The Rx Pipeline – Has The Spigot Been Turned Off?

A recent article in the New York Times by Cornell psychiatrist Richard Friedman lamented the fact that there isn’t much in the FDA pipeline regarding the development of novel drugs for mental health use. In his op-ed, Friedman blamed Big Pharma for a “crisis in drug innovation.”

Case in point: last year, the FDA’s Center for Drug Evaluation and Research approved almost forty new molecular entities (NMEs) – the highest number of such applications in more than a decade. Given the green light were agents for some exceedingly rare diseases, malignancies of all sorts, and cardiovascular pathologies. Yet with the arguable exception of Amyvid, Abbott’s new compound for the imaging of β-amyloid plaques in the brain (Alzheimer’s), none of these NMEs have known or intended psychiatric application.

[I say ‘known or intended’ since over the years many psych meds have been discovered serendipitously, though I hate for my profession to depend solely on serendipity for its advances]

There has been a recent spate of clinical trials in which potentially novel antidepressant and antipsychotic agents failed to show efficacy greater than that of placebo – sometimes as late as Stage III in development – and Big Pharma is suspected of having concluded that psychiatric drugs are just too uncertain and too risky to pursue. That’s not to mention also too expensive: estimates range to almost $2B, and up to 15 years, to develop and market a new drug. Glaxo Smith Kline has accordingly shuttered its psychiatric labs altogether. And as of this writing, both AstraZeneca and Pfizer have markedly scaled back their investments in CNS R&D.

Granted, psychiatric disorders can be chronic, recurrent, likely multi-factorial in etiology, and complex beyond our current comprehension of neuroanatomy and neuropathology. And while I personally do not support such testing, for better or worse, there is a dearth of animal models with the requisite validity to predict eventual human clinical outcomes. That being said, it is still sobering that almost all of the current psychotropics being prescribed in the United States share the same molecular targets in the brain as did their ‘primitive’ precursors from the 1950s and 1960s.

What we’re seeing in lieu of meaningful advances is a rush of what psychiatrist Daniel Carlat has labeled ‘Me Too’ drugs, those with nearly identical molecular structures and proposed mechanisms of action very similar to agents already on the market; there’s no new ground being broken thusly. And then there are the rebrandings of earlier drugs: approved antidepressants and antipsychotics attempting to win ‘official’ FDA indication for other conditions – anxiety, bipolar mania, refractory depression, chronic pain – despite the fact that off-label prescribing is already permitted and widespread.

All is not entirely dismal, though. Ketamine, a widely-prescribed anesthetic, has been shown to have powerful antidepressant effects (there’s that ‘serendipity’ thing again). And we now have a more thorough grasp of the pathophysiologies of certain CNS disorders, opening doors for further industry and academic research and collaboration. These conditions include those of the addiction spectrum, Fragile X Syndrome, pain states, and insomnia to name only a few.

Of course, this also raises the issues of intellectual property rights and patent protection, the subjects of future posts.

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Rx Booze

When I started my training in the mid-1980s, there were still nurses working at the medical center who remembered early in their own careers keeping a refrigerator on the ward that was filled with cans of beer, which the docs would prescribe for patients who were undergoing alcohol withdrawal. Prescribing beer would allow a gradual taper of their daily consumption, and would prevent their going into full-blown delirium tremens while inpatient.

Prescribing beer worked just fine in avoiding DTs before benzodiazepines were available. But it also represented a throwback to a time when medicinal use of alcohol was not nearly so innocent and altruistic.

In my post from last week on cresol, I made the observation that “if one presumes that humankind’s search for euphoria and an altered state of consciousness is not going to vanish anytime soon, then substance abuse is a problem that is here to stay.”

For this reason alone, it should have been painfully evident to policymakers that the 18th Amendment to the U.S. Constitution, enforced by the National Prohibition (Volstead) Act, was doomed to failure.

For thirteen years starting on 16 January 1920, there was a ban on the production, sale, and distribution of alcohol in the United States. But like most futile social policies, there were legal loopholes, plus illegal ways to circumvent the law, that were big enough through which to drive a Model T delivery truck. Farmers, for example, were allowed to grow grapes and produce wine (up to 200 gallons per growing season for their own consumption) under the guise of “preserving fruit.” Rabbis and priests could obtain wine, and congregations could partake, during religious ceremonies.

And physicians (as well as dentists and veterinarians) were allowed by the Treasury Department to prescribe alcohol for ‘medicinal purposes.’ Over 15,000 physicians applied for this privilege in the first six months of Prohibition alone. Having added special licensure allowed physicians to write up to 100 prescriptions for medicinal alcohol per month – a numerical allotment that was rarely if ever underutilized. Hooch was accordingly used to ‘treat’ a variety of ailments, including cancer, asthma, difficulty with lactation, diabetes, poor circulation, snakebite, anemia, typhoid, pneumonia, tuberculosis, coronary artery disease, high blood pressure, indigestion, depression – even the wonderfully vague and non-specific ‘old age.’ And if alcohol wasn’t listed as treatment for one’s ailment-du-jour, booze was still often used as a vehicle by which to ease the ingestion of other medications, as it tasted better than many pharmacy preparations.

Rx pad (courtesy Rose Melnick Medical Museum)

Rx pad (courtesy Rose Melnick Medical Museum)

So much for bubble gum flavored cough syrup.

Rx pad (courtesy Rose Melnick Medical Museum)

Rx pad (courtesy Rose Melnick Medical Museum)

Pharmacies were required to apply to be alcohol-dispensing entities. Some states were stricter than others, but especially near the Canadian and Mexican borders, and on the coasts, rules were often more lax and supplies were vast and difficult to control – pharmacies had no trouble keeping firewater in stock and their ‘sickly’ customers supplied. Prescriptions were filled for spiritus frumenti, or spirit of the grain, the term of art by which most physicians documented the necessary libation. Patients would quickly take such a prescription – they expired after three days – to a pharmacy and request the type of liquor they desired: gin, rye, scotch, whatever. Toward the end of Prohibition, when the sham was so obvious that hardly anyone even cared, more than a few pharmacies were actually filling prescriptions for champagne. And while some druggists only carried cheap alcohol better suited for cleaning, and often watered it down, it was apparently not rare that alcohol handed over the counter was brand name stuff like Jack Daniels in recognizable trademarked bottles – as long as it had a label affixed that said, “for medicinal purposes.”

See anything potentially analogous here vis a vis medicinal marijuana?

Anyway, doctors were supposed to be examining and diagnosing patients before any prescriptions were dispensed, but that stipulation was largely flouted. Every ten days, a patient willing to cough up the cash for a rote office visit could walk out with prescription-in-hand and shortly thereafter, down the street, head home with a pint of booze. There might have been some people who were given the tipple for actually-perceived medical need, but the whole process really just became a means by which physicians and pharmacists could earn a few extra bucks during hard times.

Doctors’ instructions varied, but generally they advised their patients to imbibe an ounce of alcohol every few hours or a tablespoon three times a day. One of my favorites was from a prescriber in Detroit in 1926: “take three ounces every hour for stimulation until stimulated.”

Those not even in the medical profession took notice. Bootlegger (and lawyer) George Remus incorporated a sham business entity called the Kentucky Drug Company. As a licensed supplier, this front allowed him to legally obtain and transport alcohol in company trucks to pharmacies all over the Midwest and South – that is, when he didn’t have his men hijack his own trucks en route and then divert the contents to speakeasies nearby.

The farce finally ended when Prohibition was repealed by the 21st Amendment on 5 December 1933.

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Malleus Maleficarum – a Cautionary Tale

“Who is so dense as to maintain… that all [the defendants’] witchcrafts and injuries are phantastic and imaginary, when the contrary is so evident to the senses of everyone?”
~Heinrich Institoris and Jakob Sprenger, Malleus Maleficarum (1486)

Malleus Maleficarum (‘The Hammer of the Witches’) is a book published in the late 15th century in both Germany and England. It is a polemic against those who held that witchcraft didn’t exist, or that it wasn’t the threat that the authors perceived. It is also a ‘how to’ guide for magistrates who wished to ferret out witches in their jurisdictions and prosecute (i.e., kill) them to the fullest extent of the law.

By the late medieval epoch, knowledge of witches was not new. But earlier treatises on witchcraft often framed it as a misguided pagan activity – nothing that a few days of public humiliation in the stocks and penance couldn’t cure. But after Malleus was widely read – thirteen editions were printed by 1520, thanks to the newfangled printing presses then available –the hysterics increased and civil prosecutions multiplied in many locales. Interestingly, the book was not used by the Church’s formal Inquisition – the Vatican even condemned many of its pearls – but Malleus was employed widely in secular courts which were less familiar with the Holy See’s formal teachings on demonology.

You recall what they say about knowing just enough to be dangerous?

Western religion being as it was and is, the root of all of this was sex. Women were barely contained nymphomaniacs, so it went, and those who let their passions loose and had intercourse with Lucifer promptly became witches, leading to all manner of hexes and curses, poisons and potions, pestilence, infanticide and other murders, and the stealing of penises (no joke on that last one). Thus, while there were sometimes male witches identified (not sure how those were created) it meant that half of the human population was teetering on the brink at any given moment of being co-opted by Beelzebub. That made for a lot of potential raw material for witch prosecutions.

Clerics, jurists, and authors began to take sides, and over time not everyone bought the party-line on witches. As noted, the Church expressed grave doubts about the contents of Malleus (but was either unwilling or unable to suppress its application). Cruentation (the belief that a dead body bleeds or exhibits lesions in the presence of a murderer or witch) was thought by some to be unreliable as an evidentiary standard. In the late 16th century was published by Reginald Scot The Discoverie of Witchcraft (1584), a tome referenced by no less than Shakespeare, in which the author Scot countered that the public oft had been fooled when it came to witches by ignorant superstitions, the mental derangements of observers, and charlatans. Father Friedrich Spee was a prominent German Jesuit who argued against witch trials, as then being conducted, in his work Cautio Criminalis (‘Precautions for Prosecutors’) in the early 17th century; he believed that the torture employed did not produce truthful confessions. At the same time, Inquisitor Father Alonso Salazar y Frias in Spain examined who was being burned and over what supposed transgressions; what Salazar found looked to him like many false accusations, confessions extracted through torture, and ‘evidence’ lacking all credibility. He couldn’t say bluntly that witches didn’t exist, but he did change the rules of evidence. Starting after 1610 in his jurisdiction in Spain, accusations of witchcraft had to be supported by some independent observations. And, said Salazar, there would be no more use of torture to extract the ‘truth.’ Predictably, prosecutions in both civil and ecclesiastic courts began to decline.

This didn’t happen overnight. While the skeptics of witch trials were in the minority at first, their numbers grew. The last legal witch conviction and execution took place in Switzerland in 1782 – the place where the first had also occurred in 1427.

Institoris and Sprenger would have scoffed in 1486 at the notion that dangerous witches aren’t everywhere. Three hundred years later, the last witch was judicially put to death in Europe. Today, few if any individuals lie in bed at night in fear of witches or missing parts of their anatomy.

Mindsets don’t change quickly. But they do change.

When I was in my medical training, Hormone Replacement Therapy (HRT) was the gospel. It was felt in most medical quarters to be the answer to a host of age-related problems that befall post-menopausal women – everything from stress incontinence to absent libido, and from osteoporosis to winkled and thinning skin was to be prevented by the administration of nature’s wonder-substance, estrogen (along with a progestin chaser for those still with an intact uterus).

HRT remained the gospel for years… until one day it wasn’t.

The Women’s Health Initiative of NIH, in 2002, was performing meta-analyses of data on patients taking HRT, and that massive review set off alarms when it was found that there was heightened risk of breast cancer, heart attacks, and stroke in older patients on HRT, despite the earlier touted health benefits. Suddenly what we had learned in training was heresy. The number of women taking HRT dropped precipitously, and the relatively few still taking HRT are almost always given the regimen for time-limited treatment of menopausal symptoms, not as the permanent fountain of youth that it represented in the 1980s and 1990s.

In my own specialty there are many such examples – lobotomies and insulin shock treatments of the early 20th century come quickly to mind. Even more recently than those barbarisms, when I was a new attending, a novel antipsychotic hit the market: Janssen’s Risperdal. It was said to have none of the nasty side effects of the older antipsychotics, and could be quickly and aggressively titrated for patients in which fast relief from psychosis was needed. Janssen even made up a little jingle: “Risperdal 1-2-3-BID,” earworming that the recommended manner by which to dose the Rx was 1mg twice a day followed by 2mg twice a day followed finally by 3mg twice a day, all over a rapid 72 hours from start to maintenance dosing.

I know I did this many times in practice.

Now I know of no one who would attempt to do this.

Experience taught us that Risperdal is in fact fraught with potential side effects, recommended doses are now less than half the previous average 6mg daily advertised, and the titration is usually accomplished in a much slower and deliberate manner.

It’s funny what you learn when you question dogma and actually stop, look, and listen.

There is a scene in Star Trek IV (1986) in which the crew of the Enterprise lands in 20th century San Francisco. In the one act, the ship’s doctor, McCoy, is shown talking to an old woman in a hospital waiting room, and she tells him that she’s there for kidney dialysis. He exclaims with surprise, “dialysis..! they’re still doing that?!?” He then gives the woman a pill from his 26th century doctor’s bag, and in a later shot we see the same woman dancing down the hall as she leaves the hospital, obviously cured by a treatment modality that does not yet exist and which our feeble minds cannot yet grasp.

While witchcraft and modern medicine might seem wholly disparate, I note the above because I wish I could live long enough to see with bemusement what, from our own ‘advanced’ age, will be viewed with incredulity and amazement in the future.

And in the meanwhile, be very wary of those who preach orthodoxy without some pretty convincing data.

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We’ve all heard the story of how George Washington’s demise was likely hastened by the amount of blood that was purposely extracted from him by his physicians as he lay critically ill with pneumonia. At least one of the late President’s doctors later opined as much. But bloodletting, whether by instruments or leeches, was a widely accepted practice for all matter of ailments in Western medicine well into the 19th century.

I was nonetheless taken aback recently when I read this account in the Lancet of an early 19th century bloodletting on a trauma victim, perhaps surprised all the more because he survived!

On 13 July 1824, a sergeant in the French army was stabbed in the chest while engaged in hand-to-hand combat. Though he was carried to the surgeon’s tent as soon as possible, within minutes he fainted from the loss of blood. He was immediately bled twenty ounces (570 ml) “to prevent inflammation.” During the night he was bled another 24 ounces (680 ml). Early the next morning, the chief surgeon bled the patient another 10 ounces (285 ml); during the next 14 hours, he was bled five more times. Medical attendants thus intentionally removed more than half of the patient’s normal blood supply – in addition to the initial blood loss which caused the sergeant to faint. Bleedings continued over the next several days. By 29 July, the wound had become inflamed. The physician applied 32 leeches to the most sensitive part of the wound. Over the next three days, there were more bleedings and a total of 40 more leeches. The sergeant amazingly recovered despite his treatment and was discharged on 3 October.

His physician wrote that “by the large quantity of blood lost, amounting to 170 ounces [nearly eleven pints] (4.8 liters), besides that drawn by the application of leeches [perhaps another two pints] (1.1 liters), the life of the patient was preserved.”

Apparently, by 19th century standards, thirteen pints of blood taken over the space of a month was a large but not an exceptional quantity. The medical literature of the period contains many similar accounts – some successful, some not.

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Rotational Therapy

“I have the pleasure of knowing that [my patient] continues well, and I am confident [that he] owes his life and reason to the swing.”
~Joseph Mason Cox, M.D. (1763-1818)

Ever watch youngsters spin themselves around in a circle to induce vertigo? What is the first thing that the kids do? I mean AFTER falling down? That’s right… they usually burst into laughter. Anyone who has had children will recognize this phenomenon and realize that it’s pretty universal.

Erasmus Darwin (1731-1802) had noted this sort of behaviour also. Though not as famous as Charles, his arguably better-known and -regarded grandson, Erasmus Darwin was a physician, philosopher, scientist, and minor celebrity in 18th century Staffordshire, England, but for less-auspicious reasons; despite having once been offered the position of personal physician to George III, he wasn’t particularly adept at any of his vocations.

He documented many of his disorganized and far-fetched ideas in bad verse. Here’s a sample prelude from one bloviation on the origins of life:

“By immutable immortal laws,
impress’d in nature by the great first cause…
say, Muse! How rose from elemental strife
organic forms, and kindled into life?”

This might be one reason his proposals weren’t always taken too seriously – being flaky could have been another.

Anyway, Darwin believed that spinning a person around not only induced slumber (?), but also laughter, and that this soporific/ mirthful combination was a great way to resolve mental illnesses and whatever else might ail you. The treatment was performed in one of two ways:

1. an ordinary chair, suspended from the ceiling by a swivel, was spun by hand, or
2. a pole with a horizontal metal arm was installed from floor to ceiling, and from the arm was suspended a chair that was spun around the pole.

rotating device (courtesy National Library of Medicine)

rotating device (courtesy National Library of Medicine)

The treatment was to be continued until the patient improved, or else promised to obey the doctor’s orders and get better, at which time he would be released from the spinning device and allowed to go back to his room and get some sleep. Contemporary sources noted that side effects of this protocol included anxiety and fear; nausea and vomiting; an ashen complexion; vertigo; sedation; and sudden bowel movements.

This would have gone nowhere except for the equally surprising fact that no less a personage than Benjamin Rush, M.D., signer of the Declaration of Independence and the man considered the Father of American Psychiatry, believed there might be some merit to the approach. Rush opined in his letters that spinning reduced brain congestion (?) and was thus therapeutic.

In actuality, all that Darwin and Rush produced were mentally ill patients who were then dizzy.

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Snail Water

To make Snail Water, “take garden snails, cleaned and bruised [crushed], six gallons; [then] take earthworms, washed and bruised, three gallons; of common wormwood, ground ivy, and carduruus, [mix] each one pound and a half; penniroyal, juniper berries, fennelseeds, [and] aniseeds, each half a pound; cloves and cubebs, bruised, each three ounces; spirit of wine and spring water, of each eight gallons; digest them together for the space of twenty-four hours, and then draw it off in a common alembick” ~a treatment for (non-specific) venereal disease, found in the Pharmacopoeia Paupermum, 1718, and taken originally from the well-regarded recipe of Dr Thomas Meade, St Thomas’ Hospital, Southwark, London.

Some explanation: wormwood and fennel were both used in the distillation of absinthe (the latter also being employed often for treatment of dysmenorrhea); Penny Royal, though used centuries ago to flavor soups, is a highly toxic substance more often ingested by those wishing to abort (Nirvana’s track ‘Penny Royal Tea” references this); Aniseeds taste like liquorice but were employed more commonly as a paste to kill head lice; cubebs, also known as the Java Pepper, have been used to treat infertility, but also were sprinkled on and fed to the stricken by priests during exorcisms; juniper berries, of course, are most famously known for flavoring gin; and an alembick is a vessel with a beaked cap used in distilling. Luckily, though, no one will be able to try this concoction again, since I can find nowhere the meaning of carduruus. And perhaps fortunately, it is also not known if this creation were a topical or to be ingested.

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The Baths

Recently, my elderly mother was relating memories of her nursing school training in the years after WWII at Toronto’s Western Hospital, in particular those of her psychiatric rotation. While I am not an apologist for Big Pharma, it does bear appreciating just how primitive were our collective ‘therapeutic’ interventions before Rx was widely available to address the most severe symptoms of mental illness.

There was not a psychiatric ward at the Western, so students were sent elsewhere for the rotation – across town either to the Toronto Psychiatric Hospital on Surrey Place, or to the Ontario Hospital at 999 Queen Street (aka “the 999.″) In mom’s case, it was to the latter. The cornerstone of the 999, at its opening known as the “Provincial Lunatic Asylum,” had been laid on 50 acres of an abandoned military camp in August 1846, and opened for patients four years later. Expanded over the decades, the facility had gone through several insensitive name changes by the time mom arrived, “Toronto Lunatic Asylum” and “Asylum for the Insane at Toronto” being two of the more palatable.

Mom was in nursing school in the late 1940s. Keep in mind that these were the years before Thorazine and the other antipsychotic tranquilizers were available. Benzodiazepines didn’t exist either. Lithium was known at that time to have calming effects, but would not come into widespread clinical use for another twenty years. The pharmacopoeia of the period essentially consisted of bromides, barbiturates, opiates, chloral hydrate, and paraldehyde – all indiscriminate sedatives with varying degrees of concomitant toxicity and addictive potential. All for which they were good was simple zombification of the agitated.

There were even more drastic interventions available, such as insulin coma treatments, ECT, and the lobotomy.

But surely there were therapies that were less draconian and more commonly employed on a day to day basis?

There were, and Mom remembers often being the student nurse assigned to monitor those in the hydrotherapy room. If the term ‘hydrotherapy’ evokes thoughts of Hollywood starlets lounging in scented spa waters, then you probably weren’t a mid-twentieth century psychiatric patient. In vogue starting in the late 1890s, hydrotherapy was premised on the belief that the application of hot and cold water to the disturbed could quickly produce beneficial results. Symptoms as varied as chronic insomnia, suicidality, agitation, hyperactivity, mania, and thought disorganization were all treated thus.

Though cold water immersion was used in some psychiatric wards elsewhere in North America, Mom’s experiences were with hot baths. The hydrotherapy room had soft indirect lighting and was warm and humid. Patients were restrained and placed in large stainless steel tubs, over which canvas covers were stretched and through which only the patients’ heads protruded. The afflicted were left in the baths for hours, or sometimes days, with breaks only to use the bathroom on a pre-set schedule. Falling asleep was encouraged, the goal of the baths being a diminution of restlessness and fulminate psychosis.

The bath water was typically maintained from 93°F to 99°F. Since the patients were often agitated, struggling, and yelling anyway, it was important to monitor the water temperature carefully so as not to mistake a patient screaming because of burning for one screaming merely because of mental illness.

Hydrotherapy Room (courtesy LIFE magazine)

Hydrotherapy Room (courtesy LIFE magazine)

As a student nurse, mom was assigned to sit in the hydrotherapy room and four times an hour place a thermometer under each of the canvas covers and into the water to take a reading, being careful to stay away from the protruding (and often angry) heads. Temperatures were dutifully recorded, and if they were edging out of range, an actual nurse was summoned and the hot and cold flows adjusted accordingly.

I can’t imagine many teenaged students being given such vital and yet largely unsupervised duties in this day and age.

But water temperature was not the most consequential aspect of the psychiatric rotation in the eyes of a 19 year old. At the Western, meals served to those in training were congealed, cold, and hard. But at the 999, there was a cook behind the serving line who made the food to order, hot and fresh.

Baths or no baths, the students thought they had died and gone to Heaven.

I can entirely relate to this. I don’t remember much about my medical school interviews back in the 1980s, but I can still recall which admissions committees arranged for nice meals for us. I suppose that’s human nature.

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