Amisulpride

Amisulpride, sold under the brand name Solian among others, is an antipsychotic medication used to treat schizophrenia.[2] It is also used to treat dysthymia.[5] 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.[6][7][8] It has also been found to be modestly more effective in treating schizophrenia than the typical antipsychotics.[7]

Amisulpride
Clinical data
Trade namesSolian, others
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: C
    Routes of
    administration    		By mouth, intravenous
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    Pharmacokinetic data
    Bioavailability48%[1][2]
    Protein binding16%[2]
    MetabolismHepatic (minimal; most excreted unchanged)[2]
    Elimination half-life12 hours[1]
    ExcretionRenal[1] (23–46%),[3][4] Faecal[2]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.068.916
    Chemical and physical data
    FormulaC17H27N3O4S
    Molar mass369.48 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    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.[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 marketed in all English-speaking countries except for Canada and the United States.[8] 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.[10] A poster presentation at ECNP seems to suggest that this version of amisulpride, known as LB-102 displays the same binding to D2, D3 and 5HT7 that amisulpride does.[11]

    Medical uses

    Schizophrenia

    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).[7] Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia.[12][13] 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.[14][15] Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.[16]

    Contraindications

    Amisulpride's use is contraindicated in the following disease states[2][17][6]

    Neither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.[2]

    Adverse effects
    Very Common (≥10% incidence)[18]
    • 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)[2][19][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)[2][19][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%[20]) 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.[21][22]

    • 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]

    Discontinuation

    The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[23] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[24] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[24] Less commonly there may be a felling of the world spinning, numbness, or muscle pains.[24] Symptoms generally resolve after a short period of time.[24]

    There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[25] It may also result in reoccurrence of the condition that is being treated.[26] Rarely tardive dyskinesia can occur when the medication is stopped.[24]

    Overdose

    Torsades de pointes is common in overdose.[27][28] Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).[29][30]

    Interactions

    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.),[29] 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.[29]

    Pharmacology

    Pharmacodynamics
    See also: Atypical antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications
    Amisulpride[31][32]
    SiteKi (nM)SpeciesRef
    5-HT1A>10,000Human[32]
    5-HT1B1,744Human[32]
    5-HT1D1,341Human[32]
    5-HT1E>10,000Human[32]
    5-HT2A8,304Human[32]
    5-HT2B13Human[32]
    5-HT2C>10,000Human[32]
    5-HT3>10,000Human[32]
    5-HT5A>10,000Human[32]
    5-HT64,154Human[32]
    5-HT711.5Human[32]
    α1A>10,000Human[32]
    α1B>10,000Human[32]
    α1D>10,000Human[32]
    α2A1,114Human[32]
    α2C1,540Human[32]
    β1>10,000Human[32]
    β2>10,000Human[32]
    β3>10,000Human[32]
    D1>10,000Human[32]
    D23.0Human[32]
    D33.5Rat[32]
    D42,369Human[32]
    D5>10,000Human[32]
    H1>10,000Human[32]
    H2>10,000Human[32]
    H4>10,000Human[32]
    M1>10,000Human[32]
    M2>10,000Human[32]
    M3>10,000Human[32]
    M4>10,000Human[32]
    M5>10,000Human[32]
    σ1>10,000Rat[32]
    σ2>10,000Rat[32]
    MOR>10,000Human[32]
    DOR>10,000Human[32]
    KOR>10,000Human[32]
    GHBHigh50 (IC50)Rat[33]
    NMDA
    (PCP)    		>10,000Rat[34]
    SERT>10,000Human[32]
    NET>10,000Human[32]
    DAT>10,000Human[32]
    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.[32] 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.[2]

    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).[33]

    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).[35]

    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).[32] 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.[32] 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.[32] These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.[32]

    Amisulpride also appears to bind with high affinity to the serotonin 5-HT2B receptor (Ki = 13 nM), where it acts as an antagonist.[32] The clinical implications of this, if any, are unclear.[32] In any case, there is no evidence that this action mediates any of the therapeutic effects of amisulpride.[32]

    Society and culture

    Brand names

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

    Availability

    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[2]) to treat psychosis and schizophrenia.[36][37]

    References
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    2. "PRODUCT INFORMATION SOLIAN® TABLETS and SOLUTION" (PDF). TGA eBusiness Services. Sanofi-Aventis Australia Pty Ltd. 9 September 2013. Retrieved 17 October 2013.
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