What can be prescribed for treatment-resistant depression?

Treatment Options for Treatment-Resistant Depression

For treatment-resistant depression (TRD), defined as failure to respond to at least two adequate antidepressant trials of different mechanisms of action, the most evidence-supported options include augmentation with atypical antipsychotics (particularly aripiprazole, brexpiprazole, or olanzapine-fluoxetine combination), switching to a different antidepressant class, or considering brain stimulation therapies like ECT or rTMS.

Definition of Treatment-Resistant Depression

Treatment-resistant depression (TRD) is defined by:

• Failure to achieve remission after at least two adequate trials of antidepressants with different mechanisms of action 1
• Each trial must use adequate dosing (at least minimum effective dosage) for adequate duration (at least 4 weeks) 1
• The medications should have different mechanisms of action according to the Neuroscience-based Nomenclature 1

Pharmacological Treatment Options

Switching Strategies

When first-line treatments fail, switching to a different antidepressant class is a common approach:

• The STAR*D trial showed approximately 25% of patients became symptom-free after switching medications 1
• No significant differences were found among bupropion-SR, sertraline, and venlafaxine-XR as second-line agents 1
• Advantages include avoiding polypharmacy and a narrower range of side effects 2
• Disadvantage: partial responses to initial treatment may be lost 2

Augmentation Strategies

Augmentation involves adding a non-antidepressant medication to the current antidepressant:

1. Atypical Antipsychotics (strongest evidence):

   • Aripiprazole: FDA-approved for adjunctive treatment in TRD, generally at lower doses than used for schizophrenia or bipolar disorder 3, 4
   • Brexpiprazole: FDA-approved for TRD 4
   • Olanzapine-Fluoxetine Combination (OFC): Effective in fluoxetine-resistant unipolar depression 3, 5
   • Quetiapine extended-release: FDA-approved for depression, though one trial suggested it may not be effective 3, 4
   • Cariprazine: More recently approved for TRD 4
   • Risperidone: Effective in combination with SSRIs in treatment-resistant unipolar depression, with reported remission rates of 61% to 76% 5

2. Traditional Augmenting Agents:

   • Lithium: Well-studied but not commonly used 2
   • Thyroid hormones (triiodothyronine/T3): Well-studied but not commonly used 2, 6

3. Other Experimental Augmentation Options:

   • CNS stimulants, lamotrigine, modafinil, riluzole, topiramate 2
   • Anti-inflammatory agents 6
   • S-adenosyl-L-methionine, folic acid, omega-3 fatty acids 2

Non-Pharmacological Approaches

For patients who fail multiple medication trials, brain stimulation therapies should be considered:

1. Electroconvulsive Therapy (ECT): Most established non-pharmacological treatment for TRD 6

2. Repetitive Transcranial Magnetic Stimulation (rTMS): Non-invasive option for TRD patients who fail medication trials 6

3. Other Brain Stimulation Methods:

   • Vagus Nerve Stimulation (VNS): FDA-approved as adjunctive therapy after four prior treatment failures, though benefits may take up to 1 year 2
   • Deep Brain Stimulation (DBS): Still considered experimental 2, 6
   • Magnetic Seizure Therapy: Emerging option 6

4. Psychotherapy: Often used in conjunction with pharmacotherapy 2

Novel Emerging Therapies

For highly resistant cases, consider:

• Ketamine and esketamine: Rapid-acting options for TRD 6
• Psychedelic therapies (e.g., psilocybin): Under investigation 6

Common Pitfalls and Considerations

• Diagnostic accuracy: Ensure proper diagnosis of MDD and rule out bipolar disorder, personality disorders, and active substance use disorders 1
• Treatment adequacy: Verify that previous treatments were given at adequate doses for sufficient duration (minimum 4 weeks) 1
• Comorbidities: Address comorbid conditions that may complicate treatment response
• Medication adherence: Confirm patient adherence to previous treatments
• Side effect management: Monitor and manage side effects of augmentation strategies, particularly metabolic effects and movement disorders with atypical antipsychotics 4

Treatment Algorithm

1. First step: Verify TRD diagnosis (≥2 failed adequate trials of different mechanism antidepressants)
2. Second step: Choose between switching or augmentation strategy
   • If partial response to current antidepressant: Consider augmentation
   • If minimal/no response: Consider switching to a different class
3. Third step: For augmentation, atypical antipsychotics have strongest evidence (aripiprazole, brexpiprazole, or OFC)
4. Fourth step: If multiple pharmacological approaches fail, consider brain stimulation therapies (ECT or rTMS)
5. Fifth step: For highly resistant cases, consider novel therapies like ketamine/esketamine