What are the next medication options for depression if Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), and Monoamine Oxidase Inhibitors (MAOIs) have been tried?

Medication Options for Treatment-Resistant Depression

When SSRIs, SNRIs, and MAOIs have failed to treat depression, atypical antidepressants (bupropion, mirtazapine), second-generation antipsychotics (quetiapine, aripiprazole), or anticonvulsants should be considered as the next treatment options, with bupropion being the preferred first choice due to its favorable side effect profile and efficacy. 1

Atypical Antidepressants

Bupropion

• Mechanism: Predominantly norepinephrine and dopamine reuptake inhibitor
• Advantages:
  • Different mechanism of action from previously tried medications
  • Lower rates of sexual dysfunction compared to SSRIs/SNRIs
  • No significant weight gain
  • Shown to be effective in the STAR*D trial for patients who failed initial SSRI therapy 2
• Dosing: Starting at 150mg daily, target dose 300-450mg daily
• Contraindications: Seizure disorders, eating disorders, abrupt discontinuation of alcohol or sedatives

Mirtazapine (NaSSA)

• Mechanism: Noradrenergic and specific serotonergic antidepressant
• Advantages:
  • Faster onset of action than SSRIs (statistically significant in first 4 weeks) 2
  • Helpful for patients with insomnia and poor appetite
  • Different side effect profile than SSRIs/SNRIs
• Dosing: Starting at 15mg at bedtime, target dose 30-45mg
• Side effects: Sedation, increased appetite, weight gain

Augmentation Strategies

Second-Generation Antipsychotics

• Options: Quetiapine, aripiprazole, olanzapine
• Evidence:
  • Effective as monotherapy or as augmentation to SSRIs in treatment-resistant cases 3
  • Quetiapine has demonstrated efficacy in major depressive disorder 4
• Dosing:
  • Quetiapine: 50-300mg daily (lower doses than used for psychotic disorders)
  • Aripiprazole: 2-15mg daily
• Monitoring: Metabolic parameters (weight, glucose, lipids), extrapyramidal symptoms

Anticonvulsants

• Options: Lamotrigine, valproic acid, topiramate
• Particularly useful when:
  • Comorbid bipolar features are present
  • Impulsivity and anger are prominent symptoms 3
• Lamotrigine has shown efficacy in small controlled studies 3
• Requires careful titration and monitoring of blood levels (for valproic acid)

Other Considerations

Tricyclic Antidepressants (TCAs)

• Options: Clomipramine, imipramine, desipramine
• More effective than SSRIs for some patients, but with higher side effect burden 2
• Should be considered third-line due to:
  • Cardiovascular side effects
  • Anticholinergic effects
  • Risk in overdose
  • Drug interactions

Transdermal Selegiline (MAO-B Inhibitor)

• If traditional MAOIs failed but were partially effective, consider transdermal selegiline
• Advantages over traditional MAOIs:
  • Selective MAO-B inhibition at lower doses
  • Fewer dietary restrictions
  • Lower risk of hypertensive crisis 5
• Still requires careful monitoring and medication interaction precautions

Combination Therapy

In cases of severe treatment resistance, carefully monitored combination therapy may be considered:

• Combination of an MAOI with another antidepressant showed 21% significant improvement in treatment-resistant cases 6
• CAUTION: This approach carries significant risks of serotonin syndrome and should only be implemented by psychiatrists with expertise in managing treatment-resistant depression

Important Considerations

1. Suicide Risk Assessment: Closely monitor for suicidal ideation, especially in patients under 24 years of age 4, 7

2. Medication Selection Algorithm:

   • First attempt: Bupropion (different mechanism of action)
   • If ineffective: Try mirtazapine
   • If still ineffective: Consider augmentation with second-generation antipsychotic
   • If still ineffective: Consider anticonvulsants or TCA
   • Last resort: Carefully monitored combination therapy

3. Duration of Treatment:

   • Continue effective treatment for at least 12-24 months after achieving remission 1
   • Taper medications slowly when discontinuing to avoid withdrawal effects

4. Common Pitfalls:

   • Inadequate dosing or duration before switching medications
   • Failure to monitor for side effects that may reduce adherence
   • Not addressing comorbid conditions (anxiety, substance use) that may affect treatment response
   • Overlooking drug interactions that may reduce efficacy

Remember that treatment-resistant depression often requires a comprehensive approach. Each medication trial should be given adequate time (6-8 weeks) at therapeutic doses before determining efficacy, while carefully monitoring for side effects and treatment response.