Tryptophan depletion does not lower brain GABA levels in healthy volunteers.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
P J Cowen
Publications and source records attributed to P J Cowen.
The effects of a branched chain amino acid mixture supplemented with tryptophan on biochemical indices of neurotransmitter function and decision-making.
RATIONALE: We have previously shown that a 60-g mixture of branched chain amino acids (BCAAs) lowers the plasma availability of the catecholamine precursors tyrosine (TYR) and phenylalanine (PHE) and produces biochemical and neuropsychological changes consistent with impaired dopamine neurotransmission. However, the BCAA mixture also lowers the ratio of tryptophan (TRP) to BCAA which could impair brain serotonin function. OBJECTIVES: To determine the biochemical and neuropsychological effects of a BCAA mixture supplemented with TRP. METHODS: We studied 32 healthy volunteers who were randomly and blindly allocated to either a single administration of amino acid mixture (60 g BCAA and 2 g TRP) or placebo. We carried out venous sampling to measure plasma levels of amino acids and performed selected cognitive tasks sensitive to monoamine manipulation 5 h after mixture ingestion. RESULTS: Relative to placebo, the BCAA/TRP mixture substantially lowered the ratio of TYR+PHE:BCAA and increased plasma prolactin. The ratio of TRP:BCAA was also lowered but to a lesser extent. The BCAA/TRP mixture produced significant changes in a task of decision-making where volunteers showed reduced discrimination between gambles with large and small losses. CONCLUSIONS: A 62 g BCAA/TRP mixture decreases the availability of TYR and PHE for brain catecholamine synthesis and increases plasma prolactin consistent with lowered brain dopamine function. Addition of 2 g TRP to the 60 g BCAA mixture does not prevent a reduction of the ratio TRP:BCAA relative to placebo. The effects of the BCAA/TRP mixture on decision-making suggest a general action of dopamine pathways on the processing of emotional information in risky choice, including punishment-related cues, consistent with suggestions that dopamine mechanisms mediate behavioural responses to aversive as well as appetitive stimuli in instrumental conditioning.
Adult↗
Tyrosine depletion does not cause depressive relapse in antidepressant-treated patients.
Explore the source record for details and available documents.
Adult↗
Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635.
Positron emission tomography (PET) studies with the selective 5-HT(1A) receptor ligand, [(11)C]WAY-100635, have indicated that the binding potential (BP) of brain 5-HT(1A) receptors is lowered in unmedicated subjects with acute major depression. However, it is unclear if these changes persist after recovery from depression. To resolve this issue, we used [(11)C]WAY-100635 in conjunction with PET imaging to compare 5-HT(1A) BP in 18 healthy controls and 14 male subjects with recurrent major depression who were clinically recovered and free of antidepressant medication. BP values, derived from a reference tissue model, were analysed by region of interest and statistical parametric mapping. Both analyses showed a widespread and substantial (17%) decrease in 5-HT(1A) receptor BP in cortical areas in the recovered depressed subjects. In contrast, 5-HT(1A) BP in the raphe nuclei did not distinguish depressed subjects from controls. Our results suggest a persistent dysfunction in cortical 5-HT(1A) BP as measured by [(11)C]WAY-100635 in recovered depressed men. Lowered 5-HT(1A) receptor binding availability could represent a trait abnormality that confers vulnerability to recurrent major depression.
Antidepressive Agents↗
Acute administration of nutritionally sourced tryptophan increases fear recognition.
RATIONALE: The serotonin precursor tryptophan (TRP) has been widely used as a nutritional supplement and antidepressant. Recently, however, the use of TRP has been severely restricted due to its association with the eosinophilic myalgic syndrome, an autoimmune disorder probably caused by ingestion of a contaminant produced in certain TRP manufacturing processes. OBJECTIVES: To determine the bioavailability of a nutritional source of TRP obtained from milk protein and to assess whether administration of this material produced neuroendocrine and neuropsychological effects consistent with increased brain serotonin activity. METHODS: We studied 24 healthy subjects who ingested approximately 1.8 g of nutritionally-sourced TRP or placebo in a double-blind, parallel group, design. We carried out venous sampling for amino acid and hormone estimation and performed a test of emotional processing using a facial expression recognition task. RESULTS: The nutritionally-sourced TRP caused a substantial increase in the availability of TRP in plasma. Relative to placebo the TRP material produced some evidence of an increase in plasma cortisol, and enhanced the perception of fearful and happy facial expressions. CONCLUSIONS: A nutritional source of TRP increased the availability of TRP for brain serotonin synthesis and produced endocrine and neuropsychological changes consistent with increased brain serotonin function. The effect of TRP on emotional processing may be relevant to its reported activity in primate studies of social behaviour.
Adult↗
Tryptophan depletion decreases the recognition of fear in female volunteers.
RATIONALE: Serotonergic processes have been implicated in the modulation of fear conditioning in humans, postulated to occur at the level of the amygdala. The processing of other fear-relevant cues, such as facial expressions, has also been associated with amygdala function, but an effect of serotonin depletion on these processes has not been assessed. OBJECTIVE: The present study investigated the effects of reducing serotonin function, using acute tryptophan depletion, on the recognition of basic facial expressions of emotions in healthy male and female volunteers. METHODS: A double-blind between-groups design was used, with volunteers being randomly allocated to receive an amino acid drink specifically lacking tryptophan or a control mixture containing a balanced mixture of these amino acids. Participants were given a facial expression recognition task 5 h after drink administration. This task featured examples of six basic emotions (fear, anger, disgust, surprise, sadness and happiness) that had been morphed between each full emotion and neutral in 10% steps. As a control, volunteers were given a famous face classification task matched in terms of response selection and difficulty level. RESULTS: Tryptophan depletion significantly impaired the recognition of fearful facial expressions in female, but not male, volunteers. This was specific since recognition of other basic emotions was comparable in the two groups. There was also no effect of tryptophan depletion on the classification of famous faces or on subjective state ratings of mood or anxiety. CONCLUSIONS: These results confirm a role for serotonin in the processing of fear related cues, and in line with previous findings also suggest greater effects of tryptophan depletion in female volunteers. Although acute tryptophan depletion does not typically affect mood in healthy subjects, the present results suggest that subtle changes in the processing of emotional material may occur with this manipulation of serotonin function.
Adult↗
Contrasting effects of citalopram and reboxetine on waking salivary cortisol.
RATIONALE: Acute administration of antidepressants which potentiate serotonin (5-HT) and noradrenaline (NA) function stimulates the hypothalamic-pituitary-adrenal (HPA) axis and increases salivary free cortisol in healthy subjects. The effects of repeated antidepressant administration have been less studied, but the ability of such treatment to modulate HPA axis activity may be relevant to therapeutic effects. OBJECTIVE: The objective of the study was to assess the effect of short-term treatment with two different antidepressant medications on HPA axis activity. METHODS: We studied the effect of 6-day treatment with the selective serotonin re-uptake inhibitor (SSRI) citalopram (20 mg daily) and the selective noradrenaline re-uptake inhibitor, reboxetine (8 mg daily), on diurnal salivary cortisol in a parallel group, placebo-controlled, double-blind design. RESULTS: Citalopram significantly enhanced the increase in salivary cortisol produced by waking, while the effect of reboxetine treatment was indistinguishable from placebo. There was no change in basal salivary cortisol levels sampled in a standard pattern throughout the day. CONCLUSIONS: Short-term treatment with citalopram and reboxetine produced strikingly different effects on waking salivary cortisol, arguing against a common effect of antidepressant drugs on HPA axis function. Waking salivary cortisol may be a more reliable means of assessing the effects of antidepressant treatment on the HPA axis than a standard regime of basal salivary sampling.
Adrenergic Uptake Inhibitors↗
The effect of a nutritional source of tryptophan on dieting-induced changes in brain 5-HT function.
BACKGROUND: Dieting in healthy women results in a decrease in the availability of tryptophan (TRP), the amino-acid precursor of serotonin (5-HT), for brain 5-HT synthesis. This is associated with increases in the prolactin response to 5-HT drug challenge suggesting a 'supersensitivity' of 5-HT neuroendocrine responses. The aim of the study was to assess whether increased TRP intake during dieting would prevent the changes in TRP availability and 5-HT neuroendocrine function. METHOD: Fifty female subjects underwent a 1000 kcal daily diet for 3 weeks. In the final week of the diet subjects were randomly allocated to receive either nutritionally-sourced TRP (1.8 g daily) or placebo in a double-blind, parallel group, design. RESULTS: TRP supplementation failed to modify the dieting-induced reduction in fasting TRP availability to the brain. However, in contrast to placebo-treated subjects, subjects receiving additional TRP did not show enhanced prolactin responses to intravenous TRP challenge. CONCLUSIONS: The decrease in TRP availability produced by dieting may be due to increased TRP metabolism rather than decreased TRP intake. While TRP treatment did not increase fasting TRP availability it may have modified the effect of dieting on brain 5-HT function. Further studies will be needed to see if this effect of TRP has consequences for the effectiveness of dieting as means of weight control.
Administration, Oral↗
Acute SSRI administration affects the processing of social cues in healthy volunteers.
Enhancement of serotonin neurotransmission plays an important role in the antidepressant response to agents presently available to treat depression. This response forms the major evidence for the role of serotonin in affective and social behaviour in humans. The present study investigated the effects of acute administration of the selective serotonin reuptake inhibitor (SSR1), citalopram (10 mg, i.v.) upon a measure of emotional processing in healthy female volunteers. Subjects completed a facial expression recognition task following infusion of citalopram or saline (between-subjects design, double-blind). Facial expressions associated with five basic emotions--happiness, sadness, fearfulness, anger and disgust--were displayed. Each face had been 'morphed' between neutral (0%) and each emotional standard (100%) in 10% steps, leading to a range of emotional intensities. Mood and subjective experience were also monitored throughout the testing session. Volunteers receiving citalopram detected a higher number of facial expressions of fear and happiness, with reduced response times, relative to those given the placebo. By contrast, changes in the recognition of other basic emotions were not observed following citalopram. Notable differences in mood were also not apparent in these volunteers. These results suggest that acute administration of antidepressant drugs may affect neural processes involved in the processing of social information. This effect may represent an early acute effect of SSRIs on social and emotional processing that is relevant to their therapeutic actions.
Adult↗
Acute reboxetine administration increases plasma and salivary cortisol.
We investigated the effect of a single oral dose of the selective noradrenaline reuptake inhibitor, reboxetine (4 mg), on plasma and salivary cortisol in 24 healthy volunteers in a randomized, placebo-controlled, parallel-group design. Reboxetine significantly increased both plasma and salivary cortisol, although the correlation between the responses in plasma and saliva was modest. Our results are consistent with previous neuroendocrine challenge studies showing that potentiation of brain noradrenaline function stimulates the hypothalamic-pituitary-adrenal axis. Reboxetine-induced salivary cortisol release appears to be a simple and relatively non-invasive test of hypothalamic noradrenaline function. However, placebo-controlled, within-subject designs are likely to yield a more valid measure of noradrenaline-mediated cortisol release.
Administration, Oral↗
Effects of a branched-chain amino acid drink in mania.
BACKGROUND: Administration of a complex tyrosine-free amino acid drink acutely decreases manic symptoms. Although a nutrient-based approach to illness management is attractive, complex amino acid drinks are too unpalatable for repeated administration. AIMS: To assess whether a simple, branched-chain amino acid (BCAA) drink diminishes manic symptoms acutely and following repeated administration. METHOD: Twenty-five patients with mania were randomly and blindly allocated to treatment with BCAA (60 g) or placebo daily for 7 days. RESULTS: Relative to placebo, the BCAA drink lowered mania ratings acutely over the first 6 h of treatment. In protocol completers there was a persistent advantage to the BCAA group 1 week after the end of treatment. CONCLUSIONS: A nutritional intervention that decreases tyrosine availability to the brain acutely ameliorates manic symptoms. Further studies are required to assess whether this approach has longer-term efficacy.
Adult↗
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.
Adult↗
Acute citalopram administration produces correlated increases in plasma and salivary cortisol.
RATIONALE: Intravenous administration of the selective serotonin (5-HT) re-uptake inhibitor, citalopram, increases plasma cortisol. This would be expected to produce a parallel increase in salivary cortisol concentration. OBJECTIVE: To find out whether IV citalopram produces correlated increases in plasma and salivary cortisol levels. METHODS: Twelve healthy volunteers were tested on two occasions receiving either citalopram (10 mg IV) or saline in a double-blind, randomised, cross-over design. Plasma and salivary cortisol levels were measured before and for 150 min after each infusion. RESULTS: Relative to placebo, citalopram significantly increased cortisol levels in both plasma and saliva. The size of the increases in plasma and saliva cortisol correlated significantly with each other. CONCLUSIONS: Monitoring changes in salivary cortisol might be a valid and acceptable means of measuring 5-HT-mediated cortisol release.
Adult↗
Cortisol modulation of 5-HT-mediated growth hormone release in recovered depressed patients.
BACKGROUND: Recent formulations of the pathophysiology of major depression suggest that stress-induced cortisol secretion may lower brain serotonin (5-HT) function, thereby precipitating depressive symptomatology. This implies that people who develop depression after stressful life events may be particularly vulnerable to the effect of cortisol on brain 5-HT activity. We therefore assessed the effect of a single dose of hydrocortisone on 5-HT-mediated growth hormone (GH) release in healthy volunteers and euthymic subjects recovered from at least two episodes of major depression. METHODS: Eleven recovered depressed patients and 20 healthy controls received intravenous tryptophan (TRP) 10.5 h after placebo and hydrocortisone (50 mg orally) in a double-blind, cross-over design. Plasma GH levels were sampled for 90 min after TRP infusion. RESULTS: The GH response to TRP was significantly lower in the recovered depressed patients than controls after hydrocortisone. LIMITATIONS: The number of recovered depressed subjects studied was small and the effect of hydrocortisone on TRP-induced GH release was different to that observed in a previous study. CONCLUSIONS: These findings are consistent with other evidence suggesting abnormal regulation of 5-HT neurotransmission in people vulnerable to recurrent depression.
Adult↗
Mood, eating behaviour and attention.
BACKGROUND: Obesity is a growing health problem, but most people find dieting unsuccessful. Three studies examine possible reasons for the difficulty and the extent to which dieting-related reductions in cognitive function are associated with mood and well-being. METHOD: In Study One, 49 female dieters were compared with a control group of 31 matched non-dieters on measures of well-being, mood, eating behaviour (Dutch Eating Behaviour Questionnaire), and attention. Study Two examined two measures of restraint to examine why previous studies find high restrainers are prone to react to emotion. Study Three experimentally manipulated mood using music and the standard Velten Induction Procedure to examine attention in restrainers and emotional eaters. RESULTS: Dieting was found to be associated with deficits in sustained attention. This finding was further supported by the demonstration of a significant impairment in performance following a negative mood induction in high emotional eaters whereas high restrainers were relatively unaffected by the mood challenge. CONCLUSIONS: We suggest that different aspects of eating behaviour have dissociable effects on cognitive-affective function. Trait tendencies to restrained eating are associated with attentional deficits, but are not further affected by mood disruption. It is the long-term tendency to eat when emotional that combines with current emotional state to trigger cognitive deficits.
Adult↗
Cortisol, serotonin and depression: all stressed out?
Explore the source record for details and available documents.
Depressive Disorder↗
Cerebellar responses during anticipation of noxious stimuli in subjects recovered from depression. Functional magnetic resonance imaging study.
BACKGROUND: Subjects recovered from depression have a substantial risk for recurrence of depression, suggesting persistent abnormalities in brain activity. AIMS: To test whether women recovered from depression show abnormal brain activity in functional magnetic resonance imaging (fMRI) during a conditioning paradigm with a noxious pain stimulus. METHOD: Ten unmedicated women who had recovered from major depression and eight healthy control women each received either noxious hot or non-noxious warm stimuli, the onset of which was signalled by a specific coloured light during 3-tesla echo planar imaging-based fMRI. RESULTS: Similar patterns of brain activation were found during painful stimulation for both patients and healthy controls. However, relative to healthy controls, subjects recovered from depression showed a reduced response in the cerebellum during anticipation of the noxious stimulus compared with anticipation of the non-noxious stimulus. CONCLUSIONS: Our data suggest that abnormal cerebellar function could be a marker of vulnerability to recurrent depression. This could provide a new target for therapeutic interventions.
Adult↗