Amisulpride

Schizophrenia

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.

Bipolar disorder

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.

Dysthymia

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:

Investigational

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.

Adverse effects

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.

Contraindications

Amisulpride's use is contraindicated in the following disease states

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

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.), 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.

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).

Pharmacology

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.

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

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-HT_2B receptor (see below table), though the clinical implications of this, if any, are unclear.

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, India, New Zealand and Australia (TGA approved in February 2002) to treat psychosis and schizophrenia.

Synthesis

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).