Andrew J. Cutler, MD, clinical professor of psychiatry at SUNY Upstate Medical University.

Andrew J. Cutler, MD

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 

, alongside earlier gains in anhedonia and motivation.

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.

About 30% to 50% of patients with MDD show inadequate response to antidepressant therapy, yet augmentation strategies are often delayed in routine practice.

 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.

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

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

 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.

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

 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.

What are you hoping the completed ProACt dataset will clarify?

 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.

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

 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

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. 

Rafeyan R, Papakostas GI, Jackson WC, Trivedi MH. Inadequate response to treatment in major depressive disorder: augmentation and adjunctive strategies. 

Videos

Interim ProACt data show adjunctive cariprazine may work within 2 weeks, easing reluctance to augment antidepressant therapy in MDD, Andrew Cutler, MD, says.

Why Clinicians Should Not Wait to Augment Inadequate Response in MDD

Interim data from the real-world ProACt study show adjunctive cariprazine (VRAYLAR) drove early improvement in PHQ-9, functioning, and anhedonia scores in patients with 

Nearly one-third to one-half of patients with major depressive disorder show inadequate response to antidepressant therapy despite adequate dosing and duration.

 Pivotal trials supporting FDA approval apply strict inclusion and exclusion criteria, often excluding common psychiatric comorbidities and limiting generalizability to routine practice. Real-world studies capture outcomes closer to what specialists see in everyday practice, including function and quality of life.

"For clinicians, one of the most important questions is whether the benefits demonstrated in clinical trials hold up in the real world, where patients have unique needs, experiences, and treatment journeys," said Andrew J. Cutler, MD, clinical professor of psychiatry at SUNY Upstate Medical University and investigator of the ProACt study.

ProACt is a prospective, real-world observational study evaluating adjunctive cariprazine in adults with MDD and an inadequate response to antidepressant therapy.

 In an interim analysis (n = 76) presented at Psych Congress 2026, mean PHQ-9 scores fell from 15.7 at baseline to 7.1 at week 6, a model-estimated change of -9.29 (95% CI, -11.13 to -7.45; P <.001).² Mean scores on the Functioning Assessment Short Test decreased from 37.4 to 19.9 over the same period, a change of -15.86 (95% CI, -22.53 to -9.18; P <.001).

Scores on the Snaith-Hamilton Pleasure Scale (SHAPS) and Motivation and Energy Inventory-Short Form (MEI-SF) improved as early as week 2 and continued through week 6, reflecting early gains in anhedonia, motivation, and energy.

These functional domains often drive patients to seek care in the first place. In the following Q&A, Cutler discusses what the interim ProACt findings mean for functional recovery in MDD.

Q&A: ProAct Data Show Early Functional Gains with Adjunctive Cariprazine In MDD

What gap does a real-world study like ProACt fill that the pivotal trials didn't?

 The clinical trials that we do to get medications FDA approved are very important, but there's certain rules you have to follow. The trials have lots of restrictions; they have inclusion-exclusion criteria. There are restrictions on other psychiatric concomitant conditions, other medical conditions, [and] concomitant medications, and so on. Very often the dosing in those trials is not as flexible as in the real world.

The rating scales used to get drugs approved…tend to be very symptom-based. What really matters to patients in the real world is not just symptoms but quality of life and function. Real-world studies approximate the real clinic more closely.

I find them extremely important as a companion to the clinical trials. They look at what actual clinicians and real patients are doing, so I like to tell clinicians this is your peers and your patients we're looking at. It's not as rigorous, it's often retrospective rather than prospective, and you're not controlling all the variables, but it's a very important complement that helps inform clinical practice and adds to the evidence from the clinical trials.

Why was it important to include patients with anxiety, trauma, and sleep comorbidities?

 In the ProACt study, we allowed patients with anxiety, trauma, and significant sleep issues. Those patients are often excluded from the pivotal clinical trials, [which]… may allow a little anxiety, but there’s usually a limit. In the real world, anxiety is very common alongside depression and other conditions, so this is a more realistic patient type.

Sometimes patients with trauma might have PTSD, and that would be excluded from the trials as well. Insomnia or sleep problems are usually allowed in clinical trials but [with] restrictions. A sleep disorder like obstructive sleep apnea [is not typically permitted even though] it's very common in the real world.

PHQ-9 scores dropped from 15.7 to 7.1 by week 6. What does that shift look like day-to-day?

 The PHQ-9 is a patient self-report scale versus a clinician-rated scale, and it's simply the 9 potential symptoms of depression from the DSM. You need 5 out of 9 to qualify for a major depressive episode. The PHQ-9 is more relevant to practicing clinicians because they use it more frequently [than a]… Montgomery-Åsberg Depression Rating Scale or Hamilton Depression Scale, and it's often embedded into electronic health records.

What I like about the PHQ-9 is the severity levels correlate with every 5 points. I think clinicians understand those numbers better than a MADRS score.

FAST scores fell nearly 16 points. How does that translate to real functional improvement?

 By the time a patient comes to see us when they're depressed, they've had symptoms for months or even years, so the question I always ask is, why now? Why are they coming to see me now?

Usually, the driver of seeking treatment is impairment in quality of life or function. Patients will say, "I'm afraid I'm going to lose my job," [or] a spouse says, "If you don't get help, I can't take this anymore."

[One] mom told me, "I used to be fun mom. I would do arts and crafts with my kids. We went on field trips. Now, I just lay on the couch and let them play video games, and I’m so guilty. I feel like I'm a bad mom." Those are the things that often motivate [someone to seek care.]

The FAST, the Functioning Assessment Short Test, is very useful because…it measures quality of life… [including] relationships… managing money… taking care of the house, [and]… autonomy. If we merely address symptoms, I don't think we're getting people all the way better.

Anhedonia and motivation and energy scores improved by week 2. Why does that early movement matter?

 With traditional antidepressants, it can take several weeks for symptoms to get better, and 2 of the most impairing symptoms of depression are anhedonia and low energy. Anhedonia is not only lack of pleasure but lack of motivation. If nothing seems exciting, interesting, or worth doing, you're not going to get off the couch.

Having those symptoms improve early is critical because they're the ones that impair function, which can translate into someone being able to get off the couch, get out of the house, and function better. Not all [9 potential symptoms of a depressive episode] correlate as strongly with functional impairment. Anhedonia and concentration correlate most with function… [along with] fatigue and low energy and motivation. Traditional antidepressants like SSRIs and SNRIs don’t treat those very well.

AbbVie. AbbVie highlights new real-world data supporting the effectiveness of VRAYLAR (cariprazine) at Psych Congress 2026. Published September 18, 2026. Accessed September 22, 2026. 

Articles

Interim prospective observational data from ProACt suggest adjunctive cariprazine in antidepressant-inadequate responders with MDD yields rapid, clinically meaningful improvements across symptom severity and functional domains. By week 6, patient-reported depression severity (PHQ-9) and global functioning (FAST) both improved substantially, with early signal by week 2 in anhedonia, motivation, and energy (SHAPS; MEI-SF). Broad inclusion of common comorbidities (anxiety, trauma-related symptoms, sleep disorders) aims to better mirror routine practice and inform real-world functional recovery.

Andrew Cutler, MD, says real-world MDD patients respond to adjunctive cariprazine like trial participants, with gains in mood and function within weeks.