2020 Vision J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-322382 on 16 March 2020. Downloaded from

A MODERN 2020 CENTENARY PERSPECTIVE ON TRAIL BLAZING PAPERS FROM THE JNNP ARCHIVE : a slow burner Andrew J Lees

After a period of baseline evaluation The treatment of manic psychoses by the lithium was administered in an open-label­ administration of lithium salts fashion to some of the patients and in Authors: Schou M, Juel-­Nielsen N, others double-­blind randomisation using a Stromgren E, and Voldby H placebo was used, switching the treatment Year published: 1954 at 14-­day intervals. Most of the patients Number of times cited: 617 received (0.9–1.8 g/ day) but a few were treated with lithium feasible and might be a useful addition citrate and lithium chloride. Electrocon- to careful clinical evaluation in detecting vulsive therapy was curtailed and when- toxicity.2 Cade’s findings published in the ever possible sedatives avoided during the Medical Journal of Australia had appeared trial period. Serum lithium levels were at a time when reports of toxic reactions measured routinely and, in a few cases, caused by excessive intake of a lithium-­ cerebrospinal lithium values were also based salt substitute by cardiac patients obtained. A daily 3-point­ scale was used to It took Mogens Schou and his were in the headlines in the USA. One assess the severity of and the collaborators two decades to get or two other Australian psychiatrists results reported as unequivocally positive lithium accepted for the prevention of also then confirmed lithium’s potential as a better treatment for mania than the improvement, possible improvement and mania. Along the way he was vilified no improvement. Of the 14 patients who and his scientific objectivity current practice of repeated electroshock therapy and high-­dose barbiturates but improved unequivocally usually within 2-3

questioned. These regrettable delays copyright. also drew attention to its risks. The dose weeks of starting lithium 11 were women. led to many unnecessary suicides. Graphic charts of 14 representative More profitable rebranded required to see benefit was close to the toxic range and a fatality that occurred patient responses are included at the end with less efficacy now in one of Cade’s own patients led him to of the paper showing the effects of treat- threaten lithium’s primacy as the gold temporarily ban lithium’s use following ment on both mood and motor activity. A standard treatment for bipolar 1 his appointment as the new Medical further 18 patients had a ‘possible effect’. disorder Superintendent at the Royal Park Mental In some of this group lithium induced a Hospital in Melbourne. distinct improvement but spontaneous remission could not be excluded, whereas In 1949, Cade reported that lithium could Lithium therapy was teetering on the brink of oblivion when Cade’s and in the remainder, modest benefit was seen. quieten patients with acute manic excite- Six patients did not improve despite what

Noack and Trautner’s papers came to the http://jnnp.bmj.com/ ment without causing drowsiness. The were considered therapeutic doses of rationale for his pilot trial stemmed from attention of Mogens Schou, an academic Danish psychiatrist who found it aston- lithium and in another five, a transition a series of experiments he had carried out into a depressive phase occurred requiring single-­handedly in a disused kitchen in ishing that the positive reports from Australia had not aroused greater interna- lithium withdrawal. Discontinuation of a psychiatric hospital where he demon- lithium led to prompt recurrence of mania strated that lithium salts reduced seizures tional interest and determined to carry out his own investigations. in all the responders. and deaths in guinea pigs injected with Serum lithium levels which ranged from toxic doses of urea. He had also noted that 0.5 to 2.0 mEq/L were considered to be an on September 28, 2021 by guest. Protected the animals became docile and immobile. The highly cited 1954 JNNP paper unreliable measure of lithium in the tissues Before proceeding to test lithium salts on Schou reasoned that the lack of enthu- and certainly no substitute for careful clin- patients, he then took lithium carbonate siasm for lithium related in part to the fact ical observation. The average serum level himself in increasing doses to evaluate its that the pilot trials had not ruled out some in women was somewhat higher than that 1 safety. common sources of error and he deter- in men possibly explaining their better Stimulated by Cade’s paper, Noack and mined to carry out a more rigorous study. therapeutic response. The doses needed Trautner then gave lithium salts to 100 Together with several colleagues he gave to see improvement were close to mildly psychiatric patients and confirmed its selec- lithium salts to 38 patients (21 women toxic levels and 24 mEq of lithium a day tive efficacy for the treatment of mania. and 17 men) with mania who had been were recommended. Toxic symptoms They also demonstrated that the clinical admitted to Sindssygehospitalet Risskov included nausea, vomiting diarrhoea, measurement of serum lithium levels was . Eight of the patients had addi- postural tremor of the hands and a flat- tional symptoms that the authors consid- tening of effect with fatigue. The authors Correspondence to Professor Andrew J Lees, Reta ered to be atypical for concluded that lithium was efficacious in Lila Weston Institute, Institute of Neurology, University including auditory and College London, London WC1N 1PJ, UK; ​andrew.​lees@​ the treatment of mania provided the treat- ucl.ac.​ ​uk thought disorder. ment was monitored closely by regular

Lees AJ. J Neurol Neurosurg Psychiatry April 2020 No 4 335 2020 Vision J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-322382 on 16 March 2020. Downloaded from clinical evaluation, serum lithium levels one. But even a design that is short of the Lithium’s mode of action remains and electrocardiographic recordings. They ideal may, in addition to the advantage uncertain but it is known to reduce excit- also corroborated Cade’s observations of being practically feasible, constitute atory neurotransmission through effects that lithium salts did not lead to disabling useful information if the study succeeds on dopamine, glutamate and second 3 in proving its point beyond a reasonable sedation. messenger systems and also increase doubt". The paper is notable not only for its gamma-­aminobutyric acid-­mediated inhi- confirmatory findings but because it Partly as a result of this criticism, lithium bition. It has been shown to be effective represented the first attempt to carry out remained underused by psychiatrists in the in refractory early morning and off-­period a randomised controlled trial in psychi- UK until the mid-­70s.8 9 By the late 60s, a dystonia in Parkinson’s disease14 and has atry. Nevertheless, the paper was rejected few mavericks had started to use lithium been proposed as a treatment for neuro- by The Journal of Medical Science (now in the USA and despite continuing regu- degenerative disorders with pathological the British Journal of Psychiatry) after latory anxieties the US Food and Drug overaccumulation of phosphorylated tau the eminent British psychiatrist Eliot Administration were eventually pressured protein.15 Slater had reviewed it and given it a low to grant lithium a licence for the treatment The handful of short reports published score. Although further support for lithi- of mania in 1970 but not before many by the Journal of Neurology Neurosurgery um’s efficacy soon came from two French thousands of patients had been unneces- and Psychiatry since the classic 1954 paper authors, Schou’s paper had little imme- sarily denied effective treatment for many all relate to lithium’s neurotoxicity.16 17 In diate impact in part because the Journal of years. contrast, the British Journal of Psychiatry Neurology, Neurosurgery and Psychiatry Schou continued his research into that rejected the paper has in the interim was considered an ‘out of the way’ journal lithium for the rest of his professional published >200 papers on the use of by most psychiatrists. career. In 1979, he treated 24 artists lithium in bipolar disorder but none with (a mixture of writers, composers and comparable impact. Aftermath painters) with disabling episodes of mania. Further evidence gradually accumulated By measuring productivity levels and the F unding The authors have not declared a specific quality of their art, he showed that in those grant for this research from any funding agency in the to support lithium’s efficacy in the treat- public, commercial or not-­for-­profit sectors. ment of acute mania but much to Schou’s who had very severe bipolar disorder (of chagrin, it remained the Cinderella of the type that had affected the poet Robert Competing interests None declared. the psychotropics, an unpatentable and Lowell throughout his life), lithium could Patient consent for publication Not required. 10 unprofitable orphan. In contrast, the improve creative output. Provenance and peer review Commissioned; company backed major tranquilisers, The 1954 Journal of Neurology, Neuro- internally peer reviewed. copyright. monoamine oxidase inhibitors and tricy- surgery and Psychiatry paper eventually © Author(s) (or their employer(s)) 2020. No clics were all rapidly approved by the regu- came to be regarded as an important land- commercial re-use­ . See rights and permissions. lators and entered psychiatric practice. mark in the longdrawn-­out acceptance Published by BMJ. In the 1960s, Hartigan in England and of lithium. When Cade and Schou spoke Baastrup and Schou in Denmark reported at a meeting in Denmark in 1970, Schou presented his Australian colleague as ‘the that lithium could reduce the frequency of To cite Lees AJ. J Neurol Neurosurg Psychiatry 4 5 relapses in manic-­depressive . man who introduced lithium into psychi- 2020;91:335–337. atry and described its antimanic effect’. The possibility that a trace element might Received 2 December 2019 also be a mood normaliser was considered Cade then stood up and acknowledged Accepted 12 December 2019

the Dane’s contribution by saying, ‘I feel http://jnnp.bmj.com/ by many eminent opinion leaders to be an J Neurol Neurosurg Psychiatry 2020;91:335–337. outlandish suggestion but the drug had rather like a woman who as a girl had an doi:10.1136/jnnp-2019-322382 finally become established as a recognised illegitimate child and had it adopted out. treatment for manic excitement in Conti- And now, 20 years later I am visiting the nental Europe. Acceptance in the UK was adoptive parents and finding out what References hampered by a rancorous clash between a big fine boy he has grown into, but 1 Cade JFJ. Lithium salts in the treatment of psychotic Baastrup and Schou and Blackwell and knowing far less about him than his adop- excitement. Med J Aust 1949;2:349–52. 2 Noack CH, Trautner EM. The lithium treatment of Shepherd, the latter a rising star at the tive parents’.11 maniacal psychosis. Med J Aust 1951;2:219–22. on September 28, 2021 by guest. Protected Maudsley Hospital and advocate of In the opinion of most practising 3 Schou M, Juel-­Nielsen N, Stromgren E, et al. The rigorous trial methodology to psychiatry psychiatrists, lithium carbonate should treatment of manic psychoses by the administration research. Schou accepted the methodolog- be started at a dose of 400 mg aiming for of lithium salts. J Neurol Neurosurg Psychiatry 1954;17:250–60. ical limitations of his studies but found serum levels between 0.6 and 1.0 mmol/L 4 Hartigan GP. The use of lithium salts in affective inexcusable Shepherd’s insinuations that remains the most effective therapy for disorders. Br J Psychiatry 1963;109:810–4. he had personal motives for studying the prevention of mania in bipolar affec- 5 Baastrup PC, Schou M. Lithium as a prophylactic lithium. In some acrimonious correspon- tive disorder and should be started at a agents. its effect against recurrent depressions and dence published in The Lancet, Blackwell dose of 400mg aiming for serum levels manic-depressive­ psychosis. Arch Gen Psychiatry and Shepherd wrote that Schou’s methods 1967;16:162–72. between 0.6 and 1.0mmol/l. Alterna- 6 Baastrup PC, Schou M. Prophylactic lithium? Lancet were shoddy and unconvincing and that tives that are particularly popular in the 1968;2:349–50. he was an enthusiastic advocate rather USA include the anticonvulsants, sodium 7 Blackwell B, Shepherd M. Prophylactic lithium: another 6 7 than an objective investigator. Baastrup , and therapeutic myth? an examination of the evidence to and Schou in their riposte wrote: but there is less evidence for their efficacy date. Lancet 1968;1:968–71. 12 8 Schou M. The first psychiatric use of lithium. Br J "Our study on lithium prophylaxis was in preventing relapse and in contrast Psychiatry 1992;161:279–80. the first of its kind. It could have been to lithium no evidence that they reduce 9 Healy D. Pioneers in psychopharmacology II. Int J a different design and possibly a better suicide rates.13 Neuropsychopharmacol 2000;3:351–4.

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10 Schou M. Artistic productivity and lithium prophylaxis 13 Müller-Oerlinghausen­ B, Ahrens B, Grof E, et al. 15 Matsunaga S, Kishi T, Annas P, et al. Lithium as a in manic-­depressive illness. Br J Psychiatry The effect of long-term­ lithium treatment on treatment for Alzheimer’s disease: a systematic review 1979;135:97–103. the mortality of patients with manic-depressive­ and meta-­analysis. J Alzheimers Dis 2015;48:403–10. 11 Schou M. Lithium perspectives. Neuropsychobiology and schizoaffective illness. Acta Psychiatr Scand 16 Jacome DE. Cerebellar syndrome in lithium poisoning. 1983;10:7–12. 1992;86:218–22. J Neurol Neurosurg Psychiatry 1987;50:1722. 12 Post RM. The new news about lithium: an 14 Quinn N, Marsden CD. Lithium for painful 17 Kellett JM, Metcalfe M, Bailey J, et al. Beta blockade underutilized treatment in the United States. dystonia in Parkinson’s disease. Lancet in lithium tremor. J Neurol Neurosurg Psychiatry Neuropsychopharmacology 2018;43:1174–9. 1986;1:1377. 1975;38:719–21. copyright. http://jnnp.bmj.com/ on September 28, 2021 by guest. Protected

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