From the Guidelines
For treatment-resistant depression, the most effective approach is to switch to a different antidepressant class, such as venlafaxine (75-375mg daily) or mirtazapine (15-45mg daily), as these have shown similar symptomatic relief in second-step therapies 1.
Treatment Options
When considering treatment options for resistant depression, several strategies can be employed:
- Augmentation with an atypical antipsychotic like aripiprazole (2-15mg daily) or lithium (600-900mg daily, targeting blood levels of 0.6-0.8 mEq/L) can be effective 1.
- Switching to a different antidepressant class, such as venlafaxine (75-375mg daily) or mirtazapine (15-45mg daily), may help, as these have shown similar symptomatic relief in second-step therapies 1.
- For severe cases, MAOIs such as tranylcypromine (20-60mg daily) may be considered despite dietary restrictions.
- Combining antidepressants from different classes (such as an SSRI with bupropion 150-300mg daily) may also be effective.
Key Considerations
When selecting a treatment approach, it is essential to consider the individual patient's symptom profile, previous medication response, and side effect tolerance. Close monitoring for at least 4-6 weeks is necessary to assess effectiveness. The certainty of evidence for most comparisons is low, and findings should be interpreted cautiously 1.
Evidence Summary
A systematic review and network meta-analysis found that different switching and augmentation strategies provided similar symptomatic relief for patients who did not achieve remission after an initial attempt with antidepressants 1. Another study found that 38% of patients did not achieve a treatment response during 6 to 12 weeks of treatment with second-generation antidepressants, and 54% did not achieve remission 1.
Treatment Prioritization
Prioritizing treatment approaches based on the most recent and highest-quality evidence, switching to a different antidepressant class, such as venlafaxine or mirtazapine, is a recommended approach for treatment-resistant depression 1.
From the FDA Drug Label
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
Medications for Resistant Depression:
- Sertraline: The dose may be increased up to a maximum of 200 mg/day for patients who do not respond to a 50 mg dose 2.
- Aripiprazole: Although aripiprazole is not approved for use in treating depression in the pediatric population, it may be used as an adjunctive treatment for major depressive disorder in adults 3. It is essential to note that the FDA label does not provide a comprehensive list of medications for resistant depression. However, the labels suggest that dose adjustments and combination therapy may be considered for patients who do not respond to initial treatment. Patients should be monitored closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of treatment or at times of dose changes 2 3.
From the Research
Medications for Resistant Depression
- The first step for patients with treatment-resistant depression (TRD) is to optimize the dosage and duration of antidepressants as well as to ensure their drug compliance 4.
- Augmentation strategies are currently the most evidence-based treatment options for TRD, with second-generation antipsychotics and lithium having the strongest evidence for management 4.
- Other effective augmentation strategies include the use of ketamine and esketamine 5, 6, as well as certain second-generation antipsychotics such as quetiapine or aripiprazole 6.
- Combination of antidepressants, including bupropion, tricyclics, or mirtazapine, may also be effective 6.
- Augmentation with lithium, liothyronine (T3), or lamotrigine may be considered as alternative options 6.
Non-Pharmacological Therapies
- Electroconvulsive therapy and repetitive transcranial magnetic stimulation are effective somatic therapies for TRD 4, 5.
- Psychotherapy, exercise, and focused dietary changes may also be beneficial as non-pharmacologic therapies 5.
- Other somatic therapies, such as magnetic seizure therapy, deep brain stimulation, transcranial direct current stimulation, and vagus nerve stimulation, may be considered as alternative options 7.
Treatment Approaches
- Switching to a different antidepressant, combining more than one antidepressant, or augmenting an antidepressant with another medication are common next-step treatment options for patients with TRD 6.
- A shared decision-making approach is recommended to guide treatment selection and address each patient's individual needs 6.
- Further research is needed to evaluate the efficacy of certain medications, such as ziprasidone or levothyroxine (T4), and to identify the most effective therapeutic modalities for patients with residual symptoms 8, 6, 7.