Using an experimental medicine model to understand the antidepressant potential of the N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine.

There is growing interest in the role of the glutamatergic system both in depression and as a novel target for treatments. Preclinical studies suggested that the non-competitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine might have antidepressant properties, but a randomised controlled trial failed to support this. A healthy volunteer model of emotional processing was used to assess the neuropsychological profile of action of memantine. Healthy volunteers (n=32) were randomised to receive a single dose of memantine (10 mg) or placebo, and subsequently completed a battery of tasks measuring emotional processing, including facial expression recognition, emotional memory, dot-probe and emotion-potentiated startle tasks, as well as working and verbal memory. Memantine treated volunteers showed an increased emotion-potentiated startle, and a reduced bias for negative items in emotional recognition memory. There were no effects of the drug on any other aspect of emotional or non-emotional information processing. These results suggest that a single dose of memantine produces an early anxiogenic response in the emotion-potentiated startle similar to that seen following a single dose of the selective serotonin reuptake inhibitor, citalopram. However, the overall profile of effects is more limited than that which might be expected in response to a conventional antidepressant.

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.

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.

Antidopaminergic effects of dietary tyrosine depletion in healthy subjects and patients with manic illness.

BACKGROUND: In rats, amino acid mixtures lacking tyrosine and its precursor phenylalanine decrease the release of dopamine produced by the psychostimulant drug amphetamine. Amphetamine has been proposed as a model for clinical mania. AIMS: To assess whether dietary tyrosine depletion attenuates the psychostimulant effects of methamphetamine in healthy volunteers and diminishes the severity of mania in acutely ill patients. METHOD: Sixteen healthy volunteers received a tyrosine-free amino acid mixture and a control mixture in a double-blind crossover design 4 h before methamphetamine (0.15 mg/kg). Twenty in-patients meeting DSM-IV criteria for mania were allocated blindly and randomly to receive either the tyrosine-free mixture or the control mixture. RESULTS: The tyrosine-free mixture lowered both subjective and objective measures of the psychostimulant effects of methamphetamine. Ratings of mania were lower in the patients who received the tyrosine-free mixture. CONCLUSIONS; Decreased tyrosine availability to the brain attenuates pathological increases in dopamine neurotransmission following methamphetamine administration and putatively in mania.

Tyrosine depletion attenuates the behavioural stimulant effects of amphetamine and cocaine in rats.

Neurochemical studies show that a tyrosine-free amino acid mixture depletes brain tyrosine and decreases dopamine synthesis and release. Here, we tested whether such a mixture would reduce the behavioural effects of amphetamine and other psychostimulants. A tyrosine-free amino acid mixture decreased the behavioural activation induced by both D-amphetamine (2 mg/kg s.c.) and cocaine (2 mg/kg s.c.). In contrast, the activation induced by the dopamine agonist, apomorphine (0.75 and 5 mg/kg s.c.), or the 5-hydroxytryptamine releasing agent, p-chloroamphetamine (2 mg/kg s.c.) was not altered. These findings provide behavioural evidence that tyrosine-free amino acid mixtures reduce presynaptic dopamine function in the brain.

Tyrosine depletion attenuates dopamine function in healthy volunteers.

RATIONALE: Tyrosine depletion has been shown to reduce dopamine over activity in animal and human investigations. However, the effects on basal dopamine function have not been explored. Such information could establish tyrosine depletion as an effective probe of dopamine function in healthy volunteers and would also have relevance for future therapeutic applications of this manipulation. OBJECTIVE: The present study investigated the effect of acute tyrosine depletion on dopamine function in healthy volunteers using a combination of neuroendocrine, neuropsychological and subjective measures. METHODS: On one occasion, volunteers received an amino acid drink selectively lacking tyrosine and phenylalanine (TYR-free), whilst on the other they received a balanced (BAL) amino acid drink. Plasma prolactin, amino acid levels and subjective state were monitored over 6 h following the two drinks, and volunteers also completed a battery of tests from the CANTAB, including measures of spatial memory previously found to be sensitive to changes in dopamine function. RESULTS: Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, indicative of decreased dopamine neurotransmission within the hypothalamus. Following the TYR-free drink, volunteers were impaired at spatial recognition memory and spatial working memory. Volunteers also tended to report that they felt less good following the TYR-free than the BAL mixture. CONCLUSION: Tyrosine depletion in healthy volunteers affected baseline dopamine function on the different measures employed in this study. Tyrosine depletion would thereby seem valuable as a probe of dopamine function in human volunteers. Ratings of depression and other aspects of cognitive function were unaffected, suggesting that this manipulation may be free of significant side effects when used as a treatment for conditions characterised by dopamine over activity, such as acute mania and schizophrenia.

Effect of a selective 5-hydroxytryptamine reuptake inhibitor on brain extracellular noradrenaline: microdialysis studies using paroxetine.

The clinical efficacy of selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) is normally attributed to their ability to increase brain 5-HT function although recent preclinical findings indicate that their selectivity for 5-HT over noradrenaline may be less evident in vivo. The present study investigated the effects of the SSRI, paroxetine, on extracellular levels of noradrenaline. Microdialysis was carried out in the hippocampus of the awake rat. In rats treated twice daily for 14 days with paroxetine (5 mg/kg s.c.), dialysate levels of noradrenaline showed a maintained two-fold increase compared to saline-injected controls. Paroxetine (5 mg/kg s.c.) administered once daily for 14 days did not cause a sustained increase in noradrenaline but levels showed a moderate (+58%) increase in response to a paroxetine challenge. Acute injection of paroxetine (5 mg/kg s.c.) did not elevate noradrenaline levels. Paroxetine (5 mg/kg s.c.) elevated dialysate 5-HT after both acute and repeated (twice daily for 14 days) treatment. The paroxetine-induced increase in noradrenaline (and 5-HT) was positively correlated with plasma concentrations of the drug, which were around the therapeutic range. In comparison to paroxetine, desipramine (10 mg/kg s.c.) caused a four-fold increase in dialysate noradrenaline (but did not change 5-HT) following repeated (once daily for 14 days) treatment and a two-fold increase at for acute treatment. In summary, despite its selectivity as a 5-HT reuptake inhibitor, paroxetine increased extracellular levels of noradrenaline in rat hippocampus following repeated administration. We discuss the possibility that a facilitation of noradrenaline function might be involved in the antidepressant effect of paroxetine, and possibly other SSRIs.

Attenuation of some subjective effects of amphetamine following tyrosine depletion.

Fifteen healthy volunteers received d-amphetamine (20 mg orally) 2 h after ingesting either a nutritionally balanced amino acid mixture or one lacking the catecholamine precursors, tyrosine and phenylalanine (TYR-free). Plasma tyrosine levels were significantly lowered in subjects who received the TYR-free mixture but mean plasma amphetamine levels were higher. Despite this, the TYR-free mixture appeared to decrease the subjective psychostimulant effects of amphetamine, as determined by visual analogue scales. In contrast, the TYR-free mixture failed to lower the subjective anorectic effect of amphetamine. These findings are consistent with animal experimental studies indicating that tyrosine depletion attenuates the release of dopamine produced by amphetamine but not the release of noradrenaline.

Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release.

We report the effects of a tyrosine (and phenylalanine)-free amino acid mixture on tyrosine levels, ex vivo catecholamine synthesis and in vivo catecholamine release in brain regions of the rat. Administration of a tyrosine-free amino acid load reduced tissue levels of tyrosine (-50% after 2 h) in all brain regions examined (frontal cortex, hippocampus, striatum). The tyrosine-free amino acid mixture also reduced DOPA accumulation: this effect was most marked in striatum (-44%) and nucleus accumbens (-34%), areas with a predominantly dopaminergic innervation. Smaller decreases (-20-24%) were detected in other areas (cortex, hippocampus and hypothalamus). The effect on DOPA accumulation was prevented by supplementing the mixture with tyrosine/phenylalanine. The tyrosine-free amino acid mixture did not alter 5-HTP accumulation in any region. In microdialysis experiments, the tyrosine-free amino acid mixture did not consistently alter striatal extracellular dopamine under basal conditions but markedly, and dose-dependently, reduced the release of dopamine induced by amphetamine. In contrast, the tyrosine-free amino acid mixture did not alter either basal or amphetamine-evoked release of noradrenaline in hippocampus. Overall, these studies indicate that administration of a tyrosine-free amino acid mixture to rats depletes brain tyrosine to cause a decrease in regional brain catecholamine synthesis and release. Dopaminergic neurones appear to be more vulnerable to tyrosine depletion than noradrenergic neurones.

Comparison of the effects of alpha-methyl-p-tyrosine and a tyrosine-free amino acid load on extracellular noradrenaline in the rat hippocampus in vivo.

Peripheral administration of an amino acid load lacking tyrosine and its precursor, phenylalanine, causes a lowering of central tyrosine levels. The aim of the present study was to examine the effects of tyrosine depletion on extracellular noradrenaline using microdialysis. Extracellular noradrenaline was measured in hippocampus of the anaesthetized rat under both baseline conditions (with reuptake inhibitor, desipramine, in the perfusion medium) and following administration of the alpha2-adrenoreceptor antagonist, idazoxan. The tyrosine free amino acid load did not alter either baseline noradrenaline or the twofold rise in noradrenaline evoked by idazoxan compared with saline controls. In contrast, the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, caused a marked reduction in baseline extracellular noradrenaline and abolished the rise induced by idazoxan. In conclusion, the present data indicate that under the conditions used, a tyrosine-free amino acid mixture may not be an effective means to interfere with central noradrenaline function. This contrasts with recent findings demonstrating that the tyrosine-depletion approach can be used to decrease presynaptic dopamine function.

Rapid depletion of plasma tryptophan: a review of studies and experimental methodology.

Evidence that the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays a role in the pathophysiology of mood disorders has been accumulating over the past three decades. Recent studies on this neurotransmitter have extended across the spectrum of psychiatric disorder, suggesting a role for 5-HT in psychosis, aggression, eating disorders and addiction. However, much of the evidence has come from post-mortem examination of the brain or measures of peripheral rather than central 5-HT function. The technique of tryptophan depletion allows investigation of brain 5-HT function in living subjects by examining the behavioural responses to this pharmacological challenge. This review considers the current status of tryptophan depletion as an experimental technique and discusses the implications of findings both in affective disorders and in a range of other psychiatric syndromes. MEDLINE and PSYCHLIT searches were completed for the years 1966 to November 1996 using the key words 'serotonin', '5-hydroxytryptamine', 'tryptophan' and 'depletion'. In addition relevant journals were hand-searched for the period from 1980 to December 1996. Forty-four double-blind studies in humans and three clinical case reports were identified; these cover a range of psychiatric disorders including mood disorders and psychoses, anxiety and eating disorders and specific behaviours such as appetite, aggression and craving. The studies reviewed utilized a variety of differing methodologies reducing the extent to which results can be generalized. A series of studies in depressed patients (before and after treatment with antidepressants) and their first-degree relatives have shown the importance of an intact 5-HT system in the action of antidepressants and offer new insights into the biology of affective disorder. The mood change induced by tryptophan depletion may predict those patients likely to respond to 5-HT-specific drugs. Rapid tryptophan depletion has also been reported to exacerbate both panic and aggression in vulnerable individuals. Effects in other disorders are conflicting and further research is needed to clarify these findings.

Use of a dietary manipulation to deplete plasma tyrosine and phenylalanine in healthy subjects.

The aim of the present study was to lower plasma concentrations of tyrosine, the amino acid precursor of noradrenaline and to determine whether this manipulation impaired noradrenergic function as measured by the evening rise in concentrations of plasma melatonin. Eight healthy volunteers received three drinks: (i) an essential amino acid load with tyrosine, (ii) the same load without tyrosine and its precursor, phenylalanine and (iii) tap water. The tyrosine- and phenylalanine-deficient drink lowered plasma tyrosine by approximately 50% over 5 h. However, this did not alter the evening plasma melatonin levels compared to the other two drinks. The results suggest that amino acid loading produces a modest decline in plasma tyrosine levels but this does not lower noradrenergic neurotransmission in the pineal gland.

Effect of valine on 5-HT-mediated prolactin release in healthy volunteers, and on mood in remitted depressed patients.

BACKGROUND: Animal experimental studies suggest that the amino acid valine may decrease brain serotonin (5-HT) function by inhibiting the transport of the 5-HT precursor, L-tryptophan, across the blood barrier. The aim of the present study was to assess whether valine could decrease brain 5-HT function in healthy subjects and provoke symptomatic relapse in recently remitted depressed patients taking antidepressant drug treatment. METHOD: We studied the effect of valine (30 g) on the prolactin (PRL) response to the 5-HT releasing agent, D-fenfluramine, in healthy male subjects and on the mood of 12 remitted depressed patients taking either selective serotonin re-uptake inhibitors (n = 10) or lithium and amitriptyline (n = 2). RESULTS: Valine significantly lowered the PRL response to D-fenfluramine in healthy subjects. In the remitted depressives, valine caused a mild but detectable lowering of mood on a number of measures but only one patient experienced a significant relapse in mood. CONCLUSIONS: Valine administration may decrease brain 5-HT neurotransmission in humans. This effect could explain the mild increase in depressive symptoms in patients taking 5-HT-potentiating drugs.