School of Psychiatry and Clinical Neurosciences (M521), University of Western Australia, Perth, Australia,
Psychopharmacology (Berl). 2010 Feb;208(2):223-32. doi: 10.1007/s00213-009-1722-1. Epub 2009 Nov 21.
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% CO(2) 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.
血清素能抗抑郁药（选择性 5-羟色胺再摄取抑制剂 [SSRIs]）是广泛性焦虑障碍（GAD）的一线治疗药物；然而，目前尚不清楚突触血清素（5-HT）的可用性是否对 SSRIs 的疗效很重要。本研究检验了这样一个假设，即通过急性色氨酸耗竭（ATD）短暂减少中枢 5-HT 传递，会逆转 SSRIs 在 GAD 患者中的治疗效果。
12 名（6 名男性）GAD 患者在接受 SSRIs 治疗后持续临床改善，他们在 1 周的时间内，以双盲、安慰剂对照、自身对照的方式进行了 2 天的 ATD 试验。在耗竭高峰期，参与者随机吸入 7.5%CO2 和空气，每次至少 12 分钟。使用 Spielberger 状态焦虑量表（STAI-S）和 GAD 症状视觉模拟量表（VAS；例如，担忧和紧张）以及心境状态问卷测量心理反应。
在耗竭日，游离血浆色氨酸与大中性氨基酸（LNAA）的比值下降了 92%，而在对照日下降了 2%。无论耗竭情况如何，与吸入空气相比，7.5%CO2 吸入显著增加了 STAI-S 和与 GAD 相关的 VAS 评分（所有 p < 0.05）。尽管游离色氨酸/LNAA 比值显著降低，但 ATD 对这些指标均无影响。
尽管 SSRIs 有效治疗 GAD，但目前的结果表明，其作用机制与惊恐、社交焦虑和创伤后应激障碍不同。SSRIs 成功治疗 GAD 可能涉及长期受体变化或 5-HT 下游其他神经递质系统的改变。
