The Drugs That Changed Our Minds

by Lauren Slater

  In 1991, more than 150 years after it first opened, this hospital at last closed its doors, meeting the same fate that had already befallen many other such mental hospitals in the decades following the deinstitutionalisation movement that gathered momentum in the 1960s, when US President Kennedy, whose sister Rosemary had been the victim of an early and failed prefrontal lobotomy, provided funding for community mental health centres, a move that was further encouraged by the passage of President Johnson’s Medicaid and Medicare bills. In 1955, at their peak, American mental hospitals held 560,000 patients nationwide, double the number at the turn of the twentieth century. By 1988, three decades later, that figure had fallen to 120,000.

  One of the phenomena that truly made this sea change viable – allowing patients to be treated in the least restrictive setting possible, whether that was in a community health centre or at home with their families – was the discovery, in the early 1950s, of a blockbuster drug called chlorpromazine. When branded and marketed as Thorazine in the United States and Largactil in Europe, this new drug stabilised untold thousands of schizophrenic, psychotic and otherwise mentally ill patients and eventually brought about a sustained exodus from mental hospitals in the United States and abroad.

  Great and Desperate Cures

  One way of grasping the meaning of chlorpromazine is to know the types of treatments that preceded it, treatments which the former University of Michigan psychologist Elliot Valenstein has called ‘great and desperate cures’. There was, for instance, insulin coma therapy, first used by Austrian psychiatrist Manfred Sakel in 1927, in an attempt to treat opiate addicts in withdrawal with small doses of insulin. Some of these patients, however, slipped into hypoglycaemic comas, and when they awoke, following an emergency administration of glucose, their personalities seemed altered. Addicts who had been defensive, angry, difficult were now ‘tranquil and more responsive’. This led Sakel to wonder whether deliberately inducing comas in schizophrenic patients might produce a similar recovery. He set about trying this and claimed miraculous results after inducing comas, sometimes as many as sixty times in a two-month period, in his schizophrenic patients. Perhaps unsurprisingly, patients emerging from these comas did appear more docile, but the treatment carried severe risk – including death and irreversible coma.

  Convulsive therapies were also popular during the first half of the last century. Before electroconvulsive treatment (ECT) was developed, convulsions were brought on by injecting patients with drugs. Ladislas Meduna, a psychiatrist working in Budapest, noted that epileptics who also had schizophrenia appeared to have fewer seizures and that, conversely, schizophrenics who suffered from epilepsy would often have spontaneous remissions of their psychoses after a seizure. Meduna chose first camphor and then pentylenetetrazol, a white crystalline drug employed as a respiratory or circulatory stimulant, to induce seizures in schizophrenic patients. Afterwards, his first test subjects rose from their beds and asked, in perfectly lucid ways, when they could go home. ‘I felt elated and I knew I had discovered a new treatment,’ Meduna said. ‘I felt happy beyond words.’

  What was the operating theory behind pentylenetetrazol therapy? Some claimed that it gave the mentally ill a near-death experience that set them straight once the seizures were over. Instead of scaring schizophrenics to death, the thinking went, it scared them back to life. Patients coming out of pentylenetetrazol shock often called for their mothers, or begged the nurses to hold them, childlike behaviour which their doctors considered proof that the seizure had altered their personalities for the better. No longer raucous or caught up in the clutch of hallucinations, pentylenetetrazol patients were frequently friendly and cooperative, and this led doctors to believe that with enough treatments, the positive behaviour would become habitual.

  Pentylenetetrazol therapy, however, had a host of thorny problems. When asylum doctors beyond Meduna tried it on their patients, the seizures the drug caused were horrific. The treatments filled their patients with dread, and they begged to be spared the injections, which caused their whole bodies to writhe and spasm in convulsions of such ferocity that they frequently suffered fractures: dislocated shoulders, broken femurs, clavicles, scapulae. One patient compared it to being ‘roasted alive in a white-hot furnace’. And yet it was not uncommon for patients to have as many as forty pentylenetetrazol injections.

  Other treatments, some of which caused patients degrees of discomfort we can only imagine, since seemingly they left behind no record of their experiences, involved the injection of animal blood and castor oil and massive doses of caffeine. For quite some time, sleep therapy became a popular intervention in the treatment of schizophrenia – a kinder although no less dangerous undertaking. Patients were fed a cocktail of tranquillising tonics and drugs meant to send them into slumbers that, in some cases, lasted as long as two or three weeks. The rationale: in states of deep rest the nervous system might find its precarious balance again. It’s true that some schizophrenics were actually helped by sleep therapy, but there were a number of fatalities as well. Patients’ lungs filled with fluid, pneumonias developed or vomit was aspirated – all in a time before penicillin.

  In 1938, Italian psychiatrist Lucio Bini discovered that he could cause convulsions in mental patients using electricity instead of drugs. Bini tried his new therapy on catatonic patients, some of whom were helped by this charge to their systems, as they emerged from their catatonia and began conversing with those around them. Others, however, as they lay on the table, seized to no effect at all, the voltage so high they flopped like fish, again and again, as the body was charged and changed, in a mode of treatment that seems barbaric to the modern mentality. (Electroconvulsive therapy, which actually can be extremely effective in severe depression that has failed to respond to antidepressant medications, is still used today, the theory being that the electrical current ‘resets’ the brain. But the voltage is much lower, the treatment is typically used on only one hemisphere and patients are given muscle relaxants so they do not have violent seizures.) Other hospital-based therapies of the time included ice wraps, freezing baths or just plain old restraints, with the patient simply tied to a chair while his dreams and demons wafted.

  Were the lengths to which these psychiatrists went to calm the mad mind heroic, or simply cruel? Canadian doctor Heinz Lehmann, for instance, noting that the psyches of his schizophrenic patients seemed much clearer when they were felled by high fevers, sought out ways of inducing in his patients the most extreme temperatures he could, going so far as to inject turpentine into the abdominal wall of one female patient in the hope that the infected abscess formed in the wake of such a procedure would cause a fever high enough to quell her hallucinations. Some have criticised Lehmann for what they consider cruelty, but it’s more likely that this doctor, who would later become one of the first North American prescribers of chlorpromazine, had the best of intentions, so driven was he to find ways of suppressing psychosis.

  The zenith – or, depending upon your outlook, the nadir – of these fervent efforts to cure, or at least subjugate, the mentally ill was the 1936 development, by Portuguese doctor Egas Moniz, of psychosurgery. At its best, psychosurgery was a vanguard technique that – though we are now loath to admit it – healed some patients, allowing many to be released back into the community. For instance, there is the case of the doctor, decimated by depression, who, after psychosurgery, re-established a medical surgery with nine other colleagues – and became a pilot to boot. There is also the case of a former virtuoso violinist, unable to play anything but her jangling, screeching nerves once her schizophrenia set in, so much so that she set the instrument aside for a dozen years. She too submitted to the destruction of her frontal lobes and found, afterwards, that she could make music again, such that music was still her livelihood almost twenty years later. At its worst, however, psychosurgery was an ice pick thrust carelessly through the orbit of the eye. Indeed, the very first transorbital lobotomy in the United States was performed by t
he notorious Walter Freeman on a housewife in Washington DC, using an ice pick from his own kitchen drawer.

  What this string of experimental treatments reveals is that while we tend to think of the last century and the centuries before it as eras when there were few or no viable biological therapies available to mental patients, this is at best half true. Yes, there was a period when psychoanalysis and its psychodynamic offshoots did grip the American imagination, assuming pre-eminence over medication in the 1950s, ’60s and even the ’70s, but both in the United States and in Europe we have never been without biological treatments for those suffering from mental disease or distress. Equally significant, some of these biological treatments were actually effective, even if only briefly and for uncertain reasons. For the deeply disturbed there was insulin, camphor, electricity, enemas, ice and ice picks, and for the walking wounded, from antiquity on, there were all manner of tonics and brews, this in a period when whatever medication was available was easy to procure, before pharmacies controlled the flow of chemicals.

  In the early twentieth century, for instance, opiates were widely used for all sorts of ills, even sold in syrup to calm colicky babies. Lithium baths prospered – vats of cool bubbling water said to soothe the troubled soul. Extract of conium, either on its own or coupled with iron, quinine or Fowler’s solution, was used to treat depression, as was the plant extract nux vomica. Hyoscyamus, from the passion flower, was used to diminish sleeplessness or extreme excitement. There were tinctures of veratrine and belladonna and stimulants such as ammonia, lytta and all kinds of aromatics in small amber bottles you held just below the nostrils, sniffing in comforting draughts of lavender, rosemary or cinnamon. So prevalent were and are attempts at biological cures, and so available for such a great span of time, that non-physical therapies such as psychoanalysis and other ‘talking cures’ are in fact the real oddity, a brief blip in what has otherwise been a mostly somatic approach to the treatment of human suffering in all its manifestations.

  But despite the steady and ongoing reliance on brews, tonics, leechings, electrical current, ice baths and lithium waters, on aromatics and extracts made from the garden’s crushed stamens and leaves, on convulsions and comas and high-flying fevers, prior to the development of chlorpromazine no one had ever really conceived of a drug to help heal serious mental illness. The tonics and brews of yesteryear were for the most part intended merely to manage the most severe symptoms. And while barbiturates were synthesised as early as 1903 and brought to market in 1904, and opium even earlier, these were used mostly as sedatives, to send patients into states of slumber so that doctors could attempt deep-sleep therapy. No one was trying to develop a tablet that might somehow steady the brain, because the notion of such a thing lay outside the imagination, seemingly beyond conception.

  The mind, back then, was mythic. It was a vast and uncharted territory, an Antarctica, unreachable, unfathomable, arising not from neurotransmission and chemical signalling but from, it was believed, electrical impulses impossible to decode, or, still more abstract, from one’s singular and God-given spirit. Very little was known about neurotransmitters, the chemical messengers that convey nerve impulses across a synapse, because while the neurotransmitter acetylcholine had been discovered in 1921, it was the only one researchers knew of, and it would be decades before they began to understand how or why it worked. Serotonin, noradrenaline, endorphins and complex chemical cascades – these all lay far in the future, yet to be uncovered in laboratory experiments.

  Thus while the emphasis on biological cures was not at all new, before chlorpromazine and then a second antipsychotic, reserpine, these biological treatments were largely contradictory, even paradoxical, given that measurable materials were being used to treat what many saw as the immeasurable soul. Had anyone in the nineteenth or even the early twentieth century suggested that schizophrenia arose from an ‘imbalance’ of chemicals in the brain, that person would have been seen as speaking nonsense, because schizophrenia arose, in the popular imagination, from the twisted soul and, in the medical imagination, from either a fixed and ill-fated inheritance, meaning a bad bloodline passed from person to person, or from humours – blood, bile, phlegm – gone wildly out of whack. When we finally did discover antipsychotics in the 1950s, we discovered much more than drugs. We discovered, along with capsules containing crushed and potent powders, the 1.3-kilogram (3-lb) mass of matter between our ears which, we now believe, serves as the seat of our humanity. For many people, this was a brand-new belief.

  Brilliant Colours

  Chlorpromazine was a long time coming. In fact it took almost a century to finally become what it was, a chemical called chlorpromazine hydrochloride made by chlorinating the antihistamine promazine in a laboratory at Rhône-Poulenc, a French pharmaceutical company which, from the 1930s to the 1950s, specialised in antihistamines. But although Rhône-Poulenc and the pharmacists working under its roof can be credited with creating, in 1950, the drug that came to be known as chlorpromazine (sold as Thorazine in the United States), its existence really began in the mid-nineteenth century, when organic chemists discovered that by distilling coal tars they could make brilliant colours, which they sold as dyes.

  One of these dyes, named methylene blue, turned out to contain medicinal properties (and, in fact, is still today included on the World Health Organization’s list of essential medicines, being used as an affordable antimalarial drug and also showing promise for the treatment of Alzheimer’s). In 1886, in the process of researching a cure for malaria, against which the dye did prove to be effective, German scientist and eventual Nobel laureate Paul Ehrlich discovered that this strange and potent blue liquid would selectively stain the nerve cells of the frogs he dissected, and thus seemed to have an affinity for nerves, the motorways and byways of everything we feel and are. Ehrlich, observing how the blue dye sank into and saturated only the frogs’ nerve cells, leaving the rest of the dissected animal untouched, thought to treat neuralgia with methylene blue; it didn’t work, but more than a decade later, in 1899, an Italian doctor named Pietro Bodoni, aware of Ehrlich’s research, used it to treat manic excitation in psychotic patients with good, even grand success, calming their fevered fears and rat-a-tat agitations. This makes sense in hindsight, because of all the dyes discovered in the heyday of organic chemistry, it was methylene blue that would eventually be transformed – distilled and finally synthesised – into chlorpromazine fifty years after Bodoni first tried the dye on the deeply distressed of Genoa.

  Despite the success methylene blue had in calming manic excitation in psychotic patients, the dye never quite had a chance to come into widespread use, thanks to the introduction of barbiturates, in 1904, just five years after Bodoni’s initial treatments in Genoa. Barbiturates were faster acting and cast a wider net, their highly sedative effects able to calm virtually any kind of patient with any kind of mental illness diagnosis, and to do so more effectively than methylene blue, which was not a sedative. Methylene blue, in addition, could not be used in deep-sleep therapy, while the barbiturates could.

  It is common, or even fashionable, for people to think that prior to chlorpromazine and the drugs that followed, psychiatrists were operating in the Dark Ages, using these ‘great and desperate cures’ in ways often painted as almost, if not outright, barbaric. The real story, however, is much more nuanced. Without doubt the large asylums of the past could be gruesome places, but the doctors and their proffered treatments must be seen as separate from the settings in which they practised. In addition to the successes of psychosurgery, with patients such as the doctor-cum-pilot and the violinist, there are similar stories about patients who underwent insulin coma therapies, electroconvulsive therapies and sleep therapy, and achieved happy outcomes.

  Our predecessors, then, were not practising in the Dark Ages any more than we are practising in an Enlightenment. There has always been consistent confusion, a range of questionable cures, and then the occasional goal. This is the case today as much as
it was back then. Methylene blue was a kind of goal that disappeared from psychiatric use not because it was ineffective or barbaric but because, according to British psychopharmacologist David Healy, ‘patents had been obtained on newer agents and no drug company would market an old drug even if it worked.’ In the case of methylene blue, then, ‘there were competing therapies or interest groups likely to make more money out of other therapies than they would from methylene blue.’ In the 1970s, methylene blue re-emerged as a means of treating manic depression, for which it was highly effective, but ultimately corporate profit-seeking interests rather than therapeutic outcomes won the day.

  What matters here is how we view the past. We tend to construct the story of psychiatry as a tale of ever-upwards progress – cure upon cure, each one better than before – with a triumphant emergence from the Dark Ages once chlorpromazine was synthesised. This, however, is not actually true, as is so aptly demonstrated by methylene blue, a perfectly good psychiatric drug developed a half century before chlorpromazine but relegated, temporarily, to the rubbish bin of time because of a shift in allegiance to the barbiturates, which were celebrated in their day but which in fact can be highly addictive. A close examination of the past reveals reasonable, and in some cases excellent, treatments, while a close examination of the present reveals the same. Progress has been made, but many treatments of today are no more effective than those of prior centuries. In actuality, there were no Dark Ages, nor was there a sudden coming into the light. Rather there has been a steady search for cures that has gained ground as technology has improved. But even with this technology, psychopharmacologists, if they are honest, will admit that they are still operating largely in shadow, unable to see the aetiology of the illnesses they are trying to treat, operating on hypotheses that are, in many cases, no more sound than those which existed before our time.