Let’s return to Rylie from a previous PsychSnap. She is a 20 yo woman in a first episode of major depression (severe, PHQ9-22). She started weekly psychotherapy and escitalopram, titrated to 20mg daily. Two months later, her depressive symptoms have worsened slightly (PHQ9-24). Rylie switched from escitalopram to duloxetine with a partial response (~40% improvement in her symptoms) on duloxetine 60mg. Ongoing psychotherapy, regular exercise, and a duloxetine dose increase to 90mg did not help further. Rylie’s current PHQ9 is 15, and she is back to taking duloxetine 60mg daily. What now?
We previously learned that adding bupropion to another antidepressant is not an effective antidepressant augmentation strategy despite its safety, intuitive appeal, and widespread use.
What medications are effective in depression augmentation?
An augmentation agent for major depression is a medication added to an existing antidepressant to enhance or “augment” the antidepressant effect. Several recent network meta-analyses have looked at the comparative efficacy of depression augmentation agents in adults with an inadequate response to at least 1 antidepressant. Their conclusions were similar (Zhou 2015, Nunez 2022). While extensively studied (n >200 in each medication group), bupropion and buspirone were no better than placebo in augmenting an antidepressant in major depression. In contrast, aripiprazole, quetiapine (Seroquel), and lithium were effective medications for unipolar depression augmentation (Nunez 2022).
If you read that sentence and thought, “Aripiprazole, quetiapine, and lithium are not medications that I use in primary care – psychiatrists should be managing these patients,” I agree with you. And, if primary care clinicians can learn to use one effective medication for unipolar depression augmentation, they can offer their patients treatment while they wait to connect with a psychiatrist.
How do you use low-dose aripiprazole for depression augmentation?
The rest of this PsychSnap is focused on aripiprazole (as opposed to quetiapine or lithium) for depression augmentation because it is 1) as or more effective than the other two, 2) well-tolerated, and 3) straightforward to use. I hope that this PsychSnap will help you feel confident using aripiprazole as an augmentation agent for major depression.
How effective is aripiprazole as an augmentation agent for major depressive disorder?
The relative risk of depression remission with aripiprazole for adults is 1.75 [95% CI 1.47-2.09] (Nunez 2022). The odds ratio for remission for older adults with MDD is 2.0 [95% CI 1.1-3.7] (Lenze 2015).
What about tolerability?
The main side effects of aripiprazole in depression augmentation trials were weight gain and akathisia, both of which were dose dependent. At aripiprazole doses <5mg, the rate of medically significant weight gain was 4.4% (vs 25-28% for 5mg+). Akathisia is a medication side effect experienced as a sense of inner restlessness and an urge to move. Akathisia typically begins soon after starting or increasing the dose of a dopamine-blocking medication like aripiprazole. Akathisia can sometimes be misdiagnosed as worsening anxiety or agitation. At aripiprazole doses <5mg, the rate of akathisia in depression augmentation trials was 5% (vs 15-26% at 5mg+) (Seshari 2021).
Target dose – 2-4mg daily, max dose 10-15mg.
Current aripiprazole product labeling was based on phase 3 trials that used target doses of aripiprazole 5-15mg (mean dose 11mg) (Berman, 2009). However, a 2021 meta-analysis of data from 10 studies (n=2625) looked for the optimal depression augmentation target dose. Efficacy for aripiprazole increased between 2 and 5mg and then plateaued (Furukawa 2021). Furthermore, the ED95–the dose at which 95% of responders responded–was 4mg. Only 4% of participants dropped out due to adverse effects from aripiprazole 4mg (Furukawa, 2021). For these reasons, I recommend a target dose of aripiprazole 2-4 mg daily for depression augmentation.
Titration – Patients usually start to feel better within the first 2 weeks of starting aripiprazole for depression.
Aripiprazole 2mg pills; 1mg (½ pill) for 6 days then 2mg (1 pill) daily.
If no response after 2 weeks, increase to 4mg (2 pills) daily.
If insurance balks at 2 pills daily, consider switching to the 5mg pill.
If there is no response after 4 weeks at 4-5mg, stop the medication. There is no need to taper low-dose aripiprazole after 6 weeks of exposure.
If there is a partial response and the patient is tolerating the aripiprazole well, consider titrating the dose further. Start with 5mg, and then increase the dose by 2.5mg every 4 weeks, stopping if there is no further benefit or side effects limit titration (max dose 10-15mg). While population-wise the optimal dose for aripiprazole for depression augmentation may be 4mg, some individuals may need higher doses for optimal efficacy.
If aripiprazole is helpful, how long should it be continued?
We have limited data to answer this question. The efficacy of aripiprazole in unipolar depression augmentation is established for acute treatment, not for maintenance treatment.
Try to get your patient linked with a psychiatrist. If that isn’t possible and the patient benefits from aripiprazole, continue it for 6 months from the point of depression remission. Consider reducing the dose or stopping the medication sooner if there are troublesome side effects (Takeshima 2024).
How should I stop aripiprazole if the patient has taken it for a sustained time?
Taper it over 1-3 months with close monitoring. Stop the taper if depressive symptoms return. To taper off aripiprazole 4-5mg, decrease the dose to 2mg for 1 month, then 1mg for 1 month, then stop.
What monitoring is necessary for a patient taking low-dose aripiprazole?
Monitor weight* and do a brief screening neuro exam to look for signs of extrapyramidal side effects (EPS) at each visit, specifically parkinsonism or tardive dyskinesia (TD) (<1%) (Seshari 2021). I generally look for a tremor or shuffling gait, check for cogwheeling in the arms, and pay attention to involuntary oral-buccal movements throughout the visit. This examination takes about 45 seconds.
Drug-drug interactions – Several antidepressants can affect the metabolism of aripiprazole through the CYP2D6 and CYP3A4 pathways. Antidepressants that are strong CYP2D6 inhibitors (paroxetine, fluoxetine, and bupropion) increase aripiprazole levels. The manufacturer recommends decreasing the target dose of aripiprazole by 50% in the presence of a strong CYP2D6 or CYP3A4 inhibitor. For example, if you are augmenting paroxetine with aripiprazole, the target dose of aripiprazole should be 2mg instead of 4mg. There are also many antidepressants, including escitalopram, sertraline, and venlafaxine, that do not affect the metabolism of aripiprazole. Aripiprazole does not affect the metabolism of antidepressants.
What about serotonin syndrome? Don’t worry about serotonin syndrome with the combination of aripiprazole and an antidepressant.
The green box offers sample written instructions for your patients.
Patient instructions for taking aripiprazole for depression augmentation
Aripiprazole (Abilify) is a second generation antipsychotic that can be added to an antidepressant to treat major depression. While it was initially developed to treat psychosis, aripiprazole is well-studied for depression. People often see a benefit for depression within 1-2 weeks of starting aripiprazole.
Dosing
Aripiprazole 2mg pills: take 1 mg (½ pill) for the first 6 days. If you are tolerating it after 6 days, start taking 2mg (1 full pill) daily.
If you are tolerating it and have had no response to 2mg after 2 weeks, increase the dose to 4mg (two pills) daily.
Potential side effects
Aripiprazole is often well tolerated. It can cause restlessness or an uncomfortable feeling of “needing to move,” particularly when you first start it. If you experience this, contact the clinic. It will go away if you stop the medication.
Depending on the person, aripiprazole can be activating or sedating. It can interfere with sleep. It can also cause weight gain in some people.
Rare side effects – Aripiprazole rarely causes tremors, stiffness, or involuntary movements that may not go away when you stop the medication. We will monitor you closely to ensure that we are using this medication safely.
Back to Rylie – You discuss aripiprazole augmentation of duloxetine while trying to connect Rylie with a psychiatrist. Duloxetine is a moderate 2D6 inhibitor with some 3A4 activity that has been specifically studied in combination with aripiprazole. The co-administration of duloxetine increases aripiprazole plasma concentrations by 54% (Margraff 2023). You choose a target aripiprazole dose 3mg daily, and start aripiprazole 1mg for 6 days, then 2mg daily. After taking aripiprazole 2mg for 2 weeks, Rylie is notably better with no side effects. At 4 weeks, Rylie’s depression is finally in remission. 2 months after that, she connects with a psychiatrist.
*Guidelines for metabolic monitoring in people taking a second-generation antipsychotic medication like aripiprazole include screening for hyperlipidemia and diabetes at baseline, 3 months after starting the medication, and then annually. I don’t do this routinely with aripiprazole. A depression augmentation study with a target aripiprazole dose of 10mg followed people (n=1002) for a year and found no significant change in mean fasting cholesterol or glucose levels (Seshari 2021).
Key Points
- Adding low-dose aripiprazole (2-5mg) to a partially-effective antidepressant is an effective depression augmentation strategy for adults and older adults.
- Monitor for weight gain and akathisia, particularly when starting or increasing the dose of aripiprazole.
- Aripiprazole is not well-studied for maintenance treatment of depression. Consider tapering aripiprazole 6 months after depression remission.
Related PsychSnaps:
“When a young adult is hearing voices and psychiatry is unavailable for months, how can you help? (part 2)” Emma Samelson-Jones. August, 2023.
“Is adding bupropion to an SSRI/SNRI an effective depression augmentation strategy?” Emma Samelson-Jones. June, 2025.
References:
Berman, Robert M., et al. “Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants.” CNS spectrums 14.4 (2009): 197-206.
Furukawa, Yuki, et al. “Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: Preliminary findings based on a systematic review and dose–effect meta-analysis.” The British Journal of Psychiatry 221.2 (2022): 440-447.
Lenze, Eric J., et al. “Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial.” The Lancet 386.10011 (2015): 2404-2412.
Margraff, Teresa, et al. “Discovering interactions in augmentation strategies: Impact of duloxetine on the metabolism of aripiprazole.” Basic & Clinical Pharmacology & Toxicology 133.1 (2023): 73-81.
Nunez, Nicolas A., et al. “Augmentation strategies for treatment resistant major depression: a systematic review and network meta-analysis.” Journal of affective disorders 302 (2022): 385-400.
Seshadri, Ashok, et al. “Long-term efficacy and tolerability of adjunctive aripiprazole for major depressive disorder: systematic review and meta-analysis.” The Primary Care Companion for CNS Disorders 23.4 (2021): 34898.
Takeshima, Masahiro, et al. “Impact of aripiprazole discontinuation in remitted major depressive disorder: a randomized placebo-controlled trial.” Psychopharmacology 241.8 (2024): 1555-1563.
Zhou, Xinyu, et al. “Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: systematic review and network meta-analysis.” The Journal of clinical psychiatry 76.4 (2015): 3423.
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