We observed that the majority of adolescents with coeliac disease had depressive and behavioural symptoms before their diagnosis, and that coeliac disease patients with depression (all girls) had significantly lower pre-diet tryptophan/CAA ratios and free tryptophan concentrations and significantly higher biopsy morning prolactin levels. Adolescents with coeliac disease showed improvement in psychiatric symptoms after starting a gluten-free diet, and this improvement coincided with a significant decrease in coeliac disease activity and in prolactin levels, and with a significant increase in serum concentrations of L-tyrosine and other CAAs. The increase in free L-tryptophan levels was approaching significance. The findings of this study – improvement in depressive and behavioural symptoms after the start of a gluten-free diet – are supported by the findings of our larger previous retrospective case-control study [7
]. Although the results of the amino acid analysis and prolactin levels are only preliminary, they give support to the hypothesis that impaired availability of tryptophan and the possible consequent serotonergic dysfunction may play a role in vulnerability to depressive disorders among adolescents with untreated coeliac disease. A possible role for tyrosine and the brain's catecholamine metabolism (dopamine and noradrenaline) in these disorders cannot, however, be excluded.
The decrease observed in psychiatric symptoms took place regardless of the stress accompanying being diagnosed with a chronic and restrictive illness, and improvement was not explainable in terms of physical symptoms, since both in the present and in our previous study [7
], the presence or alleviation of depression showed no association with somatic symptom severity. Our results from adolescents differ from those reported by Addolorato et al. [5
]. In their follow-up study on adult patients with coeliac disease, a significant decrease in anxiety symptoms but not in depressive symptoms appeared after one year on a gluten-free diet. Although converging with the findings of Ljungman and Myrdal (20), the few symptoms of our adolescents with coeliac disease adhering to a gluten-free diet in our present and previous [7
] studies are thus in contrast to the findings of depressive symptoms [4
] and disorders [6
] as being common among adult patients with coeliac disease, even during diet treatment.
Since the free tryptophan and the tryptophan/CAA ratios in plasma determine the availability of tryptophan to the brain [21
], our findings on depressive patients give preliminary support to suggestions of impaired availability of tryptophan as featuring in coeliac-associated depressive and behavioural disorders associated with celiac disease [9
]. As we did not have a control group of healthy adolescents, we cannot say whether L-tryptophan or L-tyrosine levels or both are generally lower among adolescents with coeliac disease, as could be expected based on the findings of Hernanz and Polanco [9
], who reported significantly decreased plasma tryptophan and tyrosine concentrations in untreated and treated children with coeliac disease compared to levels in controls.
In the present study, stress-induced biopsy-morning prolactin levels were significantly higher among depressive patients (all girls) and correlated negatively with L-tryptophan/CAA levels. This finding is only preliminary, but it is, however, interesting: Although disturbances in the central serotonergic system have been associated with depressive and impulse-control disorders among adults [see [22
]], and children aged 6 to 12 years with a recent suicide attempt have shown lower whole blood tryptophan content [23
], serotonergic dysfunction in adolescents with depression is still poorly studied. The prolactin hypersecretion response to the L-5-hydroxytryptophan challenge (L-5HTP) test reported among pre-pubertal girls with major depressive disorder [24
] and among healthy children at high risk for major depressive disorder (= high family loading for major depression) [25
], may be consistent with dysregulation of the central serotonergic system in childhood major depression [24
]. Moreover, alterations in neuroendocrine responses to L-5HTP challenge tests, such as the prolactin hypersecretion and hyposecretion of cortisol found in healthy children, have been suggested to represent a trait marker for depression in children [25
]. Thus, the high biopsy morning prolactin levels in depressed adolescents with untreated coeliac disease in the present study could be associated with serotonergic dysfunction. They could also be associated with dopaminergic dysfunction due to impaired availability of tyrosine, since dopamine is known to exert an inhibitory action on prolactin release in the hypothalamus [26
]. In the present study, however, pre-diet prolactin levels did not correlate with tyrosine levels. Moreover, the function of the intestinal Catechol-O-Methyl Transferase enzyme (COMT) – known to play an important role in the peripheral O-methylation of catecholamines – remains unstudied in untreated coeliac disease. It is of some theoretical interest that reduced COMT activity in erythrocytes has at least once been associated with conditions such as primary affective disorders in women [27
On the other hand, in the present study also non-depressed adolescents with coeliac disease had higher than normal biopsy morning prolactin levels. Significantly higher prolactin levels among untreated coeliac children (5–18 years) compared with treated patients has been reported by Reifen et al. [28
]. They suggest that prolactin may play a part in the immune modulation of the intestine and could thus serve as a potential marker for coeliac disease activity.
Our preliminary findings on amino acid levels in adolescents with coeliac disease with or without depression are unlikely to be explained by malabsorption, since pre-diet free L-tryptophan and tryptophan ratios were not correlated with the BCAA levels that reflect the level of protein nutrition. It is of theoretical interest that increased production of interferon-γ (IFN-γ), known to be the predominant cytokine produced by gluten-specific T-cells in active coeliac disease [29
], can suppress serotonin function both directly and indirectly by enhancing tryptophan and serotonin turnover [30
]. Increased IFN-γ [30
] and, for instance, such events as a stress-related increase in liver tryptophan pyrrolase enzyme activity [23
], may lead to lowered tryptophan levels by the enhanced tryptophan catabolism induced by increased activity of the kynurenine-niacin pathway [30
], even without malabsorption.