Introduction

The bupropion-dextromethorphan combination represents a novel approach in the pharmacological treatment of major depressive disorder (MDD). Approved under the brand name Auvelity in the United States, this oral combination leverages complementary mechanisms of action targeting glutamate, norepinephrine, and dopamine neurotransmitter systems, offering potential benefits in faster symptom relief and enhanced efficacy for treatment-resistant depression. In India, various brands have introduced this combination to address MDD, expanding accessibility for patients.

Pharmacological Classification

• Bupropion:
  • Class: Norepinephrine-dopamine reuptake inhibitor (NDRI).
  • Mechanism: Enhances norepinephrine and dopamine availability by inhibiting their reuptake at synaptic terminals.
• Dextromethorphan:
  • Class: NMDA receptor antagonist and sigma-1 receptor agonist.
  • Mechanism: Modulates glutamate signaling by antagonizing NMDA receptors and providing neuroprotective effects via sigma-1 receptor activation.

Indications

• FDA-Approved Indication:
  • Major Depressive Disorder (MDD): Particularly for individuals who have shown inadequate response to traditional antidepressants.
• Investigational and Off-Label Uses:
  • Anxiety disorders.
  • Bipolar depression.
  • Treatment-resistant depression.

Mechanism of Action

The combination of bupropion and dextromethorphan works synergistically to address depressive symptoms:

1. Bupropion:
   • Inhibits norepinephrine and dopamine reuptake, improving mood and cognitive function.
   • Acts as a CYP2D6 inhibitor, reducing the metabolism of dextromethorphan and increasing its plasma concentration.
2. Dextromethorphan:
   • Blocks NMDA receptors, reducing excitatory glutamate activity, which is often heightened in depression.
   • Activates sigma-1 receptors, offering neuroprotection and reducing neuroinflammation linked to stress and depression.

This dual mechanism targets multiple neurotransmitter systems, distinguishing it from traditional antidepressants like SSRIs or SNRIs.

Pharmacokinetics

• Absorption: Both drugs are rapidly absorbed after oral administration.
• Metabolism:
  • Bupropion: Extensively metabolized in the liver, primarily by CYP2B6.
  • Dextromethorphan: Metabolized by CYP2D6, but bupropion inhibits this pathway, prolonging its bioavailability.
• Half-life:
  • Bupropion: ~21 hours.
  • Dextromethorphan: Prolonged due to CYP2D6 inhibition by bupropion.
• Excretion: Primarily renal for bupropion; fecal and urinary for dextromethorphan.

Dosage and Administration

• Initial Dose: One tablet or capsule (45 mg dextromethorphan / 105 mg bupropion) once daily for the first three days.
• Maintenance Dose: One tablet twice daily, separated by at least 8 hours.
• Maximum Dose: 90 mg dextromethorphan and 210 mg bupropion per day.
• Special Instructions:
  • Take with or without food.
  • Avoid consuming alcohol to minimize the risk of adverse effects.
  • Not recommended for patients with a high risk of seizures.

Adverse Effects

Common Side Effects:

• Insomnia
• Dizziness
• Nausea
• Dry mouth
• Excessive sweating
• Anxiety

Serious Side Effects:

• Seizures (dose-dependent, particularly in patients with predisposing conditions).
• Hypertension (monitor blood pressure, especially in hypertensive patients).
• Serotonin Syndrome (when combined with serotonergic agents).
• Mania or Hypomania (in individuals with bipolar disorder).

Contraindications

• Absolute:
  • History of seizures.
  • Diagnosed eating disorders (e.g., anorexia, bulimia).
  • Use of monoamine oxidase inhibitors (MAOIs) within the past 14 days.
  • Current or previous diagnosis of bipolar disorder unless carefully monitored.
• Relative:
  • Moderate-to-severe hepatic or renal impairment.
  • History of substance abuse or dependency.

Drug Interactions

• CYP2D6 Substrates:
  • Avoid combining with drugs metabolized by CYP2D6, as bupropion inhibits this enzyme, potentially increasing toxicity.
  • Examples: Beta-blockers, SSRIs (e.g., paroxetine, fluoxetine).
• Serotonergic Agents:
  • Increased risk of serotonin syndrome when combined with SSRIs, SNRIs, or other serotonergic drugs.
• Alcohol:
  • Increases the risk of seizures and other adverse effects.

Precautions

• Suicide Risk: Monitor patients, especially young adults, for worsening depression or emergence of suicidal thoughts.
• Hypertension: Regularly monitor blood pressure.
• Neuropsychiatric Symptoms: Watch for agitation, hallucinations, or unusual behavioral changes.
• Pregnancy and Breastfeeding: Limited data; consult with a healthcare provider before use.

Brands Available in India

1. Auvelia – Lupin Ltd
2. Dexbe – Zydus Healthcare Limited
3. Bupron DX – Sun Pharmaceutical Industries Ltd
4. Buprojoy – Alkem Laboratories Ltd
5. Bropidex – La Renon Healthcare Pvt Ltd

Comparison with Alternatives

• Ketamine/Esketamine:
  • Like dextromethorphan, ketamine modulates NMDA receptors, but its administration (IV or nasal spray) is less convenient than the oral combination.
• SSRIs/SNRIs:
  • Bupropion-dextromethorphan offers a faster onset of action and targets additional neurotransmitter systems.

Monitoring

• Blood Pressure: Monitor regularly, especially in hypertensive patients.
• Mood and Behavior: Assess for suicidal ideation or manic symptoms.
• Liver and Renal Function: Regular monitoring in patients with pre-existing conditions.

Storage

• Store at room temperature (15°C–30°C) in a dry and cool place.
• Keep away from children and direct sunlight.

Emergency Management

• Overdose Symptoms:
  • Seizures, hallucinations, severe agitation, tachycardia, or respiratory depression.
• Treatment:
  • Supportive care with close monitoring.
  • Activated charcoal may be used if the overdose is recent.
  • No specific antidote is available.

Patient Education

• Adherence to the prescribed dosage schedule is crucial.
• Report any signs of worsening mood or unusual behavioral changes immediately.
• Avoid alcohol and other CNS depressants.
• Do not stop the medication abruptly; consult your physician for tapering instructions.

Future Directions

This combination represents a breakthrough in the treatment of MDD, particularly for patients resistant to traditional therapies. Ongoing clinical trials may establish its efficacy in other psychiatric disorders, such as anxiety and bipolar depression.

References

1. FDA Approval Documents for Auvelity.
2. Clinical Trials on NMDA Antagonists for Depression.
3. Product Information from Indian Pharmaceutical Companies.
4. Comparative Studies on Bupropion-Dextromethorphan vs. SSRIs and SNRIs.

This comprehensive monograph serves as an educational resource for healthcare professionals and patients seeking detailed information on the bupropion-dextromethorphan combination. Always consult with a healthcare provider for personalized advice.