Effects Of Tryptophan Depletion Research Articles

Effects of tryptophan depletion on responses to yohimbine in healthy human subjects

There is considerable evidence that both the norepinephrine (NE) and serotonin (5-HT) systems are involved in the regulation of human anxiety and fear responses. To assess the modulating effects of central 5-HT levels on NE function, 11 healthy human subjects were studied with placebo-controlled challenge tests involving tryptophan depletion followed by administration of the alpha-2-adrenergic antagonist yohimbine 0.4 mg/kg IV. Five of the 11 subjects reported a marked increase in feelings of nervousness (> or = 25 mm on a 100 mm analog scale) following the combination test, while 1/11 had this response to yohimbine alone. No subjects had an increase in nervousness during other control tests. The increase in nervousness after the tryptophan depletion-yohimbine test was statistically significant for the whole group, but there were no other unique changes in behavioral, physiologic or biochemical (MHPG, cortisol) variables with this test. These data are discussed in terms of possible functional interactions between the 5-HT and NE neurotransmitter systems.

The effect of tryptophan depletion and enhancement on subjective and behavioural aggression in normal male subjects

In order to investigate the link between aggression and 5-HT, we looked at effects of changes in plasma tryptophan on healthy male subjects. Twenty-four with high trait aggression (H) and 24 with low (L) drank an amino acid mixture with (T+) or without (T-) tryptophan. These caused plasma tryptophan enhancement and depletion, respectively, at 4.5 h. Group H subjects given T- became more angry, aggressive, annoyed, hostile and quarrelsome on subjective measures, whereas those given T+ responded in the opposite way. On a behavioural measure of aggression, group H subjects responded more aggressively after T- than T+. In contrast, there was no consistent effect on subjective or behavioural aggression in group L subjects. Feelings of well-being in group H were decreased by T- and increased by T+. In group L, T+ reduced feelings of well-being, possibly due to the sedative effect of tryptophan in this group, which correlated positively with plasma tryptophan concentration. Changes in plasma tryptophan are probably followed by changes in central 5-HT turnover. We conclude that, in those with pre-existing aggressive traits, acute falls in central 5-HT can cause increased subjective and objective aggression, while rises can have the opposite effect. The absence of changes in a low aggressive group suggests that the primary effect may be on impulsivity, possibly mediated by 5-HT1a receptors, expressing underlying aggressive traits. The findings on mood changes provide support for earlier reports of a lowering of mood with tryptophan depletion.

Effects of tryptophan depletion in panic disorder

Tryptophan (TRP) depletion is a useful paradigm for evaluating serotonin (5-HT) function in psychiatric disease. Primate studies have shown that plasma TRP depletion can be induced by the ingestion of an amino acid (AA) mixture lacking TRIP (Young et al ! 989). In this report the AA mixture without TRP reduced cerebrospinal fluid (CSF) TRP by 61% relative to a control AA mixture, which effect was associated with a 34% reduction in 5-hydroxyindole, acetic acid. Oral administration of this AA mixture following a Iow-TRP diet is known to reduce plasma TRP levels in healthy humans by over 80% of baseline levels (Zimmerman et a l i 993). In other clinical studies we have found that TRP depletion by this method produces a transient exacerbation of depressive symptoms in antidepressant-remitted depressed (Delgado et al 1990) and obsessive-compulsive patients (Barr et al 1994); however, to date there have been no studies utilizing TRP depletion in panic disorder (PD) patients. The norepinephrine (NE) and 5-HT systems have been implicated in the pathophysiology of PD (Kahn et al ! 988a, Charney et al 1992). Furthermore, the 5-HT system may provide inhibitory inputs to the principal NE nucleus, the locus coeruleus (AstonJones et ai ! 99 I). If TRP depletion sufficiently reduced presynaptic 5-HT inhibition of NE function in PD patients, this could lead to a transient increase in NE function with accompanying increases in anxiety, blood pressure, and the NE metabolite 3-methoxy-4hydroxyphenylglycol (MHPG).

A test of possible cognitive and environmental influences on the mood lowering effect of tryptophan depletion in normal males.

In a previous study we found that a tryptophan-deficient amino acid mixture, designed to lower tissue tryptophan and thus brain 5-hydroxytryptamine (5HT) levels, caused a rapid (5 h) lowering of mood in normal males. Because of the importance of this evidence indicating a direct causal connection between low 5HT and low mood, we have now investigated other possible explanations for the mood lowering effect. Research strongly supports the involvement of environmental setting and cognition in the production and experience of emotions. Therefore we investigated how these factors might influence the mood-lowering effects of tryptophan depletion. In an instructional manipulation subjects were either supplied or not supplied with information designed to account for any possible peripheral sensations that might be related to depressive affect. In an environmental manipulation subjects were exposed either to a supportive and comfortable atmosphere (positive environment), or an unrewarding and unstimulating environment (negative environment). In the control group, which received a balanced amino acid mixture, the positive and negative environments had the expected effects on the scores of the Multiple Affect Adjective Checklist, thus indicating the effectiveness of these procedures. In the tryptophan depletion group neither the instructional nor the environmental manipulation had any influence on the mood lowering effect. It may be that tryptophan depletion lowers mood in normal males because low 5HT influences mood directly rather than via cognitive processes. Our data strongly support the idea that 5HT exerts an effect on mood and that low 5HT may, in some patients, be an important factor contributing to the etiology of clinical depression.