Top 10 Treatments for Treatment-Resistant Depression (TRD)

When depression doesn’t respond to standard medications, it can feel like the options are running out — but the truth is, treatment-resistant depression (TRD) has more solutions today than ever before. Below are the top 10 treatments for treatment-resistant depression.

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1. Spravato^® (Esketamine Nasal Spray)

• FDA-approved for adults with treatment-resistant depression.
• Works on the NMDA receptor (different from SSRIs/SNRIs).
• Provides rapid relief (often within hours to days).
• Self-administered in certified clinics with medical supervision.
  

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2. Ketamine (IV/IM) Treatments

• Off-label but evidence-based option for TRD.
• Intravenous (IV) or Intramuscular (IM) delivery bypasses digestion, giving fast results.
• Rapid improvement in depressive symptoms, sometimes after the first infusion.
• Administered in clinics with medical supervision.
  

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3. Electroconvulsive Therapy (ECT)

• Gold-standard for severe or psychotic depression.
• Response rates: 60–80%.
• Involves induced seizure under anesthesia; highly effective but may cause memory side effects.

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4. Repetitive Transcranial Magnetic Stimulation (rTMS)

• Non-invasive brain stimulation that targets mood regulation circuits.
• Safe and well-tolerated; effectiveness improves with personalized protocols.
• FDA-approved and increasingly available in major cities.

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5. Transcranial Direct-Current Stimulation (tDCS)

• Delivers low-intensity electrical currents via scalp electrodes.
• Early research shows modest benefit in TRD.
• Still experimental but attractive due to safety and low cost.

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6. Medications for Augmentation

• Adding second-generation antipsychotics (e.g., aripiprazole, quetiapine) can boost antidepressant effects.
• Often covered by insurance and recommended in clinical guidelines.

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7. Olanzapine + Fluoxetine Combination (Symbyax)

• One of the only other FDA-approved pharmacologic options for TRD.
• Can be effective, but carries metabolic side effects (weight gain, diabetes risk).

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8. Cognitive Behavioral Therapy (CBT)

• When added to medication, CBT improves response and coping strategies.
• Recommended by most major clinical guidelines.
• Effective both in-person and via telehealth.

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9. Psychedelic-Assisted Psychotherapy (Psilocybin / MDMA)

• Psilocybin: Early studies show significant improvements in depression symptoms.
• MDMA-assisted psychotherapy: Investigated for PTSD, now being studied for depression.
• Still experimental and available only in clinical trials.

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10. Magnetic Seizure Therapy (MST)?

• Experimental alternative to ECT using magnetic induction to trigger seizures.
• Early data suggest fewer cognitive side effects than ECT.
• Currently available only in research settings.

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Next Steps

New interventional treatments offer a new path forward for patients who haven’t found relief with traditional antidepressants. While every patient’s experience is unique, the research and real-world outcomes are promising.

For more personalized answers and to learn if interventional treatments such as Spravato and IV/IM Ketamine therapy is right for you, schedule a consultation with Being Health today or give us a call at 888-668-7600.