Electrocortical effects of acute tryptophan depletion on emotive facial processing in depression-prone individuals

This study assessed the effects of acute tryptophan depletion (ATD), which transiently lowers CNS 5-HT, on electrocortical responses to facial expression processing in individuals with a family history of depression (FH+). Electroencephalograph (EEG)-derived event-related potentials (ERPs) were acquired from 18 FH+ individuals during a facial expression recognition task (neutral and sad, joy and surprise at 50% and 100% intensities). Both early positive (P1 and P2) and the face-specific N170 ERP components were differentially altered by emotional intensity and valence. Increased depression, confusion and total mood disturbance scores, and decreased calmness, were observed with ATD (versus placebo). ATD was also associated with enhanced P1 and P2 amplitudes for sad versus joyful expressions. The N170 was not modulated by treatment, but was affected by emotive valence. Therefore, ATD enhanced ERP-indexed early processing of sad facial expressions, and altered the processing of positive ones, in FH+ individuals.     

The effect of acute tryptophan depletion on the neural correlates of emotional processing in healthy volunteers.

The processing of affective material is known to be modulated by serotonin (5-HT), but few studies have used neurophysiological measures to characterize the effect of changes in 5-HT on neural responses to emotional stimuli. We used functional magnetic resonance imaging to investigate the effect of acute tryptophan depletion, which reduces central 5-HT synthesis, on neural responses to emotionally valenced verbal stimuli. Though no participants experienced significant mood change, emotional information processing was substantially modified following 5-HT depletion. A behavioral bias toward positive stimuli was attenuated following depletion, which was accompanied by increased hemodynamic responses during the processing of emotional words in several subcortical structures. Inter-individual differences in tryptophan depletion-elicited anxiety correlated positively with the caudate bias toward negative stimuli. These data suggest that 5-HT may play an important role in mediating automatic negative attentional biases in major depression, as well as resilience against negative distracting stimuli in never-depressed individuals.     

Impaired recognition of fear facial expressions in 5-HTTLPR S-polymorphism carriers following tryptophan depletion

RATIONALE: Genotype at the 5' promoter region (5-HTTLPR) of the serotonin transporter has been implicated in moderating the effects of acute tryptophan depletion on neurocognitive functioning. Acute tryptophan depletion has been associated with the processing of fear-relevant cues, such as emotional expressions, but the effect of genotype at the 5-HTTLPR has not been assessed. OBJECTIVE: The present study investigated the effects of acute tryptophan depletion on the recognition of standardized facial expressions of emotions in healthy volunteers classified as ll homozygotes or s carriers. MATERIALS AND METHODS: A double-blind between-groups design was used with volunteers randomly selected to ingest capsules containing an amino acid mixture specifically lacking tryptophan, or placebo capsules containing lactose. 5 h after capsule ingestion, subjects were required to identify anger, disgust, fear, happiness, sadness, and surprise expressions that progressed from neutral to each full emotional expression in 5% steps. RESULTS: Tryptophan depletion significantly impaired the recognition of fearful facial expressions in s carriers but not ll homozygotes. This impairment was specific to fear expressions. No significant differences in the recognition of other expressions were found. Free tryptophan levels were correlated with fear recognition in s carriers but not ll homozygotes. CONCLUSIONS: The effects of acute tryptophan depletion on the processing of emotional expressions varies as a function of genotype at the 5-HTTLPR. Depletion impairs the recognition of fear in s carriers but not ll homozygotes. This finding reinforces the importance of considering genotype when assessing the behavioral effects of pharmacologic modulation.     

Selective processing of social threat cues following acute tryptophan depletion

The aim of the present study was to investigate the effects of low dose tryptophan depletion on recovered depressed patients both on and off antidepressant medication on an emotional Stroop task using social threat cues.Twenty-four healthy volunteers, 24 euthymic volunteers with a history of depression not currently on antidepressant medication and 24 euthymic volunteers with a history of depression and currently on antidepressant medication were randomly allocated to double-blind treatment with either a tryptophan depleting or a balanced mixture. All participants then completed subjective mood ratings and an emotional Stroop task using social threat cues.The recovered depressed group on medication demonstrated an increase in selective processing of social threat cues on the emotional Stroop task in the tryptophan depletion compared to the control condition. This was not the case for either healthy controls or the recovered depressed group not on medication. Although none of the patients showed a clinically significant relapse following tryptophan depletion, the medicated group showed a small but statistically significant increase in self-rated depression on the Profile of Mood States (POMS).Our data indicate that low-dose acute tryptophan depletion elicits both cognitive processing typical of the depressed state and subtle changes in subjective mood in the recovered depressed group on medication, but not in the recovered depressed group not on medication. This suggests that these two groups may differ in their underlying vulnerability to compromised serotonin function.     

Effects of acute tryptophan depletion on mood and facial emotion perception related brain activation and performance in healthy women with and without a family history of depression.

The present study examined the effects of acute tryptophan (Trp) depletion (ATD), a well-recognized method to lower central serotonin (5-HT) metabolism, on brain activation during a facial emotion perception task. Brain activation was measured using fMRI, and healthy female volunteers with a positive family history of unipolar depression (FH+) were compared to healthy female volunteers without such a history (FH-). Participants viewed two morphed faces and were instructed to choose between the faces based either on the intensity of the emotional expression (direct task) or the gender of the face (incidental task). In the FH+ group, depletion led to the expected lowering of mood, which partly determined the effect of depletion on performance and brain activation. A stronger mood lowering effect was associated with less accurate performance on faces expressing a negative emotion in the incidental task and a stronger right amygdala response to fearful faces in comparison to happy faces. These results were explained in terms of a mood-induced bias leading to a stronger impact of the expressed negative emotion which subsequently leads to more interference in the incidental task and a stronger amygdala response. It was concluded that the effects of ATD on mood, performance, and brain activation in a facial emotion perception task depend on family history of depression. Performance and brain activation partly depend on the effect of ATD on mood.     

The recognition of facial emotion expressions in Parkinson's disease

A limited number of studies in Parkinson's Disease (PD) suggest a disturbance of recognition of facial emotion expressions. In particular, disgust recognition impairment has been reported in unmedicated and medicated PD patients. However, the results are rather inconclusive in the definition of the degree and the selectivity of emotion recognition impairment, and an associated impairment of almost all basic facial emotions in PD is also described. Few studies have investigated the relationship with neuropsychiatric and neuropsychological symptoms with mainly negative results. This inconsistency may be due to many different problems, such as emotion assessment, perception deficit, cognitive impairment, behavioral symptoms, illness severity and antiparkinsonian therapy. Here we review the clinical characteristics and neural structures involved in the recognition of specific facial emotion expressions, and the plausible role of dopamine transmission and dopamine replacement therapy in these processes. It is clear that future studies should be directed to clarify all these issues.     

Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink

Acute tryptophan depletion (ATD) can be used to decrease serotonin levels in the brain. Traditionally, ATD has been established by administering amino acid (AA) mixtures and studies using this method showed that serotonin is involved in learning and memory processes. This study used a recently developed gelatin-based protein drink to examine whether it 1) is superior to the traditional AA method in controlling the tryptophan levels in the placebo condition, 2) impairs long-term memory and 3) differentially affects episodic and spatial memory. Sixteen healthy subjects participated in a double-blind, placebo-controlled study. Memory was assessed using a visual verbal learning test and an object relocation task (spatial memory). Tryptophan ratio significantly decreased after ATD and did not significantly increase in the placebo condition. Delayed recall in the verbal learning test and delayed relocation of objects to positions in the spatial task were impaired after ATD. Spatial short-term memory, however, improved. The current results indicate that the tryptophan levels were essentially neutral in the placebo condition compared with those in the traditional AA mixture. Our study provides further evidence that impairment in long-term episodic and elementary spatial memory after ATD is related to lowered tryptophan levels in plasma.     

Effects of tryptophan depletion on acute smoking abstinence symptoms and the acute smoking response

Given the putative role of serotonin in the modulation of smoking withdrawal and the central actions of nicotine, this study examined the affective and neuroelectric correlates of smoking abstinence and cigarette smoking following depletion of the serotonin precursor, tryptophan. In a randomized, double-blind two session (tryptophan depletion [TD] vs. nondepletion), placebo-controlled design, spectrally analyzed electroencephalogram (EEG), self-ratings of withdrawal symptoms and mood states were assessed in 18 male cigarette smokers before smoking abstinence, 5 h postsmoking abstinence and again following sham smoking and the smoking of one cigarette. Compared to a nutritionally balanced amino acid (AA) mixture containing tryptophan (i.e., placebo mixture), oral ingestion of a similar mixture devoid of tryptophan resulted in a 70% reduction of plasma tryptophan but failed to alter the appearance or reversal (by acute cigarette smoking) of withdrawal symptoms, negative mood states and increased slow wave EEG in male smokers deprived of cigarettes. These results, although not supporting a role for the serotonergic system in acute smoking and early smoking abstinence symptoms, are discussed in relation to the neuropharmacology of smoking behavior and suggestions for future work.     

Effects of acute tryptophan depletion on cognitive function in euthymic bipolar patients.

Decreasing brain 5-HT levels by acute tryptophan depletion has been shown to selectively impair cognition in healthy volunteers. In bipolar disorder, ATD causes measurable neurophysiological effects without altering mood. The purpose of this study was to examine the effects of ATD on neuropsychological performance in 14 euthymic bipolar patients. Cognitive function was evaluated 4-6 h after ingestion of a control or depleting amino-acid drink. Plasma tryptophan levels fell significantly following the depleting drink, however there were no main effects on the ID/ED set-shift task, Paired Associates Learning or Vigil. A trend towards a decrease in the proportion of perfect solutions on the Tower of London task was observed when depleted. While ATD reduces 5-HT levels in the brain, it does not appear to alter neuropsychological performance on tests of sustained attention or associative learning. Effects on specific 'executive' functions are less clear, and should be the focus for future research.     

Modulation of neural response to happy and sad faces by acute tryptophan depletion

Background Central serotonin (5HT) plays a major role in emotional processing. We used functional neuroimaging (fMRI) to investigate the effects of experimental manipulation of central 5HT levels on the regional neural response to happy and sad facial expressions. Methods Ten healthy participants (eight men and two women) were scanned during an implicit emotional processing task after receiving a tryptophan-free (acute tryptophan depletion, ATD) or a balanced amino acid drink in a double-blind design. Results ATD lowered total plasma tryptophan concentration by 80%. There was no significant effect on subjective mood ratings, on response accuracy and on reaction times. Compared to sham depletion, ATD attenuated activation in the right medial/inferior frontal gyrus, the posterior cingulate cortex, the occipital and parietal cortex bilaterally, the right hippocampus, claustrum and insula. Conversely, ATD was associated with relatively increased activation in the left inferior frontal gyrus. ATD had differential effects on activation during the processing of happy and sad faces in the right putamen and in the left superior temporal gyrus. Conclusions In both cortical and sub-cortical regions, the neural response associated with processing emotional faces is significantly modulated by 5HT manipulation resulting from ATD. Moreover, in certain areas, this effect of 5HT depends on the emotional valence of the stimulus.     

Effect of acute tryptophan depletion on pre-frontal engagement

Background Serotonin is known to modulate cognitive functioning and has been implicated in the cognitive deficits associated with affective disorders. The present study examined regional brain activation during two tasks that are known to engage the pre-frontal cortex and are performed poorly by patients with depression and bipolar disorder. We tested the hypothesis that acute tryptophan depletion (ATD) would attenuate pre-frontal activation during both tasks.Materials and methods Ten healthy right-handed volunteers were studied using functional MRI whilst performing a 2-back verbal working memory task and a phonological verbal fluency task. Subjects were studied in two separate sessions, after either a tryptophan-free or a balanced amino acid drink, in a double-blind design. Task performance and mood were measured online.Results Relative to sham depletion, ATD attenuated activation in the right superior frontal gyrus during the 2-back task and in the medial frontal gyrus and precuneus during the verbal fluency task. ATD lowered total plasma tryptophan by 79% but had no significant effect on either task performance or mood.Conclusions The engagement of pre-frontal cortex during verbal working memory and verbal fluency tasks is significantly modulated by central serotonergic activity. The different location of these modulatory effects within the frontal cortex may reflect the engagement of distinct cognitive processes by the respective tasks.     

Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers

Rationale Disorders associated with low levels of serotonin (5-HT) are characterized by mood and cognitive disturbances. Acute tryptophan depletion (ATD) is an established method for lowering 5-HT levels and an important tool to study the effects of reduced 5-HT on mood and cognition in human subjects. The traditional ATD method, i.e., administration of separate amino acids (AAs), has several disadvantages. The AA mixture is costly, unpalatable and associated with gastrointestinal discomfort.Objectives The University of Maastricht developed a new and inexpensive method for ATD: a natural collagen protein (CP) mixture with low tryptophan (TRP) content. The reductions in plasma TRP after taking this CP mixture were compared with the reductions achieved taking the traditional AA mixture, and effects on memory and reversal learning were studied.Methods Fifteen healthy young volunteers participated in a double-blind, counterbalanced within-subject study. Reversal learning, verbal memory and pattern recognition were assessed at baseline and 3–4 h after taking the CP mixture.Results The new ATD method significantly reduced plasma TRP by 74% and the ratio between TRP and the other large AAs (TRP/LNAA) by 82%. The placebo mixture did not change these measures. Delayed recognition reaction time on the verbal learning task was increased following ATD. No other cognitive effects were found.Conclusions The CP mixture was shown to be an efficient tool for lowering plasma TRP in humans. The validity of this method with regard to behavioral changes remains to be established in healthy, vulnerable and clinical populations.This article was originally published under the DOI 10.1007/s00213-004-1933-4. Unfortunately an unrelated paper appeared in print and in the PDF version online. For this reason, all versions of the correct article are now published here under the new DOI, 10.1007/s00213-004-2141-y.     

Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers

Rationale Disorders associated with low levels of serotonin (5-HT) are characterized by mood and cognitive disturbances. Acute tryptophan depletion (ATD) is an established method for lowering 5-HT levels and an important tool to study the effects of reduced 5-HT on mood and cognition in human subjects. The traditional ATD method, i.e., administration of separate amino acids (AAs), has several disadvantages. The AA mixture is costly, unpalatable and associated with gastrointestinal discomfort.Objectives The University of Maastricht developed a new and inexpensive method for ATD: a natural collagen protein (CP) mixture with low tryptophan (TRP) content. The reductions in plasma TRP after taking this CP mixture were compared with the reductions achieved taking the traditional AA mixture, and effects on memory and reversal learning were studied.Methods Fifteen healthy young volunteers participated in a double-blind, counterbalanced within-subject study. Reversal learning, verbal memory and pattern recognition were assessed at baseline and 3–4 h after taking the CP mixture.Results The new ATD method significantly reduced plasma TRP by 74% and the ratio between TRP and the other large AAs (TRP/LNAA) by 82%. The placebo mixture did not change these measures. Delayed recognition reaction time on the verbal learning task was increased following ATD. No other cognitive effects were found.Conclusions The CP mixture was shown to be an efficient tool for lowering plasma TRP in humans. The validity of this method with regard to behavioral changes remains to be established in healthy, vulnerable and clinical populations.Errata to this article can be found at and at An updated version of this article can be found at     

Effects of acute tryptophan depletion on affective processing in first-degree relatives of depressive patients and controls after exposure to uncontrollable stress

RATIONALE: Individuals with a family history of depression may be more likely to develop depression due to an innate vulnerability of their serotonergic system. However, even though serotonergic vulnerability may constitute a risk factor in the development of depression, it does not seem to be sufficient to cause a depressive episode. Based on previous data, it is suggested that stress may be a mediating factor. OBJECTIVES: This study examined the role of serotonin (5-HT) in stress coping in individuals with or without a family history of depression. MATERIALS AND METHODS: Nineteen healthy first-degree relatives of depressive patients (FH+) and 19 healthy controls without a family history of depression (FH-) were tested in a double-blind placebo-controlled design for affective processing under acute stress exposure, following acute tryptophan depletion (ATD) or placebo. RESULTS: Significant negative effects were found of stress on affective processing in FH- and FH+. In addition, FH- responded slower to positive words after stress only following ATD, whereas FH+ responded marginally slower under stress already after placebo and before stress following ATD. CONCLUSION: Acute stress exposure reduces positive affective bias; supporting the role of stress as an important predecessor in the development of depression. Furthermore, FH+ may be more susceptible than FH- to the negative effects of stress as well as to the negative effects of ATD. The results support the assumption that the 5-HT system is involved in stress resilience and may be more vulnerable in first-degree relatives of depression.     

The effects of acute tryptophan depletion and serotonin transporter polymorphism on emotional processing in memory and attention

Polymorphism at the serotonin transporter linked polymorphic region (5-HTTLPR) has been associated with neuroticism, increased risk for affective disorders and greater vulnerability to mood change following serotonin (5-HT) depletion. The aim of the present study was to investigate whether the cognitive effects of 5-HT depletion were differentially affected by genotype at the 5-HTTLPR polymorphism, using neuropsychological measures of memory and attention. We utilized the acute tryptophan depletion (ATD) technique to temporarily reduce 5-HT synthesis in two groups of healthy volunteers pre-selected on the basis of 5-HTTLPR genotype, 15 of the ll genotype and 15 of the ss genotype, in a double-blind, placebo-controlled crossover design. As expected, ATD resulted in a robust reduction in plasma tryptophan concentration in both genotype groups. However, the genotype groups differed in terms of the effect of ATD on cognitive performance. The ss genotype group showed impaired verbal recall following depletion, while episodic memory was unimpaired by ATD in the ll genotype group. Averaging across depletion condition, the ss genotype group outperformed the ll genotype group on tests of episodic memory and attention. Neither group was significantly affected by ATD on measures of emotional state. These data confirm previous reports that ss individuals are particularly vulnerable to 5-HT depletion, but extend these findings to the cognitive domain. The unexpected finding that ss volunteers showed improved memory and attention relative to ll volunteers suggests a possible evolutionary advantage to possession of the s allele, which may offset the disadvantage of vulnerability to depression following stressful life events.     

The effects of acute tryptophan depletion on neuropsychological function

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 resulting 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 elucidate the factors determining vulnerability to the effects of serotonergic dysfunction.     

The effect of acute tryptophan depletion on probabilistic choice

Choice behaviour can be viewed as a response to reinforcement determined by an interaction between the quantities, delays and probabilities of two outcomes. The variation in the perceived value of a reinforcer with alteration of these factors (discounting) can be modelled mathematically by hyperbolic discounting functions. Making risky choices is a feature of impulsivity and has been associated with reduced serotonin (5-hydroxytryptamine, 5-HT) function. In this study, we investigated the possible role of 5-HT in modulating probability discounting using the technique of acute tryptophan (TRP) depletion in subjects undertaking an imaginary gambling task. The gambling task consisted of choosing between two 'roulette-like' dials: 'A' which provided a smaller but nearly certain 'win' and 'B' which gave a 'win' 2.5 times the amount with a probability that was systematically varied. A series of reward sizes on dial 'A' was presented ranging from 10 pence to 10,000 pounds. The probability of winning on dial 'B' at which the subjects valued the two dials equally (indifference point) was determined as a measure of willingness to take a risk. Subjects were more likely to take a risk for smaller rewards but the indifference points in the 15 subjects who received TRP depletion did not differ from 13 who had the control drink. On a surprise retesting 1 week later there was a trend (p < 0.07) for subjects to be more willing to take risks the second time, particularly in the case of small rewards. This study does not support a role for 5-HT in modulating probabilistic choice in agreement with recent evidence from experiments with animals; however, the imaginal nature of the task and modest numbers may have influenced the result.     

Acute tryptophan depletion blocks morphine analgesia in the cold-pressor test in humans

The effects of depletion of the serotonin precursor,l-tryptophan, on the threshold and tolerance to cold pressor pain, and the analgesic effect of morphine (10 mg intramuscularly), were tested in a double blind trial on human volunteers. Effects on mood were also assessed using the Profile of Mood States and the Addiction Research Center Inventory (ARCI) Scales. To deplete tryptophan, subjects were fed a tryptophan-deficient amino acid mixture 4.5 h before morphine was administered. Controls received the mixture with tryptophan, which is equivalent to a nutritionally balanced protein. The tryptophan-deficient meal reduced plasma tryptophan more than 70% but had no effect on threshold or tolerance to cold pressor pain. After morphine, tolerance to cold pressor pain increased in controls. Tryptophan depletion abolished this analgesic effect. Pain threshold was not altered by morphine. In subjects with normal tryptophan, the analgesic effect of morphine was predicted by the level of plasma morphine-6-glucuronide, but not by the level of morphine. Morphine increased scores on the LSD scale of the ARCI, but had no effect on other measures of mood. Tryptophan depletion also failed to alter mood in these subjects, who had unusually low depression scores before tryptophan depletion.     

Emotional processing as a predictor of symptom change: An acute tryptophan depletion study in depressed patients

Acute tryptophan depletion (ATD) in currently depressed patients has no immediate effect on symptoms, but leads to transient symptom improvement or worsening the next day. In view of recent findings concerning the cognitive effects of serotonin manipulations, we used ATD in fourteen depressed patients to investigate whether cognitive effects following ATD predict symptom changes. We found that symptom improvement 24 h after ATD was associated with an improved recall of positive words and with less attentional bias and recall of negative words, 5 h after ATD. These results indicate that serotonergic alterations affect emotional processing which may subsequently lead to symptom changes.     

The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers

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.