Although the Hamilton Rating Scale for Depression (HRSD) is the most frequently used rating scale for quantifying depressive states, it has been criticized for its reliability and its usability in clinical practice. This criticism is less applying to the Montgomery-Asberg Depression Rating Scale (MADRS). Goal of the present study is to investigate the reliability and validity, and clinical relationship between the HRSD and the MADRS. For 60 out-patients with diagnosed depression (DSM IV296.2x, 296.3x, 300.40 and 311.00), the HRSD and MADRS were scored at baseline and 6 weeks later by an independent rater according to a structured interview. Also the Clinical Global Impression (CGI) was assessed by a psychiatrist. Satisfying agreement was found between the totalscores (r= .75, p>.000 en r=.92, p>.000 respectively, at baseline and 6 weeks later). Furthermore agreement was found between the items of both scales, and these agree with the clinical impression. The reliability of the MADRS is more stable than the reliability of the HRSD (α = .6367 and α =.8900 vs α = .2193 and α = .8362 at baseline and at endpoint respectively). Considering the ease of scoring both scales in one interview and the widely international use of the HRSD, scoring both the HRSD and the MADRS to measure the severity of a depression seems to be an acceptabel covenant.

Traditional methods used to asses genetic effects, such as twins, adoption and family studies, have demonstrated the role genetic vulnerability factors in the etiology of major psychiatric diseases such as affective disorders and schizophrenia. It remains however impossible, using these methods, to specify the genetic variables involved and the exact mode of transmission of these diseases. New genetic approaches in psychiatry include the use of DNA markers in sophisticated strategies to examine families and populations. Genetic linkage (in families) and allelic association (in unrelated subjects) are the most frequent techniques applied searching for genes in psychiatric diseases. Advances in these methods have permitted their application to complex diseases in which the mode of genetic transmission is unknown. Affective disorders and, in particular, bipolar affective disorder (BPAD) have been examined in many molecular genetic studies which have covered a large part of the genome, specific hypotheses such as mutations have also, been studied. Most recent studies indicate that several chromosomal regions may be involved in the aetiology of affective disorders. Large multi-centre and multi-disciplinary projects are currently underway in Europe and in the US and hopefully will improve our understanding of the genetic factors involved in affective disorders. In parallel to these new developments in molecular genetics, the classical genetic epidemiology, represented by twin, adoption and family studies, have been improved, providing validated models to test the gene-environment interactions.

Several psychiatric diseases are considered to be neuro-developmental disorders. Amongst these are schizophrenia and autism, in which genetic and environmental components have been indicated. In these disorders intrinsic molecular mechanisms of brain development may be deranged due to genetic predispositions, or modified by external influences. Brain development is a delicate process of well-tuned cellular proliferation and differentiation of multipotent neural progenitor cells driven by spatiotemporal cues. One of the fundamental mechanisms is the interaction between external signals, e.g. growth factors, and internal regulators, e.g. transcription factors. An important transmitter system involved in behavioural and affective functions relevant for psychiatric disorders is the mesencephalic dopamine (DA) system. The mesencephalic DA system is organized in two anatomically and functionally different systems. DA neurons in the ventral tegmental area project to the mesolimbic system and are mostly related to control of behaviour. It has been implicated in drug addiction and affective disorders like dipolar disorder and schizophrenia. The dopamine system of the substantia nigra (nigro-striatal pathway) is implicated in movement control. Degeneration of this system, as in Parkinson's disease, or altered function in tardive dyskinesia have highlighted its importance in human disease. Recent findings in molecular neurobiology have provided the first clues to molecular mechanisms involved in developing and mature DA neurons. These may have clinical implications in novel therapeutic strategies.

An increasing number of neurodegenerative diseases have been defined at the molecular level in recent years, making it possible to determine precisely the genotype before the onset of symptoms. Pre-symptomatic testing programs are available for Huntington disease (HD), hereditary cerebral haemorrhage with amyloid-Dutch type, inherited cerebral ataxia, myotonic dystrophy, and Alzheimer disease. Although treatment options such as gene therapy have no widespread application until now, and much has to be developed, the use of predictive DNA-diagnostics has become a clinical application for a number of hereditary diseases. For psychiatric disorders such as schizophrenia or bipolar disorders, there are indications for localisation of the genetic factors, but clinical use of genetics is still far from reality. Yet, the increasing knowledge about genetics will have far-reaching influence in most fields of modern medicine and in health care provisions.

A great interindividual variability exists in biological response to drugs. This variability is partly attributable to pharmacodynamic factors (drug - receptor interactions) and partly to pharmacokinetic factors. Drugs can be eliminated from the body by renal clearance, metabolism or both. Although every tissue has some ability to metabolise xenobiotics like drugs, the liver is the principal organ of biotransformation. Major metabolising enzymes are the cytochrome-P450 mono-oxygenases, epoxide hydrolase, glucuronosyl-transferase, acetyl-transferase, sulfo-transferase and xanthine oxidase. Some of these enzymes display in a subset of subjects a ‘normal’ activity and in another subset of subjects a reduced or a greatly increased activity. This altered activity may be genetically determined and is then called genetic polymorphism. Clinically relevant metabolic differences traditionally have been defined by their genotypie expression such as ‘poor’ and ‘extensive’ metaboliser. The recent developments of powerful methods for DNA (or genomic) analysis portends a revolutionary expansion of our understanding of physiology as well as pathology. Pharmacogenetics is the study of genetic variation underlying differential response to drugs. Genotyping may become a useful tool in optimising drug treatment. Another part of the genetic research is directed towards the discovery of genetic alterations leading to diseases. Once identified, these genetic alterations can become targets for drug treatment (e.g. gene therapy). Pharmaco-genomics applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism or disease pathway. Table I gives some examples of genetic alterations that are identified together with their effects. Some of these examples will be briefly discussed here.

Het mag als een verworvenheid beschouwd worden dat er sinds kort stoffen op de markt zijn die de kans op terugval van alcoholisten verkleinen. Natuurlijk hebben deze stoffen, zoals acamprosaat en naltrexon indicaties en contra-indicaties, en die zijn in de voorgaande artikelen beschreven. Het is daarmee echter nog niet gemakkelijk geworden een richtlijn voor de dagelijkse praktijk te formuleren. Dat blijkt wel uit deze artikelen. Immers, acamprosaat is effectief gebleken, maar nu ook weer niet zó effectief dat het niet voorschrijven ervan per definitie een gemiste kans moet worden beschouwd. De Jong en Schippers wijzen er terecht op dat als stoffen té enthousiast worden voorgeschreven, zoals dat met disulfiram is gebeurd, het grote aantal mislukkingen ertoe kan leiden dat men zich weer teleurgesteld van zo'n stof afwendt. En het risico op dit soort therapeutisch enthousiasme is juist bij de behandeling van verslavingen levensgroot. Er zijn weinig ziektebeelden die bij een behandelaar zoveel machteloosheid kunnen oproepen en dus zoveel neiging naar strohalmen te grijpen.

Neuropsychiatry or Biological Psychiatry There is an urgent need to reconsider the position of psychiatry within the neurosciences because of the exploding knowledge about the relationship between brain and behaviour and the delay in implementation of new findings due to the separation of neurology and psychiatry. Biological psychiatry and psychopharmacology originate from the discovery by chance of psycho-active compounds in the early fifties and have contributed to the scientification of psychiatry. The impact of biological psychiatry for the pathophysiology of psychiatric disorders, however, is limited as a result of its biased orientation on neurotransmitters and receptors. The neuropsychiatric paradigm integrates knowledge from several domains, such as functional neuroanatomy, genetics and endocrinology and opens new vistas for the involvement of neuronal circuits in the initiation and maintenance of behavioural disturbances. In addition, novel and more specific treatment modalities may emerge.