Opposite effects of nefazodone in two human models of anxiety

Abstract.

Rationale and objectives: To explore further the role of serotonin (5-HT) in anxiety, the effects of the 5-HT reuptake inhibitor and 5-HT_2A receptor antagonist nefazodone (NF) were measured in two human models of anxiety. Methods: Twenty-nine adult healthy volunteers of both sexes underwent conditioning of skin conductance responses (CSCR) to a tone associated to an aversive white noise. Another 34 subjects performed a simulated public speaking (SPS) task, seemingly related to unconditioned fear. In both tests, subjective states were evaluated through the visual analogue mood scale (VAMS) and a bodily symptoms scale (BSS). In each experiment, subjects were randomly divided into three groups, which received 100 mg NF, 200 mg NF or placebo under double-blind condition. Results: In the CSCR test, NF decreased the number of spontaneous fluctuations of skin conductance (F=4.94; df=2,26; P=0.015). In addition, the increase in VAMS anxiety factor induced by the conditioning task was attenuated by NF (F=11.11; df=2,26; P<0.001). In contrast, the rise of VAMS anxiety induced by SPS was enhanced by NF (F=8.01; df=2,31; P=0.002). Conclusions: These results indicate that NF decreases conditioned anxiety, while enhancing unconditioned fear. Since the effects of NF may be due to impairment of 5-HT neurotransmission, consequent to overstimulation of autosomic 5-HT_1A receptors and blockade of post-synaptic 5-HT_2A receptors, the present results support the hypothesis that 5-HT facilitates conditioned anxiety, which may be related to generalised anxiety disorder, while inhibiting unconditioned fear, supposedly related to panic disorder.