European Neuropsychopharmacolog), 2 (1992) 393 404 ,~: 1992 Elsevier Science Publishers B.V. All rights reserved 0924-977X/92/$05.00

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About the centrality of mood lowering in mood disorders l Plenary Lecture E C N P Congress, M o n t e Carlo, O c t o b e r 1991 H e r m a n M. van Praag Department gf Psychiatry, A/bert Einstein Colh'ge 0/" Medici, e/Mo, t~/i'ore Medical Center, New York, N Y, USA (Received 24 April, 1992) (Accepted 29 September, 1992)

Key words: Mood disorders; 5-HT; 5-HIAA; Mood lowering; "5-HT related depression"

Summary 5-HT disturbances in depression (as exemplified by lowered CSF 5-HIAA) are not syndrome specific but related to components of the depressive syndrome, specifically to increased anxiety and aggression. These 5HT disturbances are probably core pathogenetic processes not derivative features. I hypothesized that in this subtype of depression, i.e. in "5-HT related depression", the key psychopathological disturbances are dysregulation of anxiety and aggression, while mood lowering is a "by-product". Based on this hypothesis it was predicted that agents which ameliorate anxiety and/or aggression via harmonization of 5-HTergic transmission will, in addition, exert overall antidepressant effect in "5-HT related depression". The study of the relative "weight" of the various psychopathological components of depression is a basic exercise in understanding the nature of that condition and could, as such, greatly facilitate the goal-directed search for new and innovative antidepressants.

Contents 1. 5-HT disturbances in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Are the 5-HT disturbances in depression related to a particular depression category? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Are the 5-HT disturbances in depression specific for particular components of depression'? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. M o o d . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Do the 5-HT disturbances in depression play a pathogenetic role'? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Is depression a mood disorder'? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. The central argument that " 5 - H T related depression" is not a primary mood disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Additional arguments supporting the hypothesis that certain types of depression are primary anxiety/aggression disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

t Presented in part at the 4th Annual Meeting of the E u r o p e a n College of Neuropsychopharmacology, Monte Carlo, M o n a c o , 6 9 O c t o b e r 1991.

394 394 395 395 396 398 399 400 400 400 402 403

Correspondence to." Dr. H.M. van Praag, M D , PhD, Academic Psychiatric Center, University of kimburg, P.O. Box 1918, Maastricht, The Netherlands

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1.5-HT disturbances in depression Disturbances in the serolonin (5-hydroxytryptamine, 5-HT) system have been repeatedly reporled in depression. Different strategies have been used to study this system in hulnans, such as measurement of the principle metabolite off 5-HT, i.e., 5hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF): post-mortem studies of 5-HT, 5HIAA and the various 5-HT receptors in different brain regions: challenge tests witla a variely of 5HT antagonists and both direct and indirect 5-HT agonists: and the stud S' of peripheral 5-HT related variables with possible informative value t\)r the 5HT system in the central nervous system (CNS), such as measurement of infipramine binding sites on blood platelets (reviewed by Brown and van Praag, 1991 ). NUMBER OF PATIENTS 20-

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The naost direct evidence for a 5-HT disturbance in certain types of depression was the finding of a lowered 5-HIAA concentration in CSF, both under baseline condilions and after probcnccid administration (van Praag et al., 1970), an observation that has been repeatedly, though not uniformly, confirmed (Fig. 1). Low CSF 5-HIAA was interpreted as indicative of diminished metabolism of 5-HT in (certain regions of) the CNS.

2. Are the 5-HT disturbances in depression related to a particular depression category? Having observed signs of disturbed 5-HT metabolism in some depressive patients, the next question raised was whether these disturbances were related to any particular type of depression. Low CSF 5-HIAA did not appear to be correlated with the syndromal depression types vital, personal or mixed depression, nor with the categorical distinctions unipolar/bipolar and endogenous, neurotic depression, or with the severity of the depression as expressed by the total score on the Hamilton Depression Scale (van Praag ct al., 1965). Conceiwtbly, the unpredictable occurrence el" low CSF 5-HIAA in depression could be a consequence of the biochemical heterogeneity of depression (win Praag and KorL 1971). In that case, we reasoned, the same depressive syndrolne could either be strongly linked to 5-HT disturban-

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RELATION BETWEEN CSF 5-HIAA AND MOOD LOWERING IN DEPRESSION

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About the centrality of mood lowering in mood disorders. Plenary Lecture ECNP Congress, Monte Carlo, October 1991.

5-HT disturbances in depression (as exemplified by lowered CSF 5-HIAA) are not syndrome specific but related to components of the depressive syndrome,...
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