Tryptophan Depletion Alters the Decision-Making of Healthy Volunteers through Altered Processing of Reward Cues Effects of oral 5-hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios. Effects of tryptophan depletion vs catecholamine depletion in patients with seasonal affective disorder in remission with light therapy. An index of 5-HT synthesis changes during early antidepressant treatment: α-[11C]methyl-l-tryptophan PET study Whey protein rich in alpha-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects. Use of nutritional supplements to increase the efficacy of fluoxetine in the treatment of anorexia nervosa. Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation The Effects of Acute Tryptophan Depletion on Neuropsychological Function Effects of tryptophan depletion on drug-free patients with seasonal affective disorder during a stable response to bright light therapy. The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Tryptophan depletion reduces right inferior prefrontal activation during response inhibition in fast, event-related fMRI Effect of different tryptophan sources on amino acids availability to the brain and mood in healthy volunteers SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression Impact of Experimentally Induced Serotonin Deficiency by Tryptophan Depletion on Sleep EEG in Healthy Subjects Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects. Acute tryptophan depletion attenuates conscious appraisal of social emotional signals in healthy female volunteers Tryptophan and high-carbohydrate diets as adjuncts to smoking cessation therapy Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder Atypical Antipsychotics as Augmentation Therapy in Anorexia Nervosa A Biopsychosocial Model of Interferon-Alpha-Induced Depression in Patients with Chronic Hepatitis C Infection Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants.
While accumulating evidence suggests that effective real-life decision-making depends upon the functioning of the orbitofrontal cortex , much less is known about the involvement of the monoamine neurotransmitter systems and , in particular , serotonin . In the present study , we explored the impact of depleting the serotonin precursor , tryptophan , on human decision-making . Eighteen healthy volunteers consumed an amino-acid drink containing tryptophan and 18 healthy volunteers consumed an amino-acid drink without tryptophan , before choosing between simultaneously presented gambles , differing in the magnitude of expected gains ( ie reward ) , the magnitude of expected losses ( ie punishment ) , and the probabilities with which these outcomes were delivered . Volunteers also chose between gambles probing identified non-nomative biases in human decision-making , namely , risk-aversion when choosing between gains and risk-seeking when choosing between losses . Tryptophan-depleted volunteers showed reduced discrimination between magnitudes of expected gains associated with different choices . There was little evidence that tryptophan depletion was associated with altered discrimination between the magnitudes of expected losses , or altered discrimination between the relative probabilities with which these positive or negative outcomes were delivered . Risk-averse and risk-seeking biases were also unchanged . These results suggest that serotonin mediates decision-making in healthy volunteers by modulating the processing of reward cues , perhaps represented within the orbitofrontal cortex . It is possible that such a change in the cognition mediating human choice is one mechanism associated with the onset and maintenance of anhedonia and lowered mood in psychiatric illness OBJECTIVE : In obese patients , brain serotonergic stimulation via orally administered 5-hydroxy-tryptophan ( 5-HTP ) , the precursor of serotonin , causes decreased carbohydrate intake and weight loss . Since diabetes mellitus is associated with depressed brain serotonin , hyperphagia and carbohydrate craving , we hypothesized that in diabetic patients , orally administered 5-HTP stimulates brain serotonergic activity and thus normalizes eating behaviour . To test this hypothesis , we investigated whether in diabetic patients : 1 ) predicted brain serotonin concentrations are depressed as a result of decreased availability of the precursor , tryptophan ; and 2 ) oral 5-HTP is effective in reducing energy and carbohydrate intake . SUBJECTS AND METHODS : 25 overweight non-insulin dependent diabetic out patients were enrolled in a double-blind , placebo-controlled study , and r and omized to receive either 5-HTP ( 750 mg/d ) or placebo for two consecutive weeks , during which no dietary restriction was prescribed . Energy intake and eating behaviour , as expressed by macronutrient selection , were evaluated using a daily diet diary . Plasma amino acid concentrations and body weight , as well as serum glucose , insulin and glycosylated haemoglobin were assessed . RESULTS : 20 patients ( nine from the 5-HTP group and 11 from the Placebo group ) completed the study . Brain tryptophan availability in diabetic patients was significantly reduced when compared to a group of healthy controls . Patients receiving 5-HTP significantly decreased their daily energy intake , by reducing carbohydrate and fat intake , and reduced their body weight . CONCLUSIONS : These data confirm the role of the serotonergic system in reducing energy intake , by predominantly inhibiting carbohydrate intake , and suggest that 5-HTP may be safely utilized to improve the compliance to dietary prescriptions in non-insulin dependent diabetes mellitus BACKGROUND The delivery of circulating tryptophan to the brain and its conversion to serotonin vary directly with plasma concentrations of tryptophan and inversely with those of other large neutral amino acids ( LNAAs ) . Although carbohydrate-rich , protein-free formula diets have been shown to elevate , and high-protein diets to depress , the tryptophan-LNAA ratio , few data are available about this ratio 's responses to actual meals . OBJECTIVE We determined whether carbohydrate-rich or protein-rich breakfasts , such as those Americans normally eat , produce substantial differences in the plasma tryptophan-LNAA ratio and in the corresponding ratio for tyrosine , the precursor of brain dopamine and norepinephrine . DESIGN Nine overnight-fasted subjects consumed , 3 - 7 d apart , a carbohydrate-rich ( 69.9 g carbohydrate and 5.2 g protein ) and a protein-rich ( 15.4 g carbohydrate and 46.8 g protein ) breakfast . Blood sample s collected at baseline and after 40 , 80 , 120 , and 240 min were assayed for tryptophan , tyrosine , the 5 other LNAAs , and insulin . RESULTS The carbohydrate-rich and protein-rich breakfasts had significantly different effects on both the plasma tryptophan-LNAA and tyrosine-LNAA ratios ( each P < 0.01 ) . Among the 8 subjects who consumed both breakfasts , the median difference for tryptophan : LNAA was 54 % ( range : 36 - 88 % ) and for tyrosine : LNAA was 28 % ( range : 10 - 64 % ) . Insulin concentrations rose significantly after the carbohydrate but not after the protein meal . CONCLUSIONS High-carbohydrate and high-protein breakfasts similar to those Americans normally eat can cause substantial differences in the plasma tryptophan ratio and thus , probably , in brain tryptophan concentrations and serotonin synthesis . Such meals also change the plasma tyrosine ratio and may thereby modify catecholamine synthesis BACKGROUND Although hypotheses about the therapeutic mechanism of action of light therapy have focused on serotonergic mechanisms , the potential role , if any , of catecholaminergic pathways has not been fully explored . METHODS Sixteen patients with seasonal affective disorder who had responded to a st and ard regimen of daily 10000-lux light therapy  were enrolled in a double-blind , placebo-controlled , r and omized crossover study . We compared the effects of tryptophan depletion with catecholamine depletion and sham depletion . Ingestion of a tryptophan-free amino acid beverage plus amino acid capsules was used to deplete tryptophan . Administration of the tyrosine hydroxylase inhibitor alpha-methyl-paratyrosine was used to deplete catecholamines . Diphenhydramine hydrochloride was used as an active placebo during sham depletion . The effects of these interventions were evaluated with measures of depression , plasma tryptophan levels , and plasma catecholamine metabolites . RESULTS Tryptophan depletion significantly decreased plasma total and free tryptophan levels . Catecholamine depletion significantly decreased plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels . Both tryptophan depletion and catecholamine depletion , compared with sham depletion , induced a robust increase ( P<.001 , repeated- measures analysis of variance ) in depressive symptoms as measured with the Hamilton Depression Rating Scale , Seasonal Affective Disorder Version . CONCLUSIONS The beneficial effects of light therapy in the treatment of seasonal affective disorder are reversed by both tryptophan depletion and catecholamine depletion . These findings confirm previous work showing that serotonin plays an important role in the mechanism of action of light therapy and provide new evidence that brain catecholaminergic systems may also be involved The antidepressant selective serotonin transporter inhibitors ( SSRIs ) are clinical ly active after a delay of several weeks . Indeed , the rapid increase of serotonin ( 5-HT ) caused by SSRIs , stimulates the 5-HT(1A ) autoreceptors , which exert a negative feedback on the 5-HT neurotransmission . Only when autoreceptors are desensitized , can SSRIs exert their therapeutic activity . The 5-HT(1A ) receptor antagonist pindolol has been used to accelerate the clinical effects of antidepressant by preventing the negative feedback . Using the alpha-[(11)C]methyl-L-tryptophan/positron emission tomography ( PET ) , the goal of the present double-blind , r and omized study was to compare the changes in alpha-[(11)C]methyl-L-tryptophan trapping , an index of serotonin synthesis , in patients suffering from unipolar depression treated with the SSRI citalopram ( 20 mg/day ) plus placebo versus patients treated with citalopram plus pindol ( 7.5 mg/day ) .  PET and Hamilton depression rating scale ( HDRS-17 ) were performed at baseline , and after 10 and 24 days of antidepressant treatment . Results show that the combination citalopram plus pindol , compared to citalopram alone shows a more rapid and greater increase of an index of 5-HT synthesis in prefrontal cortex ( BA 9 ) . This research is the first human PET study demonstrating that , after 24 days , the combination SSRIs plus pindolol produces a greater increase of the metabolism of serotonin in the prefrontal cortex , an area associated to depressive symptoms BACKGROUND Cognitive performance often declines under chronic stress exposure . The negative effect of chronic stress on performance may be mediated by reduced brain serotonin function . The uptake of the serotonin precursor tryptophan into the brain depends on nutrients that influence the availability of tryptophan by changing the ratio of plasma tryptophan to the sum of the other large neutral amino acids ( Trp-LNAA ratio ) . In addition , a diet-induced increase in tryptophan may increase brain serotonergic activity levels and improve cognitive performance , particularly in high stress-vulnerable subjects . OBJECTIVE We tested whether alpha-lactalbumin , a whey protein with a high tryptophan content , would increase the plasma Trp-LNAA ratio and improve cognitive performance in high stress- vulnerable subjects . DESIGN Twenty-three high stress-vulnerable subjects and 29 low stress-vulnerable subjects participated in a double-blind , placebo-controlled , crossover study . All subjects conducted a  memory-scanning task after the intake of a diet enriched with either alpha-lactalbumin ( alpha-lactalbumin diet ) or sodium caseinate ( control diet ) . Blood sample s were taken to measure the effect of dietary manipulation on the plasma Trp-LNAA ratio . RESULTS A significantly greater increase in the plasma Trp-LNAA ratio after consumption of the alpha-lactalbumin diet than after the control diet ( P = 0.0001 ) was observed ; memory scanning improved significantly only in the high stress-vulnerable subjects ( P = 0.019 ) . CONCLUSION Because an increase in the plasma Trp-LNAA ratio is considered to be an indirect indication of increased brain serotonin function , the results suggest that dietary protein rich in alpha-lactalbumin improves cognitive performance in stress-vulnerable subjects via increased brain tryptophan and serotonin activities OBJECTIVE Selective serotonin reuptake inhibitor ( SSRI ) medication does not appear to be effective in ill , malnourished anorexia nervosa ( AN ) patients . However , it may be effective in preventing relapse after weight restoration . The purpose of this study was to determine whether nutritional supplements could potentiate the effects of fluoxetine in underweight AN subjects . METHOD Twenty-six subjects with AN participated in a trial of fluoxetine . In a double-blind , placebo-controlled manner , subjects received either nutritional supplements or a nutritional placebo . The nutritional supplement included tryptophan ( the precursor of serotonin ) , vitamins , minerals , and essential fatty acids believed to influence serotonin pathway function . RESULTS There was no significant difference in weight gain between subjects treated with fluoxetine plus nutritional supplements versus fluoxetine plus a nutritional placebo . Moreover , there were no significant differences between groups on mean changes in anxiety or obsessive and compulsive symptoms . DISCUSSION The results of this study suggest that supplement strategies are not a substitute for adequate nutrition and are ineffective in increasing the efficacy of fluoxetine in underweight AN subjects Abstract Serotonin ( 5-hydroxytryptamine ; 5-HT ) circuits may play a role in cognitive performance , particularly in learning and memory . Cognitive impairment is often seen in depressed patients , in whom 5-HT turnover in the brain is thought to be lowered . A possible human pharmacological model to study the involvement of the serotonergic system in cognitive impairment is to reduce central 5-HT synthesis through L-tryptophan depletion in healthy subjects . In this study , the cognitive effects of tryptophan depletion were assessed and whether genetically or developmentally determined vulnerability factors were predictive of the cognitive impairment induced by tryptophan depletion . Sixteen healthy volunteers with a positive family history of depression and 11 without were given 100 g of an amino acid mixture with or without tryptophan , according to a double-blind , cross-over design . Tryptophan depletion specifically impaired long-term memory performance in all subjects : delayed recall performance , recognition sensitivity , and recognition reaction times were significantly impaired after tryptophan depletion relative to placebo . Short-term memory and perceptual and psychomotor functions were unchanged . There were no differences between groups with a positive and a negative family history for depression . On the basis of these results , it is concluded that tryptophan depletion specifically impairs long-term memory formation , presumably as a result of an acute decrease in 5-HT turnover in the brain Serotonin ( 5-HT , 5-hydroxytryptamine ) may have an important role in the maintenance of normal neuropsychological functioning . The method of acute tryptophan depletion ( ATD ) provides a pharmacological challenge by which central 5-HT levels can be temporarily decreased and effects on learning , memory and mood examined . Twenty healthy male volunteers were recruited to take part in this within-subject , double-blind , crossover study . Neuropsychological function was evaluated 4 - 6 h after ingestion of a control or 52 g tryptophan ( TRP ) depleting amino-acid drink . ATD significantly lowered levels of plasma total and free TRP ( p < 0.001 ) , but this did not affect mood or performance on tests of verbal and visuo-spatial learning and memory , attention or executive function . These results contradict previous findings ; however , the degree of disruption of central 5-HT levels result ing from the use of the 52 g amino-acid protocol may be an important factor in explaining the lack of effect . By utilizing more specific probes of individual 5-HT receptor subtypes , future studies can fully explore the role of 5-HT in neuropsychological functioning and may eluci date the factors determining vulnerability to the effects of serotonergic dysfunction BACKGROUND A dysfunction of the serotonin system may play a major role in the pathogenesis of seasonal affective disorder .  Bright light therapy has been shown to be effective in the treatment of winter depression in patients with seasonal affective disorder .  Light therapy-induced remission from depression may be associated with changes in brain serotonin function . METHODS After at least 2 weeks of clinical remission , 12 drug-free patients who had had depression with seasonal affective disorder underwent tryptophan depletion in a double-blind , placebo-controlled , balanced cross-over design study . RESULTS Short-term tryptophan depletion induced a significant decrease in plasma free and total tryptophan levels ( P < .001 for both , repeated measures analysis of variance ) , with peak effects occurring 5 hours after ingestion of a tryptophan-free amino acid drink . It emerged that tryptophan depletion leads to a transient depressive relapse , which was most pronounced on the day after the tryptophan-depletion testing . No clinical ly relevant mood changes were observed in the control testing . CONCLUSIONS The maintenance of light therapy-induced remission from depression in patients with seasonal mood cycles seems to depend on the functional integrity of the brain serotonin system . Our results suggest that the serotonin system might be involved in the mechanism of action of light therapy Abstract Rationale . Cognitive impairment is a common feature of depressive illness . While accumulating evidence suggests that brain serotonin ( 5-HT ) pathways play an important role in the neurobiology of depression , the extent to which altered 5-HT function is responsible for the associated changes in cognition and emotion remains unclear . Objective . The present study examined the effects of acute dietary depletion of tryptophan ( TRP ) on cognitive and affective processing in healthy volunteers and explored the putative role of 5-HT in the neuropsychology of depression . Methods . We administered computerised cognitive tests to healthy control participants following ingestion of TRP-free and nutritionally balanced amino acid drinks in a double-blind , placebo-controlled , crossover design . Results . The TRP-free amino acid mixture significantly lowered plasma total and free TRP concentrations relative to baseline values and produced selective deficits similar to those observed previously in cases of clinical depression . In particular , TRP depletion increased response times for happy but not sad targets in an affective go/no-go task and slowed responding in a visual discrimination and reversal learning task . These deficits were not due to a global sedative effect , as planning ability was unimpaired . Conclusions . The present data indicate that serotonergic factors may be more involved in the disrupted inhibitory and emotional processing characteristic of depression than in other aspects of executive function , such as planning ability . These findings support the recent proposal that serotonergic manipulation may have greater effects on tasks mediated by frontal circuitry that includes the orbitofrontal cortex than by dorsolateral prefrontal cortex circuitry CONTEXT An instructive paradigm for investigating the relationship between brain serotonin function and major depressive disorder ( MDD ) is the response to tryptophan depletion ( TD ) induced by oral loading with all essential amino acids except the serotonin precursor tryptophan . OBJECTIVE To determine whether serotonin dysfunction represents a trait abnormality in MDD in the context of specific neural circuitry abnormalities involved in the pathogenesis of MDD . DESIGN R and omized double-blind crossover study . SETTING Outpatient clinic . PARTICIPANTS Twenty-seven medication-free patients with remitted MDD ( 18 women and 9 men ; mean + /- SD age , 39.8 + /- 12.7 years ) and 19 controls ( 10 women and 9 men ; mean + /- SD age , 34.4 + /- 11.5 years ) . INTERVENTIONS We induced TD by administering capsules containing an amino acid mixture without tryptophan . Sham depletion used identical capsules containing hydrous lactose . Fluorodeoxyglucose F 18 positron emission tomography studies were performed 6 hours after TD . Magnetic resonance images were obtained for all participants . MAIN OUTCOME MEASURES Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of sham depletion and TD . Behavioral assessment s used a modified ( 24-item ) version of the Hamilton Depression Rating Scale . RESULTS Tryptophan depletion induced a transient return of depressive symptoms in patients with remitted MDD but not in controls ( P<.001 ) . Compared with sham depletion , TD was associated with an increase in regional cerebral glucose utilization in the orbitofrontal cortex , medial thalamus , anterior and posterior cingulate cortices , and ventral striatum in patients with remitted MDD but not in controls . CONCLUSION The pattern of TD-induced regional cerebral glucose utilization changes in patients with remitted MDD suggests that TD unmasks a disease-specific , serotonin system-related trait dysfunction and identifies a circuit that probably plays a key role in the pathogenesis of MDD Rationale and objective In animal and human studies , the neurotransmitter serotonin ( 5-hydroxytryptamine ; 5-HT ) has been implicated in mediating impulsiveness and aggression . To test the hypothesis that 5-HT modulates neuro-cognitive brain activation during inhibitory control , we examined the effect of acute tryptophan depletion ( ATD ) , a dietary challenge , which has been shown to decrease 5-HT synthesis in the brain , on functional brain activation during a go/no-go task . Methods Nine healthy , right-h and ed volunteers performed a rapid , event-related go/no-go task in two functional magnetic resonance imaging ( fMRI ) scanning sessions , 5 h after either a tryptophan-free or a balanced amino acid drink in a double-blind , sham depletion-controlled , counterbalanced , crossover design . The task required subjects to selectively execute or inhibit a motor response . Tryptophan depletion significantly lowered total plasma tryptophan concentration by 80 % , but did not significantly alter inhibitory performance or mood ratings . Results ATD significantly reduced right orbito-inferior prefrontal activation during the no-go condition , and increased activation in superior and medial temporal cortices . Conclusions These findings provide neuro-functional evidence of a serotonergic modulation of right inferior prefrontal during inhibitory motor control . The increased engagement of temporal brain regions may reflect compensatory mechanisms Rationale Reduced brain serotonin function is acknowledged as a vulnerability factor for affective disturbances . Since the production of serotonin is limited by the availability of its plasma dietary amino acid precursor tryptophan ( TRP ) , the beneficial effects of tryptophan-rich alpha-lactalbumin whey protein ( ALAC ) have recently been studied . The effects of ALAC remain rather modest , and alternative protein sources of tryptophan may be more effective . Objectives We tested whether hydrolyzed protein ( HPROT ) has greater effects on the plasma TRP/large neutral amino acids ( LNAA ) ratio and mood than intact ALAC protein in healthy volunteers . Material s and methods In a double-blind , r and omized cross-over study , plasma amino acids and mood were repeatedly measured in 18 healthy subjects before and after intake of  ALAC and HPROT as well as after placebo protein , pure tryptophan , and a tryptophan-containing synthetic peptide . Except for the placebo protein , all interventions contained 0.8 g TRP . Results Significantly faster and greater increases in plasma TRP/LNAA were found after HPROT than after ALAC . In addition , the effects of HPROT on plasma TRP/LNAA were comparable with the effects of the tryptophan-containing synthetic peptide and even exceeded the effect of pure tryptophan . Sixty minutes after intake , mood was improved only following intake of HPROT and pure tryptophan , whereas longer-lasting mood effects were only found after intake of HPROT . Conclusions The use of a tryptophan-rich hydrolyzed protein source may be more adequate to increase brain tryptophan and 5-HT function compared with intact alpha-lactalbumin protein or pure tryptophan Tryptophan hydroxylase ( TPH ) , being the rate-limiting enzyme in the bio synthesis of serotonin plays a major role as c and i date gene in several psychiatric disorders . Recently , a second TPH isoform ( TPH2 ) was identified in mice , which was exclusively present in the brain . In a previous post-mortem study of our own group , we could demonstrate that TPH2 is also expressed in the human brain , but not in peripheral tissues . This is the first report of an association study between polymorphisms in the TPH2 gene and major depression ( MD ) . We performed single-nucleotide polymorphism ( SNP ) , haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene .  Significant association was detected between one SNP ( P=0.0012 , global P=0.0051 ) and MD . Haplotype analysis produced additional support for association ( P<0.0001 , global P=0.0001 ) . Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system . These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders The tryptophan depletion test is a research strategy to investigate the functional consequences of decreasing the brain serotonin metabolism . Because serotonin is involved in sleep regulation and the regulation of affective states , we studied the acute polysomnographic effects of tryptophan depletion and expected to induce similar changes of sleep EEG as observed in depressed patients . A total of 12 healthy subjects ( mean age 34 ± 3 years ) had eight polysomnograms  , divided in two blocks of 4 consecutive nights . After one adaptation and 1 baseline night , subjects received a low-protein diet on day 3 and 4 until midday . On day 4 at 18.00 h , they drank an amino acid mixture either devoid of tryptophan or containing 2.3 g of tryptophan ( placebo control ) in r and omized and double-blind order , result ing in an 85 % decrease ( tryptophan depletion ) and a 144 % increase ( placebo control ) of serum tryptophan at 22.00 h. After tryptophan depletion but not placebo , significant effects on sleep EEG were observed in terms of decreased non-rapid eye movement ( non-REM ) stage 2 , increase of wake % , and of rapid eye movement ( REM ) density compared with baseline . REM latency was not altered , however the first and second REM period interval were significantly shorter after tryptophan depletion . This study underlines the impact of the serotonergic system on sleep maintenance and on REM sleep . © 1998 American College of OBJECTIVE Because the initial phase of treatment of depression with a selective serotonin reuptake inhibitor is often complicated by a delayed onset of action of the antidepressant or severe insomnia or both , we investigated whether tryptophan , an amino acid with both antidepressant-augmenting and hypnotic effects , would benefit patients with depression at the beginning of treatment with fluoxetine .  DESIGN R and omized , double-blind , placebo-controlled trial . PATIENTS Thirty individuals with major depressive disorder . INTERVENTIONS Treatment over 8 weeks with 20 mg of fluoxetine per day and either tryptophan ( 2 to 4 g per day ) or placebo . OUTCOME MEASURES Mood was assessed using the 29-item Hamilton Depression Rating Scale ( HDRS-29 ) and the Beck Depression Inventory ( BDI ) . Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using st and ard procedures . RESULTS During the first week of treatment , there was a significantly greater decrease in HDRS-29 depression scores , and a similar trend in BDI scores , in the tryptophan/fluoxetine group than in the placebo/fluoxetine group . No significant differences were noted at later time points . With respect to sleep measures , there was a significant group-by-time interaction for slow-wave sleep at week 4 . Further analysis revealed a significant decrease in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group , but not in the tryptophan/fluoxetine group . No cases of serotonin syndrome occurred , and the combination was well tolerated , although the 4 g per day dosage of tryptophan produced daytime drowsiness . CONCLUSIONS Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep . Further large-scale studies are needed to confirm these initial findings Rationale Acute tryptophan depletion ( ATD ) decreases levels of central serotonin . ATD thus enables the cognitive effects of serotonin to be studied , with implication s for the underst and ing of psychiatric conditions , including depression . Objective To determine the role of serotonin in conscious ( explicit ) and unconscious/incidental processing of emotional information . Material s and methods A r and omized , double-blind , cross-over design was used with 15 healthy female participants . Subjective mood was recorded at baseline and after 4 h , when participants performed an explicit emotional face processing task , and a task eliciting unconscious processing of emotionally aversive and neutral images presented subliminally using backward masking . Results ATD was associated with a robust reduction in plasma tryptophan at 4 h but had no effect on mood or autonomic physiology . ATD was associated with significantly lower attractiveness ratings for happy faces and attenuation of intensity/arousal ratings of angry faces . ATD also reduced overall reaction times on the unconscious perception task , but there was no interaction with emotional content of masked stimuli . ATD did not affect breakthrough perception ( accuracy in identification ) of masked images . Conclusions ATD attenuates the attractiveness of positive faces and the negative intensity of threatening faces , suggesting that serotonin contributes specifically to the appraisal of the social salience of both positive and negative salient social emotional cues . We found no evidence that serotonin affects unconscious processing of negative emotional stimuli . These novel findings implicate serotonin in conscious aspects of active social and behavioural engagement and extend knowledge regarding the effects of ATD on emotional perception Treatments that reduce the immediate effects of smoking withdrawal have potential for helping smokers quit . Serotonin-enhancing substances , such as tryptophan and high-carbohydrate diets , have been used in clinical disorders to relieve negative affect , a classic symptom of cigarette withdrawal . This research project investigated the use of tryptophan ( 50 mg/kg/day ) and high-carbohydrate diets , together with more traditional smoking cessation treatment techniques , to ameliorate the  smoking withdrawal syndrome  and to improve abstinence rates .  Subjects were r and omly assigned to receive either tryptophan ( n=16 ) or placebo ( n=15 ) . St and ard smoking cessation treatment was identical for the experimental and control groups and consisted of four 2-hr weekly sessions of multicomponent group therapy .  Smoking behavior , symptoms of nicotine withdrawal , and negative affect were assessed during a 2-week withdrawal period . Tryptophan-treated subjects who could not fully abstain were able to smoke fewer daily cigarettes . Reported anxiety and other withdrawal symptoms were lower in the tryptophan group compared with control subjects . These data suggest that serotonin-enhancing substances show promise for use as an adjunct to existing smoking cessation programs Attention-deficit/hyperactivity disorder ( ADHD ) is the most common behavioral disorder in childhood with substantial heritability . Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD . Here , we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 ( TPH2 ) , the rate-limiting enzyme of serotonin ( 5-HT ) synthesis in the brain , in children and adolescents with ADHD . We analyzed three single nucleotide polymorphisms ( SNPs ) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children .  Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test . Preferential transmissions were detected for the two SNPs in TPH2 's regulatory region ( rs4570625 , P=0.049 ; rs11178997 , P=0.034 ) , but not for the third SNP in intron 2 ( rs4565946 , P=0.3517 ) . Haplotype analysis revealed a strong trend of association between the regulatory region SNPs ( rs4570625 , rs11178997 ) and ADHD ( P=0.064 ) . Our results link potentially functional TPH2 variations to the pathophysiology of ADHD , and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes Anorexia nervosa ( AN ) is a life-threatening and difficult to treat mental illness with the highest mortality rates of any psychiatric disorder . We aim ed to garner preliminary data on the real-world use of olanzapine and aripiprazole as augmentation agents of Selective Serotonin Reuptake Inhibitors ( SSRIs ) in adult in patients affected by AN . We retrospectively evaluated the clinical charts of patients who were hospitalized between 2012 and 2014 . Patients were evaluated upon admission and discharge . We investigated eating symptomatology , and both general and eating psychopathology using : Hamilton Rating Scale for Anxiety , Hamilton Rating Scale for Depression , and Yale-Brown-Cornell Eating Disorders Scale .  The charts of 75 patients were included in this study . The sample result ed equally distributed among those receiving SSRIs and either aripiprazole or olanzapine in addition to SSRIs . Notwithst and ing a few baseline clinical differences , upon discharge all groups were significantly improved on all measures . Interestingly , aripiprazole showed the greatest effectiveness in reducing eating-related preoccupations and rituals with a large effect size . The body of evidence on medication management in AN is in dismal condition . Augmentation therapy is a well-established approach to a variety of mental disorders and it is often used in every-day clinical practice with patients affected by AN as well . Nevertheless , to date very little data is available on this topic . Results from our sample yielded promising results on the effectiveness of aripiprazole augmentation in reducing eating-related obsessions and compulsions . R and omized controlled trials are warranted to confirm these encouraging findings Background : The aim of this prospect i ve study was to gain a more comprehensive picture of the biopsychosocial effects of  interferon-α ( IFN-α ) treatment of patients with chronic hepatitis C ( HCV ) . The predictors of depressive development and changes in health-related quality of life , life satisfaction and cognitive ability were measured with the inclusion of the social context . Furthermore , the effects of IFN-α treatment on indoleamine 2,3-dioxygenase , the level of tryptophan supply in the brain , the development of neurotoxic kynurenine metabolites and the thyroid gl and s were investigated . Therefore , for the first time the conditions for the development of depressive episodes in HCV patients treated with IFN-α  were examined over the entire period of treatment as well as 3 months later , applying a holistic biopsychosocial model . Method : Psychiatric and biological assessment s were carried out at 6 different times : before , during ( at 1 , 3 , 6 and 9 months ) and after the end of IFN-α treatment . Results : During IFN-α treatment 22 ( 53.7 % ) of 41 patients fulfilled the criteria for a treatment-related depressive disorder at least once during treatment . Contributing factors are tryptophan depletion ( tryptophan to competing amino acids quotient ) , increased neurotoxic challenge ( kynurenine to kynurenic acid quotient ) , less social support , female gender , preexisting psychiatric vulnerability , means of transmission , low financial security , impaired sexual satisfaction , small circle of friends , impaired physical role , strong body pain , low general health and vitality , reduced social functioning , impaired mental health and impaired emotional role . Conclusions : The awareness of relevant risk factors of IFN-α treatment-induced depression is essential to develop preventative treatment strategies Brain catecholamines can be rapidly reduced by inhibiting their synthesis with alpha-methyl-para-tyrosine ( AMPT ) . In order to assess the role of catecholamines in antidepressant action  AMPT challenges were administered in a double-blind , placebo-controlled , crossover fashion to 14 depressed patients having maintained a therapeutic antidepressant response for > or = 2 weeks ( 3 desipramine , 2 mazindol , 5 fluoxetine , 4 sertraline ) . Each patient participated in two challenges one week apart . Each challenge included a baseline , two days of either AMPT or diphenhydramine ( active placebo ) , and a followup . Antidepressant drugs were continued throughout testing . The 3 desipramine- and 2 mazindol-responders had a rapid increase in depression score during AMPT but not placebo ( diphenhydramine ) challenge whereas only 1 of 9 selective serotonin reuptake inhibitor (SSRI)-treated patients did . The implication of this is that the antidepressant response to desipramine may be more acutely dependent on brain catecholamine content than the response to SSRIs . In the context of our previous work with tryptophan depletion , these results suggest that the neurobiological mechanisms underlying the antidepressant responses to different drugs involve alterations in the functioning of different neurotransmitter systems and reinforce the importance of changes in both the serotonin and catecholamine systems for successful antidepressant responses
Graphical abstract Excessive dieting‐induced nutritional deficiency of tryptophan : Effects on behavior and efficacy of antipsychotic and antidepressant medication .
& NA ; A growing body of evidence suggests that our diet is an important contributing factor in the development , management and prevention of a number of psychiatric illnesses .
Tryptophan , an essential amino acid , is the sole precursor of neurotransmitter 5‐hydroxytryptamine ( 5‐HT ; serotonin ) .
Administration of tryptophan can boost serotonin neurotransmission to produce therapeutically important effects in serotonin deficiency disorders .
Anorexia nervosa ( AN ) an eating disorder associated with high levels of psychiatric comorbidity including psychosis , hyperactivity , depression and anxiety has highest lethality of all psychiatric illnesses .
Evidence suggests that excessive dieting and food restriction can decrease brain tryptophan and serotonin in AN patients to precipitate depression , psychosis and hyperactivity .
There are currently no FDA approved pharmacological treatments available for AN patients ; antidepressants and antipsychotics , largely used to treat associated psychiatric comorbidities are also not very effective .
The aim of this non‐ systematic review article is to evaluate and document a potential importance of tryptophan supplementation in improving therapeutics in AN patients .