Many patients with major depressive disorder (MDD) suffer from clinically significant levels of anxiety. In fact, according to data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, nearly half of patients with MDD report significant anxiety symptoms, sometimes referred to as “anxious depression.”
Anxiety symptoms often complicate the course of illness and make it more difficult to achieve full remission from depressive symptoms despite adequate antidepressant therapy. More specifically, individuals with comorbid anxiety tend to have poorer responses to standard antidepressant treatments, take longer to improve, and face greater risks of relapse, persistent impairment, and suicidality compared to those without prominent anxiety symptoms. Even when depressive symptoms improve, lingering anxiety can make individuals more vulnerable to relapse of depression, highlighting the need for treatment strategies that address not only depression but also anxiety in this population.
In a multicenter clinical trial led by Dr. Maurizio Fava, the MGB AMC Chair of Psychiatry, researchers assessed the impact of adjunctive treatment with cariprazine on anxiety symptoms in adults diagnosed with MDD (according to DSM-5 criteria) who had not achieved sufficient improvement with standard antidepressant therapy.
Study Design
This post hoc analysis included data from a phase 3 study of cariprazine for MDD, assessing the effects of adjunctive cariprazine (1.5 or 3.0 mg per day) on depression. In this cohort, participants presented with varying degrees of anxiety at baseline, as measured using the Hamilton Rating Scale for Depression (HAM-D) Anxiety/Somatization factor scores and Hamilton Anxiety Rating Scale (HAM-A) total scores.
In this 6-week trial, participants were randomized to receive antidepressant augmentation with cariprazine 1.5 or 3 mg or placebo. The modified intent-to-treat (mITT) population included 751 patients (cariprazine 1.5 mg/day, n = 250; cariprazine 3.0 mg/day, n = 252; placebo, n = 249). Baseline demographic and clinical characteristics were generally similar across the three groups.
Based on HAM-D Anxiety/Somatization Factor scores, 627 patients (83.5%) presented with significant anxiety symptoms at baseline. HAM-A total scores indicated that 742 patients (98.8%) had at least mild anxiety symptoms and 262 (34.9%) had severe anxiety symptoms at baseline.
Improvements in Depression and Anxiety with Adjunctive Cariprazine
In patients with elevated anxiety symptoms (anxious depression), the change in depressive symptoms from baseline (on MADRS total scores) was significantly greater for those receiving augmentation with cariprazine 1.5 mg/day versus placebo. In patients without anxiety symptoms (non-anxious depression), cariprazine was also associated with greater improvements in depressive symptoms, although this finding was not statistically significant.
Furthermore, adjunctive treatment with cariprazine was also associated with significantly reduced anxiety symptoms. Both adjunctive cariprazine doses were associated with significantly greater reductions in HAM-D Anxiety/Somatization factor scores compared to placebo in patients with anxious depression at baseline. Regardless of the severity of anxiety symptoms at baseline in this cohort of patients with MDD, adjunctive treatment with cariprazine was associated with reductions in both depression and anxiety symptoms. Importantly, the research team observed no worsening of anxiety symptoms in patients receiving adjunctive cariprazine.
Clinical Implications
While most commonly used antidepressants can also be used to address anxiety symptoms in patients with MDD, anxiety symptoms are among the most common residual symptoms following antidepressant treatment, and these residual symptoms not only complicate treatment, but residual anxiety negatively affects psychosocial functioning and makes remission more difficult to achieve.
The results of this post hoc analyses are aligned with previous studies indicating that anxiety is a common feature of MDD, with the majority of patients in this group experiencing some degree of anxiety. Of note, the proportion of patients with anxiety symptoms in this study differed slightly based on what measurements were used to measure anxiety. Using the HAM-D Anxiety/Somatization factor score identified 83.5% with at least mild anxiety symptoms at baseline, whereas the HAM-A total score identified 98.8% with at least mild anxiety symptoms.
In the current study, patients with MDD who had an inadequate response to antidepressant alone, experienced reductions in both depression and anxiety symptoms when treated with adjunctive cariprazine. The largest anxiolytic effects were observed for patients with severe anxiety.
These findings support previous preclinical studies suggesting that cariprazine may have anxiolytic properties. Cariprazine differs from other atypical antipsychotics in its affinity for the D3 receptor. Cariprazine displays a greater affinity for the D3 receptor than other atypical antipsychotics, and its affinity for the D3 receptor is 10-fold greater than its affinity for the D2 receptor. This unique pharmacologic feature may play a role in reducing anxiety symptoms in patients with MDD; future research is needed to confirm this hypothesis.
The current study supports the use of an adjunctive cariprazine for managing patients with MDD, regardless of the degree of baseline anxiety symptoms.
Read More
Fava M, Masand PS, Maletic V, Chen C, Adams JL, Kerolous M. Efficacy of Adjunctive Cariprazine on Anxiety Symptoms in Patients With Major Depressive Disorder: Post Hoc Analysis of a Randomized Placebo-Controlled Trial. J Clin Psychiatry. 2025 Apr 30;86(2):24m15506.
