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* Withdrawal symptoms
* Withdrawal symptoms
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==Interactions==
[[File:Luvox.jpg|thumb|Luvox (fluvoxamine) 100 mg film-coated scored tablets]]

Fluvoxamine inhibits the following [[cytochrome P450]] enzymes:<ref name=Pharm>{{cite book| vauthors = Ciraulo DA, Shader RI | veditors = Ciraulo DA, Shader RI | title=Pharmacotherapy of Depression|year=2011|publisher=Springer|isbn=978-1-60327-435-7|page=49 |edition= 2nd |doi=10.1007/978-1-60327-435-7}}</ref><ref name="GG">{{cite book | isbn = 978-0-07-162442-8 | title = Goodman and Gilman's The Pharmacological Basis of Therapeutics | edition = 12th | vauthors = Brunton L, Chabner B, Knollman B | year = 2010 | publisher = McGraw-Hill Professional | location = New York | title-link = Goodman and Gilman's The Pharmacological Basis of Therapeutics }}</ref><ref>{{cite journal | vauthors = Baumann P | title = Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors | journal = Clinical Pharmacokinetics | volume = 31 | issue = 6 | pages = 444–69 | date = December 1996 | pmid = 8968657 | doi = 10.2165/00003088-199631060-00004 | s2cid = 31923953 }}</ref><ref>{{cite journal | vauthors = DeVane CL, Gill HS | title = Clinical pharmacokinetics of fluvoxamine: applications to dosage regimen design | journal = The Journal of Clinical Psychiatry | volume = 58 | issue = Suppl 5 | pages = 7–14 | year = 1997 | pmid = 9184622 }}</ref><ref>{{cite journal | vauthors = DeVane CL | title = Translational pharmacokinetics: current issues with newer antidepressants | journal = Depression and Anxiety | volume = 8 | issue = Suppl 1 | pages = 64–70 | year = 1998 | pmid = 9809216 | doi = 10.1002/(SICI)1520-6394(1998)8:1+<64::AID-DA10>3.0.CO;2-S | s2cid = 22297498 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bondy B, Spellmann I | title = Pharmacogenetics of antipsychotics: useful for the clinician? | journal = Current Opinion in Psychiatry | volume = 20 | issue = 2 | pages = 126–30 | date = March 2007 | pmid = 17278909 | doi = 10.1097/YCO.0b013e328017f69f | s2cid = 23859992 | url = http://www.medscape.com/viewarticle/552100_print }}</ref><ref>{{cite journal | vauthors = Kroon LA | title = Drug interactions with smoking | journal = American Journal of Health-System Pharmacy | volume = 64 | issue = 18 | pages = 1917–21 | date = September 2007 | pmid = 17823102 | doi = 10.2146/ajhp060414 | url = http://www.medscape.com/viewarticle/562754_print }}</ref><ref>{{cite web| vauthors = Waknine Y | title = Prescribers Warned of Tizanidine Drug Interactions| work = Medscape News| publisher = Medscape| date = 13 April 2007| url = http://www.medscape.com/viewarticle/555194_print| access-date = 1 February 2008}}</ref><ref>{{Cite web|url=https://www.mayoclinic.org/drugs-supplements/fluvoxamine-oral-route/precautions/drg-20066874?p=1|title=Fluvoxamine (Oral Route) Precautions|website=Mayo Clinic|access-date=2 November 2018}}</ref>

* [[CYP1A2]] (strongly) which metabolizes [[agomelatine]], [[amitriptyline]], [[caffeine]], [[clomipramine]], [[clozapine]], [[duloxetine]], [[haloperidol]], [[imipramine]], [[phenacetin]], [[tacrine]], [[tamoxifen]], [[theophylline]], [[olanzapine]], etc.
* [[CYP3A4]] (moderately) which metabolizes [[alprazolam]], [[aripiprazole]], [[clozapine]], [[haloperidol]], [[quetiapine]], [[pimozide]], [[ziprasidone]], etc.<ref name=":0">{{cite journal | vauthors = Hemeryck A, Belpaire FM | title = Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update | journal = Current Drug Metabolism | volume = 3 | issue = 1 | pages = 13–37 | date = February 2002 | pmid = 11876575 | doi = 10.2174/1389200023338017 }}</ref>
* [[CYP2D6]] (weakly) which metabolizes [[aripiprazole]], [[chlorpromazine]], [[clozapine]], [[codeine]], [[fluoxetine]], [[haloperidol]], [[olanzapine]], [[oxycodone]], [[paroxetine]], [[perphenazine]], [[pethidine]], [[risperidone]], [[sertraline]], [[thioridazine]], [[zuclopenthixol]], etc.<ref name="FDA_drug_development">{{cite journal |title=Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers |journal=FDA|date=26 May 2021|url=https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers}}</ref>
* [[CYP2C9]] (moderately) which metabolizes [[nonsteroidal anti-inflammatory drugs]], [[phenytoin]], [[sulfonylureas]], etc.
* [[CYP2C19]] (strongly) which metabolizes [[clonazepam]], [[diazepam]], [[phenytoin]], etc.
* [[CYP2B6]] (weakly) which metabolizes [[bupropion]], [[cyclophosphamide]], [[sertraline]], [[tamoxifen]], [[valproate]], etc.

By so doing, fluvoxamine can increase serum concentration of the substrates of these enzymes.<ref name = Pharm/>

Fluvoxamine may also elevate plasma levels of olanzapine by approximately two times.<ref>{{cite journal | vauthors = Spina E, de Leon J | title = Metabolic drug interactions with newer antipsychotics: a comparative review | journal = Basic & Clinical Pharmacology & Toxicology | volume = 100 | issue = 1 | pages = 4–22 | date = January 2007 | pmid = 17214606 | doi = 10.1111/j.1742-7843.2007.00017.x }}</ref> Combined olanzapine and fluvoxamine should be used cautiously and controlled clinically and by therapeutic drug monitoring to avoid olanzapine induced adverse effects and/or intoxication.<ref>{{cite journal | vauthors = Hiemke C, Peled A, Jabarin M, Hadjez J, Weigmann H, Härtter S, Modai I, Ritsner M, Silver H | display-authors = 6 | title = Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects | journal = Journal of Clinical Psychopharmacology | volume = 22 | issue = 5 | pages = 502–506 | date = October 2002 | pmid = 12352274 | doi = 10.1097/00004714-200210000-00010 | s2cid = 38073367 }}</ref><ref>{{Cite web |date=23 November 2020 |title=Movox |url=https://www.nps.org.au/medicine-finder/movox-tablets |access-date=4 November 2022 |website=NPS MedicineWise |language=en}}</ref>

The plasma levels of oxidatively metabolized [[benzodiazepine]]s (e.g., [[triazolam]], [[midazolam]], [[alprazolam]] and [[diazepam]]) are likely to be increased when co-administered with fluvoxamine. However, the clearance of [[benzodiazepine]]s metabolized by [[glucuronidation]] (e.g., [[lorazepam]], [[oxazepam]], [[temazepam]])<ref>{{Cite web|url=http://paindr.com/wp-content/uploads/2015/10/Revised-BZD_-9-30.pdf|title=Benzodiazepine Metabolism and Pharmacokinetics| vauthors = Raouf M |date=2016| veditors = Fudin J }}</ref><ref>{{cite journal | vauthors = Peppers MP | title = Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease | journal = Pharmacotherapy | volume = 16 | issue = 1 | pages = 49–57 | date = 1996 | pmid = 8700792 | doi=10.1002/j.1875-9114.1996.tb02915.x| s2cid = 1389910 }}</ref> are not affected by fluvoxamine and may be safely taken alongside fluvoxamine should concurrent treatment with a benzodiazepine be necessary.<ref>{{Cite web|url=http://www.mylan.ca/-/media/mylanca/documents/english/product%20pdf/pdfs%20dec%202015/luvox-pm-2016.01.08.pdf|title=fluvoxamine maleate: PRODUCT MONOGRAPH|date=2016}}</ref> Additionally, it appears that benzodiazepines metabolized by nitro-reduction ([[clonazepam]], [[nitrazepam]]) may also, in a somewhat similar vein, be unlikely to be affected by fluvoxamine.<ref>{{Cite web|url=http://www.medsafe.govt.nz/profs/datasheet/l/luvoxtab.pdf|title=Luvox Data Sheet|date=2017|publisher=Medsafe, New Zealand|access-date=16 September 2018|archive-date=29 March 2018|archive-url=https://web.archive.org/web/20180329045516/http://www.medsafe.govt.nz/profs/datasheet/l/luvoxtab.pdf|url-status=dead}}</ref><ref>{{Cite web |title=Faverin Tablets |url=https://www.nps.org.au/medicine-finder/faverin-tablets |access-date=4 November 2022 |website=NPS MedicineWise |date=July 2022 |language=en}}</ref>

Using fluvoxamine and [[alprazolam]] together can increase [[alprazolam]] plasma concentrations.<ref>{{cite journal | vauthors = Suzuki Y, Shioiri T, Muratake T, Kawashima Y, Sato S, Hagiwara M, Inoue Y, Shimoda K, Someya T | title = Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles | journal = European Journal of Clinical Pharmacology | volume = 58 | issue = 12 | pages = 829–33 | date = April 2003 | pmid = 12698310 | doi = 10.1007/s00228-003-0563-9 | s2cid = 32559753 }}</ref> If [[alprazolam]] is coadministered with fluvoxamine, the initial [[alprazolam]] dose should be reduced to the lowest effective dose.<ref>{{Cite book |url=https://books.google.com/books?id=AmQlBAAAQBAJ&pg=PA131|title=Psychiatric Drugs in Children and Adolescents: Basic Pharmacology and Practical Applications| vauthors = Gerlach M, Warnke A, Greenhill L |publisher=Springer-Verlag Wien|year=2014|isbn=978-3-7091-1500-8|pages=131}}</ref><ref>{{cite journal | vauthors = Fleishaker JC, Hulst LK | title = A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine | journal = European Journal of Clinical Pharmacology | volume = 46 | issue = 1 | pages = 35–9 | date = 1994 | pmid = 8005185 | doi=10.1007/bf00195913| s2cid = 2161450 }}</ref>

Fluvoxamine and [[ramelteon]] coadministration is not indicated.<ref>{{cite journal | vauthors = Obach RS, Ryder TF | title = Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics | journal = Drug Metabolism and Disposition | volume = 38 | issue = 8 | pages = 1381–91 | date = August 2010 | pmid = 20478852 | doi = 10.1124/dmd.110.034009 | s2cid = 8421997 }}</ref><ref>{{cite journal | vauthors = Pandi-Perumal SR, Spence DW, Verster JC, Srinivasan V, Brown GM, Cardinali DP, Hardeland R | title = Pharmacotherapy of insomnia with ramelteon: safety, efficacy and clinical applications | journal = Journal of Central Nervous System Disease | volume = 3 | pages = 51–65 | date = 12 April 2011 | pmid = 23861638 | pmc = 3663615 | doi = 10.4137/JCNSD.S1611 }}</ref>

Fluvoxamine has been observed to increase serum concentrations of [[mirtazapine]], which is mainly metabolized by CYP1A2, CYP2D6, and CYP3A4, by three- to four-fold in humans.<ref name="AnttilaRasanen2001">{{cite journal | vauthors = Anttila AK, Rasanen L, Leinonen EV | title = Fluvoxamine augmentation increases serum mirtazapine concentrations three- to fourfold | journal = The Annals of Pharmacotherapy | volume = 35 | issue = 10 | pages = 1221–3 | date = October 2001 | pmid = 11675851 | doi = 10.1345/aph.1A014 | s2cid = 44807359 }}</ref> Caution and adjustment of dosage as necessary are warranted when combining fluvoxamine and [[mirtazapine]].<ref name="AnttilaRasanen2001" />

Fluvoxamine seriously affects the [[pharmacokinetics]] of [[tizanidine]] and increases the intensity and duration of its effects. Because of the potentially hazardous consequences, the concomitant use of [[tizanidine]] with fluvoxamine, or other potent inhibitors of [[CYP1A2]], should be avoided.<ref>{{cite journal | vauthors = Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ | title = Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction | journal = Clinical Pharmacology and Therapeutics | volume = 75 | issue = 4 | pages = 331–41 | date = April 2004 | pmid = 15060511 | doi = 10.1016/j.clpt.2003.12.005 | s2cid = 25781307 }}</ref>


==Pharmacology==
==Pharmacology==

Revision as of 14:25, 10 August 2023

Not to be confused with Fluoxetine.

Fluvoxamine
Clinical data
Trade namesLuvox, others
AHFS/Drugs.comMonograph
MedlinePlusa695004
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classSelective serotonin reuptake inhibitor (SSRI)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability53% (90% confidence interval: 44–62%)[2]
Protein binding77–80%[2][3]
MetabolismLiver (primarily O-demethylation)
Major: CYP1A2
Minor: CYP3A4
Minor: CYP2C19[2]
Elimination half-life12–13 hours (single dose), 22 hours (repeated dosing)[2]
ExcretionKidney (98%; 94% as metabolites, 4% as unchanged drug)[2]
Identifiers
  • 2-{[(E)-{5-Methoxy-1-[4-(trifluoromethyl)phenyl] pentylidene}amino]oxy}ethanamine[4]
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.125.476 Edit this at Wikidata
Chemical and physical data
FormulaC15H21F3N2O2
Molar mass318.340 g·mol−1
3D model (JSmol)
  • FC(F)(F)c1ccc(\C(=N\OCCN)CCCCOC)cc1
  • InChI=1S/C15H21F3N2O2/c1-21-10-3-2-4-14(20-22-11-9-19)12-5-7-13(8-6-12)15(16,17)18/h5-8H,2-4,9-11,19H2,1H3/b20-14+ checkY
  • Key:CJOFXWAVKWHTFT-XSFVSMFZSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.[5] It is primarily used to treat major depressive disorder and obsessive–compulsive disorder (OCD),[6] but is also used to treat anxiety disorders[7] such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.[8][9][10]

Fluvoxamine's side-effect profile is very similar to other SSRIs: constipation, gastrointestinal problems, headache, anxiety, irritation, sexual problems, dry mouth, sleep problems and a risk of suicide at the start of treatment by lifting the psychomotor inhibition, but these effects appear to be significantly weaker than with other SSRIs (except gastrointestinal side-effects).[11] The tolerance profile is superior in some respects to other SSRIs, particularly with respect to cardiovascular complications, despite its age.[12]

It is on the World Health Organization's List of Essential Medicines.[13]

Medical uses

In many countries (e.g., Australia,[14][15] the UK,[16] and Russia[17]) it is commonly used for major depressive disorder. Fluvoxamine is also approved in the United States for obsessive–compulsive disorder (OCD),[18][6] and social anxiety disorder.[19] In Japan it is also approved to treat OCD, social anxiety disorder and major depressive disorder.[20][21] Fluvoxamine is indicated for children and adolescents with OCD.[22] The drug works long-term, and retains its therapeutic efficacy for at least one year.[23] It has also been found to possess some analgesic properties in line with other SSRIs and tricyclic antidepressants.[24][25][26] There is tentative evidence that fluvoxamine may help some people with negative symptoms of chronic schizophrenia.[27][28]

Anxiety disorders

Fluvoxamine is effective for social phobia in adults.[29]

Fluvoxamine is also effective for treating a range of anxiety disorders in children and adolescents, including generalized anxiety disorder, social anxiety disorder, panic disorder and separation anxiety disorder.[30][31][32]

Adverse effects

Gastrointestinal side effects are more common in those receiving fluvoxamine. Fluvoxamine's side-effect profile is very similar to other SSRIs.[2][18][14][16][33][34]

Common (1–10% incidence) adverse effects

Uncommon (0.1–1% incidence) adverse effects

  • Arthralgia
  • Confusional state
  • Cutaneous hypersensitivity reactions (e.g. oedema [buildup of fluid in the tissues], rash, pruritus)
  • Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, etc.)
  • Hallucination
  • Orthostatic hypotension

Rare (0.01–0.1% incidence) adverse effects

  • Abnormal hepatic (liver) function
  • Galactorrhoea (expulsion of breast milk unrelated to pregnancy or breastfeeding)
  • Mania
  • Photosensitivity (being abnormally sensitive to light)
  • Seizures

Unknown frequency adverse effects

Pharmacology

Receptor affinity profile[36][37][38]
Site Ki (nM)
SERTTooltip Serotonin transporter 2.5
NETTooltip Norepinephrine transporter 1,427
5-HT2C 5,786
α1-adrenergic 1,288
σ1 36

Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter.[39] It has negligible affinity for the dopamine transporter or any other site, with the sole exception of the σ1 receptor.[40][12] It behaves as a potent agonist at this receptor and has the highest affinity (36 nM) of any SSRI for doing so.[40] This may contribute to its antidepressant and anxiolytic effects and may also afford it some efficacy in treating the cognitive symptoms of depression.[41] Unlike some other SSRI, fluvoxamine's metabolites are pharmacologically neutral.[42]

History

Fluvoxamine was developed by Kali-Duphar,[43] part of Solvay Pharmaceuticals, Belgium, now Abbott Laboratories, and introduced as Floxyfral in Switzerland in 1983.[43] It was approved by the U.S. Food and Drug Administration (FDA) in 1994, and introduced as Luvox in the US.[44] In India, it is available, among several other brands, as Uvox by Abbott.[45] It was one of the first SSRI antidepressants to be launched, and is prescribed in many countries to patients with major depression.[46] It was the first SSRI, a non-TCA drug, approved by the U.S. FDA specifically for the treatment of OCD.[47] At the end of 1995, more than ten million patients worldwide had been treated with fluvoxamine.[48][failed verification] Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997.[49] In Japan, fluvoxamine was the first SSRI to be approved for the treatment of depression in 1999[50][51] and was later in 2005 the first drug to be approved for the treatment of social anxiety disorder.[52] Fluvoxamine was the first SSRI approved for clinical use in the United Kingdom.[53]

Society and culture

Manufacturers include BayPharma, Synthon, and Teva, among others.[54]

Research

COVID-19

There is tentative evidence fluvoxamine might be useful for reducing COVID-19 disease severity if given as an early treatment.[55][56][57] In Canada, Ontario's COVID-19 Advisory had approved it for usage if other preferred treatments were unavailable.[58]

In May 2022, based on a review of available scientific evidence, the U.S. Food and Drug Administration (FDA) chose not to issue an emergency use authorization covering the use of fluvoxamine to treat COVID-19, saying that, at the time, the data was not sufficient to conclude that fluvoxamine may be effective in treating non-hospitalized people with COVID-19 to prevent serious illness or hospitalization. The agency stated that study results suggest that further clinical trials may be warranted.[59][60]

Environment

Fluvoxamine is a common finding in waters near human settlement.[61] Christensen et al. 2007 finds it is "very toxic to aquatic organisms" by European Union standards.[61]

References

  1. ^ Use During Pregnancy and Breastfeeding
  2. ^ a b c d e f "Product Information Luvox". TGA eBusiness Services. Abbott Australasia Pty Ltd. 15 January 2013. Retrieved 21 October 2013.
  3. ^ van Harten J (March 1993). "Clinical pharmacokinetics of selective serotonin reuptake inhibitors". Clinical Pharmacokinetics. 24 (3): 203–20. doi:10.2165/00003088-199324030-00003. PMID 8384945. S2CID 84636672.
  4. ^ "Luvox". ChemSpider. Royal Society of Chemistry. Archived from the original on 15 November 2013. Retrieved 21 October 2013.
  5. ^ "Fluvoxamine Maleate Information". U.S. Food and Drug Administration (FDA). 15 July 2015. Archived from the original on 29 November 2019. Retrieved 28 November 2019.
  6. ^ a b McCain JA (July 2009). "Antidepressants and suicide in adolescents and adults: a public health experiment with unintended consequences?". P & T. 34 (7): 355–378. PMC 2799109. PMID 20140100.
  7. ^ "Fluvoxamine for the treatment of anxiety disorders in children and adolescents. The Research Unit on Pediatric Psychopharmacology Anxiety Study Group". The New England Journal of Medicine. 344 (17): 1279–1285. April 2001. doi:10.1056/NEJM200104263441703. PMID 11323729.
  8. ^ Figgitt DP, McClellan KJ (October 2000). "Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders". Drugs. 60 (4): 925–954. doi:10.2165/00003495-200060040-00006. PMID 11085201.
  9. ^ Irons J (December 2005). "Fluvoxamine in the treatment of anxiety disorders". Neuropsychiatric Disease and Treatment. 1 (4): 289–299. PMC 2424117. PMID 18568110.
  10. ^ Asnis GM, Hameedi FA, Goddard AW, Potkin SG, Black D, Jameel M, et al. (5 August 2001). "Fluvoxamine in the treatment of panic disorder: a multi-center, double-blind, placebo-controlled study in outpatients". Psychiatry Research. 103 (1): 1–14. doi:10.1016/S0165-1781(01)00265-7. ISSN 0165-1781. PMID 11472786. S2CID 40412606.
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  12. ^ a b Westenberg HG, Sandner C (April 2006). "Tolerability and safety of fluvoxamine and other antidepressants". International Journal of Clinical Practice. 60 (4): 482–491. doi:10.1111/j.1368-5031.2006.00865.x. PMC 1448696. PMID 16620364.
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  18. ^ a b "Fluvoxamine Maleate tablet, coated prescribing information". DailyMed. 14 December 2018. Retrieved 28 November 2019.
  19. ^ "Luvox CR approved for OCD and SAD". MPR. 29 February 2008. Retrieved 2 March 2019.
  20. ^ "2005 News Releases". Astellas Pharma. Archived from the original on 16 September 2018. Retrieved 16 September 2018.
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  22. ^ "Fluvoxamine Product Insert" (PDF). Jazz Pharmaceuticals, Inc. U.S. Food and Drug Administration. March 2005.
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  29. ^ Williams T, Hattingh CJ, Kariuki CM, Tromp SA, van Balkom AJ, Ipser JC, Stein DJ (October 2017). "Pharmacotherapy for social anxiety disorder (SAnD)". The Cochrane Database of Systematic Reviews. 10 (10): CD001206. doi:10.1002/14651858.CD001206.pub3. PMC 6360927. PMID 29048739.
  30. ^ "Antidepressants for children and teenagers: what works for anxiety and depression?". NIHR Evidence (Plain English summary). National Institute for Health and Care Research. 3 November 2022. doi:10.3310/nihrevidence_53342. S2CID 253347210.
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  32. ^ Correll CU, Cortese S, Croatto G, Monaco F, Krinitski D, Arrondo G, et al. (June 2021). "Efficacy and acceptability of pharmacological, psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review". World Psychiatry. 20 (2): 244–275. doi:10.1002/wps.20881. PMC 8129843. PMID 34002501.
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  35. ^ Szalavitz M (7 January 2011). "Top Ten Legal Drugs Linked to Violence". Time. Retrieved 10 September 2014.
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