What is the recommended approach for treatment of treatment-resistant depression?

From the Guidelines

The most effective approach for treating treatment-resistant depression is a stepped approach, starting with optimization of the current antidepressant treatment, followed by switching to a different antidepressant or augmentation with a second medication, as recommended by the most recent and highest quality study 1. This approach is based on the latest consensus guideline for definition of treatment-resistant depression for clinical trials, which emphasizes the importance of a personalized and multidimensional definition of treatment-resistant depression. The first step in this approach is to optimize the current antidepressant treatment by ensuring adequate dosage and duration, typically 4-8 weeks at therapeutic doses. If optimization fails, the next steps include:

• Switching to a different antidepressant, often from a different class, such as changing from an SSRI to an SNRI like venlafaxine or duloxetine
• Augmentation with a second medication, such as an atypical antipsychotic (e.g., aripiprazole 2-15 mg/day or quetiapine 150-300 mg/day), lithium (600-900 mg/day to achieve blood levels of 0.6-1.0 mEq/L), or thyroid hormone (T3/liothyronine 25-50 mcg/day) For severely resistant cases, electroconvulsive therapy (ECT) is highly recommended, as well as other evidence-based options like transcranial magnetic stimulation (TMS) and the combination of psychotherapy, particularly cognitive-behavioral therapy, with medication 1. The rationale behind these approaches is to target different neurotransmitter systems or neural pathways that may be involved in depression, as individual patients may have different underlying neurobiological mechanisms contributing to their depressive symptoms. It is essential to note that the definition of treatment-resistant depression is not universally agreed upon, and the most recent study 1 provides a consensus guideline for definition of treatment-resistant depression for clinical trials, which is based on a Delphi-method-based consensus approach. In contrast to older studies, such as 1 and 1, which provide some guidance on the treatment of treatment-resistant depression, the most recent study 1 provides a more comprehensive and up-to-date approach to treating this condition.

From the Research

Treatment-Resistant Depression

The treatment of treatment-resistant depression (TRD) is a complex issue, with various approaches and strategies available.

• The recommended approach for treatment of TRD includes augmentation or switching of the initial antidepressant, with remission rates between 25% and 50% in both cases 2.
• Augmentation strategies that have been reviewed include lithium, thyroid hormone, pindolol, psychostimulants, and second-generation antipsychotics, with triiodothyronine augmentation offering the best benefit/risk ratio for augmentation of modern antidepressants 2.
• Switching from a first-line selective serotonin reuptake inhibitor (SSRI) to venlafaxine or mirtazapine may potentially offer greater benefits, although the evidence is not unequivocal 2.
• The evidence base supporting augmentation of conventional antidepressants with atypical antipsychotics, such as aripiprazole, quetiapine, and olanzapine, is extensive and rigorous 3.
• Other effective strategies for TRD include augmentation with lithium, liothyronine (T3), lamotrigine, or combination of antidepressants, including bupropion, tricyclics, or mirtazapine 4.
• Ketamine and esketamine have also been identified as effective treatments for TRD, with a rapid onset of action 4.

Pharmacological Treatments

Pharmacological treatments for TRD are varied and include:

• Augmentation with second-generation antipsychotics, such as quetiapine or aripiprazole 3, 4
• Combination of antidepressants, including bupropion, tricyclics, or mirtazapine 4
• Augmentation with lithium, liothyronine (T3), or lamotrigine 4
• Ketamine and esketamine, which have been shown to be effective for the treatment of TRD 4

Non-Pharmacological Treatments

Non-pharmacological treatments for TRD include:

• Psychotherapies, such as cognitive behavioral therapy, which remain a treatment option 3
• Neurostimulation strategies, such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation 5
• Aerobic exercise, which has been shown to be effective in reducing symptoms of depression 3