Hector Warnes: Historical Overview of Sleep Medicine

6. Clinical Pharmacology of Sleep


             Most of the antidepressant drugs, particularly the tricyclic antidepressants (TCAs), markedly suppressrapid eye movement (REM) sleep except for trimipramine, trazodone, nefazodone, bupropion and mirtazapine. Abrupt discontinuation of REM-suppressing drugs causes increase REM density, intense dreaming and REM rebound.  Vogel’s(1990a) original research on the subject linking the shortening of REM latency, the duration of the first REM period and the heightening of REM density found in major depression have not lived up to our expectation of using REM abnormalities in Endogenous Depression as a biological marker in the diagnosis of the disorder. Vogel (1990b) went further by proposing an animal model of depression based on his clinical findings using PSG.

Jaime M. Monti (2011) clearly underlined the findings that based on electrophysiological, neurochemical, genetic and neuropharmacological approaches serotonin functions predominantly by promoting wakefulness and by inhibiting REM sleep. In regard with the use of benzodiazepines (triazolam and zolpidem) in a randomized controlled study of nearly 30 patients compared with a placebo during a withdrawal period of three nights they found that patients on triazolam developed tolerance and had rebound insomnia while patients on Zolpidem did not (1994).           

Pandi-Perumal and Monti (2006) edited an excellent book review entitled“Clinical Pharmacology of Sleep.” The prevalence of insomnia in the general population has been increasing, judging from the massive use of benzodiazepine and non-BZD receptor allosteric modulators acting on the two GABA receptor agonists which reduces neuronal excitability, the melatonin receptor agonist ramelteon and survorexant. BZD reduces delta sleep and REM sleep.  Survorexant is a selective serotonin 5 HT2A receptor antagonist and inverse agonist.

            The inability to fall asleep, the fragmentation of sleep with frequent awakening and early wakeninghave been noticed since Kraepelin and have beenlinked to different disorders.  Hyperarousal, non-reparative sleep, diurnal sleepiness and fatigue, co-morbidities (particularly snoring and sleep apneas, obesity, anxiety disorders, nightmares, periodic limb movements, parasomnia, etc.) and even increased mortality have been associated with disturbances of sleep.

There is a long list of drugs that have been found to induce sleepwalking or REM behavioral disorders (Stallman 2018).



Monti J. M. Serotonin control of sleep-wake behavior. Sleep Medicine Reviews. Vol. 15 (4); 269-81, Aug. 2011.


Monti JM, Attali P, Monti D, Zipfel A, de la Giclais B, Morselli PL.Zolpidem and rebound insomnia--a double-blind, controlled polysomnographic study in chronic insomniac patients. Pharmacopsychiatry. Vol. 27 (4):  pp. 166-175, 1994.


Pandi-Perumal SR, Monti JM, editors. Clinical Pharmacology of Sleep. Switzerland: Birkhäuser Verlag; 2006.


Stallman HM, Kohler, M. White J. Medication induced sleepwalking: a systematic review. Sleep Med Rev 2018; 37; 105-13, 2018.


Vogel GW,Buffenstein A,Minter K,Hennessey A. Drug effects on REM sleep and on endogenous depression. NeuroscBiobehavRev 1990a; 14: 49-63.


Vogel G,Neill D,Kors D,Hagler M. REM sleep abnormalities in a new animal model of endogenous depression. Neuroscience and Biobehavioral Reviews 1990b; 14: 77-83.


August 16, 2018