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Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. This paper provides a systematic overview of CNS-tests used with SSRIs in healthy subjects. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose–response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis.These criteria were applied to all individual tests found in studies of selective serotonin reuptake inhibitors (SSRIs), performed in healthy subjects since 1966, identified with a systematic MedLine search. Separate databases were created to evaluate the effects of single or multiple dose SSRI-studies, and for amitriptyline whenever the original report included this antidepressant as a positive control. Doses of the antidepressant were divided into high- and low-dose ranges, relative to a medium range of therapeutic doses. For each test, the drug effects were scored as statistically significant impairment/decrease (–), improvement/increase (+) or no change (=) relative to placebo.56 single dose studies and 22 multiple dose studies were identified, investigating the effects of 13 different SSRIs on 171 variants of neuropsychological tests, which could be clustered into seven neuropsychological domains. Low single doses of SSRIs generally stimulated tests of attention and memory. High doses tended to impair visual/auditory and visuomotor systems and subjective performance, while showing an acceleration in motor function. The most pronounced effects were observed using tests that measure flicker discrimination (improvement at low doses: 75%, medium doses: 40%, high doses: 43% of studies); REM sleep (inconsistent decrease after medium doses, decrease in 83% of studies after high doses); and EEG recordings, predominantly in alpha (decrease in 60% and 43% of studies after low and medium doses, respectively) and in theta activity (increase in 43% and 33% of studies after medium and high doses, respectively). Amitriptyline generally impaired central nervous system (CNS) functions, which increased with doses. Multiple doses caused less pronounced effects on the reported tests. The most responsive tests to amitriptyline appeared to be EEG alpha and theta, and REM sleep duration.SSRIs in healthy subjects appear to cause slight stimulating effects after low doses, which tend to diminish with dose. The most consistent effects were observed with flicker discrimination tests, EEG (alpha and beta bands), REM sleep duration, and subjective effects at higher doses. These effects are small compared with amitriptyline and other CNS-active drugs. Multiple dosing with SSRIs caused even fewer measurable differences from placebo, probably due to adaptive processes. SSRI-effects are best detected with a test battery that is sensitive to general CNS-stimulation, but such tests only comprise a very small portion of the close to 200 different methods that were found in current review. [ABSTRACT FROM AUTHOR]

Introduction: A considerable percentage of young people expose themselves to 3,4-methylenedioxy-methamphetamine (MDMA or ‘ecstasy’). Alcohol is relatively commonly used in combination with MDMA ( Barrett et al., 2005 ). As a percentage of MDMA users admit to driving under influence ( Riley et al., 2001 ), the assessment of the effects of co-administration of these substances on psychomotor performance is warranted. Hypothesis: We hypothesized that the co-administration of MDMA and ethanol would ameliorate the impairment induced by ethanol alone. Methods: We performed a double-blind, randomized, placebo- controlled study in 16 healthy volunteers (9 male, 7 female) in the age of 18–29 years. MDMA 100 mg was given orally and blood alcohol concentration (BAC) was maintained at 0.6‰ by a three hour 10% alcohol infusion regime (adjustment of infusion rate according to regular sampled breath alcohol concentration). Saccadic and smooth pursuit eye movements, a validated measure of ethanol induced sedation ( van Steveninck et al., 1999 ), were recorded using Nihon Kohden® and Cambridge Electronic Design (CED®) hardware and Spike2® software at 1 : 35 post drug administration. Results were statistically evaluated using GLM in SPSS® 11.5. Results: Results are presented in table 1 . Saccadic peak velocity was increased after MDMA (p=0.000). Co-administration showed significant increase in peak saccadic velocity compared to placebo (p=0.004), although significantly less then the increase as observed after MDMA alone (p=0.003). Smooth pursuit was significantly impaired after ethanol compared to placebo (p=0.000) and MDMA (p=0.000), co-adminstration also impaired score compared to placebo (p=0.000) and MDMA (p=0.000). Conclusions: MDMA induced arousal as measured by the saccadic peak velocity when administered alone and, to a lesser degree, in combination with ethanol. Co-administration of MDMA with ethanol however could not ameliorate the deterioration of psychomotor accuracy by ethanol as measured by smooth pursuit eye movements. These findings suggest that although MDMA might ameliorate ethanol induced sedation it does not ameliorate impaired psychomotor skills. This might give a false sense of improved performance while intoxicated and thus increases risks of for example road accidents. [ABSTRACT FROM AUTHOR]