A 68-year-old woman with a history of schizoaffective disorder presented to her psychiatrist with complaints of difficulty maintaining sleep for the past 3 months. Her psychiatric history included schizoaffective disorder with multiple psychiatric hospitalizations secondary to psychotic episodes. During her last visit 3 months prior, the patient's quetiapine was increased from 200 mg to 400 mg once a day due to worsening agitation and paranoia. Other medications included 60 mg daily of fluoxetine for depression, and 6 mg daily of ropinirole (prescribed by her primary care physician) for restless legs syndrome (RLS).
On review of current stressors, the patient's husband stated that she seemed to have become more irritable and agitated in the past 3 months after the death of her sister. He stated that his wife often walks around the house at night, at times talking to herself when she cannot fall asleep. The patient's husband also mentioned that there was increased leg movement while the patient slept.
The patient stated that quetiapine had previously helped her with falling asleep at night but now she feels more restless at night and has to get up to move her legs. She described it as “getting nervous before going to sleep and unable to stay asleep.” These uncomfortable sensations in her legs worsened at night and at rest but improved with walking and stretching her legs. On further questioning, the patient reported taking some over-the-counter medication that was provided by her husband, but it made her feel even worse.
Approximately 1 month prior to this presentation she had visited her primary care physician who increased her ropinirole from 2 mg to 6 mg daily, after which the restlessness spread to her arms and hands. The patient was frustrated by the outcome of her symptoms and wanted to know why they were getting worse despite an increase in the dose of ropinirole.
A neurological examination of the patient was unremarkable. She had a medical history of iron deficiency anemia, for which she had taken ferrous sulfate (250 mg/day) but stopped after 1 week due to constipation. There was a family history of bipolar disorder, iron deficiency anemia, and insomnia in her sister. The patient denied recent changes in weight, appetite, or concentration. She also denied any suicidal ideation. On mental status examination, her mood was irritable. She denied any psychotic symptoms or paranoid thoughts. She was alert and oriented to person, place, and time. She did not appear to be restless and was able to sit comfortably in the chair. Her ferritin levels were 20 mcg/L, and complete blood count and electrolyte levels were normal.
Challenge Faced by the Physician
This case presents many questions for the physician. What is the diagnosis of this patient? What are the medications that could be worsening her RLS? Why is her restlessness getting worse even on a higher dose of ropinirole, which is used to treat RLS? What was the over-the-counter medication that made her more restless? Does polypharmacy play a role in the patient's symptoms? What is the best next step in the management of these patient symptoms?
RLS, also called Willis-Ekbom disease, is a neurological disorder characterized by the intense urge to move one's legs due to unpleasant sensations occurring during rest or inactivity that are partially or entirely relieved by movement. Symptoms are usually worse in the evening and at night.1 The prevalence of RLS is about 2.5% to 15% of the United States population, with Northern European countries having the highest prevalence overall.2 Although the cause of RLS is believed to originate from the central nervous system as a result of dysfunction in dopamine metabolism and iron deficiency, no specific brain lesion has been found to be responsible for this syndrome. Furthermore, periodic limb movement of sleep, which is an involuntary contraction of the legs during sleep, is found to be associated with 80% of patients with RLS.3
Many mental health providers are unaware of this common sleep disorder, which often complicates the clinical picture in patients with psychotic disorders. Kang et al.3 found that RLS is more common in patients with schizophrenia as compared to healthy adults when the effect of antipsychotic medication is accounted for. In the patient in this case, the RLS symptoms worsened when her psychiatrist increased the dose of the antipsychotic medication (quetiapine). The patient's husband most likely gave her an antihistamine, which can worsen RLS. Furthermore, antidepressants are also known to worsen RLS.4 Chronic use of dopaminergic medication can cause worsening of RLS symptoms, which presents as either spreading of the symptoms to the arms or emergence of the symptoms earlier in the evening. This phenomenon is called augmentation. An increased dose of antipsychotic and augmentation triggered worsening of RLS symptoms, which consequently triggered sleep maintenance insomnia in this patient, further aggravating her psychiatric condition.
There is an association between antipsychotic use and worsening of RLS.5 However, it is difficult to distinguish between RLS and akathisia, which can also result from the use of antipsychotics. RLS is usually worse in the evening, whereas akathisia could be present any time of the day. Patients often describe akathisia as “a motor running in the body,” which makes the patient restless and unable to sit. A patient who has akathisia has a hard time sitting in the chair when seen in the clinic during the daytime, whereas RLS patients are comfortable sitting during the daytime. Table 1 shows some key differences between RLS and akathisia.
Key Differences Between Restless Legs-Syndrome and Akathisia
One approach in treating this patient was to reduce the dose of her quetiapine, which has been reported to decrease symptoms of RLS or completely eliminate it in patients with schizophrenia;6 however, this also increases the likelihood of worsening psychosis.
In patients with comorbid psychiatric disorder and RLS, consider the following approach to treatment.
Recheck iron stores in the patient to determine the need for iron supplements. If levels are below 75 mcg/L, prescribe oral iron. Also, one should investigate the causes of low ferritin levels in the patient.
Consider exacerbating factors such as the use of antihistamines, antidepressants, and antipsychotics. Selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors are known to worsen RLS as compared to bupropion.5
If augmentation (ie, worsening of RLS symptoms from being on long-term dopaminergic agonist therapy, such as with ropinirole) is suspected, choose another medication class with a different mechanism. Alpha-2-delta calcium channel ligands (gabapentin) and benzodiazepines can be helpful in these cases. Also, use of dopaminergic medications could exacerbate psychosis.
In patients with insomnia and comorbid RLS, the use of benzodiazepines has been shown to improve both disorders.7
Clinicians should educate their patients on some of the side effects of the drugs they are taking and could consider using antipsychotics such as aripiprazole, a partial dopamine agonist, instead of quetiapine in the treatment of psychosis in patients with RLS. Nonetheless, adherence to medication should be encouraged to ensure that the patient's symptoms resolve.
RLS is common in patients with psychiatric disorders. Many psychotropic medications worsen RLS. Clinical practitioners often miss the diagnosis of RLS, especially if akathisia is present. Finally, health care providers should be aware of drugs that exacerbate RLS symptoms, especially in patients taking multiple medications.
- Wilt TJ, MacDonald R, Ouellette J, et al. Pharmacologic therapy for primary restless legs syndrome: a systematic review and meta-analysis. JAMA Intern Med.2013;173(7):496–505. doi:. doi:10.1001/jamainternmed.2013.3733 [CrossRef]
- Yeh P, Ondo WG, Picchietti DL, et al. Depth and distribution of symptoms in restless legs syndrome/Willis-Ekbom Disease. J Clin Sleep Med.2016;12(12):1669–1680. doi:. doi:10.5664/jcsm.6356 [CrossRef]
- Kang SG, Lee HJ, Jung SW, et al. Characteristics and clinical correlates of restless legs syndrome in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry.2007;31(5):1078–1083. doi:. doi:10.1016/j.pnpbp.2007.03.011 [CrossRef]
- Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012;16(4):283–295. doi:. doi:10.1016/j.smrv.2011.05.002 [CrossRef]
- Mackie S, Winkelman JW. Restless legs syndrome and psychiatric disorders. Sleep Med Clin. 2015;10(3):351–357. doi:. doi:10.1016/j.jsmc.2015.05.009 [CrossRef]
- Cuellar NG. The psychopharmacological management of RLS in psychiatric conditions: a review of the literature. J Am Psychiatr Nurses Assoc. 2012;18(4):214–225. doi:. doi:10.1177/1078390312442569 [CrossRef]
- Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WGMedical Advisory Board of the Willis-Ekbom Disease Foundation. Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc. 2013;88(9):977–986. doi:. doi:10.1016/j.mayocp.2013.06.016 [CrossRef]
Key Differences Between Restless Legs-Syndrome and Akathisia
Restless Legs Syndrome
|Onset of symptom
||May or may not be related to use of a dopaminergic antagonist
||Acute symptoms may occur hours to days after initiation of a dopaminergic antagonist
||Characterized by unpleasant sensory phenomena and limb paresthesias. Patients with restless leg syndrome are often seen relaxed and alert without any leg restlessness during office visits
||Absence of limb paresthesias; however, patients are often very restless during an office visit, with sitting and rocking movements, crossing and uncrossing of legs, pacing around the office, and repetitive movements of arms and legs
||Symptoms are more prominent in the evenings and when asleep. Restlessness can progress to arms and hands with augmentation
||The absence of circadian rhythm; patients often experience generalized restlessness all through the day
||Periodic limb movement, peripheral neuropathy, vascular insufficiency
||Primary anxiety, tardive dyskinesia, psychotic agitation
|Treatment and relief
||Symptomatic relief with voluntary movement of limbs (eg, walking)
Pharmacological treatments include dopamine receptor agonists (eg, pramipexole) or alpha-2-delta calcium channel ligands (eg, gabapentin), and benzodiazepines
||Less relief from voluntary movement. Drug of choice for treatment is propranolol