From the Guidelines
The best add-on medication for patients taking an SSRI who are still experiencing depression is often bupropion (Wellbutrin), typically starting at 150 mg daily and potentially increasing to 300-450 mg daily. Bupropion works differently from SSRIs by primarily affecting dopamine and norepinephrine rather than serotonin, which can help address symptoms like low energy, poor concentration, and reduced motivation that may persist with SSRI treatment alone. According to the American College of Physicians clinical practice guidelines 1, existing evidence does not justify the choice of any second-generation antidepressant over another on the basis of greater efficacy and effectiveness. However, bupropion is associated with a lower rate of sexual adverse events than fluoxetine or sertraline. Other effective options include aripiprazole (Abilify) at 2-15 mg daily, which is FDA-approved as an adjunct therapy, or mirtazapine (Remeron) at 15-45 mg at bedtime, which can also help with sleep disturbances. Second-generation antipsychotics like quetiapine (25-300 mg) may be considered but carry more metabolic side effects. The choice should be individualized based on the patient's specific residual symptoms, side effect profile, and treatment history. Augmentation therapy should generally continue for at least 6-12 months after symptom improvement, with regular monitoring for side effects and therapeutic response. Key considerations include:
- Monitoring patient status, therapeutic response, and adverse effects of antidepressant therapy on a regular basis beginning within 1 to 2 weeks of initiation of therapy 1
- Modifying treatment if the patient does not have an adequate response to pharmacotherapy within 6 to 8 weeks of the initiation of therapy for major depressive disorder 1
- Continuing treatment for 4 to 9 months after a satisfactory response in patients with a first episode of major depressive disorder, and considering an even longer duration of therapy for patients who have had 2 or more episodes of depression 1
From the Research
Augmentation Strategies for Treatment-Resistant Depression
The most effective augmentation strategies for patients taking an SSRI who are still depressed include:
- Atypical antipsychotic agents, such as aripiprazole, olanzapine, quetiapine, and risperidone 2
- Other agents like mirtazapine, mianserin, and omega-3 fatty acids 2
- Lithium, desipramine, triiodothyronine, and modafinil, although the data for these agents is mixed 2
- Bupropion, desipramine, mecamylamine, and testosterone, which show promise but require further study 2
Network Meta-Analysis of Augmentation Agents
A network meta-analysis of 65 studies found that the following augmentation agents were effective in treating treatment-resistant depression:
- Liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine, and lisdexamfetamine 3
- Thyroid hormone (T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine) were also effective for remission rates 3
Combination Treatments for Major Depression
Combination treatments, such as adding a second-generation antipsychotic or lithium to an antidepressant, can be effective for treating major depression:
- Aripiprazole, olanzapine+fluoxetine, risperidone, and ziprasidone were more effective than quetiapine, brexpiprazole, or cariprazine 4
- Lithium was more effective and better tolerated than esketamine or second-generation antipsychotics 4
Case Reports and Small Studies
Small studies and case reports have also explored the use of combination treatments, such as bupropion and nortriptyline, for refractory depression:
- Four case reports found that the combination of bupropion and nortriptyline was effective in treating refractory depression 5