Searching for perfect sleep: the continuing evolution of GABA A receptor modulators as hypnotics

The non-benzodiazepine GABA_A receptor modulators (‘Z-drugs’) — zaleplon, zolpidem, zopiclone and eszopiclone — have become the accepted treatments for insomnia where they are available. However, recent randomized, placebo-controlled trials suggest that, for these drugs, there may be particular efficacy and tolerability profiles and distinct clinical outcomes in specific patient populations. This is particularly apparent when hypnotic/ selective serotonin reuptake inhibitor co-therapy is used to treat patients with co-morbid insomnia and psychiatric disorders, as patient recovery appears to be accelerated and enhanced by some drugs but not others. Emerging evidence of why this should be the case is that these hypnotic drugs may differ significantly from each other in their pharmacodynamic and pharmacokinetic profiles. Functional selectivity for specific GABA_A receptor subtypes may determine each drug’s clinical attributes, while the pharmacokinetic characteristics of Z-drugs also determine to a large extent how they perform in the clinic. For example, activity at GABA_A alpha 1 receptor subtypes may be associated with sedative effects, whereas activity at alpha 2 and alpha 3 receptor subtypes may be associated with anxiolytic and antidepressant effects. In summary, the distinct clinical outcomes of zaleplon, zolpidem, zopiclone and eszopiclone may be explained by each drug’s unique GABA_A receptor subunit selectivity and pharmacokinetic profile. Further investigation of GABA _A receptor subtype effects would help to increase understanding of current hypnotic drug effects, while knowledge of each drug’s specific binding profile should enable clinicians to tailor treatment to individual patient’s needs.