Elsevier

Psychoneuroendocrinology

Volume 39, January 2014, Pages 170-178
Psychoneuroendocrinology

Symptoms of depression and anxiety in anorexia nervosa: Links with plasma tryptophan and serotonin metabolism.

https://doi.org/10.1016/j.psyneuen.2013.09.009Get rights and content

Summary

Depressive, anxiety and obsessive symptoms frequently co-occur with anorexia nervosa (AN). The relationship between these clinical manifestations and the biological changes caused by starvation is not well understood. It has been hypothesised that reduced availability of tryptophan (TRP) could reduce serotonin activity and thus trigger these comorbid symptoms. The aim of this study, during re-feeding in individuals with AN, was to analyse covariations across measures of nutritional status, depressive and anxiety symptoms, and peripheral serotonin markers.

Depressive and anxiety symptoms, nutritional status and serotonin markers – whole blood serotonin content, plasma TRP and the ratio between TRP and large neutral amino acids – were assessed for 42 AN participants at admission to inpatient treatment and after re-feeding. Biological measures were compared to those obtained in 42 non-eating disordered subjects. For those with AN, psychological, nutritional and biological parameters improved significantly during hospitalisation. Levels of serotonin markers were significantly lower in the AN group compared to the control group, at admission and at discharge. Increase in the TRP/LNAA ratio was correlated with a decrease in depressive symptoms. In addition, there was a positive correlation between serotonin levels and symptoms of both anxiety and depression at discharge. We speculate that enhanced TRP availability during re-feeding, as a result of the increase in the TRP/LNAA ratio, could restore serotonin neurotransmission and lead to a decrease in depressive symptoms. The association between serotonin and anxiety and depressive symptoms would be consistent with numerous observations indicating abnormal functioning of the serotoninergic system in AN.

Introduction

Anorexia nervosa (AN), a disorder of unknown aetiology, is frequently associated with symptoms of anxiety, obsessive-compulsiveness and depression (Godart et al., 2002, Godart et al., 2007). The presence of the latter symptoms could be partly attributable to effects of a state of starvation (Keys et al., 1950, Pollice et al., 1997). Available studies in AN that have explored the link between nutritional status on the one hand, and anxiety and depressive symptoms on the other, yield inconsistent results (Mattar et al., 2011c). In addition, the pathophysiological mechanisms that might underlie these symptoms are not well understood.

Malnutrition has an impact on peripheral and central serotoninergic pathways, probably by way of tryptophan (TRP) deficiency (an essential amino acid and precursor of serotonin) (Kaye et al., 2009). Furthermore, the serotonin (5-HT) system is involved in various psychiatric disorders (depression, anxiety, obsessive symptoms and impulsivity) and in the regulation of the feeling of satiety. Consequently, it has been suggested that 5-HT activity might be important in the physiopathology of AN (Brewerton, 1995, Kaye et al., 2009). In animal models, hypothalamic 5-HT levels in rats are lowered by fasting (Haleem and Haider, 1996). Likewise, in patients with AN, there is a correlation between peripheral and central levels of serotoninergic markers (Nakatani et al., 2008, Liu et al., 2011). In addition, an increase in TRP intake leads to an increase in cerebral serotonin and/or 5-hydroxyindoleacetic acid (5HIAA – the main catabolite of serotonin), while conversely TRP depletion leads to a decrease in brain serotonin synthesis (Russo et al., 2009). However, reviews of the literature on studies measuring these peripheral serotoninergic markers in AN yield conflicting results (Attia et al., 2005). No study has evidenced differences between underweight AN patients and non-eating disordered controls on indices of blood serotonin levels (Askenazy et al., 1998, Ehrlich et al., 2008, Ehrlich et al., 2009b, Comai et al., 2010). Certain studies report a decrease in plasma TRP and a decrease in the TRP/LNAA ratio (LNAA for large neutral amino acids) in acutely underweight anorexic patients (Schreiber et al., 1991, Askenazy et al., 1998, Ehrlich et al., 2009a, Comai et al., 2010). In fact, TRP competes with other LNAAs for the same transport system across the blood–brain barrier (Fernstrom and Wurtman, 1997). The TRP/LNAA ratio is thus predictive of transfer of plasma TRP to the CSF. Other studies have evidenced alteration in the serotoninergic pathway in underweight anorexic patients – a decrease in CSF 5-HIAA (Kaye et al., 1988), a decrease in monoamine oxidase activity (Díaz-Marsá et al., 2000), and reduced platelet paroxetine binding, indicating lower levels of peripheral serotonin transporter (Bruce et al., 2006) and a drop in the secretion of prolactin after administration of serotoninergic agonists such as m-CPP (Hadigan et al., 1995) and d-fenfluramine (Monteleone et al., 1998). After re-feeding, Kaye et al., 1988, Kaye et al., 1984 showed rapid normalisation of 5HIAA levels in the CSF as soon as there was weight gain. One study noted a normalisation of plasma TRP and the TRP/LNAA ratio (Attia et al., 2005), but this result was not found by another team (Ehrlich et al., 2009a). Many issues remain unanswered: in AN, are serotonin anomalies constitutive factors, caused by restrictive eating during the acute phase, the scars of chronic malnutrition persisting after re-feeding, or a combination of some of these parameters?

Some studies have reported a decrease in anxiety and depressive symptoms in AN with weight gain (Pollice et al., 1997), and others, the normalisation of serotoninergic biological parameters (Attia et al., 2005). However, no study to date has addressed these two elements conjointly. Furthermore, no study has accurately detailed the nutritional state of the patients (Mattar et al., 2011b), all studies using either body mass index (BMI) or solely body weight to assess the nutritional status. As body weight alone is not a sensitive tool, it has recently been recommended that at least two methods should be used, such as Bioelectrical Impedance Analysis (BIA) for body composition, and BMI in order to assess nutritional status in AN more comprehensively (Mattar et al., 2011b). The simultaneous exploration of anxiety and depressive symptoms, nutritional status and the peripheral metabolism of tryptophan and serotonin could determine whether there are links among these different parameters in the acute phase and after re-feeding and weight gain. New insights into these mechanisms could help to understand AN physiopathology and to develop better therapies.

Section snippets

Materials and methods

This project was part of a multi-centre prospective study called EVHAN (Evaluation of Hospitalisation for AN, registered in Eudract n° 2007-A01110-53, Clinical trials), and was approved by the Ile de France III ethics committee and CNIL (Commission National Informatique et Libertés). Written informed consent was obtained from all patients, in accordance with the Helsinki criteria.

Description of clinical participants and non-eating disordered samples

Forty women and two men were included consecutively in the study. The mean age of the AN participants was 17.0 years (3.25) (range = 13.2–32.8) and their mean BMI 14.1 (1.41) (Table 1). Forty-two non-eating disordered subjects were matched for age and gender. Their mean age was 17.1 (3.27) (range = 13.6–33.4). Their mean BMI was 19.4 (2.24), significantly higher than in the AN group (t = 13.15, p < 0.001).

Evolution of clinical and biological variables during re-feeding

At admission, AN participants had high levels of depressive, anxiety and eating symptoms. All the

Discussion

This work is original because it studies the link between psychological state (anxiety and depressive symptoms), nutritional status and serotonin markers in AN conjointly. To our knowledge, this study is the first to have highlighted low blood serotonin, plasma tryptophan, LNAA and the TRP/LNAA ratio concomitantly with malnutrition. While there was an improvement in these parameters following re-feeding and weight gain, after re-feeding, levels nevertheless remained below those of non-eating

Role of funding sources

This study was supported by grants from the French Ministry of Health (APHP PHRCN 2007& 2011 AOM11197, Agence Nationale de la Recherche Jeune chercheur ANR- 07-JCJC-0130,Bourse de thèse Eiffel Lama mattar; Caisse Nationale de l’Assurance Maladie des Travailleurs Salariés CNAM-TS; Fondation de France; Fondation Mutuelle Générale de Education Nationale (Fondation MGEN); Bourse de l’école des Ecole des Hautes Etudes en Santé Publique (HESP) de Tamara Hubert; the French Ministry of education

Conflict of interest

All authors declare that they have no conflict of interest.

Acknowledgments

Thanks to Angela Verdier for her indispensable help in translating this article from French to English. Thanks to each member of the EVHAN group who contributed to the data collection: Jeanne Duclos, Stéphane Billard, Régine Grenier, Sylvie Lebecq, Marc-Antoine Podlipski, Claire Gayet, Malaika Lasfar, Jennifer Carrere.

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    See Appendix 2 for EVHAN Group.

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