When to adjunct or increase Vraylar (cariprazine) for anhedonia in a patient with major depressive disorder?

Adjuncting or Increasing Vraylar (Cariprazine) for Anhedonia in Major Depressive Disorder

When to Adjunct Cariprazine

Adjunct cariprazine 1.5 mg/day when a patient with major depressive disorder has failed to achieve adequate response after a systematic trial of antidepressant monotherapy (typically 6-8 weeks at therapeutic doses), particularly when anhedonia is a prominent residual symptom. 1, 2

Evidence-Based Rationale for Adjunctive Use

• Cariprazine demonstrated specific anti-anhedonic effects in patients with bipolar I depression, with benefits preserved even after adjusting for other depressive symptoms, suggesting this effect is not pseudospecific 1
• In pooled phase 3 studies of adjunctive cariprazine for MDD, patients had high completion rates (90%) with mostly mild-to-moderate treatment-emergent adverse events causing premature discontinuation in only 4.3% of cases 3
• Real-world data showed significantly greater reductions in disability claims, days, and costs with adjunctive cariprazine compared to brexpiprazole and aripiprazole in patients with MDD 4

Clinical Algorithm for Initiating Adjunctive Cariprazine

• Start with cariprazine 1.5 mg/day as the initial adjunctive dose, particularly in patients with lower baseline anhedonia severity 1
• Continue the current antidepressant at its therapeutic dose while adding cariprazine 3, 2
• Assess treatment response at 4 weeks and 6 weeks using standardized depression rating scales, with particular attention to anhedonia symptoms 1

When to Increase Cariprazine Dose

Increase cariprazine from 1.5 mg/day to 3 mg/day after 4-6 weeks if the patient shows partial response but continues to experience significant anhedonia or depressive symptoms, particularly in patients with higher baseline anhedonia severity. 1

Evidence Supporting Dose Escalation

• In patients with higher baseline anhedonia (MADRS anhedonia factor score ≥19), both cariprazine 1.5 mg/day and 3 mg/day demonstrated significantly greater reductions in MADRS total scores and anhedonia factor scores compared to placebo 1
• The 3 mg/day dose showed numerically greater improvements in the higher anhedonia subgroup (LSMD -3.26 for total MADRS vs -3.01 for 1.5 mg/day) 1
• In patients with lower baseline anhedonia, cariprazine 1.5 mg/day was superior to placebo, but 3 mg/day did not show additional benefit, suggesting a potential floor effect 1

Dose Escalation Algorithm

• For patients with prominent anhedonia at baseline: Consider increasing to 3 mg/day after 4 weeks if response to 1.5 mg/day is inadequate 1
• For patients with lower anhedonia severity: Maintain 1.5 mg/day, as higher doses may not provide additional benefit 1
• Maximum approved dose: Do not exceed 3 mg/day for adjunctive treatment of MDD 3

Safety and Tolerability Considerations

Common Adverse Events

• Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine-treated patients at twice the rate of placebo 3
• Potential dose-dependent responses were observed for akathisia and insomnia, with higher rates at 3 mg/day compared to 1.5 mg/day 3
• In long-term studies (26 weeks), the most common treatment-emergent adverse events were akathisia (15.9%) and headache (11.6%) 2

Metabolic Profile

• Cariprazine demonstrated a neutral metabolic profile with mean weight increase of <1 kg in pooled phase 3 studies 3
• Mean changes in clinical laboratory, cardiovascular, and ophthalmologic parameters were generally not clinically relevant in long-term studies 2

Treatment-Resistant Cases

In patients who have failed a first atypical antipsychotic augmentation trial (aripiprazole, risperidone, or brexpiprazole), switching to cariprazine augmentation can still produce clinical response. 5

• In a case series of treatment-resistant unipolar depression patients who failed first AA augmentation, 7 out of 10 patients responded to cariprazine augmentation 5
• HAM-D mean scores decreased from 23.9 ± 3.9 at baseline to 14.8 ± 5.3 at 4 weeks with cariprazine augmentation 5
• One patient reached responder status by week 2, suggesting some patients may show early response 5

Critical Pitfalls to Avoid

• Do not increase cariprazine dose before allowing adequate time (4-6 weeks) at the initial 1.5 mg/day dose to assess response, as premature dose escalation may increase side effects without additional benefit 1, 3
• Do not exceed 3 mg/day as this is the maximum approved dose for adjunctive MDD treatment, and higher doses increase risk of akathisia and insomnia without proven additional efficacy 3
• Do not discontinue the antidepressant when adding cariprazine, as the evidence supports adjunctive use rather than monotherapy switching 3, 2
• Monitor closely for akathisia, particularly when increasing to 3 mg/day, as this is the most common dose-dependent adverse event 3

Expected Timeline for Response

• Initial response may be observed as early as 2 weeks in some patients 5
• Full assessment of response should occur at 4-6 weeks after initiating or increasing cariprazine 1
• By week 26 of long-term treatment, 53.3% of patients achieved remission (MADRS total score ≤10) 2