Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery

@article{Atkin2018DrugsFI,
  title={Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery},
  author={Tobias Atkin and Stefano Comai and Gabriella Gobbi},
  journal={Pharmacological Reviews},
  year={2018},
  volume={70},
  pages={197 - 245}
}
Although the GABAergic benzodiazepines (BZDs) and Z-drugs (zolpidem, zopiclone, and zaleplon) are FDA-approved for insomnia disorders with a strong evidence base, they have many side effects, including cognitive impairment, tolerance, rebound insomnia upon discontinuation, car accidents/falls, abuse, and dependence liability. Consequently, the clinical use of off-label drugs and novel drugs that do not target the GABAergic system is increasing. The purpose of this review is to analyze the… 

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References

SHOWING 1-10 OF 351 REFERENCES

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

The distinct clinical outcomes of zaleplon, zolpidem, zopicl one and eszopiclone may be explained by each drug’s unique GABAA receptor subunit selectivity and pharmacokinetic profile.

Discovery and development of orexin receptor antagonists as therapeutics for insomnia

Based on the publication of recent non‐clinical and clinical data, orexin receptor antagonists potentially represent a targeted, effective and well‐tolerated new class of medications for insomnia.

The Clinical and Forensic Toxicology of Z-drugs

  • N. Gunja
  • Medicine
    Journal of Medical Toxicology
  • 2013
Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.

The Pharmacology and Mechanisms of Action of New Generation, Non-Benzodiazepine Hypnotic Agents

The new generation hypnotic drugs, zolpidem, zopiclone and zaleplon, are at least as efficacious in the clinic as benzodiazepines and may offer advantages in terms of safety, according to recent studies using genetically modified mice.

A review of the pharmacological and clinical profile of mirtazapine.

The novel antidepressant mirtazapine has a dual mode of action that enhances the release of norepinephrine and 5-HT1A-mediated serotonergic transmission and seems to be safe and effective during long-term use.

Tricyclic antidepressant pharmacology and therapeutic drug interactions updated

  • P. Gillman
  • Biology, Psychology
    British journal of pharmacology
  • 2007
New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions

In the Zzz Zone: The Effects of Z-Drugs on Human Performance and Driving

  • N. Gunja
  • Psychology
    Journal of Medical Toxicology
  • 2013
The risk–benefit analysis of Z-drugs in the treatment of insomnia, particularly in the elderly, may not favor treatment due to the increased risks of falls and motor vehicle collisions.

Quetiapine for insomnia: A review of the literature.

Given its limited efficacy data, its adverse-effect profile, and the availability of agents approved by the Food and Drug Administration for the treatment of insomnia, quetiapine's benefit in the Treatment of insomnia has not been proven to outweigh potential risks, even in patients with a comorbid labeled indication.

Pharmacological profile of antidepressants and related compounds at human monoamine transporters.

Drugs used to treat insomnia in 2002: regulatory-based rather than evidence-based medicine.

The present analysis suggests that the identified trends in the pharmacologic treatment of insomnia have continued and that antidepressants were used as frequently as insomnia drugs for the Treatment of insomnia in 2002.
...