Drug-induced sleep disruption

In general, drug-induced sleep disruption is not regarded as a serious safety risk when considering progression to a phase 1 clinical trial however, for certain indications and patient populations, dmg-induced sleep disruption may be an unacceptable adverse effect. In this context, it is useful to consider the benefit of studying dmg-induced effects on sleep in preclinical models. Given that all mammalian species have measurable sleep/wake cycles, there is the expectation that rodent or non-rodent species used in standard safety assessment studies can serve as... 

Forster 1998). Similar effects were seen with benzodiazepines (Drexler et al. 2010) and barbiturates (Lukatch and Maciver 1996) which are used clinically to induce sedation. To date, brain slice assays have not been utiUzed in the assessment of potential sedative effects, and this is unlikely to be used as a routine screen in preclinical safety assessment. However, in cases such as those discussed above, where in vitro correlates of in vivo effects are seen, brain slice studies could be used to gain mechanistic understanding of a sedative effect or to enable comparison of compounds from different chemical series or classes. Furthermore, if mechanistic studies revealed a potential mechanism of drug-induced sleep disruption (e.g., identified the involvement of a specific receptor), it would be possible to develop much higher-throughput cell-based assays to screen out this activity during chemical design. 

Another antidepressant, namely trazodone, also has significant sedating properties. This may be due to its serotonin 2A antagonist properties, which may act to induce and restore slow-wave sleep (Fig. 7—14). Trazodone can be used safely with most other psychotropic drugs and so is a popular choice when a patient must take another medication that disrupts sleep, such as an SSRI. Other sedating antidepressants that block serotonin 2A receptors include mirtazapine and nefazodone. These agents are occasionally also used for their sedative-hypnotic properties. 

---