Antidepressant Augmentation: Adding Aripiprazole, Lithium, Bupropion or Thyroid Hormone

Antidepressant augmentation means adding a second medication to an antidepressant that has helped partly but not enough. Four drugs are FDA-approved as add-ons for major depression in adults: aripiprazole (Abilify), brexpiprazole (Rexulti), extended-release quetiapine (Seroquel XR) and cariprazine (Vraylar), all atypical antipsychotics. Lithium, thyroid hormone (T3) and bupropion are also used as add-ons and have trial evidence behind them, but none is FDA-approved for that purpose, so their use as augmenters is off-label or, for bupropion, a combination of two antidepressants.

No add-on is best for everyone. In the largest head-to-head trials, the advantages of augmenting over switching were modest and not every comparison was statistically significant, and each option trades benefit against a different set of side effects and monitoring needs. This guide compares them so you can weigh the choice with your prescriber. For the bigger picture of what to do when treatment has not worked, start with two antidepressants haven't worked: what a psychiatrist considers next.

Augment, switch or optimize?

Before adding anything, prescribers usually ask whether the current antidepressant has had a fair trial: an adequate dose for long enough, taken consistently, with problems such as alcohol, poor sleep, thyroid disease or another medical cause considered. Medical conditions to rule out covers that checklist.

If the drug has helped partly and is well tolerated, adding something keeps the gains you already have. If it has not helped at all, or side effects are a problem, switching is often more sensible. The trials below compare these paths directly.

The FDA-approved add-ons compared

All four approved add-ons are atypical antipsychotics, and all carry the class boxed warning about increased mortality in older adults with dementia-related psychosis, along with the antidepressant-class warning about suicidal thoughts in young people.

Monitoring and risks shared by all four

• Metabolic changes: higher blood sugar, cholesterol and triglycerides, and weight gain, which is why the labels call for monitoring weight, blood sugar and lipids. See antipsychotics and metabolic monitoring.
• Tardive dyskinesia, involuntary movements that can be irreversible; the risk is one reason to review periodically whether the add-on is still needed.
• Akathisia, an inner restlessness that can feel like worsening anxiety. It should be reported early, not endured.

The approved add-ons have more formal FDA backing, but approval reflects which manufacturer ran trials for which use, not proof that they outperform the older off-label options.

What the head-to-head trials show

VAST-D: veterans with depression not helped by one antidepressant

The VAST-D trial randomized 1,522 patients at 35 Veterans Health Administration centers to switch to bupropion, add bupropion, or add aripiprazole. Remission at 12 weeks was 22.3% after switching, 26.9% with added bupropion and 28.9% with added aripiprazole; only aripiprazole beat switching on remission. Response was higher with aripiprazole (74.3%) than with switching (62.4%) or added bupropion (65.6%). Aripiprazole brought more sleepiness, akathisia and weight gain, while anxiety was more common in both bupropion groups, and the authors described the remission advantage as statistically significant but modest. The participants were 85.2% men, which limits how far the results generalize.

OPTIMUM: adults 60 and older

In OPTIMUM, 619 adults aged 60 or older with treatment-resistant depression were randomized to add aripiprazole, add bupropion, or switch to bupropion. Remission occurred in 28.9%, 28.2% and 19.3% respectively, and well-being improved significantly more with aripiprazole than with switching to bupropion; the rate of falls was highest with bupropion augmentation. In a second step, 248 patients who had not benefited were randomized to add lithium or switch to nortriptyline, with remission in 18.9% and 21.5%. For older adults, geriatric psychiatry for aging parents covers the wider considerations.

Lithium as an add-on

Lithium is FDA-approved only for bipolar I disorder; its use to augment an antidepressant in unipolar depression is off-label. The evidence is older but consistent. A 2014 meta-analysis of 9 placebo-controlled trials with 237 patients found an odds ratio of 2.89 for response with added lithium versus placebo, and concluded it works with newer antidepressants as well as with tricyclics, while noting the trials were small.

Lithium has a second reason to be discussed: a 2013 meta-analysis of 48 randomized trials found that lithium reduced the number of suicides compared with placebo in people with mood disorders, including in unipolar depression. That does not make it the right add-on for everyone, but it is relevant when suicide risk is part of the picture.

The trade-off is monitoring. Lithium's boxed warning notes that toxicity is closely related to blood levels and can occur at doses close to therapeutic levels. Before starting, the label calls for checking kidney function, vital signs, electrolytes, thyroid function, current medications and pregnancy status, followed by regular blood-level checks, especially after any change in dose or in medicines such as diuretics or anti-inflammatories. Taking lithium: blood levels and monitoring walks through it, and this article on lithium and mental health gives background.

Thyroid hormone (T3)

Liothyronine (T3, Cytomel) is FDA-approved for hypothyroidism and certain thyroid conditions, not depression, so using it to augment an antidepressant in someone with normal thyroid function is off-label. Its label carries a boxed warning that thyroid hormones should not be used to treat obesity or for weight loss.

The best-known comparison comes from STAR*D's third step. In 142 outpatients who had not remitted after two treatments, remission was 15.9% with added lithium and 24.7% with added T3, a difference that was not statistically significant. Lithium caused more side effects, and more people stopped it because of them (23.2% versus 9.6%); the authors suggested T3 had slight practical advantages. If your thyroid function has not been checked, it is reasonable to ask your prescriber whether it should be, and a thyroid problem should be treated in its own right.

Bupropion and other combinations

Bupropion is FDA-approved on its own for major depression and for preventing seasonal depression; adding it to an SSRI or SNRI is a combination of two antidepressants rather than an approved add-on use. In STAR*D's second step, among people who had not remitted on citalopram, added bupropion and added buspirone produced similar remission rates (29.7% and 30.1%), but bupropion led to a greater reduction in symptom scores and fewer dropouts due to intolerance (12.5% versus 20.6%). In VAST-D and OPTIMUM, added bupropion did about as well as added aripiprazole on remission, with more anxiety in veterans and more falls in older adults.

Bupropion may be considered when fatigue, low motivation or SSRI-related sexual side effects are prominent, and it is contraindicated in seizure disorder and with a current or past diagnosis of bulimia or anorexia nervosa, as covered in SSRI, SNRI or bupropion.

Adding mirtazapine to an SSRI or SNRI is another common combination, but a UK trial of 480 primary care patients found no clinically important benefit over placebo, with more side effects. See mirtazapine vs trazodone for its profile.

What STAR*D does and does not tell you

STAR*D, a large real-world sequence trial in more than 4,000 adults, is often quoted as showing that most people eventually remit. Its summary paper reported remission rates of 36.8%, 30.6%, 13.7% and 13.0% for the first through fourth treatment steps, and an overall cumulative remission rate of 67%. A 2023 reanalysis of the patient-level data, using the protocol-specified Hamilton scale and excluding people who did not meet entry criteria, found a cumulative remission rate of 35.0%, about half the published figure.

Two lessons hold regardless of which number you accept. First, remission rates fall with each additional step, so it pays to make each step count with a full dose, enough time and good adherence. Second, people who needed more steps relapsed more often during follow-up, which argues for continued monitoring after improvement. STAR*D's own augmentation comparisons, lithium versus T3 and bupropion versus buspirone, found no significant difference in remission.

Choosing among add-ons

Psychotherapy is an add-on too. Adding CBT, behavioral activation or interpersonal therapy to medication is a legitimate augmentation strategy; medication, therapy or both summarizes the evidence.

What to track once an add-on starts

A simple weekly log of mood, sleep, energy and any side effects, kept for the first couple of months, gives your prescriber much better information than memory at a follow-up visit.

Common mistakes at the add-on stage

• Adding a drug before the first one has had a fair trial, which makes it impossible to tell what helped.
• Adding two things at once, so neither benefit nor side effects can be attributed.
• Staying on an add-on that has not helped, out of reluctance to change course; set a review point when it starts.
• Missing a bipolar pattern. Periods of reduced need for sleep, racing thoughts or unusual energy change the treatment plan and should be mentioned even if they were years ago.
• Ignoring the non-drug pieces. Sleep, alcohol, physical activity and psychotherapy all affect whether any medication works.
• Stopping lithium or an antipsychotic abruptly when feeling better, rather than planning the change with the prescriber.

Questions to ask before adding a medication

• Has my current antidepressant had a full trial at an adequate dose for long enough?
• Should we check thyroid function, sleep, alcohol use or other medical causes first?
• Why this add-on rather than a switch, and what result would tell us it is working?
• What monitoring will this need: weight, blood sugar, lipids, lithium levels, movement checks?
• How long would I stay on it if it helps, and how would we stop it later?
• Could my diagnosis be bipolar spectrum rather than unipolar depression?

Never add, stop or change a psychiatric medication on your own; these combinations need monitoring. If you are thinking about suicide or are in crisis, call or text 988 (the 988 Suicide & Crisis Lifeline) or go to the nearest emergency room.

How the practice approaches incomplete response

Dr. Lewis's practice offers psychiatric evaluation and medication management together with psychotherapy, lab testing, and nutrition and lifestyle psychiatry, so a plan for depression that has not fully responded can combine medication changes with therapy and lab testing. Read about medication management and lab testing at the practice, or start with a free discovery call. If you need care that is in network with your plan, ask the team on the discovery call about options. The full set of comparisons is in the Choosing Psychiatric Care guide.

Frequently asked questions

Does taking an antipsychotic mean I have psychosis?

No. Aripiprazole, brexpiprazole, quetiapine XR and cariprazine are each FDA-approved as add-on treatments for major depression, separately from their uses in psychotic disorders.

How long before I know whether an add-on is working?

Add-on trials are typically short; VAST-D measured remission at 12 weeks and OPTIMUM ran each step for about 10 weeks. Your prescriber will set a review point and track symptoms with a scale such as the PHQ-9; see PHQ-9 and GAD-7 scores explained.

Is buspirone an augmentation option?

Yes, it is used as an add-on. In STAR*D, added buspirone produced remission rates similar to added bupropion, though with more dropouts due to side effects. See buspirone vs SSRIs for anxiety for its profile.

Can genetic testing tell me which add-on will work?

Pharmacogenomic tests can flag how you metabolize some drugs, but they do not predict which add-on will relieve depression. See pharmacogenomic testing and its limits.

What if two add-ons have not worked either?

Options approved specifically for treatment-resistant depression include olanzapine-fluoxetine and esketamine nasal spray, which is given only in certified settings under a REMS program. Neuromodulation such as ECT and TMS is another path; depression treatment options compared describes them.

Do I have to stay on the add-on forever?

Not necessarily. Many people stay on a combination that works for a period of stability, then discuss with their prescriber whether to simplify. Lower-risk tapering is planned, never abrupt; switching antidepressants covers how changes are sequenced.

Sources

1. ABILIFY (aripiprazole) tablets prescribing information. Otsuka America Pharmaceutical via DailyMed (U.S. National Library of Medicine), 2025. dailymed.nlm.nih.gov
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3. SEROQUEL XR (quetiapine extended-release) tablets prescribing information. AstraZeneca via DailyMed (U.S. National Library of Medicine), 2025. dailymed.nlm.nih.gov
4. VRAYLAR (cariprazine) capsules prescribing information. Allergan/AbbVie via DailyMed (U.S. National Library of Medicine), 2026. dailymed.nlm.nih.gov
5. Olanzapine and fluoxetine capsules prescribing information. Teva Pharmaceuticals via DailyMed (U.S. National Library of Medicine), 2026. dailymed.nlm.nih.gov
6. Lithium carbonate capsules prescribing information. DailyMed (U.S. National Library of Medicine), 2026. dailymed.nlm.nih.gov
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14. Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression. New England Journal of Medicine (Lenze et al., OPTIMUM), 2023. pubmed.ncbi.nlm.nih.gov
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18. SPRAVATO (esketamine) nasal spray prescribing information. Janssen Pharmaceuticals via DailyMed (U.S. National Library of Medicine), 2026. dailymed.nlm.nih.gov

Educational information, not medical, tax or legal advice. Decisions about diagnosis, medication and treatment belong with a clinician who knows your history.