Which psychotropic medications can cause jitteriness or exacerbate restless‑legs syndrome in an adult patient?

Psychotropic Medications That Cause Jitteriness or Restless Legs Syndrome

Several classes of psychotropic medications can trigger or worsen jitteriness and restless legs syndrome (RLS), with antidepressants and antipsychotics being the primary culprits that should be discontinued whenever clinically feasible.

High-Risk Medication Classes

Antidepressants

• Serotonergic antidepressants (SSRIs and SNRIs) are well-documented to exacerbate RLS symptoms and should be avoided or discontinued when possible 1, 2, 3.
• Tricyclic antidepressants have been reported to worsen RLS symptoms 1.
• Bupropion is specifically recommended against for RLS treatment by the American Academy of Sleep Medicine, suggesting it may worsen symptoms 2.
• Bupropion can cause CNS toxicity including restlessness, agitation, and tremor, particularly when combined with dopaminergic agents 4.

Antipsychotics (Dopamine Antagonists)

• All antipsychotics that block dopamine receptors can trigger or significantly worsen RLS due to their dopamine antagonism 1, 2.
• Lurasidone specifically blocks dopamine receptors, a well-established mechanism for triggering RLS symptoms 2.
• Monitor for early RLS signs when starting any antipsychotic: urge to move legs with uncomfortable sensations, symptoms worsening at rest, relief with movement, and evening/nighttime predominance 2.

Antihistamines

• Centrally acting H1 antihistamines (e.g., diphenhydramine) should be discontinued as they are associated with RLS 2, 3.
• The American Academy of Sleep Medicine recommends addressing antihistaminergic medications as potential exacerbating factors 2.

Lithium

• Lithium has been reported to exacerbate RLS symptoms 1.

Medications That May Cause Jitteriness Without Necessarily Worsening RLS

Alpha-2-Delta Ligands (First-Line RLS Treatment)

• Gabapentin and pregabalin commonly cause dizziness and somnolence, which are typically transient and mild 2.
• These side effects do not represent true jitteriness or akathisia but may be perceived as such by patients 2.

Dopamine Agonists

• Ropinirole, pramipexole, and rotigotine can cause dizziness and somnolence, increasing fall risk 2.
• These agents are now recommended against as standard RLS treatment due to high augmentation risk (7-10% annually) 2, 3.

Critical Management Algorithm

Step 1: Identify and Discontinue Offending Agents

• Review all medications for serotonergic antidepressants, dopamine antagonists, and antihistamines 2, 3.
• Discontinue these medications if clinically feasible, as this is a primary treatment recommendation 2.

Step 2: Assess Iron Status

• Check morning fasting serum ferritin and transferrin saturation after avoiding iron supplements for ≥24 hours 2.
• Supplement if ferritin ≤75 ng/mL or transferrin saturation <20% 2, 3.

Step 3: Consider Alternative Psychiatric Medications

• For depression: Consider non-serotonergic options or carefully weigh risks versus benefits 1, 2.
• For psychosis: Choose antipsychotics with less dopamine antagonism when RLS develops, though specific alternatives are not detailed in guidelines 2.

Step 4: Treat RLS if Symptoms Persist

• First-line: Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) 2, 3.
• Avoid: Dopamine agonists due to augmentation risk 2, 3.
• Refractory cases: Consider low-dose opioids (methadone 5-10 mg daily, extended-release oxycodone) 2, 3.

Common Pitfalls to Avoid

• Do not assume psychiatric medications are irreplaceable—the American Academy of Sleep Medicine explicitly recommends discontinuing exacerbating medications as a primary intervention 2.
• Do not confuse medication side effects with primary anxiety or agitation—jitteriness from bupropion or akathisia from antipsychotics requires medication adjustment, not additional anxiolytics 4.
• Do not start dopamine agonists for RLS in patients on antipsychotics—this creates competing dopaminergic effects and high augmentation risk 2, 5.
• Monitor carefully when combining bupropion with dopaminergic agents (levodopa, amantadine), as cumulative dopamine agonist effects can cause restlessness, agitation, tremor, and ataxia 4.