Chemistry:Hypnotic

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Short description: Drug whose use induces sleep
refer to caption
Zolpidem tartrate, a common but potent sedative–hypnotic drug. Used for severe insomnia.

Hypnotic (from Greek Hypnos, sleep[1]), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep[2] (or surgical anesthesia[note 1]) and to treat insomnia (sleeplessness).

This group of drugs is related to sedatives. Whereas the term sedative describes drugs that serve to calm or relieve anxiety, the term hypnotic generally describes drugs whose main purpose is to initiate, sustain, or lengthen sleep. Because these two functions frequently overlap, and because drugs in this class generally produce dose-dependent effects (ranging from anxiolysis to loss of consciousness), they are often referred to collectively as sedative–hypnotic drugs.[3]

Hypnotic drugs are regularly prescribed for insomnia and other sleep disorders, with over 95% of insomnia patients being prescribed hypnotics in some countries.[4] Many hypnotic drugs are habit-forming and—due to many factors known to disturb the human sleep pattern—a physician may instead recommend changes in the environment before and during sleep, better sleep hygiene, the avoidance of caffeine and alcohol or other stimulating substances, or behavioral interventions such as cognitive behavioral therapy for insomnia (CBT-I), before prescribing medication for sleep. When prescribed, hypnotic medication should be used for the shortest period of time necessary.[5]

Among individuals with sleep disorders, 13.7% are taking or prescribed nonbenzodiazepines, while 10.8% are taking benzodiazepines, as of 2010, in the USA.[6] Early classes of drugs, such as barbiturates, have fallen out of use in most practices but are still prescribed for some patients. In children, prescribing hypnotics is not yet acceptable—unless used to treat night terrors or sleepwalking.[7] Elderly people are more sensitive to potential side effects of daytime fatigue and cognitive impairments, and a meta-analysis found that the risks generally outweigh any marginal benefits of hypnotics in the elderly.[8] A review of the literature regarding benzodiazepine hypnotics and Z-drugs concluded that these drugs can have adverse effects, such as dependence and accidents, and that optimal treatment uses the lowest effective dose for the shortest therapeutic time period, with gradual discontinuation in order to improve health without worsening of sleep.[9]

Falling outside the above-mentioned categories, the neurohormone melatonin and its analogues (such as ramelteon) serve a hypnotic function.[10]

History

Le Vieux Séducteur by Charles Motte [fr].
(A corrupt old man tries to seduce a woman by urging her to take a hypnotic draught in her drink)

Hypnotica was a class of somniferous drugs and substances tested in medicine of the 1890s and later. These include Urethan, Acetal, Methylal, Sulfonal, paraldehyde, Amylenhydrate, Hypnon, Chloralurethan and Ohloralamid or Chloralimid.[11]

Research about using medications to treat insomnia evolved throughout the last half of the 20th century. Treatment for insomnia in psychiatry dates back to 1869, when chloral hydrate was first used as a soporific.[12] Barbiturates emerged as the first class of drugs in the early 1900s,[13] after which chemical substitution allowed derivative compounds. Although they were the best drug family at the time (with less toxicity and fewer side effects), they were dangerous in overdose and tended to cause physical and psychological dependence.[14][15][16]

During the 1970s, quinazolinones[17] and benzodiazepines were introduced as safer alternatives to replace barbiturates; by the late 1970s, benzodiazepines emerged as the safer drug.[12]

Benzodiazepines are not without their drawbacks; substance dependence is possible, and deaths from overdoses sometimes occur, especially in combination with alcohol and/or other depressants. Questions have been raised as to whether they disturb sleep architecture.[18]

Nonbenzodiazepines are the most recent development (1990s–present). Although it is clear that they are less toxic than barbiturates, their predecessors, comparative efficacy over benzodiazepines have not been established. Such efficacy is hard to determine without longitudinal studies. However, some psychiatrists recommend these drugs, citing research suggesting they are equally potent with less potential for abuse.[19]

Other sleep remedies that may be considered "sedative–hypnotics" exist; psychiatrists will sometimes prescribe medicines off-label if they have sedating effects. Examples of these include mirtazapine (an antidepressant), clonidine (an older antihypertensive drug), quetiapine (an antipsychotic), and the over-the-counter allergy and antiemetic medications doxylamine and diphenhydramine. Off-label sleep remedies are particularly useful when first-line treatment is unsuccessful or deemed unsafe (as in patients with a history of substance abuse).

Types

Main pages: Barbiturate, Quinazolinone, Benzodiazepine, and Nonbenzodiazepine

Barbiturates

Main page: Chemistry:Barbiturate

Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, hypnotics, and anticonvulsalgesic effects; however, these effects are somewhat weak, preventing barbiturates from being used in surgery in the absence of other analgesics. They have dependence liability, both physical and psychological. Barbiturates have now largely been replaced by benzodiazepines in routine medical practice – such as in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less dangerous in overdose. However, barbiturates are still used in general anesthesia, for epilepsy, and for assisted suicide. Barbiturates are derivatives of barbituric acid.

The principal mechanism of action of barbiturates is believed to be positive allosteric modulation of GABAA receptors.[20]

Examples include amobarbital, pentobarbital, phenobarbital, secobarbital, and sodium thiopental.

Quinazolinones

Main page: Chemistry:Quinazolinone
See also: Methaqualone

Quinazolinones are also a class of drugs which function as hypnotic/sedatives that contain a 4-quinazolinone core. Their use has also been proposed in the treatment of cancer.[21]

Examples of quinazolinones include cloroqualone, diproqualone, etaqualone (Aolan, Athinazone, Ethinazone), mebroqualone, Afloqualone (Arofuto), mecloqualone (Nubarene, Casfen), and methaqualone (Quaalude).

Benzodiazepines

Benzodiazepines can be useful for short-term treatment of insomnia. Their use beyond 2 to 4 weeks is not recommended due to the risk of dependence. It is preferred that benzodiazepines be taken intermittently—and at the lowest effective dose. They improve sleep-related problems by shortening the time spent in bed before falling asleep, prolonging the sleep time, and, in general, reducing wakefulness.[22][23] Like alcohol, benzodiazepines are commonly used to treat insomnia in the short-term (both prescribed and self-medicated), but worsen sleep in the long-term. While benzodiazepines can put people to sleep (i.e., inhibit NREM stage 1 and 2 sleep), while asleep, the drugs disrupt sleep architecture by decreasing sleep time, delaying time to REM sleep, and decreasing deep slow-wave sleep (the most restorative part of sleep for both energy and mood).[24][25][26]

Other drawbacks of hypnotics, including benzodiazepines, are possible tolerance to their effects, rebound insomnia, and reduced slow-wave sleep and a withdrawal period typified by rebound insomnia and a prolonged period of anxiety and agitation.[27][28] The list of benzodiazepines approved for the treatment of insomnia is fairly similar among most countries, but which benzodiazepines are officially designated as first-line hypnotics prescribed for the treatment of insomnia can vary distinctly between countries.[23] Longer-acting benzodiazepines such as nitrazepam and diazepam have residual effects that may persist into the next day and are, in general, not recommended.[22]

It is not clear as to whether the new nonbenzodiazepine hypnotics (Z-drugs) are better than the short-acting benzodiazepines. The efficacy of these two groups of medications is similar.[22][28] According to the US Agency for Healthcare Research and Quality, indirect comparison indicates that side-effects from benzodiazepines may be about twice as frequent as from nonbenzodiazepines.[28] Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia.[23] However, the UK National Institute for Health and Clinical Excellence (NICE) did not find any convincing evidence in favor of Z-drugs. A NICE review pointed out that short-acting Z-drugs were inappropriately compared in clinical trials with long-acting benzodiazepines. There have been no trials comparing short-acting Z-drugs with appropriate doses of short-acting benzodiazepines. Based on this, NICE recommended choosing the hypnotic based on cost and the patient's preference.[22]

Older adults should not use benzodiazepines to treat insomnia—unless other treatments have failed to be effective.[29] When benzodiazepines are used, patients, their caretakers, and their physician should discuss the increased risk of harms, including evidence which shows twice the incidence of traffic collisions among driving patients, as well as falls and hip fracture for all older patients.[4][29]

Their mechanism of action is primarily at GABAA receptors.[30]

Nonbenzodiazepines

Nonbenzodiazepines are a class of psychoactive drugs that are very "benzodiazepine-like" in nature. Nonbenzodiazepine pharmacodynamics are almost entirely the same as benzodiazepine drugs, and therefore entail similar benefits, side-effects and risks. Nonbenzodiazepines, however, have dissimilar or entirely different chemical structures, and therefore are unrelated to benzodiazepines on a molecular level.[19][31]

Examples include zopiclone (Imovane, Zimovane), eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien, Stilnox, Stilnoct).

Research on nonbenzodiazepines is new and conflicting. A review by a team of researchers suggests the use of these drugs for people that have trouble falling asleep (but not staying asleep),[note 2] as next-day impairments were minimal.[32] The team noted that the safety of these drugs had been established, but called for more research into their long-term effectiveness in treating insomnia. Other evidence suggests that tolerance to nonbenzodiazepines may be slower to develop than with benzodiazepines.[failed verification] A different team was more skeptical, finding little benefit over benzodiazepines.[33]

Others

Melatonin

Melatonin, the hormone produced in the pineal gland in the brain and secreted in dim light and darkness, among its other functions, promotes sleep in diurnal mammals.[34] Ramelteon and tasimelteon are synthetic analogues of melatonin which are also used for sleep-related indications.

Antihistamines

Main page: Chemistry:H1 antagonist

In common use, the term antihistamine refers only to compounds that inhibit action at the H1 receptor (and not H2, etc.).

Clinically, H1 antagonists are used to treat certain allergies. Sedation is a common side-effect, and some H1 antagonists, such as diphenhydramine (Benadryl) and doxylamine, are also used to treat insomnia.

Second-generation antihistamines cross the blood–brain barrier to a much lower degree than the first ones. This results in their primarily affecting peripheral histamine receptors, and therefore having a much lower sedative effect. High doses can still induce the central nervous system effect of drowsiness.

Antidepressants

Some antidepressants have sedating effects.

Examples include:

Serotonin antagonists and reuptake inhibitors
Tricyclic antidepressants
Tetracyclic antidepressants

Antipsychotics

While some of these drugs are frequently prescribed for insomnia, such use is not recommended unless the insomnia is due to an underlying mental health condition treatable by antipsychotics as the risks frequently outweigh the benefits.[42][43] Some of the more serious adverse effects have been observed to occur at the low doses used for this off-label prescribing, such as dyslipidemia and neutropenia,[44] [45][46][47] and a recent network meta-analysis of 154 double-blind, randomized controlled trials of drug therapies vs. placebo for insomnia in adults found that quetiapine did not demonstrated any short-term benefits in sleep quality.[48] Examples of antipsychotics with sedation as a side effect that are occasionally used for insomnia:[49]

First-generation
Second-generation

Miscellaneous drugs

Alpha-adrenergic agonist
Cannabinoids
Orexin receptor antagonist
Gabapentinoids

Effectiveness

A major systematic review and network meta-analysis of medications for the treatment of insomnia was published in 2022.[50] It found a wide range of effect sizes (standardized mean difference (SMD)) in terms of efficacy for insomnia.[50] The assessed medications included benzodiazepines (e.g., temazepam, triazolam, many others) (SMDs 0.58 to 0.83), Z-drugs (eszopiclone, zaleplon, zolpidem, zopiclone) (SMDs 0.03 to 0.63), sedative antidepressants and antihistamines (doxepin, doxylamine, trazodone, trimipramine) (SMDs 0.30 to 0.55), the antipsychotic quetiapine (SMD 0.07), orexin receptor antagonists (daridorexant, lemborexant, seltorexant, suvorexant) (SMDs 0.23 to 0.44), and melatonin receptor agonists (melatonin, ramelteon) (SMDs 0.00 to 0.13).[50] The certainty of evidence varied and ranged from high to very low depending on the medication.[50] Certain medications often used as hypnotics, including the antihistamines diphenhydramine, hydroxyzine, and promethazine and the antidepressants amitriptyline and mirtazapine, were not included in analyses due to insufficient data.[50]

Risks

The use of sedative medications in older people generally should be avoided. These medications are associated with poorer health outcomes, including cognitive decline.

Therefore, sedatives and hypnotics should be avoided in people with dementia, according to the clinical guidelines known as the Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D).[51] The use of these medications can further impede cognitive function for people with dementia, who are also more sensitive to side effects of medications.

See also

Notes

  1. ↑ When used in anesthesia to produce and maintain unconsciousness, "sleep" is metaphorical as there are no regular sleep stages or cyclical natural states; patients rarely recover from anesthesia feeling refreshed and with renewed energy. The word is also used in art.
  2. ↑ Because the drugs have a shorter elimination half life they are metabolized more quickly: nonbenzodiazepines zaleplon and zolpidem have a half life of 1 and 2 hours (respectively); for comparison the benzodiazepine clonazepam has a half life of about 30 hours. This makes the drug suitable for sleep-onset difficulty, but the team noted sustained sleep efficacy was not clear.

References

  1. ↑ "Definition of HYPNOTIC" (in en). https://www.merriam-webster.com/dictionary/hypnotic. 
  2. ↑ "Dorlands Medical Dictionary:hypnotic". http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/four/000051451.htm. 
  3. ↑ "17: Hypnotics and Sedatives". Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). The McGraw-Hill Companies, Inc.. 2006. ISBN 978-0-07-146804-6. http://accessmedicine.mhmedical.com/content.aspx?bookid=374&sectionid=41266223. Retrieved 2014-02-06. 
  4. ↑ 4.0 4.1 National Prescribing Service (2 February 2010). "NPS News 67: Addressing hypnotic medicines use in primary care". http://www.nps.org.au/health_professionals/publications/nps_news/current/nps_news_67. 
  5. ↑ "Criteria for selection of appropriate benzodiazepine hypnotic therapy". The Journal of Clinical Psychiatry. 52 52 (Suppl): 42–46. September 1991. PMID 1680126. 
  6. ↑ "Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010". Pharmacoepidemiology and Drug Safety 25 (6): 637–645. June 2016. doi:10.1002/pds.3951. PMID 26711081. 
  7. ↑ Psychiatry (3rd ed.). New York: Oxford. 2005. p. 238. 
  8. ↑ "Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits". BMJ 331 (7526): 1169. November 2005. doi:10.1136/bmj.38623.768588.47. PMID 16284208. 
  9. ↑ "What's wrong with prescribing hypnotics?". Drug and Therapeutics Bulletin 42 (12): 89–93. December 2004. doi:10.1136/dtb.2004.421289. PMID 15587763. 
  10. ↑ "Melatonin as a hypnotic: pro". Sleep Medicine Reviews 9 (1): 51–65. February 2005. doi:10.1016/j.smrv.2004.04.003. PMID 15649738. 
  11. ↑ Pacific Record of Medicine and Surgery - Volume 5 - Page 36 1890
  12. ↑ 12.0 12.1 "Benzodiazepines". A Historical Dictionary of Psychiatry. Oxford University Press. 2005. pp. 41–2. ISBN 978-0-19-517668-1. https://books.google.com/books?id=M49pEDoEpl0C&pg=PA41. Retrieved 2014-02-06. 
  13. ↑ "Barbiturates". http://www.ch.ic.ac.uk/rzepa/mim/drugs/html/barbiturate_text.htm. 
  14. ↑ "Suicide in Brisbane, 1956 to 1973: the drug-death epidemic". The Medical Journal of Australia 1 (24): 737–743. June 1975. doi:10.5694/j.1326-5377.1975.tb111781.x. PMID 239307. 
  15. ↑ "Sleep and hypnotic drugs". Drugs 9 (6): 448–478. 1975. doi:10.2165/00003495-197509060-00004. PMID 238826. 
  16. ↑ "[New hypnotics: perspectives from sleep physiology]". Vertex 18 (74): 294–299. July–August 2007. PMID 18265473. 
  17. ↑ "Synthetic Approaches Towards Quinazolines, Quinazolinones and Quinazolinediones on Solid Phase". QSAR & Combinatorial Science 23 (6): 440–459. July 2004. doi:10.1002/qsar.200420018. ISSN 1611-020X. 
  18. ↑ "Benefit-risk assessment of zaleplon in the treatment of insomnia". Drug Safety 28 (4): 301–318. 2005. doi:10.2165/00002018-200528040-00003. PMID 15783240. 
  19. ↑ 19.0 19.1 "Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia". The Annals of Pharmacotherapy 32 (6): 680–691. June 1998. doi:10.1345/aph.17111. PMID 9640488. 
  20. ↑ "How theories evolved concerning the mechanism of action of barbiturates". Epilepsia 53 (Suppl 8): 12–25. December 2012. doi:10.1111/epi.12025. PMID 23205959. 
  21. ↑ "In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase-mediated cancer diagnosis and therapy". Molecular Cancer Therapeutics 5 (12): 3001–3013. December 2006. doi:10.1158/1535-7163.MCT-06-0465. PMID 17172404. 
  22. ↑ 22.0 22.1 22.2 22.3 "Technology Appraisal Guidance 77. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia". National Institute for Clinical Excellence. April 2004. http://www.nice.org.uk/nicemedia/pdf/TA077fullguidance.pdf. 
  23. ↑ 23.0 23.1 23.2 "Treatment options for insomnia". American Family Physician 76 (4): 517–526. August 2007. PMID 17853625. http://www.aafp.org/afp/2007/0815/p517.html. 
  24. ↑ "The diagnosis and management of benzodiazepine dependence". Current Opinion in Psychiatry 18 (3): 249–255. May 2005. doi:10.1097/01.yco.0000165594.60434.84. PMID 16639148. 
  25. ↑ "Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse". Behaviour Research and Therapy 43 (1): 1–14. January 2005. doi:10.1016/j.brat.2003.12.002. PMID 15531349. 
  26. ↑ "Chronic benzodiazepine usage and withdrawal in insomnia patients". Journal of Psychiatric Research 38 (3): 327–334. 2004-06-01. doi:10.1016/j.jpsychires.2003.10.003. PMID 15003439. 
  27. ↑ Handbook of Integrative Clinical Psychology, Psychiatry, and Behavioral Medicine: Perspectives, Practices, and Research. Springer Publishing Company. 13 December 2009. pp. 128–30. ISBN 978-0-8261-1094-7. https://books.google.com/books?id=4Tkdm1vRFbUC. 
  28. ↑ 28.0 28.1 28.2 "Manifestations and management of chronic insomnia in adults". Evidence Report/Technology Assessment (Agency for Healthcare Research and Quality) (125): 1–10. June 2005. doi:10.1037/e439752005-001. PMID 15989374. 
  29. ↑ 29.0 29.1 "Five Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation. American Geriatrics Society. http://www.choosingwisely.org/doctor-patient-lists/american-geriatrics-society/. , which cites
  30. ↑ "GABA and glycine". Basic Neurochemistry: Molecular, Cellular and Medical Aspects (7th ed.). Elsevier. 2006. pp. 291–302. ISBN 978-0-12-088397-4. 
  31. ↑ "GPs' attitudes to benzodiazepine and 'Z-drug' prescribing: a barrier to implementation of evidence and guidance on hypnotics". The British Journal of General Practice 56 (533): 964–967. December 2006. PMID 17132386. 
  32. ↑ "Diagnosis and treatment of chronic insomnia: a review". Psychiatric Services 56 (3): 332–343. March 2005. doi:10.1176/appi.ps.56.3.332. PMID 15746509. "Evidence for the utility of currently available nonbenzodiazepine hypnotics points to their primary efficacy as sleep-onset, rather than as sleep-maintenance, agents. Once again, longer-term randomized, double-blind, controlled studies that demonstrate efficacy of these agents have not been performed, but safety over the longer term has been demonstrated in open-label studies, with minimal evidence of rebound phenomena. By comparison with benzodiazepines, there has been less evidence of subjective and objective next-day residual effects associated with zolpidem or subjective next-day impairment with zaleplon, even when the latter has been delivered in the middle of the night.". 
  33. ↑ "Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia". The Annals of Pharmacotherapy 32 (6): 680–691. June 1998. doi:10.1345/aph.17111. PMID 9640488. "New developments in benzodiazepine receptor pharmacology have introduced novel nonbenzodiazepine hypnotics that provide comparable efficacy to benzodiazepines. Although they may possess theoretical advantages over benzodiazepines based on their unique pharmacologic profiles, they offer few, if any, significant advantages in terms of adverse effects.". 
  34. ↑ "Melatonin as a chronobiotic". Sleep Medicine Reviews 9 (1): 25–39. February 2005. doi:10.1016/j.smrv.2004.05.002. PMID 15649736. 
  35. ↑ "Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders". Drugs & Aging 4 (4): 331–355. April 1994. doi:10.2165/00002512-199404040-00006. PMID 8019056. 
  36. ↑ "Levate (amitriptyline), dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/levate-amitriptyline-342936#showall. 
  37. ↑ "Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study". The Journal of Clinical Psychiatry 62 (6): 453–463. June 2001. doi:10.4088/JCP.v62n0609. PMID 11465523. 
  38. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. https://archive.org/details/bnf65britishnati0000unse. 
  39. ↑ "Efficacy and side effects of mianserin, a tetracyclic antidepressant". Postgraduate Medical Journal 59 (690): 229–231. April 1983. doi:10.1136/pgmj.59.690.229. PMID 6346303. 
  40. ↑ "Mirtazapine: a newer antidepressant". American Family Physician 59 (1): 159–161. January 1999. PMID 9917581. 
  41. ↑ "Insomnia in patients with depression: some pathophysiological and treatment considerations". CNS Drugs 23 (4): 309–329. 2009. doi:10.2165/00023210-200923040-00004. PMID 19374460. 
  42. ↑ Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Reviews, No. 43. Rockville: Agency for Healthcare Research and Quality. 2011. 
  43. ↑ "Safety of low doses of quetiapine when used for insomnia". The Annals of Pharmacotherapy 46 (5): 718–722. May 2012. doi:10.1345/aph.1Q697. PMID 22510671. 
  44. ↑ Højlund M (2022-09-12). Low-dose Quetiapine: Utilization and Cardiometabolic Risk (Ph.D. thesis). University of Southern Denmark. doi:10.21996/mr3m-1783.
  45. ↑ "Use of low-dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator-controlled cohort study". World Psychiatry 21 (3): 444–451. October 2022. doi:10.1002/wps.21010. PMID 36073694. 
  46. ↑ "Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis". The Lancet. Psychiatry 7 (1): 64–77. January 2020. doi:10.1016/s2215-0366(19)30416-x. PMID 31860457. 
  47. ↑ "Dose-dependent effects of antipsychotics on efficacy and adverse effects in schizophrenia". Behavioural Brain Research 402: 113098. March 2021. doi:10.1016/j.bbr.2020.113098. PMID 33417992. 
  48. ↑ "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis" (in English). Lancet 400 (10347): 170–184. July 2022. doi:10.1016/S0140-6736(22)00878-9. PMID 35843245. 
  49. ↑ "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–962. September 2013. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
  50. ↑ 50.0 50.1 50.2 50.3 50.4 "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis". Lancet 400 (10347): 170–184. July 2022. doi:10.1016/S0140-6736(22)00878-9. PMID 35843245. 
  51. ↑ Citation error. See inline comment how to fix. [verification needed]

Further reading

External links



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