Effects of acute tryptophan depletion on memory,attention and executive functions: A systematic review

The serotonergic system is implicated in the regulation of mood and cognition. Acute tryptophan depletion (ATD) is an experimental procedure for lowering central serotonin levels. Here, the effects of ATD on psychomotor processing, declarative memory, working memory, executive functions and attention are discussed. The most robust finding is that ATD impairs the consolidation of episodic memory for verbal information. Semantic memory appears to be unaffected by ATD although a limited variety of tasks examined effects in this domain. Similarly, evidence suggests ATD does not influence verbal, spatial and affective working memory. Most studies investigating effects on executive functions have produced non-specific or negative findings. In terms of attention, ATD either does not affect or may improve focused attention and ATD likely does not impact sustained and divided attention or attentional set-shifting. Although ATD is known to affect mood in certain vulnerable populations, the effects of ATD on cognition in non-vulnerable participants are independent of mood changes. Suggestions for future directions and implications for psychiatric illnesses are discussed.     

Acute tryptophan loading decreases functional connectivity between the default mode network and emotion‐related brain regions

It has been shown that the functional architecture of the default mode network (DMN) can be affected by serotonergic challenges and these effects may provide insights on the neurobiological bases of depressive symptomatology. To deepen our understanding of this possible interplay, we used a double‐blind, randomized, cross‐over design, with a control condition and two interventions to decrease (tryptophan depletion) and increase (tryptophan loading) brain serotonin synthesis. Resting‐state fMRI from 85 healthy subjects was acquired for all conditions 3 hr after the ingestion of an amino acid mixture containing different amounts of tryptophan, the dietary precursor of serotonin. The DMN was derived for each participant and session. Permutation testing was performed to detect connectivity changes within the DMN as well as between the DMN and other brain regions elicited by the interventions. We found that tryptophan loading increased tryptophan plasma levels and decreased DMN connectivity with visual cortices and several brain regions involved in emotion and affect regulation (i.e., putamen, subcallosal cortex, thalamus, and frontal cortex). Tryptophan depletion significantly reduced tryptophan levels but did not affect brain connectivity. Subjective ratings of mood, anxiety, sleepiness, and impulsive choice were not strongly affected by any intervention. Our data indicate that connectivity between the DMN and emotion‐related brain regions might be modulated by changes in the serotonergic system. These results suggest that functional changes in the brain associated with different brain serotonin levels may be relevant to understand the neural bases of depressive symptoms.     

Investigating the effects of estradiol or estradiol/progesterone treatment on mood, depressive symptoms, menopausal symptoms and subjective sleep quality in older healthy hysterectomized women: a questionnaire study

Clinical studies have documented that estrogen treatment often ameliorates mood disturbances and depressive symptoms occurring during the menopausal transition. The relevance of gonadal hormones for mood and well-being in healthy older nondepressed women is less well understood. Fifty-one healthy hysterectomized women (mean age 64) participated in a placebo-controlled double-blind study on the effects of gonadal hormones on cognition. They received either estradiol (2 mg estradiol valerate), estradiol plus progesterone (100 mg micronized progesterone) or placebo. Mood, well being, menopausal symptoms, depressive symptoms and subjective sleep quality were measured at baseline and after 4 and 24 weeks of treatment using three questionnaires. Thirty-five women could be included into the final analysis. Strong increases in estradiol and progesterone levels occurred in response to the treatment. The two hormones, however, had no effects on mood, well-being, menopausal symptoms, sleep quality and depressive symptoms. The current small study suggests that older healthy nondepressed hysterectomized women do not react with positive or negative mood changes to estradiol or estradiol/progesterone treatment.     

Tamoxifen fails to affect central serotonergic tone but increases indices of anxiety in female rhesus macaques

The selective estrogen receptor modulator (SERM), tamoxifen, effectively slows the progression of estrogen-positive breast cancer and aids in the prevention of cancer in at-risk women. Tamoxifen is well characterized with regards to its effects on breast cancer, but its effects on other estrogen-related systems, particularly neural circuits regulating brain function and mood, are poorly understood. Using ovariectomized rhesus monkeys, we examined the effects of tamoxifen, with and without estrogen replacement therapy (ERT), on social behavior and central serotonin (5HT) systems thought to influence these behaviors. Relative to placebo treatments, estrogen treatment increased serotonergic tone, based on response in prolactin and cortisol to fenfluramine, a 5HT releasing agent. Tamoxifen neither blocked nor enhanced this effect, indicating it to be neither an antagonist nor an agonist on serotonergic activity. In contrast, CSF measures of the 5HT metabolite, 5HIAA, were not significantly affected by treatment. Tamoxifen-treated animals showed increases in measures of anxiety, compared with ERT-treated animals, suggesting that this SERM may be anxiogenic. Co-treatment with estrogen attenuated the anxiogenic properties of tamoxifen. These data show that tamoxifen administration increased anxiety levels, but the affect was not associated with differences in central levels of the serotonin tone.     

Increase in prefrontal cortex serotonin 2A receptors following estrogen treatment in postmenopausal women

OBJECTIVE: This study investigated the effect of estrogen on brain serotonin 2A (5-HT(2A)) receptors in postmenopausal women and whether there was any correlation of receptor changes with cognition and mood. METHOD: Ten postmenopausal subjects underwent positron emission tomography measurements of 5-HT(2A) receptor binding with [(18)F]deuteroaltanserin before and after estrogen replacement therapy. RESULTS: 5-HT(2A) receptor binding was significantly increased after estrogen replacement therapy in the right prefrontal cortex (right precentral gyrus [Brodmann's area 9], inferior frontal gyrus [Brodmann's area 47], medial frontal gyrus [Brodmann's area 6, 10] and the anterior cingulate cortex [Brodmann's area 32]). In the inferior frontal gyrus [Brodmann's area 44]), receptor up-regulation was correlated with change in plasma estradiol. Verbal fluency and Trail Making Test performance, but not mood, were significantly improved by estrogen without correlation with receptor changes. CONCLUSIONS: Estrogen increases 5-HT(2A) receptor binding in human prefrontal regions.     

Tryptophan depletion as a clinical tool: Current status and future directions

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays important roles in many basic functions: mood, feeding, anxiety, sleep, emesis, sexual function, thermoregulation, and cardiovascular tone. Over the past 10 years, tryptophan depletion (TD) studies of 5-HT function have emerged as an important clinical tool for studying brain serotonergic systems, and their relevance to practising psychiatrists has grown steadily. In this review, we discuss the evolution of TD studies and their continuing utility in understanding the role of 5-HT in psychiatric disorders and the development of more effective treatments.     

Prefrontal cortex as the site of estrogen's effect on cognition

The hippocampus has long been presumed the primary site of action of estrogens on cognition; and explicit memory is considered the cognitive function most vulnerable to menopausal loss of estrogen. We hypothesize instead that the prefrontal cortex and its neural circuitry are prime mediators of estrogen's role in cognition. We also propose that previously reported menopausal cognitive decline, presumed to be hippocampally mediated, may be secondary to executive dysfunction. We used a cross sectional design to compare the performance of nine menopausal women on hormone replacement therapy (HRT) and 10 menopausal women with no prior exposure to HRT on a battery of neuropsychological tests. The battery was comprised primarily of tests of memory and executive functioning. Executive functioning is mediated by the frontal lobes and encompasses working memory, directed attention, the inhibition of inappropriate responses, cognitive set switching, and behavioral monitoring. Unlike most previous studies, we used a memory measure that yields multiple scores reflecting various problem-solving strategies and error types, thus isolating spared and impaired cognitive processes. Results yielded both qualitative and quantitative evidence for disruption of cognitive processes subserved by the frontal lobes rather than the hippocampus: 1) despite intact free recall on a list-learning task (CVLT), untreated menopausal women were relatively impaired in correctly recognizing words previously learned and distinguishing them from items not on the list (discriminability), 2) untreated women also had difficulty inhibiting inappropriate responses in the form of perseverative errors, and 3) the non-HRT group consistently performed worse on the N-back test of working memory. The prefrontal cortex is critical for intact working memory and estrogen enhances performance on working memory tasks. In conclusion, this study provides preliminary evidence for executive dysfunction in untreated menopausal women as women with HRT outperformed women without HRT on tests requiring directed attention, inhibition of inappropriate responses, and cognitive set switching.     

Aging, estradiol and time of day differentially affect serotonin transporter binding in the central nervous system of female rats

Estrogen-related changes in serotonergic neuronal transmission, including changes in the number of serotonin transporter (SERT) binding sites, have been cited as a possible cause for changes in mood, memory and sleep that occur during the menopausal transition. However, both aging and estradiol regulate SERT binding sites in the brain. The goal of this experiment was to determine how aging and estrogen interact to regulate SERT levels in the forebrain of young and reproductively senescent female Sprague–Dawley rats using [³H]paroxetine. The density of specific [³H]paroxetine binding in various brain regions was compared in young (2–4 months) and reproductively senescent (10–12 months) female rats at three times of day. In most brain regions examined, estrogen and aging independently increased the number of [³H]paroxetine binding sites. The only region that displayed a reduction in [³H]paroxetine binding with age was the suprachiasmatic nucleus (SCN). Time of day influenced [³H]paroxetine binding in the SCN and the paraventricular thalamus (PVT), two regions known to be involved in the regulation of circadian rhythms. Aging and/or estrogen also altered the pattern of binding in these regions. Thus, based on the results of this study, we conclude that aging and estrogen both act to regulate SERT binding sites in the forebrain of female rats, and that this regulation is region specific.     

Acute tryptophan depletion promotes an anterior‐to‐posterior fMRI activation shift during task switching in older adults

Studies have long reported that aging is associated with declines in several functions modulated by the prefrontal cortex, including executive functions like working memory, set shifting, and inhibitory control. The neurochemical basis to this is poorly understood, but may include the serotonergic system. We investigated the modulatory effect of serotonin using acute tryptophan depletion (ATD) during a cognitive switching task involving visual‐spatial set shifting modified for a functional MRI environment. Ten healthy women over 55 years were tested on two separate occasions in this within‐group double‐blind sham‐controlled crossover study to compare behavioral and physiological brain functioning following ATD and following a (“placebo”) sham depletion condition. ATD did not significantly affect task performance. It did modulate brain functional recruitment. During sham depletion women significantly activated the expected task‐relevant brain regions associated with the Switch task including prefrontal and anterior cingulate cortices. In contrast, following ATD participants activated posterior regions of brain more during switch than repeat trials. In addition to the main effects of depletion condition, a comparison of the ATD relative to the sham condition confirmed this anterior‐to‐posterior shift in activation. The posterior (increased) activation clusters significantly and negatively correlated with the reduced prefrontal activation clusters suggesting a compensation mechanism for reduced prefrontal activation during ATD. Thus, serotonin modulates an anterior‐to‐posterior shift of activation during cognitive switching in older adults. Neural adaptation to serotonin challenge during cognitive control may prove useful in determining cognitive vulnerability in older adults with a predisposition for serontonergic down‐regulation (e.g., in vascular or late life depression). Hum Brain Mapp 35:712–722, 2014. © 2012 Wiley Periodicals, Inc.     

Two weeks of transdermal estradiol treatment in postmenopausal elderly women and its effect on memory and mood: verbal memory changes are associated with the treatment induced estradiol levels.

The present randomized double blind study investigated the effects of a 2 week transdermal estradiol treatment on memory performance in 38 healthy elderly women. Cognitive performance was tested at baseline and after 2 weeks of estradiol or placebo treatment using verbal, semantic, and spatial memory tests as well as a mental rotation task and the Stroop. Initial results showed no differences after treatment between placebo or estradiol treated subjects. However, within treatment group analysis revealed that estradiol treated subjects who reached higher estradiol levels (larger than 29 pg/ml) performed significantly better after treatment in the delayed recall of the paired associate test (verbal memory) than subjects who reached lower estradiol levels (P < 0.05). A nonsignificant trend was observed for the immediate recall condition (P < 0.10). These findings were strengthened by correlations between treatment-induced estradiol levels and changes in verbal memory performance. In addition, there was an association between estradiol levels and mood changes. However mood changes were not significantly associated with changes in verbal memory performance (P > 0.20). The present study supports the idea that estradiol replacement has specific effects on verbal memory in healthy postmenopausal women, with delayed recall being more affected. It suggests that these effects can occur relatively rapidly, and that there may be a dose response relationship of estradiol to memory enhancement. Furthermore, the fact that these results were obtained in women who had been menopausal for an average of 17 years before entering the study indicates that the brain maintains a sensitivity for estrogens even after years of low estradiol plasma concentrations.     

Effects of hypothalamic serotonin depletion on lordosis behavior and gonadal hormone receptors

The effects of chronic depletion of serotonin on feminine sexual behavior (lordosis), cytosolic progestin receptors and estradiol nuclear receptors were investigated. Intrahypothalamic administration of 5,7-dihydroxytryptamine (5,7-DHT) markedly enhanced lordotic responding in estradiol benzoate (EB)-primed, 5,7-DHT-treated female rats and in EB-progesterone primed, 5,7-DHT-treated male rats. Cytosolic progestin receptors were measured in preoptic-hypothalamic nuclei related to reproductive function in sham and 5,7-DHT-treated rats after EB priming. In both sexes, no differences between sham and 5,7-DHT-treated subjects were noted for progestin binding in the medial preoptic nucleus, ventromedial nucleus or arcuate-median eminence area. Estrogen-nuclear complexes were measured in the same brain nuclei of female rats following EB priming, and no differences between sham and 5,7-DHT-treated rats were found. Under the conditions employed, it would appear that, despite marked elevations in lordotic responsivity, the accumulation of estrogen nuclear receptors and the levels of estrogen inducible progestin receptors remain unaltered after chronic depletion of serotonin. Thus, serotonergic influences on lordosis do not appear to involve changes in the expression of steroid receptor levels in preoptic-hypothalamic nuclei known to mediate hormone-dependent neuroendocrine processes.     

Pharmacogenetics,pharmacogenomics and personalized psychiatry: Are we there yet?

Previous studies suggest an important role for serotonergic (5-HT) modulation of the acoustic startle reflex (ASR) and prepulse inhibition (PPI). Acute challenge of brain serotonin by means of tryptophan depletion test (TDT) represents an established human challenge tool for temporary reduction of tryptophan (-TRP) levels and central nervous serotonin. Under these experimental conditions, PPI was found attenuated in males, but greater biochemical effects of TDT in the central nervous system of females are known. Therefore, in order to explore influence of 5-HT on various standard startle parameters in females, 16 young healthy females participated in a double-blind, cross-over TDT study. Acoustic stimuli were presented in 15 pulse-alone trials (100 dB, 40 ms) randomly followed by 25 pulse-alone or prepulse (70 dB, 30 ms; 120 ms interval) trials alongside electromyographic eyeblink recordings and mood state assessments. During 81% depletion of free plasma TRP, mean ASR magnitudes were significantly reduced compared to control (+TRP) condition while there were no differences in habituation or PPI nor did startle parameters correlate with mood states. Changes of plasma TRP and mood states correlated in tendency negatively in (-TRP) for depression and positively in (+TRP) for fatigue. In conclusion, this first study of startle parameters after TDT in a homogenous female population demonstrates that depletion of brain 5-HT in women only influences ASR.     

Cerebral dysfunctions of emotion-cognition interactions in adolescent-onset schizophrenia

ObjectiveSchizophrenia is among the most severe of psychiatric disorders, leading to impairments of affective and cognitive abilities. These dysfunctions affect each other mutually. Adolescent-onset schizophrenia (AOS) constitutes a particularly severe form of the disorder. In this study, possible dysfunctions of the neural correlates underlying the interaction of negative emotion and working memory in AOS were investigated.MethodDuring functional magnetic resonance imaging, 12 patients with AOS and 12 non-AOS adolescents performed a verbal n-back task. Intermittently, negative and neutral emotions were induced by olfactory stimulation. Group differences in working memory, emotion, and their interaction were evaluated.ResultsIn patients with AOS, lower performance sensitivity was observed, along with dorsolateral prefrontal, anterior cingulate, and inferior parietal hypoactivation during working memory demands. For negative versus neutral emotion induction, patients with AOS mainly showed increased brain activation compared with control subjects in widespread brain regions including the left orbitofrontal cortex and the medial frontal gyrus. Finally, during the interaction of emotion and cognition, altered patterns of activation in patients with AOS were found in the thalamocortical network, including the angular and the middle cingulate gyri extending to the precuneus. These activation differences were further decomposed by parameter estimates.ConclusionsOur results provide new insights into the neural correlates underlying the mutual influence of affective and cognitive symptoms in AOS. During the n-back task, areas typically associated with working memory performance were found hypoactivated in patients relative to the control subjects, including the dorsolateral prefrontal and parietal cortex and the anterior cingulate. However, patients with AOS mainly demonstrated increased activation in key areas of emotion processing, such as the left orbitofrontal cortex and medial frontal areas, during negative emotion induction. A dysfunctional thalamocortical network during the interaction mainly included regions involved in the integration of converging information—either on the subcortical (thalamus) or on a higher-order cortical level (comprising the angular gyrus). These findings point to dysfunctional emotion-cognition interactions in AOS, which may explain its poor prognosis. J. Am. Acad. Child Adolesc. Psychiatry, 2008;47(11): 1299–1310.     

Tryptophan,mood, and cognitive function

In separate experiments we investigated the duration of the effects of acute tryptophan depletion (ATD) on mood and cognition. The results showed that ATD's effects consist of lowering of mood only in subjects with a family history of unipolar depression. A specific impairment of memory consolidation was seen in all subjects. In subjects without any vulnerability for mood disorders, performance on so-called 'frontal tasks,' measuring higher attentional functions tended to improve after ATD. The effects of ATD on mood and cognition were manifest as long as biochemical indices of low tryptophan remained low. In conclusion, ATD is a model for impairment of memory, next to being a model of mood disorders in vulnerable subjects. Moreover, ATD could be used as a challenge to demonstrate individual vulnerability of the serotonergic system.     

Memory, mood, dopamine, and serotonin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse serves as a model of basal ganglia injury and Parkinson's disease. The present study investigated the effects of MPTP-induced lesioning on associative memory, conditioned fear, and affective behavior. Male C57BL/6 mice were administered saline or MPTP and separate groups were evaluated at either 7 or 30 days post-lesioning. In the social transmission of food preference test, mice showed a significant decrease in preference for familiar food 30 days post-MPTP compared to controls. Mice at both 7 and 30 days post-MPTP lesioning had increased fear extinction compared to controls. High Performance Liquid Chromatography analysis of tissues homogenates showed dopamine and serotonin were depleted in the striatum, frontal cortex, and amygdala. No changes in anxiety or depression were detected by the tail suspension, sucrose preference, light-dark preference, or hole-board tests. In conclusion, acute MPTP lesioning regimen in mice causes impairments in associative memory and conditioned fear, no mood changes, and depletion of dopamine and serotonin throughout the brain.     

The effect of acute tryptophan depletion on emotional distraction and subsequent memory

Serotonin is a key neurotransmitter involved in emotional regulation and memory. A number of studies using acute tryptophan depletion (ATD) in healthy subjects have shown that a temporary serotonin reduction both induces a negative emotional bias and impairs long-term memory. However, little is known about the specific effects of ATD on emotional memory. Using functional magnetic resonance imaging (fMRI), we investigated the effect of ATD on negative memory and executive function in healthy volunteers. Our emotional oddball task required participants to distinguish infrequently presented targets from distracting negative and neutral pictures. Memory for the distracting pictures was tested 1 h following the fMRI session. ATD selectively enhanced memory for negative distractors relative to neutral distractors and increased activation in response to the negative distractors in the left orbital-inferior frontal, dorsomedial prefrontal and bilateral angular gyri. ATD also induced greater activation in the left inferior frontal gyrus and anterior cingulate across all stimuli. Stronger frontal activation to distractors was positively correlated with memory performance on ATD but not control days, indicating a possible compensatory mechanism for coping with increased task demand under the ATD challenge. These findings highlight the importance of serotonin in negative memory with implications for mood disorders.     

Effects of experimental acute tryptophan depletion on acoustic startle response in females

Previous studies suggest an important role for serotonergic (5-HT) modulation of the acoustic startle reflex (ASR) and prepulse inhibition (PPI). Acute challenge of brain serotonin by means of tryptophan depletion test (TDT) represents an established human challenge tool for temporary reduction of tryptophan (−TRP) levels and central nervous serotonin. Under these experimental conditions, PPI was found attenuated in males, but greater biochemical effects of TDT in the central nervous system of females are known. Therefore, in order to explore influence of 5-HT on various standard startle parameters in females, 16 young healthy females participated in a double-blind, cross-over TDT study. Acoustic stimuli were presented in 15 pulse-alone trials (100 dB, 40 ms) randomly followed by 25 pulse-alone or prepulse (70 dB, 30 ms; 120 ms interval) trials alongside electromyographic eyeblink recordings and mood state assessments. During 81% depletion of free plasma TRP, mean ASR magnitudes were significantly reduced compared to control (+TRP) condition while there were no differences in habituation or PPI nor did startle parameters correlate with mood states. Changes of plasma TRP and mood states correlated in tendency negatively in (−TRP) for depression and positively in (+TRP) for fatigue. In conclusion, this first study of startle parameters after TDT in a homogenous female population demonstrates that depletion of brain 5-HT in women only influences ASR.     

Brain activation during working memory 1 month after mild traumatic brain injury: a functional MRI study.

OBJECTIVE: To assess patterns of regional brain activation in response to varying working memory loads shortly after mild traumatic brain injury (MTBI). BACKGROUND: Many individuals complain of memory difficulty shortly after MTBI. Memory performance in these individuals can be normal despite these complaints. METHODS: Brain activation patterns in response to a working memory task (auditory n-back) were assessed with functional MRI in 12 MTBI patients within 1 month of their injury and in 11 healthy control subjects. RESULTS: Brain activation patterns differed between MTBI patients and control subjects in response to increasing working memory processing loads. Maximum intensity projections of statistical parametric maps in control subjects showed bifrontal and biparietal activation in response to a low processing load, with little additional increase in activation associated with the high load task. MTBI patients showed some activation during the low processing load task but significantly increased activation during the high load condition, particularly in the right parietal and right dorsolateral frontal regions. Task performance did not differ significantly between groups. CONCLUSION: MTBI patients differed from control subjects in activation pattern of working memory circuitry in response to different processing loads, despite similar task performance. This suggests that injury-related changes in ability to activate or to modulate working memory processing resources may underlie some of the memory complaints after MTBI.     

Challenging the serotonergic system in Parkinson disease patients: effects on cognition, mood, and motor performance

BACKGROUND: Parkinson disease (PD) is a neuropsychiatric disease that is characterized by motor and neuropsychiatric symptoms. Multiple neurotransmitter systems, including the serotonergic system, are involved in the pathophysiology of this disease. The exact role of the serotonergic system in PD is still unclear. OBJECTIVE: To investigate the role of serotonin on specific aspects of cognition, mood, and motor performance in PD. METHODS: In a double-blind, randomized, placebo-controlled, crossover design, the effects of a nonspecific serotonergic challenge with citalopram, a selective serotonin reuptake inhibitor, and a 5-HT1a receptor-specific challenge with buspirone on the Visual Verbal Learning Task, Concept Shifting Task, Profile of Mood State Questionnaire, motor section of the Unified Parkinson Disease Rating Scale (section 3), Simple Reaction Time Task, and Finger Precuing Task were studied in 21 PD patients in early stages of their disease and 21 age-, sex-, and education-matched healthy volunteers. RESULTS: The serotonergic challenges resulted in similar effects for both groups. No changes of scores on the cognitive tasks (Visual Verbal Learning Task and Concept Shifting Task) were observed. Results of the Profile of Moods State Questionnaire indicated that, at baseline, PD patients scored less than controls on all 5 subscales. Motor performance (measured by reaction time) was negatively affected by the interventions. CONCLUSIONS: The effects of nonspecific and 5-HT1a receptor-specific challenging of the serotonergic neurotransmitter system had similar effects in both PD patients and healthy control subjects. These findings indicate that serotonergic function is not impaired in early PD and that serotonin, although involved in the pathophysiology of PD, does not seem to play a direct role in cognition, mood, and motor performance in PD patients, but may be involved in hypokinesia.     

Mood changes following acute tryptophan depletion in healthy adults

A decrease in central serotonergic activity following plasma tryptophan depletion has been shown to provoke a deterioration of mood. We studied the impact of sex and aggressive traits on mood changes following tryptophan depletion in healthy volunteers. Twelve healthy subjects (6 males, 6 females, 24-31 years), who were screened for psychiatric and non-psychiatric medical illness, were administered a tryptophan-depleting amino acid mixture (TD) and a placebo mixture on two different occasions in a double-blind crossover design. Psychometric measures included the preliminary determination of aggressive traits and depression and repeated assessments of mood and emotionality. The tryptophan-free amino acid mixture caused a marked depletion of plasma tryptophan with lowest levels occurring between 3 and 5 h after TD. Maximum changes in mood occurred about 10 h after TD, but only in high-aggressive women who scored significantly higher in arousal, anger and depressed mood, whereas low-aggressive women and men did not show any effect of TD. In addition, we could not confirm an increase in aggressive mood (anger) after TD in males with higher scores of trait aggression, presumably because the level of trait aggression was not high enough in this group. Due to the small sample size, our results that tryptophan depletion exerts a rapid mood-lowering effect on healthy women with pre-existing aggressive traits can only be seen as preliminary and have to be confirmed in further studies with larger samples.