8 For a long time it has been known that EEG meanwhile activity is altered by drugs. Quantitative EEG analysis helps to delineate Wortmannin mw effects of antidepressants on brain activity. Elevated rapid eye movement (REM) density, which is a measure of frequency of REM, characterizes an endophenotype in family studies of depression. For example, for paroxetine REM density after 1 week of treatment was a predictor Inhibitors,research,lifescience,medical of treatment response.56 Most antidepressants suppress REM sleep in depressed patients and normal controls, but REM suppression appears not to be crucial for antidepressant effects. Sleep EEG

variables like REM latency and other variables were shown to predict the response to treatment with an antidepressant or the course of the depressive disorder. Some of these predictive sleep EEG markers of the long-term Inhibitors,research,lifescience,medical course of depression appear to be closely related to hypolhalamo-piluilary-adrenocortical system activity.8,54 Challenge studies To experimentally induce fear, or panic anxiety, several approaches with a large variety of agents have been conducted for further elaboration of the physiological

basis of pathologic anxiety. Targets are the identification of more effective anxiolytic compounds avoiding addictive effects. In early human clinical psychopharmacology, a variety of challenge Inhibitors,research,lifescience,medical paradigms were investigated to establish the proof of concept in healthy volunteers. Different types of models for patients Inhibitors,research,lifescience,medical and healthy volunteers are available (Table III). Table III Panic anxiety-inducing agents. Adapted from ref 57: Nutt D, Lawson C Panic attacks: a neurochemical overview of models and mechanisms. Br J Psychiatry ; 1992;160:165-178. Copyright © Royal College of Psychiatrists 1992 However, these challenge paradigms fulfil the requirements of Inhibitors,research,lifescience,medical test-retest consistence and standardized responsiveness to reference drugs only in part. Most of them have been developed for the purpose of pathophysiological studies,58 using rating instruments

validated for clinical practice. Adapting these models to the requirements of pharmaceutical trials involves possibly a wider use of other biomarkers, and better AV-951 characterization has to be carried out.59 Whether human models can significantly enhance and accelerate phase I studies remains elusive. For example, experimental panic induction with cholecystokinin tetrapeptide (CCK4) is considered a suitable model to investigate the pathophysiology of panic attacks and a variety of studies in patients and healthy volunteers have been conducted. Some clinical trials have proven the validity of CCK4 studies in selective serotonin reuptake inhibitors,60 benzodiazepine trials61 and experimental studies with neuropeptides and neurosteroids.44,62 In contrast, CCK4 antagonist studies63,64 have shown equivocal effects in patients with panic disorder. Moreover, studies in healthy men showed stimulatory effects of escitalopram upon panic symptoms elicited by choleystokinin tetrapeptide.