Amineptine

Usage

• Amineptine was prescribed for major depressive disorder, particularly in cases of endogenous origin (depression stemming from internal factors rather than external stressors).
• Pharmacological Classification: Tricyclic antidepressant (TCA) with unique properties distinguishing it from typical TCAs.
• Mechanism of Action: Primarily enhances dopamine reuptake inhibition and, to a lesser extent, norepinephrine reuptake inhibition, resulting in increased dopamine and norepinephrine levels in the synaptic cleft. This distinguishes it from most TCAs, which mainly target serotonin reuptake. It also acts on the hypothalamic-pituitary-adrenal (HPA) axis, possibly contributing to its antidepressant effects.

Alternate Names

• International Nonproprietary Name (INN): Amineptine
• Other names: 7-[(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)amino]heptanoic acid; S 1694
• Brand Name: Survector (withdrawn from market)

How It Works

• Pharmacodynamics: Amineptine primarily inhibits dopamine reuptake, leading to increased dopamine concentrations in the synaptic cleft, which is believed to be the primary mechanism responsible for its antidepressant effect. It has a weaker effect on norepinephrine reuptake inhibition. Unlike typical TCAs, it has minimal effects on serotonin, histamine, and muscarinic acetylcholine receptors, resulting in a different side effect profile. It also appears to influence the HPA axis, which is often dysregulated in depression.
• Pharmacokinetics: Amineptine is rapidly absorbed after oral administration. Peak plasma concentrations are reached approximately 1 to 1.5 hours after ingestion. It has a large volume of distribution, indicating extensive tissue penetration. The half-life of the parent drug is short (around 0.8 hours), while its active metabolite has a longer half-life (around 2.5 hours). The drug is metabolized extensively in the liver, primarily by demethylation and glucuronidation. Elimination is rapid, mostly through renal excretion.
• Mode of Action: At the cellular level, amineptine binds to the dopamine transporter, blocking the reuptake of dopamine into the presynaptic neuron, resulting in increased dopamine levels in the synapse. A similar, but weaker, effect is seen at the norepinephrine transporter. Its modulation of the HPA axis could also involve the regulation of corticotropin-releasing hormone (CRH).
• Receptor Binding/Enzyme Inhibition: Primarily targets dopamine transporter and, to a lesser extent, the norepinephrine transporter. Minimal binding at serotonin, adrenergic, histamine, and muscarinic receptors.
• Elimination Pathways: Hepatic metabolism is the main route of elimination, followed by renal excretion of metabolites.

Dosage

Amineptine is no longer available on the market and the following information is for historical reference only.

Standard Dosage

Adults:

• Initial dose: 100 mg/day, usually divided into two doses (morning and midday).
• Maintenance dose: Can be increased to 200 mg/day based on individual response and tolerability.

Children:

• Not recommended for use in children under 15 years of age.

Special Cases:

• Elderly Patients: No dose adjustment is typically required, though caution is advised due to increased risk of side effects.
• Patients with Renal Impairment: Dosage adjustment may be necessary depending on the degree of impairment.
• Patients with Hepatic Dysfunction: Close monitoring and possible dosage reduction are recommended.
• Patients with Comorbid Conditions: Caution is advised in patients with cardiovascular disease, seizure disorders, hyperthyroidism, pheochromocytoma, history of mania or psychosis, narrow-angle glaucoma, or urinary retention.

Clinical Use Cases

Amineptine is not used in these clinical settings.

Dosage Adjustments

Dosage adjustments may be required based on individual patient factors, such as renal/hepatic dysfunction, drug interactions, and tolerance.

Side Effects

Common Side Effects

• Nausea, vomiting, abdominal pain, diarrhea
• Headache, dizziness, insomnia
• Dry mouth
• Sweating
• Tremor

Rare but Serious Side Effects

• Liver toxicity (elevated liver enzymes, jaundice, hepatitis)
• Serotonin syndrome
• Cardiac arrhythmias
• Seizures
• Drug abuse and dependence

Long-Term Effects

Potential for tolerance, dependence, and withdrawal symptoms with prolonged use.

Adverse Drug Reactions (ADR)

• Hepatitis
• Severe acne
• Psychomotor excitation
• Cardiovascular events (rare)

Contraindications

• Hypersensitivity to amineptine
• History of chorea
• Concurrent use of MAO inhibitors
• Severe liver disease
• History of substance abuse

Drug Interactions

• CNS stimulants and antidepressants: Potential for additive effects and increased risk of side effects.
• Liver enzyme inducers (e.g., phenytoin, carbamazepine, rifampicin): Can reduce amineptine’s efficacy.
• Cimetidine, diltiazem, disulfiram, methylphenidate, ritonavir, verapamil: May increase amineptine plasma concentration.
• Numerous other drugs (e.g., adrenaline, amiodarone, SSRIs, antihistamines): Consult drug interaction resources for detailed information.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Not established. Use not recommended due to lack of safety data.
• Breastfeeding: Not recommended as the drug may be excreted in breast milk.

Drug Profile Summary

• Mechanism of Action: Dopamine reuptake inhibitor with secondary norepinephrine reuptake inhibitor activity. Minimal effects on serotonin, histamine, and muscarinic receptors.
• Side Effects: Common: GI disturbances, headache, dizziness, insomnia; Serious: Liver toxicity, serotonin syndrome, seizures, dependence.
• Contraindications: Hypersensitivity, chorea, concurrent MAOIs, severe liver disease, substance abuse history.
• Drug Interactions: Extensive drug interactions, particularly with CNS-active drugs and liver enzyme inducers.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: Historically: Adults—Initial 100 mg/day, maintenance up to 200 mg/day. Children—Not recommended.
• Monitoring Parameters: Liver function tests, cardiac function (in at-risk patients).

Popular Combinations

Amineptine is no longer used clinically. Historically it was used in some places as a combination therapy, but this is no longer recommended.

Precautions

• Pre-existing medical conditions: Careful evaluation is essential for patients with liver or kidney disease, cardiovascular disease, or history of seizures or substance abuse.
• Special Populations:
  • Pregnant Women: Avoid use.
  • Breastfeeding Mothers: Avoid use.
  • Children & Elderly: Not recommended for children under 15. Caution advised in elderly due to increased side effect risk.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Amineptine?

A: Amineptine is no longer available. Historically, the initial adult dose was 100 mg/day, which could be increased to 200 mg/day.

Q2: What are the primary side effects?

A: Common side effects included GI disturbances, headache, dizziness, insomnia. Serious side effects included liver damage, serotonin syndrome, and seizures.

Q3: Is Amineptine addictive?

A: Yes, amineptine carries a risk of dependence and withdrawal symptoms.

Q4: Can Amineptine be used during pregnancy?

A: No, amineptine is contraindicated during pregnancy due to safety concerns.

Q5: How does Amineptine differ from other TCAs?

A: Amineptine acts primarily as a dopamine reuptake inhibitor, unlike most TCAs, which primarily affect serotonin reuptake.

Q6: Why was Amineptine withdrawn from the market?

A: Due to hepatotoxicity and potential for abuse and dependence.

Q7: What are the contraindications to its use?

A: Contraindications include hypersensitivity, chorea, concurrent MAOI use, severe liver disease, and history of substance abuse.

Q8: How is Amineptine metabolized?

A: Primarily through hepatic metabolism, followed by renal excretion.

Q9: Are there any drug interactions I should be aware of?

A: Amineptine has numerous drug interactions, notably with CNS-active drugs and liver enzyme inducers. Consult resources for a comprehensive list.