What are the treatment options 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 with different mechanisms of action, recommended options include medication augmentation strategies (particularly with atypical antipsychotics), psychotherapy combinations, and neuromodulation techniques like transcranial magnetic stimulation. 1

Definition and Diagnosis

• TRD is defined as failure to respond to at least two adequate trials of antidepressants with different mechanisms of action in the current depressive episode 1
• An adequate trial requires the minimal approved dosage administered for at least four weeks 1
• Discontinuation due to side effects before completing four weeks 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

Pharmacological Treatment Options

Augmentation Strategies

• Aripiprazole augmentation can be considered after inadequate response to at least one antidepressant treatment at adequate dose for at least 4 weeks 3
• Olanzapine-fluoxetine combination (OFC) is FDA-approved for treatment-resistant depression, defined as failure to respond to two separate trials of different antidepressants of adequate dose and duration in the current episode 4
• Atypical antipsychotics in combination with antidepressants show evidence of efficacy 5
• Other augmenting agents with evidence include lithium and thyroid hormones, though they are less commonly used 5

Switching Strategies

• Switching within and between classes of antidepressants is a common strategy 5
• Benefits of switching include avoidance of polypharmacy and a narrower range of side effects 5
• However, partial treatment responses from the initial treatment might be lost when switching 5
• Monotherapy switches have shown limited effectiveness in achieving remission 5

Non-Pharmacological Approaches

Psychotherapy

• Psychotherapy added to usual care (with antidepressants) shows moderate-quality evidence of benefit for depressive symptoms, response, and remission rates 6
• Cognitive-behavioral therapy (CBT) as an adjunct to medication has shown benefits that extend to medium and long-term outcomes 6
• An economic analysis from the UK healthcare perspective revealed that adjunctive CBT was cost-effective over nearly four years 6

Neuromodulation Therapies

• Transcranial magnetic stimulation (TMS) can be considered for patients who have failed medication trials 1
• Electroconvulsive therapy (ECT) is an effective option for TRD 5, 7
• Vagus nerve stimulation is FDA-approved as adjunctive therapy after four prior treatment failures, though benefits are seen only after prolonged use 5
• Other neuromodulation options like deep brain stimulation remain experimental 5

Novel and Experimental Approaches

• Ketamine and esketamine can be used as augmentation for TRD and may help reduce suicidal ideation 7
• For highly refractory cases, esketamine/ketamine is considered a treatment option by the Depression and Anxiety society 1
• Other experimental treatments being explored include pindolol, CNS stimulants, hormones, herbal supplements, omega-3 fatty acids, S-adenosyl-L-methionine, folic acid, lamotrigine, modafinil, riluzole, and topiramate 5

Treatment Algorithm

1. Verify TRD diagnosis: Confirm failure of at least two adequate antidepressant trials with different mechanisms of action 1
2. First-line approach: Augmentation with atypical antipsychotics (aripiprazole or olanzapine-fluoxetine combination) 3, 4
3. Alternative augmentation: Consider lithium or thyroid hormone augmentation 5
4. Add psychotherapy: Particularly cognitive-behavioral therapy as an adjunct to medication 6
5. For non-responders to above: Consider neuromodulation therapies (TMS or ECT) 1, 5
6. For highly refractory cases: Consider ketamine/esketamine 1, 7

Common Pitfalls and Caveats

• Ensure adequate dosing and duration (minimum effective dosage for at least 4 weeks) before declaring treatment failure 1
• Treatment resistance increases with each failed medication trial; after two treatment failures, chances of remission decrease significantly 5
• Combination strategies are generally recommended if partial response was achieved with the current treatment 5
• The longer patients are unsuccessfully treated, the worse their long-term prognosis tends to be 5
• Pharmacogenetic testing has limited evidence and is not recommended as a standard approach 7