REM Sleep Effects as a Biomarker for the Effects of Antidepressants in Healthy Volunteers

Abstract

The potential use of rapid eye movement (REM) sleep effects as a biomarker for the therapeutic effects of antidepressants in healthy volunteers is reviewed. A literature search was performed to select studies investigating the effects of antidepressants on REM sleep. To assess the specificity of REM sleep effects as a biomarker, the effects of other central nervous system drugs on REM sleep were also investigated. A significant REM sleep reduction was shown for 16 of 21 investigated antidepressants after single-dose (mean reduction 34.1%) and for 11/13 drugs after multiple-dose administration (mean reduction 29.2%). The median increase in REM latency was approximatety 60% after single- or multiple-dose administration. REM sleep effects were linearly normalized to therapeutic doses, by dividing the REM sleep effect by the investigated dose and multiplying by the therapeutic dose. Normalized REM sleep effects were highly variable (range -27.0% to 81.8% for REM sleep; range -17.0% to 266.3% for REM latency) and demonstrated no relationship with relevant pharmacological properties of the investigated drugs. No quantifiable dose-response relationship could be constructed after single and multiple dose administration. REM sleep effects were not specific for antidepressants. Benzodiazepines, for example, caused an average dose normalized REM sleep reduction of 8.7% and a median 8.6% increase of REM latency. This review demonstrates that although REM sleep effects occur with most of the antidepressants, it is by itself of limited value as a biomarker for antidepressant action. The specificity for antidepressants is limited, and it does not show a quantitative dose-response relationship to antidepressant agents. This is at least partly due to the complex relationships between drug pharmacokinetics and the variable time course of REM and other sleep stages throughout the night. Models that take these complex relationships into account may provide more comprehensive and quantifiable results.

Subjective and polysomnographic effects of milnacipran on sleep in depressed patients

“…This is a phenomenon common to virtually all antidepressants and occurs in both depressed patients and volunteers (Rijnbeek et al, 2003).…”

Guidelines for the Recording and Evaluation of Pharmaco-Sleep Studies in Man: The International Pharmaco-EEG Society (IPEG)

“…In some such cases, sleep measures can be used as biomarkers of pharmacological action even when the primary drug indication cannot be specifically related to the sleep effects (e.g. REM sleep suppression with antidepressants [20]). Importantly, PSG is not limited to defining sleep initiation simply by looking at sleep latency and sleep maintenance with wake time after sleep onset, but new parameters are being routinely used.…”

“…• prediction of antidepressant treatment responses in major depressive disorder patients [314,319,320] and more generally as a biomarker for the effects of all classes of antidepressants [20,321,322,323];…”

“…While pharmaco-sleep research has demonstrated its value in the development of CNS-active compounds in many instances, and while validated quantitative methods have been available for a long time to study the effects of drugs on brain functions in patients and volunteers [19,20,21], there is still reluctance to apply this method in large-scale clinical trials or for decision-making drug studies outside the area of sleep medications. There are a number of reasons contributing to this situation:…”

Advanced Analysis of Pharmaco-Sleep Data in Humans

“…The objectives of these studies are multifarious such as supporting registration of a new drug, providing evidence of efficacy, evaluating central nervous system side effects or providing basic pharmacodynamic data at an early stage in drug development [13,14,15]. Generally, pharmacosleep studies have an important role in characterizing the effect of central nervous system-active drugs since an influence on sleep initiation, continuity and architecture may have a significant impact on the clinical use of the drug [16,17].…”