Able Psychiatry

Glossary

What Is Augmentation Therapy?

Written by the Able Psychiatry clinical team

Updated September 27, 2026

Augmentation therapy is the practice of adding a second medication, one that is not itself an antidepressant, alongside an existing antidepressant when that antidepressant has only partly relieved major depressive disorder. The original antidepressant is continued, and the new medication is meant to boost its effect rather than replace it.

Key takeaways

  • Augmentation differs from switching (stopping one antidepressant to start another) and from combination therapy (adding a second antidepressant instead of a non-antidepressant).
  • In the STAR*D trial, the NIMH-funded study of real-world depression treatment, the overall cumulative remission rate across up to four successive treatment steps was 67%, though remission fell at each additional step: 36.8%, 30.6%, 13.7%, and 13.0%.
  • Brexpiprazole (Rexulti) is FDA-approved specifically for “adjunctive treatment to antidepressants for major depressive disorder (MDD) in adults” — one of several atypical antipsychotics approved for this use.
  • When STAR*D compared two augmentation agents head-to-head after two failed antidepressant trials, remission occurred in 15.9% of patients augmented with lithium versus 24.7% augmented with T3 (thyroid hormone), a difference that was not statistically significant.

How augmentation therapy works

A common scenario: someone starts an SSRI or another first-line antidepressant and improves, but not all the way. Rather than stop and switch, or simply wait longer, a prescriber may add a second medication that works through a different mechanism, aiming to add to the benefit already there. This is one of several options considered when standard treatment hasn’t fully worked, including for what’s sometimes called treatment-resistant depression.

The decision to augment, rather than switch, usually comes after an adequate trial of the current antidepressant — enough time, at an adequate dose, for it to show its full effect. How long that takes depends partly on the medication’s own half-life, since blood levels and full clinical effect don’t appear instantly.

Types of augmentation medications

  • Atypical antipsychotics: aripiprazole, brexpiprazole, and quetiapine extended-release are among the antipsychotics FDA-approved specifically as adjunctive treatments for major depressive disorder, taken alongside — not instead of — an antidepressant.
  • Thyroid hormone (T3/liothyronine): studied and used as an augmentation strategy, including as one of the two options compared head-to-head in the STAR*D trial’s third treatment step.
  • Lithium: an older augmentation option, also compared against T3 in STAR*D; in that comparison it produced more side effects and more treatment dropouts.
  • The choice itself: which agent, if any, fits depends on your specific symptoms, other medications, and history — a decision made as part of your overall medication management and discussed with your prescriber.

Example of augmentation therapy

In the STAR*D trial’s third treatment step, 142 adult outpatients with major depressive disorder who had not achieved remission after an initial antidepressant trial and a second switch-or-augmentation trial were randomly assigned to add either lithium or T3 to their current antidepressant for up to 14 weeks. After a mean of 9.6 weeks, remission occurred in 15.9% of the lithium group versus 24.7% of the T3 group — not a statistically significant difference — but lithium was associated with more side effects, and more than twice as many patients on lithium left treatment because of side effects (23.2% versus 9.6%).

What people get wrong

Augmentation is sometimes read as a sign the first antidepressant “didn’t work.” In practice, it’s usually considered when a medication is helping somewhat, and the goal is to build on that partial benefit rather than start over. It also isn’t the same as raising the dose of the original medication — it means adding a second, different medication to it.

Augmentation therapy vs. switching vs. combination therapy

Augmentation Switching Combination therapy
What happens A non-antidepressant medication is added The current antidepressant is stopped and a different one started A second antidepressant, usually a different class, is added
Original antidepressant Continued Discontinued Continued
Example agent Atypical antipsychotic, thyroid hormone, lithium A different SSRI, SNRI, or other antidepressant class A second antidepressant, such as bupropion added to an SSRI

All three are strategies for when the current treatment hasn’t fully relieved depression. Which one a prescriber recommends depends on how much benefit the current medication is providing, side effects, and personal history — a conversation to have with your prescriber, not a decision to make alone.

Frequently asked questions

Does augmentation mean my first antidepressant failed?
Not usually. Augmentation is typically considered when an antidepressant is providing partial relief, and the goal is to build on that response rather than replace a medication that isn’t working at all. Whether to augment, switch, or combine is a decision to make with your prescriber based on how you’ve responded.

What medications are used for augmentation?
Options studied and FDA-approved for this use include certain atypical antipsychotics — brexpiprazole is approved specifically as an adjunctive treatment to antidepressants for major depressive disorder — as well as thyroid hormone and lithium, both studied in the STAR*D trial.

How is augmentation different from combination therapy?
Augmentation adds a medication that is not itself an antidepressant. Combination therapy instead adds a second antidepressant, usually from a different class than the first. Both keep the original medication in place; switching does not.

Is augmentation only used for treatment-resistant depression?
No. It’s considered whenever an antidepressant alone hasn’t fully relieved symptoms, which can include but isn’t limited to treatment-resistant depression. Your prescriber weighs your response, side effects, and history before recommending it.

The bottom line

Augmentation therapy adds a second, non-antidepressant medication to an antidepressant that’s helping some but not enough, rather than stopping it. Large trials like STAR*D show it can work, though remission rates for any single augmentation strategy are modest — which is why the choice of agent, and whether to augment at all, is made individually with your prescriber.

Sources

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