Amisulpride, sold under the brand names Socian and Barhemsys, is a medication used in the treatment of schizophrenia, acute psychotic episodes, depression, and nausea and vomiting. It is specifically used at lower doses intravenously to prevent and treat postoperative nausea and vomiting, at low doses by mouth to treat depression, and at higher doses by mouth to treat psychosis.
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.
Amisulpride is indicated for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.
Amisulpride is believed to work by blocking, or antagonizing, the dopamine D2 receptor, reducing its signalling. The effectiveness of amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynaptic dopamine D2 and D3 autoreceptors. 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 expired by 2008, and generic formulations became available. It is marketed in all English-speaking countries except for Canada.
Medical uses
Schizophrenia 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.
Depression Amisulpride is approved and used at low doses in the treatment of dysthymia and major depressive disorder. Whereas typical doses used in schizophrenia block postsynaptic dopamine D2-like receptors and reduce dopaminergic neurotransmission, low doses of amisulpride preferentially block presynaptic dopamine D2 and D3 autoreceptors and thereby disinhibit dopamine release and enhance dopaminergic neurotransmission. A 2010 Cochrane review found that low-dose amisulpride was effective in the treatment of dysthymia. Likewise, a 2024 literature review found that low-dose amisulpride was effective for dysthymia. The drug is approved for depression specifically in Italy, Greece, and certain other European countries.
Postoperative nausea and vomiting Amisulpride is indicated for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.
Available forms Amisulpride is available in the form of 100, 200, and 400mg oral tablets. In the United States, it is available in the form of a 5mg/2mL (2.5mg/mL) solution for intravenous administration.
Contraindications Amisulpride's use is contraindicated in the following disease states and populations
Pheochromocytoma Concomitant prolactin-dependent tumours e.g. prolactinoma, breast cancer Movement disorders (e.g. Parkinson's disease and dementia with Lewy bodies) Lactation 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.
Adverse effects The adverse effect frequencies listed below are when prescribed as an antipsychotic, at much higher doses than are used to treat depression and nausea and vomiting.
Very Common (≥10% incidence) Extrapyramidal side effects (EPS; including dystonia, tremor, akathisia, parkinsonism).
Common (≥1%, <10% incidence)Truven Health Analytics, Inc. DRUGDEX System (Internet) [cited 2013 Sep 19]. Greenwood Village, CO: Thomsen Healthcare; 2013.
Insomnia Somnolence Hypersalivation Nausea Headache Hyperactivity Vomiting
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)
Hyponatraemia Bradycardia Hypotension Palpitations Urticaria Seizures Mania Oculogyric crisis Tardive dyskinesia
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.
Discontinuation 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 feeling 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 transient withdrawal related rebound psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Overdose Torsades de pointes is common in overdose. Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).
Interactions Amisulpride should not be used in conjunction with drugs that prolong the QT interval (such as citalopram, bupropion, clozapine, tricyclic antidepressants, sertindole, ziprasidone, etc.), as this can cause potential life threatening arrhythmias (Torsades de pointes, Ventricular tachycardia, and Ventricular fibrillation)
Pharmacology
Pharmacodynamics
+ Amisulpride Site Ki (nM) Species Ref 10000+ Human 10000+ Human 10000+ Human 5-HT1A 10000+ Human 5-HT1B 1744 Human 5-HT1D 1341 Human 5-HT1E 10000+ Human 5-HT2A 8304 Human 5-HT2B 13 Human 5-HT2C 10000+ Human 5-HT3 10000+ Human 5-HT5A 10000+ Human 5-HT6 4154 Human 5-HT7 11.5 Human α1A 10000+ Human α1B 10000+ Human α1D 10000+ Human α2A 1114 Human α2C 1540 Human β1 10000+ Human β2 10000+ Human β3 10000+ Human D1 10000+ Human D2 3.0 Human D3 3.5 Rat D4 2369 Human D5 10000+ Human H1 10000+ Human H2 10000+ Human H4 10000+ Human M1 10000+ Human M2 10000+ Human M3 10000+ Human M4 10000+ Human M5 10000+ Human σ1 10000+ Rat σ2 10000+ Rat 10000+ Human 10000+ Human 10000+ Human 50 () Rat () 10000+ Rat 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 ( = 50 nM for amisulpride).
Amisulpride, sultopride and sulpiride respectively present decreasing in vitro affinities for the D2 receptor (IC50 = 27, 120 and 181 nM) and the D3 receptor (IC50 = 3.6, 4.8 and 17.5 nM).
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.
Amisulpride shows stereoselectivity in its actions. Aramisulpride ((R)-amisulpride) has higher affinity for the 5-HT7 receptor (Ki = 47 nM vs. 1,900 nM) while esamisulpride ((S)-amisulpride) has higher affinity for the D2 receptor (4.0 nM vs. 140 nM).
Pharmacokinetics The oral bioavailability of amisulpride is 48%. Its plasma protein binding is 16%. The drug is metabolized by the liver but its metabolism is minimal. Its elimination half-life is 12hours. Amisulpride is eliminated in urine (23–46%) and feces and is excreted mostly unchanged.
Chemistry Amisulpride is a benzamide derivative. It is structurally related to other benzamide dopamine receptor antagonists employed as antipsychotics and antiemetics including levosulpiride, metoclopramide, nemonapride, remoxipride, sulpiride, sultopride, tiapride, and veralipride. Chemically, it is also known as aminosultopride, differing from sultopride only in possessing an amino substituent on its benzene ring.
History Amisulpride was introduced by Sanofi-Aventis in the 1990s. Its patent expired by 2008, and generic formulations became available.
United States clinical development