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The tryptophan link to psychopathologyRusso, Sascha

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Chapter 2Tryptophan as a link betweenpsychopathology and somatic states

Sascha Russo1, MD, Ido P. Kema2, PhD, Maria R. Fokkema2, MSc, Jim C.Boon1,MD, Pax H.B. Willemse3, MD, PhD, Elisabeth G.E. de Vries3, MD, PhD,Johannes A. den Boer1, MD, PhD and Jakob Korf1, MD, PhD

1 Department of Biological Psychiatry,2 Department of Laboratory Medicine,3 Department of Medical Oncology,

University Hospital Groningen, the Netherlands

AbstractSeveral somatic illnesses and treatments with pro-inflammatorydrugs or hormones are associated with psychiatric co-morbidity. Wepropose that availability of the essential amino acid tryptophan,which is the precursor of serotonin, may be involved in psychiatricsymptoms. Tryptophan depletion experiments have shown to provoke varioussymptoms such as depression and anxiety thereby pointing to anonspecific role of the cerebral serotonin system. The catabolism oftryptophan is stimulated by stress, various hormones and inflamma-tion via the induction of the enzymes tryptophan pyrrolase (in theliver) and indoleamine 2,3 di-oxygenase (ubiquitous). Under thesecircumstances the production of serotonin is also attenuated due tothe exhaustion of enzymatic co-factors. It is argued that the coupling of peripheral tryptophan levels to cere-bral serotonin concentrations has physiological significance whichcould explain why aberrations within the serotonergic system arefound in so many conditions. The clinical implications and therapeu-tic consequences of the variability of tryptophan and consequently inthe serotonergic metabolism are discussed.

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IntroductionMany somatic diseases are associated with disturbed emotionalfunctioning. Co-morbidity of depression, anxiety or irritability withvarious diseases such as rheumatoid arthritis, viral infection andCushing's disease has been well documented (1;2). Classically,such psychopathology is considered to be the psychological reactionto a severe life event . A strong correlation between physical impair-ment and mood should therefore be expected. Several clinical stu-dies, however, indicate a weak or absent relation (3;4). A weak cor-relation may imply that other factors are playing a role in the precipi-tation of psychiatric illness in somatically ill patients. The presentreview is an attempt to identify an underlying physical mechanismthat may contribute to the development of psychiatric disturbances. We propose that the essential amino acid tryptophan (TRP) mayserve as a link between somatic and psychiatric illnesses. Via thisamino acid cerebral serotonergic (5-HTergic) function is modulated.Several reviews implicate aspects of TRP metabolism in psychiatricdiseases (5;6). Although the possible relation of 5-HT function andpsychiatric illness has been investigated for more than four decades(7), surprisingly little attention has been paid to the possible conse-quences of TRP modulation during somatic disease. In the presentreview, the focus lies on the significance of fluctuations in the availa-bility of TRP in a wide variety of somatic diseases and treatmentsand the occurrence of psychiatric co-morbidity. Moreover, the possi-ble biological significance of availability of TRP, and thus 5-HT, willbe discussed.

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Physiological metabolism of tryptophan.TRP is an essential amino acid of which the daily dietary intake isapproximately 20 mmol. Reference values range between 45-60mmol/L plasma (8). In contrast to the other amino acids which arenot protein bound, 50-85% of TRP is bound to albumin. There isdiscussion whether the protein bound fraction of TRP is able tocross the blood brain barrier (BBB). A high correlation between freeTRP and cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA)levels in primates has been reported (9). Adding albumin to injectedTRP has been shown to inhibit single pass cerebral uptake in the rat(10). However, the binding of TRP to albumin is unstable so it mayhardly limit cerebral TRP uptake (11). In fact, dissociation of TRPfrom albumin has already been observed in rabbit cerebral microcir-culation (12). Therefore, it seems plausible that a large fraction ofprotein-bound TRP can be transported over the BBB. Under non-pathological conditions TRP is subjected to three majormetabolic routes. This is illustrated in figure 1. It is either incorpora-ted in tissue proteins, converted into 5-HT or ultimately catabolizedto CO2 and water. Under normal circumstances (excluding growth),the net synthesis and degradation of protein are in balance, therefo-re the metabolic flux of dietary TRP through this pathway is negligi-ble.About 1% of dietary TRP is converted to 5-HT. The first and rate-limiting step in this process is the hydroxylation to 5-hydroxytryptop-han (5-HTP) via the enzyme TRP-5-hydroxylase (EC 1.14.16.4).This is in turn decarboxylated by the pyridoxal phosphate (vitaminB6) dependent enzyme, aromatic acid decarboxylase (EC 4.1.1.28).A great proportion of the 5-HT synthesis takes place in the entero-chromaffin cells predominantly found in the gut. Ten to 20% of theconversion of TRP to 5-HT however takes place after crossing theBBB. The central availability of TRP is marginally dependent on thecerebral demand, but is determined by the transport of TRP overthe BBB where it competes with the other large neutral amino acids.These include phenylalanine, tyrosine, threonine, leucine, isoleucineand valine. Under physiological circumstances, the cerebral enzymeTRP hydroxylase is unsaturated. Oral administration of TRP leads tothe elevation of the 5-HT metabolite, 5-HIAA in cerebrospinal fluid

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(CSF) both in clinical and animal studies (Bender 1983). Conversely,rapid TRP depletion, through the ingestion of an amino acid bever-age void of TRP, resulted in impaired cerebral 5-HT formation.Plasma levels of TRP were thus reduced to approximately 10% ofbaseline levels a few hours after ingestion (13). Microdialysis stu-dies on rats indicated that dietary depletion of TRP diminishes cere-

bral 5-HT release in both acute and chronic phases (14). In vervetmonkeys, CSF levels of 5-HIAA are diminished following TRP deple-tion (9). Together, these experiments indicate that dietary TRPdepletion leads to a rapid reduction of cerebral 5-HT synthesis.The third and final pathway is the enzymatic degradation of TRP tokynurenine. About 99% of dietary TRP is metabolized along this oxi-dative or kynurenine pathway. Usually, nicotinamide adenine dinu-cleotide and H2O are formed via TRP oxygenase (EC 1.13.11.11)which is found mainly in the liver.

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Figure 1: summarized model of oxidative (down) and hydroxylase (right) pathways of TRP.

(* = tetrahydrobiopterin dependent reaction, + = pyridoxal phosphate dependent reaction).

Induction of TRP catabolismThe oxidative TRP catabolism can be induced by a variety of exter-nal and internal mechanisms. For e.g., TRP oxidase activity of theliver is induced by the adrenal stress hormone cortisol (15). In ratsundergoing immobilization stress , a decrease in plasma TRP levelsof 20% was observed (16). In volunteers, administration of cortisolalso results in a reduction of plasma TRP levels (17). Induction of oxidative TRP catabolism also occurs via the enzymeindoleamine 2,3 di-oxygenase (IDO, EC 1.13.11.17) (18). IDO activi-ty in non-pathological conditions is minimal, but the enzyme is highlyinducible in a variety of tissues by pro-inflammatory cytokines suchas interferons (19). In diseases such as AIDS and cancer, the for-mation of endogenous interferon-gamma appears to be increased,whereas plasma TRP levels are decreased (20). Severe TRP deple-tion, by impairing protein formation, may be related to anti-tumor,antiviral and antibacterial effects (19). Dietary supplementation ofTRP given to patients exhibiting IDO induction does not appear tobe effective as more TRP will be degraded along the oxidative path-way. Therefore, no increase in 5-HT and protein synthesis will beexhibited. Furthermore, in macrophages and microglia (the latter arelocated in the brain), TRP is ultimately metabolized to quinolinicacid, an excitotoxic agonist, due to its interaction with glutamatereceptors of the NMDA type. In non-inflammatory states de novosynthesis of quinolinic acid does not take place in the brain (21). Ingerbils, central nervous system (CNS) quinolinic acid production ishighly increased in inflammatory states (22). Although quinolinic acidis a relatively weak agonist for most receptor subtypes, it has a rela-tively high affinity to the N-methyl-D-aspartate (NMDA) receptorcomplex containing NR2b subunits (23). Excessive TRP may lead toconvulsions and apoptosis (24). During activation of the oxidativepathway of tryptophan, cerebral 5-HT synthesis is compromised bysome other factors. In this pathway vitamin B6 is needed for theconversion of 3-hydroxykynurenine to 3-hydroxyanthranilic acid. Theenzyme kynureninase, catalyzing the formation of 3-hydroxyanthra-nilic acid, forms pyridoxamine at the active site during the transfor-mation thereby inactivating itself. Reactivation takes place in thepresence of high concentrations of vitamin B6, which displaces pyri-

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doxamine (25). This may compromise the (also vitamin B6 depen-dent) 5-HT synthesis. Kynurenine, of which elevated levels arefound during induction of the oxidative pathway of tryptophan, mayalso compete with TRP for passage over the BBB. Another pathwaythat may compromise 5-HT synthesis, during inflammation, is theformation of neopterin. Neopterin production is stimulated by interfe-ron-gamma and serves a role in the oxidative armature of activatedleucocytes. This compound is formed at the cost of tetrahydrobiop-terin, a co-factor in 5-HT synthesis, which has the same precursor,7,8-dihydroneopterin (26).

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TRP depletion studiesTRP depletion paradigms have been used in a broad range of psy-chiatric disorders (27;28). During depression, mood is negativelyinfluenced by TRP depletion both in unmedicated patients and inthose remitting on an SSRI (29). In autistic patients, TRP depletionprovokes anxiety and anger (30), whereas in individuals with buli-mia, binge eating and increased irritability have been reported(31;32). In patients with panic disorder, anxiety symptoms are incre-ased or unchanged after TRP depletion (33;34). TRP depletedpatients with premenstrual syndrome showed increased irritability.(35). In patients with obsessive compulsive disorder, compulsivebehavior was found to be enhanced after TRP depletion (36). Inhealthy individuals, mild effects of TRP depletion have been repor-ted on mood, hostility and irritability (37;38). Taken together, most of the TRP depletion experiments emphasizea role for 5-HT in emotional behavior. However, not a single symp-tom, but a variety of symptoms were provoked, indicating that con-founding variables such as diagnosis and method of assessmentmight play a role. So depletion of TRP may provoke symptoms,depending on the susceptibility of the individual. The most con-sistent behavior reported in this context is aggression-related. Itshould be emphasized that the TRP depletion experiments are shortlasting (several hours only) and may therefore only have conse-quences in vulnerable individuals, whereas long-term depletion mayprecipitate other symptoms as well.

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Altered TRP metabolism in some endocri-nological states

Reports on the effects of oral contraceptives on TRP metabolismhave been available since the late sixties (39;40). Among the mostfrequently reported side-effects are depressed mood, irritability andemotional instability (41). Rose et al. observed increased excretionof xanthurenic acid, a metabolite of TRP, in women under oralcontraceptive therapy. This could be due to the estrogen componentthat triggers the liver enzyme TRP-oxygenase. In addition, duringoral contraceptive therapy, 5-HTP decarboxylase, which produces 5-HT, is no longer saturated with its co-factor vitamin B6, thus affec-ting 5-HT synthesis (42). Plasma levels of total TRP appear to benormal under oral contraceptive therapy (43);(44). To date, theseside effects of oral contraceptives are only discussed incidentally.One study found no effects of modern contraceptives on vitamin B6status, presumably because they contain less estrogen compared tothose studied previously (50 mg estrogen vs. 30 mg) (45). Post partum, Maes et al. found lower plasma TRP values in 31women (mean 51mmol/L) compared to controls (mean 63 mmol/L)(46;47). Abou-Saleh et al. found plasma TRP levels of 41mmol/Lversus 48 mmol/L in controls. These TRP values correlated withdepression scores (47). Recently, Maes et al. found no relation bet-ween post partum TRP levels and depressive symptoms (48). In 15 Cushing's disease patients, cortisol levels were associatedwith depression and lowered plasma TRP (mean 64 mmol/L) com-pared to 15 treated patients with normalized cortisol levels (mean 70mmol/L) (49).In diabetes mellitus patients, several aberrations of TRP metabolismare reported, although few studies have been performed in humans.In diabetic rats, several indications for reduced cerebral availabilityare present (50). Cangiano et al. found normal plasma TRP levels in20 diabetic patients. However, they did observe elevated levels ofamino acids competing with TRP for transport over the BBB, sug-gesting less central availability of TRP in these patients (51).Fierabracci et al. observed a blunted increase in concentration in 15non-regulated insulin dependent diabetic patients, when compared

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to regulated patients after TRP loading, suggesting enhanced cata-bolism (52).Together these data show multiple relations between endocrinologyand central 5-HT neurotransmission though not always via fluctua-tions of plasma TRP levels.

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Gastrointestinal diseases andTRP metabolism

In celiac disease, a relation between attenuated levels of TRP incerebrospinal fluid of seven patients and the presence of depressivesymptoms has been found. Both biochemical and clinical disturban-ces were reversible by a year gluten-free diet. The authors suggestthat this could be indicative of poor intestinal absorption of TRP(53). In 12 patients suffering from celiac disease, beneficial effectsof 6 months treatment with 80 mg/day of vitamin B6 supplementa-tion have been reported (54). The underlying mechanism however isunclear. Low plasma TRP levels in 15 untreated children sufferingfrom celiac disease (mean 13 mmol/L) were found as compared to12 treated children (mean 31 mmol/L) and 12 healthy control chil-dren (mean 81 mmol/L) (55). Low plasma TRP values have alsobeen reported in 40% of 32 patients diagnosed with Crohn's disease(56). Carcinoids are neuroendocrine malignancies originating from cellscharacterized by their ability to produce and secrete biogenic ami-nes 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 con-sumption of the precursor TRP. A few case-reports indicate a rela-tionship between carcinoid and depression, stupor, anxiety , hostility,sleeping disorders or psychosis (57-59). In a retrospective study of22 carcinoid patients 50% exhibited depressive symptoms (60).Recently we observed low TRP levels in carcinoid patients (Russoet al. 2002, in press).In conclusion, a number of gastrointestinal diseases are associatedwith psychological disturbances. TRP stores are especially vulnera-ble to intestinal mal-absorption, probably because TRP is the leastabundant but essential amino acid.

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Infectious and inflammatory diseasesIn 27 patients suffering from atopic dermatitis, a correlation wasfound between psychological factors, elevated levels of interferon-gand decreased NK cell activity (61). Fassbender et al found a corre-lation between depressive symptoms, regional brain inflammatorymarkers, assessed with magnetic resonance imaging, and activationof the hypothalamus-pituitary-adrenal axis in patients suffering frommultiple sclerosis. Surprisingly, depression did not correlate withphysical impairment (4). Also, in non-inflammatory diseases such ascancer, cellular immune activation (elevated neopterin TRP levels)correlated with depressive symptomatology (20). These dataemphasize that depression is often directly linked with inflammatoryprocesses. However, it is not yet clear which immunological mecha-nisms are responsible for these psychiatric symptoms but enhancedTRP catabolism is probably one of them. In 52 systemic lupuserythematosus patients lower plasma TRP levels (mean 53 mmol/L)were found when compared to 49 controls (mean 73 mmol/L) (62).Meyer et al. found decreased plasma TRP levels in 50 sarcoidosispatients (mean 48 mmol/L) when compared to 18 healthy controls(mean 59 mmol/L)(63). In another study, HIV-1 patients' plasmaTRP levels were negatively correlated with neuropsychiatric symp-toms (64). This again illustrates the inverse relationship betweenimmune activation and the availability of TRP and therefore cerebral5-HT tone.

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Interferon treatmentSince the eighties, interferon-alpha and beta have become availableby recombinant DNA techniques. They are used to treat variousdiseases because of their immunomodulatory effects. Acute sideeffects include fever, nausea, vomiting, diarrhea, depression andmalaise although most of these symptoms are transient. Shortlyafter the introduction of interferon therapy also severe long-termpsychiatric side effects, in particular depression, have been repor-ted. In a study by Otsubo et al. 37% of 81 patients investigated werediagnosed with depression according to DSM III-R criteria duringinterferon therapy (65). Anxiety, irritability and psychosis have alsobeen described in those receiving interferon therapy (66;67). Someauthors have reported impulsive suicide during interferon-alpha the-rapy (68). High dose interferon treatment (800 x 106 IU daily) resul-ted in elevated levels of irritability in 9 lung cancer patients duringthe first week of treatment (69). This subject has recently beenreviewed (35). According to some authors, psychiatric side effectsare the main reason for the discontinuation of interferon therapy(66). Brown et al. related interferon treatment to increased TRPcatabolism (70). In addition to affective side effects, interferon thera-py also influences cognitive functioning (71-73). In interferon therapyand advanced HIV infection, the cumulation of quinolinic acid hasbeen hypothesized to cause cognitive symptoms. These disturban-ces appear to persist even one year after discontinuation of therapyas seen in 14 cancer patients (74). Recently, beneficial effects ofparoxetine, a serotonin specific reuptake inhibitor (SSRI), ondepressive symptoms were reported during interferon therapy.Prophylactic treatment with this compound decreased the percenta-ge of patients with depression following high dose interferon treat-ment in 40 patients from 45% to 11% (75).

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Medical consequences.Alterations in TRP availability may have major consequences inmedical practice. Firstly it may explain precipitation of psychiatricdisorders in some somatic diseases and therapies, as reviewedhere. Secondly however, it may also have therapeutic consequen-ces. The first treatment option is to provide information about thenature of the symptoms to the patient and his or her relatives, whichmay help to cope with undesirable behavior. Regular TRP monito-ring may help to understand the occurrence of unrecognized co-morbid psychopathology, such as depression, irritability and aggres-sion. Normalization of TRP metabolism or antidepressant medica-tion (e.g. SSRI therapy) may improve quality of life in a wide varietyof somatic illnesses and also in cases where the pathophysiology ofpsychiatric symptoms is not clear since 5-HT is not etiologically lin-ked to any specific disease. In this context it is important to differen-tiate between etiology and pathophysiology of psychiatric diseases(76). Finally, delineation of the TRP link has implications for ourunderstanding of the mechanism of action of antidepressants. If thisproposed link is crucial, it can be anticipated that psychopathologyin somatic patients, concomitant with low TRP, respond to SSRI the-rapy and not to other (e.g. nor-adrenaline specific) antidepressants,whereas in TRP-normal patients, other therapeutic interventionsagainst psychiatric co-morbidity are to be considered. Moreover,optimal therapeutic responses with SSRI's may only be achievedwhen sufficient TRP is available to maintain a minimal cerebral 5-HTtransmission. Furthermore, SSRI's are also able to modulate theinflammatory response itself (77). This could add to the therapeuticeffect in auto immune disorders, but might disturb beneficial respon-ses in, for example, interferon therapy. Anyway, these findings sup-port the hypothesis that irritable and depressive behavior in somaticpatients may be linked to factors other than the burden of the disea-se alone.

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Somatic states and tryptophan:a consideration

As illustrated previously, in several somatic diseases with high co-morbidity of affective symptoms, disturbances of the metabolism ofthe essential amino acid TRP have been reported. These somaticconditions can serve not only as a suitable model for TRP depletioninduced psychopathology, but they can also give information regar-ding the function of the 5-HT system. In particular, the psychopatho-logical consequences of long-term aberrations of TRP metabolismcan thus be assessed. Such aberrations in somatic states are foundat the level of TRP uptake in the gut, as in gastrointestinal diseases.In states accompanied by gross immune activation such as interfe-ron treatment, advanced cancer or AIDS, TRP depletion seems tobe most pronounced. This is probably related to activation of IDO. Inhypercortisolaemia, plasma levels of TRP can be decreased throughthe induction of usual TRP catabolism in the liver. After uptake ofTRP in the brain, biochemical conversions can be disturbed, as isthe case with psychological disturbances associated with oralcontraceptive therapy. These findings can be extrapolated to otherstates where TRP catabolism via the oxidative pathway is enhan-ced. In these conditions, TRP metabolism is shifted away from 5-HTformation that is further impaired due to the decreased availability ofvitamin B6 and tetrahydrobiopterin. This could be related to thebehavioral adaptations often noted in immune activated states. Wepropose that TRP, the amino acid most sensitive to depletion andthe precursor of 5-HT, has a signaling role in physiology. It is there-fore not surprising that 5-HT modulates a range of cerebral proces-ses which continue to function in its absence (78). TRP depletion isassociated with both external and internal unfavorable circumstan-ces such as inflammation, stress-hormone release and food deple-tion. Of the somatic states mentioned above, depression is the mostreported psychiatric condition. However, depression is a syndromalentity, which was developed and classified in a psychiatric settingbased on clusters of symptoms. Most researchers in the previouslymentioned studies have focussed on the depressive symptoms thus

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Figure 2: metabolism of tryptophan under normal, inflammatory andhormonally induced situations. Size of arrows indicates quantitativesignificance.

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avoiding classification problems. It could be possible that psychopa-thology caused solely by TRP depletion, presents itself in ways thatdo not match DSM IV classification and consequently is underrepor-ted. Another problem that may contribute to the high rates ofdepression reported in somatic patients lies in the fact that mostdepression rating scales also include somatic symptoms. In thiscontext it is remarkable that increased irritability is spontaneouslyreported to occur as an (unexpected) symptom in studies performedin patients suffering from diseases that are associated with TRPdegradation (69;79-82). This is in accordance with the symptomsfound in TRP depletion experiments in healthy volunteers.Further studies should be performed to investigate which pattern ofsymptoms is specific for psychiatric co-morbidity in somatic patients.

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