Can atomoxetine and mirtazapine cause akathisia?

Can Atomoxetine and Mirtazapine Cause Akathisia?

Yes, atomoxetine can cause akathisia, while mirtazapine is paradoxically both a rare cause of akathisia and an effective treatment for antipsychotic-induced akathisia.

Atomoxetine and Akathisia

Atomoxetine is documented to cause akathisia as an adverse effect. The FDA drug label explicitly warns that patients and caregivers should monitor for the emergence of akathisia (psychomotor restlessness), particularly early during treatment and when doses are adjusted 1. This warning appears alongside other behavioral symptoms including anxiety, agitation, panic attacks, insomnia, irritability, hostility, and aggressiveness 1.

Clinical Context for Atomoxetine

• The most common adverse effects of atomoxetine in pediatric trials include nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence 2
• Akathisia represents a less common but clinically significant adverse effect that requires monitoring 1
• Patients should be instructed to report new-onset restlessness or inability to sit still, especially during the first weeks of treatment or dose escalation 1

Mirtazapine and Akathisia: A Dual Role

Mirtazapine as a Cause of Akathisia (Rare)

Mirtazapine can rarely induce akathisia, even after prolonged treatment. A documented case report describes severe akathisia developing in a 72-year-old woman after nearly 20 years of continuous mirtazapine treatment 3. The patient experienced:

• Intense "inner restlessness" and constant leg/foot movements 3
• 3-kg weight loss over one week 3
• Remarkable distress, insomnia, and pacing 3
• Complete resolution after mirtazapine discontinuation, with symptom recurrence upon rechallenge, confirming causality 3

This case demonstrates that akathisia can emerge even after many years of stable treatment, not just during initiation 3.

Mirtazapine as a Treatment for Akathisia (Well-Established)

Paradoxically, low-dose mirtazapine (7.5-15 mg daily) is an effective treatment for antipsychotic-induced akathisia. The evidence supporting this therapeutic use is substantially stronger than reports of mirtazapine causing akathisia:

• Controlled trial data: Mirtazapine demonstrated a 53.8% response rate versus 7.7% for placebo (p=0.004) in treating antipsychotic-induced akathisia 4
• Comparative efficacy: In head-to-head comparison, mirtazapine showed 43.3% response rate versus propranolol 30.0% and placebo 6.7% (p=0.0051) 4
• Better tolerability: Mirtazapine was better tolerated than propranolol, with only mild transient sedation as the primary side effect 4
• Mechanism: The therapeutic effect is attributed to mirtazapine's marked antagonism at serotonin 5-HT2A/2C receptors 5, 4

Recent case evidence confirms efficacy in severe, treatment-resistant akathisia. A 2024 case report documented complete resolution (Barnes Akathisia Rating Scale score from 8 to 0) of haloperidol-induced akathisia that had failed standard treatments including benzodiazepines and benztropine 6. Mirtazapine 15 mg provided substantial improvement in mood, mobility, and daily functioning 6.

Clinical Algorithm for Management

If Akathisia Develops on Atomoxetine:

1. Confirm the diagnosis by assessing subjective restlessness and objective motor manifestations 2
2. Consider dose reduction as first-line intervention 1
3. If symptoms persist despite dose adjustment, discontinue atomoxetine and consider alternative ADHD medications 1
4. Do not add mirtazapine to treat atomoxetine-induced akathisia, as this represents off-label use without supporting evidence

If Akathisia Develops on Mirtazapine:

1. Discontinue mirtazapine immediately given the rarity but documented occurrence 3
2. Symptoms should resolve within days to weeks after discontinuation 3
3. Do not rechallenge with mirtazapine if akathisia was confirmed 3

If Using Mirtazapine to Treat Antipsychotic-Induced Akathisia:

1. Start with low doses: 7.5-15 mg once daily 5, 7, 6, 4
2. Expect response within 8-10 days of treatment initiation 7
3. Monitor for mild sedation (most common side effect, usually transient) 7, 4
4. Consider mirtazapine particularly useful when:
   • Beta-blockers are contraindicated (asthma, bradycardia, hypotension) 5, 4
   • Comorbid depression or negative symptoms are present 4
   • Standard treatments have failed 6

Important Caveats

• The akathisia-inducing potential of mirtazapine is extremely rare compared to its established therapeutic use for antipsychotic-induced akathisia 5, 3, 4
• Akathisia from antipsychotics is primarily associated with dopamine D2 receptor blockade 2, making it mechanistically distinct from the rare cases with mirtazapine
• Mirtazapine's 5-HT2A antagonism likely explains its anti-akathisia properties, representing a different mechanism than traditional treatments like propranolol 5, 4
• Atomoxetine warnings about aggressive behavior or hostility should not be confused with akathisia, though both involve behavioral activation 2