Vasopressin in CSF and plasma in depressed suicide attempters: preliminary results

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Abstract

Increased plasma arginine vasopressin (AVP) concentrations have been reported in depressed suicide attempters. Plasma AVP is primarily produced by the magnocellular system in response to increased plasma osmolality, and central AVP may be independently regulated. In the present study we investigated cerebrospinal fluid (CSF) and plasma AVP concentrations in depressed patients and controls. Nineteen drug-free depressed psychiatric inpatients (nine suicide attempters) and nine neurological control subjects underwent lumbar puncture and psychiatric evaluation. CSF and plasma concentrations of AVP, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and cortisol were assayed. In 15 depressed patients (eight suicide attempters), the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed to examine the hypothalamic–pituitary–adrenocortical (HPA) system. There were no differences between depressed subjects and controls in all parameters measured. Suicide attempters did not differ from nonattempters. In depressed patients, plasma AVP correlated positively with cortisol. There was no relationship between CSF AVP and monoamine metabolites in CSF.

Introduction

Neuroendocrine studies suggest that hyperactivity of the HPA system with increased secretion of corticotropin-releasing hormone (CRH) may play a causal role in the development and course of depression (reviews: Holsboer, 1999, Holsboer, 2000, Keck and Holsboer, 2001). HPA system abnormalities have been reported in suicidal behavior (review: Brunner and Bronisch, 1999). Increased CRH concentrations were found in the cisternal CSF of suicide victims (Arató et al., 1989). In vivo determinations of CRH concentrations in lumbar CSF of suicide attempters, however, showed either no differences (Banki et al., 1987, Roy, 1992) or decreased CSF CRH concentrations (Brunner et al., 2001). Patients who had made repeated suicide attempts had lower CSF CRH concentrations than nonrepeaters (Träskman-Bendz et al., 1992).

AVP is colocalized with CRH in the parvicellular neurons of the hypothalamic paraventricular nucleus (PVN) and plays an important role as a corticotropin (ACTH) secretagogue. Evidence has accumulated that in depression as in chronic stress, there is a shift from CRH to AVP controlled pituitary–adrenal activation (De Goeij et al., 1992, Wotjak et al., 2001; review: Scott and Dinan, 1998). Almost nothing is known concerning the role of AVP in suicidal behavior. Inder et al. (1997) found higher plasma AVP concentrations in depressed patients who had attempted suicide. However, AVP in the peripheral circulation is primarily produced in magnocellular hypothalamic neurons and released from the posterior pituitary in response to increased plasma osmolality. Animal experiments provide evidence that plasma AVP concentrations do not necessarily reflect central AVP release (review: Landgraf et al., 1998). AVP in the CSF, on the other hand, appears largely to represent the central nervous system (CNS) AVP pool (review: Robinson and Coombes, 1993). An effective blood–CSF barrier to AVP has been demonstrated, and the concentration of AVP in CSF is not influenced by changes in plasma osmolality (Landgraf et al., 1988; review: Sørensen, 1986). The aim of this study was to determine AVP concentrations both in the CSF and plasma in depressed patients with and without suicide attempts and controls. To our knowledge, this is the first report on CSF AVP concentrations in suicide attempters. In contrast to Inder et al. (1997), we only included patients who had been off all antidepressants for at least 2 weeks because antidepressants are known to influence AVP concentrations in CSF (De Bellis et al., 1993, Altemus et al., 1994) and plasma (Gibbs and Vale, 1983, Faull et al., 1993).

Nonsuppression of cortisol in the dexamethasone suppression test (DST) is associated with subsequent completed suicide (Lester, 1992, Coryell and Schlesser, 2001). In this study the Dex/CRH test was performed which has proven to be the most sensitive neuroendocrine function test for detecting a dysregulation of the HPA system (Zobel et al., 2001). Inder et al. (1997) reported a positive association between plasma AVP and cortisol in depressed patients. Based on these findings, we postulated a positive relationship between CSF AVP and an increased ACTH and cortisol response to CRH.

Animal studies showed that central AVP has a facilitatory effect on aggressive behavior (review: Ferris, 1996). On the other hand, serotonin may inhibit aggression probably by suppressing the AVP system (Ferris and Delville, 1994, Delville et al., 1996, Ferris et al., 1997). In personality-disordered subjects, CSF AVP levels were correlated directly with life history of aggression and inversely with the prolactin response to d-fenfluramine stimulation (Coccaro et al., 1998). A vast number of studies consistently reported reduced CSF 5-HIAA concentrations in suicide attempters (review: Lester, 1995), especially in impulsive violent attempters (Mann and Malone, 1997, Cremniter et al., 1999). It was speculated that a presynaptic serotonergic deficit may increase the risk of suicidal behavior by predisposing vulnerable individuals to impulsive and autoaggressive behavior in stressful life events (review: Mann, 1998). To examine the relationship between AVP and 5-HT we measured 5-HT and 5-HIAA concentrations in both CSF and plasma. We hypothesized that CSF AVP concentrations would correlate inversely with the measures of the 5-HT system. The dopamine metabolite HVA was determined in CSF and plasma because dopaminergic alterations have been reported in suicide attempters (review: Lester, 1995).

Section snippets

Subjects

Nineteen psychiatric inpatients (12 female, seven male) aged 38±3 (mean±S.E.M., range 18–61) years were enrolled in the study after providing written informed consent. The study design had been approved by the ethical committee. All patients had depressive spectrum disorder. Diagnoses according to ICD-10 were depressive disorder, single episode (F32, n=6), depressive disorder, recurrent (F33, n=3), bipolar disorder, most recent episode depressed (F31, n=2), adjustment disorder with depressed

Biochemical parameters

There were no differences between all depressed subjects (n=19) and controls (n=9) in all biochemical parameters measured in CSF and plasma (Wilks multivariate tests of significance). Dividing the depressed patients in those who had attempted suicide prior to admission (n=9) and those who had not (n=10), revealed no significant intergroup differences either (Table 1).

Comparing the concentrations of AVP, 5-HIAA, and HVA in CSF and plasma, significant differences were found (Wilks multivariate

AVP in plasma

We found no significant differences in AVP concentrations in plasma between depressed patients who had attempted suicide prior to admission and those who had not. The results of this study do not confirm a previous report on increased plasma AVP concentrations in suicide attempters (Inder et al., 1997). This discrepancy may be due to several factors. (1) One-third of the depressed patients in the study reported by Inder et al. (1997) were treated with antidepressants. In our study, however, we

Conclusions

This study showed for the first time no differences in CSF AVP concentrations between depressed suicide attempters, depressed nonsuicidal patients, and neurological control subjects. This paper extends a previous report on plasma AVP concentrations in suicide attempters (Inder et al., 1997) by additional determinations of CSF AVP. In contrast to plasma AVP, CSF AVP is not influenced by plasma osmolality and is more likely to be a marker of central AVP secretion. The major limitations of this

Acknowledgements

The authors would like to thank Dr. A. Yassouridis for statistical analysis as well as J. Drancoli and C. Weiser for excellent technical assistance. We thank E. Binder for her helpful suggestions to the manuscript. This work was supported by a grant from the German Federal Research Ministry within the promotional emphasis ‘Competence Nets in Medicine’.

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