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 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. 

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

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.