Serotonin
Abnormalities in serotonin (5-HT) regulation are present in eating disorders both in the acute phase of the illness and after recovery (Kaye et al. 2005a, 2005b). Since 5-HT plays many important roles in the brain, it is important to understand which behaviors or characteristics of our patients are influenced by these abnormalities. Several studies have been performed in an attempt to better understand the impact of 5-HT function in the etiopathogenesis, maintenance and clinical characteristics of eating disorders. In BN, for example, a decrease in 5-HT activity has been associated with impulsivity, affective instability, self-harming behavior and interpersonal insecurity (Steiger et al. 2001, 2004).
In this area of research, Bruce et al. (2006) recently found significantly reduced platelet [3H]-paroxetine binding in AN patients compared with controls. Paroxetine binding was inversely related to dieting preoccupations, affective instability, social avoidance, anxiousness and compulsivity. These findings suggest that certain pathological personality traits may be associated with reduced 5-HT activity in subjects with an active eating disorder. Using the same methodology, Steiger and colleagues (2006) explored the intrafamilial correspondence of 5-HT function in BN subjects and their unaffected first-degree relatives. Paroxetine binding was significantly reduced in BN subjects and their female first-degree relatives compared with controls, even after exclusion of all the relatives with a reported psychiatric disorder. Significant within-family correlations were observed, leading to the hypothesis that some heritable trait might influence both 5-HT activity and the risk of developing BN (Steiger et al. 2006).
Neuroimaging studies that used ligands specific to the study of 5-HT receptor activity have given further support to the research in the field. In women with AN, Bailer and colleagues (2007) conducted a study exploring the activity of both 5-HT1A and 5-HT2A serotonin receptors. They found significantly increased activity of the 5-HT1A receptor in several brain areas, whereas cerebral blood flow and 5-HT2A receptor activity were similar to those of healthy controls. However, the activity of the 5-HT1A receptors in supragenual cingulate, frontal and parietal regions was significantly correlated with harm avoidance. In a study in recovered subjects, Bailer and colleagues (2005) found that serotonin 5-HT1A receptor binding was increased in women who had recovered from binge-eating/purging type AN. In contrast, in women who had recovered from restricting AN, serotonin 5-HT1A receptor binding was not increased, but was significantly correlated with harm avoidance. Both observations support the hypothesis of serotonin-mediated persistent neurobiological alterations in AN that seem to be linked to anxiety and affect regulation.
Mondelli and colleagues (2006) performed a preliminary study to investigate the neuroendocrine response after citalopram infusion in a small sample of AN subjects and controls. The authors found that serotonergic control of anterior pituitary function, at least via the pathways activated by citalopram, was preserved in anorexia. They also observed that cortisol levels were higher following citalopram than following placebo in healthy women, but not in AN cases, thus indicating a lack of cortisol response to citalopram-induced adrenocorticotropic hormone (ACTH) response in these patients. This finding would suggest impairment of the adrenal function.
Another approach to studying the role of 5-HT function abnormalities in AN involves the use of the âactivity-based anorexiaâ in animal models. Two recent studies explored the role of fenfluramine (a serotonin agonist that increases 5-HT activity) and 8-OH-DPAT (a drug that reduces serotonergic neurotransmission) in conditioning the onset and the severity of activity-based anorexia in female rats (Atchley and Eckel 2005, 2006). When fenfluramine was used, rats did not display more reduction of food intake, but did show an accelerated rate of weight loss, probably because of the effects of 5-HT on metabolism (Atchley and Eckel 2005). When 8-OH-DPAT was used, the authors observed no differences with regard to food intake, but noted a significant reduction in hyperactivity, which was linked to less severe weight loss (Atchley and Eckel 2006). In conclusion, modulation of the serotonergic system affects the development of activity-based anorexia in rats, and this lends further support to the implication of this system in the etiology of AN.
Dopamine
Animal studies show that both a dopaminergic deficit and very high levels of dopaminergic stimulation may decrease feeding (Brambilla et al. 2001). In addition, dopamine (DA) function seems to affect the regulation of motor activity (Casper 2006) and reward (Di Chiara 1999). The findings of previous studies of the central secretion of DA and its metabolites in AN are contradictory. In contrast, the results of pharmacological stimulation tests probing the functional state of hypothalamic postsynaptic D2 receptors and therefore, indirectly, of presynaptic DA secretion support the hypothesis of central DA hyperactivity in AN (Brambilla et al. 2001).
Recent studies have confirmed that DA function might have a role in eating disorders. Castro-Fornieles and colleagues (2006) found that plasma levels of homovanillic acid were significantly higher in early-onset adolescent AN subjects than in a control group of similar age. The patients with higher levels of the metabolite were those with more severe depression. In addition, improvement of weight and depression was correlated with normalization of the homovanillic acid levels. Other studies seem to suggest that abnormalities in DA function are not simply present in the acutely ill, but may be a âtraitâ. Subjects with AN have an altered frequency of functional polymorphisms of the D2-receptor gene that seems to affect the efficiency of receptor transcription and translation (Bergen et al. 2005). A study using positron emission tomography imaging with the radioligand [11C]-raclopride was performed in a sample of recovered AN subjects (Frank et al. 2005). The study found increased dopamine D2/D3 receptor binding, which supports the hypothesis of decreased intrasynaptic DA concentration or increased density or affinity of the D2/D3 receptors in recovered AN patients. Furthermore, the DA receptor binding was correlated with harm avoidance. According to the authors, these findings might suggest a role of DA function in some âcoreâ anorexic symptoms, such as eating restraint, ability to lose weight, excessive exercise, and insensitivity to normal rewards (Frank et al. 2005).
Hypothalamicâpituitaryâadrenal (HPA) axis
Extensive evidence supports the notion of hyperactivity of the HPA axis in the acute phase of AN. Bliss and Migeon (1957) first found increased plasma levels of cortisol in underweight patients with AN. This finding was replicated by several other authors, who also reported normal circadian rhythms of cortisol and ACTH with increased plasma cortisol concentrations throughout the day, enhanced frequency and amplitude of cortisol secretory bursts, increased urinary free cortisol levels, non-suppression of cortisol after dexamethasone administration, normal or increased cortisol responses to ACTH stimulation, decreased ACTH response to corticotropin-releasing factor (CRF), and enhanced levels of CRF in the cerebrospinal fluid (CSF) (for a review, see Brambilla and Monte-leone 2003). HPA axis abnormalities were shown to normalize in long-term weight-restored AN patients (for a review, see Brambilla and Monteleone 2003), and it has therefore been assumed that the HPA axis hyperactivity in underweight AN individuals is secondary to malnutrition.
Only slight modifications of HPA axis activity were reported in the acute phase of BN. Despite this, 20â60% of patients with BN were found to be nonsuppressors of DST (dexamethasone suppression test) in the symptomatic phase, but not after successful treatment of BN (for a review, see Brambilla and Monteleone 2003).
In the past two years, interest has focused on exploring the role of hyper-cortisolaemia in both the determination of regional body composition and the prediction of body weight (BW) and menstrual recovery in AN. Since cortisol has antilipolytic effects, and growth hormone (GH) is lipolytic, Misra and colleagues (2005a) investigated the role of both hormones in body fat and lean mass distribution in a sample of 23 adolescents with AN. They showed that high plasma cortisol concentrations (measured as the area under the curve from 8.00 pm to 8.00 am) predicted lower lean mass in the extremities and increased lean mass in the trunk. Moreover, girls with AN who had high cortisol and low GH plasma concentrations (based on median values for both hormones in the group) were more likely to recover weight early, and their regional fat mass did not differ from that of healthy controls. Instead, girls with AN who had low cortisol and high GH levels were less likely to recover weight, and had lower trunk fat than controls. In a subsequent study by the same group (Misra et al. 2006a), it has been shown that girls with AN with higher cortisol levels before entering a 1-year treatment program gained more fat mass with weight gain, and their increase in body fat predicted menstrual recovery. Therefore, girls with AN who have increased cortisol concentrations seem to have a greater likelihood of menstrual recovery. The role of cortisol in predicting menstrual recovery in AN may stem not from its effect on the gonadal axis, which actually seems to be inhibitory (Saketos et al. 1993), but from the effect on body composition in AN (Misra et al. 2005a).
Finally, in a small open study that included only five women with restricting-type AN (Schule et al. 2006), the antidepressant mirtazapine (at a dose of 45 mg/ day over three weeks) has been shown to decrease daytime salivary cortisol concentrations, with a trend towards an increase in BW, suggesting that interventions which aim to decrease HPA axis activity may be of therapeutic value in AN. Double-blind placebo-controlled studies are needed to verify this hypothesis.
As for BN, Birketvedt and colleagues (2006) observed decreased diurnal secretion of cortisol (from 6.00 am to 2.00 pm), which tended to excessively increase after daytime meals, and an enhanced ACTH response to CRF administration in a small sample of female remitted BN patients. Therefore, although in remitted BN patients the adrenal glands seem to show hyposecretion of cortisol during the daytime, they show a hyperactive response to both physiological stimuli (meals) and exogenous CRF. Even if this study needs replication, it may suggest the persistence of dysregulation of the HPA axis in BN, which may represent a vulnerability factor for the development of eating disorders.
Hypothalamicâgrowth hormoneâinsulin-like growth factor I axis
In emaciated AN women, increased plasma levels of GH and reduced plasma concentrations of insulin-like growth factor I (IGF-I), GH binding protein (GHBP) and IGF-I binding proteins (IGFBP), especially IGFBP-3, were comm...