02. Cariprazine Dosing for Bipolar Disorder In Older Adults

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Bipolar I in Older Adults: Unique Challenges

Today, I want to tackle a topic that’s becoming more relevant: bipolar I disorder in older adults. Treating bipolar disorder is already a balancing act. But aging adds extra challenges — comorbidities, polypharmacy, and symptom changes.

One clinical nugget up front: older patients often have more pronounced depressive symptoms and cognitive issues. Intense manic episodes can be less obvious. So, watch for subtler mood and thinking changes when you assess these patients.

Here’s the issue: there’s limited prospective research on medications for older adults with bipolar disorder. This can leave us feeling a bit on our own sometimes when we’re choosing treatments that had been mostly tested in younger populations. That’s exactly why I was keen to dig in to this post hoc analysis by Garel and his colleagues.

Post-Hoc Analysis Fills Research Gap

This study looked back at data from studies on Cariprazine, a newer antipsychotic we use quite a bit, to see how it stacked up in older versus younger adults with bipolar I disorder. While it’s not a brand-new dedicated study for just older adults, and we absolutely need more of those, looking back at this existing data gives us some really valuable clues.

So let’s pull back the curtain on this paper from the American Journal of Geriatric Psychiatry. Cariprazine, quick reminder, it’s that atypical antipsychotic that acts as a partial agonist on those dopamine D3 and D2 receptors and also on the serotonin 5-HT1A receptor.

It’s approved for treating acute manic or mixed episodes and depressive episodes in bipolar I disorder plus schizophrenia and as an add-on for major depressive disorder in the US. The key thing is the official prescribing info right now doesn’t give us different dosing instructions for older adults compared to younger ones.

Study Design: Depression And Mania Data

Researchers pooled data from six large placebo-controlled trials:

• 3 focused on bipolar I depression
• 3 focused on acute manic/mixed episodes

They re-categorized participants:

• Older age group: ≥50 years
• Younger age group: ≤49 years

In depression trials, ~1/3 were older adults. In mania/mixed trials, ~1/4 were older.

Similar Depression Efficacy Across Age Groups

For acute bipolar I depression, the study examined Cariprazine doses of 1.5 mg and 3 mg daily, plus a pooled group, versus placebo.

Key findings:

• Older adults: the pooled group showed significant symptom improvement over placebo.
• Individual doses in the older adults didn’t reach significance — probably due to smaller sample sizes.
• Younger adults: both doses and pooled group showed significant benefit.

Importantly, there was no significant difference in treatment effect between age groups. Secondary measures (CGI-S) backed this up.

Clinical pearl:

• The 1.5 mg dose appears effective in older adults.
• This supports starting at the recommended dose, with the option to titrate to 3 mg, regardless of age.

Mania Efficacy Varies By Dose

For acute bipolar I mania or mixed episodes, the study looked at Cariprazine doses of 3-6 mg and 9-12 mg daily versus placebo.

Key findings:

• Older adults: 3–6 mg/day significantly improved mania scores.
• 9–12 mg/day did not show significant benefit in older adults.
• Younger adults: both dose ranges were effective.
• Comparing groups:
  • For 3–6 mg/day, no difference in treatment effect by age.
  • For 9–12 mg/day, younger adults had better outcomes.

Clinical pearl:

• In older adults, stick to 3–6 mg/day for mania/mixed states.
• Higher doses weren’t more effective and actually less effective than in younger adults.

So the big picture on efficacy is pretty positive and consistent. Cariprazine seems to work well for both depressive and manic or mixed episodes in bipolar I disorder. And here’s the key. The treatment effect is similar for older and younger patients when you stay within those recommended dose ranges.

Age alone doesn’t mean the medication won’t work as well which is really helpful information when you’re choosing treatments for your older patients.

Safety Profile: Similar Across Age Groups

Overall, the study found that cariprazine was generally tolerated similarly in older and younger adults in the bipolar I depression trials. The safety profile matched what they’d seen in previous studies. Looking at who stopped treatment because of side effects, the rates were pretty similar between Cariprazine and placebo for depression in both age groups.

In the mania mixed trials, more patients on Cariprazine stopped treatment due to side effects compared to placebo in both age groups. Importantly, stopping rates were numerically higher in the 9 to 12 mg per day dose in the older group compared to 3 to 6 mg per day dose. This just reinforces that point about staying within the 3 to 6 mg range for those older patients.

Watch For Akathisia — And Ask Specifically

A side effect we always watch closely with these kinds of medications is akathisia, that feeling of inner restlessness and needing to move. This analysis found that more patients on Cariprazine got akathisia compared to placebo in both older and younger groups. Interestingly, maybe surprisingly, the number of older patients who reported akathisia was numerically lower than in the younger group.

The authors thought that maybe older patients weren’t reporting it as much. They might be putting it down to other things that can happen as you get older while younger patients might be more clued in about medication side effects and actively look out for akathisia.

An akathisia clinical pearl for you. Akathisia can happen with Cariprazine in older adults just like in younger adults but older patients might not tell you about it on their own. Instead of just asking them, “are you having any side effects?”, specifically ask them if they feel restless like they have to move or can’t sit still.

In this study, though it happened, very few patients in any group or on any dose actually stopped treatment specifically because of akathisia. The paper also lists other common side effects like headache, nausea, insomnia and constipation showing how often they occur in each group. While there were some differences in the numbers, the general pattern was consistent.

Keep in mind that movement disorders and motor side effects in general can be more common and stick around longer in older patients when they’re taking antipsychotics. So staying observant about these things is key.

No Increased Risk of Mood Switching

This analysis also looked at whether Cariprazine increased the risk of switching from depression to mania or from mania to depression.

The findings were reassuring. The analysis didn’t suggest Cariprazine caused an increased risk in either the older or younger patients.

Clinical Takeaways Support Standard Dosing

So what’s the ultimate takeaway for you, the clinician in the trenches with me? This post hoc analysis, even with the caveat that it wasn’t originally built just to compare age groups, gives us solid data.

It tells us that Cariprazine looks to be similarly effective and generally well tolerated in both older and younger adults with bipolar I disorder when you’re treating acute depression or acute mania or mixed episodes as long as you’re using the recommended dose ranges. This means you’ll likely not need to adjust the dose just because of age, based on this study. But you absolutely still need to be on the lookout for side effects like akathisia. Older patients just might not bring it up themselves.

Understanding Study Limitations

As with any research, it’s crucial to understand its limitations. The authors themselves are quite transparent about these. The very first thing they point out is this was a pooled post hoc analysis, not a trial designed from the ground up to compare age groups.

The original studies were not prospectively designed to detect statistical differences between these subgroups. Also, when they pooled the data, ethnicity information was simply unavailable. So we can’t see if ethnicity might have played a role.

There’s also a practical limitation related to how Cariprazine is used around the world. The authors note that indications for Cariprazine can differ across countries partly due to how pharmaceutical companies market the drug globally. For instance, in the US and Canada, it’s approved for the acute treatment of manic or mixed episodes and depression in bipolar I disorder. But outside of North America, it’s only approved for schizophrenia. This difference in approved uses could potentially limit how broadly these findings about bipolar disorder can be applied in other regions.

Regarding safety, the original studies were not designed to compare adverse events specifically between the age subgroups. So while they can tell us the rates of side effects, the direct comparison wasn’t a primary goal.

Effective Treatment Improves Function in Elderly

A final super important clinical pearl. Treating symptoms effectively in older adults with bipolar disorder is really important because how bad their symptoms are directly impacts how well they function. This study suggests Cariprazine used within the recommended doses appears to be a good, effective option that can help your older patients feel better and function well.

I’d personally be mindful about sticking to that 3 to 6 mg range of Cariprazine when treating mania in older adults. Whereas, there might be reason to consider going above this range as clinically indicated for younger adults.

I really hope breaking down this paper has given you some clear actionable insights and practical points you can use in your daily practice.

Abstract

Effect of Cariprazine on Outcomes in Older-aged and Younger-aged Patients with Bipolar I Disorder: A Post-hoc Analysis

Nicolas Garel, M.D., MSc, FRCPC; Annemieke Dols, M.D., Ph.D.; Jun Yu, Ph.D.; Christine Di Cresce, Ph.D.; Soham Rej, M.D., MSc, FRCPC; Martha Sajatovic, M.D.

Objectives

To evaluate cariprazine in adults with older- and younger-age bipolar I disorder (OABD-I and YABD-I) and compare treatment effects between them.

Design and setting

Pooled post-hoc analysis of studies in depressive or acute manic/mixed episodes associated with bipolar I disorder.

Participants

475/1383 patients (34.3%) in 3 depression trials and 238/1037 patients (23.0%) in 3 manic/mixed trials were OABD-I.

Interventions

Depression: placebo, cariprazine 1.5 mg/day, 3.0 mg/day, pooled 1.5-3.0 mg/day. Manic/mixed: placebo, cariprazine 3.0-6.0 mg/day, and 9.0-12.0 mg/day.

Measurements

Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression of Severity (CGI-S), and Young Mania Rating Scale (YMRS).

Results

In bipolar I depression, mean change from baseline in MADRS was significantly greater for the pooled cariprazine group vs. placebo in OABD-I (−13.72 vs. −11.98; p < 0.05) and for each cariprazine group vs. placebo among YABD-I. There was no significant difference in treatment effect between OABD-I and YABD-I for either individual cariprazine group vs. placebo.

For mania/mixed states, mean change in YMRS was significantly greater for cariprazine 3.0-6.0 mg/day vs. placebo in OABD-I (−19.04 vs. −12.45; p < 0.001) and for both cariprazine groups in YABD-I (−12.49, −19.66 and −18.05 for placebo, cariprazine 3.0–6.0 mg/day and 9.0–12.0 mg/day, respectively [both p < 0.0001 vs. placebo]). There was no significant difference in treatment effect between OABD-I and YABD-I for cariprazine 3.0–6.0 mg/day vs. placebo; there was a significantly higher treatment effect for cariprazine 9.0–12.0 mg/day vs. placebo in the YABD-I subpopulation vs. OABD-I (4.20; p < 0.05).

Conclusions

Cariprazine appears to be effective for both depressive and manic/mixed episodes of bipolar I disorder, regardless of age.

Key Words

1. Cariprazine
2. older age bipolar disorder
3. bipolar mania
4. bipolar depression

Reference

Garel, N. M.D., MSc, FRCPC; Dols, A. M.D., Ph.D.; Yu, J. Ph.D.; Di Cresce, C. Ph.D.; Rej, S. M.D., MSc, FRCPC & Sajatovic, M. M.D. (2025). Effect of Cariprazine on Outcomes in Older-aged and Younger-aged Patients with Bipolar I Disorder: A Post-hoc Analysis. The American Journal of Geriatric Psychiatry, Volume 33, Issue 4, 372 – 386.