Ryan M. Bottary

This activity offers CE credits for:
1. Physicians (CME)
2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

To understand the negative effects of restless leg syndrome (RLS) and the clinical implications for psychiatrists.

At the end of this CE activity, participants should be able to:

• Understand the prevalence and causes of RLS as well as associated comorbidities

• Identify differential diagnoses and treatment options

• Describe the medication considerations for patients with comorbid psychiatric conditions

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

 This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of CME Outfitters, LLC, and Psychiatric Times. CME Outfitters, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

CME Outfitters designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note to Nurse Practitioners and Physician Assistants:

 AANPCP and AAPA accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit ™.

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Ryan Bottary has no disclosures to report.

John W. Winkelman, MD, PhD, has no disclosures to report.

Richard P. Allen, PhD, (peer/content reviewer) has no disclosures to report.

 staff and CME Outfitters staff have no disclosures to report.

Faculty of this CME/CE activity may include discussion of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational uses (any uses not approved by the FDA) of products or devices. CME Outfitters, LLC, and the faculty do not endorse the use of any product outside of the FDA-labeled indications. Medical professionals should not utilize the procedures, products, or diagnosis techniques discussed during this activity without evaluation of their patient for contraindications or dangers of use.

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an urge to move the legs-often accompanied by uncomfortable sensations-that worsens with rest, is most pronounced in the evening, and is partially or fully relieved by movement. Symptoms may be mild and occur only intermittently, but medical intervention is often initiated when symptoms cause significant distress or impair daily functioning. RLS may emerge idiopathically or in association with pregnancy, iron deficiency, or renal disease.

An RLS diagnosis relies primarily on the patient’s self-reported symptoms ascertained through a clinical interview. The 5 essential diagnostic criteria for RLS, established by the International RLS Study Group (IRLSSG), are listed in 

 and can be easily remembered using the acronym “URGED.” In addition, a 10-item scale facilitates identification of RLS severity (

RLS negatively affects sleep, mood, and quality of life. Mood and anxiety disorders occur more frequently in patients with RLS than in the general population and commonly prescribed psychiatric medications have been linked to worsening or de novo RLS symptoms.

 First-line RLS treatments may also produce adverse psychiatric effects.

Clinically significant RLS appears in 2% to 3% of the general population.

 After age 35, the prevalence of RLS is twice as high in women as in men.

 RLS onset may occur at any point after early childhood; however, later in life symptom onset is more rapid and is more likely to be comorbid with another medical condition (eg, neuropathy, iron deficiency, renal disease).

While the precise etiology of RLS is not clear, there is a familial and genetic component. Brain iron deficiency may be a potential causative factor.

 Patients with RLS show reduced ferritin and increased transferrin levels in cerebrospinal fluid. Neuroimaging studies demonstrate reduced brain iron concentration, particularly in the substantia nigra. Iron’s ability to modulate dopamine neurotransmission further informs clinical observations that RLS symptoms are reduced or resolved with the use of dopaminergic agents, generated or worsened with dopamine-blocking medication, and alleviated with both oral and intravenous supplemental iron treatments.

Mood and anxiety disorders are the most commonly reported psychiatric comorbidities in RLS and may be a direct consequence of troubling RLS symptoms.

Patients with RLS are 2.6 times more likely to experience major depression compared with patients who have non-neurological somatic disorders. In one study, more that 76% of patients with comorbid RLS and MDD reported that RLS symptoms predated depressive symptoms.

 In fact, the probability of new-onset clinical depression was 1.5 greater in women with RLS during a 6-year observation period.

 Patients with comorbid RLS and MDD are more likely to report depressive symptoms such as sleep disturbances, depressed mood, reduced interest, and suicidal thoughts as being entirely due to RLS symptoms.

RLS and associated sleep features, such as periodic leg movements of sleep, can significantly affect sleep by reducing sleep quality and duration. Disturbed sleep-like that observed in RLS-increases the risk of depressive disorders, and poor sleep quality is a clinical feature of depression. Further complicating diagnosis, insomnia and non-restorative sleep associated with RLS can result in decreased concentration, irritable mood, and agitation that may be interpreted as evidence of depression.

In some patients, successful treatment of RLS may minimize or resolve depressive symptoms. However, the presence of core features of depression such as excessive feelings of guilt, worthlessness, and anhedonia may indicate the need for independent treatment for comorbid depression.

Troubling RLS symptoms, anticipatory anxiety about RLS symptoms, and RLS-induced sleep loss may worsen or contribute to the development of anxiety disorders. Compared with non-RLS controls, patients with RLS are 5 times more likely to experience panic attacks or have comorbid panic disorder or generalized anxiety disorder. Furthermore, acute sleep loss may trigger panic attacks in those with panic disorder, which suggests that RLS-induced sleep disturbances may worsen panic disorder symptoms or provoke symptoms of a latent panic disorder.

Treatment options, challenges, and considerations

Pharmacologic treatment of RLS should be considered for patients who experience moderate to severe symptoms that significantly affect sleep or impair daily functioning. Optimal treatment plans for RLS take into account individual patient factors including 24-hour symptom distribution, severity of sleep disturbance, comorbid psychiatric conditions, medical status, and lifestyle. Long-term treatment is often the expectation, and the goal should be relief, but not necessarily total resolution, of RLS symptoms.

The most common RLS treatments include dopamine receptor agonists, calcium channel Î±-2-Î´ ligands and, in severe RLS or in cases of treatment-emergent worsening of RLS symptoms, Î¼-receptor agonist opioid medications.

Dopamine agonists, when prescribed within FDA-approved dosage ranges (

), are highly effective for alleviating RLS symptoms and improving quality of life. Pramipexole and ropinirole, the short-acting dopamine agonists, have also been shown to affect mood positively in RLS patients with mild to moderate symptoms of depression. Pramipexole improved depressive symptoms in patients with MDD with comparable efficacy to fluoxetine, albeit at higher dosages than currently recommended for RLS (≥ 1 mg/d) and with a high rate of treatment-emergent adverse effects.

Long-term use of dopaminergic treatments carries the risk of augmentation, an iatrogenic worsening of RLS symptoms. Augmentation may be challenging to separate from normal disease progression and loss of treatment efficacy over time caused by medication tolerance. Worsening of RLS symptoms may occur independently of treatment because of changes in lifestyle (eg, decreased daytime activity; sleep deprivation; alcohol, antihistamine, dopamine antagonist, or serotonergic reuptake blocker intake) and health status (eg, iron deficiency, decreased kidney function, pregnancy), which should be monitored in patients with suspected augmentation. Key considerations for diagnosing augmentation include the appearance of earlier daytime or evening onset of RLS symptoms compared with baseline, decreased latency to symptom onset at rest, increased symptom intensity, and/or spreading of symptoms to previously unaffected parts of the body (eg, arms).

Augmentation can occur in up to 82% of patients with RLS who use the short-acting dopamine precursor carbidopa/levodopa. With pramipexole and ropinirole, augmentation occurs in roughly 30% to 60% of patients, although these rates can continue to rise over many years. With rotigotine, a longer-acting dopamine agonist, augmentation occurs in 10% to 20% of patients. Dopaminergic medications can also produce troubling de novo psychiatric symptoms in some patients, including impulse control disorders (eg, pathological gambling, shopping, hypersexity).

The Î±-2-Î´ calcium channel ligands gabapentin enacarbil and pregabalin provide RLS symptom relief (

). Given the minimal risk of augmentation with these agents and the chronicity of RLS treatment, recent consensus guidelines have suggested initiating treatment of de novo mild to moderate RLS with an Î±-2-Î´ ligand instead of a dopamine agonist.

 Anxiolytic properties of Î±-2-Î´ ligands may also make medications like pregabalin, which has efficacy for generalized anxiety disorder, well suited for patients with comorbid anxiety disorders. Moreover, Î±-2-Î´ ligands do not appear to increase-and in fact may decrease-impulse control disorders such as pathological gambling. However, the use of anticonvulsants is associated with an increased risk of suicidality, and suicidal ideation has been reported in RLS patients treated with pregabalin.

 Patients should be informed of this risk and monitored for emerging suicidal thoughts or behaviors.

Î¼-Receptor opioid agonists, such as prolonged-release oxycodone/naloxone and methadone, while not currently FDA approved for RLS (see 

), can be tried when first-line RLS treatments fail, RLS symptoms are severe, or as an alternative if patients experience severe augmentation. However, opioid therapy for RLS is generally contraindicated in patients with a history of substance use disorders, and prescribing physicians should monitor patients for possible signs of misuse or diversion. Of note is the emergence, or worsening, of RLS with discontinuation of opioid medications used recreationally or for pain relief.

Iron deficiency has a direct physiological link to RLS, and conditions that produce iron deficiency, such as renal disease and pregnancy, increase the risk of worsening symptoms of RLS. For these reasons, it is recommended that all patients with RLS have full, fasting iron panels (ferritin, iron, and total iron-binding capacity) conducted at initial presentation and regularly thereafter. Treatment with oral or intravenous iron (see 

) should be considered for patients with serum ferritin levels lower than 50 to 75 ng/mL or transferrin saturation less than 20%.

While effective for treating symptoms of depression and anxiety, patients who take serotonergic antidepressants, such as SSRIs or SNRIs, are at increased risk for new-onset or worsening RLS. In one prospective study, 2% to 10% of patients treated with SSRIs (citalopram, escitalopram, sertraline, paroxetine, and fluoxetine) and SNRIs (duloxetine and venlafaxine) experienced treatment-emergent RLS.

 It has been proposed that the deleterious effects of SSRIs and SNRIs on RLS symptoms may result from serotonergically mediated dopamine inhibition.

It is important to note that RLS has not been found to be a treatment-emergent adverse effect of non-serotonergic antidepressants, such as the selective norepinephrine-reuptake inhibitor reboxetine and the norepinephrine-dopamine-reuptake inhibitor bupropion, that may improve RLS symptoms in the short term.

 Therefore, careful consideration of classes of antidepressants-opting for non-serotonergic agents when indicated-is essential to reduce possible iatrogenic adverse effects.

Little evidence exists for the efficacy of anxiolytics, such as benzodiazepines, in the treatment of RLS. However, this class of medications may reduce associated features such as periodic limb movement disorder, which has been observed in more than 80% of patients with RLS. Antihistamines such as diphenhydramine and hydroxyzine-sometimes prescribed to manage insomnia or anxiety, respectively-may aggravate RLS symptoms.

Second-generation antipsychotics, such as quetiapine, risperidone, and olanzapine, work primarily through dopamine antagonism. Not surprisingly, these medications have been associated with treatment-emergent RLS symptoms.

 Pramipexole and gabapentin may be used for treating antipsychotic-induced RLS.

Similar to the negative associations patients with insomnia may develop about sleep, or individuals with panic disorder form in anticipation of another panic attack, patients with RLS may adopt dysfunctional attitudes and beliefs about RLS symptoms. Anticipatory anxiety surrounding evening onset of symptoms may compel patients to advance or increase their RLS medication dose. Thus, clinicians are strongly encouraged to educate patients about the potential deleterious effects of medication misuse while promoting behavioral approaches (stretching, cognitive activities) to manage symptoms without additional medication. Cognitive behavioral therapy may also be helpful for addressing dysfunctional beliefs and improving the quality of life of patients with RLS.

The high rate of comorbid psychiatric conditions in RLS makes recognition of this disorder important in psychiatric settings. RLS affects sleep and mood, 2 factors that influence the course of psychiatric conditions. While patients with RLS may be successfully treated with a number of medications, comorbid psychiatric conditions present a unique challenge because many commonly prescribed psychiatric medications may worsen RLS symptoms. It is up to the clinician and patient to decide on a treatment plan that reduces the distress RLS may cause while balancing treatment of comorbid psychiatric conditions.

Leslie is a 67-year-old woman with a long history of RLS, which had been well controlled for nearly 15 years with ropinirole. She also has GERD, hypothyroidism, and MDD, which is particularly troublesome when RLS is inadequately controlled. She was treated with 450 mg of bupropion, 100 mg of lamotrigine, and 0.5 mg of clonazepam for depression and sleep problems.

Over the past few years, her RLS had worsened and had progressed to her arms, which required an earlier daytime dose and increased total dosage of ropinirole. Gabapentin was added but soon discontinued because she experienced “weepiness” when taking the drug. In an effort to counteract augmentation, ropinirole was cross-tapered to a 3-mg rotigotine patch. After a period of initial benefit, symptom control became more difficult and pregabalin was added, which proved effective in increasing doses (up to 200 mg). Because of emergent daytime sleepiness, clonazepam was tapered and discontinued. Once pregabalin was started, she became “weepy” again.

Because of RLS augmentation and worsening of mood symptoms with gabapentin and pregabalin, Leslie was transitioned to 10 mg of methadone and rotigotine and pregabalin were discontinued. This effectively controlled RLS symptoms. Because she experienced treatment-resistant depression, 100 mg of sertraline was added but soon discontinued because it led to worsening of RLS symptoms. Leslie continues to have mild treatment-resistant depression, although her RLS symptoms have nearly resolved.

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PLEASE NOTE THAT THE POST-TEST IS AVAILABLE ONLINE ONLY ON THE 20TH OF THE MONTH OF ACTIVITY ISSUE AND FOR 18 MONTHS AFTER.

Mr. Bottary is Clinical Research Coordinator, Massachusetts General Hospital, Boston, MA.

Dr. Winkelman is Associate Professor of Psychiatry, Harvard Medical School and Chief, Sleep Disorders Clinical Research Program, Massachusetts General Hospital, Boston, MA.

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 Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom disease). 

 Winkelmann J, Prager M, Lieb R, et al. “Anxietas tibiarum”. Depression and anxiety disorders in patients with restless legs syndrome. 

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Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. 

Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. 

 Food and Drug Administration. Statistical Review and Evaluation: Antiepileptic Drugs and Suicidality. 2008; 

http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM192556.pdf

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Articles

While patients with restless legs syndrome may be successfully treated with a number of medications, comorbid psychiatric conditions present a unique challenge because many commonly prescribed psychiatric medications may worsen RLS symptoms.

Ryan M. Bottary

Articles

Restless Legs Syndrome: Clinical Implications for Psychiatrists