Studies of novel antipsychotics in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and antipsychotics; a clear response of the biomarker to a therapeutic dose; a dose±response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of neuroleptics in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 65 different studies, investigating the effects of 23 different neuroleptics on 101 different (variants of ) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness, and of visual-visuomotor-auditory and motor skills were most sensitive to antipsychotics, although over half of all the studies failed to show statistically signi®cant differences from placebo. The most consistent effects were observed using prolactin response and saccadic eye movements, where 96% and 83% of all studies resp. showed statistically signi®cant effects. The prolactin inducing dose equivalencies relative to haloperidol of 19 different antipsychotic agents correlated with the lowest recommended daily maintenance dose (r 2 =0.52). This relationship could re¯ect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind prolactin release and antipsychotic activity (probably D 2 -receptor antagonism). The number of tests used in human psychopharmacology appears to be excessive. Future studies should look for the most speci®c and sensitive test within each of the domains that are most susceptible to neuroleptics.

Studies of novel antipsychotics in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and antipsychotics; a clear response of the biomarker to a therapeutic dose; a dose±response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of neuroleptics in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 65 different studies, investigating the effects of 23 different neuroleptics on 101 different (variants of ) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness, and of visual-visuomotor-auditory and motor skills were most sensitive to antipsychotics, although over half of all the studies failed to show statistically signi®cant differences from placebo. The most consistent effects were observed using prolactin response and saccadic eye movements, where 96% and 83% of all studies resp. showed statistically signi®cant effects. The prolactin inducing dose equivalencies relative to haloperidol of 19 different antipsychotic agents correlated with the lowest recommended daily maintenance dose (r 2 =0.52). This relationship could re¯ect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind prolactin release and antipsychotic activity (probably D 2 -receptor antagonism). The number of tests used in human psychopharmacology appears to be excessive. Future studies should look for the most speci®c and sensitive test within each of the domains that are most susceptible to neuroleptics.

This study aimed to evaluate eye blinking as a marker for central dopaminergic activity by investigating the effects of sulpiride (D2-antagonist) and lisuride (D2-agonist) on spontaneous eye blinks. Twelve healthy subjects were included in a randomized, double-blind, placebo-controlled, three-period crossover trial. They received sulpiride 400 mg, lisuride 0.2 mg and placebo on different occasions. Eye blinks, prolactin, finger tapping, eye movements and visual analogue scales were measured at baseline and regularly for 12 h after administration. No effect of sulpiride or lisuride was observed on the number of eye blinks. Sulpiride caused an increase in prolactin (643 U/ml) [confidence interval (CI) 549-737). Lisuride caused a decrease in smooth pursuit eye movements (-4.1%) (CI -7.3 to -0.9) and visual analogue scales for mood (-2.1 mm) (CI -3.7 to -0.4). Spontaneous eye blink rate was not affected by sulpiride and lisuride, which makes eye blinking not suitable as a marker for central D2 activity.

This study investigates the CNS effects of sumatriptan and rizatriptan, with temazepam as an active comparator, in healthy female volunteers. Sixteen volunteers completed a randomized, double-blind, crossover study and on four separate occasions received either 100 mg sumatriptan, 20 mg rizatriptan or 20 mg temazepam. The main parameters were eye movements, EEG, body sway, visual analogue scales and a cognitive test battery. Rizatriptan and sumatriptan decreased saccadic peak velocity by 18.3 (95% CI: 5.7, 30.8) and 15.0 (2.2, 27.9) degrees/sec, respectively, about half the decrease induced by temazepam (35.0 (22.1, 47.8) degrees/sec). Body sway increased (30% for rizatriptan (16%, 45%) and 14% for sumatriptan (1%, 27%), respectively). Temazepam caused larger, similar effects. In contrast to temazepam, sumatriptan and rizatriptan decreased reaction times of recognition tasks and increased EEG alpha power (significant for sumatriptan, 0.477 (0.02, 0.935). Therapeutic doses of sumatriptan and rizatriptan caused CNS effects indicative of mild sedation. For EEG and recognition reaction times the effects were opposite to temazepam, indicating central stimulation.

The sensitivity of several neurophysiological and cognitive tests to different levels of hypoxia was investigated. Cerebral hypoxia in healthy volunteers may be a disease model for dementia or other forms of brain dysfunction. Twelve healthy subjects were included in a randomized, single-blind, placebo-controlled, three-period cross-over trial. They received three air/N2 gas mixtures via mask breathing [aimed at peripheral oxygen saturation (SPO2) values of > 97% (placebo), 90% and 80%, with normal end-tidal CO2]. Central nervous system effects were tested regularly for 130 min by saccadic and smooth pursuit eye movements, electro-encephalogram, visual analogue scales and cognitive tests. Treatments were well tolerated. Compared to SPO2 90%, SPO2 80% reduced saccadic peak velocity by 16.4 degrees/s [confidence interval (CI) -26.3, -6.4], increased occipital delta power by 14.3% (CI 3.6, 25.1), and significantly increased most cognitive reaction times. SPO2 80% also decreased correct responses for the binary choice task and serial word recognition [-1.3 (-2.2, -0.3) and -3.5 (-6.2, -0.8), respectively] compared to SPO2 90%. Cognitive performance was decreased by SPO2 80% and increased by SPO2 90% compared to placebo. Sensitive effect measurements can be identified for these interventions. The applicability as a model for cognitive impairment should be investigated further.