What is the best treatment plan for a patient with persistent depression and suicidality who is currently taking 30mg of Remeron (mirtazapine) and 1mg of Rexulti (brexpiprazole)?

Treatment Plan for Persistent Depression and Suicidality on Current Regimen

Immediate Action: Optimize Mirtazapine Dose

Increase mirtazapine from 30 mg to 45 mg daily immediately, as the patient is on a subtherapeutic dose and has not reached the maximum recommended dose. 1

• The maximum recommended dose of mirtazapine is 45 mg daily, and your patient is currently only on 30 mg 1
• Mirtazapine demonstrates a faster onset of action than SSRIs and is particularly effective for patients with depression accompanied by anxiety, insomnia, or sleep disturbances 2, 1, 3
• The sedating effects of mirtazapine are paradoxically less frequent at higher dosages, so increasing to 45 mg may actually improve tolerability while enhancing efficacy 3, 4

Augmentation Strategy with Brexpiprazole

Increase brexpiprazole (Rexulti) from 1 mg to the therapeutic target dose of 2-3 mg once daily, as 1 mg is below the effective dose range established in clinical trials. 5

• Phase III trials demonstrated that adjunctive brexpiprazole 2 or 3 mg once daily (not 1 mg) was significantly more effective than antidepressant monotherapy in improving depressive symptoms in adults with MDD who had incomplete response to previous treatment 5
• Brexpiprazole has a unique receptor binding profile with low intrinsic D2 activity, suggesting lower potential for activation-like adverse effects such as akathisia compared to aripiprazole 5
• The drug was specifically approved by the FDA for adjunctive therapy with antidepressants in patients with MDD who demonstrate incomplete response 5

Critical Safety Monitoring for Suicidality

Assess for suicidal thoughts and behaviors at every visit, particularly during the first 1-2 months after medication changes, as the risk for suicide attempts is greatest during this period. 2, 6

• SSRIs and second-generation antidepressants are associated with an increased risk for nonfatal suicide attempts, making close monitoring essential 2
• Monitor specifically for emergence of agitation, irritability, or unusual changes in behavior, as these symptoms can indicate worsening depression 6
• Mirtazapine appears to be safe in overdose, with patients recovering fully after taking 30-50 times the normal daily dose, making it an appropriate choice for suicidal patients 7

Timeline for Response Assessment

Allow 6-8 weeks at optimized doses (mirtazapine 45 mg + brexpiprazole 2-3 mg) before declaring treatment failure. 2, 1

• Begin assessing therapeutic response within 1-2 weeks of dose optimization, but if adequate response has not occurred by 6-8 weeks, treatment modification should be considered 1
• The American College of Physicians strongly recommends modifying treatment if patients do not have an adequate response within 6-8 weeks of initiation at therapeutic doses 2, 1

If Current Regimen Fails After 6-8 Weeks

Switch to an SNRI (venlafaxine 37.5-225 mg daily or duloxetine 40-120 mg daily) as these demonstrate statistically significantly better response and remission rates than SSRIs in treatment-resistant depression. 6

• SNRIs may have greater effect on both depression and anxiety symptoms due to their dual action on serotonin and norepinephrine reuptake 6
• The American College of Physicians found no significant difference between switching versus augmenting strategies overall, but switching medication classes often provides better outcomes than continuing ineffective treatment 6
• Alternatively, consider adding bupropion SR 150-400 mg daily, which has significantly lower discontinuation rates due to adverse events (12.5%) compared to buspirone (20.6%, p<0.001) and addresses sexual dysfunction concerns 6

Common Pitfalls to Avoid

• Do not continue ineffective treatment beyond 8 weeks at therapeutic doses, as this delays recovery and worsens outcomes 6
• Do not use brexpiprazole 1 mg as the target dose, as clinical trials established efficacy at 2-3 mg daily 5
• Do not stop mirtazapine at 30 mg without first optimizing to 45 mg, as the patient has not received a full therapeutic trial 1
• Do not add multiple serotonergic agents simultaneously, as this increases serotonin syndrome risk 6

Duration of Continuation Therapy

Continue treatment for 4-9 months after satisfactory response in patients with a first episode of major depressive disorder, and for patients with 2 or more episodes, consider years to lifelong maintenance therapy. 2, 1