NEW ORLEANS -- Adjunctive cariprazine (Vraylar) was linked with a reduction in depressive symptoms for patients with major depressive disorder (MDD), who had an inadequate response to current therapy, according to a phase III study.
When added to a first-line antidepressant, 1.5 mg of once-daily cariprazine resulted in significantly greater average reductions in Montgomery-Åsberg Depression Rating Scale (MADRS) total score over 6 weeks compared with placebo, reported Gary Sachs, MD, of Massachusetts General Hospital in Boston.
Treatment with 1.5-mg cariprazine demonstrated significant differences from placebo by only week 2 of treatment and 44% of patients were considered MADRS responders -- defined as a 50% or greater reduction from baseline in total score -- by week 6, he said in a poster presentation at the American Psychiatric Association (APA) meeting.
In the third trial arm, patients were treated with 3 mg/day of cariprazine added to a first-line antidepressant. While these patients also saw greater reductions in MADRS score compared with placebo by week 6, the difference wasn't statistically significant.
At the end of the trial, 39.3% of patients in this higher-strength group were considered MADRS responders versus 34.9% of those on placebo.
"I think for the individual patient, I would give them a longer chance to respond at 1.5 mg, but if they didn't have adverse effects [AEs], I wouldn't hesitate to at least try a higher dose," Sachs explained in an interview with ľֱ. He added that in a , doses ranging from 2 to 4.5 mg were efficacious at reducing total MADRS score.
For the secondary trial endpoint of change in Clinical Global Impressions-Severity Score, patients on 1.5 mg and 3 mg saw a 0.3-point and 0.2-point larger drop in score than placebo, respectively.
As for other measures, patients on the 1.5-mg dose saw significantly greater treatment effects than placebo, while those on the 3-mg dose saw non-significant improvements:
- 17-item Hamilton Depression Rating Scale: -2.1 for 1.5 mg; -1.2 for 3 mg
- Hamilton Rating Scale for Anxiety: -1.3; -0.8
- Clinical Global Impressions-Improvement: -0.3; -0.3
Vraylar belongs to the class of atypical antipsychotics, and was first FDA approved in 2015. The agent currently holds three indications: for the treatment of adults with schizophrenia (1.5-6 mg/day), the acute treatment of manic or mixed episodes associated with bipolar I disorder (3-6 mg/day) and the treatment of depressive episodes associated with bipolar I disorder (1.5 or 3 mg/day).
Based on the findings of a clinical program, including the current data, developer for cariprazine in February 2022 seeking a fourth indication for the adjunctive treatment of major depressive disorder in patients who are receiving ongoing antidepressant therapy.
The label currently holds a boxed warning regarding increased mortality in elderly patients with dementia-related psychosis, and suicidal thoughts and behaviors.
"This is a new therapeutic area for this compound. In a way, what it does is make the job of the treating psychiatrist easier," said Sachs, pointing out how often times patients with depression, much like the ones in this study, have suffered with depression for 12 to 15 years. "Whether you have highs or only lows, it really doesn't matter very much. Those are people who spend a lot of time depressed."
"There's a temptation to keep giving standard antidepressant after standard antidepressant," he said. "That's sort of going, 'Well vanilla didn't work; we'll try French vanilla.'"
"The conundrum of DSM-5 is that even though [patients] might have a first-degree relative with bipolar disorder -- even though they may have failed multiple standard antidepressant drugs -- we're left with a diagnosis where we don't have an alternative that have been proven to have efficacy," Sachs added, pointing out that's exactly where this trial comes in. "I don't have to have a long discussion on why I'm treating them with something that is approved for a condition that they don't have."
"Now we have another class of medications that we use that are really quite different. We don't know what makes these drugs efficacious," Sachs explained. "It seems to me that anybody who had been ill -- and you see in this study for 6 months or longer -- hadn't responded to an adequate dose of a standard antidepressant, I would think that this is high on the menu for reasonable choices for any patient like that."
The 116-center study included 250 patients randomized to the 1.5-mg dose, 252 to the 3-mg dose, and 249 to placebo. Patients had a mean age of about 45; were majority female and predominantly white with a BMI around 30.
The current duration of MDD episode ranged from 6.8 months to 8.3 months with an average lifetime number of depressive episodes between 6 and 7.
Across all treatment groups, the average weight gain was under 2.2 lbs (1 kg). The most common treatment-emergent AEs included akathisia, nausea, headache, insomnia, and somnolence. More patients in the 3-mg group discontinued treatment due to AEs (7.1% vs 1.2% in the 1.5-mg group vs 2.4% in the placebo group) No deaths occurred in the study, according to Sachs and colleagues.
Disclosures
The study was supported by AbbVie. Some co-authors are company employees.
Sachs disclosed relationships with Signant Health, Abbott Laboratories, Allergan, Astellas, AstraZeneca, Blackthorn, Bristol-Myers Squibb, Intra-Cellular Therapies, Otsuka, Pfizer, Sunovion, Takeda, Wyeth, Repligen, and Sanofi.
Primary Source
American Psychiatric Association
Sachs G, et al "Cariprazine for the adjunctive treatment of major depressive disorder: results of a randomized phase 3 placebo-controlled study" APA 2022; Poster P7-037.