Amisulpride – Mechanism of Action | Psychopharmacology | Clinical Application

Amisulpride is a highly selective dopamine D2/D3 receptor antagonist that is described as having atypical properties even though it does not block serotonin receptors. [Rein et al 1997]

Its characterisation as atypical comes from its selective affinity for receptors in limbic structures but not in the striatum, which means a low extrapyramidal symptom burden exists. [Perrault et al 1997]

A prospective study, of a cohort of first-episode, antipsychotic-naïve schizophrenia patients, were examined before and after 6 weeks of treatment with amisulpride (selective dopamine D2/3  receptor antagonist).

A dose-dependent striatal volume increase in antipsychotic-naïve schizophrenia patients in response to six weeks dopamine D_2/3 receptor blockade by amisulpride was clinically relevant and correlated to a reduction in positive symptoms. [Andersen et al., 2020]

• Amisulpride selectively binds to D2/D3 receptors with no affinity for dopamine D1, D4, or D5 receptor subtypes.
• In addition, amisulpride has little to no affinity for serotonergic (5HT), adrenergic (α1), histaminergic (H1), or cholinergic receptors (AChR).
• However, in animal studies, amisulpride was found to be a potent 5HT-7 antagonist which may underpin its antidepressant effects. [Abbas A et al., 2009]

Read more on the role of D3 receptors in negative symptoms. 

Dual Effect: 

At low doses, amisulpride blocks presynaptic autoreceptors, which facilitates dopamine release and thus resolves dopaminergic hypoactivity and the symptoms of depression.

At higher doses, amisulpride blocks postsynaptic dopamine D2 and D3 receptors in the limbic region and prefrontal regions, which is responsible for its antipsychotic effects. [Scatton et al 1997]

Comparison to Sulpiride:

• Sulpiride is also a substituted benzamide with selective dopaminergic blocking activity.
• Sulpiride is a D2/ D3/ antagonist with additional low-affinity D4 antagonist properties [D₄ receptor is involved in the modulation of corticostriatal glutamatergic neurotransmission.].
• Its D2 presynaptic antagonism is associated with anti-depressant properties. The D3 antagonism shows benefits in negative symptoms.
• Sulpiride penetrates the blood-brain barrier poorly because of its low lipid solubility
• It is administered BD.
• Higher doses ≥ 800 mg are used for positive psychotic symptoms in schizophrenia; < 800 mg are used for negative symptoms.

Pharmacokinetics

Oral amisulpride is rapidly absorbed, has a bioavailability of approximately 50%, and reaches a maximum serum concentration of 42-56 µg/L within 1-4 hours. Steady-state concentrations are generally reached after 3 days. Amisulpride has an elimination half-life of 12 hours and is excreted mainly via the kidneys with a renal clearance of 17-20 L/h. [Sparshatt et al 2009]

Drug interactions

Amisulpride has two inactive and zero active metabolites; it is weakly metabolised by the cytochrome P450 isoenzyme system thus avoiding clinically relevant metabolic interactions. [Spina and de Lean 2007] Furthermore, amisulpride is not an inhibitor of any of these CYP450 enzymes. [Gillet et al 2000]

• Research shows that amisulpride’s optimal dose correlates closely with clinical response, dopamine occupancy, and extrapyramidal symptom burden.
• Amisulpride’s recommended dosage for acute psychosis is 400 to 800 mg/day divided across two doses with a maximum dose of 1200 mg/day permitted.
• However, for negative symptoms, a lower dose of 50 to 300 mg/day is recommended.

Amisulpride has a very favourable safety profile compared to other atypical antipsychotics with a very low incidence of cardiac, CNS, or gastrointestinal side effects reported. [Coulouvrat and Dondey-Nouvel 1999]

However, it is associated with an elevation in serum prolactin levels, which is due to its potent D2 antagonist properties.

Increase in plasma prolactin levels was associated with D2 receptor antagonism and found to be markedly greater with amisulpride than with other atypical agents (risperidone, olanzapine, and quetiapine) in a 2-week study in patients with schizophrenia. [Fric M et al., 2003]

Hyperprolactinaemia has been reported in patients receiving amisulpride dosage of as low as 50 mg/day as an augmentation to antidepressant therapy. [Raj and Sidhu., 2008]

• Common side effects in 5 to 10% of patients include insomnia, anxiety, and agitation.
• Other side effects that are less common (<2%) include somnolence, constipation, dry mouth, nausea, and vomiting.

Furthermore, it has been reported that amisulpride has a dose-dependent effect on the QTc interval with overdoses associated with QT prolongation and Torsades de Pointes. [Isbister et al. 2010]

Read more on QTc prolongation risk with psychotropic, including antipsychotic medications. 

Ethnic differences are anticipated; however, age and gender have no significant influence on its cardiotoxicity in cases of overdose.

1.In the Lancet Psychiatry, a recently published pragmatic rater-blind, semi-randomised trial of amisulpride, aripiprazole, and olanzapine showed that amisulpride was more efficacious. [Johnsen et al. 2020] After 52 weeks of therapy, PANSS total score reduction was:

1. Amisulpride reduced PANSS total score by 32.7 (3.1) points
2. Aripiprazole reduced PANSS total score by 21.9 (3.9) points
3. Olanzapine reduced PANSS total score by 23.3 (2.9) points

2. A meta-analysis of antipsychotic medications in negative symptoms of schizophrenia showed that amisulpride was the only antipsychotic that was superior to placebo in the treatment of predominant negative symptoms.  However, a parallel reduction of depression makes it difficult to differentiate whether the improvements are due to negative symptoms or due to depression.  [Krause M, et al., 2018]

3. Very low-dose amisulpride (100/day) is effective and well-tolerated as a treatment for very late-onset schizophrenia-like psychosis (ATLAS trial), with benefits maintained by prolonging treatment. [Howard R et al., 2018]

Amisulpride (100-400 mg/day) has been proposed as an option for the management of clozapine-induced sialorrhea (hypersalivation).

Finally, amisulpride injection (5 mg/2 mL) was recently approved as a post-operative antiemetic for the rescue treatment of postoperative nausea and vomiting (PONV) in patients who have failed the current standard of care for nausea after a surgical procedure. [BARHEMSYS, prescribing information]

Amisulpride is a safe and effective antipsychotic therapy for the treatment of positive and negative symptoms in schizophrenia.

Amisulpride has a unique dose-dependent receptor pharmacology as shown by its efficacy at low doses to treat depressive symptoms and (potentially) negative symptoms in schizophrenia and positive symptoms at higher doses.

Learn More: 

Simplified Guide to Oral Antipsychotics