Cade's identification of lithium for manic-depressive illness--the prospector who found a gold nugget.

John Cade's identification of lithium as a treatment of manic-depressive illness has been judged as a landmark biomedical advance and as an initiator of modern psychopharmacology. His personal background, interests, character, experiences, and key observational skills are sketched to provide the background and logic for his discovery and to argue against his simple self-description as a clinician administrator. The Cade story illustrates the potential strengths of clinical research whereby the clinician observes "signals," formulates hypotheses and explanations, and then pursues or encourages their validity and application. The suggestion that Cade simply "rediscovered lithium" is rejected.

'On periodical depressions and their pathogenesis' by Carl Lange (1886).

Carl Lange was the founding father of neurology in Denmark, authoring several pioneering works within this field; however, these remained largely unknown internationally as he did not have them translated into a major language. He became a pioneer of psychophysiology with his contribution to the so-called James-Lange theory of emotion. His treatise on'periodical depressions' ('the Lange theory of depressions', 1886), is not only an early historical landmark but also a masterly 'modern' description concerning the nosology and nosography of recurrent depressions. Moreover, it is a landmark in the early history of lithium therapy, sadly ignored by Lange's contemporaries, but which little more than half a century later, with Cade's rediscovery of lithium's therapeutic effect in mood disorders in 1949, ushered in modern psychopharmacology.

A half-century of participant observation in psychiatry. Part II: Affective disorders. / Pól wieku obserwacji uczestniczacej w psychiatrii. Czesc II. Choroby afektywne.

The last half-century, thanks to the efforts of outstanding researchers, brought about great progress in the pathogenesis and clinics of affective illnesses. The catecholamine and serotonin hypothesis delineated in the 1960s have retained significant merit. Since the 1990s, the theories have pointed on excessive immune activation and impairment of neuroplasticity under stress. Since the 1970s, asystematic subclassification of unipolar and bipolar affective disorder has proceeded. Epidemiological studies of the last half-century indicated a significantly higher prevalence of depression compared with previous decades. The 21st century brought evidence for agreater frequency of various forms of bipolar affective disorder. During the last 50years, the etiopathogenesis, diagnosis and treatment of affective disorders were my favorite and fascinating clinical and research topics. This initiated in 1970 when I began my work in the Department of Psychiatry, Medical Academy in Poznan, on account of the introduction of lithium salts for the treatment of these disorders. In 1976-1977, I received afellowship of the National Institutes of Health at the University of Pennsylvania in Philadelphia and participated in research that elucidated the mechanism of lithium transport across cell membranes. I carried out the studies on the pathogenesis of affective disorders for more than 40 years afterward. They concerned abnormalitiesof transport across cell membranes, the activity of stress system, excessive pro-inflammatory activation, molecular genetics, dysfunctions of cognition and neurotrophins, especially the brain-derived neurotrophic factor (BDNF). Atthe beginning of the 21st century, I coordinated two Polish epidemiological projects DEP-BI and TRES-DEP. For my research on bipolar disorders, I received many international awards. I am also the author of the book The faces of manic-depressive illness which had three Polish editions as well as English and Russian versions.

Lithium: underappreciated and underused?

Lithium is a remarkable drug with a fascinating history. Although less popular than other anticonvulsant and atypical antipsychotic mood-stabilizing drugs, lithium is beneficial in bipolar disorder and may be superior to other drugs for treatment-resistant depression and for reducing suicidal behaviors. Various studies have demonstrated that lithium has neuroprotective and neurotrophic cellular effects in the brain, suggesting it may be "brain healthy" for patients with mood disorders and useful for patients with other neurodegenerative disorders. In this article, I describe the history of lithium and review important aspects of its clinical use.

Lithium treatment at 52.

The paper reviews briefly and comments in detail on selected events in the history of lithium treatment. The events include Cade's discovery of lithium's antimanic action, the discovery and establishment of its prophylactic action, the ensuing debate, amelioration and prevention of side effects and risks, use during pregnancy, non-compliance, selection of patients, information and instruction, the question whether new and better prophylactic agents are about to oust lithium, the use of combination treatment, the effect of lithium on suicidal behavior, the benefits of prophylactic lithium treatment, and the design of future comparative trials.

50 Years with lithium treatment in affective disorders: present problems and priorities.

Lithium has been used as a treatment for various psychiatric- and somatic-illnesses for more than 50 years. Today the main use of lithium is for the prevention of episode recurrences in bipolar disorder. The main emphasis of this review will be on the efficacy and effectiveness of lithium prophylaxis in bipolar disorder but the review will also discuss other indications for lithium treatment, the historical development, pharmacokinetic and -dynamic issues, unwanted effects of lithium and the organisation of treatment services. Finally, although not the main purpose of this review, a short description of alternative mood stabilizing drugs will also be presented.

Van Gogh and lithium. Creativity and bipolar disorder: perspective of a writer.

Penelope Rowe, educated at Sydney University in the 1960s and the mother of three daughters, is the author of three published novels and two collections of short stories. She agrees with Graham Greene that 'the creative writer perceives his world once and for all in childhood and adolescence and his whole career is an effort to illustrate his private world in terms of the great public world we all share. In the childhood of Judas, Jesus was betrayed.' More optimistically she also agrees with the great poet Seamus Heaney, who says 'there is the responsibility of the writer to address, amplify and analyse the music of what happens, and also the other music, the "siren music", of what might be, that is "the crediting of marvels" '.

Mania pre-lithium.

The changes that lithium brought are most fully understood when we grasp the difficulties for management that acute mania presented. Restraint in canvas camisoles, padded cells, paraldehyde, water-baths and salts-Epsom, not Lithium-met mania in echos of Bedlam still heard in the early 1950s. It is a part of psychiatric history important to remember.

Early North American research on lithium.

Research and clinical interest in lithium in the USA lagged behind that in Europe, largely because of the experience of deaths due to lithium in cardiac patients. The first American report on lithium was published in 1960 by Sam Gershon, the Australian psychiatrist who had undertaken lithium studies in Melbourne in conjunction with the physiologist Trautner. Major USA clinical trials originated in the 1960s; and the clinical significance of lithium was recognised in a special section in the American Journal of Psychiatry in 1968. The US Food and Drug Administration (FDA) approval of lithium for control of manic episodes was finally given in 1970.

Van Gogh and lithium. Creativity and bipolar disorder: perspective of a lawyer/parliamentarian.

Neil Cole has been the State Member for Melbourne since 1988 and was a Melbourne City Councillor for 3 years. He was the first Member of Parliament in Australia to confront the stigma of mental illness by publicly acknowledging his manic depression. Prior to entering parliament he was a Community Lawyer at Flemington Community Legal Service for 7 years. Neil was National Convenor of the Nuclear Free Zone Secretariat (1986-88), Chairperson Joint Parliamentary Economic and Budget Review Committee (1991-92) and Shadow Attorney General from 1992 to 1995. He is Deputy Chair of the Joint Parliamentary Law Reform Committee of the Victorian Parliament. Neil has written three plays with 'Alive at Williamstown Pier' being his first. He is currently employed as a consultant to the Mental Health Research Institute at Royal Park Melbourne.

Van Gogh and lithium. Creativity and bipolar disorder: perspective of a writer/photographer.

Diana Dennison has suffered from manic depression since her teenage years in the 1960s but only realised that she had the condition when, in her 30s, she learnt that her uncle was manic depressive. Diana endured her low states with either no medication or with what was for her the unsatisfactory effect of tricyclic antidepressants. Her untreated hypomanic states cut a swathe through her life. She has never been hospitalised for her condition. Her marriage did not survive but her daughters did and she is now a proud and doting grandmother who skis and scuba dives. Only in the last 4 years did Diana seek help for the treatment of her condition. Diana is a free-lance writer, researcher and photographer.

Van Gogh and lithium. Creativity and bipolar disorder: perspective of a psychologist/writer.

Margo Orum is the author of Fairytales in reality: My victory over manic depression. Manic depression first appeared in her life 14 years ago, when she was 31. In the first 5 years she had seven episodes (four manias and three depressions). She then embarked on a period of personal growth, including therapy with a psychologist: a period that she now sees as a turning point in helping her to better manage her illness. In the 9 years since then, she has had only two episodes. Both occurred when she was temporarily off lithium. Currently Margo is completing a PhD in psychology and is a casual teacher at Macquarie University.

Cade's observation of the antimanic effect of lithium and early Australian research.

John Cade had a major influence on the treatment of affective disorders following his report in 1949. His discovery of the efficacy of lithium as an antimanic agent was the result of an inevitable progression from the hypothesis of a metabolic basis for mania to clinical trials. Starting with animal studies, he progressed to patients. Further reports on lithium in the Medical Journal of Australia quickly followed in 1950 and 1951. The present paper reports on these and other Australian studies over the next few years. Lithium has moved in 50 years from a novel status to an internationally recognised major treatment of affective disorders.

The early European lithium studies.

Cade's discovery of lithium's antimanic effect soon became known in Europe and was confirmed by a Danish controlled trial. The same investigators discovered a prophylactic action of lithium against both manic and depressive recurrences, which was confirmed by a Swiss-Czech-Danish cooperative trial. The evidence of these studies was met with skepticism based on methodological speculations, but a Danish randomised, placebo-controlled, double-blind trial of discontinuation design established the prophylactic action of lithium, as did a number of European controlled trials of start design and discontinuation design. The review ends with personal memories of John Cade.

The impact of the discovery of lithium on psychiatric thought and practice in the USA and Europe.

The discovery of lithium has had a major impact on modern psychiatry. By launching the psychopharmacology revolution, lithium forced psychiatrists to become more adept at diagnosis. Lithium research has also provided a window into secular changes in bipolar illness which adversely impact response, produced pharmacoeconomic data on the social costs of psychiatric illness, and played a role in the birth of patient-run advocacy movements. In addition, the development of lithium has demonstrated the closely intertwined purposes of clinical and basic research, and the continued importance of research in the clinical setting.