What is the evidence-based practice (EBP) guidance for treating resistant depression?

Evidence-Based Practice Guidance for Treatment-Resistant Depression

Treatment-resistant depression (TRD) should be defined as failure to respond to at least two different antidepressant medications of different mechanisms of action, administered at adequate doses for at least 4 weeks each during the current depressive episode. 1

Definition and Diagnosis of TRD

Diagnostic Criteria

• TRD requires:
  • Minimum of two failed antidepressant treatments with <25% improvement despite adequate dosing and duration 1
  • Both treatment failures should be within the current episode and within the past two years 1
  • Failed medications should have different mechanisms of action 1
  • Adequate dose defined as at least the minimum approved dosage 1
  • Adequate duration defined as at least 4 weeks of treatment 1

Partially Responsive Depression (PRD)

• Distinguished from TRD as showing partial response (25-49% improvement) to at least one treatment 1
• Can be defined after a single treatment failure 1

Assessment Tools

• Maudsley Staging Model (MSM) is the preferred instrument to assess TRD status 1
• Montgomery-Åsberg Depression Rating Scale (MADRS) is recommended for clinical assessment 1
• Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) recommended for patient-reported outcomes 1

Treatment Approaches for TRD

Pharmacological Strategies

1. FDA-Approved Options:

   • Olanzapine-fluoxetine combination (OFC) is FDA-approved specifically for TRD (defined as failure to respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) 2
   • Aripiprazole augmentation (FDA-approved for TRD) 3
   • Other approved atypical antipsychotic augmentation options include brexpiprazole, cariprazine, and quetiapine extended-release 3

2. Optimization Strategies:

   • Ensure adequate dosing (at least minimum approved dosage) 1
   • Ensure adequate duration (minimum 4 weeks) 1
   • Discontinuation before 4 weeks without clear evidence of lack of response should not be considered treatment failure 1

3. Combination/Augmentation Strategies:

   • Atypical antipsychotic augmentation has the strongest evidence 3
   • Consider benefits against potential adverse events (weight gain, akathisia, tardive dyskinesia) 3
   • Other augmenting agents with evidence include lithium and thyroid hormones 4

4. Switching Strategies:

   • Switch to a medication with a different mechanism of action 4
   • Benefits include avoiding polypharmacy and narrower range of side effects 4
   • Disadvantage: partial responses to initial treatment may be lost 4

Non-Pharmacological Approaches

1. Brain Stimulation Therapies:

   • Electroconvulsive therapy (ECT) has strong evidence for TRD 4
   • Transcranial magnetic stimulation (TMS) 4
   • Vagus nerve stimulation (VNS) - benefits may take up to 1 year to manifest 4

2. Psychotherapy:

   • Often used in conjunction with pharmacotherapy 4
   • A failed course of psychotherapy should not be included in the definition of TRD 1

Special Considerations

Exclusion Criteria for TRD Diagnosis

• Rule out bipolar disorder 1
• Exclude active and severe substance use disorder 1
• Consider comorbid personality disorders 1
• Verify treatment adherence through documentation 1

Monitoring and Assessment

• Measure both symptom reduction and functional improvement
• Core outcome measures should include:
  • Depressive severity
  • General psychiatric status
  • Functional impairment
  • Quality of life
  • Adherence to treatment 1

Clinical Implications

• TRD is associated with higher rates of mortality (29-35% higher than treatment-responsive depression) 5
• Suicide risk is seven times higher in TRD compared to treatment-responsive depression 5
• TRD doubles hospitalization rates and increases length of stay by 36% 5
• Long-term outcomes are worse the longer patients remain unsuccessfully treated 4

Common Pitfalls to Avoid

1. Pseudo-resistance factors:

   • Misdiagnosis (especially unrecognized bipolar disorder)
   • Inadequate dosing or duration of treatment
   • Poor medication adherence
   • Unaddressed medical comorbidities
   • Chronic stressors 5

2. Treatment approach errors:

   • Continuing ineffective strategies for too long
   • Not systematically documenting response to treatments
   • Failing to consider augmentation strategies after partial response
   • Not considering non-pharmacological approaches when appropriate

By following these evidence-based guidelines for diagnosis and treatment of TRD, clinicians can improve outcomes for this challenging condition that significantly impacts morbidity, mortality, and quality of life.