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Amisulpride

Amisulpride: A Targeted Approach in Schizophrenia and Beyond

Introduction

Amisulpride is an atypical antipsychotic agent belonging to the substituted benzamide class, primarily used in the treatment of schizophrenia and other psychotic disorders. Its unique mechanism of action, focusing predominantly on dopaminergic modulation, distinguishes it from other antipsychotics, both typical and atypical. With its selective dopamine D2/D3 receptor antagonism and minimal affinity for other receptor systems, amisulpride is often associated with a lower risk of extrapyramidal symptoms (EPS) at low doses and specific efficacy in managing negative symptoms of schizophrenia.

1. Chemical and Pharmacological Background:

Chemical Identity

  • IUPAC Name: 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-ethylsulfonyl-2-methoxybenzamide

  • Molecular Formula: C17H27N3O4S

  • Molecular Weight: 369.48 g/mol

Amisulpride is structurally related to sulpiride but has greater selectivity and potency at dopamine receptor subtypes, particularly D2 and D3.

2. Mechanism of Actions

Amisulpride works by selectively antagonizing dopamine D2 and D3 receptors, predominantly in the limbic system rather than the striatum, which accounts for its relatively lower risk of motor side effects.

Dopaminergic Modulation

  • Low doses (50–300 mg/day): Preferential presynaptic D2/D3 receptor blockade, increasing dopaminergic transmission → beneficial in negative symptoms like social withdrawal, lack of motivation.

  • High doses (400–800 mg/day): Postsynaptic D2/D3 antagonism, reducing dopaminergic hyperactivity → effective in positive symptoms such as delusions, hallucinations, and agitation.

This dose-dependent dual action is one of amisulpride’s most significant pharmacological advantages.

3. Pharmacokinetics

Parameter Description
Absorption Rapid and well-absorbed orally
Bioavailability ~48% (oral)
Time to Peak (Tmax) 1–3 hours
Half-life 12–20 hours
Protein Binding Low (~17%)
Metabolism Minimal hepatic metabolism; largely excreted unchanged
Excretion Primarily renal (urine)

Due to its renal clearance, dosage adjustments are necessary in patients with renal impairment.

4. Clinical Uses

1. Schizophrenia

  • Acute and chronic management

  • Particularly effective in treating both positive and negative symptoms

  • May have advantages in first-episode psychosis and treatment-resistant cases

2. Dysthymia and Depression (Off-label in some countries)

  • Low-dose amisulpride has shown antidepressant effects by enhancing dopaminergic transmission

  • Particularly useful in patients with low mood, apathy, and cognitive dullness

3. Bipolar Disorder (Adjunctive use)

  • Some evidence supports its role in acute mania or as maintenance in bipolar depression, although it's not approved for this indication in most regions

4. Negative Symptom Predominant Schizophrenia

  • Amisulpride’s limbic-selective dopamine blockade provides substantial benefit in primary negative symptoms, making it a preferred option in such clinical profiles.

5. Dosing and Administration

Amisulpride is administered orally and occasionally intramuscularly for acute agitation.

Oral Dosage

  • Positive symptoms: 400–800 mg/day (up to 1200 mg/day in severe cases)

  • Negative symptoms or dysthymia: 50–300 mg/day

  • Split dosing is often used for better tolerability, especially at higher doses

Intramuscular (IM) Use

  • Reserved for short-term control of acute agitation in psychotic disorders

  • Typically 50–400 mg/day for up to a few days

6. Side Effects and Safety Profile

Amisulpride has a favorable side effect profile, especially at lower doses, but like all antipsychotics, it is not devoid of adverse effects.

Common Side Effects

  • Insomnia

  • Anxiety

  • Weight gain

  • Gastrointestinal discomfort

Endocrine

  • Hyperprolactinemia: Due to dopamine blockade in the pituitary

    • Can lead to galactorrhea, amenorrhea, gynecomastia, sexual dysfunction

Neurological

  • Extrapyramidal symptoms: Less frequent at low doses, but can occur at high doses

  • Rare tardive dyskinesia or neuroleptic malignant syndrome (NMS)

Cardiac

  • QT prolongation: Risk increases with higher doses or concurrent QT-prolonging medications

  • Regular ECG monitoring recommended in long-term use

7. Contraindications and Precautions

Contraindications

  • Known hypersensitivity to amisulpride

  • Pheochromocytoma

  • Breast cancer or prolactin-dependent tumors

  • QT prolongation or arrhythmias

Precautions

  • Renal impairment: Dosage adjustment necessary

  • Elderly: Increased risk of cerebrovascular events and mortality

  • Monitor serum electrolytes, particularly potassium and magnesium

8. Drug Interactions

  • CNS depressants (benzodiazepines, opioids): Enhanced sedation

  • QT-prolonging agents (macrolides, quinolones, certain antidepressants): Additive risk

  • Levodopa: Antagonistic interaction (dopamine blockade)

  • Antihypertensives: Potential for hypotension

Amisulpride has minimal CYP450 involvement, which reduces the risk of hepatic metabolic interactions, a significant benefit compared to other antipsychotics.

9. Amisulpride vs Other Antipsychotics

Feature Amisulpride Other Atypicals (e.g., Risperidone, Olanzapine)
Dopamine selectivity High (D2/D3 only) Broader (D2, 5-HT2A, others)
EPS risk (low dose) Low Variable
Prolactin elevation High Moderate to high
Sedation Low Often higher (especially with olanzapine)
Metabolic side effects Moderate High with olanzapine, clozapine
Weight gain Moderate Often higher with other atypicals

10. Amisulpride in Special Populations

Pediatrics

  • Not generally recommended

  • Research is limited, and risks of hormonal disturbances are higher

Elderly

  • Use with caution; risk of orthostatic hypotension and cerebrovascular events

  • Lower starting doses

Pregnancy and Lactation

  • Category C

  • Avoid unless benefits outweigh risks

  • Crosses placenta; excreted in breast milk

Renal Impairment

  • Requires dosage adjustment based on creatinine clearance

11. Emerging Research and Off-Label Applications

1. Depression and Dysthymia

  • Studies suggest benefit in treatment-resistant depression, especially in patients with dopaminergic deficiency symptoms

2. Cognitive Enhancement

  • Some trials show improvement in cognitive deficits in schizophrenia, particularly attention and working memory, though not approved for this use

3. Functional Dyspepsia (Low-dose)

  • Explored due to its prokinetic-like dopamine antagonism in the gut

12. Clinical Monitoring

Regular monitoring should be part of amisulpride therapy, especially in long-term use:

Parameter Frequency
ECG (QT interval) Baseline, then annually or as needed
Prolactin levels Every 6–12 months
Weight/BMI Every 3–6 months
Renal function Periodically
Sexual/reproductive health Based on symptoms

Patient education on signs of prolactin-related side effects and cardiac symptoms is essential.

13. Conclusion

Amisulpride stands out among antipsychotics for its selective dopaminergic action, dual-dose response, and favorable safety profile, especially in the treatment of negative symptoms of schizophrenia. It bridges the gap between efficacy and tolerability, offering a targeted approach that is especially beneficial in early psychosis, treatment-resistant schizophrenia, and patients sensitive to EPS. However, its potential for prolactin-related side effects and cardiac risks underscores the need for proper monitoring and patient selection. With emerging research supporting its role in depression, cognition, and gut disorders, amisulpride continues to be a topic of evolving interest in psychopharmacology.