Amisulpride

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Amisulpride
Amisulpride.svg
Amisulpride-xtal-1990-ball-and-stick-model.png
Clinical data
Trade names Solian, others
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU: C
Routes of
administration
Oral, IV
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability 48%[2][1]
Protein binding 16%[1]
Metabolism Hepatic (minimal; most excreted unchanged)[1]
Biological half-life 12 hours[2]
Excretion Renal[2] (23–46%),[3][4] Faecal[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C17H27N3O4S
Molar mass 369.48 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)

Amisulpride is an antipsychotic medication used to treat schizophrenia.[1] In Italy, at a lower dosage of 50 mg per day, it is also used as a treatment for dysthymia.[5] It is usually classed with the newer generation of antipsychotics, the so called 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.[6][7][8] It has also been found to be slightly more effective in treating schizophrenia than the typical antipsychotics.[7]

Amisulpride, like all other approved antipsychotics, 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.[5]

It was introduced by Sanofi-Aventis in the 1990s. Its patent had expired by 2008 and hence generic formulations are now available.[9] It is not marketed in the Canada or the United States, although in all other English-speaking countries it is marketed.[8]

Medical uses[edit]

Schizophrenia[edit]

In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, amisulpride was ranked second, demonstrating high effectiveness. 11% more effective than olanzapine (3rd), 32-35% more effective than haloperidol, quetiapine, and aripiprazole, and 25% less effective than clozapine (1st).[7] Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia.[10][11] 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.[12][13] Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.[14]

Adverse effects[edit]

Very Common (≥10% incidence)[15]
  • 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).[7]
Common (≥1%, <10% incidence)[1][16][17][6]
  • 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)[7]
  • 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)[1][16][17][6]


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%[18]) 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.[19][20]

  • 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.[7]

Contraindications[edit]

Amisulpride's use is contraindicated in the following disease states[1][17][6]

Neither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.[1]

Interactions[edit]

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.),[21] 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.[21]

Overdose[edit]

Torsades de pointes is common in overdose.[22][23] Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).[21][24]

Pharmacology[edit]

Amisulpride function primarily as a D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 2.2 nM and 2.4 nM, respectively. Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory pre-synaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low dose amisulpride has also been used to treat dysthymia.[1]

Amisulpride and its relative sulpiride have been shown to bind to and activate the GHB receptor at doses that are used for therapeutic purposes.[25]

Though it has long been widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychotic properties of amisulpride, it has recently been shown that it also acts as a potent antagonist at the 5-HT7 receptor.[26] 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.[26] 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.[26] These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.[26]

Amisulpride also appears to bind with high affinity to the 5-HT2B receptor (see below table), though the clinical implications of this, if any, are unclear.

Molecular target Binding Affinity (Ki in nM)[27]
SERT >10000
NET >10000
DAT >10000
5-HT1A >10000
5-HT1B 1744
5-HT1D 1341
5-HT1E >10000
5-HT2A 8304
5-HT2B 13
5-HT2C >10000
5-HT3 >10000
5-HT5A >10000
5-HT6 4154
5-HT7 11.5[26]
α1A >10000
α1B >10000
α1D >10000
α2A 1114
α2C 1540
β1 >10000
β2 >10000
β3 >10000
M1 >10000
M2 >10000
M3 >10000
M4 >10000
M5 >10000
D1 >10000
D2 2.2
D3 2.4
D4 2370
D5 >10000
H1 >10000
H2 >10000
H4 >10000
δ opioid >10000
κ opioid >10000
μ opioid >10000
Prostaglandin E3 receptor >10000
Prostaglandin E4 receptor >10000

Availability[edit]

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, India, New Zealand and Australia (TGA approved in February 2002[1]) to treat psychosis and schizophrenia.[28][29]

Brand names include: Amazeo, Amipride (AU), Amival, Solian (AU, IE, RU, UK, ZA), Soltus, Sulpitac (IN), Sulprix (AU) and Socian (BR).

References[edit]

  1. ^ a b c d e f g h i j k "PRODUCT INFORMATION SOLIAN® TABLETS and SOLUTION" (PDF). TGA eBusiness Services. Sanofi-Aventis Australia Pty Ltd. 9 September 2013. Retrieved 17 October 2013. 
  2. ^ a b c 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. PMID 12404702. doi:10.1002/hup.320. 
  3. ^ Caccia, S (May 2000). "Biotransformation of Post-Clozapine Antipsychotics Pharmacological Implications". Clinical Pharmacokinetics. 38 (5): 393–414. doi:10.2165/00003088-200038050-00002. 
  4. ^ 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. 
  5. ^ a b 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. PMID 11920152. doi:10.1038/sj.mp.4001040. 
  6. ^ a b c d Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  7. ^ a b c d e f g 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. PMID 23810019. doi:10.1016/S0140-6736(13)60733-3. 
  8. ^ a b Brayfield, A, ed. (June 2017). "Amisulpride: Martindale: The Complete Drug Reference". MedicineComplete. Pharmaceutical Press. Retrieved 5 August 2017. 
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  10. ^ 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. PMC 4164462Freely accessible. PMID 20091599. doi:10.1002/14651858.CD006624.pub2. 
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  15. ^ Sandoz Limited Summary of Product Characteristics, archived from the original on 2014-08-17, retrieved 2014-08-17 
  16. ^ a b Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Sep 19]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  17. ^ a b c Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. 
  18. ^ 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. 
  19. ^ McKeage, K; Plosker, GL (2004). "Amisulpride: a review of its use in the management of schizophrenia.". CNS Drugs. 18 (13): 933–956. ISSN 1172-7047. PMID 15521794. doi:10.2165/00023210-200418130-00007. 
  20. ^ 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. PMID 18710798. doi:10.1016/j.schres.2008.07.005. 
  21. ^ a b c Taylor, D; Paton, C; Shitij, K (2012). Maudsley Prescribing Guidelines in Psychiatry (11th ed.). West Sussex: Wiley-Blackwell. ISBN 978-0-47-097948-8. 
  22. ^ 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. PMID 20531221. doi:10.1097/JCP.0b013e3181e5c14c. 
  23. ^ 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. PMID 21716272. doi:10.1038/clpt.2011.107. 
  24. ^ Levine, M; Ruha, AM (July 2012). "Overdose of atypical antipsychotics: clinical presentation, mechanisms of toxicity and management." (PDF). CNS Drugs. 26 (7): 601–611. PMID 22668123. doi:10.2165/11631640-000000000-00000. 
  25. ^ 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. PMID 7914168. doi:10.1016/0014-2999(94)90248-8. 
  26. ^ a b c d e 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): 119–128. PMC 2821721Freely accessible. PMID 19337725. doi:10.1007/s00213-009-1521-8. 
  27. ^ National Institute of Mental Health. "PDSP Ki Database". University of North Carolina. Archived from the original on 8 November 2013. Retrieved 5 July 2013. 
  28. ^ 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. PMID 11408792. doi:10.1159/000054913. 
  29. ^ Kaplan, A. (2004). "Psychotropic Medications Around the World". Psychiatric Times. 21 (5).