This, then, is what it has been all about. Today I mark the end of an academic career that ranged over 45 years. 1952 was the starting point. In that year, as a medical student, I was accepted as a research assistent by Prof. G.G.J. Rademaker, a neurophysiologist and at the time head of the Department of Neurology at the Academic Hospital in Leiden. The neurological research period was followed by a mycological one. Having received my MD degree and doing my military service, I was asked to carry out a study into the prevalence, prevention and treatment of mycological infections in military personel. For this reason I worked for more than 1, 5 years in Baarn at the section Medical Mycology of the Phytopathological Laboratory, an interacademic institution of the Universities of Amsterdam and Utrecht (1956-1958). Immediately after the military service I became a resident in psychiatry and started – together with the biochemist Prof. B. Leijnse – a research program into the biological determinants of depression. The period of psychiatric investigation lasted until this very day, albeit in different locations, i.e. Rotterdam, Groningen, Utrecht, New York and Maastricht respectively.

Herman van Praag has made major contributions to the scientific and conceptual development of psychiatry. Despite progress in delineating reliable diagnostic criteria, our classification system ignores clinical insights available from patients' subjective experiences of illness. Hence a ‘coarsening of diagnosis’ has occurred, weakening the nosologic infrastructure of scientific psychiatry. This paper will discuss these ideas and emphasize the central role of psychopharmacology in advancing psychiatry, with lithium's discovery as a paradigm.

Molecular genetics has now been widely incorporated into genetic epidemiological research in psychiatry. 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 BPAD. These include genes on chromosomes 18, 21, 4, 5, 11 and X. Other studies have reported the presence of anticipation in BPAD and in unipolar affective disorder (UPAD). This phenomenon describes the increase in clinical severity and decrease in age of onset observed in successive generations. This mode of transmission correlates with the presence of specific mutations (trinucleotide repeat sequences). Associations with these mutations have been reported in different populations of BPAD-patients and may represent a genetic factor involved in the transmission of the disorder.

These findings are all preliminary and require to be confirmed. Large multi-centres 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 addition, genetic approaches used in psychiatry are being combined with an assessment of non-genetic susceptibility factors. The investigation of interactions between gene and environment is one of the most promising areas dealing with complex multi-factorial diseases such as the affective disorders.

Clozapine (Leponex®) has been shown to be therapeutically effective in patients resistant to long-term medication with classical antipsychotics. The mode of action of clozapine is not clear, but several cerebral receptors have been implicated, including the dopamine D2, D3 and D4 types, α-adrenergic, serotonin (type 2A) and glutamate (NMDA-type) receptors. Moreover, clozapine has anti-cholinergic and antihistaminergic potencies. Thusfar, receptor profiles are based virtually exclusively on in vitro binding assays. It appeared, that pharmacological and physiological stimuli activate particular gene expression, in vivo, so at cellular level the action of e.g. antipsychotics can now be traced. In this communication we present data on the in vivo profile of clozapine as revealed with Fos-protein expression. The immediate early gene c-fos is, as other members of the class of such genes, rapidly and transiently induced in the brain. The prototypic members of this class all encode nuclear proteins that regulate gene transcription. Recent studies have shown that the antipsychotics haloperidol (Haldol®) and clozapine, when given acutely, induce different patterns of Fos-like immunoreactivity in the forebrain of the rat. The most marked effects of haloperidol were found in the striatum, the nucleus accumbens and the lateral septum.

Most people usually think of emotion as a subjective feeling of a certain kind, the kind for which labels like happy, sad, and frightened are appropriate. However, there is much evidence to suggest that this is too narrow a way to define emotions, and that a different and broader conceptualization is needed. If we examine the history of theories of emotion we find a great diversity of views. For example, Darwin, in his 1872 book ‘The Expression of the Emotions in Man and Animals’, conceived of emotions as expressive behaviors that had the function of communicating intentions from one animal to another in the presence of conflicts or emergencies. Emotional expressions, from this point of view, regulated interpersonal relations and increased the chances of individual survival.

Research in psychiatry could speeden its progress by taking the manifest heterogenity and variability of symptom expression within diagnostic groups more fully into account. Since Kraepelin symptom variation has been recognized to have both biological and environmental roots. If investigated systematically, such variations in illness experience will yield new subtypes that will provide greater insight into the onset, course and vulnerability of mental disorders. Studies ranging from population surveys to the laboratory have demonstrated that psychopathology is not randomly distributed in a population, nor is it constantly present in the lives of individuals. At both the population and the person levels, psychopathology varies with time and place. At the population level, illness processes localize in risk groups, who often reside in specific neighbourhoods or social settings. The individual experience of psychopathology also fluctuates with time, place and culture. This variability requires methods for case detection and treatment planning that take this into account.

The dopamine (DA) hypothesis of schizophrenia, postulating that schizophrenia is characterized by increased dopamine function, has been the most influential theory on the pathogenesis of schizophrenia. It has recently been revised based on the appreciation that the core symptoms of schizophrenia may not be the positive (psychotic) symptoms, but rather the negative symptoms and the cognitive deficits found in schizophrenic patients. This revision has prompted the hypothesis that schizophrenia is characterized by both decreased prefrontal dopamine activity (causing deficit symptoms) and increased dopamine activity in mesolimbic dopamine neurons (causing positive symptoms).

Notwithstanding this revision of a role for dopamine in schizophrenia, it has become increasingly evident that dysfunction of other monoaminergic systems may be as important in contributing to the pathophysiology of schizophrenia. Specifically, the putative role of serotonin (5-hydroxytryptamine, 5-HT) in schizophrenia is gaining considerable attention. Several observations, such as the ability of the 5-HT antagonist, ritanserin, to alleviate schizophrenic symptoms and, when added to haloperidol (Haldol®), to decrease its extrapyramidal side-effects (EPS), have stimulated studies into a role of 5-HT in schizophrenia. The finding that clozapine (Leponex®), clinically superior to conventional neuroleptics, is a weak DA2 antagonist but a potent 5-HT1c and 5-HT2 antagonist has further stimulated 5-HT-related research in schizophrenia.

Biological schizophrenia research has been dominated by the dopamine hypothesis for decades, but in recent years a more diversified view has gained increasing attention. Several neurotransmitters are now being discussed, and especially their interaction in complex circuitries.

The demonstration of an atypical profile of clozapine (Leponex®), with lessened extrapyramidal side effects and somewhat increased efficacy, has stimulated this research field considerably. This agent has high affinity not only for the different dopamine receptor subtypes, but also for serotonergic, alpha-adrenergic and muscarinic receptors. Different workers have stressed one or more of these sites as being of major importance for the atypical profile of clozapine, and several drug companies have made attempts to mimic the profile of clozapine by developing molecules with affinity for these receptors in varying proportions. A number of such agents have reached or will soon reach the market and appear to be promising, even though they may not match clozapine in terms of atypicality.

The present explosive growth of interest in the therapeutic possibilities of exposure to light was triggered by a patient, Herbert Kern. He suffered from episodic depressive and manic complaints and discovered, by registering these over the years, a seasonal pattern in their occurrence. Discussions with scientists of the NIMH resulted in his participation in a bright light-treatment experiment when he was depressed in the winter of 1980-1981. He recovered.

Next, the same group of investigators defined the criteria for a new syndrome, Seasonal Affective Disorder (SAD): a history of major affective disorder (according to the Research Diagnostic Criteria), at least two consecutive years in which the depressions have occurred during fall or winter and remitted in the following spring or summer, and the absence of any clear-cut seasonally changing psychosocial variable, such as work, stress and so on.

Since the seminal work of Geller and Blum there is a vast expanding literature relating anxiety symptoms to serotonin (5-hydroxytryptamine; 5-HT). The general picture emerging from animal research is that increasing 5-HT function is anxiogenic. However, animal research is confined by the fact that extrapolations from animal behavior to human emotions have limited validity. Human anxiety can range from normal emotions to clinical syndromes. It can be a component of different physical and mental disorders, but also the central feature of a syndromes.

During the last decade, a wealth of knowledge about the origin and anatomical distribution of 5-HT neuronal systems has been obtained. Our understanding of the neuroanatomy and neurochemistry of anxiety has also considerably advanced, but the picture is still puzzling. We are faced with a large number of 5-HT-receptor subtypes, each with its own specific distribution and presumably specific function. The complexity of the 5-HT system in terms of receptor heterogeneity offers a dazzling opportunity to the development of new drugs affecting selective 5-HT functions, but it also precludes that firm conclusions can be drawn when less selective agents are being used.

Novel anxiolytics notwithstanding, in the latest fifteen years there have been no major innovations in the treatment of anxiety disorders. Fascinating research is going on, but real breakthroughs will require adequate models of disease, based on the disordered physiology of each type of pathological anxiety. In this brief overview, we will address both the field of potential anxiolytics in 1997, and the development of new experimental models of anxiety disorders.

Abnormality of the serotonin (5-hydroxytryptamine – 5-HT) system and particularly hypersensitivity of postsynaptic 5-HT receptors remained the leading hypothesis for the underlying pathophysiology of obsessive compulsive disorder (OCD) during the 1980s. A number of lines of evidence supported this serotonergic hypothesis, not least the treatment studies which demonstrated clearly and consistently that anti-obsessional efficacy was a function of serotonin re-uptake inhibition. Studies of markers and biological probes provided further evidence: platelet studies, for example, linked reductions in 5-HT activity with clinical response, and treatment response was correlated with decreased 5-hydroxyindolacetic acid (5-HIAA) levels within the cerebrospinal fluid of OCD patients.

Added to this was the evidence from the behavioral or physiological responses observed following serotonergic challenge with the serotonin agonists meta-chlorophenylpiperazine, a compound with high affinity for 5-HT1A-, 5-HT1D- and 5-HT2C-receptors.

Some 40 years ago phencyclidine (PCP) was developed as the prototype of a proposed new class of ‘dissociative’ general anesthetics, so called because it induced a marked dissociation from the environment without complete loss of consciousness. In the earliest clinical trials of PCP anesthesia, it was observed that as many as half the subjects experienced severe psychotic reactions during and beyond emergence. This striking clinical observation at once marked the failure of PCP as a suitable general anesthetic, and the beginning of a remarkable new era in basic and clinical neuroscience which can serve as an example of the interaction between clinical observation and basic science. At once, clinical researchers turned their focus upon the characterization of the PCP-induced psychosis, and recognized striking similarities between PCP-induced symptoms and signs and both the negative and positive symptoms of schizophrenia, proposing the PCP psychosis as a new model of that illness. Several years later PCP suddenly emerged as a major drug of abuse, with the result that emergency rooms and psychiatric inpatient units were observing and treating large numbers of these patients, in many of whom a diagnosis of schizophrenia could not be ruled out until toxicological analyses were performed. This natural experiment yielded a huge amount of additional data, and contributed a strong public-health based impetus to research into the nature and treatment of PCP intoxication.

Over the past decades extensive research has been performed on the presumed relationship between neurotransmitter functionality in the central nervous system and psychopathological states. Originally, in the mid-sixties it was hypothesized that depressive states may be associated with disorders in brain noradrenalin and/or serotonin (5-hydroxytryptamine; 5-HT) metabolism or function resulting in the socalled monoamine hypothesis of depression. Subsequent investigations revealed that altered 5-HT metabolism is not related to mood disorder per se, but to components of the depressive syndrome and more specifically to increased anxiety and/or signs of dysregulated aggression, including violent suicidal attempts.

Concerning aggression and other types of disruptive or impulsive behavior, research on their neurobiological determinants has been focussed mainly on indicators of central 5-HT function.

It is now generally agreed that healthy individuals are characterized by cognitive decline during the later decades of adult life. The acquisition of new information becomes less efficient, which, coupled with a diminished retention of this information for later use, results in substantially poorer memory performance. The ability to plan new activities, solve problems and make complex decisions, as well as cognitive flexibility is noticeably diminished. In addition, attentional processes appear to be invariably poorer in old subjects than in young subjects (for review). While it is quite clearly established that elderly subjects (i.e. after 65 years of age) show a deterioration of cognitive functioning, there is also evidence that this deterioration may start in middle age (40 years). There is large individual variance in age groups; for instance, some old individuals perform on many neurocognitive tests as well as young individuals do. Rowe and Kahn proposed in their influential article to discern between successful aging and usual aging. Successful aging would be due to the effect of chronological age, whereas additional factors would be responsible for usual aging. An important point is the nature of the borderland between usual cognitive aging and pathological conditions such as dementia. Various health-related factors are thought to be important in this respect. They may be a determinant for the transition between successful aging to normal aging and into the borderland with dementia. The Brain & Behavior Research Institute in Maastricht investigates the determinants of successful and pathological aging in a number of related and multidisciplinary projects. This paper describes some major findings of this research programme and gives a theory on the interaction of vulnerability factors and protective factors in their effect on cognitive aging.