REM sleep reduction as a biomarker for the effects of antidepressants in healthy volunteers

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The potential use of REM sleep as a predictive biomarker for therapeutic effects of antidepressants in healthy volunteers was investigated. A literature search was performed to select studies investigating the effects of different antidepressants on REM sleep in healthy volunteers after single or multiple dose administration. To assess the specificity of REM sleep as a biomarker for the effects of antidepressants, the effects of other CNS drugs on REM sleep were also investigated. A significant REM sleep reduction (mean 29.9%) was shown for 16 of the 21 investigated antidepressants after single dose and (mean 28.9%) for 11 of the 13 investigated antidepressants after multiple dose administration. Significant effects were observed at therapeutic doses of various antidepressants and generally increased with rising doses. REM sleep effects for each antidepressant were linearly normalized to therapeutic doses, by dividing the REM-effect by the investigated dose and multiplying by the therapeutic dose. These normalized REM sleep reductions were highly variable and showed no relationship with relevant pharmacological properties of the used drugs. No quantifiable dose–response relationship could be constructed after single dose administration. A dose– response relationship with a REM sleep response after multiple dose administration could not be evaluated without the confounding factor of time. REM sleep reduction was not specific for antidepressants. Benzodiazepines for instance caused a dose normalized REM- sleep reduction of 10.4% on average. The limited value of REM sleep as a biomarker in healthy volunteers could be explained by the different sleep pattern in healthy volunteers compared with depressive patients. It is known that REM sleep duration is induced in depressive patients and that antidepressants mostly reduce these higher REM sleep durations. However, it is still not known if the therapeutic effect of antidepressants is due to these REM sleep reductions. The limited value of REM sleep as a biomarker could also partly be explained by the complex relationship between the pharmacokinetics of the individual drugs and the variable time course of REM-sleep and other sleep stages throughout the night. Models that take these complex relationships into account may provide more comprehensive and quantifiable results, which could allow dose-REM sleep effect relationship and/or correlations with the pharmacology of the antidepressants. Although REM sleep reduction occurs with most of the antidepressants, it is of limited value as a biomarker for antidepressant action in healthy volunteers. Its specificity for antidepressants is limited, and it does not show a quantitative dose–response relationship to antidepressant agents.