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Psychopharmacology (Berl). 2011 Jun;215(4):739-48. doi: 10.1007/s00213-011-2177-8. Epub 2011 Feb 19.

Effects of tryptophan depletion and tryptophan loading on the affective response to high-dose CO2 challenge in healthy volunteers.

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Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.



It has been reported that in panic disorder (PD), tryptophan depletion enhances the vulnerability to experimentally induced panic, while the administration of serotonin precursors blunts the response to challenges.


Using a high-dose carbon dioxide (CO(2)) challenge, we aimed to investigate the effects of acute tryptophan depletion (ATD) and acute tryptophan loading (ATL) on CO(2)-induced panic response in healthy volunteers.


Eighteen healthy volunteers participated in a randomized, double-blind placebo-controlled study. Each subject received ATD, ATL, and a balanced condition (BAL) in separate days, and a double-breath 35% CO(2) inhalation 4.5 h after treatment. Tryptophan (Trp) manipulations were obtained adding 0 g (ATD), 1.21 g (BAL), and 5.15 g (ATL) of l-tryptophan to a protein mixture lacking Trp. Assessments consisted of a visual analogue scale for affect (VAAS) and panic symptom list. A separate analysis on a sample of 55 subjects with a separate-group design has also been performed to study the relationship between plasma amino acid levels and subjective response to CO(2).


CO(2)-induced subjective distress and breathlessness were significantly lower after ATD compared to BAL and ATL (p < 0.05). In the separate-group analysis, ΔVAAS scores were positively correlated to the ratio Trp:ΣLNAA after treatment (r = 0.39; p < 0.05).


The present results are in line with preclinical data indicating a role for the serotonergic system in promoting the aversive respiratory sensations to hypercapnic stimuli (Richerson, Nat Rev Neurosci 5(6):449-461, 2004). The differences observed in our study, compared to previous findings in PD patients, might depend on an altered serotonergic modulatory function in patients compared to healthy subjects.

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