Biomarkers for the effects of benzodiazepines in healthy volunteers

Abstract

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. 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. In the current review, all individual tests found in studies of benzodiazepine agonists registered for anxiety in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 56 different studies, investigating the effects of 16 different benzodiazepines on 73 different (variants of ) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness were most sensitive to benzodiazepines. The most consistent effects were observed on saccadic peak velocity (SPV) and visual analogue scores ( VAS) of alertness, where 100% and 79% of all studies respectively showed statistically significant effects. A dose-response relationship could be constructed for temazepam and SPV, which was used to determine dose equivalencies relative to temazepam, for seven different benzodiazepines. These dose equivalencies correlated with the lowest recommended daily maintenance dose (r2 = 0.737, P < 0.05). This relationship between SPV reduction and clinical efficacy could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind SPV reduction and anxiolytic activity for benzodiazepines (probably sedation). The number of tests used in human psychopharmacology appears to be excessive and their sensitivity and reproducibility low.

Figure 1

The effects on DSST (r² = 0.03) and subjective alertness (r² = 0.29) of benzodiazepine doses normalized to fraction of therapeutic dose.

Figure 2

The averaged significant effects of benzodiazepines on neuropsychological domains, subjective assessment and neurophysiological parameters (see text for explanation). Averaged overall scores (♦) and effects after low dose (), therapeutic (medium) dose () and above therapeutic (high) benzodiazepine dose ().

Figure 3

SPV-decreasing dose equivalencies compared with lowest daily therapeutic maintenance dose for various benzodiazepines (see text for explanation). The 95% confidence interval (95% CI) of the linear regression is shown in thin lines. Insert: reference curve for temazepam dose (x-axis) and SPV-decrease relative to baseline (y-axis).

Figure 4

SPV-decreasing dose equivalencies compared with dissociation constants at benzodiazepine binding site for various benzodiazepines (see text for explanation). The 95% confidence interval (95% CI) of the linear regression is shown in thin lines.