A critique of recent studies on placebo effects of antidepressants: importance of research on active placebos

RATIONALE: Limited published data show that drug efficacy can be influenced by stressors. Thus, drug testing in stressed animals may unravel important variables determining drug effects. OBJECTIVES: The experiments tested the anxiolytic efficacy of the benzodiazepine chlordiazepoxide under conditions of acute stress. METHODS: Previously group-housed rats were injected with 0, 3, and 10 mg/kg chlordiazepoxide, thereafter being exposed to two types of stress: novelty (transfer to an individual cage) and social defeat. Controls were group-housed animals. Anxiety was assessed on the plus maze. RESULTS: Speed of locomotion was increased by chlordiazepoxide in both stressed groups but not in controls. Chlordiazepoxide exerted a marked reduction in anxiety in controls and defeated rats but not in novelty exposed animals. The effects of novelty exposure were considerably weaker when drug testing was performed 24 h later. CONCLUSIONS: Stress exposure had an impact on the behavioral effects of chlordiazepoxide. Changes in locomotor activity induced by the drug appear to depend on the presence of a stressor, while anxiolytic efficacy appears to depend on the type of the stressor. Since it has been shown that drug efficacy changes in a variety of behavioral situations and drug classes, it is suggested that experimental background is an important variable in determining behavioral effects of drugs.