Amisulpride, sold under the brand name Solian among others, is an antipsychotic medication used to treat schizophrenia. It is also used to treat dysthymia. It is usually classed with the atypical antipsychotics. Chemically it is a benzamide and like other benzamide antipsychotics, such as sulpiride, it is associated with a high risk of elevating blood levels of the lactation hormone, prolactin (thereby potentially causing the absence of the menstrual cycle, breast enlargement, even in males, breast milk secretion not related to breastfeeding, impaired fertility, impotence, breast pain, etc.), and a low risk, relative to the typical antipsychotics, of causing movement disorders. It has also been found to be modestly more effective in treating schizophrenia than the typical antipsychotics.
|Trade names||Solian, others|
|AHFS/Drugs.com||International Drug Names|
|By mouth, intravenous|
|Metabolism||Hepatic (minimal; most excreted unchanged)|
|Elimination half-life||12 hours|
|Excretion||Renal (23–46%), Faecal|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||369.48 g/mol g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Amisulpride is believed to work by reducing signalling via the dopamine D2 receptor. In amisulpride's case this is by blocking, or antagonizing, the receptor. Amisulpride's effectiveness in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynaptic dopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse. This increased dopamine concentration is theorized to act on dopamine D1 receptors to relieve depressive symptoms (in dysthymia) and the negative symptoms of schizophrenia.
It was introduced by Sanofi-Aventis in the 1990s. Its patent had expired by 2008 and hence generic formulations are now available. It is marketed in all English-speaking countries except for Canada and the United States. A New York City based company, LB Pharmaceuticals, has announced the development of a version of amisulpride specifically targeting the United States although it is unclear when that product would actually be on the market. A poster presentation at ECNP[clarification needed] seems to suggest that this version of amisulpride, known as LB-102 displays the same binding to D2, D3 and 5HT7 that amisulpride does.
In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, amisulpride was ranked second and demonstrated high effectiveness. 11% more effective than olanzapine (3rd), 32-35% more effective than haloperidol, quetiapine, and aripiprazole, and 25% less effective than clozapine (1st). Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia. Amisulpride augmentation, similarly to sulpiride augmentation, has been considered a viable treatment option (although this is based on low-quality evidence) in clozapine-resistant cases of schizophrenia. Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.
- Concomitant prolactin-dependent tumours e.g. prolactinoma, breast cancer
- Movement disorders (e.g. Parkinson's disease and dementia with Lewy bodies)
- Children before the onset of puberty
Neither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.
- Very Common (≥10% incidence)
- Extrapyramidal side effects (EPS; including dystonia, tremor, akathisia, parkinsonism). Produces a moderate degree of EPS; more than aripiprazole (not significantly, however), clozapine, iloperidone (not significantly), olanzapine (not significantly), quetiapine (not significantly) and sertindole; less than chlorpromazine (not significantly), haloperidol, lurasidone (not significantly), paliperidone (not significantly), risperidone (not significantly), ziprasidone (not significantly) and zotepine (not significantly).
- Hyperprolactinaemia (which can lead to galactorrhoea, breast enlargement and tenderness, sexual dysfunction, etc.)
- Weight gain (produces less weight gain than chlorpromazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zotepine and more (although not statistically significantly) weight gain than haloperidol, lurasidone, ziprasidone and approximately as much weight gain as aripiprazole and asenapine)
- Anticholinergic side effects (although it does not bind to the muscarinic acetylcholine receptors and hence these side effects are usually quite mild) such as
- - constipation
- - dry mouth
- - disorder of accommodation
- - Blurred vision
- Rare (<1% incidence)
- Blood dyscrasias such as leucopenia, neutropenia and agranulocytosis
- QT interval prolongation (in a recent meta-analysis of the safety and efficacy of 15 antipsychotic drugs amisulpride was found to have the 2nd highest effect size for causing QT interval prolongation)
Hyperprolactinaemia results from antagonism of the D2 receptors located on the lactotrophic cells found in the anterior pituitary gland. Amisulpride has a high propensity for elevating plasma prolactin levels as a result of its poor blood-brain barrier penetrability and hence the resulting greater ratio of peripheral D2 occupancy to central D2 occupancy. This means that to achieve the sufficient occupancy (~60–80%) of the central D2 receptors in order to elicit its therapeutic effects a dose must be given that is enough to saturate peripheral D2 receptors including those in the anterior pituitary.
- Somnolence. It produces minimal sedation due to its absence of cholinergic, histaminergic and alpha adrenergic receptor antagonism. It is one of the least sedating antipsychotics.
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a felling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Amisulpride should not be used in conjunction with drugs that prolong the QT interval (such as citalopram, venlafaxine, bupropion, clozapine, tricyclic antidepressants, sertindole, ziprasidone, etc.), reduce heart rate and those that can induce hypokalaemia. Likewise it is imprudent to combine antipsychotics due to the additive risk for tardive dyskinesia and neuroleptic malignant syndrome.
|Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.|
Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 3.0 and 3.5 nM, respectively. Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low-dose amisulpride has also been used to treat dysthymia.
Amisulpride and its relatives sulpiride, levosulpiride, and sultopride have been shown to bind to the high-affinity GHB receptor at concentrations that are therapeutically relevant (IC50 = 50 nM for amisulpride).
Though it was long widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychotic properties of amisulpride, it was subsequently found that the drug also acts as a potent antagonist of the serotonin 5-HT7 receptor (Ki = 11.5 nM). Several of the other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor as well, and selective antagonists of the receptor show antidepressant properties themselves. To characterize the role of the 5-HT7 receptor in the antidepressant effects of amisulpride, a study prepared 5-HT7 receptor knockout mice. The study found that in two widely used rodent models of depression, the tail suspension test, and the forced swim test, those mice did not exhibit an antidepressant response upon treatment with amisulpride. These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.
Amisulpride also appears to bind with high affinity to the serotonin 5-HT2B receptor (Ki = 13 nM), where it acts as an antagonist. The clinical implications of this, if any, are unclear. In any case, there is no evidence that this action mediates any of the therapeutic effects of amisulpride.
Society and cultureEdit
Amisulpride is not approved by the Food and Drug Administration for use in the United States, but it is used in Europe (France, Germany, Italy, Switzerland, Russia, United Kingdom, etc.), Israel, Mexico, India, New Zealand and Australia (TGA approved in February 2002) to treat psychosis and schizophrenia.
- "PRODUCT INFORMATION SOLIAN® TABLETS and SOLUTION" (PDF). TGA eBusiness Services. Sanofi-Aventis Australia Pty Ltd. 9 September 2013. Retrieved 17 October 2013.
- Rosenzweig, P.; Canal, M.; Patat, A.; Bergougnan, L.; Zieleniuk, I.; Bianchetti, G. (2002). "A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers". Human Psychopharmacology. 17 (1): 1–13. doi:10.1002/hup.320. PMID 12404702.
- Caccia, S (May 2000). "Biotransformation of Post-Clozapine Antipsychotics Pharmacological Implications". Clinical Pharmacokinetics. 38 (5): 393–414. doi:10.2165/00003088-200038050-00002. PMID 10843459.
- Noble, S; Benfield, P (December 1999). "Amisulpride: A Review of its Clinical Potential in Dysthymia". CNS Drugs. 12 (6): 471–483. doi:10.2165/00023210-199912060-00005.
- Pani, L; Gessa, GL (2002). "The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia" (PDF). Molecular Psychiatry. 7 (3): 247–253. doi:10.1038/sj.mp.4001040. PMID 11920152.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
- Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
- Brayfield, A, ed. (June 2017). "Amisulpride: Martindale: The Complete Drug Reference". MedicineComplete. Pharmaceutical Press. Retrieved 5 August 2017.
- De Silva, V; Hanwella, R (2008). "Pharmaceutical patents and the quality of mental healthcare in low- and middle-income countries". The Psychiatrist. 32 (4): 121–123. doi:10.1192/pb.bp.107.015651.
- "Pipeline". LB Pharmaceuticals. Retrieved 2019-08-29.
- "Presentations". LB Pharmaceuticals. Retrieved 2019-08-29.
- Komossa, K; Rummel-Kluge, C; Hunger, H; Schmid, F; Schwarz, S; Silveira da Mota Neto, JI; Kissling, W; Leucht, S (January 2010). "Amisulpride versus other atypical antipsychotics for schizophrenia". The Cochrane Database of Systematic Reviews (1): CD006624. doi:10.1002/14651858.CD006624.pub2. PMC 4164462. PMID 20091599.
- Leucht, S; Corves, C; Arbter, D; Engel, RR; Li, C; Davis, JM (January 2009). "Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis". Lancet. 373 (9657): 31–41. doi:10.1016/S0140-6736(08)61764-X. PMID 19058842.
- Solanki, RK; Sing, P; Munshi, D (Oct–Dec 2009). "Current perspectives in the treatment of resistant schizophrenia". Indian Journal of Psychiatry. 51 (4): 254–60. doi:10.4103/0019-5545.58289. PMC 2802371. PMID 20048449.
- Mouaffak, F; Tranulis, C; Gourevitch, R; Poirier, MF; Douki, S; Olié, JP; Lôo, H; Gourion, D (2006). "Augmentation Strategies of Clozapine With Antipsychotics in the Treatment of Ultraresistant Schizophrenia". Clinical Neuropharmacology. 29 (1): 28–33. doi:10.1097/00002826-200601000-00009. PMID 16518132.
- Nuss, P.; Hummer, M.; Tessier, C. (2007). "The use of amisulpride in the treatment of acute psychosis". Therapeutics and Clinical Risk Management. 3 (1): 3–11. doi:10.2147/tcrm.2007.3.1.3. PMC 1936283. PMID 18360610.
- Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
- Sandoz Limited Summary of Product Characteristics, archived from the original on 2014-08-17, retrieved 2014-08-17
- Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Sep 19]. Greenwood Village, CO: Thomsen Healthcare; 2013.
- Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
- McKeage, K; Plosker, GL (2004). "Amisulpride: a review of its use in the management of schizophrenia". CNS Drugs. 18 (13): 933–956. doi:10.2165/00023210-200418130-00007. ISSN 1172-7047. PMID 15521794.
- Natesan, S; Reckless, GE; Barlow, KB; Nobrega, JN; Kapur, S (October 2008). "Amisulpride the 'atypical' atypical antipsychotic — Comparison to haloperidol, risperidone and clozapine". Schizophrenia Research. 105 (1–3): 224–235. doi:10.1016/j.schres.2008.07.005. PMID 18710798.
- Joint Formulary Committee, BMJ, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6.
Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
- Haddad, Peter; Haddad, Peter M.; Dursun, Serdar; Deakin, Bill (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. p. 207–216. ISBN 9780198527480.
- Moncrieff J (July 2006). "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica. 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655.
- Sacchetti, Emilio; Vita, Antonio; Siracusano, Alberto; Fleischhacker, Wolfgang (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN 9788847026797.
- Isbister, GK; Balit, CR; Macleod, D; Duffull, SB (August 2010). "Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes". Journal of Clinical Psychopharmacology. 30 (4): 391–395. doi:10.1097/JCP.0b013e3181e5c14c. PMID 20531221.
- Joy, JP; Coulter, CV; Duffull, SB; Isbister, GK (August 2011). "Prediction of Torsade de Pointes From the QT Interval: Analysis of a Case Series of Amisulpride Overdoses". Clinical Pharmacology & Therapeutics. 90 (2): 243–245. doi:10.1038/clpt.2011.107. PMID 21716272.
- Taylor, D; Paton, C; Shitij, K (2012). Maudsley Prescribing Guidelines in Psychiatry (11th ed.). West Sussex: Wiley-Blackwell. ISBN 978-0-47-097948-8.
- Levine, M; Ruha, AM (July 2012). "Overdose of atypical antipsychotics: clinical presentation, mechanisms of toxicity and management". CNS Drugs. 26 (7): 601–611. doi:10.2165/11631640-000000000-00000. PMID 22668123.
- 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.
- Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL (2009). "Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo". Psychopharmacology. 205 (1): 119–28. doi:10.1007/s00213-009-1521-8. PMC 2821721. PMID 19337725.
- Maitre, M.; Ratomponirina, C.; Gobaille, S.; Hodé, Y.; Hechler, V. (Apr 1994). "Displacement of [3H] gamma-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics". European Journal of Pharmacology. 256 (2): 211–214. doi:10.1016/0014-2999(94)90248-8. PMID 7914168.
- Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B (1997). "Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity". J. Pharmacol. Exp. Ther. 280 (1): 83–97. PMID 8996185.
- Blomme, Audrey; Conraux, Laurence; Poirier, Philippe; Olivier, Anne; Koenig, Jean-Jacques; Sevrin, Mireille; Durant, François; George, Pascal (2000), "Amisulpride, Sultopride and Sulpiride: Comparison of Conformational and Physico-Chemical Properties", Molecular Modeling and Prediction of Bioactivity, Springer US, pp. 404–405, doi:10.1007/978-1-4615-4141-7_97, ISBN 9781461368571
- Lecrubier, Y.; et al. (2001). "Consensus on the Practical Use of Amisulpride, an Atypical Antipsychotic, in the Treatment of Schizophrenia". Neuropsychobiology. 44 (1): 41–46. doi:10.1159/000054913. PMID 11408792.
- Kaplan, A. (2004). "Psychotropic Medications Around the World". Psychiatric Times. 21 (5).