What is the recommended treatment approach for a patient with depression and psychosis who is already on a Selective Serotonin Reuptake Inhibitor (SSRI) and considering adding mirtazapine?

Treatment of Depression with Psychosis in Patients Already on SSRIs

For a patient with depression and psychosis already on an SSRI, add an atypical antipsychotic immediately—mirtazapine alone is insufficient for psychotic features and should not be used as monotherapy in this context.

Critical Distinction: Depression with Psychosis Requires Antipsychotic Treatment

The presence of psychotic features fundamentally changes the treatment algorithm. While the evidence provided discusses mirtazapine's role in various contexts, the most relevant guideline evidence addresses psychotic symptoms directly:

• Patients with psychotic symptoms require the addition of antipsychotics, not simply augmentation with another antidepressant 1
• The OCD treatment algorithm specifically notes that "the addition of antipsychotics in those with psychotic symptoms" is indicated when psychosis is present 1

Why Mirtazapine Is Not the Answer Here

Limited Evidence for Psychotic Depression

• While one small case series reported remission of psychotic features with mirtazapine in three treatment-resistant patients 2, this represents extremely weak evidence (case reports only)
• Mirtazapine is FDA-approved only for major depressive disorder without psychotic features 3
• No controlled trials demonstrate efficacy of mirtazapine monotherapy or augmentation specifically for depression with psychosis

Mirtazapine's Actual Role in Depression

• Mirtazapine combined with SSRIs/SNRIs showed no clinically important benefit in treatment-resistant depression without psychosis in the largest randomized trial (n=480), with only a -1.83 point difference on BDI-II that did not reach clinical significance 4
• More participants withdrew from mirtazapine due to adverse effects (46 vs. 9 in placebo group) 4
• The combination was not cost-effective for the NHS 4

Recommended Treatment Algorithm

Immediate Action

1. Add an atypical antipsychotic to the existing SSRI regimen 1

   • Options include aripiprazole, olanzapine, risperidone, quetiapine, or ziprasidone (all FDA-approved for acute mania in adults) 1
   • These agents have evidence for treating psychotic symptoms in mood disorders 1

2. Optimize the current SSRI to maximum tolerated dose if not already done 1

   • Ensure at least 8 weeks at therapeutic dose before considering the SSRI inadequate 1

If Inadequate Response After 6-8 Weeks

1. Consider switching antidepressants rather than adding mirtazapine 1

   • Switch to a different SSRI, SNRI, or other second-generation antidepressant 1
   • All second-generation antidepressants are considered equally effective for treatment-naïve patients 5

2. Maintain the antipsychotic throughout any antidepressant adjustments 1

Important Safety Considerations

Mirtazapine-Specific Warnings

• Risk of agranulocytosis (2 cases in 2,796 patients in premarketing trials) 3
• Monitor for sore throat, fever, stomatitis, or infection with low WBC count 3
• Can cause QTc prolongation, particularly in overdose or with other QTc-prolonging medications 3
• Common adverse effects include sedation (19% vs. 5% placebo), weight gain (10% vs. 1% placebo), and increased appetite (11% vs. 2% placebo) 3

Antipsychotic Considerations

• Atypical antipsychotics increase risk of death in elderly patients with dementia-related psychosis, but this must be weighed against the severity of psychotic depression 1
• Monitor for metabolic side effects, extrapyramidal symptoms, and cardiovascular effects 1

Common Pitfalls to Avoid

• Do not use mirtazapine as monotherapy for psychotic depression—the evidence base is insufficient and psychotic features require antipsychotic treatment 1, 2
• Do not add mirtazapine to an SSRI expecting significant benefit—the MIR trial showed no clinically meaningful improvement and higher dropout rates 4
• Do not confuse treatment-resistant depression with psychotic depression—these require different treatment approaches 1, 4
• Do not delay antipsychotic treatment while attempting antidepressant augmentation strategies 1