From the Guidelines
Treatment-resistant depression (TRD) should be managed through a stepwise approach, prioritizing optimization of the current antidepressant, followed by augmentation strategies, and considering newer approaches like transcranial magnetic stimulation (TMS) or ketamine, as evidenced by the most recent guideline from 2022 1.
Key Considerations
- Optimization of the current antidepressant is crucial, ensuring adequate dosage and duration, usually 6-8 weeks at therapeutic doses.
- Augmentation strategies are recommended, including adding medications like lithium (600-900 mg/day), second-generation antipsychotics such as aripiprazole (2-15 mg/day) or quetiapine (150-300 mg/day), or thyroid hormone (T3, 25-50 mcg/day) 1.
- Switching to a different antidepressant class is another option, particularly to venlafaxine (75-375 mg/day), bupropion (300-450 mg/day), or mirtazapine (15-45 mg/day).
- For more severe TRD, electroconvulsive therapy (ECT) remains highly effective, typically administered 2-3 times weekly for 6-12 treatments.
- Newer approaches include ketamine (0.5 mg/kg IV infusion) or esketamine nasal spray (56-84 mg twice weekly initially), and TMS, which has been found to have benefits in improving symptoms and facilitating remission, outweighing the harms, with only minimal and manageable adverse events 1.
Psychotherapy Integration
- Psychotherapy, particularly cognitive behavioral therapy or interpersonal therapy, should be integrated throughout treatment, as it provides additional benefits in addressing the complex neurobiology of treatment-resistant depression.
Evidence Basis
- The 2022 guideline from the U.S. Department of Veterans Affairs and U.S. Department of Defense 1 provides the most recent and highest-quality evidence for the management of TRD, supporting the use of TMS and other augmentation strategies.
- The lack of a consensus definition for TRD, as noted in the 2020 review 1, highlights the need for a standardized approach to managing this condition, emphasizing the importance of a stepwise treatment strategy.
From the FDA Drug Label
Treatment of treatment resistant depression. (1.6) Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax. Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder or treatment resistant depression. (2.5,2. 6) Treatment Resistant Depression in adults (2. 6) Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily
The evidence-based treatment for treatment-resistant depression (TRD) is olanzapine and fluoxetine in combination, with a recommended starting dose of 5 mg of oral olanzapine and 20 mg of fluoxetine once daily in adults 2.
- Key points:
- Olanzapine monotherapy is not indicated for TRD.
- The combination of olanzapine and fluoxetine is used for TRD.
- The recommended starting dose is 5 mg of oral olanzapine and 20 mg of fluoxetine once daily in adults.
From the Research
Treatment-Resistant Depression (TRD) Definition and Management
- Treatment-resistant depression is defined as the absence of remission despite trials of two or more antidepressant medications and can occur in up to 31% of patients with major depressive disorder 3.
- Management strategies for TRD include adding psychotherapy, switching antidepressant medication class, or augmenting with additional medications 3, 4.
Pharmacological Interventions for TRD
- Current guidelines recommend augmentation with a second-generation antidepressant, an atypical antipsychotic, tricyclic antidepressants, lithium, or a triiodothyronine medication as pharmacologic options 3.
- Ketamine and esketamine can also be used as augmentation for treatment-resistant depression and may help reduce suicidal ideation 3.
- Augmenting current antidepressant treatment with mianserin or with an antipsychotic (cariprazine, olanzapine, quetiapine or ziprasidone) improves depressive symptoms over the short-term (8 to 12 weeks) 5.
- Lithium was found to be somewhat more effective and better tolerated than esketamine or second-generation antipsychotics as an adjunct to antidepressants for acute major depressive episodes 6.
Non-Pharmacological Interventions for TRD
- Electroconvulsive therapy and repetitive transcranial magnetic stimulation may be effective for TRD 3, 7.
- Nonpharmacologic therapies include psychotherapy, exercise, and focused dietary changes 3.
- Cognitive behavior therapy (with or without continued citalopram) had similar response and remission rates to those who received other medication regimens for patients who did not respond to citalopram 7.
Limitations and Future Directions
- The optimal strategy for treating TRD has yet to be identified, and further controlled clinical trials are essential to identify the most effective treatment strategies 4.
- There is limited evidence regarding the effectiveness of psychotherapy for treatment-resistant depression, and more research is needed to determine its efficacy 7.
- The evidence regarding the effects of augmenting current antidepressant therapy with buspirone or switching current antidepressant treatment to mianserin is currently insufficient, and further trials are needed to increase the certainty of these findings 5.