Psychosomatic Medicine 65:665-671 (2003)
© 2003 American Psychosomatic Society
Tryptophan as a Link between Psychopathology and Somatic States
Sascha Russo, MD,
Ido P. Kema, PhD,
M. Rebecca Fokkema, MSc,
Jim C. Boon, MD,
Pax H. B. Willemse, MD, PhD,
Elisabeth G. E. de Vries, MD, PhD,
Johannes A. den Boer, MD, PhD and
Jakob Korf, PhD
From Department of Biological Psychiatry (S.R., J.C.B., J.A.D.B., J.K.), Department of Laboratory Medicine (I.P.K., M.R.F.), Department of Medical Oncology (P.H.B.W., E.G.E.D.V.), University Hospital Groningen, The Netherlands
Address reprint requests to: S. Russo, MD, University Hospital Groningen, Division of Biological Psychiatry, Hanzeplein 1, Box 30.001, 9700 RB Groningen, The Netherlands. Email: s.r.russo{at}acggn.azg.nl
Received for publication February 14, 2002; revision received September 30, 2003.
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ABSTRACT
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OBJECTIVE: Several somatic illnesses are associated with psychiatric comorbidity. Evidence is provided that availability of the essential amino acid tryptophan, which is the precursor of serotonin, may cause this phenomenon.
METHODS: We performed a database search to find relevant articles published between 1966 and 2002. For our search strategy, we combined several diseases from the categories hormonal, gastrointestinal, and inflammatory with the search terms "tryptophan" and "serotonin."
RESULTS: The catabolism of tryptophan is stimulated under the influence of stress, hormones and inflammation by the induction of the enzymes tryptophan pyrrolase (in the liver) and IDO (ubiquitous). Because of the reduction in blood levels of tryptophan under these circumstances the formation of cerebral serotonin is decreased.
CONCLUSIONS: It is argued that the coupling of peripheral tryptophan levels and cerebral serotonin levels has physiological significance. The clinical implications and therapeutic consequences of changes in tryptophan and consequently serotonin metabolism are discussed.
Key Words: tryptophan, • serotonin, • review, • psychiatry, • somatic, • depression.
Abbreviations: TRP = tryptophan;; 5-HT = 5-hydroxytryptamine;; BBB = blood-brain barrier;; 5-HIAA = 5-hydroxyindoleacetic acid;; 5-HTP = 5-hydroxytryptophan;; CSF = cerebrospinal fluid;; IDO = indoleamine 2,3 dioxygenase;; NMDA = N-methyl-D-aspartate;; CNS = central nervous system;; SSRI = serotonin-specific reuptake inhibitor.
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INTRODUCTION
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Many somatic diseases are associated with disturbed emotional functioning. The co-morbidity of depression, anxiety, or irritability with various diseases such as rheumatoid arthritis, viral infection, and Cushing’s disease has been well documented (1, 2). Classically, such psychopathology is considered to be the psychological reaction to a severe life event. A strong correlation between physical impairment and mood should therefore be expected. Several clinical studies, however, indicate a weak or absent relation (3, 4). A weak correlation may imply that other factors are playing a role in the precipitation of psychiatric illness in patients who are somatically ill. The present review is an attempt to identify an underlying physical mechanism that may contribute to the development of psychiatric disturbances.
We propose that the essential amino acid TRP may serve as a link between somatic and psychiatric illnesses. Via this amino acid cerebral serotonergic (5-HTergic) function is modulated. Several reviews implicate aspects of TRP metabolism in psychiatric diseases (5, 6). Although the possible relation of 5-HT function and psychiatric illness has been investigated for more than four decades (7), surprisingly little attention has been paid to the possible consequences of TRP modulation during somatic disease. In the present review, the focus lies on the significance of fluctuations in the availability of TRP in a wide variety of somatic diseases and treatments and the occurrence of psychiatric co-morbidity. Moreover, the possible biological significance of availability of TRP, and thus 5-HT, will be discussed.
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PHYSIOLOGICAL METABOLISM OF TRYPTOPHAN
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TRP is an essential amino acid of which the daily dietary intake is 
20 mmol. Reference values range between 45 and 60 µmol/l plasma (8). In contrast to the other amino acids, which are not protein bound, 50% to 85% of TRP is bound to albumin. There is discussion whether the protein-bound fraction of TRP is able to cross the BBB. A high correlation between free TRP and cerebrospinal fluid 5-HIAA levels in primates has been reported (9). Adding albumin to injected TRP has been shown to inhibit single-pass cerebral uptake in the rat (10). However, the binding of TRP to albumin is unstable so it may hardly limit cerebral TRP uptake (11). In fact, dissociation of TRP from albumin has already been observed in rabbit cerebral microcirculation (12). Therefore, it seems plausible that a large fraction of protein-bound TRP can be transported over the BBB.
Under nonpathological conditions, TRP is subjected to three major metabolic routes. This is illustrated in Figure 1. It is either incorporated in tissue proteins, converted into 5-HT or ultimately catabolized to CO2 and water. Under normal circumstances (excluding growth), the net synthesis and degradation of protein are in balance, therefore, the metabolic flux of dietary TRP through this pathway is negligible.
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Fig. 1. Figure summarized model of oxidative (down arrow) and hydroxylase (right arrow) pathways of TRP. * = Tetrahydrobiopterin-dependent reaction; + = pyridoxal phosphate dependent reaction.
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About 1% of dietary TRP is converted to 5-HT. The first and rate-limiting step in this process is the hydroxylation to 5-HTP via the enzyme TRP-5-hydroxylase (EC 1.14.16.4). This is in turn decarboxylated by the pyridoxal phosphate (vitamin B6)-dependent enzyme, aromatic acid decarboxylase (EC 4.1.1.28). A great proportion of the 5-HT synthesis takes place in the enterochromaffin cells predominantly found in the gut. Ten to twenty percent of the conversion of TRP to 5-HT, however, takes place after the BBB is crossed. The central availability of TRP is marginally dependent on the cerebral demand, but is determined by the transport of TRP over the BBB where it competes with the other large neutral amino acids. These include phenylalanine, tyrosine, threonine, leucine, isoleucine, and valine. Under physiological circumstances, the cerebral enzyme TRP hydroxylase is unsaturated. Oral administration of TRP leads to the elevation of the 5-HT metabolite, 5-HIAA in CSF both in clinical and animal studies (15). Conversely, rapid TRP depletion through the ingestion of an amino acid beverage void of TRP resulted in impaired cerebral 5-HT formation. Plasma levels of TRP were thus reduced to 10% of baseline levels a few hours after ingestion (13). Microdialysis studies on rats indicated that dietary depletion of TRP diminishes cerebral 5-HT release in both acute and chronic phases (14). In vervet monkeys, CSF levels of 5-HIAA are diminished after TRP depletion (9). Together, these experiments indicate that dietary TRP depletion leads to a rapid reduction of cerebral 5-HT synthesis.
The third and final pathway is the enzymatic degradation of TRP to kynurenine. About 99% of dietary TRP is metabolized along this oxidative or kynurenine pathway. Usually, nicotinamide adenine dinucleotide and H2O are formed via TRP oxygenase (EC 1.13.11.11), which is found primarily in the liver.
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INDUCTION OF TRP CATABOLISM
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The oxidative TRP catabolism can be induced by a variety of external and internal mechanisms. For example, TRP oxidase activity of the liver is induced by the adrenal stress hormone cortisol (15). In rats undergoing immobilization stress, a decrease in plasma TRP levels of 20% was observed (16). In volunteers, administration of cortisol also results in a reduction of plasma TRP levels (17).
Induction of oxidative TRP catabolism also occurs via the enzyme IDO (EC 1.13.11.17) (18). IDO activity in nonpathological conditions is minimal, but the enzyme is highly inducible in a variety of tissues by proinflammatory cytokines, such as interferons (19). In diseases such as AIDS and cancer, the formation of endogenous interferon-
appears to be increased, whereas plasma TRP levels are decreased (20). Severe TRP depletion, by impairing protein formation, may be related to antitumor, antiviral, and antibacterial effects (19). Dietary supplementation of TRP given to patients exhibiting IDO induction does not appear to be effective as more TRP will be degraded along the oxidative pathway. Therefore, no increase in 5-HT and protein synthesis will be exhibited. Furthermore, in macrophages and microglia (the latter are located in the brain) TRP is ultimately metabolized to quinolinic acid, an excitotoxic agonist, due to its interaction with glutamate receptors of the NMDA type. In noninflammatory states de novo synthesis of quinolinic acid does not take place in the brain (21). In gerbils, CNS quinolinic acid production is highly increased in inflammatory states (22). Although quinolinic acid is a relatively weak agonist for most receptor subtypes, it has a relatively high affinity to the NMDA receptor complex containing NR2b subunits (23). Excessive TRP may lead to convulsions and apoptosis (24). During activation of the oxidative pathway of tryptophan, cerebral 5-HT synthesis is compromised by some other factors. In this pathway, vitamin B6 is needed for the conversion of 3-hydroxykynurenine to 3-hydroxyanthranilic acid. The enzyme kynureninase, by catalyzing the formation of 3-hydroxyanthranilic acid, forms pyridoxamine at the active site during the transformation thereby inactivating itself. Reactivation takes place in the presence of high concentrations of vitamin B6, which displaces pyridoxamine (25). This may compromise the (also vitamin B6 dependent) 5-HT synthesis. Kynurenine, of which elevated levels are found during induction of the oxidative pathway of tryptophan, may also compete with TRP for passage over the BBB. Another pathway that may compromise 5-HT synthesis, during inflammation, is the formation of neopterin. Neopterin production is stimulated by interferon- and serves a role in the oxidative armature of activated leukocytes. This compound is formed at the cost of tetrahydrobiopterin, a cofactor in 5-HT synthesis, which has the same precursor 7,8-dihydroneopterin (26).
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TRP DEPLETION STUDIES
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TRP depletion paradigms have been used in a broad range of psychiatric disorders (27, 28). During depression, mood is negatively influenced by TRP depletion both in patients who were not medicated and in those remitting on an SSRI (29). In patients with autism, TRP depletion provokes anxiety and anger (30), whereas in individuals with bulimia, binge eating and increased irritability have been reported (31, 32). In patients with panic disorder, anxiety symptoms are increased or unchanged after TRP depletion (33, 34) . Patients with premenstrual syndrome who were TRP depleted showed increased irritability. (35). In patients with an obsessive-compulsive disorder, compulsive behavior was found to be enhanced after TRP depletion (36). In healthy individuals, mild effects of TRP depletion have been reported on mood, hostility, and irritability (37, 38).
Taken together, most of the TRP depletion experiments emphasize a role for 5-HT in emotional behavior. However, not a single symptom, but a variety of symptoms were provoked, indicating that confounding variables such as diagnosis and method of assessment might play a role. So depletion of TRP may provoke symptoms, depending on the susceptibility of the individual. The most consistent behavior reported in this context is aggression related. It should be emphasized that the TRP depletion experiments are brief (several hours only) and may therefore only have consequences in vulnerable individuals, whereas long-term depletion may precipitate other symptoms as well.
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ALTERED TRP METABOLISM IN SOME ENDOCRINOLOGICAL STATES
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Reports on the effects of oral contraceptives on TRP metabolism have been available since the late 1960s (39, 40). Among the most frequently reported side effects are depressed mood, irritability and emotional instability (41). Rose et al. observed increased excretion of xanthurenic acid, a metabolite of TRP, in women under oral contraceptive therapy. This could be due to the estrogen component that triggers the liver enzyme TRP-oxygenase (Figure 2). In addition, during oral contraceptive therapy, 5-HTP decarboxylase, which produces 5-HT, is no longer saturated with its co-factor vitamin B6, thus affecting 5-HT synthesis (42). Plasma levels of total TRP appear to be normal under oral contraceptive therapy (43, 44). To date, these side effects of oral contraceptives are only discussed incidentally. One study found no effects of modern contraceptives on vitamin B6 status, presumably because they contain less estrogen compared with those studied previously (50 mg of estrogen vs. 30 mg) (45).
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Fig. 2. Figure metabolism of tryptophan under normal, inflammatory, and hormonally induced situations. Size of arrows indicates quantitative significance.
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Postpartum, Maes et al. found lower plasma TRP values in 31 women (mean 51 µmol/l) compared with controls (mean 63 µmol/l) (46, 47). Abou-Saleh et al. found plasma TRP levels of 41 vs. 48 µmol/l in controls. These TRP values correlated with depression scores (47). Recently, Maes et al. found no relation between post partum TRP levels and depressive symptoms (48). In 15 patients with Cushing disease, cortisol levels were associated with depression and lowered plasma TRP (mean 64 µmol/l) compared with 15 treated patients with normalized cortisol levels (mean = 70 µmol/l) (49).
In patients with diabetes mellitus, several aberrations of TRP metabolism are reported, although few studies have been performed in humans. In diabetic rats, several indications for reduced cerebral availability are present (50). Cangiano et al. (51) found normal plasma TRP levels in 20 patients with diabetes. However, they did observe elevated levels of amino acids competing with TRP for transport over the BBB, suggesting less central availability of TRP in these patients. Fierabracci et al. observed a blunted increase in concentration in 15 patients with nonregulated insulin-dependent diabetes, when compared with patients who were regulated after TRP loading, which suggests enhanced catabolism (52). Together, these data show multiple relations between endocrinology and central 5-HT neurotransmission although not always via fluctuations of plasma TRP levels.
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GASTROINTESTINAL DISEASES AND TRP METABOLISM
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In celiac disease, a relation between attenuated levels of TRP in cerebrospinal fluid of seven patients and the presence of depressive symptoms has been found. Both biochemical and clinical disturbances were reversible after the patients were on a gluten-free diet for one year. The authors suggest that this could be indicative of poor intestinal absorption of TRP (53). In 12 patients suffering from celiac disease, the beneficial effects of 6 months of treatment with 80 mg/d of vitamin B6 supplementation have been reported (54). The underlying mechanism however is unclear. Low plasma TRP levels in 15 untreated children suffering from celiac disease (mean 13 µmol/l) were found as compared with 12 treated children (mean 31 µmol/l) and 12 healthy control children (mean 81 µmol/l) (55). Low plasma TRP values have also been reported in 40% of 32 patients diagnosed with Crohn’s disease (56).
Carcinoids are neuroendocrine malignancies originating from cells characterized by their ability to produce and secrete biogenic amines, including 5-HT. Most carcinoid tumors originate in the gut. Peripherally produced 5-HT, however, cannot pass through the BBB. Hypothetically, a central depletion might arise due to peripheral consumption of the precursor TRP. A few case reports indicate a relationship between carcinoid and depression, stupor, anxiety, hostility, sleeping disorders, or psychosis (57–59). In a retrospective study of 22 patients with carcinoid, 50% exhibited depressive symptoms (60). Recently we observed low TRP levels in carcinoid patients (S. Russo, J. Boon, I. Kema, P. Willemse, J. den Boer, J. Korf, E. de Vries, manuscript submitted).
In conclusion, several gastrointestinal diseases are associated with psychological disturbances. TRP stores are especially vulnerable to intestinal malabsorption, probably because TRP is the least abundant but essential amino acid.
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INFECTIOUS AND INFLAMMATORY DISEASES
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In 27 patients suffering from atopic dermatitis, a correlation was found between psychological factors, elevated levels of interferon-, and decreased NK cell activity (61). Fassbender et al. found a correlation between depressive symptoms, regional brain inflammatory markers, assessed with magnetic resonance imaging, and activation of the hypothalamus-pituitary-adrenal axis in patients suffering from multiple sclerosis. Surprisingly, depression did not correlate with physical impairment (4). Also, in noninflammatory diseases such as cancer, cellular immune activation (as measured by elevated neopterin and decreased TRP levels) correlated with depressive symptomatology (20). These data emphasize that depression is often directly linked with inflammatory processes. However, it is not yet clear which immunological mechanisms are responsible for these psychiatric symptoms but enhanced TRP catabolism is probably one of them. In 52 patients with systemic lupus erythematosus, lower plasma TRP levels (mean 53 µmol/l) were found when compared with 49 controls (mean 73 µmol/l) (62). Meyer et al. found decreased plasma TRP levels in 50 patients with sarcoidosis (mean 48 µmol/l) when compared with 18 healthy controls (mean 59 µmol/l) (63). In another study, HIV-1 patients’ plasma TRP levels were negatively correlated with neuropsychiatric symptoms (64). This again illustrates the inverse relationship between immune activation and the availability of TRP and therefore cerebral 5-HT tone.
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INTERFERON TREATMENT
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Since the 1980s, interferon-
and -ß have become available with the use of recombinant DNA techniques. They are used to treat various diseases because of their immunomodulatory effects. Acute side effects include fever, nausea, vomiting, diarrhea, depression, and malaise, although most of these symptoms are transient. Shortly after the introduction of interferon therapy, severe long-term psychiatric side effects, in particular depression, have been reported. In a study by Otsubo et al., 37% of 81 patients investigated were diagnosed with depression according to DSM-III-R criteria during interferon therapy (65). Anxiety, irritability, and psychosis have also been described in those patients receiving interferon therapy (66, 67). Some authors have reported impulsive suicide during interferon- therapy (68). High-dose interferon treatment (800 x 106 IU daily) resulted in elevated levels of irritability in nine patients with lung cancer during the first week of treatment (69). This subject has recently been reviewed (35). According to some authors, psychiatric side effects are the main reason for the discontinuation of interferon therapy (66). Brown et al. related interferon treatment to increased TRP catabolism (70). In addition to affective side effects, interferon therapy also influences cognitive functioning (71–73). In interferon therapy and advanced HIV infection, the accumulation of quinolinic acid has been hypothesized to cause cognitive symptoms. These disturbances appear to persist even one year after discontinuation of therapy, as seen in 14 patients with cancer (74). Recently, the beneficial effects of paroxetine, a SSRI, on depressive symptoms were reported during interferon therapy. Prophylactic treatment with this compound decreased the percentage of patients with depression after high-dose interferon treatment in 40 patients from 45% to 11% (75).
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MEDICAL CONSEQUENCES
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Alterations in TRP availability may have major consequences in medical practice. First, it may explain precipitation of psychiatric disorders in some somatic diseases and therapies, as reviewed here. Second, however, it may also have therapeutic consequences. The first treatment option is to provide information about the nature of the symptoms to the patient and his or her relatives, which may help to cope with undesirable behavior. Regular TRP monitoring may help to understand the occurrence of unrecognized comorbid psychopathology, such as depression, irritability, and aggression. Normalization of TRP metabolism or antidepressant medication (eg, SSRI therapy) may improve quality of life in a wide variety of somatic illnesses and also in cases where the pathophysiology of psychiatric symptoms is not clear because 5-HT is not etiologically linked to any specific disease. In this context, it is important to differentiate between etiology and pathophysiology of psychiatric diseases (76). Finally, the delineation of the TRP link has implications for our understanding of the mechanism of action of antidepressants. If this proposed link is crucial, it can be anticipated that psychopathology in somatic patients, concomitant with low TRP, respond to SSRI therapy and not to other (eg, norepinephrine specific) antidepressants, whereas in patients with normal levels of TRP, other therapeutic interventions against psychiatric comorbidity are to be considered. Moreover, optimal therapeutic responses with SSRIs may only be achieved when sufficient TRP is available to maintain a minimal cerebral 5-HT transmission. Furthermore, SSRIs are also able to modulate the inflammatory response itself (77). This could add to the therapeutic effect in auto immune disorders, but might disturb beneficial responses in, for example, interferon therapy. These findings support the hypothesis that irritable and depressive behavior in somatic patients may be linked to factors other than the burden of the disease alone.
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SOMATIC STATES AND TRYPTOPHAN: A CONSIDERATION
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As illustrated previously, in several somatic diseases with high comorbidity of affective symptoms, disturbances of the metabolism of the essential amino acid TRP have been reported. These somatic conditions can serve not only as a suitable model for TRP depletion induced psychopathology, but they can also give information regarding the function of the 5-HT system. In particular, the psychopathological consequences of long-term aberrations of TRP metabolism can thus be assessed. Such aberrations in somatic states are found at the level of TRP uptake in the gut, as in gastrointestinal diseases. In states accompanied by gross immune activation such as interferon treatment, advanced cancer or AIDS, TRP depletion seems to be most pronounced. This is probably related to activation of IDO. In hypercortisolemia, plasma levels of TRP can be decreased through the induction of usual TRP catabolism in the liver. After uptake of TRP in the brain, biochemical conversions can be disturbed, as is the case with psychological disturbances associated with oral contraceptive therapy. These findings can be extrapolated to other states where TRP catabolism via the oxidative pathway is enhanced. In these conditions, TRP metabolism is shifted away from 5-HT formation that is further impaired due to the decreased availability of vitamin B6 and tetrahydrobiopterin. This could be related to the behavioral adaptations often noted in immune activated states. We propose that TRP, the amino acid most sensitive to depletion and the precursor of 5-HT, has a signaling role in physiology. It is therefore not surprising that 5-HT modulates a range of cerebral processes, which continue to function in its absence (78). TRP depletion is associated with both external and internal unfavorable circumstances such as inflammation, stress-hormone release, and food depletion.
Of the somatic states mentioned above, depression is the most reported psychiatric condition. However, depression is a syndromal entity, which was developed and classified in a psychiatric setting based on clusters of symptoms. Most researchers in the previously mentioned studies have focused on the depressive symptoms thus avoiding classification problems. It could be possible that psychopathology caused solely by TRP depletion, presents itself in ways that do not match DSM-IV classification and consequently is underreported. Another problem that may contribute to the high rates of depression reported in somatic patients lies in the fact that most depression rating scales also include somatic symptoms. In this context it is remarkable that increased irritability is spontaneously reported to occur as an (unexpected) symptom in studies performed in patients suffering from diseases that are associated with TRP degradation (69, 79–82). This is in accordance with the symptoms found in TRP depletion experiments in healthy volunteers. Additional studies should be performed to investigate which pattern of symptoms is specific for psychiatric co-morbidity in somatic patients.
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ABSTRACT
INTRODUCTION
