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Barry Blackwell: The Final Story of Lithium

 

        Viewed historically this editorial may well be the Alpha and Omega of clinical psychopharmacology.

        Discovered in a pile of rocks in a Brazilian iron ore mine in 1800 lithium soon became a remedy in search of a disorder (Blackwell 2017). When lithium carbonate was found to dissolve kidney stones (Johnson 1985) lithium became a treatment for gout, including its effect on co-morbid affective symptoms. "Occasionally maniacal symptoms arise which I myself have witnessed". (Garrod 1863). Lithium was listed in the British Pharmacopea the following year and in Merk's Index in 1889. By now its use had proliferated to include lithium bromide in epilepsy (Locock 1857), as a mild tonic (Gibb 1863), as a sedative (Levy 1874) and, in America for general nervousness (Mitchell 1870).

        Lithium's first definitive use in affective disorders was at Bellvue Hospital in New York during the late 19th century. with lithium bromide for "acute mania with excitation or acute mania with depression" (Hammond 1871), Its effect was attributed to "an ability to diminish the amount of blood in cerebral blood vessels causing congestion." After a decade its use declined and disappeared, attributed to lithium toxicity and high dosages.

        While its use declined in America it prospered in Denmark sponsored by the Lange brothers. Carl (1834-1900) was a neuropathologist with an outpatient practice treating "periodic depression" often with episodes recurring over a lifetime but without mania (Lange 1886). Fritz (1842-1907) was an asylum psychiatrist, focused on an etiologic theory of "acute auto-intoxication due to uric acid diathesis" (Lange 1908). Both brothers died in the first decade of the twentieth century and once again lithium faded into the background.

        The Twentieth Century

        John Cade      

        John Cade published his discovery of the effect of lithium on acute mania in 1949. Three excellent books describe his life and discovery, all on INHN.org.

        Reviewed and published 60 or more years after his discovery in a single decade (2009-2019) (Schioldann 2009; de Moore and Westmore 2016; Brown 2019). This hiatus illustrates the manner in which Cade's stature was enhanced by Schou’s discovery of prophylaxis in bipolar disorder in 1967 and persisted until Cade's untimely death in 1980 at age 68.

        The Cade Clan

        For 150 years in England the Catholic Cades were nearly all pharmacists or doctors until Frederick Cade, born in 1802, migrated to Australia. By 1842 he was established as a "druggist" in Melbourne, home of the future generations.

        In January 1912, when John was born, his father David endowed him with three names, memorializing his paternal grandparents: John, Frederick and Joseph. The fate of a proud lineage rested on John's shoulders, a task he would fulfill.

        John Cade's Early Life

        John's father David began his professional life as a country family doctor. His mother was a devout Catholic, "a strong pioneer type woman, a nurse who became a conscientious Matron, kind and genial.”

        David described his young son as a "strange mixture of gravity and brightness who, quite early, manifested a spirit of investigation and experimentation.”

        After World War 1 erupted in 1915, John’s father David, already a veteran of the Boer War, volunteered and served in Gallipoli and France. When he returned home, suffering from “war weariness” (probably PTSD), he gave up general practice for the less demanding job as resident doctor at Beechwood Hospital for the Insane.

        John, in his early years, mingled with the mentally ill patients and developed an affection for them. He also became a collector of stones, insects and words, obsessively labelling and organizing them.

        Becoming a Doctor

        As a teenager he was studious, excelling in biology. chemistry and physics, inevitably headed for medicine at the University of Melbourne where he won the forensic prize in his final year.

        Following the British tradition, he obtained a doctoral degree in medicine and published three articles, including a statistical study in 1940 collaborating with McFarlane Burnet who later won a Nobel Prize in Medicine.

        After considering pediatrics as a career, he reverted to psychiatry and, following in his father’s footsteps, became resident doctor at Beechwood. In 1937 he married Jean, the nurse who had cared for him as patient with severe pneumococcal pneumonia in pre-antibiotic days. Staff who had worked for his father and knew John as a child welcomed him back.

        John’s clinical work was innovative and diligent. He saw his patients daily, kept scrupulous notes, socialized with them and recognized those who matched Kraepelin’s descriptions, suggesting a biological etiology for which there were no effective remedies.

        Cade recognized the stigmata of nutritional deficiency in many of his patients and spread awareness of this throughout the region leading to the hiring of the first dietician, “a turning point in the care of the mentally ill,”

        Cade as a Prisoner of War

        In the run up to the Second World War, like his father, John enlisted as a general medical officer, becoming captain and then major in the 2/9th Field Ambulance. By mid-1940, now a full-time military doctor, he was shipped to the Malay Peninsula and then to the tiny island of Singapore. Here they were quickly killed or captured by the Japanese. In February 1942 those who survived and surrendered were force marched to Changi, in the southwest corner of the island, surrounded by the sea on three sides. In three years of brutal capture John served both as a general medical officer in a 100-bed hospital and in charge of a 12 bed psychiatric ward that earned him the affectionate title of “Mad Major”.

        His fellow prisoners regarded him as an outstanding doctor and a great officer although the Japanese barbarity to which he was exposed had a lasting effect on his persona; it taught him the essential survival skill of never allowing his emotions to spill over, a trait his future colleagues parsed as “uptight”.

        Unlike his father whose psyche was unraveled by war John gained strength from the ordeal. It also fostered determination and coming back to the notion that severe mental symptoms were somehow anchored in an underlying physical or chemical problem. Lacking any professional research training he was determined to make it an essential part of his future practice.

        Back home to Melbourne

        Arriving home, about to turn 34, his wife could barely recognize him. “He looked dreadful, his knee bones stuck out, his skin was terrible, he looked as if he’d been starved.” He was!

        Demobilized and prepared for action John was assigned resident doctor for the Bundoora Repatriation Hospital, 20 kilometers north of Melbourne, including more than 50 buildings spread over 160 acres, housing 200 repatriated warriors with severe mental illness from two World Wars.

        The family moved into the resident’s red brick bungalow, with a gate through the back fence and a gravel path leading to the hospital entrance. John’s new home was as much a part of the asylum as any of the wards that housed its inmates.

        Implementing his research Plan

        The most detailed and informative account of Cade’s research, based on a review of surviving archived documents and interviews with family members is de Moore and Westmore’s 2016 book.

        John’s workday was governed by his temperament, manifested in rituals. Everyday two cups of scalding tea for breakfast, mid- morning, lunch, afternoon and dinner. Before dinner he was welcomed home with a glass of sherry. All this in parallel with a daily ration of 7 cigarettes, smoked at strategic intervals.

        These rituals he adapted to both his clinical and administrative work, including primitive research plans he was incubating.

        Cade was a prodigious and punctilious reader who annotated and underlined the books he read in his library. Included was Ewen Cameron’s 1945 Advances in Endocrinology. Reading how the thyroid glands over and under activity affected the body and mind (myxedema and mania) was it possible that an excess of some unknown chemical orbiting the body might make someone manic in excess and maybe deficiency caused depression?

        Cade was pragmatic with limited resources. There were no imaging devices, blood tests were intrusive and unrewarding. He would emulate Thudichum and begin with urine. So, he collected and purchased glass jars and began gathering early morning urine samples (presumably concentrated) from diagnostic cohorts.

        With his hypothesis set he need a laboratory to proceed. After starting in his garage, he found an empty unoccupied ward with hot and cold running water he called the Shed. Each patient’s urine was decanted into jars, labelled and shelved in the family refrigerator, (Jean was not happy). Without equipment to analyze the urine and not knowing what to look for he decided to inject it into the abdominal cavity of live guinea pigs of all colors, housed in the house and shed, fed on scraps and treated by his children as pets.

        One by one, regardless of diagnosis the animals died. John working alone and in secret, intense and frustrated became convinced urine from manic patients killed more animals, spurring him to look at urea and uric acid. When manic urine had no excess urea he focused on uric acid. At Changi and Bundoora, he routinely prepared medicines from basic ingredients and knew uric acid was insoluble in water, so he made lithium urate and lithium carbonate. Injected into the guinea pigs they became calm but remained awake and passive.

        So, John’s interest shifted from uric acid to lithium and he began to experiment on himself, varying the dose, terrifying his wife and despite his compulsive temperament leaving absolutely no records. The next step was inevitable; he sought a suitable manic patient to treat with the dose levels he had worked on.

        The First Lithium Treated Patient

        Bill Brand was the first of ten patients John Cade would include in his life changing publication. Bill’s full life history is nine pages long, beginning when he was age 19 and became ill after volunteering for military service in World War 1, while on board ship to England. From the start his symptoms were typical of severe and prolonged mania but they were mis-diagnosed an ineffectively treated.

        His first diagnosis was cerebrospinal fever, and he was suspected of malingering. Subsequent diagnoses spread over years were dementia, concussion, epilepsy, and shell shock (although he never saw active duty). Despite his years long illness and a rating of 100% disability he was never awarded a military pension.

        Living with his parents he eked out an existence but in 1923 aged 27, he married a working-class girl who fled after seven years. In 1943, in his early forties police removed him from his parents’ home, ranting and raving, and he ended up at Bandoora where three years later he came under John Cade’s care. Notorious among nurses and attendants he was nicknamed Monkey. John’s notes recorded a two- year history of being restless, excitable, lack of concentration, noisy, dirty and destructive. Cade decided to use ECT; in 1946 primitive, without anesthesia or muscle relaxants. After nine treatments Bill was transformed, clean tidy, well behaved, an excellent and willing worker. After several months he went home but quickly relapsed. Re-admitted, on March 6, 1948, John noted that Bill’s uric acid was extremely high and concluded that lithium might induce tranquility. He began treatment with lithium citrate in increasing amounts but after Bill developed vomiting and bed-wetting, he switched to lithium carbonate twice daily. Within ten days Bill returned completely to normal.

        John counselled his wife to maintain complete silence and secrecy about what he was doing until he was ready to go public.

        Bill’s metamorphosis was as unpredicted as it was exhilarating. By the last day of June, Bill Brand, as sane as any man on earth, was allowed brief temporary leave from the asylum. The symptoms that had tarnished him for three decades all simply dissolved in the air.  

        John Cade began treatment of additional long term mania patients with success. (Cade 1949).

        But around Christmas 1948 bill stopped taking lithium, troubled by side effects and on January 20 he was readmitted as manic as ever. Restarted on lithium he was back to normal in three weeks, had brief relapses over the next three months after which he remained normal for six months, pottering around the hospital grounds. He remained well throughout 1949 until October, the month after John Cade’s paper was published.

        He began vomiting, was bad tempered and testy, arguing about continuing to take lithium. A fractious relationship continued for seven months until John gave in and stopped the medication. Within two weeks Bill’s relapse was complete. John responded with increasing doses of lithium in escalating amounts to toxic levels; Bill’s hands shook holding a cup and his walking was wobbly. John was close to losing his well pried back emotions. Both Bill and John were fed up with one another. Bill began refusing food, was despondent and wept.

        After reluctantly reducing the dose further in December Bill improved and was able to move to a new community outpatient setting. After a few weeks he returned to Bandoora in early February 1950 but once again began to relapse when the dose was reduced to mitigate side effects.  Cade began to have doubts about “whether Bill would be better off as a carefree restless case of mania than the dyspeptic little man he looks on adequate lithium.” Then John underlines his notes; “Lithium discontinued.”

        From late March until mid-May Bill’s mental state deteriorated further. John vacillates: “his state seems as much a threat to life as any side effects of lithium.”

        The Final Act

        On May 12 John starts lithium again. It makes little difference to Bill’s mental state and physically he continues to decline. He ceases eating and his flesh begins to melt away. Half demented he picks away at his skin which becomes infected with open sores. His bony wrists and ankles are wrapped in sheets. Lithium is stopped and he lapses into coma, complicated by seizures then a prolonged convulsion, checked by a barbiturate injection. A feeding tube is inserted through his nose and nutrition poured in. Bill lingered for ten days until the evening of May 23,1950 when life leached away.

        With tragic irony the military Repatriation Board met the month before Bill died and awarded the maximum pension he had been seeking lifelong.

        At a Coroner’s meeting five months later, October 25, 1950, Cade responded to cross examination with a concise synopsis without deception. He was acquitted of blame and the report concluded, “Death was from bronchopneumonia following lithium poisoning consequent on treatment with lithium salts, which the state of the deceased warranted.”

        For the rest of his life, in the course of many talks and lectures, John Cade always asserted that Bill Brand fully recovered and led a normal life.

        The Fall Out

        In the same year Bill Brand died John Cade reaped the public rewards for his discovery. He was promoted to Superintendent of Bandoora and invited to give the twin Beattie Smith public lectures to the Melbourne public and a professional audience.

        Cade began with a provocative denigration of Freudian psychoanalysis, compatible with Catholic dogma, “It cast a blight on the mind of man that will last fifty years.”

        This bold assertion was coupled with profound humility over his own research. “I might kindly describe myself as an enthusiastic amateur, full of curiosity, with a fair determination, golden opportunities, inadequate knowledge and woeful technique.” He embellished this with a captivating metaphor; “But even a small boy, fishing after school in a muddy pond with a string and a bent pin, occasionally hauls forth a handsome fish.” Cade’s wife Jean, his most ardent supporter, capped this off by adding, “John was not even a researcher’s bootlace.”

        The ultimate accolade came two years later; John Cade was appointed Superintendent of Royal Park Mental Hospital in the heart of Melbourne, the city’s receiving hospital for newly diagnosed patients with mental illness. It was a dramatic increase in status and public profile, although a challenging time. In 1948 and 1950 major public reports had slammed the administration and poor conditions of all Victoria’s mental hospitals.

        Cade was a capable but rigid administrator up to the task. In addition to administration his interests had shifted. According to his son, now a physician himself, Cade relinquished his interest in lithium and, following further reports of fatal toxicity and its total ban in America, he also banned it at Park Royal that lasted until 1956. “He had done what he could and was happy to leave the rest to others.” His interests had shifted to the etiology of schizophrenia and treatment with insulin coma.

        Eduard Trautner; an unusual and remarkable character

        Trautner’s intervention in the lithium saga was timely but bizarre. Catholic by birth, but an atheist by choice, Trautner served in the German army in World War 1 before studying medicine in Berlin where he also acquired laboratory skills.

        Detesting Hitler and fearing fascism he fled to Spain and then England where he was rounded up in 1940 as “an enemy alien and potential spy.” At Winston Churchill’s instigation he joined a “hotchpot of 2000 of England’s rejects” forced aboard the liner Dunera and transported to Sydney, Australia in mid-1940, the same way as convicts in the early 19th century. On arrival, aged 50 he was placed in an internment camp. He was rescued by a Professor of Physiology at the University of Melbourne with a talent of collecting strays with scientific talent.

        When Trautner learned of Cade’s 1949 paper he joined forces with the psychiatrist Charles Noack and began a systematic study of lithium’s therapeutic efficacy and toxic effects using a new method, flame spectrophotometry, to measure blood levels in 100 patients treated at Mont Park Hospital (Trautner, Morris, Noack and Gershon 1955).

        Sam Gershon Arrives

        Sam, an infant immigrant from Poland at age two, thrived in Australia and graduated from Melbourne’s School of Medicine beginning as a resident in the psychiatry program round 1950. He had read Cade’s paper and as a resident at Prince Albert Hospital he treated a few patients with lithium.

        Eager to learn more from the psychiatrist who had discovered the drug he transferred to Royal Park Hospital hoping to work under John Cade. Instead, he was disappointed and felt rejected. Concerned about toxicity, further deaths in the region and the FDA’s total ban in America Cade had banned its use at Park Royal and moved on. Irritated my Sam’s youthful bustle and enthusiasm, himself a person of formality and reserve, while Gershon was outgoing and ambitious. Their brief relationship was highly formal and slightly hostile.

        By the end of 1952 Sam had been transferred to Ballarat Hospital. The Professor of Physiology at the University had introduced him to Trautner. Sam eagerly joined his team where they developed a close professional and personal relationship. Sam’s wife, Lisl, described Trautner as, “he was his own person, he didn’t care about convention or what people thought of him. He was a jovial person, a bon vivant, very European, cosmopolitan. He was devoted to science but also to living; he looked like Yoda from Star Wars.”

        So, Trautner rose like a comet that lit up the Melbourne sky. His thick heavily accented voice exposed with every syllable his Germanic background in a country reeling from post war Teutonic sensitivities about the former enemy. Trautner, in defense, anglicized his name from Edouard to Edward. This might not have inured John Cade from his opinion of this extroverted atheist, a libertine exported from England as a suspected Nazi sympathizer. John hated war and what it had done to his father and his beloved comrades in the 2/9th Field Ambulance.

        Cade never expressed his feelings openly, but one can imagine how a button downed, formal person like Cade might have harbored xenophobic feelings towards this odd couple, a lapsed Catholic, German radical and a Polish born Jewish Australian. Working on his doorstep, Cade no doubt knew they were creating the technology that would render lithium safe yet there is no evidence he reached out, communicated, encouraged or even mentioned it. A highly talented and caring physician he never acknowledged or spoke about what might have saved Bill Brand’s life, might have exposed toxic lithium levels earlier.

        Having made their discovery, the duo did not remain in Australia. Trautner stayed until the end of the decade then slipped away as mysteriously as he had arrived. Gershon migrated to America where he maintained a career long enthusiasm and advocacy for lithium.

        A Lengthy Hiatus

        As the ideal treatment for acute mania lithium, although now safe, had a short life. It suffered from being a simple ion, not patentable and not a moneymaker rivalled by newer synthetic compounds vigorously advertised. By the mid 1950’s chlorpromazine dominated as the antipsychotic in the asylums, available in America and Australia, active for mania, although sedation was sometimes a problem. Cade, still a national hero in his native country, was overshadowed by the rapid discovery, often by serendipity, of new compounds for all the major psychiatric disorders within two decades.

        But in 1968 lithium emerged from the wilderness and Cade’s discovery and his reputation would be back in the forefront of clinical psychopharmacology.

        The turn to Prophylaxis

        In 1951 Strömgren, in Denmark, learned of Trautner’s work at a conference in Paris and drew it to the attention of “his brilliant research assistant, Mogens Schou.” So Schou collaborated with colleagues in Denmark on the first double-blind placebo-controlled trial of lithium in 38 cases of acute psychotic mania (Schou, Juel-Nielson, Strömgren and Voldby 1954).

        Even before the results were published Schou wrote to Cade congratulating him on the original discovery. They soon became close friends, exchanging approximately 40 letters between 1953 and 1970 by which time the scope of lithium therapy had been vastly inflated by discovery of its prophylactic effect in 1968, (Baastrup and Schou 1967).

        Schou and Cade also met on three occasions between 1963 and 1975.

        Schou confessed he was unable to replicate Cade’s experiments in guinea pigs and while he admired him greatly, he also described him as “an artist” compared to himself as “a systematic scientist.”

        Controversy and adulation

        In 1968 I had completed my psychopharmacology fellowship, graduated from residency and was a senior research fellow working with Michael Shepherd at the Maudsley Hospital. He asked me to analyze and critique the study Baastrup and Schou had published, claiming lithium was prophylactic in preventing recurrent treatment resistant depression and bipolar disorder (Baastrup and Schou 1967).

        Shepherd had an acquaintance with Schou and knew he had a brother suffering from treatment refractory depression who was included in the trial which had no control, was not double blind and might therefore be biased. This was the time when the randomized double blind controlled design was considered the essential methodology for testing a treatment. Colleagues at the Maudsley had recently used it to reveal that insulin coma therapy for schizophrenia was no better than placebo and the Institute was gathering a reputation for being overly critical.

        There were other statistical and methodologic flaws and our rebuttal was published in the Lancet with the provocative title, “Prophylactic Lithium; Another Therapeutic Myth” (Blackwell and Shepherd 1968). Naturally, this caused considerable controversy and the ad hominem flavor made matters worse. The full story is told in my book Treating the Brain; An Odyssey (Blackwell 2020), and in the end the matter reached a benevolent and constructive outcome after Schou devised a creative design that proved his point.

        Soon afterwards, in the fall of 1968, I migrated to America where I met and was befriended by Frank Ayd, an entrepreneurial self- made psychopharmacologist in private practice and member of the ACNP, well acquainted with all the pioneers and their discoveries. Together we planned and implemented the Taylor Manor Conference in Baltimore at the hospital where Frank worked. We invited 16 of the leading pioneers to tell the stories of their discovery, each received an award and the texts were published in our book, Discoveries in Biological Psychiatry (Ayd and Blackwell 1970). I gave an opening talk on “The Process of Discovery” combining my experience of the tyramine-cheese interaction and a review of the literature, including Merton’s sociology of discovery.  Ayd gave a talk on “The Impact of Biological Psychiatry.” Additional speakers and their topics were:

        Joel Elkes: Beginning in a new science

        Irvine Page: Neurochemistry

        Lothar Kalinowsky: Treatments before Pharmacotherapy

        Chauncey Leake: A drug from idea to use

        Tracy Putnam: Diphenylhydantoin and related compounds; pharmacology

        Frank Berger: Anxiety and the discovery of the tranquilizers

        Irvin Cohen: The Benzodiazepines

        Hugo Bein:  Reserpine

        Pierre Deniker: Neuroleptic chemotherapy

        Jorgen Ravn: The Thioxanthenes

        Nathan Kline: MAO Inhibitors

        Ronald Kuhn: Imipramine

        John Cade: Lithium

        This was a congenial gathering of peers, the seed bed and origin of modern psychopharmacology rendered by the true pioneers. There were no icons or leaders, only equals.

        It is curious that Frank placed Cade last in the presentations since lithium for mania was the first of the modern psychotropic agents. In his closing comments Ayd begins with the statement, “The chemical revolution in psychiatry began in the early 1950s with the initial announcements on chlorpromazine and reserpine … He overlooks lithium and does not mention it at all, spending his entire time on neuroleptics. Cade on the other hand begins by detailing the impact of the FDA ban on lithium unaware that it would be lifted after 21 years while the Conference was still in session. Cade thanks Schou… “The person who has done the most to achieve this recognition   by validating and extending my original observations.” Although Schou made it clear he was unable to replicate or understand any of Cade’s experiments in guinea pigs.

        Cade makes no mention of Trautner’s work or of the need for plasma monitoring. His account of his first patient ends with… “a month later he is completely well and ready to return to home an seems cleared for work”.

        It is clear that Ayd believes the real start of the modern era in psychopharmacology began with chlorpromazine in 1952. Schioldann differs with this point of view; the second volume of his history of Lithium is titled The Birth of Modern Psychopharmacology 1949 (Schioldann 2009). This controversy persists today and hinges on the fact that Cade’s contribution to the field was confined to the discovery of lithium’s effect in acute mania in 1949 and his interest and reputation were only reignited and enhanced after Schou’s discovery of prophylaxis in 1967. The details of this disagreement are told in my book (Blackwell 2020).

        After the Baltimore Conference Cade flew to Denmark to join Schou. In 1974 they shared the Kittay Award, the world’s richest prize in psychiatry. Two years later John was awarded the Order of Australia, the highest accolade his country could bestow on a citizen.

        Sam Gershon Tireless Advocate

        In America, now that FDA has rescinded its ban, lithium has taken on a new life as a mood stabilizer and Sam undertakes to ensure this is safe and effective. He is the Founding Member and first President of the International Society for Bipolar Disorder (ISBD). They offer up to 4 research grants for young investigators. He is Founder and Editor in Chief of the journal Bipolar Disorders.

        Sam is tireless in promoting safe plasma levels and with colleagues invented the “Lithiumeter,” a visual scale for measuring the optimal plasma level – 0.6-1.2 me/L (Malhi, Tanious and Gershon 2011).

        Founded in 2009, The South Australian Health and Medical Research Institute (SAHMRI) in 2014 created the Gershon Medal for achievement in translational neuroscience.

        Lithium Today

        Despite everything Sam can do, the organization, awards, and journal he has initiated lithium still struggles. A problem is compliance; the need for continuing lab visits (akin to anti-coagulant monitoring) sometimes persisting for years and complicated by troubling side effects. Compliance was only identified a problem in the mid-1970s before which it was coded as “patient dropout”. Since then, a vast literature has evolved. My book, Treatment Compliance and The Therapeutic Alliance (Blackwell 1997) has a comprehensive chapter on the topic of lithium compliance in manic-depressive disorder by Kay Redfield Jamison, also told in her own words. (Jamison 1997).

        A recent study found that faulty compliance was associated with indefinite   length of treatment, stigma of mental illness and dislike of mood control (loss of hypomania) (Peselow, Long, Steiner, Pizano et al. 2016).

        Manic symptoms, the first year of treatment and troubling side effects are also common causes of poor compliance while younger and male patients are at higher risk.  Pill boxes, family monitoring and mitigation of side effects are also helpful.

        In 2005 the FDA approved a finger-stick blood test (like diabetes testing) that takes less than 3 minutes for checking blood levels and compliance.

        Lithium is the only mood stabilizer that can prevent suicide and patients who stop lithium are at greater risk. (Baldessarini, Tondo and Hennen 2001)

        A contributory problem is the fact that lithium while inexpensive is not backed by high end advertising and the pharmaceutical industry now focusses its sales at Me-Too compounds with large profits. There are anti-epileptics, mood stabilizers and atypical anti-psychotics approved for this indication. All of them are substantially more expensive than lithium and none of them have been shown more effective than lithium in controlled studies. Mood stabilizers bought from pharmacies are substantially more expensive than supermarkets, like Costco.

        The Evidence to Date

        Two recent studies confirm the superiority of lithium over mood stabilizers. Kessing, Bauer, Nolem et al. (2018) found that in 8 of 9 studies involving 14,000 patients, lithium monotherapy was associated with improved outcome compared to another mood stabilizer including valproate, lamotrigine, olanzapine, quetiapine, carbamazepine and unspecified atypical anti-psychotics. Hafeman, Rooks, Merranko et al. (2020) studied 340 participants ages 7-17 with 2,638 six month follow up periods (mean follow up 10 years). Lithium use was associated with decreased suicidality, less depression and better psychosocial function.

        A Cautionary Tale

        In 2014 JAMA published an article by Hampton, Daubresse, Chang et al. about adverse effects due to psychotropic drugs in the emergency room. They reported that 16.4% of 10,000 visits were due to lithium with just over half (53%) admitted overnight. Since this was a statistical, population-based study no data were obtained on diagnosis, who prescribed the drug, what training they had or what were the side effects.

        In the Clinical Review and Education Section a reviewer expressed the opinion that psychiatrists were over prescribing lithium and its use should be restricted.

        In a letter to the Editor, I said it was a disservice to science, medicine and psychiatry to suggest that sloppy monitoring or over prescribing of a highly specific and effective drug should become an excuse for limiting its appropriate use. I added the stipulated number of references.

        A reply came back from three junior editors who said their score did not reach the required number for publication. They would send me phone number of the author but if he failed to respond nothing could be done.

        A Final Word

        From 1800 to 2021 lithium has led a roller coaster life. From an inexpensive metallic ion in search of an ailment, then becoming the first specific treatment for a psychiatric disorder in 1949, manic psychosis, soon replaced by the flood of anti-psychotics beginning with chlorpromazine in 1952. Then a silent hiatus until the discovery of prophylaxis for recurrent bipolar disorder in 1967 where it became dominant for over two decades until the pioneer period (1949-1980) morphed into a modern era (1980-2021) during which the pharmaceutical industry moved from innovative drug discovery to heavily promoted, highly lucrative, me-too products. Lithium became subordinate to a flood of mood stabilizers. Despite its clinical superiority and safety if scrupulously monitored, the burden of that requirement seems too much for patient and prescriber to persist. Seductive advertising and industry “KOL’s” endorsement of alternative “mood stabilizers” may contribute.

        This journey from the discovery of lithium to its fading present, from the pioneer to the modern era, is the alpha & omega, linking from start to finish the fates of lithium and academic clinical psychopharmacology (Blackwell 2020).

 

References:

Ayd FA, Blackwell B, editors. Discoveries in Biological Psychiatry. Philadelphia, Lippincott; 1970.

Baldessarini RJ, Tondo L, Hennen J. Treating the suicidal patient with bipolar disorder; suicide risk with lithium. Ann N Y Acad Sci 2001;932:24-38.

Baastrup PC, Schou M. Lithium as a prophylactic agent: its effect against recurrent depressions and manic-depressive psychosis. Arch Gen Psychiatry 1967;16(2):162-72.

Blackwell B, editor. Chronic mental illness, Vol. 5. Treatment compliance and the therapeutic alliance. Harwood Academic Publishers; 1997.

Blackwell B. Review. Johan Schioldann: History of the Introduction of Lithium into Medicine and Psychiatry: Birth of Modern Psychopharmacology 1949. Adelaide: Academic Press: 2009 (363 pages). inhn.org.books. September 14, 2017.

Blackwell B. Treating the Brain: An Odyssey. INHN Publisher. Amazon.com; 2020.

Blackwell B, Shepherd M. Prophylactic Lithium: Another Therapeutic Myth? An Examination of the Evidence to Date. The Lancet 1968;7549(Vol. 291):968–71.

Brown W. Lithium: A Doctor, a drug and a breakthrough. New York and London; Liveright; 2019.

de Moore G, Westmore A. Finding Sanity, John Cade, Lithium and the Taming of Bipolar Disorder. Sydney/Melbourne/ Aukland/London Allen & Unwin; 2016.

Garrod AB. The Nature and Treatment of Gout. London, Walton & Maberly; 1863.

Gibb GD. Notes on the action of the bromides of lithium and zinc. Report of the 34th meeting of the British Association of Advances in Science. Sept. 1863.

Hafeman DM, Rooks B, Merranko J, Liao F, Gill MK, Goldstein TR, Diler R, Ryan N, Goldstein BI, Axelson DA, Strober M, Keller M, Hunt J, Hower H, Weinstock LM, Yen S, Birmaher B. Lithium versus other mood stabilizing medications in a longitudinal study of youth diagnosed with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2020;59(10):1146-55.

Hammond WA. A treatise on Disease of the Nervous System. New York. D Appleton & Co; 1871, pp. 380-4.

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August 12, 2021