stave off the progress of dementia lobbied hard for approval, as did the politically potent Alzheimer’s Association.  An enormously costly and dangerous treatment of extremely dubious value was thus licensed, to Wall Street’s initial delight.²  On this occasion, the publicity attending the FDA’s decision, and the release of the clinical trial data, led clinicians to advise against its use, and many insurance companies to refuse to cover the costs of the treatment.  For a time, this served to inhibit the market for this particular desperate remedy — Biogen’s revenue from Adulhem’s first quarter amounted to a dismal $300,000. Medicare’s recent announcement that it will only pay for the drug for patients enrolled in a clinical trial — the mere prospect that it might cover the prescription of Aduhelm had caused a fifteen per cent increase in premiums for Medicare Part B’s beneficiaries — has further crimped Biogen’s hopes to profit from the drug, even after its price had been halved in an effort to secure approval.³

In this contemporary example, of course, many families and clinicians are likely to be aware of the controversy surrounding Aduhelm, which may prompt some questioning and hesitation about authorizing its use.  No such red flags were raised for the treatments proffered to the mentally ill in the first half of the twentieth century.  Exposed only to hyperbolic estimates of a novel therapy’s efficacy, it is not surprising that resistance to their employment was so muted.

Making matters worse, patients’ families (and patients themselves, come to that) were poorly placed to question the advice they received from the experts to whom their loved ones had been consigned.  Even were they to venture to consult leading academic experts — Adolf Meyer at Johns Hopkins University, for example, the most influential psychiatrist of the age, or John Fulton, a leading neurophysiologist at Yale — they would almost certainly have been advised to proceed.  Likewise, the most plutocratic of families, whose relations were confined at such elite facilities as the McLean Hospital in Boston, the Institute of Living in Hartford, Connecticut, the Bloomingdale Asylum in New York, or the psychiatric branch of the Pennsylvania Hospital, would have been counseled to consent to these treatments.  They were, the psychiatric profession assured its clientele, the best options modern medicine had to offer.

Another factor that led even those who had a choice in the matter to demand these novel therapies: the propensity of medical journalists to greet these interventions as miracle cures.  Henry Cotton’s surgical evisceration of his patients had led some of the most eminent medical men in England to hail him as psychiatry’s Lister, the counterpart of the surgeon who had revolutionized surgery by recognizing the importance of avoiding sepsis.  When the New York Times reviewed his work, the praise was equally fulsome.  Cotton had undertaken “the most searching, aggressive and profound scientific investigation that has yet been made in the whole field of mental and nervous disorders… There can seemingly be no doubt that chronic infections at work in the tissues are responsible for serious disturbances of the system and brain.”  His successes were “startling” and “dramatic.”⁴  (In reality, over 40 percent of those subjected to abdominal surgery died, and Cotton left in his wake hundreds of dead patients and thousands of maimed subjects of his experiments.)⁵

In 1936, Manfred Sakel came from Vienna to demonstrate insulin coma therapy to New York psychiatrists, claiming that his treatment cured the great majority of cases of schizophrenia.  The Reader’s Digest spoke of a “Bedside Miracle” and Time assured its audience that “Sakel has cured hundreds of cases of schizophrenia at his Vienna clinic by means of insulin injections.”⁶  Not to be outdone, the New York Times science reporter dubbed him “the Pasteur of psychiatry.”⁷  Sakel went on to earn a fortune.  His followers boasted that the hypoglycemia the treatment produced selectively attacked the brain cells causing mental illness.  The damage was real.  The cures were not, and though it took decades, insulin coma therapy eventually vanished from the scene.

Shortly after Walter Freeman brought lobotomy to the United States, Thomas Henry, the science reporter for the Washington Evening Star, gushed that it was “one of the greatest surgical innovations of this generation.”  Mental illness “can be attacked with the surgeon’s knife as easily as can an inflamed appendix or diseased tonsils.”⁸  Six months later, his New York Times counterpart William Laurence informed his readers about the new “surgery of the soul” that “changed the apprehensive, anxious and hostile creatures of the jungle into creatures as gentle as the organ grinder’s monkey.”  Psychosurgery “cuts away the sick parts of the human personality” and cures the mentally ill.⁹  It was, as the Houston Post would have it, “a personality rejuvenator” that severed “the ‘worry nerves’ of the brain” and was “only a little more dangerous than an operation to remove an infected tooth.”¹⁰  Such encomiums probably played a major role in Joseph Kennedy’s decision to have his daughter Rosemary lobotomized by Freeman and his neurosurgeon partner James Watts.  The operation left her incontinent, barely able to walk, and reduced to a near-vegetative state.

One might hope that this sort of journalistic hucksterism has been left behind.  Certainly, one can think of some responsible contemporary journalists who approach stories of miracle cures with healthy skepticism.  Sadly, though, there are others who breathlessly announce new medical breakthroughs that are nothing of the sort, or who tout the merits of some novel intervention that promises to revolutionize the treatment of mental illness.

Here are two revealing examples.  The first is the saga of deep brain stimulation, or DBS, a new form of psychosurgery that emerged in the early twenty-first century touted as a more precise operation that avoided the horrors of lobotomy, since it did not involve severing the frontal lobes, but instead installed a device that allowed electrical stimulation of certain regions of the brain, thereby tackling the problem of treatment resistant depression.  According to the proponents of DBS, using modern imaging technology, these implants could with a high degree of “precision” be surgically placed in regions of the brain that supposedly exhibited “brain circuit anomalies” associated with depression.  A handful of anecdotal reports appeared in the medical literature touting miraculous results, none of them employing any kind of controls.

That was enough for CBS’s 60 Minutes to devote a major portion of one of its programs, broadcast in September 2006, to touting the merits of the new “brain pacemaker” as a miraculous new therapy for the millions of people suffering from major depression, a claim they put forth even when I, as one of those consulted in the making of the program, warned them that there were no controlled studies of the “treatment” and that they were downplaying the major risks and side-effects of this form of psychosurgery, not to mention the speculative and scientifically worthless claims about the brain that its promoters relied upon. Five years later, in February 2011, NBC News got in on the act, asking “Deep Brain Stimulation: Can It Zap Mental Illness?” — and citing two enthusiasts for the procedure as it suggested that indeed it could.¹¹

As it happens, two medical device makers who hoped to profit from the potentially huge market proceeded to embark on controlled trials for DBS.  There are, after all, twenty million people supposedly suffering from major depression in the United States alone, and two million or more of them have treatment-resistant depression, i.e., depression that fails to respond to existing interventions.  Significantly, Medtronic and St Jude/Abbott, who sponsored the trials, chose to target completely different portions of the brain for the electrodes they implanted.

But if the brain regions were different, the results of the controlled trials were not.  Medtronic enrolled thirty patients in a sham-controlled trial for sixteen weeks, “Our results,” the authors report with evident chagrin, “failed to demonstrate a significant difference between the active and the sham-controlled groups during the blinded phase of the study.”  Even worse, “psychiatric adverse events…were more frequent in the active group than in the control group” including “worsening depression (5 subjects vs 3 subjects), insomnia (4 subjects vs 3 subjects, irritability (3 subjects vs no subjects), suicidal ideation (2 subjects vs no subjects), hypomania (2 subjects vs no subjects), disinhibition (2 subjects vs no subjects), and mania (1 subject vs no subjects).  There was one completed suicide among the active treatment group, but since it occurred after the person had stopped treatment because of failure to improve, and was awaiting removal of the electrodes, the authors decided that that adverse event did not count!  All in all, as this recital shows, the trial was an unmitigated disaster.  Or, as Darin Dougherty, the lead author of the study later put it, “We fell off a cliff….Given the investments in these pivotal trials, the manufacturers would have to have some awfully compelling reason to revisit these targets…from a regulatory standpoint.”¹²

In the St. Jude Medical/Abbott trial, 60 patients were randomly assigned to active treatment, and 30 to a blinded control group, with the electrodes being implanted in Brodmann area 25, the target preferred by the team conducting the experiment, led by Helen Mayberg and Andres Lozano.  The expectation was that those given active treatment would improve twice as much as the control group.  The trial was scheduled to last six months, followed by a further six months of open treatment (that is, treatment where everyone knew what was going on).  Both treatment and placebo patients improved slightly over the six-month controlled portion of the trial, but the data were unambiguous: “at the end of the 6-month blinded, controlled phase, there was no statistically significant difference in the primary efficacy outcome between the stimulation group…and the control group, or in remission.”  And 6 more months in which both groups received stimulation that everyone knew they were getting failed as well.  Unsurprisingly, the company funding the trial stopped it.¹³

Rather than accepting that the failed controlled studies had undermined this whole set of speculations, Mayberg and her colleagues proceeded to explain them away.  Perhaps those enrolled in the trial had been sick for too long.  Perhaps the treatment was “less effective for patients with extremely chronic depression.”  Maybe the stimulus applied was the wrong one.  Or again, “differences in benefit might not be seen until after 1-2 years of treatment in this group.”  Or perhaps “gross anatomical placement of electrodes in subcallosal cingulate DBS might not be adequate for optimal treatment delivery.”  So, despite the failures, “Subsequent studies are merited.”¹⁴  That was precisely the “logic” Henry Cotton used to explain why patients who had teeth, tonsils and colons removed had failed to recover: other hidden reservoirs of infection must yet exist, requiring more surgery, or the surgery had been undertaken too late, the poisons spread by focal sepsis having produced irremediable structural changes in the brain.

True to their convictions, Mayberg and her colleagues continued their experiments.  A new paper of theirs, published on line in the American Journal of Psychiatry on October 4, 2019, purported to show that “Deep brain stimulation (DBS) of an area in the brain called the subcallosal cingulate (SCC) provides a robust antidepressant effect that is sustained over a long period of time in patients with treatment-resistant depression.”  Here we have yet another uncontrolled, unblinded study, with a small sample size.  Data are cherry-picked and subjected to convoluted statistical analysis that focuses on only a portion of the sample looked at over varying periods of time. The authors seem to have viewed their results through a lens provided by Candide.  Inconvenient facts are passed over as quickly as possible. 5 of their already small sample dropped out after 1,2,5,8 and 11 years.  Then there is a brief but telling paragraph on safety.  Among these 28 patients, the authors report 56 serious adverse events.  One unfortunate patient was unlucky enough to experience ten of these, and after two years of this medical horror show, had the electrodes removed from his or her brain and dropped out of the study.  That leaves another 46 serious adverse events spread among the remaining 27 patients.

What are we talking about here?  19 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 where 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.  What do the authors conclude? “The results here support the long-term safety and sustained efficacy of SCC DBS in an open-label long-term follow-up study.”  The subsequent acknowledgement that “it should be emphasized that the absence of a long-term control group…precludes firm conclusions regarding the role of chronic DBS in these long-term outcomes” is immediately followed by more happy talk about the wonders of their experiment and the grand future it portends for their version of psychosurgery.¹⁵

More recently still, journalists have been happy to suggest that DBS could prove a sovereign remedy for the plague of opioid addiction that has spread across the United States.  One reporter’s story regaled us with the story of a heroic neurosurgeon who implanted this device after seven hours of neurosurgery.  It was, we were solemnly assured, akin to the medical miracle that is a heart pacemaker.  This one was a brain pacemaker, rejiggering the functions of the brain.  Think about that for a second: a heart pacemaker has a relatively simple, if vital, task to perform: causing the muscular pump that is one’s heart to maintain a steady beat in cases where it is prone to beat irregularly or too slowly.  The human brain is not a pump.  It is a fantastically complicated organ composed of about 200 billion nerves cells, interconnected in hundreds of trillions of ways.  Despite all the progress of neuroscience over the past half-century, our understanding of how it is put together, and how all those myriad connections function, remains strikingly primitive.  The idea of a “brain pacemaker” is so ludicrous on its face as to disqualify anyone who uses it.  To accept such a bizarre analogy is to show oneself incapable of serious commentary on subjects of this sort.  The same could be said of the notion of “precise” placement of devices within the brain, and of the sort of speculations about the localization of depression or addiction in particular regions of the brain that people like Helen Mayberg trot out to support their baseless experimentations.

Helen Mayberg, the inimitable Helen Mayberg, is, quelle surprise, the reporter’s go-to source for confirmation of how promising this new approach is likely to be.  She duly obliges, claiming that “the logic of the effort is sound and that the circuitry of this part of the brain is well-mapped compared with other regions.  The key question is whether the researchers have found the precise spot for the insertion of the electrodes.  The precision of where you put it is key,” she said, “Different nodes are good for different kinds of problems because circuits are abnormal in different ways.”  Alcoholics, spousal abusers, criminals, you’re next!  For your behaviors too, one presumes, can be solved by implanting suitable brain pacemakers.  And if they don’t work?  Why, the surgeon put the damned thing in the wrong place.  Sorry about that.  As you will note, Dr. Mayberg has thereby provided herself with a wonderful get-out-of jail free card when addicts don’t recover.

The surgery the Post reporter focuses on is the first of four trial cases designed to establish that “the technique is safe so that a full-scale clinical trial can be conducted.”  Let us set aside the fantasy of tens of thousands of opioid addicts being subjected to seven hours of psychosurgery (a nice fantasy for medical device makers to entertain).  Let us set aside the parade of serious side effects that we know those in the controlled trials of DBS for depression suffered.  What justifies the experiment?  The surgeon in question is quoted as acknowledging that “doctors and researchers do not yet fully understand how this works” — a statement that should more accurately read: “we have not the slightest clue of how this might work.”  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.  As for the “inspiration” to perform the surgery, it turns out it was anecdotal reports from China!  The Director of the National Institute on Drug Abuse, Nora Volkow, “spoke with a handful of the patients who underwent the procedure in China and concluded that the surgery had potential.¹⁶  This is the quality of reasoning from the person who heads this major federal agency, and the gatekeeper that guides what dangerous interventions are allowed on an experimental basis?

My second example is a briefer one, and concerns the quality of reporting on the usefulness or otherwise of ECT as another treatment for depression.  The report in question appeared in the pages of the New York Times on September 14, 2021.  We are exhorted these days to “follow the science,” and that is a laudable injunction.  But if we are to do so, we have to have accurate reporting of science.  And that is conspicuously absent in this case.

The article in question is headlined “ECT Can Be a Good Treatment Option for Serious Depression: Electroconvulsive Therapy Can Effectively Treat Depression, And Is As Safe as Antidepressant Drugs Along With Psychotherapy, A New Analysis Found.”  It was triggered, the journalist Nicholas Bakalar claims, by the publication of an article in Lancet Psychiatry.  Few readers of the Times will have access to the original research, and will assume that these are the questions Tyler Kaster and his colleagues sought to address.  Nothing could be further from the truth.  The academic paper makes no attempt whatsoever to tackle these issues.  It has nothing to say about the efficacy (or lack thereof) of ECT, antidepressants, or psychotherapy, and the assertion in the pages of the Times that it draws conclusions about these controversial issues is, in the contemporary vernacular, fake news.

Kaster et al. address an entirely different question: using a large retrospective study of Canadian in-patients, he and his colleagues examined whether patients given ECT experienced an increased risk for serious medical events when compared with a matched control group.  In a period of thirty days after their course of treatment, were the ECT patients hospitalized for non-psychiatric reasons more frequently than their untreated counterparts, or were they more likely to die (excluding suicide) during this brief period?  To this, the answer is no, they were not.  The authors had hypothesized that the general anesthesia the ECT patients received would likely result in a slightly elevated risk of medical complications, but this did not materialize.

A thirty-day follow-up period is, of course, extremely brief, though probably sufficient to address the limited question the study’s authors asked with a reasonable degree of confidence.  Were they to have attempted to draw conclusions about the efficacy of ECT as a treatment for depression (or about the value or otherwise of antidepressants or psychotherapy, come to that), it would have been quite otherwise.  Any study with a thirty-day follow-up period that attempted to address these matters would rightly be ridiculed by any informed observer, and to their credit, Kaster et al. make no such effort.  Unfortunately, however, readers of the New York Times would be led to assume exactly the opposite.  That is lamentable.