Interim data from the real-world ProACt study suggest clinicians may not need to wait weeks to know whether adjunctive cariprazine is working, with PHQ-9 and Functioning Assessment Short Test scores continuing to improve through week 6 in patients with major depressive disorder (MDD), alongside earlier gains in anhedonia and motivation.¹ Meta-analyses show augmentation with atypical antipsychotics produces greater response rates than antidepressant monotherapy alone, and evidence suggests early response within the first 2 weeks of augmentation can predict eventual improvement.^1,2

About 30% to 50% of patients with MDD show inadequate response to antidepressant therapy, yet augmentation strategies are often delayed in routine practice.² Atypical antipsychotics carry the strongest evidence among augmentation options and are FDA-approved for this indication, but many clinicians reach for them only after multiple antidepressant trials. Consensus reviews find augmentation more effective than switching or combining antidepressants for many patients with partial response.²

Despite mixed feelings among prescribers about metabolic and movement-related risks, evidence-based augmentation strategies remain underused relative to their potential benefit.¹ In the following Q&A, Cutler discusses how quickly clinicians should expect to see movement with augmentation and how real-world data like ProACt can inform decisions for a skeptical colleague.

Q&A: Why Clinicians Should Not Wait to Augment Inadequate Response in MDD

HCPLive: What does this data suggest about how long clinicians should wait before judging whether augmentation is working?

Andrew Cutler, MD: Unfortunately, people are not feeling urgency to treat depression all the way. My good friend Dr. Rakesh Jain and I surveyed a large database of what prescribers are actually doing for MDD, and we found they start an SSRI and then do nothing for 7 months. That’s unacceptable that you allow somebody to have inadequate treatment that long.

In the real world, they'll then switch from [an] SSRI to another SSRI or an SNRI. The next thing they do is [add] another antidepressant called bupropion, which is not evidence-based or FDA approved [for this use]. Eventually, [at] fourth or fifth line, people are adding an atypical antipsychotic. The 5 atypical antipsychotics are FDA approved [and] have the best evidence. We should be using them earlier.

There's now evidence you don't have to wait weeks. If you're not seeing somebody getting…at least 20% to 25% better in the first 2 weeks, you should do something. That something can be raise the dose, switch, or augment.

Part of the problem is we adjust our expectations to what our medicines can do, and because traditional antidepressants get people better but not all the way, we sort of say, “Oh, you’re better. That’s good.”

I understand the reluctance to use atypical antipsychotics. There are risks: weight gain and metabolic issues, drug-induced movement disorders, and so on.

You have to consider what's the risk of inadequately treating the illness. The fact is, it causes [a] big impact [on] people's lives, and there's even a risk of suicide. So, we should be more aggressive.

Now, the same thing applies when you add an atypical antipsychotic. You should see movement in the first 2 weeks. You don't have to wait 6 or 8 weeks. What's interesting about the newer atypical antipsychotics is it appears that they move the needle within 1 week.

HCPLive: How does real-world data like this change the conversation with a skeptical colleague?

Andrew Cutler, MD: I think a lot of clinicians have become skeptical because they realize [the pivotal trial population] is small… [and] hand-selected…not representative of [their] own patients.

They [may not] understand the rating scales as well, [or] what they mean, [and some have] been burned when they see this data that looks so good and the [medicine doesn’t] get as good results. Real-world data is extremely helpful [for informing] clinical practice and [giving] reassurance it's worth trying 1 of these medicines.

HCPLive: What are you hoping the completed ProACt dataset will clarify?

Andrew Cutler, MD: I'm hoping it helps overcome the reluctance to use an evidence-based, FDA-approved atypical antipsychotic like cariprazine. The newest agents, cariprazine, lumateperone, and brexpiprazole, are extremely effective, safe, well tolerated, and can work fast.

HCPLive: Any patient subgroups you're especially watching as more data comes in?

Andrew Cutler, MD: Clinical trials don't [always] get good representation across ethnic groups, races, and even genders, although MDD tends to have a female preponderance [of] two-thirds women [to] one-third men. I'm also really interested in the older population, [which] tends to be underrepresented; you're more careful with older people [so] they might have more medical problems, more medications.

The other population that we don't allow into studies are people with [a history of or current] substance abuse. There is some evidence if you effectively treat depression, you can make a dent in the substance abuse because sometimes people are self-medicating.

There's [also] a high association of obesity, cardiovascular disease, and diabetes with depression. Sometimes, those patients…may not be allowed in the clinical trials. We know that successfully treating depression can lead to decreases in these issues. People take better care of themselves; they follow lifestyle changes or the medication regimen. It's been shown that treatment of depression not only can decrease suicide but can decrease cardiovascular and metabolic risk.

Read part 1 of our interview with Cutler here: ProACt Data Show Early Functional Gains with Adjunctive Cariprazine In MDD

References

1. AbbVie highlights new real-world data supporting the effectiveness of VRAYLAR (cariprazine) at Psych Congress 2026. AbbVie. Published September 18, 2026. Accessed September 22, 2026. https://news.abbvie.com

2. Rafeyan R, Papakostas GI, Jackson WC, Trivedi MH. Inadequate response to treatment in major depressive disorder: augmentation and adjunctive strategies. J Clin Psychiatry. 2020;81(3):OT19037BR3.