Varea, Vicente*; de Carpi, Javier Martín*; Puig, Conchita*; Alda, José Angel†; Camacho, Eva‡; Ormazabal, Aida§; Artuch, Rafael§; Gómez, Lilianne*
There is pharmacological and biochemical evidence for an association between some affective psychiatric disorders and abnormal serotonergic neurotransmission (1-3). In recent years an important role has been postulated for L-tryptophan, a precursor of serotonin, in the genesis of these disorders. The depletion of L-tryptophan by dietary exclusion of the amino acid has caused clinical deterioration of patients with major depressive syndrome (4) and the appearance of depressive symptoms in healthy subjects with a family history of affective disorders (5,6). A greater susceptibility to tryptophan deficiency and resultant changes in serotonin synthesis may be the cause of these changes. Women appear to be more susceptible to these changes which may be explained by differences in the metabolic pathways of tryptophan in females.
In 1998, Ledochowski et al. (7) described the association between lactose malabsorption and depression in female patients. The authors studied a population of 30 women volunteers classified by H2-breath test as either positive or negative for lactose malabsorption. The patients with lactose malabsorption had significantly higher Beck's inventory depression scores. The physiopathologic mechanism, according to the authors, is the formation of complexes between non-absorbed lactose and tryptophan, which has a negative effect on the absorption of tryptophan. The fact that this association is of significance only in women is a consequence of greater activity of the liver enzyme tryptophan-2,3-dioxygenase, which is estrogen dependent. This enzymatic pathway leads to the synthesis of kynurenine instead of serotonin formation. Given the frequency with which lactose malabsorption is found in the general population, the authors concluded that these patients are at higher risk for depressive disorders and proposed that patients with depression should be screened for lactose malabsorption. These same authors also obtained similar results in patients with fructose intolerance. In this case, the formation of fructose-tryptophan complexes was thought to explain the changes in the serotoninergic pathway (8).
In 1999 Ledochowski et al. (9) found diminished serum tryptophan in patients with fructose malabsorption and were again able to establish that this condition was closely related to depressive symptoms in female patients. The results published by these authors in 2000 (10) confirm their previous findings, demonstrating that a diet low in fructose and sorbitol given to patients with fructose malabsorption resulted in improvement not only of gastrointestinal symptoms but also of their early signs of depression.
Our objective was to search for evidence of an association between sugar malabsorption and depression in adolescents.
MATERIALS AND METHODS
We studied two groups of adolescent patients aged 12 - 18 years. The first group, designated group G (gastrointestinal origin), included 14 patients (nine females, five males) with lactose or fructose intolerance. A second group, designated P (psychiatric origin), included seven patients (five females, two males) with depressive symptoms. To avoid changes in serotonin metabolism secondary to antidepressive treatment, patients in the second group were studied at the time of diagnosis before the initiation of treatment. Biochemical results of patients were compared with those obtained in a healthy control population (11 boys, 10 girls, 11 - 18 years old). Written informed consent for the scientific purposes of this study was obtained from parents. The ethical committee of our hospital approved the study.
The following were obtained in both groups:
1. Previous history of GI symptoms.
3. Dietary questionnaire on consumption of milk products.
4. Biochemical studies: liver function, serum total protein, albumin, glucose, cholesterol, triglycerides, iron and ferritin were performed by standard automated procedures. Plasma tryptophan and kynurenine levels were analysed by reverse phase high-performance liquid chromatography (Series 200; Perkin Elmer, Norwalk CT) following a previously reported procedure (11). Briefly, the mobile phase consisted of potassium phosphate buffer (0.015 mol/L, pH 6.4) plus acetonitrile (88/12 v/v). Both metabolites were separated in a nucleosil C-18 column (250 × 5 mm; 5-μm particle size; Teknokroma) in conjunction with an ODS guard column (20 × 4 mm; Teknokroma). Tryptophan was analyzed by fluorescence detection (excitation, 285 nm; emission, 365 nm) and kynurenine by ultraviolet detection (365 nm). Chromatographic data were processed with the Turbochrom Navigator program (Perkin Elmer).
5. H2-breath tests to detect lactose and fructose intolerance. Breath hydrogen concentrations were measured after the administration of the two sugars on different days, resulting in two absorption curves with measurements at 30-minute intervals over a period of 3 hours. The fructose and lactose dose content was 1 g/kg of body weight, diluted in water to a concentration of 10 gm/100 cc.
6. Baseline psychiatric evaluation consisting of a sociodemographic questionnaire, Hamilton depression scale, general clinical impression of both the physician and the patient (Clinical Global Impression) and General Health Questionnaire for evaluation of social and work activity. If the psychiatric study ruled out depressive disorders, no further follow-up visits were scheduled. If there was evidence of pathology, follow-up visits were scheduled 1 month, 3 months and 6 months later.
The Mann-Whitney U-test was used to search for differences between patients and controls, and the Spearman test was used for correlation studies. Statistical analysis was performed with the SPSS. 12.0 program (SPSS, Chicago, IL).
Group G (Gastrointestinal Origin)
We studied 14 patients with sugar intolerance. Of the 13 patients with lactose malabsorption, eight also had fructose malabsorption. Only one patient with fructose malabsorption was able to absorb lactose normally. The results for these patients are presented in (Table 1). The laboratory results for liver function test, serum proteins and albumin, blood glucose, aminoacidemia, cholesterol, triglycerides, iron and ferritin were normal for all patients.
The psychiatric study detected depressive symptoms in four of the patients (28.5%), three girls and one boy. Only one of these patients had decreased serum tryptophan values. In three patients without depressive symptoms we found tryptophan concentrations below the lower limit of our control group, but there were no statistically significant differences between tryptophan values in our patients (range, 20-73 μmol/L; median, 58 μmol/L) and the controls (range, 45-82 μmol/L; median, 64 μmol/L). We did not find lower tryptophan values in girls (range, 33-73 μmol/L; median, 53 μmol/L) than in boys (range, 20-73 μmol/L; median, 64 μmol/L). There were neither age-dependent nor sex-dependent differences in tryptophan values of statistical significance in our control group. No correlation was observed between the different variables of the study either in patients or in controls. We were unable to detect elevated levels of kynurenine in any of the cases with lower than normal tryptophan values.
Group P (Psychiatric Origin)
We studied seven patients with depressive symptoms. The results obtained for these patients appear in (Table 2).
Of the patients in this group, five were found to have sugar malabsorption (71.42%), four of whom had lactose malabsorption (57%); three of these had both lactose and fructose malabsorption and one had only lactose malabsorption. The fifth patient had only fructose malabsorption. All the patients in this group had normal laboratory results (liver function test, serum proteins and albumin, blood glucose, aminoacidemia, cholesterol, triglycerides, iron and ferritin).
There were no statistically significant differences between tryptophan values in depressive patients (range, 31-73 μmol/L; median, 57 μmol/L) and those of controls (range, 45-82 μmol/L; median, 64 μmol/L). We found diminished tryptophan levels in only one patient, who was unable to tolerate both sugars. As in the intolerant group, there were no statistically significant differences in tryptophan levels between boys in this group (range, 53-56 μmol/L; median, 54.5 μmol/L) and girls (range, 31-73 μmol/L; median, 59 μmol/L). No correlation was observed between tryptophan levels, age and kynurenine levels in this group of patients.
There are two hypotheses regarding the distribution of lactase deficiency. One hypothesis suggests that lactase sufficiency segregates with populations which domesticate cattle and depend on milk for food after weaning. The second hypothesis suggests that enzyme deficiency is located in an autosomal dominant gene located on chromosome 2 (2q21). This mutation is responsible for both the congenital defect and late-onset lactase deficiency in adults. Prevalence of lactase deficiency in populations with high rates of lactose intolerance varies between 60% and 95%. The presence of the gene for lactose intolerance in adults is 0.60% in non-tolerant groups and 0.05% in tolerant groups. The expected lactose intolerance rate in our patients is 15%, as in other southern European populations (12). Estimated prevalence for the population of Galicia (northwestern Spain) is 32% for 2 g/kg of lactose and 13% for milk (13).
Although there is little published data, recent studies show a prevalence of fructose malabsorption in the USA of 39 - 80% for adult patients with nonspecific gastrointestinal symptoms depending on the dose ingested (14). As fructose tests involve quantities higher than those normally consumed in meals, fructose malabsorbers may only experience symptoms during testing.
Comparing the expected prevalence of lactose intolerance (15%) with the prevalence found in our patients with depression (Fig. 1) (57%), it is clear that the intolerance rate is considerable, especially keeping in mind that these cases were recruited strictly on the basis of psychological symptoms. Comparison of the prevalence of depressive disorders in the Spanish adolescent population (2.85%) (15,16) with the prevalence observed in our sugar-intolerant patients (28.57%) reveals a similar pattern (Fig. 2). These facts suggest that there could be a relationship between sugar intolerance and depressive disorders, both in the psychiatric group and in the gastrointestinal group.
Serotonin in the brain is related to the availability of its precursor amino acid, tryptophan. Several processes impair tryptophan metabolism. The formation of complexes between tryptophan and unabsorbed fructose and lactose may interfere with its absorption (7-10). Tryptophan reaches the brain when ingested food is rich in this amino acid and not excessively rich in neurotransmitter precursors (tyrosine, phenylalanine) that could compete with it and decrease serotonin biosynthesis. Diets low in tryptophan produce tryptophan deficiency in only 2 days. Transformation of tryptophan into kynurenine can block also the formation of serotonin (2,3) and can lead to the appearance of depression.
Five of our patients had low tryptophan values, one girl from the P group and four (three girls, one boy) from the G group, of which only one girl had depressive symptoms. Two patients, one from each group, had high kynurenine but normal tryptophan. Elevated kynurenine did not reflect a decrease in tryptophan.
As some depressive symptoms are due to decreased serotonin and tryptophan, we expected to find these results for our depressive patients. However, we did not find statistically significant differences in tryptophan levels between the 10 lactose-intolerant patients without depression (range, 20-73 μmol/L; median, 57 μmol/L) and the 11 patients classified as depressive after the study (range, 31-73 μmol/L; median, 57 μmol/L). We found decreased L-tryptophan in only one female patient in the depression group. The fact that laboratory tests were performed at the time of diagnosis of depression suggests the possibility that tryptophan is markedly lower when symptoms are most evident. There is support for this in published studies showing that in female patients with first-degree relatives with depression, symptoms appear approximately 6 hours after initiation of a tryptophan-free diet (5,17). Administration of a tryptophan-free amino acid mixture causes a reduction of up to 75 - 90% in its levels in the ensuing 4 to 6 hours, coinciding with the appearance of symptoms. Levels normalize and symptoms disappear over the 24 hours after repletion of tryptophan (18). Another possible explanation of the divergence of our data from the expected low levels of tryptophan in depressed patients is the existence of other mechanisms in the genesis of depression in adolescents (19) or the need to find other possible markers of serotonin metabolism in these patients.
Our sugar-intolerant patients would be expected to show decreased tryptophan and depressive symptoms after a large ingestion of the malabsorbed sugar. However, lactose intolerance tends to lower the intake of dairy products. We detected the same behavior in our patients, whose daily milk consumption was below the amount recommended for their age group. This behavior makes it difficult to detect tryptophan deficiency. Four patients had low serum tryptophan. They all had lactose intolerance and two of them also had fructose malabsorption, one with clinical intolerance and the other without gastrointestinal symptoms. This last patient (case 7, group G) was diagnosed with depression. In this case, asymptomatic fructose malabsorption would lead to associated malabsorption of tryptophan, altered serotonin metabolism and depression. In group G, those with asymptomatic fructose malabsorption would be at the greatest risk for decreased levels of tryptophan and development of depressive symptoms. Of those four patients with depression, three had asymptomatic fructose malabsorption. Of these, one had low levels of tryptophan and the other two were normal. Of the five patients in the P group with sugar malabsorption, three had asymptomatic fructose malabsorption.
In the group of adolescent patients with depressive symptoms, we found a prevalence of carbohydrate malabsorption (mainly lactose and, to a lesser extent, fructose) higher than expected for the general population and a higher prevalence of depressive disorders in the lactose/fructose intolerant group than in the general population. Tryptophan malabsorption secondary to the formation of unabsorbable complexes may explain this association, but we were unable to detect diminished levels of free serum tryptophan. The fact that these patients reduce their consumption of milk and milk products on their own and keep their fructose consumption below the level at which they experience symptoms may explain the difference between our findings and expected tryptophan levels in patients presumed to have deficient serotonin metabolism. Alternatively, it is possible that measurement of free serum tryptophan is not the most reliable marker of this metabolic pathway, and more effective parameters such serotonin determination should be used.
We are grateful to Susan M. DiGiacomo, of the Fundació Sant Joan de Déu, for editorial assistance in the preparation of the English-language version of this article.
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