What is the best course of action for an adult patient with treatment-resistant depression and suicidal ideation, currently on Remeron (Mirtazapine) 45 mg and Rexulti (Brexpiprazole) 1 mg, with elevated liver enzymes (hypertransaminasemia)?

Management of Treatment-Resistant Depression with Suicidal Ideation and Elevated Liver Enzymes

You should immediately discontinue Rexulti due to the elevated liver enzymes (ALT 122, AST 59) and the FDA warning about hepatic failure with brexpiprazole, then optimize the Remeron dose and add lithium augmentation for its potent anti-suicidal properties while implementing urgent safety protocols. 1, 2, 3

Immediate Safety Measures

• All medications must be controlled and dispensed daily by a third party (family member or trusted person) who stores medications securely and reports any behavioral changes immediately. 1, 4
• Explicitly instruct family to remove all firearms and lethal medications from the home environment. 4
• Schedule immediate follow-up within 24-48 hours and establish a procedure for clinical staff to initiate contact if the patient misses appointments. 4
• Systematically inquire about suicidal ideation at every contact, distinguishing between passive ideation versus active planning with intent. 1, 4

Medication Management

Discontinue Rexulti (Brexpiprazole)

• The FDA label for brexpiprazole does not list hepatic failure as a contraindication, but your patient's transaminase elevations (ALT 122, AST 59) warrant extreme caution, especially given that duloxetine (another augmentation agent) has been associated with hepatic failure presenting as elevated transaminases. 5, 2
• Brexpiprazole carries an FDA black box warning for increased risk of suicidal thoughts and behaviors in patients under age 25, and your patient is actively suicidal. 2
• Taper brexpiprazole slowly over 1-2 weeks to avoid discontinuation symptoms. 5

Optimize Remeron (Mirtazapine)

• Mirtazapine 45 mg is already at the maximum recommended dose, so further dose escalation is not appropriate. 3
• Mirtazapine has excellent safety in overdose (patients have survived 30-50 times the normal daily dose without complications), making it appropriate for suicidal patients. 6
• Continue mirtazapine as the antidepressant foundation while adding augmentation. 7

Add Lithium Augmentation

• Lithium provides an 8.6-fold reduction in suicide attempts in patients with mood disorders and is the first-line augmentation strategy for treatment-resistant depression with suicidal ideation. 8, 1, 4
• Start lithium 300 mg twice daily, targeting a therapeutic level of 0.6-1.0 mEq/L. 7
• Obtain baseline labs: comprehensive metabolic panel (including creatinine for renal function), thyroid function tests, pregnancy test if applicable, and ECG. 7
• Monitor lithium levels weekly until stable, then monthly, along with renal and thyroid function every 3-6 months. 7

Alternative Augmentation if Lithium is Contraindicated

• If renal function is impaired or lithium is otherwise contraindicated, consider quetiapine 150-300 mg daily or aripiprazole 5-15 mg daily as second-line augmentation options. 7
• However, avoid aripiprazole if liver enzymes remain elevated, as it shares similar metabolic pathways with brexpiprazole. 2

Medications to Avoid

• Do not prescribe benzodiazepines, as they may reduce self-control and disinhibit suicidal behavior, potentially precipitating suicide attempts. 1, 4, 3
• Do not switch to venlafaxine (SNRI), as it is associated with greater suicide risk than other antidepressants and overdose fatalities. 1
• Do not prescribe tricyclic antidepressants due to high lethality in overdose (fatal toxicity index 5-8 times higher than SSRIs). 1, 4

Monitor for Specific Adverse Effects

• Assess for akathisia at every contact during medication changes, as this is a critical warning sign that may drive suicidal urges, particularly with antipsychotic augmentation agents. 9, 4
• Watch for behavioral activation, agitation, or worsening suicidal ideation during the first 2-4 weeks of any medication change. 4, 3
• Monitor liver enzymes weekly for the first month, then monthly for 3 months to ensure normalization after discontinuing brexpiprazole. 5

Essential Psychotherapeutic Interventions

• Initiate cognitive-behavioral therapy focused on suicide prevention immediately, as it reduces suicidal ideation and cuts suicide attempt risk by half compared to treatment as usual. 4
• Develop a safety planning intervention, which reduces suicidal behavior with a number needed to treat of 16. 4
• Ensure the patient has 24/7 access to crisis resources, including the National Suicide Prevention Lifeline (988). 8

Advanced Treatment Options if First-Line Fails

• If the patient remains acutely suicidal despite these interventions, consider ketamine infusion (0.5 mg/kg IV) for rapid reduction of suicidal ideation within 24 hours, with effects lasting up to 1 week. 1, 4
• If mood swings, manic symptoms, or rapid cycling develop during treatment, this confirms the need for lithium or valproate as primary mood stabilizer. 1, 4

Critical Pitfalls to Avoid

• Do not rely on "no-suicide contracts" as their value is not established, and both family and clinician should not relax vigilance just because a contract has been signed. 8, 4
• Do not assume safety based on initial improvement—be particularly vigilant during the early stages of treatment when medication changes are made. 4
• Do not abruptly discontinue mirtazapine, as sudden cessation may cause serious withdrawal symptoms including worsening depression and suicidal ideation. 3