Treatment-resistant depression and the role of augmentation
A 45-year-old woman with major depressive disorder has not responded to two adequate trials of antidepressants: sertraline 200 mg daily for 8 weeks and venlafaxine 225 mg daily for 10 weeks. She has been adherent and has had adequate plasma levels. She continues to have moderate to severe depression with anhedonia, insomnia, and suicidal ideation without intent or plan. She has no psychotic symptoms. She has a history of hypothyroidism treated with levothyroxine 100 mcg daily, and her TSH is 2.5 mIU/L. She is reluctant to try another medication due to weight gain and sexual dysfunction from previous trials. She asks about other options.
1. What are the evidence-based augmentation strategies for treatment-resistant depression, and how would you choose among them for this patient?
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Evidence-based augmentation strategies:
- Atypical antipsychotics: Quetiapine, aripiprazole, olanzapine (with fluoxetine), brexpiprazole. Effective but risk of metabolic side effects.
- Lithium: Augmentation with lithium (plasma level 0.6–1.0 mEq/L) has good evidence, especially for suicidal risk.
- Thyroid hormone: Triiodothyronine (T3) 25–50 mcg daily; evidence is mixed but reasonable given her hypothyroidism history.
- Bupropion: Augmentation of SSRI/SNRI (though she has tried two antidepressants, adding bupropion may help with anhedonia and sexual dysfunction).
- Mirtazapine: Combination with SSRI/SNRI can improve sleep and appetite.
- Psychotherapy: Adding cognitive-behavioral therapy or interpersonal therapy.
- Other somatic treatments: Electroconvulsive therapy (ECT) for severe or psychotic depression; transcranial magnetic stimulation (rTMS) for non-psychotic depression; ketamine/esketamine for rapid response.
Choosing for this patient:
- She is reluctant to try another medication due to weight gain and sexual dysfunction. Therefore, choose an augmentation with a favorable side-effect profile.
- Aripiprazole is weight-neutral and has low sexual dysfunction risk; it is a first-line augmentation.
- Lithium is weight-neutral but requires monitoring; good if suicidal risk.
- T3 is well tolerated and may address subclinical thyroid issues.
- Psychotherapy (CBT) is essential.
- rTMS is a non-pharmacological option with no systemic side effects.
- Esketamine is effective but requires monitoring.
Plan: Discuss options, prioritize aripiprazole 2–5 mg augmentation or lithium, and add CBT. Monitor side effects and suicidal ideation closely.
2. What are the risks and benefits of using lithium augmentation in this patient?
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Benefits:
- Lithium is one of the most effective augmenting agents for treatment-resistant depression, with response rates around 30–50%.
- It has anti-suicidal properties, which is relevant given her suicidal ideation.
- It is weight-neutral and does not cause sexual dysfunction.
- It may be particularly effective in patients with a family history of bipolar disorder or recurrent depression.
Risks:
- Narrow therapeutic index: requires regular monitoring of plasma levels (target 0.6–1.0 mEq/L), renal function, thyroid function, and calcium.
- Thyroid: can cause hypothyroidism; she already has hypothyroidism, so monitor TSH closely and adjust levothyroxine.
- Renal: can cause nephrogenic diabetes insipidus and chronic kidney disease; monitor creatinine and eGFR.
- Drug interactions: NSAIDs, ACE inhibitors, thiazides increase lithium levels.
- Tremor, weight gain, acne, and cognitive effects.
- Overdose toxicity: nausea, vomiting, ataxia, confusion, seizures.
In this patient: Her hypothyroidism is a relative concern but manageable with monitoring. Her suicidal ideation makes lithium an attractive option due to anti-suicidal effects. However, she needs to be reliable for follow-up and blood tests. Discuss the monitoring requirements and potential interactions. If she prefers to avoid lithium, consider aripiprazole or T3.