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Is this neglect due to ignorance of the source, disregard for its relevance, or did this unmentioned and perhaps long forgotten material influence Cade at a pre-conscious level? To this end the reviewer will comment later, but the readers must decide for themselves. Each of 30 chapters is scrupulously referenced; there are photographs of the principal protagonists and copious indexes of persons and subjects.

Birth of Modern Psychopharmacology Gout is one of the earliest diseases described in the literature, from the time of Sydenham who suffered from and wrote about the condition Sydenham, ; it was considered an affection of the nervous system, with melancholia an inseparable companion Roose, Neurosis was also considered an etiologic factor Duckworth, Uric acid was discovered in calculi in Scheele, and identified as an etiologic contributor to uric acid diathesis, linked to diet Parkinson, Mania was also reported to be a manifestation alone Whytte, or in conjunction with melancholia Lorry, The belief that gout, melancholia and mania were co-morbid was widely held throughout the 19 th century in America and Europe, endorsed by many of the leading mental health physicians, discussed at international conferences and articles about the subject were published in leading psychiatric journals of the day Pinel, ; Esquirol, ; Trousseau, ; Reynolds, ; Rayner, Naturally enough, treatments proliferated, some from antiquity and others directed mainly towards the presumed uric acid diathesis.

Deterred by its drastic purgative effects, a spectrum of other remedies flourished, including cautery, moxibustion, acupuncture, blood-letting, non-protein diets and abstemious life styles. Lithium enters the stage with its discovery in by the Brazilian Jose Bonifacio de Andrada e Silva who found it in a pile of rocks in an iron ore mine Johnson, It was not chemically identified as a metallic ion and named lithium, Greek for stone, until later Vaquelin, It was first mentioned as a potential therapeutic agent when lithium carbonate was found to be four times better than sodium carbonate as a solvent for uric acid Lipowitz, Clinical utility was suggested two years later when lithium carbonate was shown to dissolve a human kidney stone in vitro Ure, , then first used in vivo by Binswanger in Sollman, During almost a century, between its first use and until its lethal side effect was recognized, lithium was used in various formulations for a variety of conditions in addition to gout.

In 19 th century America the rationale and sequence of indications for lithium use were reversed. Hammond made no mention of gout or co-morbidity but in New York Leale took on where Hammond left off. At a conference in London, England Leale, he resurrected the concept of co-morbidity. An interesting comment on poor compliance, a problem that would not be widely noted or named until more than 90 years later Blackwell, In Denmark, lithium would finally emerge as a treatment for specific mental disorders.

Pride of place is accorded the Lange brothers during the last quarter of the 19 th century and the first decade of the 20 th , , after which its popularity dwindled and was eventually extinguished. Carl Lange was an academic neuropathologist in private neurology practice and his younger brother, Fritz Lange , was an asylum psychiatrist at Middlefort Lunatic Asylum. Towards the end of the 19 th century criticism came on both fronts from leading contemporary colleagues Levinson, ; Pontoppidan, ; Christiansen, In the last edition of his book, Henry Maudsley touched on the occasional co-morbidity of gout and mental disorders, downplayed the significance of uric acid and mentioned neither Carl Lange nor lithium Maudsley, He viewed the diagnosis as more likely being manic depressive disorder in which the manic phase had been missed, but did not mention lithium in its treatment, although he did use it for epilepsy Kraepelin, The author also adds a more contemporary note by citing a study which showed a correlation between cyclic changes in manic-depressive illness and changes in daily uric acid excretion, particularly in the early stages of remission - whether natural or lithium induced.

The authors speculated that lithium interferes with the active transport of organic acids in the kidney and the brain Anumonye et. Since the uric acid diathesis did not exist there was no reason to mention any medicinal remedies for it. This logical assumption was later mistakenly characterized as the deliberate abandonment of prophylactic lithium treatment by the father of Mogens Schou, Amdisen, creating a mythical father-son disagreement Schou, The lithium story began with the fallacious uric acid diathesis which invited alkaline remedies as a treatment repertoire for its allegedly protean manifestations, including psychiatric symptoms.

Equally fallacious was the premise that because lithium was a preferred remedy based on its superior solvent properties in vitro this would transfer to in vivo use, an assumption never clinically confirmed. In addition the earliest use was with lithium bromide- bromide itself having sedative properties. The first to use lithium in the acute phase of manic-depressive illness was possibly Hammond , while Da Costa suggested prophylaxis using lithium citrate. Both Lange brothers were the first to use lithium carbonate for acute treatment and prophylaxis of periodical depression, finding it superior to the bromide salt.

In the first decades of the s, the uric acid diathesis was discarded as an erroneous concept by leading Danish psychiatrists Faber, and lithium was ushered out with it. In doing so, he cites seven sources beginning with Johnson and Amdisen whose conclusions are both ambivalent and equivocal. Essentially, in addition to a childhood living on the grounds of mental hospitals where his father was a psychiatrist and with a demonstrated interest and involvement in research as a medical student and postgraduate, Cade's views were influenced by his experiences as an officer and general medical practitioner in a Japanese prisoner of war camp during World War II.

These experiences shaped a conviction about the organic etiology of severe mental illness, coupled with the simplistic idea, derived from thyroid disease that depression might be due to the absence of a centrally mediated metabolite and mania due to an excess akin to myxedema and thyrotoxicosis Cade, He communicated these ideas to his wife in a letter en route home from captivity and remained loyal to them in his final publication Cade, where, not for the first time, he expressed his negative views about Freud and psychoanalysis.

Identifying urea as the culprit, he described its toxic effects, proceeding from ataxia to quadriplegia, myoclonus, tonic convulsions and eventually status epilepticus leading to death. Putting aside this distraction, Cade returned to his attempt to find a toxic substance in the urea of manic patients and selected uric acid as a candidate. Confronted by its insolubility in water, he chose the most soluble urate, which happened to be lithium.

Now, using a 0. This result of lithium was accompanied by making the animals lethargic and unresponsive for up to two hours before returning to normal.


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Close inspection of cards by the author describing his experiments in guinea pigs deposited by his wife in the Medical History Museum at the University of Melbourne contain none that describe his experiments with lithium Four Items. Series 22, c. Schou noted that the apathy and slow reaction might be due to intoxication or a direct action on the brain. Experiments in mice and rats also failed to show any comparable effects.

I have at least not been able to produce such an effect in guinea pigs or rats with anything but strongly toxic doses. One would be suffocated by hospital boards, research committees, ethical committees and head of a department.

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His successor, after Jones' move to Australia, discovered a half empty large canister of lithium presumed to date from the early 20 th century. Without any control, the results were unequivocal; the manic patients all recovered between a few days and a couple of weeks, relapsing if lithium was discontinued or they were non-compliant.

The schizophrenic patients showed a reduction in excitement or restlessness, but no improvement in the core symptoms, although he later reported two patients diagnosed as schizophrenic who did respond Cade, Cade never publicly admitted the cause of death and, years later, in four publications he portrayed the final outcome as successful Cade, ; Cade, ; Cade ; Cade, Mogens Schou and Cade began corresponding in Subsequently, Cade learned of lithium's potential as a prophylactic agent in recurrent manic-depressive disorders and Schou accurately predicted it would become far more widely used worldwide.

Meanwhile, routine plasma monitoring had made it a far safer drug to use by work done in his own backyard Noack and Trautner, , something Cade also never publicaly acknowledged. The question arises as to how quickly the use of lithium spread around the globe. A first unpublished account of its use by a British psychiatrist in was reported as a personal communication years later Johnson, The first published account after Cade was in Australia Roberts, of just two cases, one of which, a female with chronic mania, was fatal.

Also in , a world authority on gout and uric acid published a paper on lithium as a salt substitute Talbott, suggesting that monitoring serum levels might stave off toxicity. In a letter written in , Schou congratulated them on a method of primary importance in the development of lithium as a safe and efficient procedure Goodwin and Ghaemi, Cade, for the reason given above, remained silent Gershon and Daverson, In and , Schou collaborated with colleagues in Denmark on the use of lithium in 38 manic patients in a double-blind placebo-controlled study, Schou et.

This might be the point at which lithium could be considered a scientifically-based safe and effective treatment of acute mania. According to the author, both Stromgren and Schou disavowed any influence of the Lange brothers in their decision to study lithium; Schou also denied hearing his father speak of it. This apt and colorful quotation coveys a strong and synergistic relationship between the two men and a somewhat humble contribution made by Cade.

The author spends 13 pages addressing this somewhat controversial and provocative topic which plays a recurrent theme throughout the discovery of all the earliest treatments in psychopharmacology Ban, While it is a term sometimes used by the discoverers themselves, others have viewed it as dismissive or even derogatory.

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This penultimate chapter begins, appropriately, by singling out America as most tardy in the recognition of lithium for mania. This ban stubbornly persisted until due largely to the failure of academic psychiatry and the FDA to recognize the fact that toxicity could be avoided by blood monitoring Noack and Trautner, Paradoxically, the ban on use in mania, but still not for prophylaxis, was lifted in at exactly the time Cade was invited to present his work for the first time in America Ayd and Blackwell, He also shared an interest in literary skills with a younger brother and journalist although his scientific articles tended toward brevity and had been criticized for that.

After medical training, Cade undertook a post graduate doctoral degree without thesis , a mirror of the British practice preparing for an academic or research career, and also an approach he urged his colleagues to pursue following his discovery of lithium. During the span of his career, he fulfilled many teaching assignments, helping to train as many as psychiatric residents, as well as medical students, between and his retirement in Like Frank Ayd, he wrote a column for thousands of fellow Catholics on a whole range of medical, psychiatric, ethical and social issues.

In addition to a synopsis of his own career, Schou provides a profile of his relationship with John Cade. In addition to a long correspondence, they met on three occasions between and Because I have played a personal and significant role in the controversies swirling around lithium Blackwell, and this is the second book I have reviewed on the topic Blackwell, , I have shunned commenting as far as possible in my review of the book itself and have chosen to address five important aspects that play central roles in the enigmatic story of Cade and lithium.

He did not start out wanting to be one. From till he was a medical student and in his final year he attended 12 psychiatric lectures. Following graduation he spent a year as an intern in medicine and pediatrics ending with a near fatal episode of pneumonia in pre-antibiotic days. After recovering, he decided to follow his father and become a psychiatrist. For the next two years he experienced on the job training in a rich clinical environment and also studied for a post graduate degree in general medicine M. Also during this time he became involved in research and had two publications. Driven by a strong sense of urgency and creative ideas incubated at Changi, Cade returned to Bandoora Repatriation Hospital in and almost immediately supplemented his demanding work as Superintendent with his intense solitary search in guinea pigs for a toxic cause of mania.

Pharmacology - ANTIDEPRESSANTS - SSRIs, SNRIs, TCAs, MAOIs, Lithium ( MADE EASY)

It is equally unlikely that lithium or uric acid diathesis were mentioned in the curriculum of medical school or postgraduate medical studies. Even supposing, however unlikely, that Cade did know of the early Danish work decades earlier, why would he fail to acknowledge that in his own work? Most scientists bolster the credibility of novel findings by citing prior work that corroborates their own.

The extent to which early and long-buried knowledge may be overlooked in the discovery process is the subject of an essay on Adumbration Blackwell, This tells the story of the tardy discovery of the sometimes fatal interaction between MAO inhibitors and tyramine containing foods five years after these drugs were introduced for the treatment of tuberculosis and depression. A compelling archive of information in prominent journals that might have predicted this toxic interaction was unknown to basic scientists and clinicians working for several pharmaceutical companies, as well as academic and journeyman physicians in various disciplines who treated thousands of patients.

A second discovery was an excellent article, the best and most comprehensive I have come across, on the history and role of the word Ban, More than three centuries of usage in three languages have blurred the precise definition of the word serendipity. Ban cites three dictionaries with differing definitions. The essence common to all three is a search in which the outcome is unexpected. In none of them is there any hint that the word might or can be used in a derogatory way which both Schou and Cade assumed to be the case.

He was also a disciplined clinician well versed in classical nosology and epistemology. Shepherd says nothing about the possibility that the same person might use different methods for separate tasks. Attempts to decipher the logic and cognitive style of his inquiries into uric acid, lithium and mania have also been frustrating due, at least in part, to lack of data.

This clearly defines two distinct time periods: from to and from then to the present. Within less than three years of his discovery Cade had banned the use of lithium in the hospital where he was superintendent, a topic about which he remained silent although it coincided with the death of his first patient due to lithium toxicity, followed by the death of another patient at a different hospital and preceded by a total ban on its use in America.

During this time he was also sent to Britain for six months to study changing trends in mental health care possibly applicable to Melbourne. It was during this period, from to , that the CINP was formed and convened its first three international Conferences, none of which Cade participated in nor did any psychiatrist from Australia. Lithium was not mentioned in the main program in any of the first three meetings in , and It was in that Schou first wrote to Cade informing him of an interest in prophylaxis, congratulating him on his discovery and initiating a continuous correspondence.

All agreed and each received the same Taylor Manor Award. This meeting provides a different perspective on events in the field. Three drugs were in use before lithium: LSD, amphetamine and diphenylhydantoin.

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