Can Fetzima (Levomilnacipran) Cause Restlessness?
Yes, Fetzima (levomilnacipran) can cause restlessness and agitation, as explicitly stated in the FDA-approved medication guide, which lists "feeling very agitated or restless" as a symptom requiring immediate medical attention. 1
Direct Evidence from FDA Labeling
The FDA medication guide for levomilnacipran specifically warns patients to contact their healthcare provider immediately if they experience "feeling very agitated or restless," particularly when this symptom is new or worsening. 1 This is listed among serious adverse effects that warrant urgent medical evaluation, alongside suicidal thoughts, aggressive behavior, and other behavioral changes. 1
Mechanism and Clinical Context
Levomilnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) with preferential selectivity for norepinephrine reuptake inhibition over serotonin. 2, 3 The noradrenergic effects of this medication can manifest as:
- Activation symptoms: Including restlessness, agitation, and anxiety, particularly during treatment initiation or dose changes 1
- Cardiovascular stimulation: Elevated pulse and blood pressure, which may contribute to subjective feelings of restlessness 3
- Central nervous system effects: Overstimulation similar to other norepinephrine-potentiating agents 4
Clinical Timing and Management
Restlessness associated with levomilnacipran typically occurs early in treatment, especially within the first few weeks of medication initiation or following dose increases. 1 The FDA guidance emphasizes that patients and providers should:
- Monitor closely for new or worsening restlessness during the first few months of treatment 1
- Pay particular attention during dose adjustments 1
- Contact the healthcare provider immediately if restlessness develops or worsens 1
Differentiation from Akathisia
While the evidence provided discusses akathisia (a severe form of restlessness) primarily in the context of antipsychotic medications 4, 5, the restlessness caused by levomilnacipran appears to be related to its noradrenergic activation profile rather than dopamine receptor blockade. 3 This distinction is important because:
- Antipsychotic-induced akathisia results from dopamine receptor antagonism and presents as severe motor restlessness with pacing and physical agitation 4
- SNRI-induced restlessness stems from norepinephrine potentiation and may present as subjective agitation, anxiety, or activation 1, 3
Risk Factors and Monitoring
Patients at higher risk for experiencing restlessness with levomilnacipran include:
- Those starting treatment or undergoing dose escalation 1
- Younger patients (under 24 years), who have increased risk of activation symptoms with antidepressants 1
- Patients with pre-existing anxiety disorders or agitation 1
If restlessness develops, do not dismiss it as anxiety or treatment resistance. 1 Consider whether the symptom is medication-related and evaluate the need for dose reduction or discontinuation. 1
Common Pitfalls
- Misinterpreting restlessness as worsening depression or anxiety rather than recognizing it as a medication side effect 1
- Failing to inquire specifically about restlessness, as patients may not spontaneously report this symptom 1
- Continuing dose escalation despite emerging restlessness, which can worsen the symptom 1