Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).
Azapirones have shown benefit in general anxiety and augmenting SSRIs in social anxiety and depression. Evidence is not clear for panic disorder and functional gastrointestinal disorders.
Azapirones have more tolerable adverse effects than many other available anxiolytics, such as benzodiazepines or SSRIs. Unlike benzodiazepines, azapirones lack abuse potential and are not addictive, do not cause cognitive/memory impairment or sedation, and do not appear to induce appreciable tolerance or physical dependence. However, azapirones are considered less effective with slow onset in controlling symptoms.
List of azapirones
The azapirones include the following agents:
- Alnespirone (S-20,499)
- Binospirone (MDL-73,005)
- Buspirone (Buspar)
- Enilospirone (CERM-3,726)
- Eptapirone (F-11,440)
- Gepirone (Ariza, Variza)
- Ipsapirone (TVX-Q-7,821)
- Revospirone (BAY-VQ-7,813)
- Tandospirone (Sediel)
- Zalospirone (WY-47,846)
Tandospirone has also been used to augment antipsychotics in Japan as it improves cognitive and negative symptoms of schizophrenia. Buspirone is being investigated for this purpose as well. Gepirone was abandoned after FDA rejection.
Buspirone was originally classified as an azaspirodecanedione, shortened to azapirone or azaspirone due to the fact that its chemical structure contained this moiety, and other drugs with similar structures were labeled as such as well. However, despite all being called azapirones, not all of them actually contain the azapirodecanedione component, and most in fact do not or contain a variation of it. Additionally, many azapirones are also pyrimidinylpiperazines, though again this does not apply to them all.
Drugs classed as azapirones can be identified by their -spirone or -pirone suffix.
- 5-HT1A receptor (as partial or full agonists)
- 5-HT2A receptor (as inverse agonists)
- D2 receptor (as antagonists or partial agonists)
- α1-adrenergic receptor (as antagonists)
- α2-adrenergic receptor (as antagonists)
While some of the listed properties such as 5-HT2A and D2 blockade may be useful in certain indications such as in the treatment of schizophrenia (as with perospirone and tiospirone), all of them except 5-HT1A agonism are generally undesirable in anxiolytics and only contribute to side effects. As a result, further development has commenced to bring more selective of anxiolytic agents to the market. An example of this initiative is gepirone, which is currently in clinical trials in the United States for the treatment of major depression and generalized anxiety disorder. Another example is tandospirone which has been licensed in Japan for the treatment of anxiety and as an augmentation to antidepressants for depression.
5-HT1A receptor partial agonists have demonstrated efficacy against depression in rodent studies and human clinical trials. Unfortunately, however, their efficacy is limited and they are only relatively mild antidepressants. Instead of being used as monotherapy treatments, they are more commonly employed as augmentations to serotonergic antidepressants like the SSRIs. It has been proposed that high intrinsic activity at 5-HT1A postsynaptic receptors is necessary for maximal therapeutic benefits to come to prominence, and as a result, investigation has commenced in azapirones which act as 5-HT1A receptor full agonists such as alnespirone and eptapirone. Indeed, in preclinical studies, eptapirone produces robust antidepressant effects which surpass those of even high doses of imipramine and paroxetine.
Azapirones are poorly but nonetheless appreciably absorbed and have a rapid onset of action, but have only very short half-lives ranging from 1–3 hours. As a result, they must be administered 2-3 times a day. The only exception to this rule is umespirone, which has a very long duration with a single dose lasting as long as 23 hours. Unfortunately, umespirone has not been commercialized. Although never commercially produced, Bristol-Myers Squibb applied for a patent on Oct 28, 1993 and received the patent on Jul 11, 1995 for an extended release formulation of buspirone. An extended release formulation of gepirone is currently under development and if approved, should help to improve this issue.
Metabolism of azapirones occurs in the liver and they are excreted in urine and feces. A common metabolite of several azapirones including buspirone, gepirone, ipsapirone, revospirone, and tandospirone is 1-(2-pyrimidinyl)piperazine (1-PP). 1-PP possesses 5-HT1A partial agonist and α2-adrenergic antagonist actions and likely contributes overall mostly to side effects.
- Eison AS (June 1990). "Azapirones: history of development". Journal of Clinical Psychopharmacology. 10 (3 Suppl): 2S–5S. doi:10.1097/00004714-199006001-00002. PMID 1973936.
- Cadieux RJ (May 1996). "Azapirones: an alternative to benzodiazepines for anxiety". American Family Physician. 53 (7): 2349–53. PMID 8638511.
- Chessick CA, Allen MH, Thase M, Batista Miralha da Cunha AB, Kapczinski FF, de Lima MS, dos Santos Souza JJ, et al. (2006). Chessick CA, ed. "Azapirones for generalized anxiety disorder". Cochrane Database of Systematic Reviews. 3 (3): CD006115. doi:10.1002/14651858.CD006115. PMID 16856115.
- Feighner JP, Boyer WF (1989). "Serotonin-1A anxiolytics: an overview". Psychopathology. 22 Suppl 1 (1): 21–6. doi:10.1159/000284623. PMID 2567039.
- Masdrakis VG, Turic D, Baldwin DS (2013). "Pharmacological treatment of social anxiety disorder". Mod Trends Pharmacopsychiatri. 29: 144–53. doi:10.1159/000351960. PMID 25225024.
- Van Ameringen M, Mancini C, Wilson C (July 1996). "Buspirone augmentation of selective serotonin reuptake inhibitors (SSRIs) in social phobia". Journal of Affective Disorders. 39 (2): 115–21. doi:10.1016/0165-0327(96)00030-4. PMID 8827420.
- Bouwer C, Stein DJ (April 1997). "Buspirone is an effective augmenting agent of serotonin selective re-uptake inhibitors in severe treatment-refractory depression". South African Medical Journal. 87 (4 Suppl): 534–7, 540. PMID 9180827.
- Dimitriou EC, Dimitriou CE (December 1998). "Buspirone augmentation of antidepressant therapy". Journal of Clinical Psychopharmacology. 18 (6): 465–9. doi:10.1097/00004714-199812000-00009. PMID 9864079.
- 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.
- Yamada K, Yagi G, Kanba S (April 2003). "Clinical efficacy of tandospirone augmentation in patients with major depressive disorder: a randomized controlled trial". Psychiatry and Clinical Neurosciences. 57 (2): 183–7. doi:10.1046/j.1440-1819.2003.01099.x. PMID 12667165.
- Chessick CA, Allen MH, Thase M, et al. (2006). "Azapirones for generalized anxiety disorder.". Reviews (3): CD006115. doi:10.1002/14651858.CD006115. PMID 16856115.
- Masdrakis VG, Turic D, Baldwin DS (Sep 20, 2013). "Pharmacological treatment of social anxiety disorder.". Mod Trends Pharmacopsychiatri. 29: 144–53. doi:10.1159/000351960. PMID 25225024.
- Stahl, SM; Lee-Zimmerman, C (May 1, 2013). "Serotonergic drugs for depression and beyond". Curr Drug Targets. 14 (5): 578–85. doi:10.2174/1389450111314050007. PMID 23531115.
- Imai, H; Tajika, A; Chen, P; Pompoli, A; Guaiana, G; Castellazzi, M; Bighelli, I; Girlanda, F; Barbui, C; Koesters, M; Cipriani, A; Furukawa, TA (Sep 30, 2014). "Azapirones versus placebo for panic disorder in adults.". The Cochrane database of systematic reviews. 9: CD010828. doi:10.1002/14651858.CD010828.pub2. PMID 25268297.
- Grover M, Camilleri M (Feb 2013). "Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases.". J Gastroenterol. 48 (2): 177–81. doi:10.1007/s00535-012-0726-5. PMC . PMID 23254779.
- Newton RE, Marunycz JD, Alderdice MT, Napoliello MJ (March 1986). "Review of the side-effect profile of buspirone". The American Journal of Medicine. 80 (3B): 17–21. doi:10.1016/0002-9343(86)90327-X. PMID 2870641.
- Davidson JR, Feltner DE, Dugar A (2010). "Management of Generalized Anxiety Disorder in Primary Care: Identifying the Challenges and Unmet Needs". Prim Care Companion J Clin Psychiatry. 12 (2). doi:10.4088/PCC.09r00772blu. PMC . PMID 20694114.
- "The Use of Common Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances: Alphabetical list of stems together with corresponding INNs".
- Sumiyoshi T, Matsui M, Nohara S, et al. (October 2001). "Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment". The American Journal of Psychiatry. 158 (10): 1722–5. doi:10.1176/appi.ajp.158.10.1722. PMID 11579010.
- Sumiyoshi T, Park S, Jayathilake K, Roy A, Ertugrul A, Meltzer HY (September 2007). "Effect of buspirone, a serotonin1A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study". Schizophrenia Research. 95 (1–3): 158–68. doi:10.1016/j.schres.2007.06.008. PMID 17628435.
- Piskulić D, Olver JS, Maruff P, Norman TR (August 2009). "Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5-HT(1A) receptor agonist". Human Psychopharmacology. 24 (6): 437–46. doi:10.1002/hup.1046. PMID 19637398.
- "The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances" (PDF). 2004. Retrieved 1 April 2010.
- Hamik; Oksenberg, D; Fischette, C; Peroutka, SJ (1990). "Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites". Biological Psychiatry. 28 (2): 99–109. doi:10.1016/0006-3223(90)90627-E. PMID 1974152.
- Barnes NM, Costall B, Domeney AM, et al. (September 1991). "The effects of umespirone as a potential anxiolytic and antipsychotic agent". Pharmacology, Biochemistry, and Behavior. 40 (1): 89–96. doi:10.1016/0091-3057(91)90326-W. PMID 1685786.
- Ahlenius S, Wijkström A (November 1992). "Mixed agonist-antagonist properties of umespirone at neostriatal dopamine receptors in relation to its behavioral effects in the rat". European Journal of Pharmacology. 222 (1): 69–74. doi:10.1016/0014-2999(92)90464-F. PMID 1361441.
- Sumiyoshi T, Suzuki K, Sakamoto H, et al. (February 1995). "Atypicality of several antipsychotics on the basis of in vivo dopamine-D2 and serotonin-5HT2 receptor occupancy". Neuropsychopharmacology. 12 (1): 57–64. doi:10.1016/0893-133X(94)00064-7. PMID 7766287.
- Weiner DM, Burstein ES, Nash N, et al. (October 2001). "5-hydroxytryptamine2A receptor inverse agonists as antipsychotics". The Journal of Pharmacology and Experimental Therapeutics. 299 (1): 268–76. PMID 11561089.
- Hirose A, Kato T, Ohno Y, et al. (July 1990). "Pharmacological actions of SM-9018, a new neuroleptic drug with both potent 5-hydroxytryptamine2 and dopamine2 antagonistic actions". Japanese Journal of Pharmacology. 53 (3): 321–9. doi:10.1254/jjp.53.321. PMID 1975278.
- Kato T, Hirose A, Ohno Y, Shimizu H, Tanaka H, Nakamura M (December 1990). "Binding profile of SM-9018, a novel antipsychotic candidate". Japanese Journal of Pharmacology. 54 (4): 478–81. doi:10.1254/jjp.54.478. PMID 1982326.
- Odagaki Y, Toyoshima R (2007). "5-HT1A receptor agonist properties of antipsychotics determined by [35S]GTPgammaS binding in rat hippocampal membranes". Clinical and Experimental Pharmacology & Physiology. 34 (5–6): 462–6. doi:10.1111/j.1440-1681.2007.04595.x. PMID 17439416.
- Roth BL, Tandra S, Burgess LH, Sibley DR, Meltzer HY (August 1995). "D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs". Psychopharmacology. 120 (3): 365–8. doi:10.1007/BF02311185. PMID 8524985.
- Herrick-Davis K, Grinde E, Teitler M (October 2000). "Inverse agonist activity of atypical antipsychotic drugs at human 5-hydroxytryptamine2C receptors". The Journal of Pharmacology and Experimental Therapeutics. 295 (1): 226–32. PMID 10991983.
- Rauly-Lestienne I, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Cussac D (October 2007). "Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties". Naunyn-Schmiedeberg's Archives of Pharmacology. 376 (1–2): 93–105. doi:10.1007/s00210-007-0182-6. PMID 17786406.
- Itzhak Y, Ruhland M, Krähling H (February 1990). "Binding of umespirone to the sigma receptor: evidence for multiple affinity states". Neuropharmacology. 29 (2): 181–4. doi:10.1016/0028-3908(90)90058-Y. PMID 1970425.
- Kennett GA, Dourish CT, Curzon G (February 1987). "Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression". European Journal of Pharmacology. 134 (3): 265–74. doi:10.1016/0014-2999(87)90357-8. PMID 2883013.
- Blier P, Ward NM (February 2003). "Is there a role for 5-HT1A agonists in the treatment of depression?". Biological Psychiatry. 53 (3): 193–203. doi:10.1016/S0006-3223(02)01643-8. PMID 12559651.
- Robinson DS, Rickels K, Feighner J, et al. (June 1990). "Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression". Journal of Clinical Psychopharmacology. 10 (3 Suppl): 67S–76S. doi:10.1097/00004714-199006001-00013. PMID 2198303.
- Bielski RJ, Cunningham L, Horrigan JP, Londborg PD, Smith WT, Weiss K (April 2008). "Gepirone extended-release in the treatment of adult outpatients with major depressive disorder: a double-blind, randomized, placebo-controlled, parallel-group study". The Journal of Clinical Psychiatry. 69 (4): 571–7. doi:10.4088/jcp.v69n0408. PMID 18373383.
- Koek W, Patoiseau JF, Assié MB, et al. (October 1998). "F 11440, a potent, selective, high efficacy 5-HT1A receptor agonist with marked anxiolytic and antidepressant potential". The Journal of Pharmacology and Experimental Therapeutics. 287 (1): 266–83. PMID 9765347.
- Koek W, Vacher B, Cosi C, et al. (May 2001). "5-HT1A receptor activation and antidepressant-like effects: F 13714 has high efficacy and marked antidepressant potential". European Journal of Pharmacology. 420 (2–3): 103–12. doi:10.1016/S0014-2999(01)01011-1. PMID 11408031.
- Prinssen EP, Colpaert FC, Koek W (October 2002). "5-HT1A receptor activation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy". European Journal of Pharmacology. 453 (2–3): 217–21. doi:10.1016/S0014-2999(02)02430-5. PMID 12398907.
- Maurel JL, Autin JM, Funes P, Newman-Tancredi A, Colpaert F, Vacher B (October 2007). "High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity". Journal of Medicinal Chemistry. 50 (20): 5024–33. doi:10.1021/jm070714l. PMID 17803293.
- Holland RL, Wesnes K, Dietrich B (1994). "Single dose human pharmacology of umespirone". European Journal of Clinical Pharmacology. 46 (5): 461–8. doi:10.1007/bf00191912. PMID 7957544.
- US patent 5431922, Nicklasson AGM, "Method for administration of buspirone", issued 1995-07-11, assigned to Bristol-Myers Squibb Company url=http://www.google.com/patents/US5431922
- Manahan-Vaughan D, Anwyl R, Rowan MJ (December 1995). "The azapirone metabolite 1-(2-pyrimidinyl)piperazine depresses excitatory synaptic transmission in the hippocampus of the alert rat via 5-HT1A receptors". European Journal of Pharmacology. 294 (2–3): 617–24. doi:10.1016/0014-2999(95)00605-2. PMID 8750726.
- Blier P, Curet O, Chaput Y, de Montigny C (July 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.
- Löscher W, Witte U, Fredow G, Traber J, Glaser T (September 1990). "The behavioural responses to 8-OH-DPAT, ipsapirone and the novel 5-HT1A receptor agonist Bay Vq 7813 in the pig". Naunyn-Schmiedeberg's Archives of Pharmacology. 342 (3): 271–7. doi:10.1007/bf00169437. PMID 2149168.
- Zuideveld KP, Rusiç-Pavletiç J, Maas HJ, Peletier LA, Van der Graaf PH, Danhof M (December 2002). "Pharmacokinetic-pharmacodynamic modeling of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in rats". The Journal of Pharmacology and Experimental Therapeutics. 303 (3): 1130–7. doi:10.1124/jpet.102.036798. PMID 12438536.