The official guidelines indicate that benzodiazepines and z-drugs (e.g. Ambien) should be used for the short-term management of insomnia. Yet many patients are prescribed these drugs indefinitely. What accounts for this discrepancy between guidelines and clinical practice?

Admittedly, many patients suffer from intractable insomnia that only responds to z-drugs or benzodiazepines. But physicians tend to prescribe these medications as first-line agents for patients presenting with insomnia. This leaves alternative drugs that may be safer for long-term use unexplored.

Protracted benzodiazepine use is a significant risk factor for the later development of dementia. This raises the question how to better observe the short-term use of these drugs in clinical practice. One possibility is that alternative drugs could be prioritized in treatment algorithms, like suvorexant, remelteon and hydroxyzine.

Orphan drugs could also be repurposed as sleep aids safer for long-term use. The antihistamine latrepirdine, which has a short half-life limiting the next-day hangover effect, is a prime candidate.

Sleep Disorders and Mental Health

It has long been appreciated that sleep disorders are highly comorbid with psychiatric illness. Ford and Kamerow’s epidemiological study suggests that 40% of respondents with insomnia and 46.5% of respondents with hypersomnia suffer with concurrent mental illness.

Depression is associated with altered sleep architecture, shortened rapid eye movement (REM) sleep latency, increased REM density, and impaired slow wave sleep (SWS). Moreover, the vast majority of antidepressants suppress and in some cases abolish REM sleep. Chronically suppressed REM sleep results in a robust REM rebound upon antidepressant discontinuation.

The link between sleep disorders and major depressive disorder (MDD) is so significant that some neuropsychiatrists have speculated that depression may be primarily a sleep disorder. At minimum, depression involves dysregulated circadian rhythm and sleep homeostasis.

The causality of this link remains nebulous because acute sleep-deprivation results in a rapid antidepressant effect, whereas chronic, uncontrolled insomnia likely contributes to the pathogenesis of depression. The former observation has served as the basis for the argument that insomnia and especially early morning awakening may be a compensatory response to restore neurotransmitter homeostasis and combat depressive symptomatology.

Treatment Algorithms For Insomnia

The observation that sleep disturbances are core features of depression highlights the importance of identifying a pharmacological strategy for patients with a concurrent sleep disorder and psychiatric illness. The most widely-adopted approach is to exploit the side effect profiles of sedating antidepressants like mirtazepine or doxepin. These medications are commonly used off-label for insomnia. The alpha-adrenergic antagonist Trazodone has also been employed for this purpose. However, recent evidence has emerged suggesting that Trazodone loses efficacy after two weeks of use, putatively due to adrenergic receptor upregulation.

Therefore, polypharmacy may be indicated if patients are uncomfortable with the side effect burden of sedating antidepressants. Side effects may range from the insidious onset of weight gain to anticholingeric-related cognitive impairment in the elderly.

The tricyclic antidepressant trimipramine has been used successfully for the treatment of insomnia for decades, but this drug is an acetylcholine receptor antagonist and therefore may contribute to cognitive impairment in vulnerable populations.

Are Recently Approved Sleep Drugs Any Better?

What, then, are the best sleep medications when a sedating antidepressant has unacceptable side effects?

The recently-approved drugs suvorexant and ramelteon might represent the best first-line agents to treat comorbid sleep disorders and psychiatric illness in this context. However, we should be cautious until postmarketing surveillance confirms the safety of these newer drugs.

Suvorexant and ramelteon are sleep-promoting medications with novel pharmacodynamic profiles. Remelteon is a melatonin agonist which binds to the melatonin receptors MT1 and MT2 with high affinity and specificity, whereas suvorexant highjacks endogenous orexinergic circuits by antagonizing orexin receptors to promote sleep. (Melatonin is an endogenous sleep-promoting, chronobiotic neurohormone produced by the pineal gland and orexin is a wake-promoting neuropeptide implicated in the pathogenesis of narcolepsy.)

Some psychiatrists have expressed skepticism about the superiority of remelteon over simple supplementation with exogenous melatonin. Others have argued that remelteon may be more effective because it has a six-fold higher binding potency for the MT1 receptor and a three-fold higher affinity for the MT2 receptor.

The efficacy of these newer agents is hit-or-miss compared with benzodiazepines and z-drugs. But if they don’t carry the same risk of cognitive impairment and early mortality, it’s worth asking whether they might be more suitable for the long-term management of insomnia (if they work in the first place).

Cognitive Dissonance in Psychiatry

Cognitive dissonance exists vis-à-vis the use of benzodiazepines and z-drugs. The official recommendation is that these medications should be used for the short-term management of insomnia only (i.e., 2-4 weeks). In practice, a large segment of the patient population is dependent on these drugs indefinitely.

Benzodiazepines and z-drugs are effective because they enhance inward chloride currents by modulating the GABA-A receptor. But they’re associated with protracted cognitive impairment that in some cases does not remit upon discontinuation of the offending drug. Globally “turning down the gain” on neurotransmission by manipulating the ratio of excitatory to inhibitory inputs represents a kind of shotgun approach to the problem of insomnia. By comparison, suvorexant and remelteon are agents which more selectively affect sleep/wake circuitry by targeting melatonin and orexin receptors.

Additional clinical experience and research is needed to clarify the actual efficacy of these newer drugs. But it is worth asking whether non-GABAergic drugs should be prioritized in treatment algorithms. It is also interesting that no short-acting antihistamines have been repurposed for the treatment of insomnia, given that currently available antihistamine sleep aids (e.g. hydroxyzine) have long half-lives that can impair next-day functioning.

Sleep quality and parameters like delta power are important correlates of both IQ and resilience to dementia. Enhancing sleep quality with more selective drugs in patients presenting with low sleep efficiency may be a promising strategy to enhance cognitive function. Sleep enhancement may also mitigate the risk of later developing neurodegenerative disease, and improve mood and general well being in the long run.

References

Bunney, B., & Bunney, W. (2013). Mechanisms of Rapid Antidepressant Effects of Sleep Deprivation Therapy: Clock Genes and Circadian Rhythms Biological Psychiatry, 73 (12), 1164-1171 DOI: 10.1016/j.biopsych.2012.07.020

Ford, D. (1989). Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA: The Journal of the American Medical Association, 262 (11), 1479-1484 DOI: 10.1001/jama.262.11.1479

Mendelson, W. (2005). A Review of the Evidence for the Efficacy and Safety of Trazodone in Insomnia The Journal of Clinical Psychiatry, 66 (04), 469-476 DOI: 10.4088/JCP.v66n0409

Mets MA, van Deventer KR, Olivier B, & Verster JC (2010). Critical appraisal of ramelteon in the treatment of insomnia. Nature and science of sleep, 2, 257-66 PMID: 23616713

Nutt D, Wilson S, & Paterson L (2008). Sleep disorders as core symptoms of depression. Dialogues in clinical neuroscience, 10 (3), 329-36 PMID: 18979946

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