Buspirone, sold under the brand name Buspar, is an anxiolytic drug that is primarily used to treat generalized anxiety disorder (GAD). It is also commonly used to augment antidepressants in the treatment of major depressive disorder. Unlike most anxiolytics, the pharmacology of buspirone is not related to that of benzodiazepines, barbiturates, or carbamates (it is not a GABA receptor agonist), and so buspirone does not carry the risk of physical dependence and withdrawal symptoms for which those drug classes are known. Buspirone is not considered to be a drug-of-abuse, is safer in overdose than traditional anxiolytics, and is significantly less impairing at therapeutic doses.
|By mouth (oral)|
|Metabolism||Hepatic (via CYP3A4)|
|Metabolites||5-OH-Buspirone; 6-OH-Buspirone; 8-OH-Buspirone; 1-PP|
|Elimination half-life||2.5 hours|
|Chemical and physical data|
|Molar mass||385.50314 g/mol g·mol−1|
|3D model (JSmol)|
Buspirone is approved in the United States by the Food and Drug Administration (FDA) for the short- or long-term treatment of anxiety disorders or can also be used for the short-term relief of the symptoms of anxiety. Likewise in Australia, buspirone is licensed for the treatment of anxiety disorders. In the United Kingdom, buspirone is indicated only for the short-term treatment of anxiety.
Buspirone has no immediate anxiolytic effects, and hence has a delayed onset of action; its full clinical effectiveness may require 2 to 4 weeks to manifest. The drug has been shown to be similarly effective in the treatment of GAD to benzodiazepines including diazepam, alprazolam, lorazepam, and clorazepate. Buspirone is not known to be effective in the treatment of other anxiety disorders besides GAD, although there is some limited evidence that it may be useful in the treatment of social phobia as an adjunct to selective serotonin reuptake inhibitors (SSRIs).
Although not approved for this indication, studies such as STAR*D have shown buspirone to be an effective augmentation agent alongside treatment with selective serotonin reuptake inhibitors (SSRIs) for clinical depression and is also used to counter the sexual dysfunction (anorgasmia and erectile dysfunction) associated with SSRIs. The drug has also been found to be effective in the treatment of depression as a standalone drug.
Several clinical trials, most randomized double-blind trials (and in one buspirone was used as an adjunct to atomoxetine) and one open-label, have been conducted to evaluate the utility of buspirone in the treatment of attention deficit hyperactivity disorder (ADHD), with mostly positive results.
Buspirone may be useful in the management of irritability, agitation, and aggression in older patients with dementia and in pediatrics, although further research is necessary to more clearly establish its effectiveness.
Known side effects associated with buspirone include dizziness, headaches, nausea, nervousness, and paresthesia. Buspirone is relatively well-tolerated, and is not associated with sedation, cognitive and psychomotor impairment, muscle relaxation, physical dependence, or anticonvulsant effects. In addition, buspirone does not produce euphoria, and is not a drug of abuse.
Buspirone appears to be relatively benign in cases of single-drug overdose, although no definitive data on this subject appear to be available. In one clinical trial, buspirone was administered to healthy male volunteers at a dosage of 375 mg/day, and produced side effects including nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. In early clinical trials, buspirone was given at dosages even as high as 2,400 mg/day, with akathisia, tremor, and muscle rigidity observed. Deliberate overdoses with 250 mg and up to 300 mg buspirone have resulted in drowsiness in about 50% of individuals. One death has been reported in association with 450 mg buspirone together with alprazolam, diltiazem, alcohol, cocaine.
Buspirone has been shown in vitro to be metabolized by the enzyme CYP3A4. This finding is consistent with the in vivo interactions observed between buspirone and these inhibitors or inducers of cytochrome P450 3A4 (CYP3A4), among others:
- Itraconazole: Increased plasma level of buspirone
- Rifampicin: Decreased plasma levels of buspirone
- Nefazodone: Increased plasma levels of buspirone
- Haloperidol: Increased plasma levels of haloperidol
- Carbamazepine: Decreased plasma levels of buspirone
- Grapefruit: Significantly increases the plasma levels of buspirone. See grapefruit–drug interactions.
- Fluvoxamine: Moderately increase plasma levels of buspirone.
|Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.|
Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity. It is a preferential full agonist of presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and a partial agonist of postsynaptic 5-HT1A receptors. In accordance, an animal study found that buspirone dose-dependently decreases serotonin levels in specific brain areas while increasing dopamine and norepinephrine levels. It is thought that the main effects of buspirone are mediated via its interaction with the 5-HT1A receptor. Some of its effects may be mediated via oxytocin release secondary to 5-HT1A receptor agonism.[non-primary source needed] Buspirone also has lower affinity for the serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors.
In addition to binding to serotonin receptors, buspirone is an antagonist of the dopamine D2 receptor with weak affinity. It preferentially blocks inhibitory presynaptic D2 autoreceptors, and antagonizes postsynaptic D2 receptors only at higher doses. In accordance, buspirone has been found to increase dopaminergic neurotransmission in the nigrostriatal pathway at low doses, whereas at higher doses, postsynaptic D2 receptors are blocked and antidopaminergic effects such as hypoactivity and reduced stereotypy, though notably not catalepsy, are observed in animals. Buspirone has also been found to bind with much higher affinity to the dopamine D3 and D4 receptors, where it is similarly an antagonist.
A major metabolite of buspirone, 1-(2-pyrimidinyl)piperazine (1-PP), occurs at higher circulating levels than buspirone itself, and is known to act as a potent α2-adrenergic receptor antagonist. It may be responsible for the increased noradrenergic and dopaminergic activity observed with buspirone in animals. In addition, 1-PP may play an important role in the antidepressant effects of buspirone. Buspirone also has very weak and probably clinically unimportant affinity for the α1-adrenergic receptor. However, buspirone has been reported to have shown "significant and selective intrinsic efficacy" at the α1-adrenergic receptor expressed in a "tissue- and species-dependent manner".
Buspirone has a low oral bioavailability of 3.9% relative to intravenous injection due to extensive first-pass metabolism. The time to peak plasma levels following ingestion is 0.9 to 1.5 hours. It is reported to have an elimination half-life of 2.8 hours, although a review of 14 studies found that the mean terminal half-life ranged between 2 and 11 hours, and one study even reported a terminal half-life of 33 hours. Buspirone is metabolized primarily by CYP3A4, and prominent drug interactions with inhibitors and inducers of this enzyme have been observed. Major metabolites of buspirone include 5-hydroxybuspirone, 6-hydroxybuspirone, 8-hydroxybuspirone, and 1-PP. 6-Hydroxybuspirone has been identified as the predominant hepatic metabolite of buspirone, with plasma levels that are 40-fold greater than those of buspirone after oral administration of buspirone to humans. The metabolite is a high-affinity partial agonist of the 5-HT1A receptor (Ki = 25 nM) similarly to buspirone, and has demonstrated occupancy of the 5-HT1A receptor in vivo. As such, it is likely to play an important role in the therapeutic effects of buspirone. 1-PP has also been found to circulate at higher levels than those of buspirone itself and may similarly play a significant role in the clinical effects of buspirone.
Alkylation of 1-(2-pyrimidyl)piperazine (1) with 3-chloro-1-cyanopropane (2, 4-chlorobutyronitrile) gives 3, which is reduced either by hydrogenation over Raney nickel catalyst, or with LAH. The resulting 1° amine (4) from the previous step is then reacted with 3,3-tetramethyleneglutaric anhydride (5, 8-Oxaspiro[4.5]decane-7,9-dione) in order to yield buspirone (6).
Buspirone was first synthesized, by a team at Mead Johnson, in 1968, but was not patented until 1975.[additional citation(s) needed] It was initially developed as an antipsychotic drug acting on the D2 receptor, but was found to be ineffective in the treatment of psychosis and was repurposed as an anxiolytic. In 1986, Bristol-Myers Squibb gained FDA approval for buspirone in the treatment of GAD. The patent placed on buspirone expired in 2001 and it is now available as a generic drug.
Society and cultureEdit
Female sexual dysfunctionEdit
Buspirone/testosterone (tentative brand name Lybridos) is a combination formulation of buspirone and testosterone which is under development by a pharmaceutical company called Emotional Brain for the treatment of female sexual dysfunction.
- J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 192–. ISBN 978-1-4757-2085-3.
- Mahmood I, Sahajwalla C (1999). "Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug". Clin Pharmacokinet. 36 (4): 277–87. doi:10.2165/00003088-199936040-00003. PMID 10320950.
- Zhu M, Zhao W, Jimenez H, Zhang D, Yeola S, Dai R, Vachharajani N, Mitroka J (2005). "Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes". Drug Metab. Dispos. 33 (4): 500–7. doi:10.1124/dmd.104.000836. PMID 15640381.
- Loane C, Politis M (2012). "Buspirone: what is it all about?". Brain Research. 1461: 111–8. doi:10.1016/j.brainres.2012.04.032. PMID 22608068.
- "buspirone (Rx) - BuSpar, Buspirex, more." Medscape Reference. WebMD. Retrieved 14 November 2013.
- Gammans RE, Mayol RF, LaBudde JA (1986). "Metabolism and disposition of buspirone". Am. J. Med. 80 (3B): 41–51. doi:10.1016/0002-9343(86)90331-1. PMID 3515929.
- Alan F. Schatzberg; Charles B. Nemeroff (2009). The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 490–. ISBN 978-1-58562-309-9.
- Wong H, Dockens RC, Pajor L, Yeola S, Grace JE, Stark AD, Taub RA, Yocca FD, Zaczek RC, Li YW (2007). "6-Hydroxybuspirone is a major active metabolite of buspirone: assessment of pharmacokinetics and 5-hydroxytryptamine1A receptor occupancy in rats". Drug Metab. Dispos. 35 (8): 1387–92. doi:10.1124/dmd.107.015768. PMID 17494642.
- "Commonly Prescribed Psychotropic Medications". NAMI. Archived from the original on 2014-06-16. Retrieved 25 June 2014.
- Howland RH (2015). "Buspirone: Back to the Future". J Psychosoc Nurs Ment Health Serv. 53 (11): 21–4. doi:10.3928/02793695-20151022-01. PMID 26535760.
- "BUSPIRONE HCL (buspirone hydrochloride) tablet [Watson Laboratories, Inc.]". DailyMed. Watson Laboratories, Inc. July 2013. Retrieved 14 November 2013.
- "BUSPAR® (buspirone hydrochloride) Tablets 5 mg & 10 mg PRODUCT INFORMATION" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. January 2010. Retrieved 14 November 2013.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- "Buspirone 10mg Tablets". electronic Medicines Compendium. Actavis UK Ltd. 10 September 2012. Retrieved 14 November 2013.
- Joint Formulary Committee. British National Formulary (BNF). Pharmaceutical Press. p. 224.
- Benjamin J. Sadock; Virginia A. Sadock; Pedro Ruiz (22 September 2014). Kaplan and Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry. Wolters Kluwer Health. pp. 3211–. ISBN 978-1-4698-8375-5.
- Masdrakis VG, Turic D, Baldwin DS (2013). Pharmacological treatment of social anxiety disorder. Mod Trends Pharmacopsychiatri. Modern Trends in Pharmacopsychiatry. 29. pp. 144–53. doi:10.1159/000351960. ISBN 978-3-318-02463-0. PMID 25225024.
- "The STAR*D Trial: First Results". Psych Central. The Carlat Psychiaty Report. Retrieved 15 September 2014.
- National Institute Of Health. "Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — All Medication Levels". Retrieved 12 August 2012.
- Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ (March 2006). "Medication augmentation after the failure of SSRIs for depression". The New England Journal of Medicine. 354 (12): 1243–52. doi:10.1056/NEJMoa052964. PMID 16554526.
- Appelberg BG, Syvälahti EK, Koskinen TE, Mehtonen OP, Muhonen TT, Naukkarinen HH (June 2001). "Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study". The Journal of Clinical Psychiatry. 62 (6): 448–52. doi:10.4088/JCP.v62n0608. PMID 11465522.
- Svetel, M; Vojvodić, N; Filipović, S. R; Dragasević, N; Sternić, N; Kostić, V. S (1999). "Buspirone in the treatment of cerebellar ataxia". Srpski Arhiv Za Celokupno Lekarstvo. 127 (9–10): 312–5. PMID 10649900.
- Goldstein I, Kim NN, Clayton AH, DeRogatis LR, Giraldi A, Parish SJ, Pfaus J, Simon JA, Kingsberg SA, Meston C, Stahl SM, Wallen K, Worsley R (2017). "Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review". Mayo Clin. Proc. 92 (1): 114–128. doi:10.1016/j.mayocp.2016.09.018. PMID 27916394.
- Malhotra S, Santosh PJ (April 1998). "An open clinical trial of buspirone in children with attention-deficit/hyperactivity disorder". Journal of the American Academy of Child and Adolescent Psychiatry. 37 (4): 364–71. doi:10.1097/00004583-199804000-00013. PMID 9549956.
- Mohammadi MR, Hafezi P, Galeiha A, Hajiaghaee R, Akhondzadeh S (November 2012). "Buspirone versus Methylphenidate in the Treatment of Children with Attention- Deficit/ Hyperactivity Disorder: Randomized Double-Blind Study". Acta Medica Iranica. 50 (11): 723–8. PMID 23292622.
- Sutherland SM, Adler LA, Chen C, Smith MD, Feltner DE (April 2012). "An 8-week, randomized controlled trial of atomoxetine, atomoxetine plus buspirone, or placebo in adults with ADHD". The Journal of Clinical Psychiatry. 73 (4): 445–50. doi:10.4088/JCP.10m06788. PMID 22313788.
- Davari-Ashtiani R, Shahrbabaki ME, Razjouyan K, Amini H, Mazhabdar H (December 2010). "Buspirone versus methylphenidate in the treatment of attention deficit hyperactivity disorder: a double-blind and randomized trial". Child Psychiatry and Human Development. 41 (6): 641–8. doi:10.1007/s10578-010-0193-2. PMID 20517641.
- Sontheimer DL, Ables AZ (March 2001). "Is imipramine or buspirone treatment effective in patients wishing to discontinue long-term benzodiazepine use?". The Journal of Family Practice. 50 (3): 203. PMID 11252203.
- "Buspirone monograph". Drugs.com. Retrieved 2011-08-27.
- Geddes, John; Gelder, Michael G.; Mayou, Richard (2005). Psychiatry. Oxford [Oxfordshire]: Oxford University Press. p. 237. ISBN 978-0-19-852863-0.
- Fulton, Bret; Brogden, Rex N. (1997). "Buspirone". CNS Drugs. 7 (1): 68–88. doi:10.2165/00023210-199707010-00007. ISSN 1172-7047.
- Richard C. Dart (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 886–. ISBN 978-0-7817-2845-4.
- Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ (December 1998). "Grapefruit juice substantially increases plasma concentrations of buspirone". Clinical Pharmacology and Therapeutics. 64 (6): 655–60. doi:10.1016/S0009-9236(98)90056-X. PMID 9871430.
- Lamberg, T. S; Kivistö, K. T; Laitila, J; Mårtensson, K; Neuvonen, P. J (1998). "The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone". European Journal of Clinical Pharmacology. 54 (9–10): 761–766. doi:10.1007/s002280050548. ISSN 0031-6970. PMID 9923581.
- Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
- Boess FG, Martin IL (1994). "Molecular biology of 5-HT receptors". Neuropharmacology. 33 (3–4): 275–317. doi:10.1016/0028-3908(94)90059-0. PMID 7984267.
- Hamik A, Oksenberg D, Fischette C, Peroutka SJ (1990). "Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites". Biol. Psychiatry. 28 (2): 99–109. doi:10.1016/0006-3223(90)90627-e. PMID 1974152.
- Peroutka SJ, Switzer JA, Hamik A (1989). "Identification of 5-hydroxytryptamine1D binding sites in human brain membranes". Synapse. 3 (1): 61–6. doi:10.1002/syn.890030109. PMID 2521959.
- Waeber C, Schoeffter P, Palacios JM, Hoyer D (1988). "Molecular pharmacology of 5-HT1D recognition sites: radioligand binding studies in human, pig and calf brain membranes". Naunyn Schmiedebergs Arch. Pharmacol. 337 (6): 595–601. doi:10.1007/bf00175783. PMID 2975354.
- Bonhaus DW, Weinhardt KK, Taylor M, DeSouza A, McNeeley PM, Szczepanski K, Fontana DJ, Trinh J, Rocha CL, Dawson MW, Flippin LA, Eglen RM (1997). "RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist". Neuropharmacology. 36 (4–5): 621–9. doi:10.1016/s0028-3908(97)00049-x. PMID 9225287.
- Nelson DR, Thomas DR (1989). "[3H]-BRL 43694 (Granisetron), a specific ligand for 5-HT3 binding sites in rat brain cortical membranes". Biochem. Pharmacol. 38 (10): 1693–5. doi:10.1016/0006-2952(89)90319-5. PMID 2543418.
- Borsini F, Giraldo E, Monferini E, Antonini G, Parenti M, Bietti G, Donetti A (1995). "BIMT 17, a 5-HT2A receptor antagonist and 5-HT1A receptor full agonist in rat cerebral cortex". Naunyn Schmiedebergs Arch. Pharmacol. 352 (3): 276–82. doi:10.1007/bf00168557. PMID 8584042.
- Plassat JL, Amlaiky N, Hen R (1993). "Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase". Mol. Pharmacol. 44 (2): 229–36. PMID 8394987.
- Lovenberg TW, Baron BM, de Lecea L, Miller JD, Prosser RA, Rea MA, Foye PE, Racke M, Slone AL, Siegel BW (1993). "A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms". Neuron. 11 (3): 449–58. doi:10.1016/0896-6273(93)90149-l. PMID 8398139.
- Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM, Schwartz JC (1993). "Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation". Proc. Natl. Acad. Sci. U.S.A. 90 (18): 8547–51. Bibcode:1993PNAS...90.8547R. doi:10.1073/pnas.90.18.8547. PMC 47394. PMID 8397408.
- Blier P, Curet O, Chaput Y, de Montigny C (1991). "Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--II. Effects of acute administration of 1-PP and long-term administration of tandospirone on noradrenergic neurotransmission". Neuropharmacology. 30 (7): 691–701. doi:10.1016/0028-3908(91)90176-c. PMID 1681447.
- Bergman J, Roof RA, Furman CA, Conroy JL, Mello NK, Sibley DR, Skolnick P (2013). "Modification of cocaine self-administration by buspirone (buspar®): potential involvement of D3 and D4 dopamine receptors". Int. J. Neuropsychopharmacol. 16 (2): 445–58. doi:10.1017/S1461145712000661. PMC 5100812. PMID 22827916.
- Uvnäs-Moberg K, Hillegaart V, Alster P, Ahlenius S (1996). "Effects of 5-HT agonists, selective for different receptor subtypes, on oxytocin, CCK, gastrin and somatostatin plasma levels in the rat". Neuropharmacology. 35 (11): 1635–40. doi:10.1016/S0028-3908(96)00078-0. PMID 9025112.
- Chiodera P, Volpi R, Capretti L, Caffarri G, Magotti MG, Coiro V (April 1996). "Different effects of the serotonergic agonists buspirone and sumatriptan on the posterior pituitary hormonal responses to hypoglycemia in humans". Neuropeptides. 30 (2): 187–92. doi:10.1016/S0143-4179(96)90086-4. PMID 8771561.
- Tunnicliff G (1991). "Molecular basis of buspirone's anxiolytic action". Pharmacol. Toxicol. 69 (3): 149–56. doi:10.1111/j.1600-0773.1991.tb01289.x. PMID 1796057.
- Zuideveld KP, Rusiç-Pavletiç J, Maas HJ, Peletier LA, Van der Graaf PH, Danhof M (2002). "Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats". J. Pharmacol. Exp. Ther. 303 (3): 1130–7. doi:10.1124/jpet.102.036798. PMID 12438536.
- Fava M (2007). "The combination of buspirone and bupropion in the treatment of depression". Psychother Psychosom. 76 (5): 311–2. doi:10.1159/000104708. PMID 17700052.
- Theodore A. Stern; Maurizio Fava; Timothy E. Wilens; Jerrold F. Rosenbaum (27 April 2015). Massachusetts General Hospital Psychopharmacology and Neurotherapeutics E-Book. Elsevier Health Sciences. pp. 29–. ISBN 978-0-323-41323-7.
- David J. Nutt; James C. Ballenger (15 April 2008). Anxiety Disorders. John Wiley & Sons. pp. 395–. ISBN 978-0-470-98683-7.
- Dockens, RC; Salazar, DE; Fulmor, IE; Wehling, M; Arnold, ME; Croop, R (November 2006). "Pharmacokinetics of a newly identified active metabolite of buspirone after administration of buspirone over its therapeutic dose range". Journal of Clinical Pharmacology. 46 (11): 1308–12. doi:10.1177/0091270006292250. PMID 17050795.
- Jajoo, HK; Mayol, RF; LaBudde, JA; Blair, IA (1989). "Metabolism of the antianxiety drug buspirone in human subjects". Drug Metabolism and Disposition. 17 (6): 634–40. PMID 2575499.
- Zhu, M; Zhao, W; Jimenez, H; Zhang, D; Yeola, S; Dai, R; Vachharajani, N; Mitroka, J (April 2005). "Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes". Drug Metabolism and Disposition. 33 (4): 500–7. doi:10.1124/dmd.104.000836. PMID 15640381.
- Taylor DP, Moon SL (1991). "Buspirone and related compounds as alternative anxiolytics". Neuropeptides. 19 Suppl: 15–9. doi:10.1016/0143-4179(91)90078-w. PMID 1679210.
- Allen LE, Ferguson HC, Kissel JW (May 1972). "Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro(4.5)decane-7,9-diones". Journal of Medicinal Chemistry. 15 (5): 477–9. doi:10.1021/jm00275a009. PMID 5035267.
- Wu Y-H, Rayburn LE, Ferguson JW (1972). "Psychosedative agents. 2. 8-(4-Substituted 1-piperazinylalkyl)-8-azaspiro[4.5]decane-7,9-diones". J. Med. Chem. 15 (5): 477–479. doi:10.1021/jm00275a009. PMID 5035267.
- US Patent 3907801 N-(8 (4-pyridyl-piperazino)-alkyl(9 -azaspiroalkanediones
- Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 149–. ISBN 978-3-88763-075-1.
- I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 57–. ISBN 978-94-011-4439-1.