|AHFS/Drugs.com||International Drug Names|
|ATC code||N05AL05 (WHO)|
|Metabolism||Hepatic (minimal; most excreted unchanged)|
|Biological half-life||12 hours|
|Excretion||Renal (23–46%), Fecal|
|Chemical and physical data|
|Molar mass||369.48 g/mol|
|3D model (Jmol)||Interactive image|
|(what is this?)|
Amisulpride (sold as Amazeo, Amipride (AU), Amival, Solian (AU, IE, RU, UK, ZA), Soltus, Sulpitac (IN), Sulprix (AU), Socian (BR), is an atypical antipsychotic used to treat psychosis in schizophrenia and episodes of mania in bipolar disorder. In Italy, it is also used as a treatment for dysthymia.
It was introduced by Sanofi-Aventis in the 1990s. Its patent had expired by 2008 and hence generic formulations are now available.
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, it is worth noting that the supporting evidence is limited to the theory, case reports, a small randomised double-blind placebo-controlled trial and a couple of open-label studies) in clozapine-resistant cases of schizophrenia. A randomised, double-blind, placebo-controlled clinical trial has been conducted to evaluate the efficacy of celecoxib as an adjunct to amisulpride, with significant success. Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.
Amisulpride has been tried as a treatment for acute mania in a few open-label studies. These findings should be interpreted with caution, not just due to the fact that these clinical trials were all open-label and hence low-quality but also because several case reports have been made documenting the precipitation of mania in schizophrenia patients that received amisulpride.
At low doses, it is also used to treat dysthymia where it appears to be at least as effective as conventional antidepressants according to a recent Cochrane review. Studies showed that at dose < 50 mg amisulpride has preferential affinity for pre-synaptic dopamine D2 and D3 autoreceptor subtypes (pre-synaptics autoreceptors serves as a negative feedback loop control). By blocking these autoreceptors amisulpride is preventing neurons from stopping the release of dopamine, leading to an increase of dopamine concentration in the brain. This mode of action could explain its strong antidepressant properties. In this indication, amisulpride is significantly more effective than:
and equal to:
Low-dose amisulpride has been found to be an effective treatment for postoperative emesis in a recent randomised, double-blind, placebo-controlled clinical trial. In a small (N=11) clinical trial amisulpride combined with either mirtazapine or citalopram was found an effective treatment for psychotic depression in elderly patients, although it should be noted that this trial was not placebo-controlled and hence the level of evidence it provides to amisulpride's efficacy in this indication is low. In a medium-sized (N=106) single-blind study it was found efficacious and well-tolerated in improving depressive symptoms in cancer patients undergoing chemotherapy.
- 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
- 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.
- Concomitant prolactin-dependent tumors e.g. prolactinoma, breast cancer
- Movement disorders (e.g. Parkinson's disease and dementia with Lewy bodies)
- Children before the onset of puberty
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.
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.
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. 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 5-HT2B receptor (see below table), though the clinical implications of this, if any, are unclear.
|Molecular target||Binding Affinity (Ki in nM)|
|Prostaglandin E3 receptor||>10000|
|Prostaglandin E4 receptor||>10000|
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) to treat psychosis and schizophrenia.
Dopamine receptor antagonist.
4-amino-5-mercapto-2-methoxybenzoic acid (1) is alkylated with diethyl sulfate to 4-amino-5-(ethylthio)-2-methoxybenzoic acid (2) and then this is oxidized with H2O2 to 4-amino-5-(ethylsulfonyl)-2-methoxybenzoic acid (3). A mixed anhydride is prepared via reaction with ethyl chloroformate (4) and then amidation with 1-ethyl-(2-aminoethyl)pyrrolidine (5) to give amisulpride as the product (6).
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