What is the best medication regimen for a patient with depression, auditory hallucinations, and suicidal ideation due to the voices, who was previously on Rexulti (brexpiprazole) and Auvelity (dextromethorphan/bupropion)?

Acute Management of Depression with Psychotic Features and Suicidal Ideation

In this acute setting, immediately restart an atypical antipsychotic at therapeutic doses—specifically olanzapine 5-10 mg daily or risperidone 0.5-2 mg daily—to address the command auditory hallucinations driving suicidal thoughts, while simultaneously reinitiating antidepressant therapy with close monitoring for the first 1-2 weeks. 1, 2, 3

Immediate Antipsychotic Management

The priority is controlling the psychotic symptoms (auditory hallucinations) that are directly contributing to suicidal ideation. Since the patient was previously on Rexulti (brexpiprazole), she has demonstrated tolerance to atypical antipsychotics.

Recommended first-line antipsychotic options:

• Olanzapine 5 mg orally at bedtime initially, can increase to 10 mg daily 1, 2, 4

  • Generally well-tolerated with lower risk of extrapyramidal symptoms
  • Effective for controlling hallucinations and severe agitation
  • Can be given as oral disintegrating tablet if adherence is a concern

• Risperidone 0.5 mg daily initially, titrate to 1-2 mg daily in divided doses 1, 2

  • Current research supports low dosages
  • Extrapyramidal symptoms may occur at doses ≥2 mg daily
  • Effective for problematic hallucinations and agitation

• Quetiapine 25-50 mg twice daily, can titrate to 200 mg twice daily 1, 2

  • More sedating, which may be beneficial for acute agitation
  • Lower risk of extrapyramidal symptoms
  • Monitor for orthostatic hypotension

Avoid haloperidol and other first-generation antipsychotics as they carry significant risk of extrapyramidal symptoms and may be slightly inferior for hallucination control. 2, 5

Antidepressant Management

Since the patient was previously on Auvelity (dextromethorphan/bupropion combination), consider restarting this or switching to an alternative based on the following:

Option 1: Restart Auvelity

• If previous response was good and discontinuation was due to non-adherence rather than inefficacy 6
• This combination has rapid onset of action for depression
• Bupropion has lower rates of sexual dysfunction compared to SSRIs 7, 3

Option 2: Switch to an SSRI or SNRI

• Sertraline 50 mg daily or escitalopram 10 mg daily are preferred in patients with suicidal ideation 7, 3
• These have established safety profiles and moderate efficacy
• All second-generation antidepressants have similar efficacy; choice should be based on adverse effect profile 3

Option 3: Consider mirtazapine 15-30 mg at bedtime

• May have specific benefit for auditory hallucinations based on case evidence 8
• Sedating properties beneficial for acute agitation and insomnia
• No worsening of extrapyramidal symptoms when combined with antipsychotics

Critical Safety Monitoring

Mandatory close monitoring protocol for the first 1-2 weeks: 3

• Week 1-2: Assess patient every 3-7 days for:

  • Emergence or worsening of suicidal ideation
  • New agitation, irritability, or unusual behavioral changes
  • Response of hallucinations to antipsychotic therapy
  • Adverse effects (akathisia, sedation, orthostatic hypotension)

• Weeks 3-8: Continue weekly to biweekly assessments 3

  • SSRIs and other antidepressants are associated with increased risk of suicide attempts compared to placebo, particularly in the first 1-2 months 7, 9
  • If no adequate response by 6-8 weeks, modify treatment strategy 3

Important Caveats and Pitfalls

Avoid benzodiazepines as monotherapy for the hallucinations, as they can paradoxically worsen agitation in 10% of patients and may cause delirium. 2, 1 However, low-dose lorazepam 0.5-1 mg may be used as a crisis medication for severe acute agitation in combination with antipsychotics. 1

Do not use tricyclic antidepressants (amitriptyline, imipramine) as they are potentially lethal in overdose and have not been proven effective in this population. 10

Monitor for akathisia when initiating or increasing antipsychotic doses, as this can paradoxically increase suicidal ideation and self-destructive impulses. 9 If akathisia develops, reduce the antipsychotic dose or switch agents.

Ensure medication dispensing is controlled by a third party (family member, pharmacy) given the acute suicidal risk, with only small quantities dispensed at a time. 10

Treatment Duration

Once acute symptoms stabilize, continue combination therapy for at least 4-9 months for a first episode of major depression with psychotic features. 3 Given the presence of psychotic symptoms and suicidal ideation, longer maintenance treatment is likely indicated, potentially 12+ months. 3