Treatment-resistant depression, or TRD, is a major depressive disorder that does not improve after treatment with two antidepressants. About half of people with depression may experience it, and TRD is linked to a higher risk of suicide.

What Are the Risk Factors of Treatment-Resistant Depression?

Some people have a higher risk of treatment-resistant depression. Risk factors include:

• Being assigned male at birth.

• A history of layoffs.

• Low socioeconomic status.

• Depression onset in childhood.

• Severe depression symptoms.

• Suicidal thoughts or behavior.

• Recurrent depression.

• Chronic pain.

For example, a man with chronic back pain and severe depression who has just been fired may have a higher chance of developing treatment-resistant depression.

What Are the Types of Treatment?

Depending on what a person is taking now and how their symptoms respond to medications, a doctor can choose between adding another medication or switching antidepressants.

A doctor will most likely make one change at a time to track the results. Depending on the drug, it can take four to eight weeks for the effects of a new medication to appear.

When changing or adding medication, your doctor will check the interactions between all of the medications you are taking. To check this yourself, you could use the Drugs.com Interaction Checker.

What Medications Can Be Used for Treatment-Resistant Depression?

Note: The drugs described here are for educational purposes. The choice of medication should rely on your doctor’s expertise and knowledge of your medical history.

One add-on option is a second-generation antipsychotic, such as aripiprazole, brexpiprazole, or quetiapine. These medications may help with major depression that includes prominent anxiety symptoms.

Other options include lithium, thyroid hormone, ketamine, another antidepressant, stimulants, or stimulant-like drugs.

It is important to consult with your doctor because each medication has limitations and contraindications. For example, lithium might not be prescribed to people with kidney or thyroid disease, and thyroid hormone should be used cautiously in people older than 60.

What Should I Know About Lithium?

Lithium treatment requires periodic blood-level monitoring every three to six months. Target lithium serum levels are 0.5–0.8 mEq/L.

How Effective Is Lithium for TRD?

In terms of effectiveness, meta-analyses show that, compared with placebo, the probability of response to lithium was two to three times higher.

Another benefit is that lithium greatly reduces suicide risk. It also enhances the effects of other antidepressants and may reduce the likelihood of hospitalization.

Who Is Most Likely to Respond to Lithium?

Lithium is more likely to be effective if a patient has:

• Severe depressive symptoms.

• Visible slowing of physical movements, speech, and thought processes.

• A history of more than three major depressive episodes.

• Weight loss.

• A first-degree relative with a mood disorder.

What should I ask my doctor before starting lithium?

• Why am I being prescribed this treatment specifically, instead of a different one?

• How long should I wait before I may see an effect?

• What are the potential side effects of the treatment?

• What should I do if I experience negative side effects?

• What next steps should I take?

Scientific Sources:

• Acero-González et al. (2025). Lithium Augmentation in Treatment-Resistant Depression: A Qualitative Review of the Literature https://doi.org/10.1002/phar.70063

• Cleare et al. (2025). Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression: a pragmatic, open-label, parallel-group, randomised controlled superiority trial in the UK https://doi.org/10.1016/S2215-0366(25)00028-8

• Scott et al. (2023) Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression. https://doi:10.1177/02698811221104058

• Voineskos et al. (2020). Management of Treatment-Resistant Depression: Challenges and Strategies https://doi.org/10.2147/NDT.S198774

• Thase et al. (2026) https://www.uptodate.com/contents/treatment-resistant-major-depressive-disorder-in-adults

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