For an adult patient with Avoidant/Restrictive Food Intake Disorder (ARFID) and anxiety, already taking a Selective Serotonin Reuptake Inhibitor (SSRI), should mirtazapine be added as an adjunct to target appetite?

Should Mirtazapine Be Added to SSRI for ARFID to Target Appetite?

No, mirtazapine should not be routinely added as adjunct to an SSRI in adult ARFID patients, primarily due to the significant risk of serotonin syndrome when combining serotonergic agents, and because there is no established evidence supporting combination therapy over monotherapy in ARFID. 1

Evidence-Based Rationale Against Combination Therapy

Critical Safety Concern: Serotonin Syndrome Risk

• Mirtazapine can precipitate serotonin syndrome when combined with SSRIs, a potentially life-threatening condition characterized by mental status changes, autonomic instability, neuromuscular symptoms, seizures, and gastrointestinal symptoms 1
• The FDA explicitly warns that the risk of serotonin syndrome is increased with concomitant use of other serotonergic drugs, including SSRIs 1
• If concomitant use is deemed clinically warranted, patients must be informed of the increased risk and monitored closely for symptoms 1

Lack of Evidence for Combination Therapy in ARFID

• There are no studies to date reporting on the use of mirtazapine in patients with ARFID in combination with SSRIs 2
• The limited ARFID literature examines mirtazapine as monotherapy, not as adjunctive treatment 2, 3
• Current evidence for mirtazapine in ARFID comes from pediatric inpatient populations, not adults on concurrent SSRIs 2, 3

Alternative Clinical Algorithm

If Appetite Stimulation Is the Primary Goal

Option 1: Switch from SSRI to Mirtazapine Monotherapy

• Discontinue the SSRI using appropriate tapering to avoid discontinuation syndrome 1
• Initiate mirtazapine at 15 mg/day administered as a single dose at bedtime 4
• Mirtazapine promotes appetite and weight gain (17% of patients report increased appetite vs. 2% with placebo; 7.5% experience ≥7% body weight gain vs. 0% with placebo) 1
• In pediatric ARFID patients, mirtazapine was associated with shorter hospital stays, fewer nasogastric feeding tube days, and faster weight gain 3

Option 2: Optimize SSRI Monotherapy for Anxiety

• If the SSRI is effectively managing comorbid anxiety, continue SSRI monotherapy 5
• SSRIs (sertraline or escitalopram) are first-line agents for comorbid anxiety in restrictive eating disorders 5
• Address appetite through non-pharmacological interventions including cognitive behavioral therapy and nutritional counseling 5

Decision-Making Framework

Choose mirtazapine monotherapy when:

• Appetite stimulation and weight gain are the primary treatment targets 1, 3
• Anxiety symptoms are mild or can be managed with psychotherapy 6
• The patient has comorbid depression that could benefit from mirtazapine's antidepressant effects 4, 6

Continue SSRI monotherapy when:

• Anxiety is the predominant comorbidity requiring pharmacological management 5
• The patient has already achieved partial response to SSRI therapy 5
• Appetite can be addressed through behavioral interventions 5

Critical Monitoring If Combination Is Unavoidable

If clinical circumstances absolutely require combining mirtazapine with an SSRI despite the risks:

• Monitor closely for serotonin syndrome symptoms, particularly within the first 24-48 hours after initiating combination therapy 1
• Watch for mental status changes, autonomic instability (tachycardia, labile blood pressure, hyperthermia), neuromuscular symptoms (tremor, rigidity, myoclonus), and gastrointestinal symptoms 1
• Discontinue both medications immediately if serotonin syndrome symptoms emerge and initiate supportive treatment 1
• Use the lowest effective doses of both agents to minimize risk 1

Additional Safety Considerations for Mirtazapine

• Somnolence occurs in 54% of mirtazapine-treated patients (vs. 18% placebo), which may impair performance and requires caution with activities requiring alertness 1
• Mirtazapine carries a black box warning for increased risk of suicidal thoughts and behaviors in patients under age 25 1, 2
• Monitor for activation of mania/hypomania, particularly in patients with undiagnosed bipolar disorder 1
• Avoid concomitant use with benzodiazepines and alcohol due to additive CNS depression 1

Common Pitfalls to Avoid

• Never combine mirtazapine with SSRIs without explicit discussion of serotonin syndrome risk and close monitoring plan 1
• Do not assume that appetite-stimulating effects justify the combination when safer alternatives exist 1, 3
• Avoid using mirtazapine as adjunct when switching to monotherapy would be safer and potentially more effective 4, 3
• Do not overlook the importance of psychotherapy and nutritional counseling as primary interventions in ARFID 5