What Is the Optimal Dose of Aripiprazole for Treating Depression That Hasn't Responded to Antidepressants?

What you need to know

• Low doses of aripiprazole (2-5 mg) may be most effective for augmenting antidepressant treatment in depression that hasn’t responded to antidepressants alone.
• Higher doses (above 10 mg) do not appear to provide additional benefits.
• Side effects may increase up to 5 mg but do not seem to increase further at higher doses when the medication is flexibly prescribed.

What is aripiprazole and how is it used for depression?

Aripiprazole is a medication that was originally developed to treat conditions like schizophrenia and bipolar disorder. However, it has also been found to be helpful when added to antidepressant treatment for people with major depressive disorder who haven’t had an adequate response to antidepressants alone.

When someone with depression doesn’t improve enough with antidepressant treatment, doctors have several options. They may increase the dose of the antidepressant, switch to a different antidepressant, combine two antidepressants, or add another type of medication to augment (boost) the effects of the antidepressant. Aripiprazole is one medication that can be used for this augmentation approach.

While aripiprazole has been shown to be effective for this purpose, there has been uncertainty about the optimal dose to use. The recommended dose range is quite wide - from 2 mg up to 15 mg per day. This wide range can be confusing for doctors and patients. Using too low a dose may not provide enough benefit, while using too high a dose may cause unnecessary side effects without adding more therapeutic effect.

What did this study investigate?

This study aimed to determine the optimal dose of aripiprazole when used as an add-on treatment for depression that hasn’t responded adequately to antidepressants alone. The researchers conducted a systematic review and meta-analysis of existing clinical trials to examine the relationship between aripiprazole dose and its effects on:

1. Efficacy (how well it improves depression symptoms)
2. Tolerability (whether people stop taking it due to side effects)
3. Acceptability (whether people stop taking it for any reason)

By analyzing data from multiple studies together, they hoped to provide clearer guidance on the best dosing approach.

How was the study conducted?

The researchers searched multiple databases to find all relevant randomized controlled trials that:

• Included adults with major depressive disorder who had not responded adequately to at least one antidepressant treatment
• Compared different doses of aripiprazole added to ongoing antidepressant treatment
• Were double-blind (meaning neither patients nor researchers knew who was receiving which dose)
• Lasted 4-12 weeks (focusing on acute treatment effects)

They ended up including 10 studies with a total of 2,625 participants. Most studies used flexible dosing, where the dose could be adjusted within a certain range based on response and side effects.

The researchers then conducted a dose-effect meta-analysis. This advanced statistical technique allowed them to model the relationship between aripiprazole dose and its effects across the different studies.

What were the key findings?

Efficacy

The analysis found that aripiprazole’s effectiveness for improving depression increased up to doses between 2 mg and 5 mg per day. Beyond this dose range, there didn’t appear to be additional benefit in terms of depression symptom improvement.

Specifically, they estimated that:

• The dose needed to achieve 50% of the maximum effect (ED50) was 1.7 mg
• The dose needed to achieve 95% of the maximum effect (ED95) was 4.0 mg

This suggests that most of aripiprazole’s antidepressant benefit is achieved at relatively low doses.

Tolerability

The likelihood of stopping aripiprazole due to side effects also increased up to about 5 mg per day. However, at higher doses, there wasn’t a clear further increase in discontinuation due to side effects.

This pattern suggests that side effects may become more prominent up to 5 mg, but don’t necessarily worsen further at higher doses when the medication is flexibly prescribed (allowing dose adjustments based on individual response).

Acceptability

There was no significant difference between aripiprazole and placebo in terms of overall discontinuation rates (stopping for any reason) across the dose range studied.

What do these findings mean for patients and doctors?

These results suggest that when adding aripiprazole to ongoing antidepressant treatment:

1. Starting with a low dose (around 2 mg) and potentially increasing up to about 5 mg may provide the optimal balance of effectiveness and tolerability for most patients.

2. Pushing to higher doses (above 10 mg) is unlikely to provide additional benefit for depression symptoms.

3. Side effects may increase as the dose is increased up to 5 mg, but may not necessarily worsen further at higher doses if the medication is flexibly prescribed with careful monitoring.

4. The overall acceptability of treatment appears similar to placebo across the dose range, suggesting aripiprazole is generally well-tolerated when used appropriately.

This information can help guide doctors in finding the most appropriate dose for individual patients. Starting low and increasing gradually up to about 5 mg as needed may be a reasonable approach for many people.

Limitations to keep in mind

While these findings are helpful, there are some important limitations to consider:

• The number of studies was relatively small, leading to some uncertainty in the results, especially for tolerability and acceptability.
• Most studies were funded by pharmaceutical companies, which could potentially bias the results.
• The studies only looked at short-term treatment (up to 12 weeks), so we don’t know about long-term effects.
• People with other serious psychiatric conditions were excluded, so the findings may not apply to all patients.

Conclusions

• Low doses of aripiprazole (around 2-5 mg per day) appear to provide the most benefit when added to antidepressants for treatment-resistant depression.
• Increasing to higher doses is unlikely to improve depression symptoms further but may increase side effects in some people.
• Starting at a low dose and increasing gradually if needed, while monitoring for side effects, may be the best approach for most patients.
• More research is still needed to confirm these findings and examine long-term effects.