Effects of acute tryptophan depletion in serotonin reuptake inhibitor-remitted patients with generalized anxiety disorder
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Serotonergic antidepressants [selective serotonin reuptake inhibitor (SSRI)] are first-line treatments for generalised anxiety disorder (GAD); however, it is not known if synaptic serotonin (5-HT) availability is important for SSRI efficacy. The present study tested the hypothesis that temporary reduction in central 5-HT transmission, through acute tryptophan depletion (ATD), would reverse the therapeutic effect of the SSRIs in GAD patients.
Twelve patients (six males) with GAD, who showed sustained clinical improvement with SSRI treatment, underwent ATD in a double-blind, placebo-controlled, within-subjects design over 2 days, 1 week apart. At the peak time of depletion, the participants inhaled 7.5% CO2 and air in random order for at least 12 min each. Psychological responses were measured using the Spielberger State Anxiety Inventory (STAI-S) and GAD-symptom visual analogue scales (VASs; e.g., worry and tense) and Profile of Mood States.
Free plasma tryptophan to large neutral amino acid (LNAA) ratio decreased by 92% on the depletion day and decreased by 2% on the control day. Irrespective of depletion condition, 7.5% CO2 inhalation significantly increased STAI-S and GAD-related VAS scores (all p < 0.05) compared with air inhalation. ATD had no effect on any of these measures despite the substantial reduction in free tryptophan/LNAA ratio.
Although SSRIs treat GAD effectively, the present results suggest that the mechanism of action is different to that seen in panic, social anxiety, and post-traumatic stress disorders. Successful SSRI treatment of GAD may involve long-term receptor changes or alterations in other neurotransmitter systems downstream of serotonin.
KeywordsTryptophan Serotonin GAD Anxiety SSRI
Data from a preliminary analysis of this dataset were presented in poster form at the British Association of Psychopharmacology Summer Meeting, Harrogate UK, July 2008. We would like to acknowledge the substantial help of Ann Rich, Jon Nash, and Kelly Morris at the Bristol, UK site. Dr. Mike Franklin at Oxford, UK performed the amino acid assays. Dr. Caroline Bell played a pivotal role in securing funding for this project. Dr. Jenny Palmer, Dr. Simone Forward, and Dr. Lucinda Morris contributed significantly to the conduct of the study at the Perth, Australia site.
This study was funded by Raine Medical Research Foundation Priming Grant, Perth, Australia and Wellcome Trust Project Grant, Bristol, UK. Dr Dana Hince, Dr John Potokar and Dr Hayley Robinson have no conflicts of interest to declare. Professor David Nutt states that, over the past 20 years, he and his research group have received funds (research grants, speaker’s fees, or consultancy payments) from every major pharmaceutical company with an interest in the psychiatric field. He has undertaken Consultancies/advisory board work for Pfizer, GSK, Novartis, Organon, Cypress, Lilly, Janssen, Lundbeck, BMS, Astra Zeneca, Sanofi, Servier, Hythiam, and Sepracor and received speaking honoraria from these companies as well as Wyeth, Reckitt-Benkiser, and Cephalon. He has received grants or clinical trial payments from MSD, GSK, Novartis, Servier, Janssen, Lundbeck, Pfizer, Wyeth, and Organon. He has also received legal fees from companies, medical defense organizations, and the British Legal Aid board in relation to court cases regarding the effects of psychotropic drugs. Associate Professor Hood has undertaken advisory board work for Eli Lilly/Boehringer-Ingelheim and GlaxoSmithKline and received travel sponsorship/speakers fees from Eli Lilly, GlaxoSmithKline, Pfizer, Organon, Janssen, Lundbeck, Bristol-Myers-Squibb, Astra Zeneca, Servier, Sanofi-Aventis, Wyeth, and Cephalon. He has received clinical trials payments from Servier & Sanofi-Aventis. Dr. Simon Davies has no direct conflict of interest in relation to this manuscript. However, he has performed consultancy for Roche on one occasion and has undertaken speaking engagements for Pfizer and Lilly, with fees in all cases being paid to the University of Bristol. He was previously funded to produce educational materials for the Lundbeck Institute.
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