From the Guidelines
When SSRIs have failed, bupropion (Wellbutrin) is often a good first choice as an atypical antidepressant, typically started at 150 mg daily and potentially increased to 300-450 mg daily, due to its unique mechanism of inhibiting norepinephrine and dopamine reuptake rather than serotonin, as supported by studies such as STAR*D 1.
Alternatives to SSRIs
Other options include:
- Mirtazapine (Remeron), usually prescribed at 15-45 mg at bedtime, which can help with sleep and appetite issues while working on both serotonin and norepinephrine systems.
- Venlafaxine (Effexor) or duloxetine (Cymbalta), both SNRIs, targeting both serotonin and norepinephrine, may be effective when SSRIs alone aren't sufficient.
- For treatment-resistant depression, adding an atypical antipsychotic like aripiprazole (Abilify) at 2-15 mg daily to an existing antidepressant can be beneficial, as seen in studies evaluating treatment-resistant MDD 1.
- Trazodone is sometimes used at 50-150 mg for depression with significant sleep disturbance.
Considerations for Switching Medications
When switching medications, it's crucial to cross-taper gradually under medical supervision to minimize withdrawal effects and maintain therapeutic coverage, as highlighted in guidelines for treating depressive disorders 1. These alternatives work through different neurotransmitter systems or combinations thereof, potentially addressing aspects of depression that SSRIs alone couldn't target effectively, thus offering hope for patients who have not responded to initial SSRI treatment.
From the Research
Atypical Antidepressants When SSRIs Have Failed
When SSRIs have failed, several strategies can be employed to optimize treatment. These include:
- Optimizing SSRI dosing by starting at a low dose and slowly increasing the dose to reach the target dose 2
- Ensuring an adequate trial before switching to a different drug 2
- Augmentation therapy with drugs such as benzodiazepines, buspirone, beta blockers, tricyclic antidepressants, and valproate sodium 2
- Switching to a non-SSRI agent, such as venlafaxine or mirtazapine, which have been shown to be effective in treating major depression 3, 4
Next-Step Strategies
The next-step strategies for patients who do not respond to SSRIs include:
- Raising the dose, which was the most frequently reported next-step strategy for patients with minimal response after 4 weeks of adequate SSRI therapy, partial response after 8 weeks of adequate SSRI therapy, and relapse on long-term SSRI therapy 3
- Switching to a non-SSRI agent, which was the most frequently chosen option for nonresponders to an adequate trial of SSRI therapy 3
- Augmentation therapy with another agent, such as lithium or valproic acid, which are commonly used in combination with SSRIs to treat bipolar depression 5
Atypical Antidepressant Options
Atypical antidepressant options that can be considered when SSRIs have failed include:
- Venlafaxine, which has been shown to be effective in treating major depression and has a dose-efficacy curve that increases up to around 75-150 mg 4
- Mirtazapine, which has been shown to be effective in treating major depression and has a dose-efficacy curve that increases up to a dose of about 30 mg 4
- Bupropion, which is sometimes used in combination with SSRIs to treat depression, although combinations of more than one antidepressant are not commonly used 5