Sulpiride Explained

Sulpiride, sold under the brand name Dogmatil among others, is an atypical antipsychotic (although some texts have referred to it as a typical antipsychotic)^[1] medication of the benzamide class which is used mainly in the treatment of psychosis associated with schizophrenia and major depressive disorder, and is sometimes used in low dosage to treat anxiety and mild depression. Sulpiride is commonly used in Asia, Central America, Europe, South Africa and South America. Levosulpiride is its purified levo-isomer and is sold in India for similar purposes. It is not approved in the United States, Canada, or Australia. The drug is chemically and clinically similar to amisulpride.

Medical uses

Sulpiride's primary use in medicine is in the management of the symptoms of schizophrenia. It has been used as both a monotherapy and adjunctive therapy (in case of treatment-resistance) in schizophrenia.^{[2] [3] [4] [5] [6]} It has also been used in the treatment of dysthymia.^[7] There is evidence, although low quality, that Sulpiride could accelerate antidepressant response in patients with major depressive disorder.^[8] There is also evidence of its efficacy in treating panic disorder.^{[9] [10]} Sulpiride is indicated for the treatment of vertigo in some countries.^[11] In Japan, Sulpiride is both approved as a treatment for schizophrenia and for major depressive disorder (low dose).^{[12] [13]}

Contraindications

Contraindications

• Hypersensitivity to sulpiride
• Pre-existing breast cancer or other prolactin-dependent tumors
• Phaeochromocytoma
• Intoxication with other centrally-active drugs
• Concomitant use of levodopa
• Acute porphyria
• Comatose state or CNS depression
• Bone-marrow suppression

Cautions

• Pre-existing Parkinson's disease
• Patients under 18 years of age (insufficient clinical data)
• Pre-existing severe heart disease/bradycardia, or hypokalemia (predisposing to long QT syndrome and severe arrhythmias)
• Patients with pre-existing epilepsy. Anticonvulsant therapy should be maintained
• Lithium use — increased risk of neurological side effects of both drugs

Pregnancy and lactation

• Pregnancy: Animal studies did not reveal any embryotoxicity or fetotoxicity, nor did limited human experience. Due to insufficient human data, pregnant women should be treated with sulpiride only if strictly indicated. Additionally, the newborns of treated women should be monitored, because isolated cases of extrapyramidal side effects have been reported.
• Lactation: Sulpiride is found in the milk of lactating women. Since the consequences are unclear, women should not breastfeed during treatment.

Side effects

Sulpiride is usually well tolerated, producing few adverse effects. Their incidences are as follows:^{[2] [14] [15] [16] [17] [18] [19] [20]}

Common (>1%) adverse effects:

• Dizziness
• Headache
• Extrapyramidal side effects

- Tremor

- Dystonia

- Akathisia — a sense of inner restlessness that presents itself with the inability to stay still

- Parkinsonism

• Somnolence (not a very prominent adverse effect considering its lack of α₁ adrenergic, histamine and muscarinic acetylcholine receptor affinity)
• Insomnia
• Weight gain or loss
• Hyperprolactinemia (elevated plasma levels of the hormone, prolactin which can, in turn lead to sexual dysfunction, galactorrhea, amenorrhea, gynecomastia, etc.)
• Nausea
• Vomiting
• Nasal congestion
• Anticholinergic adverse effects such as:

- Dry mouth

- Constipation

- Blurred vision

• Impaired concentration

Rare (<1% incidence) adverse effects:

• Tardive dyskinesia — a rare, often permanent movement disorder that, more often than not, results from prolonged treatment with antidopaminergic agents such as antipsychotics. It presents with slow (hence tardive), involuntary, repetitive and purposeless movements that most often affect the facial muscles.
• Neuroleptic malignant syndrome — a rare, life-threatening complication that results from the use of antidopaminergic agents. Its incidence increases with concomitant use of lithium (medication) salts
• Blood dyscrasias — rare, sometimes life-threatening complications of the use of a number of different antipsychotics (most notably clozapine) which involves abnormalities in the composition of a person's blood (e.g. having too few white blood cells per unit volume of blood). Examples include:

- Agranulocytosis — a significant drop in white blood cell count, leaving individuals wide open to life-threatening opportunistic infections

- Neutropenia

- Leucopenia

- Leukocytosis^[21]

• Seizures
• Torsades de pointes

Unknown incidence adverse effects include:

• QTc interval prolongation which can lead to potentially fatal arrhythmias.
• Cholestatic jaundice^[22]
• Elevated liver enzymes
• Primary biliary cirrhosis^[23]
• Allergic reactions
• Photosensitivity — sensitivity to light
• Skin rashes
• Depression
• Catatonia
• Palpitations
• Agitation
• Diaphoresis — sweating without a precipitating factor (e.g. increased ambient temperature)
• Hypotension — low blood pressure
• Hypertension — high blood pressure
• Venous thromboembolism (probably rare)

Overdose

Sulpiride has a relatively low order of acute toxicity. Substantial amounts may cause severe but reversible dystonic crises with torticollis, protrusion of the tongue, and/or trismus. In some cases all the classical symptoms typical of severe Parkinson's disease may be noted; in others, over-sedation/coma may occur. The treatment is largely symptomatic. Some or all extrapyramidal reactions may respond to the application of anticholinergic drugs such as biperiden or benzatropine. All patients should be closely monitored for signs of long QT syndrome and severe arrhythmias.

Interactions

Sulpiride neither inhibits nor stimulates cytochrome P450 family (CYP) of oxidizing enzymes in human, thus would not cause clinically significant interactions with other drugs, which are metabolized by CYPs. However, the risk or severity of adverse effects can be increased when sulpiride is combined with other drugs, but this is not related to substrates, inducers and inhibitors of CYPs.

Pharmacology

Pharmacodynamics

Sulpiride^[24]

	Affinity (Ki, nM)
DAT	>10,000
	>10,000
5-HT2A	4,786
5-HT3	>10,000
5-HT6	5,011
5-HT7	5,011
α1	>10,000
α2	>10,000
	>10,000
	9.8
	8.05
	54
H1	>10,000
	>10,000
Affinity values are toward cloned human receptors.

Sulpiride is a selective antagonist at dopamine D₂, D₃ and to a lesser extent D₄ receptors. Antagonism at 5-HT_1A dominates in doses exceeding 600 mg daily. In doses of 600 to 1,600 mg sulpiride shows mild sedating and antipsychotic activity. Its antipsychotic potency compared to chlorpromazine is only 0.2 (1/5). In low doses (in particular 50 to 200 mg daily) its prominent feature is antagonism of presynaptic inhibitory dopamine and serotonin receptors, accounting for some antidepressant activity and a stimulating effect. Additionally, it alleviates vertigo.

The benzamide neuroleptics (including sulpiride, amisulpride, and sultopride) have been shown to activate the endogenous gamma-hydroxybutyrate receptor in vivo at therapeutic concentrations.^[25] Sulpiride was found in one study in rats to upregulate GHB receptors.^[26] GHB has neuroleptic properties and it is believed binding to this receptor may contribute to the effects of these neuroleptics.

Sulpiride, along with clozapine, and valproate has been found to activate DNA demethylation in the brain.^[27]

History

Sulpiride was discovered in 1966 as a result of a research program by Justin-Besançon and C. Laville at Laboratoires Delagrange who were working to improve the anti-dysrhythmic properties of procainamide; the program led first to metoclopramide and later to sulpiride.^{[28] [29]} Laboratoires Delagrange was acquired by Synthelabo in 1991^{[30] [31]} which eventually became part of Sanofi.^[32]

Society and culture

Brand names

Sulpiride is marketed under the brand names Dogmatil (DE, HK, SG, PH), Dolmatil (IE, UK, NL), Eglonyl (RU, ZA, HR, SI), Espiride (ZA), Modal (IL), Prometar (UY), Equilid (BR) and Sulpor (UK), among many others.^[33]

Medicinal forms

These include tablet and oral solution^[34]

Patient Aversions

Some individuals from the Caribbean region may have an aversion to taking the medication due to the association with the brand name of Dogmatil. Dogmatil has been associated with dog medication.

Research

Sulpiride has been studied for use as a hormonal contraceptive in women in whom conventional oral contraceptives are contraindicated and to potentiate progestogen-only contraceptives.^{[35] [36]} The contraceptive effects of sulpiride are due to its prolactin-releasing and antigonadotropic effects and the hyperprolactinemia–amenorrhea state that it induces.

Since the use of psychotropic drugs is efficient in treating irritable bowel syndrome (IBS), sulpiride is studied as potential sole maintenance therapy in the treatment of IBS.^{[37] [38] [39]}

Notes and References

1. Book: 978-0-85711-084-8 . British National Formulary (BNF) . Joint Formulary Committee . 2013 . Pharmaceutical Press . London, UK . 65 . registration .
2. Book: 978-0-470-97948-8 . The Maudsley prescribing guidelines in psychiatry . Taylor D, Paton C, Shitij K . 2012 . Wiley-Blackwell . West Sussex .
3. Wang J, Omori IM, Fenton M, Soares B . Sulpiride augmentation for schizophrenia . The Cochrane Database of Systematic Reviews . 1 . CD008125 . January 2010 . 20091661 . 10.1002/14651858.CD008125.pub2 .
4. Lai EC, Chang CH, Kao Yang YH, Lin SJ, Lin CY . Effectiveness of sulpiride in adult patients with schizophrenia . Schizophrenia Bulletin . 39 . 3 . 673–83 . May 2013 . 22315480 . 3627763 . 10.1093/schbul/sbs002 .
5. Soares BG, Fenton M, Chue P . Sulpiride for schizophrenia . The Cochrane Database of Systematic Reviews . 2 . CD001162 . 2000 . 10796605 . 10.1002/14651858.CD001162 .
6. Sulpiride versus other antipsychotics for schizophrenia (Protocol). Omori IM, Wang J, Soares B, Fenton M . The Cochrane Database of Systematic Reviews. 4. CD008126. October 2009. 10.1002/14651858.CD008126.
7. Pani L, Gessa GL . The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia . Molecular Psychiatry . 7 . 3 . 247–53 . 2002 . 11920152 . 10.1038/sj.mp.4001040 . 3153728 .
8. Uchida H, Takeuchi H, Suzuki T, Nomura K, Watanabe K, Kashima H . 10727911 . Combined treatment with sulpiride and paroxetine for accelerated response in patients with major depressive disorder . Journal of Clinical Psychopharmacology . 25 . 6 . 545–51 . December 2005 . 16282835 . 10.1097/01.jcp.0000185425.00644.41 .
9. Bell C, Bhikha S, Colhoun H, Carter F, Frampton C, Porter R . 32951554 . The response to sulpiride in social anxiety disorder: D2 receptor function . Journal of Psychopharmacology . 27 . 2 . 146–51 . February 2013 . 22745189 . 10.1177/0269881112450778 .
10. Nunes EA, Freire RC, Dos Reis M, de Oliveira E, Silva AC, Machado S, Crippa JA, Dursun SM, Baker GB, Hallak JE, Nardi AE . 14870287 . 6 . Sulpiride and refractory panic disorder . Psychopharmacology . 223 . 2 . 247–9 . September 2012 . 22864966 . 10.1007/s00213-012-2818-6 .
11. Web site: Medicinanet - Equilid 50 . 2018-09-05.
12. Web site: Search results detail Kusurino-Shiori(Drug information Sheet). www.rad-ar.or.jp. 2020-03-16.
13. Towlson EK, Vértes PE, Müller-Sedgwick U, Ahnert SE . Brain Networks Reveal the Effects of Antipsychotic Drugs on Schizophrenia Patients and Controls . Frontiers in Psychiatry . 10 . 611 . 2019-09-12 . 31572229 . 6752631 . 10.3389/fpsyt.2019.00611 . free .
14. Lepola U, Koskinen T, Rimón R, Salo H, Gordin A . Sulpiride and perphenazine in schizophrenia. A double-blind clinical trial . Acta Psychiatrica Scandinavica . 80 . 1 . 92–6 . July 1989 . 2669445 . 10.1111/j.1600-0447.1989.tb01305.x . 28719315 .
15. Munk-Andersen E, Behnke K, Heltberg J, Nielsen H, Gerlach J . Sulpiride versus haloperidol, a clinical trial in schizophrenia. A preliminary report . Acta Psychiatrica Scandinavica. Supplementum . 311 . 31–41 . 1984 . 6367362 . 10.1111/j.1600-0447.1984.tb06857.x . 31689174 .
16. Gerlach J, Behnke K, Heltberg J, Munk-Anderson E, Nielsen H . Sulpiride and haloperidol in schizophrenia: a double-blind cross-over study of therapeutic effect, side effects and plasma concentrations . The British Journal of Psychiatry . 147 . 3 . 283–8 . September 1985 . 3904885 . 10.1192/bjp.147.3.283 . 24056594 .
17. Standish-Barry HM, Bouras N, Bridges PK, Watson JP . A randomized double blind group comparative study of sulpiride and amitriptyline in affective disorder . Psychopharmacology . 81 . 3 . 258–60 . 1983 . 6417717 . 10.1007/bf00427274 . 28134446 .
18. Quinn N, Marsden CD . A double blind trial of sulpiride in Huntington's disease and tardive dyskinesia . Journal of Neurology, Neurosurgery, and Psychiatry . 47 . 8 . 844–7 . August 1984 . 6236286 . 1027949 . 10.1136/jnnp.47.8.844 .
19. Peselow ED, Stanley M . Clinical trials of benzamides in psychiatry . Advances in Biochemical Psychopharmacology . 35 . 163–94 . 1982 . 6756060 .
20. Edwards JG, Alexander JR, Alexander MS, Gordon A, Zutchi T . Controlled trial of sulpiride in chronic schizophrenic patients . The British Journal of Psychiatry . 137 . 6 . 522–9 . December 1980 . 7011469 . 10.1192/bjp.137.6.522 . 789670 .
21. Levkovitz H, Abramovitch Y, Nitzan I . 43471005 . Leukocytosis related to the therapeutic dosage of sulpiride . Biological Psychiatry . 35 . 12 . 963 . June 1994 . 8080896 . 10.1016/0006-3223(94)91244-0 .
22. Melzer E, Knobel B . Severe cholestatic jaundice due to sulpiride . Israel Journal of Medical Sciences . 23 . 12 . 1259–60 . December 1987 . 3326861 .
23. Ohmoto K, Yamamoto S, Hirokawa M . Symptomatic primary biliary cirrhosis triggered by administration of sulpiride . The American Journal of Gastroenterology . 94 . 12 . 3660–1 . December 1999 . 10.1111/j.1572-0241.1999.01634.x . 10606349 . 33986018 .
24. Web site: PDSP Ki Database. 13 November 2020. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Bryan Roth. Roth BL, Driscol J.
25. Maitre M, Ratomponirina C, Gobaille S, Hodé Y, Hechler V . Displacement of [3H] gamma-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics . European Journal of Pharmacology . 256 . 2 . 211–4 . April 1994 . 7914168 . 10.1016/0014-2999(94)90248-8 .
26. Ratomponirina C, Gobaille S, Hodé Y, Kemmel V, Maitre M . Sulpiride, but not haloperidol, up-regulates gamma-hydroxybutyrate receptors in vivo and in cultured cells . European Journal of Pharmacology . 346 . 2–3 . 331–7 . April 1998 . 9652377 . 10.1016/S0014-2999(98)00068-5 .
27. Dong E, Nelson M, Grayson DR, Costa E, Guidotti A . Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation . Proceedings of the National Academy of Sciences of the United States of America . 105 . 36 . 13614–9 . September 2008 . 18757738 . 2533238 . 10.1073/pnas.0805493105 . 2008PNAS..10513614D . free .
28. Book: Sneader W . Drug Discovery: A History. 31 October 2005. John Wiley & Sons. 978-0-470-01552-0. 205–.
29. Sanger GJ . Translating 5-HT receptor pharmacology . Neurogastroenterology and Motility . 21 . 12 . 1235–8 . December 2009 . 19906028 . 10.1111/j.1365-2982.2009.01425.x . 35544028 . free .
30. Web site: Conard D . Les Echos . October 17, 1991 . Synthélabo rachète les laboratoires Delagrange .
31. Web site: Bibliothèque nationale de France . Laboratoires Delagrange . August 24, 2016 .
32. Web site: Meek T . PMLiVE . May 24, 2013 . A look back at Sanofi's merger with Synthélabo .
33. Web site: Sulpiride . Drugs.com .
34. Web site: Sulpiride 200mg/5ml Oral Solution . EMC . Datapharm .
35. Buvat J, Decroix-Blacker C, Legal F, Gasnault JP . [One thousand months of contraception with sulpiride] ]. fr . Revue Française de Gynécologie et d'Obstétrique . 71 . 1 . 53–61 . January 1976 . 959705 . 15 April 2018 . 15 April 2018 . https://web.archive.org/web/20180415190721/https://www.popline.org/node/429364 . dead .
36. Payne MR, Howie PW, McNeilly AS, Cooper W, Marnie M, Kidd L . Sulpiride and the potentiation of progestogen only contraception . British Medical Journal . 291 . 6495 . 559–61 . August 1985 . 2994800 . 1418199 . 10.1136/bmj.291.6495.559 .
37. New regimen for treatment of irritable bowel syndrome with emphasis on Sulpride as the sole maintenance therapy. Journal of Drug Delivery and Therapeutics . 2019 . 10.22270/jddt.v9i5.3424 . El-Reshaid K, Al-Bader S . 9. 5. 154–157. 208163204. free.
38. Komarov FI, Rapoport SI, Ivanov SV, Kharaian LV, Kolesnikov DB, Kurikov AV . [Sulpiride treatment of irritable colon syndrome] . Russian . Klin Med (Mosk) . 78 . 7 . 22–6 . 2000 . 10979637.
39. Sato M, Murakami M . [Treatment for irritable bowel syndrome--psychotropic drugs, antidepressants and so on] . Japanese . Nihon Rinsho . 64 . 8 . 1495–500 . August 2006 . 16898620 .