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Keynote Lecture Latest Advances in Psychiatry LATEST ADVANCES IN PSYCHIATRY A At 83 years of age, Professor Angst still takes more than a keen interest in research into mood disorders and in particular is actively engaged in analysing the data collected from an epidemiological cohort he began to observe more than 30 years ago.1 Furthermore, he still does not shy away from questioning perceived wisdom when data he and his colleagues have collected point to a different conclusion. Prospective trials show that there is a high lifetime prevalence of psychiatric disorders – of the order of 40-50 per cent 1-5 – and prevalence rates for mood disorders, anxiety disorders and substance abuse/dependence of 20-30 per cent. Professor Angst personally felt that in reality the prevalence rates for psychiatric disorders may be higher because the figures are based on retrospective data and not lifelong prospective studies. However, the lifetime prevalence rates of major depressive disorder (MDD) compared with bipolar disorder (BD) have been generally overestimated in Professor Angst’s view. The discrepancy may be due to trial selection criteria largely based on the classification systems, DSM-IV and ICD-10. So, instead of the 1:1 ratio of MDD to BP Professor Angst and colleagues have obser ved in the Zurich study, 1 others have recorded much higher ratios of MDD to BP of around 4:1.2-5 If broader diagnostic criteria that reflect more closely the real-life experience of those with mood disorders are applied to patient populations, then a higher proportion of bipolar disorders would emerge. For example, when Professor Angst’s diagnostic specifier for bipolarity6 criteria were applied to stud- www.progressnp.com Mood disorders: pearls of wisdom from a lifetime of observation Professor Jules Angst provided a fascinating account of some of the work that has led him to challenge fundamental thinking about bipolar disorder in his Keynote Lecture on the classification, course and treatment of mood disorders, at the ninth Latest Advances in Psychiatry Symposium in London in March 2010. Steve Titmarsh had the privilege of listening and here provides a brief overview. ies where the ratio of MDD to BP is much higher than 1:1, then overdiagnosis of major depressive disorder was reduced, revealing a higher proportion of patients with bipolar disorders; this was the case in a patient study across 18 countries7 and in two well-known prospective epidemiological studies (EDSP Munich,8 NCS-R USA9). Identifying such ‘hidden’ or subthreshold bipolar patients might make it possible to make an earlier diagnosis of bipolar disorder, for which there is an average delay of 10 years from onset of depressive symptoms, and perhaps specific treatment could be employed earlier. In any case, Professor Angst explained, the risk of someone with depression becoming bipolar is about 1.25 per cent per year – and the risk of becoming bipolar remains the same no matter how many episodes of depression have been experienced before a hypomanic or manic episode manifests. So that, he argued, if people with depression lived to be more than a 100 years old, they would all become bipolar. The risk of switching from mania to depression is 3 per cent per year. Continuum of mood disorders Professor Angst explained that his obser vations, in particular of the male conscripts and female subjects on the electoral role in the canton of Zurich in his native Switzerland, whom he has followed from age 19 and 20 years to age 49 and 50 years, have led him to the conclusion that mood disorders exist on a continuum from depression via bipolar disorders to mania. He felt that there are no distinct classes between the different disorders. The divisions between the disorders defined by classification systems are arbitrar y, but they make sense clinically because they help with treatment decisions. In reality, almost ever yone exhibits at least mild ‘symptoms’ of mood disorders; it is part of normal human experience. For example, people in love have traits similar to hypomania. The difference between those who are in love and people who are pathologically hypomanic is that people in love do not exhibit the kind of dangerous risky behaviours – gambling, driving too fast, etc. – that people who are ill are prone to. Other clues to the hidden bipolar pathology are family history and comorbid disorders such as anxiety and substance abuse. Mania is significantly associated with family history of mania, Professor Angst explained. Bipolar disorder is significantly associated with anxiety disorders and substance abuse, such as alcoholism, in contrast to major depressive disorder, which is significantly associated with suicide. Around 30 per cent of bipolar patients, as defined by DSM-IV cri- Progress in Neurology and Psychiatry 27 Keynote Lecture Latest Advances in Psychiatry Jules Angst, MD, is Emeritus Professor of Psychiatry at the University of Zurich and Honorary Doctor of Heidelberg University, Germany. He trained under Manfred Bleuler and was Professor of Clinical Psychiatry and Head of the Research Department of Zurich University Psychiatric Hospital (the Burghölzli) from 1969 to 1994. He continues to work full-time in epidemiological and clinical research. His 1966 monograph established and validated the distinction between bipolar disorders, depression and schizoaffective disorders on the basis of genetics, course and personality. He was the first to show the unfavourable long-term course of mood disorders. His recent main research has been in epidemiology covering the classification, comorbidity and course of mood and anxiety disorders including subdiagnostic syndromes (recurrent brief depression, bipolar-II disorders, hypomania, minor bipolar disorder and anxiety), obsessive-compulsive disorder, neurasthenia, perimenstrual syndromes and migraine. Professor Angst has received many awards in recognition of his work, including the Anna Monika Award (1967 and 1969), Paul Martini Prize for Methodology in Medicine (1969), Otto Naegeli Prize (1983), Eric Strömgren Medal Professor Angst with Dr David Baldwin, Chairman of PSIG, at the ninth Latest Advances in Psychiatry Symposium in March 2010 after one week. If there is no response after two weeks, it is fairly certain the patient will not respond to the treatment. Combination therapy has been shown to be more ef fective than monotherapy in terms of reducing the number of relapses and in reducing suicide rates. Finally, something perhaps a little more surprising: lithium and clozapine therapy may protect against dementia: several studies show that the drugs attenuate the development of dementia.11-14 References (1987) and the Emil Kraepelin Medal of the Max Planck Institute, Munich (1992). He has also received the Selo Prize NARSAD/Depression Research, USA (1994), Mogens Schou Award for Research in Bipolar Disorder, USA (2001), the Burghölzli Award for Social Psychiatry (2001), the Lifetime Achievement Award of the International Society of Psychiatric Genetics (2002) and the Wagner-Jauregg Medal (2007). teria, have a family history of mania compared with 14 per cent among people with depression. Pharmacological myths Professor Angst was keen to dispel a couple of myths about drug treatment. First, he contended that there is no statistical evidence that antidepressants induce hypomanic episodes more frequently than placebo. The idea is a result of wrong statistical thinking and computations, he said. The natural history of bipolar disorder is an up and down course, by definition, and studies have shown that there is around a 30 per cent spontaneous switch rate from depression to hypomania. As Professor Angst explained in his autobiographical notes published in Acta Psychiatrica Scandinavica last year:10 ‘Switches to hypomania can only occur in response to treatment, non-responders, who prevail among placebotreated patients, cannot switch; the statistics have therefore to correct for responders; unbiased metaanalyses were negative.’ Similarly, Professor Angst contended that, contrary to the general view, correct statistical analysis of trial data shows that antidepressants start to induce change within the first 12 days of their administration and do not take a number of weeks to have an effect as has been assumed. That has implications for treatment. Treatment recommendations Professor Angst’s observations over many years lead him to the conclusion that people with depression should be treated with an antidepressant first – whether they are bipolar or not. If there is a response, such as an increase in activity signaled by something such as the patient sleeping less in the first week or two, then a mood stabiliser should be added. If there is no response, then the dose of antidepressant should be doubled 28 Progress in Neurology and Psychiatry 1. Angst J, Gamma A, Neuenschwander M, et al. Prevalence of mental disorders in the Zurich cohort study: a twenty year prospective study. Epidemiol Psychiatr Soc 2005;14:68-76. 2. Zimmermann P, Wittchen U, Lieb R, et al. Early developmental stages of psychopathology (EDSP) Study. Arch Gen Psychiatry 2009:66:1341-52. 3. de Graaf R, Bijl RV, Smit F, et al. Psychiatric and Sociodemographic Predictors of Attrition in a Longitudinal Study The Netherlands Mental Health Survey and Incidence Study (NEMESIS). Am J Epidemiol 2000;152:1039-47. 4. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;51:8-19. 5. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:593-602. 6. Angst J, Gamma A, Benazzi F, et al. Diagnostic specifier for bipolarity. J Affect Disord 2004;73:133-46. 7. Angst J. Diagnostic concepts of bipolar disorders: a European perspective. Clin Psychol Sci Pract 2009;16:161-5. 8. Zimmermann P, Bruckl T, Nocon A, et al. Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity. Arch Gen Psychiatry 2009;66:1341-52. 9. Angst J, et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry (in press). 10. Angst J. From psychoanalysis to epidemiology: autobiographical notes. Acta Psychiatr Scand 2009:119:87–97. 11. Gasse C, et al. Does lithium therapy protect against dementia? (abstract). In: Fifth European Stanley Conference on Bipolar Disorder. October 5 - 7 2006, Barcelona, Spain. The Stanley Medical Research Institute. 12. Nuñez PV, Orestes FV, Gattaz WF. Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatry 2007;190:359-60. 13. Angst J, Gamma A, Gerber-Werder R, et al. Does long-term medication with lithium, clozapine or antidepressants prevent or attenuate dementia in bipolar and depressed patients? Int J Psychiatr Clin Prac 2007;11:2-8. 14. Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia? Bipolar Disord 2010;12:87-94. www.progressnp.com