Adding Vraylar (Cariprazine) to SSRI for Treatment-Resistant Depression
Augmenting an SSRI with cariprazine 2-4.5 mg/day is an effective and FDA-approved strategy for treatment-resistant major depressive disorder, demonstrating statistically significant improvement in depressive symptoms compared to placebo when added to ongoing antidepressant therapy. 1, 2
Evidence for Efficacy
Cariprazine at the higher dose range (2-4.5 mg/day) shows clear benefit as augmentation therapy:
The pivotal randomized controlled trial demonstrated a statistically significant reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week 8 compared to placebo (least squares mean difference = -2.2; adjusted P = .0114) when cariprazine 2-4.5 mg/day was added to ongoing antidepressant therapy 2
The lower dose range (1-2 mg/day) did not achieve statistical significance for the primary endpoint, though it showed benefit at earlier timepoints (weeks 2 and 4) 2
Response rates (≥50% reduction in symptoms) and remission rates were numerically higher with cariprazine augmentation, particularly at the 2-4.5 mg/day dose 2
Long-term data (26 weeks) showed sustained benefit, with 53.3% of patients achieving remission (MADRS ≤10) by week 26 3
Dosing Strategy
Start cariprazine at 1.5 mg/day and titrate to 2-4.5 mg/day based on response and tolerability:
The FDA-approved dosing for adjunctive treatment in MDD begins at 1.5 mg once daily, with increases to 3 mg/day after adequate assessment 1
Clinical trials used flexible dosing within the 2-4.5 mg/day range, which proved most effective 2
Mean effective dose in real-world settings was approximately 1.7 mg/day, though this included patients with bipolar depression 4
Expected Adverse Effects
Akathisia is the most common and clinically significant adverse effect, occurring in a dose-dependent manner:
In fixed-dose trials for adjunctive MDD treatment, akathisia occurred in 8% of patients on 1.5 mg/day and 12% on 3 mg/day, compared to 3% on placebo 1
In the flexible-dose trial (2-4.5 mg/day), akathisia occurred in 22.3% of patients 2
Other common adverse effects (≥5% and twice placebo rate) include: insomnia (13.6%), nausea (12.8%), restlessness, fatigue, constipation, increased appetite, dizziness, and extrapyramidal symptoms 1, 2
Long-term safety data showed 79% of patients experienced at least one treatment-emergent adverse event, with akathisia (15.9%) and headache (11.6%) most common 3
Discontinuation due to adverse events occurred in approximately 6-14% of patients across trials 1, 2, 3
Metabolic and Cardiovascular Safety
Cariprazine demonstrates a relatively favorable metabolic profile compared to some other atypical antipsychotics:
Mean changes in metabolic parameters (lipids, glucose, weight), vital signs, and ECG parameters were generally similar between cariprazine and placebo groups 2
Weight increase occurred in <1-2% of patients in bipolar depression trials 1
Increased appetite was reported in 1-3% of patients 1
Timeline for Response
Expect to see initial improvement within 2-4 weeks, with continued benefit through 8 weeks:
Significant differences from placebo were detected as early as week 2 in the 2-4.5 mg/day group 2
The primary endpoint assessment occurred at week 8, which represents an adequate trial duration 2
Long-term studies showed continued improvement through 26 weeks 3
Critical Clinical Considerations
Monitor closely for akathisia and extrapyramidal symptoms, particularly during dose titration:
Akathisia is dose-dependent and represents the primary tolerability concern 1, 2
Consider prophylactic or concurrent use of beta-blockers (e.g., propranolol) or benzodiazepines if akathisia develops, or reduce the cariprazine dose 1
Dystonia can occur, particularly in susceptible individuals during the first few days of treatment, though it occurs more frequently with higher potency first-generation antipsychotics 1
Ensure adequate trial of initial SSRI before adding cariprazine:
Treatment-resistant depression is typically defined as inadequate response to at least one adequate trial of an antidepressant (appropriate dose and duration of 6-12 weeks) 5, 6
The American College of Physicians recommends at least 6-12 weeks for the acute phase of treatment before considering augmentation strategies 6
Continue both medications for at least 4-9 months after achieving response:
Guidelines recommend continuation phase treatment of 4-9 months after initial response to prevent relapse 6
For patients with recurrent depression, maintenance treatment of ≥1 year may be necessary 6
Comparison to Other Augmentation Strategies
Cariprazine represents one of several evidence-based augmentation options for treatment-resistant depression:
The American College of Physicians found that different switching and augmentation strategies provided similar symptomatic relief, though the certainty of evidence is low for most comparisons 5
Other atypical antipsychotics (aripiprazole, quetiapine, brexpiprazole) also have evidence for augmentation in treatment-resistant depression, and selection should consider adverse effect profiles and patient-specific factors 5
Switching to a different SSRI or SNRI is an alternative strategy with similar overall efficacy to augmentation approaches 5, 6
Common Pitfalls to Avoid
Do not use the lower dose range (1-2 mg/day) as the target dose – the evidence clearly supports 2-4.5 mg/day for efficacy in MDD 2
Do not discontinue prematurely due to mild akathisia – consider dose reduction or symptomatic management before abandoning an otherwise effective strategy 1, 2
Do not fail to counsel patients about neuropsychiatric adverse effects – particularly important for monitoring suicidal thoughts, though no suicide-related adverse events were reported in the pivotal trial 2
Do not add cariprazine before ensuring an adequate trial of the initial SSRI – at least 6-12 weeks at therapeutic dose is necessary to define treatment resistance 5, 6