Effects of acute tryptophan depletion on mood in bulimia nervosa.

BACKGROUND: The present study investigated the role of serotonin in the pathophysiology of bulimia nervosa (BN) by studying the affective and appetitive responses of women ill with BN to an acute tryptophan depletion (ATD) paradigm. METHODS: Twenty-two women with BN and 16 healthy control women (CW) were studied on 2 separate days during the follicular stage of the menstrual cycle. Participants drank a control mix of essential amino acids (100 g + 4.6 g tryptophan) on one day and a tryptophan deficient (100 g - 4.6 g tryptophan) mixture (ATD) on the other in a double-blind fashion. Mood/appetite ratings and blood samples were taken at baseline and at intervals up to 420 minutes. Participants were then presented with an array of foods and were allowed to binge and vomit if they desired. RESULTS: CW and BN women had a similar and significant reduction in plasma tryptophan levels and the tryptophan: LNAA ratio after ATD. After ATD, the BN women had a significantly greater increase in peak (minus baseline) depression, mood lability, sadness and desire to binge compared to the CW. BN subjects and CW had similar peak changes in mood after the control amino acid mixture. BN subjects and CW consumed similar amounts of food after the two amino acid treatments. CONCLUSIONS: Women with BN seem more vulnerable to the mood lowering effects of ATD, suggesting they have altered modulation of central 5-HT neuronal systems.     

The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects.

BACKGROUND: Efforts to model putative serotonergic deficits associated with affective disorders have frequently involved acute tryptophan depletion (ATD) as a manipulation strategy aimed at lowering brain serotonin synthesis. In an attempt to widen the scope of the measurement probes used in these investigations, the central actions of ATD and a subsequent dose of fenfluramine were examined via utilization of quantitative electroencephalography (EEG) and mood ratings. METHODS: Electroencephalograms (EEG) and subjective mood ratings were assessed in 28 healthy men before and after double-blind ingestion of a tryptophan-depleting (T-) amino acid mixture, or a nutritionally balanced (B) amino acid mixture containing tryptophan, and again after a single-blind oral dose of D,L-fenfluramine hydrochloride (60 mg). RESULTS: Compared to the B mixture, the T- mixture reduced total plasma tryptophan by more than 75% 5 hours after ingestion. Tryptophan depletion was associated with a modest lowering of mood and a slowing of EEG as indicated by increases in delta amplitude. Fenfluramine caused no change in mood but increased fast wave (beta) activity in anterior recordings when administered after the T-, but not after the B mixture. CONCLUSIONS: Quantitative EEG measurements may be a promising method for studying the central mechanisms underlying serotonin-mediated changes in mood and behavior.     

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.     

Impact of acute tryptophan depletion on mood and eating-related urges in bulimic and nonbulimic women

Background

Previous research has shown that many people experience a temporary worsening of mood following acute tryptophan depletion (ATD) and that concurrent use of serotonergic medications may influence such mood responses. We investigated mood and other consequences of ATD in women with bulimia nervosa who were or were not using concurrent serotonergic medications compared with women without bulimia.

Methods

Women self-referred for treatment of bulimia who were either not currently using psychoactive medications (n = 26) or who were using serotonin reuptake inhibitor medications exclusively (n = 13), as well as medication-free normal-eater control women (n = 25) completed interviews and questionnaires assessing eating and comorbid psychopathology and then participated in an ATD procedure involving balanced and tryptophan-depleted conditions.

Results

In the tryptophan-depleted condition, the groups displayed similar and significant decrements in plasma tryptophan levels and mood. Women with bulimia who were using serotonin reuptake inhibitors, but not the other groups, also reported an increased urge to binge eat in the tryptophan-depleted condition.

Limitations

Application of medication in participants with bulimia was not random.

Conclusion

Acute reductions in serotonin availability produced similar mood-reducing effects in bulimic and nonbulimic women. To the extent that ATD affected subjective experiences pertinent to eating (i.e., urge to binge eat), such effects appeared to depend upon ATD-induced competition with the therapeutic effects of serotonergic medications.     

Effects of acute tryptophan depletion on executive function in healthy male volunteers

Background  

Neurocognitive impairment is frequently described in a number of psychiatric disorders and may be a direct consequence of serotonergic dysfunction. As impairments in executive functions are some of the most frequently described, the purpose of this study was to examine the performance of normal volunteers on a range of executive tasks following a transient reduction of central serotonin (5-HT) levels using the method of acute tryptophan depletion (ATD).     

Effects of acute tryptophan depletion on mood and cognitive functioning in older recovered depressed subjects.

OBJECTIVE: Previous studies show that acute tryptophan depletion (ATD), by administration of an amino acid drink lacking tryptophan, can produce clinically significant depressive symptoms in subjects who have recovered from major depression. This is more likely in female patients who have had suicidal ideation, recurrent depression, and treatment with specific serotonin reuptake inhibitors. These risk factors are frequent in older recovered depressed people. The authors investigated the effects of ATD on mood and cognitive functioning in this group. METHODS: Sixteen recovered depressed (RD) subjects and 17 healthy-comparison subjects, over 60 years old, participated in a double-blind, placebo-controlled, crossover study involving administration of a tryptophan-depleting and a placebo drink. Mood ratings scales were administered at baseline and at 4 and 7 hours post-drink on each test day. A battery of neuropsychological tests, including the modified Mini-Mental State Examination (MMSE) was administered between 4 and 6 hours post-drink. RESULTS: Depletion of plasma free tryptophan was 71% at 4 and 7 hours after the active drink. There was no evidence of mood change at any time in either group. On the MMSE, however, the ATD/RD group showed a significant decrease compared with placebo. CONCLUSIONS: There was no evidence of mood disturbance during ATD in any subject. This may imply less sensitivity to acute disturbance of the 5HT system than in younger recovered patients.     

Interactive effects of sex and 5-HTTLPR on mood and impulsivity during tryptophan depletion in healthy people.

BACKGROUND: Serotonin (5-HT) plays a central role in mood regulation and impulsivity. We studied whether healthy men and women react differently on mood and impulsivity measures during acute tryptophan depletion (ATD). We also studied the relative contribution of a functional length triallelic polymorphism in the promoter region of the serotonin transporter, designated 5-HTTLPR, to the behavioral responses to ATD. METHODS: Thirty-nine men and 44 women participated in a randomized, double-blind, parallel group ATD study. Behavioral measures of impulsivity and mood were obtained. RESULTS: During ATD, women reported mood reduction and showed a cautious response style, which is commonly associated with depression. Men showed an impulsive response style and did not report mood reduction. The 5-HTTLPR influenced the mood response to ATD in women. CONCLUSIONS: Healthy men became more impulsive, whereas healthy women showed mood reduction in response to ATD. This suggests that 5-HT could be one mechanism contributing to the sex differences in the prevalence of mood and impulsivity disorders. The influence of 5-HTTLPR on mood responses in women further substantiates the relevance of this variant in the pathophysiology of at least a subgroup of patients with major depressive disorder.     

No effects of acute tryptophan depletion on anxiety or mood in weight-recovered female patients with anorexia nervosa

European Archives of Psychiatry and Clinical Neuroscience - Previous studies have suggested that individuals recovered from anorexia nervosa (AN) are characterized by increased serotonergic (5-HT)...     

Neuropsychological performance and mood states following acute interferon-beta-1b administration in healthy males

Interferon-beta-1b (IFN-beta-1b) has been shown to reduce the relapse rate in patients with relapsing-remitting multiple sclerosis (MS) and disease progression in patients with secondary progressive MS. While acute administration of IFN-beta-1b is known to cause flu-like symptoms, chronic medication has been suggested to cause mood alterations and anxiety attacks, and secondary to this neuropsychological deficits that may impair daily life. It is unknown, however, whether the latter symptoms are induced by acute IFN-beta-1b administration. Therefore, we examined the impact of a single subcutaneous injection of IFN-beta-1b in 8 healthy males. In a crossover design, each subject was injected subcutaneously with either 8 million IU IFN-beta-1b or placebo (NaCl) at 8:00 h. Flu-like symptoms (body temperature, heart rate, blood pressure), mood status ['profile of mood states', Befindlichkeitsskala (BFS)] and neuropsychological performance (trail marking test, verbal memory test, d2 attention test) and were assessed at baseline, 4, 8 and 24 h after injection. IFN-beta-1b increased body temperature, heart rate and fatigue. Nevertheless, acute IFN-beta-1b injection did not impair any parameters of neuropsychological performance. Thus, although IFN-beta-1b produces physiological symptoms indicative of sickness behavior, these data suggest that IFN-beta-1b administration does not have an impact on the cognitive capacity following acute administration.     

Time series fMRI measures detect changes in pontine raphé following acute tryptophan depletion

Serotonin is synthesized from its precursor, tryptophan, by brainstem raphé neurons and their synaptic terminals in limbic regions. The omission of tryptophan from an Acute Tryptophan Depletion (ATD) diet transiently diminishes serotonin synthesis, alters raphé activity, and mimics symptoms of depression. Raphé functional magnetic resonance imaging (fMRI) poses challenges using signal-averaging analyses. Time-series properties of fMRI blood oxygenation level dependent (BOLD) signals may hold promise, so we analyzed raphé signals for changes with the ATD diet. Eleven remitted (previously depressed) patients were awake with eyes-closed during seven-minute resting scans with 0.5 s⁻¹ sampling. BOLD signal time-series data were frequency-filtered using wavelet transforms, yielding three octave-width frequency bands from 0.25 to 0.03 s⁻¹ and an unbounded band below 0.03 s⁻¹. Spectral power, reflecting signal information, increased in pontine raphé at high frequencies (0.25 to 0.125 s⁻¹) during ATD (compared to control, balanced, diet, P < 0.004) but was unchanged at other frequencies. Functional connectivity, the correlation between time-series data from pairs of regions, weakened between pontine raphé and anterior thalamus at low frequencies during ATD (P < 0.05). This preliminarily supports using fMRI time-series features to assess pontine raphé function. Whether, and how, high frequency activity oscillations interfere with low frequency signaling requires further study.     

Serial reversal learning and acute tryptophan depletion

Cognitive flexibility (i.e. the ability to adapt goal-directed behaviour in response to changed environmental demands) has repeatedly been shown to depend on the prefrontal cortex (PFC). Recent data from primate studies moreover show that depletion of prefrontal 5-HT impairs reversal learning of visual stimuli [Clarke HF, Walker SC, Crofts HS, Dalley JW, Robbins TW, Roberts AC. Prefrontal serotonin depletion affects reversal learning but not attentional set shifting. J Neurosci 2005;25:532-8; Clarke HF, Walker SC, Dalley JW, Robbins TW, Roberts AC. Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific. Cereb Cortex 2007;17:18-27]. It is not clear however if 5-HT serves a general role in reversal learning or if it is involved only in specific reversal problems. A first aim of these experiments was to study the role of 5-HT in serial reversal learning of a spatial discrimination. Literature has, moreover, repeatedly shown that the PFC is involved in the initial acquisition of a reversal problem but hardly when the task is well practiced. A second aim concerns the role of 5-HT in early versus late reversal learning. With the current experiment, we aim to clarify whether 5-HT is differentially involved in early versus late reversal learning. To this end, we tested rats on a serial two-lever reversal task and induced a temporary reduction of 5-HT availability in these rats by restricting dietary intake of the 5-HT precursor tryptophan at an early and a late reversal. Our results indicate that acute tryptophan depletion (ATD) did not affect either early or late reversal learning, nor extinction and suggest that spatial reversal learning, in contrast to visual reversal learning, might not be dependent on 5-HT. The data furthermore provide insight in the behavioural strategies employed in serial reversal learning and suggests the formation of a learning-set.     

Effects of tryptophan depletion on the serotonin transporter in healthy humans.

BACKGROUND: Lowering of brain serotonin by acute tryptophan depletion (TD) frequently leads to transient symptoms of depression in vulnerable individuals but not in euthymic healthy subjects with a negative family history of depression. The effects of TD on regional serotonin transporter binding potential (5-HTT BP), an index of 5-HTT density and affinity, were studied in healthy individuals using 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile ([11C]DASB) positron emission tomography (PET). Adaptive decreases in 5-HTT density and/or affinity during TD would be a possible compensatory mechanism to maintain sufficient extracellular serotonin levels during TD, thereby preventing a depressive relapse. METHODS: Regional noninvasive 5-HTT BP was found in 25 healthy subjects using [11C]DASB PET. Fourteen subjects were scanned twice, once after TD and once after sham depletion, and 11 other healthy subjects were scanned twice to measure test-retest reliability of the method. RESULTS: None of the healthy subjects experienced depressive symptoms during TD and there was no difference in regional 5-HTT BP during TD as compared with sham depletion. CONCLUSIONS: Acute changes in 5-HTT density or affinity are unlikely to play a role in protecting healthy subjects against mood symptoms during TD. Other mechanisms that may be associated with greater resilience against acute lowering of extracellular serotonin should be explored to gain further insight into the neurochemical basis of different vulnerabilities to short-term depressive relapse.     

Symptomatic relapse in bulimia nervosa following acute tryptophan depletion

BACKGROUND: Preclinical and clinical studies suggest that lowered brain serotonin neurotransmission may contribute to the pathophysiology of bulimia nervosa (BN). The aim of our study was to test this hypothesis by examining the psychological effects of a dietary-induced impairment in serotonin activity in subjects known to be at risk for manifestation of the clinical syndrome of BN. METHODS: An 85.8 g amino acid mixture lacking the serotonin precursor tryptophan and a balanced mixture were administered to 10 clinically recovered, medication-free female subjects with a history of BN in a double-blind, crossover design. Twelve healthy female subjects with no history of psychiatric disorder were studied as a comparison group. Observer and self-rated measures of mood and eating disorder cognitions were made for the 7 hours following administration of each amino acid mixture. RESULTS: Compared with healthy controls, subjects with a history of BN had significant lowering of mood, increases in ratings of body image concern, and subjective loss of control of eating following the tryptophan-free mixture. CONCLUSIONS: Our results suggest that diminished serotonin activity may trigger some of the cognitive and mood disturbances associated with BN. Our findings support suggestions that chronic depletion of plasma tryptophan may be one of the mechanisms whereby persistent dieting can lead to the development of eating disorders in vulnerable individuals.     

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.     

Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion

This study investigated the relationship between depressive symptom response during tryptophan (TRP) depletion and a functional polymorphism of the promoter region of the serotonin (5-HT) transporter gene (SLC6A4).(1) Forty-three subjects in remission from a major depressive episode who underwent TRP depletion were genotyped. DNA was extracted from blood lymphocytes or from cheek cells.(2) The two common alleles are designated long (l) and short (s). Depressive symptoms were measured with the 25-item Hamilton Depression Rating Scale (HDRS).(3) There was a significant association between the l homozygous genotype and the depressive response to TRP depletion, with a significant main effect of time (F = 8.763, df = 3, 38, P = <0.001), and time x l homozygous allele interaction (F = 3.676, df = 3, 38, P = 0.02). Individuals whose genotype predicted increased 5-HT transporter activity may be more susceptible to depressive changes in response to transient 5-HT perturbations. The use of endophenotypic markers for affective disorders such as the mood response to TRP depletion may facilitate studies of complex genetic traits such as depression by decreasing its heterogeneity.     

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.     

Serotonergic function, substance craving, and psychopathology in detoxified alcohol-addicted males undergoing tryptophan depletion

Alcohol addiction is associated with alterations of central nervous dopaminergic and serotonergic functions. Acute tryptophan depletion has not yet been applied in detoxified alcohol-addicted patients in order to investigate its impact on psychopathology, psychoneuroendocrinology, and substance craving behaviour. 25 alcohol-addicted males randomly either received a tryptophan-free or tryptophan-containing amino acid drink and 7 days later the respective other drink. Anxiety, depression, and craving were assessed before and 5 h after the drink. Tryptophan, 5-HIAA, dopamine, norepinephrine, epinephrine, and HVA in serum were measured before and after both treatments. Nocturnal urinary cortisol measurements and genotyping for the HTTLPR polymorphism of the SLC6A4 gene were performed. Tryptophan depletion resulted in a significant reduction of total and free serum tryptophan while the tryptophan-rich drink increased serum levels. Both treatments caused a significant increase of serum serotonin levels, however, serum 5-HIAA was decreased after depletion but increased after sham depletion. Dopamine and norepinephrine were elevated after tryptophan depletion and sham. Depletion increased depression scores (MADRS), while the full amino acid drink improved state and trait anxiety ratings (STAI) and substance craving. Urinary cortisol excretion was not affected by both treatments. Patients with the ll genotype of the serotonin transporter gene displayed lower baseline tryptophan levels compared to patients with the heterozygous genotype. Results suggest an impaired serotonergic function in alcohol-addicted males.