What are the CINP (Collegium Internationale Neuro-Psychopharmacologicum) guidelines for treating treatment-resistant depression?

CINP Guidelines for Treatment-Resistant Depression

The Collegium Internationale Neuro-Psychopharmacologicum (CINP) guidelines define treatment-resistant depression (TRD) as failure to respond to at least two adequate trials of antidepressants with different mechanisms of action, with an adequate trial requiring minimum effective dosage administered for at least four weeks. 1

Definition and Diagnosis of TRD

• TRD is commonly defined as depression that has failed to respond (decrease in depressive severity of at least half) or achieve remission following two or more treatment attempts of adequate dose and duration 1
• An adequate antidepressant trial requires minimum effective dosage administered for at least 4 weeks 1
• Discontinuation of treatment before completing four weeks due to side effects should not be considered a treatment failure for establishing TRD 1
• For long current episodes, only treatment failures within the last two years should be considered when defining TRD 2

Diagnostic Tools for TRD

• Five main staging models exist for assessing TRD severity 1:
  • Antidepressant Treatment History Form (ATHF)
  • Thase and Rush Staging Model (TRSM)
  • European Staging Model
  • Massachusetts General Hospital Staging model (MGH-s)
  • Maudsley Staging Method (MSM)
• The Maudsley Staging Method is the preferred instrument to assess TRD status with 69% consensus among experts 1
• MSM is the only model with prospective validity testing and includes disease characteristics such as duration and symptom severity 1

Treatment Strategies for TRD

First-Line Approaches

• Optimize the dosage and duration of current antidepressant treatment and ensure medication adherence 3
• Augmentation with atypical antipsychotics is considered a first-line approach for TRD 2, 4
• Aripiprazole augmentation can be considered after inadequate response to at least one antidepressant treatment at adequate dose for at least 4 weeks 2

Pharmacological Options

• Augmentation strategies have stronger evidence than switching or combining antidepressants 3
• Second-generation antipsychotics and lithium have the strongest evidence for augmentation in TRD 3, 4
• Approved atypical antipsychotics for TRD include aripiprazole, brexpiprazole, cariprazine, quetiapine extended-release, and olanzapine-fluoxetine combination 4
• Combining bupropion with escitalopram can be effective, with bupropion SR starting at 150 mg once daily for 3 days, then increasing to 150 mg twice daily 5

Non-Pharmacological Approaches

• Electroconvulsive therapy (ECT) is effective for TRD but should be considered after pharmacological options 3, 6
• Transcranial magnetic stimulation (TMS) can be considered for patients who have failed medication trials 2, 3
• Esketamine/ketamine is a treatment option for highly refractory cases 2
• Vagus nerve stimulation is approved as adjunctive therapy after four prior treatment failures, but benefits are seen only after prolonged use 6

Monitoring and Assessment

• Montgomery–Åsberg Depression Rating Scale (MADRS) is the preferred outcome instrument to assess treatment response, together with patient-reported QIDS-SR 1
• Allow at least 4 weeks at therapeutic doses to evaluate efficacy of treatment 5
• Monitor for common side effects including headache, dizziness, dry mouth, insomnia, anxiety, nausea, and constipation 5
• When using atypical antipsychotics, monitor for weight gain, akathisia, and tardive dyskinesia 4

Common Pitfalls in TRD Management

• Failure to ensure adequate dosing and duration before declaring treatment failure 2
• Not considering comorbidities such as substance use disorders, personality disorders, or bipolar disorder that may complicate treatment 5
• Inadequate documentation of previous treatment failures making it difficult to establish TRD diagnosis 1
• Continuing ineffective treatment beyond 6-8 weeks without considering alternative strategies 5

Treatment Algorithm for TRD

1. Verify TRD diagnosis by confirming failure of at least two adequate antidepressant trials with different mechanisms of action 1
2. Consider augmentation with atypical antipsychotics as first-line approach 2, 4
3. If augmentation fails, consider switching to another antidepressant class or using combination strategies 6
4. For highly refractory cases, consider non-pharmacological approaches such as ECT, TMS, or esketamine 2, 3
5. Monitor response closely and adjust treatment if no improvement after 4-6 weeks 5