Antidepressants & Restless Leg Syndrome (RLS)

Do you know of a condition “which causes such suffering that it should be known by every physician”?(1) That is what Ekbom, the neurologist who described this condition, said in 1960.

This condition, also known as anxietas tibiarum (the anxiety of the shin bone), is now called RLS or Restless Leg Syndrome. RLS is seen in several medical conditions such as iron deficiency, chronic kidney disease and peripheral neuropathy, all of which are also associated with higher frequency of depression. Antidepressant use can also precede new-onset or worsening of RLS in some cases, though a clear-cut causal association is still controversial.

Restless leg syndrome is defined as having following four essential clinical consensus criteria:

  • (a) Compelling urge to move the legs with or caused by uncomfortable sensations inside the legs.
  • (b) Symptoms begin or worsen with rest or inactivity.
  • (c) Symptoms are partially or totally relieved by movement; and
  • (d) Symptoms are worse in the evening or at night.

In addition to these four essential criteria, following three criterias can support the RLS diagnosis:

  • family history
  • response to dopaminergic treatment, and
  • presence of periodic leg movements in sleep

It is important to do a full medical workup before labeling antidepressants as a likely cause for restless leg syndrome.


Post Contribution by Dr. Lena Palaniyappan

Read the following two course chapters addressing the following details:

(1) Restless Legs Syndrome/Periodic Limb Movements:

Diagnosis & Management

  1. Diagnosis of RLS
  2. Laboratory Workup
  3. Treatment for intermittent RLS
  4. Treatment for daily RLS
  5. Treatment for refractory RLS

Medications/substances associated with symptoms of Restless Legs Syndrome includes

  1. Alcohol
  2. Nicotine
  3. Caffeine
  4. Serotonergic antidepressants
  5. Antipsychotics
  6. Dopamine-blocking antiemetics (eg, metoclopramide)
  7. Centrally-acting antihistamines

Several medications have been implicated in onset of restless leg syndrome, with antidepressants having the most evidence (2).

Let’s answer this question first:

Which of the following antidepressant is known to be associated with higher rates of restless legs syndrome and periodic limb movements, causing significant disruption in sleep?

Answer: Mirtazapine is known to have the highest risk of RLS (Restless Leg Syndrome) and PLM (Periodic Limb Movements).

Read Our Second Course chapter for more details on this topic:

(2) Antidepressants & risk of RLS (Restless Leg Syndrome) and PLM (Periodic Limb Movements):

  1. Higher risk antidepressants
  2. Moderate risk antidepressants
  3. Lower risk antidepressants
  4. No risk/preferred antidepressants


  1. Winkelman, J. Restless Legs Syndrome. History of Neurology: Seminal Citations. Arch Neurol. 1999;56(12):1526-1527.
  2. Kolla BP, Mansukhani MP, Bostwick JM. The influence of antidepressants on restless legs syndrome and periodic limb movements: A systematic review. Sleep Med Rev. 2018;38:131-140. 
  3. Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018;41:27-44. doi:10.1016/j.sleep.2017.11.1126



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