[Loss of sense and meaning, a neglected topic in psychiatry]. / Zinverlies; een verwaarloosd onderwerp in de psychiatrie.

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.

Stress and suicide are we well-equipped to study this issue?

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.

The cognitive paradox in posttraumatic stress disorder: a hypothesis.

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.

Can stress cause depression?

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.

Itinerary: Concerning the professional and spiritual objectives of my life.

In this paper I look back on my life, on what have I tried to achieve professionally, and on what trends and theories I have opposed. Next I discuss the convictions and considerations that constituted the building blocks for the spiritual foundation of my life. I reach the conclusion that the building blocks were derived from Judaism and explain why that is so. Finally, I conclude that the scientific and the theological ingredients of my life relate reciprocally and do not exist independently.

Cardiological risk factors for depressive symptoms after a first myocardial infarction.

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.

Why has the antidepressant era not shown a significant drop in suicide rates?

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.

Mood congruent memory bias induced by tryptophan depletion.

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.

Dissociable hormonal, cognitive and mood responses to neuroendocrine challenge: evidence for receptor-specific serotonergic dysregulation in depressed mood.

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.

Crossroads of corticotropin releasing hormone, corticosteroids and monoamines. About a biological interface between stress and depression.

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.

Anxiety/aggression--driven depression. A paradigm of functionalization and verticalization of psychiatric diagnosis.

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.

Past expectations, present disappointments, future hopes or psychopathology as the rate-limiting step of progress in psychopharmacology.

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.

Clinical correlates of depression following myocardial infarction.

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.

Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: findings from a double-blind, placebo-controlled trial.

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.

Nosologomania: a disorder of psychiatry.

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.

On what evidence should education concerning depression be based?

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.