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Medications that make the restless legs syndrome worse
Why antihistamines can trigger restless legs syndrome symptoms
The following antihistamine medications most associated with a flare-up of RLS symptoms are:
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Diphenhydramine: Found in Benadryl and many over-the-counter sleep aids (like ZzzQuil or "PM" versions of pain relievers).
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Chlorpheniramine: Commonly found in multi-symptom cold and allergy medications (such as Chlor-Trimeton).
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Doxylamine: Often found in nighttime cold medicines like NyQuil.
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Hydroxyzine: A prescription antihistamine (Vistaril, Atarax) used for itching or anxiety.
Safer antihistamine alternatives are second and third generation antihistamines. These are generally considered to be nondrowsy because they do not cross into the brain as easily. For many people with RLS, these are less likely to cause issues. Antihistamines recommended in RLS are:
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Loratadine (Claritin)
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Cetirizine (Zyrtec)
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Fexofenadine (Allegra)
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Levocetirizine (Xyzal)
Mirtazapine is often cited in literature as having the strongest association with RLS in pharmacological antidepression treatments. This is likely due to its potent antihistamine properties combined with its effect on serotonin. Serotonin decreases dopamine which in turn worsens RLS.
Avoid antihistamines (like those in over the counter "PM" sleep aids). These medications cross the blood-brain barrier and can interfere with dopamine, the chemical in the brain that regulates movement and contributes to worsening restless legs syndrome (RLS).
Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)
SNRIs are effective antidepressants. However, they also increase serotonin leading to a decrease in dopamine and are frequently linked to RLS. SNRIs linked to RLS include:
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Venlafaxine (Effexor)
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Desvenlafaxine (Pristiq)
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Duloxetine (Cymbalta)
Antidepression medications that do not worsen restless legs syndrome
Tricyclic antidepressants (TCAs) are older antidepressants that are sometimes used for sleep or nerve pain. TCAs for depression that do not worsen RLS include:
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Amitriptyline (Endep, Tryptanol)
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Nortriptyline (Allegron)
RLS friendly antidepressant and antianxiety medication alternatives that are considered to be "weight-neutral" or even potentially helpful for RLS are:
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Bupropion (Zyban, Prexaton). In Australia, this is primarily registered for smoking cessation, but it is often used off label for depression in RLS patients because it increases dopamine and noradrenaline rather than serotonin.
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Vortioxetine (Trintellix): Some recent studies suggest it may be better tolerated by RLS patients than traditional SSRIs.
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Agomelatine (Valdoxan): Since it works on melatonin and specific serotonin receptors (without a broad increase in serotonin levels), it is often considered a safer choice for sleep and RLS.
Figure 3: Valdoxan tablet box
Do antidepressants affect the restless legs syndrome?
Figure 1: Woman swallowing a happy pill
Many antidepressant medications are known to either cause or worsen RLS as a side effect. This typically happens because most antidepressants increase serotonin levels in the brain, which facilitates an inhibitory effect on dopamine. Dopamine is the primary neurotransmitter involved in regulating leg movement. The following classes and specific medications are frequently associated with triggering or exacerbating RLS symptoms.
Mirtazapine (Avanza, Axit)
Mirtazapine belongs to a class of medications called Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs).
Do antipsychotics make the restless legs syndrome worse?
Antipsychotic medications are among the most common triggers for RLS. While antidepressants typically worsen RLS by increasing serotonin, antipsychotics do so by directly blocking dopamine (the chemical responsible for smooth muscle movement and coordination).
The connection between antipsychotics and restless legs syndrome
RLS is thought to be caused by a lack of dopamine activity in certain parts of the brain. Antipsychotics (neuroleptics) are used to manage symptoms like psychosis or mood instability. They block dopamine receptors (D2 receptors) triggering or intensifying the "urge to move" characteristic of RLS.
Antipsychotics most likely to worsen restless legs syndrome
Both older "typical" and newer "atypical" antipsychotics can cause RLS, though the risk level varies. First-generation (typical) antipsychotics have a very high affinity for dopamine receptors and are most likely to cause RLS as a side effect. These antipsychotics include:
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Haloperidol (Haldol, Serenace)
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Chlorpromazine (Largactil)
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Flupentixol (Fluanxol)
Giraffes are among the champion low-sleepers of the animal kingdom, surviving on just 1.9 to 4.6 hours of sleep per day, often taken in quick, standing power naps lasting only a few minutes. Because they are prime targets for predators, spending hours lying down to sleep is too dangerous.
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are the most common class of antidepressants. While they work well for mood, they often worsen RLS. Common SSRIs include:
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Sertraline (Zoloft)
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Escitalopram (Lexapro, Esipram)
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Fluoxetine (Prozac, Lovan)
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Citalopram (Cipramil)
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Paroxetine (Aropax)
Figure 2: Sertraline chemical structure
Second-Generation (Atypical) antipsychotics while generally "gentler" on the motor system, many still frequently cause or worsen RLS including:
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Risperidone (Risperdal)
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Olanzapine (Zyprexa)
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Ziprasidone (Zeldox)
Lower-risk antipsychotic alternatives
While no antipsychotic is entirely "RLS safe," some have a lower tendency to block dopamine in the areas of the brain that control movement. Lower RLS risk antipsychotics include:
Figure 4: Haloperidol chemical structure
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Quetiapine (Seroquel): In very low doses, it is sometimes better tolerated than others, though it remains a common trigger for many.
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Clozapine (Clopine): This is considered the least likely to cause RLS or other movement disorders because it dissociates from dopamine receptors very quickly. However, it requires intensive blood monitoring and is usually reserved for treatment-resistant cases.
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Aripiprazole (Abilify): Because this is a "partial agonist" (it acts like a thermostat, increasing or decreasing dopamine activity as needed), some patients find it doesn't trigger RLS as severely as full blockers.
Did you now that RLS doesn't always stop when you finally fall asleep. Around 80% of people with RLS suffer from a related condition called Periodic Limb Movement Disorder (PLMD). Their legs will involuntarily twitch, jerk, or flex every 20 to 40 seconds all night long, severely fragmenting their sleep without them even fully realizing it.
Does Lithium affect the restless legs syndrome?
Lithium is a well-documented medication trigger that can cause or significantly worsen RLS symptoms. Case studies have suggested that lithium might induce RLS. RLS is fundamentally linked to a dysfunction in how the brain handles dopamine (the chemical messenger responsible for smooth muscle movement). Lithium is known to modulate and sometimes suppress dopamine signaling, which can directly bring about or intensify RLS symptoms.
Do Beta-blockers worsen the restless legs syndrome?
While the exact underlying mechanism isn't completely proven, clinical evidence frequently links beta-blockers (such as propranolol, metoprolol, and atenolol) to the exacerbation of RLS.
Beta-blockers reduce heart rate and blood pressure, which can slightly alter peripheral blood flow in the limbs. Changes in local circulation are thought to intensify the uncomfortable "creeping" or "crawling" sensations of RLS.
A note of caution
If you suspect that one or more of the medications you are taking may lead to worsening RLS don’t stop or reduce the medication as this can lead to serious consequences. Discuss medication management with your healthcare provider.
For more information on risk factors for RLS see the pages below:
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Demographics (age, gender, genetics and pregnancy)
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Medical disorders that are a risk factor for RLS
Did you know that RLS runs in families. Genetics play a massive role. Up to half of all people with RLS have a family history of the condition. When RLS is inherited (often called primary RLS), it typically starts early in life (before age 45) and tends to progress slowly over the decades.
Last reviewed: 05/09/2026