Cardiac slowing and acute tryptophan depletion: a comment on the paper by van der Veen et al.

Abstract

We note with interest the recent article Acute tryptophandepletion in healthy males attenuates phasic cardiac slow-ing but does not affect electro-cortical response to negativefeedback by van der Veen et al. (2008). In that study, acutetryptophan depletion (ATD, a dietary method to transientlylower central serotonin levels) attenuated cardiac decelera-tion, possibly reflecting a decreased impact of negativefeedback stimuli due to improved punishment prediction.This is congruent with preclinical data suggesting that ATDreduces cardiopulmonary reflex bradycardia and baroreflexgain (Kellett et al. 2004).The group of van der Veen et al. has previouslyemphasised the role of higher cortical centers in ATDaction (Evers et al. 2005, 2006); we wish to underline therole of brainstem systems here. There is evidence that 5-HT-containing pathways within the brainstem can haveprofound influences on the neurones involved in control ofthe heart (Lehnert et al. 1987) and these are mediated by avariety of 5-HT receptors that act at different brainstemsites (Jeggo et al. 2005; Kellett et al. 2005). Whilst theevidence suggests that these pathways are not tonicallyactive at rest, they are recruited during several differentreflexes which modify heart rate (Jordan 2005).We have now used the ATD procedure in clinical trialsof over 100 subjects and have found it to be safe, effectiveand well-tolerated. Our protocol (Hood et al. 2005) is basedon the standard described by Young et al. (1985) withwomen consuming 80% of the mixture because of lowerbody weight (Smith et al. 1997). On two occasions,however, we have observed adverse effects that werereported to local HRECs—both of these were cardiovascu-lar side effects involving significant episodes of bradycar-dia. Unblinding of patient data revealed that these incidentsboth occurred on the ATD occasion.Case #1 is a 64-year-old woman who presented withobsessive compulsive disorder (OCD, moderate checking,counting and mild hoarding symptoms), which respondedto escitalopram 15 mg/day. She participated in a ATD studyof patients who had selective serotonin reuptake inhibitor(SSRI)-remitted OCD. There was a past history of majordepression and mild hypertension, the latter well-controlledon amlodipine 5 mg/day. On the first testing day (ATDoccasion), the study progressed uneventfully until mid-afternoon when, shortly after having a venous blood sampleextracted from an in situ cannula present in her leftantecubital fossa, she experienced a vasovagal episodelasting less than 1 min. She was nauseated immediatelyprior to this episode and a transient drop in blood pressurewas noted (from 135/84 PR 72 to 104/56 PR 67). As aprecautionary measure, a 500-mL bag of IV saline/dextrosewas administered to maintain blood pressure, and thedecision was made to abort the study (despite the patient’srequest that she felt able to continue). Over the subsequent45 min we proceeded to prepare her for discharge home tothe care of her family, and this included feeding her a dietrich in tryptophan (the study depleted the body of this), andshe consumed some of the chocolate-flavoured milk thatshe had to hand. During the procedure of putting on hershoes (which may have involved some straining), she feltnauseated again, vomited and had a second vasovagal