The birth of modern psychiatry - Hans Jacob Schou and the Dianalund Sanatorium.

Hans Jacob Schou (1887-1952) was a well-educated Danish specialist in nervous diseases. He was persuaded in 1922 to take over the leadership of the only large scale private institution in Denmark for patients with nervous diseases, The Colony of Philadelphia, near Dianalund, on the island of Zealand. He pioneered a development of this conservative institution into a modern charity hospital for patients with all kinds of nervous and mental disorders. His newly erected sanatorium (1928) for neurotic patients came to symbolize the need for inclusion of all patients - disregarding the seriousness of their illness and disregarding their social status - in the realm of Danish psychiatry. Thus, Schou created the foundations for modern Danish psychiatry.

[Harald Selmer - the father of Danish psychiatry]. / Harald Selmer - dansk psykiatris bygmester. En pioner fylder 200 år.

Harald Selmer is rightly called the father of Danish psychiatry. He was born in 1814, and received in 1831 his degree in medicine from the University of Copenhagen. At the age of 32 he published his famous book on the "general rules ..." of a national system of psychiatric hospitals with high professional standards. He was chosen to lead the erection of the first of these hospitals, the later university psychiatric hospital in Aarhus, opening in 1852. Not only was Harald Selmer in charge of the construction of this monumental hospital, he was also the appointed director of the hospital for the first 27 years of the hospital's history, until his retirement in 1879. Harald Selmer was recognized as a great builder, a great leader and - very important - as an excellent writer, who understood the art of communicating his messages in a clear and convincing language. Harald Selmers tombstone is still to be found on the old hospital burial ground.

[Danish pioneers of psychopharmacology]. / Psykofarmakologiens danske pionerer.

Although a small country, Denmark has played an important role in the development of modern psychopharmacology due to an active and ambitious pharmacological industry, excellent researchers and last but not least, far-sighted clinicians. The most prominent among these clinicians are portrayed here. Mogens Schou advocated throughout his long life for the benefits of lithium treatment for bipolar patients, Lars Gram for the use of drug monitoring in the pharmacological treatment of depressed patients, Erik Jacobsen invented Antabus for treatment of alcohol dependence and later became one of the first presidents of the Collegium Internationale Neuropsychopharmacologicum (CINP) and finally, Claus Braestrup was the first to describe the benzodiazepine receptor.

Low-frequency repetitive transcranial magnetic stimulation inferior to electroconvulsive therapy in treating depression.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is a potential new antidepressant method and alternative to electroconvulsive therapy (ECT). The efficacy of right prefrontal low-frequency rTMS was shown in a previous placebo-controlled, randomized study but has never been compared with ECT. The aim of this study was to compare the antidepressant efficacy and adverse effects of right prefrontal low-frequency rTMS with that of ECT. METHODS: Sixty inpatients with major depression were randomized to 15 days of 1-Hz right prefrontal rTMS or 9 unilateral ECTs. Depressive symptoms and adverse effects were recorded using the Hamilton Scale for Depression and the Udvalg for Kliniske Undersøgelser side effect scale, supplied by neuropsychological assessment of cognitive functions. RESULTS: Repetitive transcranial magnetic stimulation was significantly less effective than ECT. The intention-to-treat analysis revealed a 26% (confidence interval, 3%-51%) higher rate of partial remission (P = 0.035) by the end of week 3. There was no difference found between the 2 methods on the Udvalg for Kliniske Undersøgelser rating scale. However, psychological examination revealed ECT to have more adverse effects on cognitive functions, whereas the rTMS group improved particularly with respect to visual memory. CONCLUSIONS: Repetitive transcranial magnetic stimulation was significantly less effective than ECT, but ECT had more adverse effects on cognitive function. The outcome does not point to right frontal low-frequency rTMS using the present stimulus design as a first-line substitute for ECT, but rather as a treatment option for patients with depression who are intolerant to other types of treatment or not accepting ECT.

[The physician's role elucidated through literature and philosophy]. / Laegerollen belyst gennem litteratur og filosofi.

The primary aim of the described course at the Faculty of Health Sciences, Aarhus University, is to provide the medical student with an opportunity to reflect on the preconditions to being a "good physician" through the reading of literature and philosophy. The course gives the student a number of analytical, methodological and practical tools for understanding and handling the demands of his or her future career as a health professional.

Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6).

OBJECTIVES: In industry-generated pivotal studies, lamotrigine has been found to be superior to placebo and comparable to lithium in the maintenance treatment of bipolar I disorder. Here, we directly compared lamotrigine to lithium under conditions similar to clinical routine conditions. METHODS: Adult bipolar I disorder patients with at least two episodes within the last five years and an index episode requiring treatment were randomized to lithium (n = 78; doses adjusted to obtain serum levels of 0.5-1.0 mmol/L) or to lamotrigine (n = 77; up-titrated to 400 mg/day) as maintenance treatments. Randomization took place when clinically appropriate, and comedication was allowed within the first six months after randomization. The patients were enrolled from March 2001 to December 2005, and observations were censored December 2006, allowing a subgroup of patients to be followed for more than five years. The primary outcome measure was time to predefined endpoints indicating insufficient maintenance treatment, and the major secondary outcome measure was time to any study endpoint. Data were analyzed primarily by Cox proportional regression models. RESULTS: For the primary outcome measure, the crude Hazard Rate Ratio (HRR) (lamotrigine relative to lithium) was 0.92 [95% confidence interval (CI): 0.60-1.40]. When the primary endpoints were broken down by polarity, the HRRs (lamotrigine relative to lithium) for mania and depression were, respectively, 1.91 (95% CI: 0.73-5.04) and 0.69 (95% CI: 0.41-1.22). There was no between-group difference in terms of staying in study [HRR: 0.85 (95% CI: 0.61-1.19)]. Most treatment failures occurred within the first 1.5 years of treatment, and, among patients followed for at least five years, practically no patients were maintained successfully on monotherapy with either of the drugs. The lithium-treated patients reported diarrhea, tremor, polyuria, and thirst more frequently. Two cases, probably lamotrigine-related, of benign rash occurred. CONCLUSIONS: No differences in maintenance effectiveness between lithium and lamotrigine could be demonstrated. Lamotrigine was better tolerated than lithium, but apparently this did not influence the outcome.

[Melancholia and depression--from madness to illness]. / Melankoli og depression--fra galskab til folkesygdom.

In present time depression affects 3-5% of the population in the western countries. Has this illness always existed? Can it be traced backwards in historical periods? The answer is a reluctant yes. The term "depression" has been in use in psychiatry for only 150 years and the very term "psychiatry" for 200 years. Before 1800, in classical times, only few elements of modern depression were part of the concept of "melancholia". Classical melancholia was a madness of the few, presenting with "psychotic" symptoms according to present terminology. The depression of modern man is a much broader concept including elements of well-being and capacity to work. Thus, although psychotic symptoms seem to connect the terms melancholia and depression, scientific, social and cultural developments separate the two. This is yet a testimony to the fact that concepts of illness and diseases changes rapidly and distinctively over historical periods.

Long-term outcome of patients with bipolar disorder commenced on lithium prophylaxis during hospitalization: a complete 15-year register-based follow-up.

OBJECTIVES: From placebo-controlled studies of up to two years duration, it has been established that lithium has preventive efficacy in bipolar disorder (BD). However, the effectiveness of lithium under routine conditions seems less pronounced. In the present study, the overall 15.3-year outcome in BD patients commenced on lithium is described. METHODS: Ninety-one patients with BD consecutively commenced on prophylactic lithium treatment during hospitalization at the Aarhus University Psychiatric Hospital from 1981 to 1983 were followed until death or censoring occurred during up to 15.3 years of observation. Register-based outcome measures, available for all patients, included accumulated duration of admission and number of admissions. In addition, serious attempts were made to collect detailed information on treatment during follow up. Simple descriptive statistics were applied; potential independent associations between baseline variables and outcome were examined using logistic regression models. RESULTS: Of the 91 patients, 27 patients died (six from suicide) during the observation period, which was an excess mortality compared to the general population. Fifty percent of the patients were admitted for more than one month per 20 months of observation and admitted more than once for each four years of observation. Only 19 (21%) patients were not admitted to hospital during the observation period. No statistically significant predictors of poor outcome could be identified. In addition to lithium prophylaxis given for variable lengths of time, the majority of the 36 (40%) patients, from whom treatment data were available, received various other drug treatments during follow-up. CONCLUSIONS: The overall outcome in patients beginning prophylactic treatment is unsatisfactory. However, due to the observational design and the lack of detailed treatment information during the long follow-up period, inferences about the efficacy of lithium cannot be made from this study.

[Lithium intoxication: assessment, treatment and prevention]. / Forgiftning med lithium: vurdering, behandling og forebyggelse.

A 64-year-old woman with bipolar disorder had received treatment with lithium for 33 years when she was admitted to the Department of Neurology with clinical signs and symptoms of an apoplectic insult. Her serum lithium level was 2.42 mmol/l. She was treated conservatively with electrolyte solutions and diuretics. Hemodialysis was judged unnecessary, and the patient recovered after 11 days. Patients given long-term lithium treatment should be instructed about risk factors, and their serum lithium and serum creatinine levels should be monitored regularly in order to prevent intoxication.

Guidelines for maintenance treatment of bipolar disorder: are there discrepancies between European and North American recommendations?

Practice policies and guidelines for the long-term management of bipolar patients have appeared in many parts of Europe and North America. Although recommendations in most areas do concur remarkable differences are apparent both regarding diagnostic practice and pharmacological management. Differences among recommendations point towards professional and cultural differences between Europe and North America but also towards areas with unresolved research questions and lack of scientific evidence.

Pain thresholds during and after treatment of severe depression with electroconvulsive therapy.

Pain and depression are often associated suggesting that both conditions share a common neurobiological mechanism, which modulate emotional function and processing of noxious information. Pain thresholds are hypothesized to be altered in depressed patients and normalized with the amelioration of depression. The purpose of this study was therefore to determine pain thresholds in patients during and after treatment with electroconvulsive therapy (ECT) of severe depression and in healthy controls. Seventeen depressed patients (Hamilton depression score > 18) and an age and gender matched control group of same size participated in the study. Pain detection and tolerance thresholds to pressure and pain tolerance thresholds to the Cold Pressor Test by exposure to ice-water was measured twice in depressed patients during and after ECT and twice in controls with a similar time interval. While ECT significantly improved Hamilton depression score (from mean 23.9 (SD:5) to mean 12.5 (SD:5.7)) there was no significant change in pain thresholds during and after ECT in the patient group. However, depressed patients had significantly lower pain tolerance in the Cold Pressor Test on both examinations and on pressure pain tolerance on the second examination day than their corresponding control subjects. The differential effect of ECT on depression score and pain processing indicate that mood and noxious processing are not medicated directly by the same systems but that a complex relationship between pain and depression exists.

Repetitive transcranial magnetic stimulation as add-on antidepressant treatment. The applicability of the method in a clinical setting.

Recent research indicates that repetitive transcranial magnetic stimulation (rTMS) over the frontal cortex has an antidepressant effect. The aim of the present pilot study was to assess the antidepressant effect, side-effects and the applicability in daily clinical practice of left prefrontal high-frequency rTMS. Fifteen inpatients with major depression (ICD-10 and DSM-IV) were randomized to receive 15 days of real left prefrontal high-frequency rTMS (20 trains of 10 s, 60-s interval, 10 Hz, 90% of motor threshold) or sham rTMS as add on to conventional antidepressant treatment. Depressive symptoms and side-effects were evaluated blindly during the treatment period. Five out of eight patients receiving real rTMS suffered from local discomfort during treatment. Three of them dropped out and the project was closed for that reason. Real rTMS did not add efficacy to standard antidepressant medication. This pilot study did not confirm the antidepressant effect of left frontal high-frequency rTMS. Unwanted effects led to considerable patient drop-out and premature termination of the study. The result suggests that alternative treatment delivery technology should be considered.

[Preventive drug therapy of depressions]. / Forebyggende, medikamentel behandling af depressionssygdommen.

At least 5-10 per cent of the Danish population will during their lifetime experience more than one episode of major depression but only a minority of this group will receive the necessary and sufficient prophylactic treatment against their illness. Randomised controlled studies have shown that the majority of commonly used antidepressant drugs, new as well as old ones, possess prophylactic efficacy. Thus, treatment efficacy is not a major problem but the treatment efficiency in everyday clinical practice is unsatisfactory. This is partly due to a lack of relevant treatment facilities for psychiatric patients, partly to a lack of knowledge among patients and their relatives but also among doctors of the indications for prophylactic treatment against recurrent depression and the technical issues involved. A short practical guideline for prophylactic treatment against recurrent depression will appear from the article.

[Psychopharmacological treatment of bipolar disease]. / Psykofarmakologisk behandling af bipolar sygdom.

This paper gives an update on the psychopharmacological treatment of bipolar disorder. The antimanic efficacy of lithium is well documented. The same applies to valproate, which is also efficacious in mixed mania. Conventional antipsychotics act fast in mania and do not require blood tests, but they have considerable neurological side effects. The newer antipsychotics, olanzapine, risperidone, and ziprasidone, have also been shown to have antimanic efficacy. Clozapine is extremely effective, also when other treatment fails. For the treatment of bipolar depression, lithium, lamotrigine, and antidepressants all seem to work, but antidepressants may sometimes precipitate mania or worsen the course of illness. For prophylaxis, lithium is still to be considered the first drug of choice. However, for several reasons, for instance treatment failure or side effects, long-term treatment with antiepileptics may often be necessary. Among the antiepileptics, carbamazepine, valproate, and lamotrigine are the best studied.