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A recent article in Science reported the results of a genome-wide analysis of a variety of psychiatric and neurological conditions, conducted by an international consortium. Psychiatric disorders showed some degree of genetic risk sharing; conversely, the genetic risk profiles of neurological disorders lacked virtually any resemblance to each other as well as to mental diseases. Even though the spectrum of studied diseases was incomplete, the findings are unsurprising. Of course, neurological disorders and mental disorders share a common substrate in the brain, which has led to different methods attempting to discover the material basis of mental disorders. Yet, there is and continues to be an important difference regarding the causal role of the environment, viz. psychological and social factors. However, in terms of the way diseases manifest themselves, i.e. the symptoms experienced by patients, there is considerable overlap between psychological and somatic factors. Body and mind may be separated in medical textbooks, but not in the waiting room.

Background: In 1911 Bleuler's Dementia praecox oder Gruppe der Schizophrenien served to launch schizophrenia as a group of nosological entities characterized by a "splitting of the psychic functions." Today, at the centenary of this opus magnum, we find that the term is still in force but not the concept originally envisaged by Bleuler., Method: For the sake of this conceptual analysis a literature search was carried out in PubMed, Embase, and the historical literature., Results: The current schizophrenia concept, as operationalized in the DSM and other psychiatric classifications, is primarily indebted to Kraepelin and his degenerationist take on psychopathology. That approach is now obsolete, but the product still prevents us from moving beyond the notion of schizophrenia as a single-disease concept with multiple etiologies, multiple clinical expressions, and an unfavorable outcome., Conclusions: If we aim to investigate the biological underpinnings of psychotic symptoms, first a deconstruction of the schizophrenia concept will need to take place. In this paper we highlight a method--called functionalization--which allows for such a deconstruction., Limitations: Functionalization will probably require a new scientific language, which will be largely discontinuous with our current nosological and diagnostic systems.

Inherent in human existence is one's need to give sense to one's life. It is this need that drives life forward. In this paper the terms 'giving sense' and 'giving meaning' are used more or less interchangeably. A life acquires meaning when goals are set and attempts are made to achieve them. Giving meaning to one's existence often involves engaging in altruistic activity. The need to give sense to one's life can be felt to be 'self generated' or metaphysically inspired, in other words inspired by a supernatural authority. Sense-deficiency is a mental condition which is barely recognised in psychiatry and hardly ever treated. Thorough research is needed to find the causes and the appropriate treatment and, in particular, to discover to what extent the spiritual domain is able to perform therapeutic functions. A discussion of certain aspects of this domain should be given a definitive place in the curriculum of trainee psychiatrists.

One of Kraepelin's major contributions has been the introduction of the nosological principle in psychiatry. Mental pathology, he presumed, is subdividable in discrete entities each based on a specific pathophysiology. Kraepelin provided the diagnostic process in psychiatry with a solid infrastructure. It has been used in biological psychiatric research until this very day. Searching for the biological determinants of categorical entities has been its major goal. The yield of those efforts has been meagre, in that none of the biological findings reported so far seemed to be specific for a particular nosological entity. The question thus arises: is nosology the right model to classify mental disorders. It is suggested that it is not. The disease categories presently delineated are utterly heterogeneous, and therefore cannot be expected to have a well-defined pathophysiology. The nosological system cannot be rejected (as yet), but it has to be upgraded by incorporation of a strong dynamic-functional component. The functional components should become the focus of biological psychiatric research. The question whether an alternative classificatory model, such as the reaction form model, has to be preferred in biological psychiatry should become a matter of serious discussion.

Posttraumatic stress disorder (PTSD) is characterized by a peculiar cognitive state. The traumatic event(s) are partly hypermemorized, partly blurred, whereas the ability to store and retrieve new information is impaired. The question is raised as to what the biological systems might be that 'carry' this cognitive paradox. Four possible candidate systems are discussed. It is concluded that understimulation of the corticosteroid receptors, particularly the glucocorticoid receptors (GRs), overactivity of the noradrenaline (NA) and vasopressin (VA) systems, and deficits in the 5-Hydroxytryptamine (5-HT) system, particularly the 5-HT(1A) system, could generate a cognitive syndrome similar to the one observed in PTSD. A dual hypothesis is launched holding that (a) in PTSD, downregulation of the 5-HT(1A) receptor system is the primary lesion, while the other dysfunctions mentioned are subsidiaries and that (b) underdevelopment of or damage to the 5-HT(1A) receptor system will make a person PTSD-prone.

The central issue raised in this paper is: can stress cause depression? Phrased more precisely: can stress cause brain disturbances thought to underlie (certain forms of) depression or particular components of the depressive syndrome. Focussing on 5-hydroxytryptamine (5-HT) and the stress hormones, this question was answered in the affirmative, based on the following two considerations: changes in the 5-HT and stress hormone systems produced by sustained stress mimic to a substantial extent the disturbances in these systems that may be observed in depression. Substantial evidence indicates that the 5-HT and stress hormone disturbances in depression are of pathophysiological significance and not merely a consequence of the depressed state or a product of stress generated by the depressed state. Furthermore, the question was raised whether a depression type could be identified particularly stress-inducible. This question, too, was answered in the affirmative. The depression type in question was named anxiety/aggression-driven depression and characterized on three levels: psychopathologically, biologically and psychologically. Preferential treatment of this depression type was discussed. In studying stress-inducible depression, biological depression research should shift focus from depression per se to the neurobiological sequelae of stress. Treatment of stress-inducible depressions and particularly its prevention should be geared towards reduction of stress and stress sensitiveness, utilising both biological and psychological means.

Stress often precedes psychiatric disorders. This holds particularly for the group of mood disorders. A crucial question is whether stress is an epiphenomenon or a decisive factor in the causation of (certain forms of) mood disorder. Certainty about this question can only be obtained when it can be demonstrated that stress phenomena may induce changes in brain functioning similar to the ones supposedly associated with (certain forms of) depression. Since the phenomenology of stress syndromes, as well as their emotional intensity, are highly variable, careful diagnosis is a first requirement. In studies into the significance of stress in the occurrence of depression this degree of finesse has not been achieved. The major shortcomings are discussed. Those should be systematically addressed to provide this type of research with the necessary acuity

Stress almost always precedes suicidality. Stress also is a harbinger of a variety of psychiatric disorders, most notably depression. Depression is a major precursor of suicidal behavior. Consequently, the question of whether stress is an epiphenomenon or a decisive factor in the causation of suicidality and (certain forms of) mood disorders is crucial. Certainty about this question can only be obtained when it can be demonstrated that stress phenomena may induce changes in brain functioning similar to the ones supposedly associated with suicidality and with (certain forms of) depression. Since the phenomenology of stress syndromes, as well as their emotional intensity, are highly variable, careful definition of the stress syndrome to be studied is a first requirement. In studies into the significance of stress in the occurrence of suicidality and depression, this degree of finesse has not been achieved. The major shortcomings have been discussed. These should be systematically addressed to provide research into the relation between stress and psychopathology with the necessary acuity.

Objective: To detect possible cardiological risk factors in the acute phase of MI for developing depressive symptoms after first MI., Design: Retrospective analysis of cardiac and psychiatric data of 111 consecutive patients admitted with a first MI., Methods: During one year, all consecutive patients with a first MI, less than 12 hours chest pain and a maximal aspartate aminotransferase (ASAT) value of at least 80 U/l, admitted to the University Hospital of Maastricht, were screened for the presence of depressive symptoms using the 90-item 'Symptom checklist' (SCL-90) questionnaire at one month post-MI. Inclusion criteria were fulfilled by 111 patients; 28 patients refused to participate in the study., Results: No correlation was found between LVEF, peak ASAT, peak CK value and characteristics, location or mode of treatment of the MI and depressive symptoms post-MI. A statistically significant negative correlation was found between SCL-90 depression score and cardiac tissue loss as defined by cumulative ASAT release at 24, 48 and 72 hours after the acute event (p values 0.029, 0.028 and <0.009, respectively) at the one month post-MI screening., Conclusions: No cardiological parameters were correlated to depressive symptoms post-MI. If there was a connection at all, this appeared to be a negative correlation between infarct size as measured by ASAT release and the occurrence of depressive symptoms at one month post-MI.

Over the past decades the rate of completed suicide has remained quite stable, that of suicide attempts even seems to have increased (to the extent it has been studied in defined regions). These are puzzling observations, since depression is the major suicide precursor and since antidepressants over the years have been increasingly used in the treatment of depression. These observations have not attracted sufficient attention, possibly because they do not accord with consensus opinions about depression treatment in psychiatry today. In this paper a number of possible explanations are discussed. They not only deserve but are definitely in need of systematic investigation.

In these studies patients with first myocardial infarction (MI) were selected for studies focusing on epidemiology, risk factors and treatment of depression post-MI. Two consecutive cohorts of first MI patients were included. The first cohort was selected between May 1994 and May 1997 (n = 206), and the second between May 1997 and October 1999 (n = 206). All patients were screened every 3 months for depression using the SCL-90 and the Zung (cohort 1) or SCL-90, BDI and HADS (cohort 2) until 12 months post-MI. Patients scoring above the cut-off of one of the questionnaires were interviewed using a standardised interview in order to evaluate whether DSM-IV criteria for major depression were met; patients of the second cohort were also interviewed 1 month post-MI, independently of the score of the questionnaires. Of both cohorts data concerning major cardiac events and increased health care consumption were assessed during a 1 to 6 years follow-up period. Patients with major depression were offered treatment in the double-blind placebo-controlled trial with fluoxetine (n = 54). Depression appeared to be a predictor of increased health care consumption, but not of major cardiac events such as cardiac death and recurrent infarction in first myocardial infarction (MI) patients up to 6 years post-MI. This finding is in contrast to findings in the literature indicating that in patient populations with mixed first and recurrent MI, depression is a risk factor for cardiac mortality. In contrast to depression, symptoms of anxiety do predict cardiac mortality and recurrent MI in patients following first MI independently of other risk factors of cardiac mortality. Recognition of risk factors for post-MI depression may help the cardiologist to identify patients at risk for depression. Examples of such risk factors are, according to our studies, complications during admission, such as arrhythmic disorders and recurrent angina pectoris, and prescription of benzodiazepines. Patients at risk can be screened for depression using a 4-item questionnaire, and, if scoring is positive, be referred for psychiatric evaluation. Although the effectivity of antidepressive treatment in MI patients has as yet not been proven, we found that fluoxetine is a cardiac-safe antidepressive agent, but only in mild depression more effective than placebo. The positive effect of antidepressive treatment on cardiac prognosis has as yet not been shown.

The aim of this study was to establish the association of trait anxiety and anger with hormonal responses to acute challenges with two different 5-HT agonists in a mixed group of patients with depressed mood. Fifteen patients and 16 normal controls received single oral doses of 0.5 mg/kg meta-chlorophenylpiperazine (MCPP), a 5-HT(2C) agonist, and 10 mg of ipsapirone, a 5-HT(1A) agonist, according to a double-blind, placebo-controlled, cross-over design. Dutch-adapted versions of the Spielberger Trait-Anxiety Inventory and the Spielberger Trait-Anger Scale administered assessed at study entry. Hormonal responses, expressed as drug-placebo differences, to MCPP and ipsapirone (changes in cortisol, ACTH and prolactin) were measured. Blood levels of MCPP and ipsapirone were also measured. MCPP and ipsapirone elevated cortisol, ACTH and prolactin. In the patient group, there was a significant correlation between trait anxiety and the cortisol response to MCPP. No significant correlations between the ACTH and prolactin responses to MCPP and levels of anxiety/anger were observed in the patients. No significant correlations could be established between levels of anxiety/anger and hormonal responses to ipsapirone. This study provided evidence for an association between measures of anxiety/aggression and the hormonal response to MCPP. Thus, in subjects with depressed mood, high levels of anxiety suggest a higher probability of 5-HT(2C) disturbances.

Mental disorders are frequently preceded by stressful events or situations. Depression is a typical case in point. This raises the question, is depression - or possibly better: are certain forms of depression - caused by stress? Can stress be a true pathogenic factor? Phrased differently: can stress destabilize neuronal systems in the central nervous system to such an extent that depressive symptoms are generated? This question is discussed with the corticotrophin releasing hormone (CRH) and MA systems and hypothalamic-pituitary-adrenal (HPA) axis as major foci. The following issues are explored: the effect of antidepressants on corticosteroid receptor gene expression; the behavioral sequellae of CRH administration; CRH disturbances in depression; the impact of early life adversity on the development of the CRH system and on stress reactivity; the interrelationships of stress hormones and monoaminergic (MA ergic) transmission and finally the therapeutic potential of CRH and cortisol antagonists. The available data suggest that CRH overdrive and cortisol overproduction may play a pathogenic role in the occurrence of certain types of depression, directly and/or indirectly, i.e. by induction or exacerbation of disturbances in MA ergic transmission. Stress should, thus, become a major focus of biological depression research.

Background: We evaluated the cognitive profile of 48 patients with major depression following their first myocardial infarction (MI)., Methods: The cognitive performance of the patients was compared with the performance of 48 non-depressed MI patients and 48 healthy controls., Results: Depressed MI patients performed slower on a simple cognitive speed related measure compared with non-depressed MI patients and healthy controls. Attention and speed-related aspects of cognitive functioning were not affected. Surprisingly, (depressed) MI patients showed even better performances with respect to memory function., Limitation: No patients with non-MI-related depression were included., Conclusions: The cognitive profile of major depression after MI differs from that of non-cardiac-related depressive disorder, as described in the literature. This may reflect a different etiology of post MI depression from non-cardiac-related depression.

Fifteen patients with major depression, dysthymia, or anxiety disorder with depressed mood (DSM-IV diagnoses) and 16 controls received single oral doses of 0.5mg/kg metachlorophenylpiperazine (m-CPP), a 5-HT(2C) agonist, and 10 mg ipsapirone, a 5-HT(1A) agonist, according to double-blind, placebo-controlled, cross-over design. The groups' levels of cortisol, adrenocorticotrophic hormone (ACTH) and prolactin did not differ at baseline. Both 5-HT agonists significantly elevated cortisol, ACTH, and prolactin. The cortisol response to ipsapirone was significantly blunted in major depression and dysthymia patients. Neuroendocrine responses to m-CPP did not differ between groups, but m-CPP selectively increased profile of mood states (POMS) depression and tenseness scores in patients. No effects of ipsapirone on mood were found. However, ipsapirone impaired memory performance in controls, but tended to improve memory performance in patients. The results support the evidence for both hypothalamic and possibly hippocampal 5-HT(1A) receptor desensitisation and non-hypothalamic, 5-HT(2C) receptor sensitisation, probably fronto-cortical, in patients with major depression and dysthymia.

Background: Mood congruent memory bias predicts a more superior recall memory of learnt material congruent with the mood state at the time of learning. The present study is the first report of an experimental study in which a biological mood induction was used to test this hypothesis. The influence of acute tryptophan (TRP) depletion, inducing low serotonin neurotransmission and a depression of mood, on memory bias was evaluated in healthy volunteers (16 with and 11 without a family history of major affective disorder)., Methods: Twenty-seven subjects received 100 g of an amino acid mixture with and without TRP according to a placebo-controlled, double-blind, balanced, cross-over design. An affective memory test consisting of a 30-word list with words of positive, neutral, and negative affective valence and a mood questionnaire were assessed at 6 and 24 h following treatment administration., Results: TRP depletion impaired delayed recall of neutral and positive words, but not of negative words. There was no interaction of family history and treatment and there was no post hoc association between the influence of TRP-depletion on mood and on affective memory bias., Conclusion: Experimentally induced serotonergic depletion in normal individuals shifts affective memory bias towards negative affective valent verbal stimuli.

Over the past decades the rate of completed suicide has remained quite stable, whereas that of suicide attempts seems to have increased (to the extent it has been studied in defined regions). These are puzzling observations, since depression is the major suicide precursor and and since antidepressants have been increasingly used over the years in the treatment of depression. These observations have not attracted sufficient attention, possibly because they do not accord with consensus opinions about depression treatment in psychiatry today. This paper discusses a number of possible explanations that not only deserve, but are definitely in need of systematic investigation.

A new subtype of depression is proposed, named: anxiety/aggression-driven depression. The psychopathological, psychopharmacological and biochemical evidence on which this construct is based, is being discussed. Selective postsynaptic 5-HT1A agonists together with CRH and/or cortisol antagonists are hypothesized to be a specific biological treatment for this depression type, in conjunction with psychological interventions to raise the stressor-threshold and to increase coping skills. The development of this depression construct has been contingent on the introduction of two new diagnostic procedures, called functionalization and verticalization of psychiatric diagnosis. These procedures are explained and it is stressed that they are essential to psychiatric diagnosing, in order to put this process on a scientific footing.

In 1974 I published a paper in which we predicted that biological depression research would lead to new, innovative antidepressants, to more sophisticated prescription of antidepressants and ultimately to 'functional psychopharmacology'. These expectations have not materialized. The reasons why are discussed and the conclusion is reached that there are reasons to believe that, belated, they will come true. I consider it no bold venture to uphold them. Copyright 2001 John Wiley & sons, Ltd.

Objective: Post-MI depression increases mortality, especially in the first 18 months after MI. Identifying patients at risk for post-MI depression is therefore important. In the present study we investigated possible correlates for post-MI depression on an a priori basis., Method: Based on the literature, four clinically easily attainable variables were selected as possible correlates for post-MI depression. These were prescription of benzodiazepines during acute hospitalization, cardiac complications during acute hospitalization, history of depression, and not being able to stop smoking within six months after MI. A consecutive cohort of 173 first-MI patients was screened with the SCL-90 depression scale and DSM-III-R criteria for major depression. Of this cohort 35 depressed patients were compared with 35 non-depressed post-MI patients, matched for gender, age, and severity of MI., Results: In univariate analyses, complications during hospitalisation (OR = 2.14; CI = 0.89-5.14), prescription of benzodiazepines (OR = 3.67; CI = 1.11-12.1), history of depression (OR = 3.0; CI = 0.87-10.4), and not being able to stop smoking (OR = 4.5; CI = 1.11-18.2) were clinical correlates for post-MI depression. Multivariate analyses showed that none of these variables were independent of the others in predicting depression., Conclusions: A number of easily measurable patient characteristics identify those MI-patients at risk of post-MI depression. Further investigations should focus on the predictive value of these factors in relation to post-MI depression.

Objective: Depression and hostility are significant risk factors for mortality and morbidity after myocardial infarction (MI). Much research is still needed to identify effective ways to reduce emotional distress in patients with cardiovascular disease. This double-blind, placebo-controlled study investigated the efficacy and safety of the antidepressant fluoxetine in patients with depression after their first MI., Methods: Fifty-four patients with major depression after MI were randomly assigned to receive a flexible-dose regimen of fluoxetine or placebo for the first 9 weeks of a double-blind, placebo-controlled trial. Patients without serious adverse effects who wished to continue participating in the study were given fluoxetine or placebo for an additional 16 weeks. To evaluate the efficacy of fluoxetine, the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Hostility Scale of the 90-item Symptom Check List (SCL-90) were used as primary measures of outcome. To evaluate the safety of fluoxetine, cardiac function was measured before and after treatment with echocardiography and electrocardiography., Results: The a priori difference in antidepressive efficacy (4-point difference in HAMD-17 scores between the fluoxetine and placebo groups) was not met. However, the response rate among patients receiving fluoxetine was significantly greater than that among patients receiving placebo at week 25 (48 vs. 26%, p = .05). Among patients with mild depression (HAMD-17 score < or =21), HAMD-17 scores were significantly different (p < .05) between the fluoxetine and placebo groups at weeks 9 (by 5.4 points) and 25 (by 5.8 points). Also, hostility scores at week 25 were significantly reduced among patients receiving fluoxetine (p = .02). Analysis of electrocardiographic and echocardiographic parameters revealed no decrease in cardiac function as a result of treatment with fluoxetine., Conclusions: Although the overall difference between the fluoxetine and placebo groups was not significant, there was a trend favoring fluoxetine in this relatively small sample. The response rate in the group receiving fluoxetine was comparable with that observed in other studies of patients with cardiovascular disease. In addition, fluoxetine seemed to be particularly effective in patients with mild depression and was associated with a statistically significant reduction in hostility. The results of this study suggest that fluoxetine can be safely used to treat patients with post-MI depression beginning 3 months after the event.

For many years, psychiatry has been devoted to nosology. This disease model conceives psychiatric conditions as discrete entities, with a particular pathophysiology and predictable relations between phenomenology, course and outcome. This model witnessed a true revival with the introduction of the DSM III. Its foundations, however, are weak. Many of the disorders, so delineated, are of doubtful validity. This is demonstrated, taking major depression as a paradigm. The nosological way of thought, moreover, carries with it harmful side effects, such as proliferation of new diagnoses, magnification of comorbidity, border problems and neglect of the factor psychogenesis. The question is raised of a possible alternative disease model and the reaction form model is considered to be just that. This model is defined and discussed and the conclusion is reached that it fits clinical practice and biological research better than the nosological disease model. A reconstruction of the diagnostic process in psychiatry is proposed, in such a way that it gains in sophistication and at the same time creates opportunities for comparative studies of the merits of the nosological and the reaction form model for psychiatric practice and research.

Nosological classification in psychiatry, as it is currently applied, does not facilitate biological and psychopharmacological research.• Syndromal acuity has disappeared. Consequently, it is impossible to determine: (i) vi/hether a particular drug affects a particular symptom configuration; (ii) what exactly the behavioral correlate of a particular biological disturbance is. The problem of unfocused diagnoses is greatly magnified by the phenomenon called comorbidity.• The boundary between distress and disorder is illdefined.• Symptom configuration and certain nonsymptomatological variables such as duration and severity are prematurely linked, so as to conceptualize categorical entities. The validity of those constructs has not been sufficiently demonstrated. This undermines the validity of biological studies and leads to "nosologomania," ie, an ever-growing series of undervalidated psychiatric "disorders."• Symptoms are grouped horizontally as if they all had the same diagnostic "valence." This, however, is highly unlikely.• The nosological disease model is unconditionally and uncritically accepted. Alternative models are ignored, particularly the reaction-form model, though it has substantial heuristic value, and deserves to be thoroughly scrutinized.(Research) strategies to remedy this situation are pointed out.

Recent studies of cerebral pathology in patients with schizophrenia have focused on symptomatological and electrophysiological correlates of reduced temporal lobe structure volumes. Volume deficits of the left superior temporal gyrus have been correlated with auditory hallucinations as well as to left-sided P300 amplitude reduction. However, caution is needed to interpret correlational data as evidence of a specific relationship. Therefore, a controlled study was undertaken on schizophrenic patients with and without auditory hallucinations. MRI-defined volumes of the left superior temporal gyrus and other temporal lobe structures were quantified from 3-mm coronal slices in 15 schizophrenic patients with chronic auditory hallucinations (hallucinators), 15 schizophrenic patients without auditory hallucinations (nonhallucinators) and 17 healthy controls. In all subjects a simple oddball paradigm was used to elicit P300 responses at temporal and centro-parietal electrode sites. No evidence was found for volume reductions of temporal lobe structures in the combined patient group compared with controls, or in the hallucinators compared with the nonhallucinators. The patients did show left P300 amplitude reduction compared with controls, particularly in the hallucinator group. Correlations between volumes of left temporal lobe structures and left P300 amplitudes were low and not significant. The results of the present study do not indicate that auditory hallucinations and associated abnormal electrophysiological activity are the consequence of atrophy of localized temporal lobe structures. However, replication in a larger sample of subjects is needed before firm conclusions can be drawn.

Background: Acute tryptophan (TRP) depletion was evaluated in healthy volunteers with or without a family history of major affective disorder (FH+ versus FH-)., Methods: Twenty-seven subjects (16 FH+, 11 FH-) received 100 g of an amino acid mixture with and without TRP according to a placebo-controlled, double-blind cross-over design and a diet devoid of TRP for the next 24 hours., Results: The ratio TRP/large neutral amino acids declined to 22% of baseline values after 6 hours, and increased during the night reaching 85% of baseline after 24 hours. Overall, after 6 hours, TRP depletion lead to a lowering of mood, but after 24 hours, these changes were no longer detected. Mood changes and gastrointestinal side effects were significantly more evident in FH+ subjects than in FH- subjects., Conclusions: Our data support the hypothesis that subjects with a positive family history for depression are predisposed to increased vulnerability to the adverse consequences of serotonergic imbalance.

Disease depresses. As a consequence depressed mood is almost ubiquitous in medicine. This is as true for physical disorders as it is for mental disorders. Depressed mood, moreover, seldom comes alone but is generally accompanied by other troublesome phenomena. In other words, the transition from distress towards depression is a gradual one, at least from the clinical point of view. One could therefore rightfully assume, that most physicians will be well versed in diagnosing and treating depression. Regrettably that is not the case. Depression is an under-diagnosed and under-treated disorder. Hence sophisticated educational programs to enhance the diagnostic and therapeutic skills of those frequently encountering depressive and depressed patients are much in need. The Dep Relief program is a CD-ROM program well suited for this purpose. It is wide-ranging, evidence-based, easily adaptable to various audiences and scrutinized by a panel of international experts. In short, it is an important tool to disseminate up-to-date information about mood disorders.

Serotonin (5-hydroxytryptamine; 5-HT) circuits may play a role in cognitive performance, particularly in learning and memory. Cognitive impairment is often seen in depressed patients, in whom 5-HT turnover in the brain is thought to be lowered. A possible human pharmacological model to study the involvement of the serotonergic system in cognitive impairment is to reduce central 5-HT synthesis through L-tryptophan depletion in healthy subjects. In this study, the cognitive effects of tryptophan depletion were assessed and whether genetically or developmentally determined vulnerability factors were predictive of the cognitive impairment induced by tryptophan depletion. Sixteen healthy volunteers with a positive family history of depression and 11 without were given 100 g of an amino acid mixture with or without tryptophan, according to a double-blind, cross-over design. Tryptophan depletion specifically impaired long-term memory performance in all subjects: delayed recall performance, recognition sensitivity, and recognition reaction times were significantly impaired after tryptophan depletion relative to placebo. Short-term memory and perceptual and psychomotor functions were unchanged. There were no differences between groups with a positive and a negative family history for depression. On the basis of these results, it is concluded that tryptophan depletion specifically impairs long-term memory formation, presumably as a result of an acute decrease in 5-HT turnover in the brain.

Thirteen healthy subjects were subjected to tryptophan (TRP) depletion, lysine (LYS) depletion, and a placebo condition in a double blind cross-over study. The aim of the study was to test the specificity of psychological effects induced by TRP depletion. Subjects ingested a 100 g amino acid mixture with or without TRP or LYS. Six hours later, plasma TRP levels had decreased by 77% in the TRP depletion test and LYS levels by 51% in the LYS depletion condition. After 6 h of TRP depletion, subjects reported significantly more tiredness and lowering of mood, compared to subjects in the placebo group, and memory performance declined. After 6 h of LYS depletion, no significant differences in mood and memory compared to placebo were found. We conclude that the effects of TRP depletion on mood and memory are specific for the depletion of TRP and are not caused by the depletion of an amino acid per se. This supports the hypothesis that TRP depletion affects brain serotonin metabolism and not only brain protein metabolism in general.

Serotonin seems to play an important role in the regulation of dopaminergic and cholinergic neurotransmitter activities. In patients with Parkinsons' Disease, serotonergic activity is generally reduced, which is considered a compensating mechanism for the reduced dopaminergic activity. At the same time, reduction of serotonin activity may play a role in the expression of cognitive and affective symptoms. Functional intervention with serotonergic agents makes it possible to temporarily enhance or reduce the availability of serotonin in the brain. This will provide the opportunity to study motor, cognitive and affective symptoms in an integrated approach. This type of research has hardly been preformed in patients with Parkinson's Disease.