Diagnosis and Treatment of Restless Legs Syndrome in Psychiatric PracticePublished on Psychiatric Times(http://www.psychiatrictimes.com)

Diagnosis and Treatment of Restless Legs Syndrome inPsychiatric PracticeSeptember 08, 2009 | Sleep Disorders [1], Circadian Rhythm Sleep Disorders [2], Comorbidity InPsychiatry [3], Major Depressive Disorder [4], Restless Legs Syndrome [5], Somatoform Disorder [6]By Hochang Benjamin Lee, MD [7]

Restless legs syndrome (RLS) is a neurosensory disorder first described by Sir Thomas Willis in1672. As early as the 19th century, Theodor Wittmaack observed the comorbidity of RLS withdepression and anxiety. He termed this condition “anxietas tibiarum” and believed it to be a form ofhysteria.

After reading this article, you will be familiar with:

• Pathogenesis of restless legs syndrome (RLS)• Comorbidity of RLS and psychiatric disorders• Treatment options for RLS in patients with psychiatric disorders

Who will benefit from reading this article?Psychiatrists, geriatric psychiatrists, psychologists, primary care physicians, nurse practitioners, andother health care professionals. To determine whether this article meets the continuing educationrequirements of your specialty, please contact your state licensing and certification boards.

Restless legs syndrome (RLS) is a neurosensory disorder first described by Sir Thomas Willis in 1672.As early as the 19th century, Theodor Wittmaack1 observed the comorbidity of RLS with depressionand anxiety. He termed this condition “anxietas tibiarum” and believed it to be a form of hysteria.Once thought to be rare, data now suggest that RLS is relatively common but underrecognized andundertreated.2 Several clinical and population-based studies have reported a high prevalence ofpsychiatric comorbidities—particularly depression and anxiety—in patients with RLS.3 Thus, forpsychiatrists, understanding the clinical features and treatment of RLS has become critical in theirdaily practice. The symptomatic overlap between RLS and mood disorders and the potential impactof psychiatric medications on RLS symptoms make RLS a diagnostic and treatment challenge.This article provides an overview of the clinical features of and treatment strategies for RLS. It alsooffers a survey of the current literature on issues in the diagnosis and treatment of RLS amongpsychiatric patients.Clinical features and diagnosisThe case vignette illustrates the importance of evaluating for RLS symptoms in patients with majordepressive disorder (MDD) who complain of insomnia.CASE VIGNETTELisa is a 45-year-old married woman who came to see a psychiatrist initially for depressivesymptoms. During the initial evaluation, she complained of difficulty in falling asleep and otherdepressive symptoms such as low mood, difficulty with concentration, poor appetite, and low energyalong with daytime fatigue. Depression was diagnosed. An SSRI was prescribed on an as-neededbasis, and the patient was advised to take a nightly dose of diphenhydramine to help her sleep.Three days later—after staying up nearly all night—Lisa called her doctor in despair and complainedof worsening insomnia. On more detailed questioning about the insomnia, Lisa revealed that for thepast 2 years, she has experienced leg discomfort when she gets into bed. She is so uncomfortablethat she needs to walk or ride on her exercise bike past 2 or 3 am until the discomfort subsides.While not painful, this leg discomfort sometimes prevents her from relaxing and watching televisionbecause she just “has to move” her legs.Lisa describes a deep uncomfortable sensation that feels like “bugs crawling in her legs.” She alsoreveals that her mother used to suffer from similar nighttime leg restlessness. For the past 3 nights,Lisa’s leg discomfort has been more intense and has lasted most of the night.After secondary causes of RLS, such as iron deficiency anemia, pregnancy, uremia, and neuropathy,were ruled out, a diagnosis of RLS was made. SSRI and diphenhydramine therapy were stopped.

Page 1 of 7

Diagnosis and Treatment of Restless Legs Syndrome in Psychiatric PracticePublished on Psychiatric Times(http://www.psychiatrictimes.com)

Low-dose dopamine agonist therapy was started, after which the symptoms subsided. However,despite resolution of the RLS symptoms, her depressive symptoms continued. Titrated bupropionwas given until the depressive symptoms fully resolved.The RLS diagnosis and epidemiology workshop at the NIH established 4 criteria for diagnosis of RLS4:1. An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasantsensations in the legs2. The urge to move or unpleasant sensations that begin or worsen during periods of rest orinactivity, such as lying or sitting3. The urge to move or unpleasant sensations that are partially or totally relieved by movement,such as walking or stretching, at least as long as the activity continues4. The urge to move or unpleasant sensations that are worse in the evening or night than during theday or only occur in the evening or nightA diagnostically supportive but not essential feature of RLS includes a history of the disorder infirst-degree relatives. A polygenetic disorder with its phenotype contributed by a number of variants,RLS is a highly familial trait with heritability estimates of about 50%.5 Recent linkage studies infamilies with RLS revealed several loci but have not led to the identification of disease-causingsequence variants.6,7

Another supportive diagnostic feature is a history of positive response to dopaminergic therapy, suchas levodopa (L-dopa) or a dopamine receptor agonist.4 Periodic limb movements during sleep(PLMS), although not specific to RLS, occur in at least 80% of RLS patients and correlate with clinicalratings of RLS severity.8 While polysomnography or actigraphy evidence of PLMS is not necessary fordiagnosis, PLMS supports the diagnosis of RLS and provides an objective, indirect measure of RLSseverity.4 In more severe cases, symptoms of RLS occur during the daytime, disrupting restfulactivities such as sitting or trying to nap. Ascertaining the degree of interference with daytimeactivities may provide a measure of RLS severity.Differential diagnosIs of RLSThe diagnosis of RLS is made after identifying the presence of the above-mentioned 4 cardinalfeatures and excluding other causes of symptoms that mimic RLS, such as leg cramps, positionaldiscomfort, neuroleptic-induced akathisia, peripheral neuropathy, arthritis, anxiety, claudication ofthe legs, and peripheral vascular disease.9 Because a diagnostic biological marker for RLS is notavailable, the standard for diagnosis remains a clinical one based on the patient’s subjectivecomplaints and history.Nocturnal leg cramps (“charley horse”) are often mistaken for RLS; the former is usually the result ofthe painful contraction of a single muscle in the leg that can be relieved through stretching. Duringmuscle cramps, the muscle bulk is prominent and the associated sharp pain is easily distinguishedfrom RLS sensations.Patients with peripheral neuropathy commonly report numbness, burning, and pain that aresuperficially felt in the skin. Although these sensory symptoms can increase at night, they areusually present throughout the day, and complete relief is not obtained by sustained movement orwalking. Peripheral vascular disease or claudication is generally associated with pain during walkingand relieved when sitting or lying down. Arthritis pain is centered in joints and is relieved by rest.Nei-ther peripheral vascular disease nor arthritis is associated with the circadian patterncharacteristic of RLS.Once thought to be rare, data now suggest that RLS is relatively common but under-recognized and undertreated. Several studies have reported a high prevalence ofdepression and anxiety in patients with RLS. Neuroleptic-induced akathisia is a whole-body sensation; there is no pronounced circadian patternand no insomnia. Usually, movement provides no relief, and prior exposure to neuroleptic medicationis easily established. Hypotensive akathisia is a feeling of restlessness, which may be localized in thelegs when an individual with orthostatic hypotension sits still; the restless feeling should not occurwhen the patient is supine and it does not have a circadian pattern, unlike RLS.Positional discomfort occurs after prolonged sitting (but not lying) in the same position and is usuallyrelieved by a simple change in position. For some people who fidget, movements of their feet arevolitional—especially when they are bored or anxious. Their movements are not associated withdiscomfort or an urge to move as in RLS, and their volitional movements lack a circadian pattern.Secondary RLSRLS is usually idiopathic. As noted, however, RLS can be secondary to other medical conditions.9 Ahigh prevalence (greater than 20%) of RLS has been reported in studies based on clinical populationswith a variety of medical conditions, such as iron deficiency, pregnancy (particularly during the third

Page 2 of 7

Diagnosis and Treatment of Restless Legs Syndrome in Psychiatric PracticePublished on Psychiatric Times(http://www.psychiatrictimes.com)

trimester), rheumatoid arthritis, and uremia secondary to end-stage renal disease.10 In secondaryRLS, the initial treatment strategy should focus on addressing the underlying medical condition.Several neurological disorders have also been reported to be associated with RLS. RLS may becommon among patients with Parkinson disease and both disorders respond to dopaminetherapy.11,12 Studies have also demonstrated that subtle nerve damage (eg, peripheral neuropathy)is more common among patients with late-onset RLS.13 RLS is frequently comorbid with otherneurological conditions, such as multiple sclerosis, Charcot-Marie-Tooth disease type 2,cryoglobulinemic neuropathy, and spinocerebellar ataxia. Lower back pain, myelopathy, andarthropathy have been reported to be associated with RLS as well.14

TreatmentAfter secondary causes of RLS are ruled out, the initial treatment strategy should focus on sleephygiene measures.15 Exercise and hot baths around bedtime are frequently effective in treatment ofmild RLS. If medication is necessary, the American Academy of Sleep Medicine evidence-basedpractice parameter guidelines list dopaminergic agents as the first line of treatment.16 Second-linetreatment options are opioids, benzodiazepines, and specific anticonvulsants (such as gabapentinand carbamazepine).16

Nonergot dopamine agonists such as pramipexole, ropinirole, and rotigotine have been foundeffective in double-blind studies.17 In fact, 2 dopamine agonists, pramipexole and ropinirole, are theonly medications that are approved by the FDA for treatment of moderate to severe RLS. The makerof rotigotine—another dopamine agonist delivered through a transdermal patch—filed for approval tomarket the drug for RLS. However, rotigotine was recently recalled in the United States and someEuropean countries because of problems with the delivery mechanism.Ergot-derived agonists, such as bromocriptine, pergolide, and cabergoline, have also been found tobe effective in treating RLS.17 However, potentially serious adverse effects, such as heart valveabnormality, limit their use. Generally, treatment with dopamine agonists should start with thelowest dose possible followed by slow titration. Adverse effects—including nausea, orthostatichypotension, dizziness, and daytime somnolence—should be monitored carefully.17

(L-dopa) is also effective in treating RLS.18 Until nonergot dopamine agonists were available, (L-dopa)was the most popular pharmacological agent, particularly for intermittent symptoms, because of itsrapid onset of action. However, long-term treatment of RLS with (L-dopa) is frequently associatedwith augmentation and rebound. Augmentation refers to the clinical phenomenon of earlier onset,increased severity, or involvement of other parts of the body with RLS symptoms.19 Unlike long-termcomplications of (L-dopa)–induced dyskinesia in patients with Parkinson disease, augmentationusually resolves with cessation of (L-dopa) in patients with RLS. The rebound effect causes increasedrestlessness at night or in the morning as the dose wears off, or as tolerance to the drug builds up.While the risk may be less with dopamine agonists than with (L-dopa), augmentation has beenassociated with dopamine agonists.20,21

Opiates, particularly oxycodone, are considered second-line agents for patients with moderate tosevere RLS.16 Because of concerns about the risk of opioid dependency, sedation, and exacerbationof sleep apnea, opiates have been primarily prescribed for RLS patients who cannot toleratedopaminergic agents. Among opiates, codeine is considered to have the least abuse or dependencypotential and has been reported to be effective in treating RLS.22

The efficacy of the anticonvulsant gabapentin has also been demonstrated in controlled studies, anda prodrug of gabapentin—gabapentin enacarbil—is in the FDA pipeline with an indication for RLStreatment.23 In controlled trials, efficacy has also been reported for other anticonvulsants, such ascarbamazepine and valproic acid, but these are rarely prescribed.24,25

Psychiatric comorbidities of RLSPrevious clinic-based studies reported a high prevalence of comorbidity between RLS and depressionor anxiety disorders.3 Notably, Winkelmann and colleagues26 used a structured psychiatric measure,the Munich–Composite International Diagnostic Interview for DSM-IV, to assess psychopathologyamong 130 RLS patients. Compared with 2265 community residents, those with RLS had anincreased risk of having panic disorder (odds ratio [OR], 4.7; 95% confidence interval [CI], 2.1 to10.1), generalized anxiety disorder (OR, 3.5; 95% CI, 1.7 to 7.1), and MDD (OR, 2.6; 95% CI, 1.5 to4.4) over a 12-month period.27

Several population-based studies have reported increased rates of anxiety and depression inpatients with RLS.3 Data from the Baltimore Epidemiologic Catchment Area study showed strongassociations between RLS and MDD (OR, 4.7; 95% CI, 1.6 to 14.5) and panic disorder (OR, 12.9; 95%CI, 3.6 to 46.0) among 1024 community residents over 12 months.27

Page 3 of 7

Diagnosis and Treatment of Restless Legs Syndrome in Psychiatric PracticePublished on Psychiatric Times(http://www.psychiatrictimes.com)

The underlying cause for the high prevalence of comorbidities between RLS and depression isunclear. Certainly, symptomatic overlap exists between MDD and RLS because RLS can trigger orexacerbate at least 4 of the 9 depressive symptoms listed in DSM-IV for MDD.3 Dysphoria, insomniaor excessive sleepiness (particularly during the day), decreased concentration, fatigue or loss ofenergy, and psychomotor retardation are common among RLS patients. Alternatively, an underlyingshared pathophysiological mechanism between RLS and MDD might be responsible for thecomorbidity.Many studies have established the role of dopaminergic pathology in RLS.28 A recent systematicreview supported a role for diminished dopaminergic neurotransmission in major depression basedon the following evidence29:• Diminished dopamine release from presynaptic neurons or impaired signal transduction has beenimplicated.• Animal models of depression have shown considerable responsiveness to dopamineneurotransmission.• Several studies have shown reduced concentration of dopamine metabolites in cerebrospinal fluidand in brain regions that mediate mood and motivation.• Neuroimaging studies have shown reduced dopamine transmission and compensatoryup-regulation of D2 receptors.In fact, bupropion, which has proven efficacy in the treatment of depression, acts, at least in part, bypromoting dopaminergic function. Several clinical trials recently reported a potential role fordopamine agonists—the first-line agents for RLS—in managing treatment-resistant depression orbipolar depression.30

Potential associations between other psychiatric disorders and RLS have been reported recently.Several studies found that RLS and PLMS are common among children or adults withattention-deficit/hyperactivity disorder (ADHD).31,32 It is still unclear whether sleep disruption fromRLS rather than RLS itself is associated with ADHD-like symptoms of restlessness, overactivity, andinattention. High rates of RLS-like symptoms in patients with schizophrenia33 and somatoform paindisorder34 have been reported as well.Effect of psychiatric medicationsBecause RLS and psychiatric disorders are frequently comorbid, give careful consideration whenchoosing a medication for RLS in a patient with a psychiatric disorder. Many psychiatric medicationscan affect RLS symptoms. However, other than a number of case series or anecdotal reports, fewstudies have examined the direct effects of psychiatric medications on RLS symptoms, althoughseveral have examined the effect of these medications on the severity of PLMS. While PLMS occur inat least 80% of RLS patients and correlate with RLS severity, it is unclear whether medication effectson PLMS can be used to infer the effect of psychiatric medicine on RLS.Predictably, all typical antipsychotics with dopamine receptor blocking properties exacerbate PLMS.35

Commonly used antiemetics, such as metoclopramide, promethazine, and prochlorperazine, alsoexacerbate RLS symptoms because of their dopamine receptor blocking properties. With their lowerbinding affinity for the dopamine D2 receptor, newer atypical antipsychotics are less likely toexacerbate PLMS. However, exacerbation of RLS-like symptoms with olanzapine36 and risperidone37

has been reported. Insufficient data are available about effects of clozapine, quetiapine, andziprasidone on RLS or PLMS. Aripiprazole, a partial dopamine agonist, theoretically might have afavorable effect on RLS symptoms, but a systematic study is needed.Although it has been suggested that various tricyclic antidepressants (TCAs) and SSRIs exacerbateRLS or PLMS, the specific mechanisms are unknown.38-41 In contrast, bupropion, a dopamine agonist,might alleviate RLS symptoms.40 The effect of trazodone and mirtazapine on RLS symptoms isunclear.Given the effects of these medications on RLS symptoms, it is important to screen for RLS symptomsbefore starting antidepressant therapy. For a patient with severe RLS and mild depressivesymptoms, it is reasonable to treat RLS first to see whether improvements in sleep and energy leadto resolution of depressive symptoms. When treating depression in patients with severe RLS,consider trying a non-SSRI or non-TCA (eg, bupropion) first. Keep in mind that there are nocomparative studies of the efficacy and safety of bupropion and SSRIs in comorbid depression andRLS.In the treatment of mood disorders, especially bipolar disorder, anticonvulsants (eg, valproic acid)are commonly prescribed to stabilize mood. In general, anticonvulsants that are associated with painrelief ameliorate RLS symptoms. Gabapentin and carbamazepine are second-line agents in thetreatment of RLS, and valproic acid might also be helpful in reducing RLS symptoms.16,25,26 While

Page 4 of 7

Diagnosis and Treatment of Restless Legs Syndrome in Psychiatric PracticePublished on Psychiatric Times(http://www.psychiatrictimes.com)

anecdotal reports of RLS induced by lithium exist, no systematic study has tested the effect of thisagent on PLMS or RLS symptoms.42

Benzodiazepines and hypnotics are often prescribed to treat insomnia related to psychiatricdisorders; these medications have not been shown to exacerbate PLMS. Among them, clonazepam ispreferred over short-acting benzodiazepines for the treatment of anxiety and insomnia in patientswith RLS because of its longer half-life. However, studies that examined the effect of clonazepam onPLMS and RLS did not find a consistent reduction in PLMS; patients instead reported a more restfulsleep.43

Antihistamines are commonly taken for sleep problems. However, certain drugs in this class,including diphenhydramine, can exacerbate PLMS and RLS and should be avoided.Dopamine agonists and psychiatric symptomsIn randomized, double-blind, placebo-controlled trials of pramipexole or ropinirole for RLS treatment,none of the participants treated with dopamine agonists experienced neuropsychiatric symptoms.Use caution when interpreting the clinical safety data because the RLS treatment studies havesystematically excluded patients with psychiatric comorbidity. Therefore, clear data do not exist onthe potential neuropsychiatric adverse effects of dopamine agonist treatment of RLS in patients withcomorbid psychiatric disorders.Dopamine agonist treatment of Parkinson disease has been associated with hallucinations,delusions, confusion, and mania.44,45 Lower recommended doses of dopamine agonists seem lesslikely to induce psychotic symptoms in RLS patients without psychiatric comorbidity. However, thepotential for inducing or exacerbating behavioral symptoms in RLS patients with psychiatricdisorders from dopamine agonist therapy cannot be ignored.Compulsive gambling,46 overeating,47 and hypersexuality48 have also been associated with dopamineagonist treatment of Parkinson disease and, to a lesser degree, RLS. Therefore, those clinicians whotreat RLS in patients with impulse-control disorder or affective disorders (eg, bipolar disorder) shouldbe aware of the potential for initiating or exacerbating impulsive behavior or mood symptoms.Another problematic adverse effect of dopamine agonist treatment of Parkinson disease is daytimesomnolence. Sleep attacks (ie, sudden and overwhelming sleepiness without awareness of fallingasleep), particularly while driving, have been described in patients taking dopamine agonists andrepresent a serious public safety issue.49,50 Therefore, dopamine agonists should be prescribed andtitrated with caution, especially for older patients who have RLS, to reduce the adverse effect ofdaytime somnolence.ConclusionRLS is a common treatable disorder, closely associated with depression and anxiety in both clinicalpopulations and the community. Given the potential impact of various psychiatric drugs on RLSsymptoms, medications need to be chosen judiciously to avoid exacerbating RLS symptoms. As morepatients with psychiatric disorders receive a diagnosis of RLS and are treated with dopamineagonists, uncommon, yet problematic psychiatric adverse effects related to pharmacotherapy forRLS may develop. Future systematic studies are warranted to guide the optimum treatment of RLS inpatients with psychiatric conditions, particularly depression and/or anxiety.[Note: The above artice is an expired CME and is here for informational purposes.] References: 1. Wittmaack T. Pathologie und Therapie der Sensibilität-Neurosen. Leipzig, Germany: E Schäfer;1861:459.2. Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome(RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primarycare study. Sleep Med. 2004;5:237-246.3. Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, anddepression. Sleep. 2005;28:891-898.4. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, specialconsiderations, and epidemiology. A report from the restless legs syndrome diagnosis andepidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-119.5. Winkelmann J. Genetics of restless legs syndrome. Curr Neurol Neurosci Rep. 2008;8:211-216.6. Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legssyndrome identifies common variants in three genomic regions. Nat Genet. 2007;39:1000-1006.7. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. NEngl J Med. 2007;357:639-647.

Page 5 of 7

Diagnosis and Treatment of Restless Legs Syndrome in Psychiatric PracticePublished on Psychiatric Times(http://www.psychiatrictimes.com)

8. Montplaisir J, Boucher S, Poirier G, et al. Clinical, polysomnographic, and genetic characteristics ofrestless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord.1997;12:61-65.9. Earley CJ. Clinical practice. Restless legs syndrome. N Engl J Med. 2003;348:2103-2109.10. Hening WA. Current guidelines and standards of practice for restless legs syndrome. Am J Med.2007;120(1, suppl 1):S22-S27.11. Krishnan PR, Bhatia M, Behari M. Restless legs syndrome in Parkinson’s disease: acase-controlled study. Mov Disord. 2003;18:181-185.12. Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson disease andrestless legs syndrome. Arch Neurol. 2002;59:421-424.13. Polydefkis M, Allen RP, Hauer P, et al. Subclinical sensory neuropathy in late-onset restless legssyndrome. Neurology. 2000;55:1115-1121.14. Banno K, Delaive K, Walld R, Kryger MH. Restless legs syndrome in 218 patients: associateddisorders. Sleep Med. 2000;1:221-229.15. Silber MH, Ehrenberg BL, Allen RP, et al; Medical Advisory Board of the Restless Legs SyndromeFoundation. An algorithm for the management of restless legs syndrome [published correctionappears in Mayo Clin Proc. 2004;79:1341]. Mayo Clin Proc. 2004;79:916-922.16. Littner MR, Kushida C, Anderson WM, et al; Standards of Practice Committee of the AmericanAcademy of Sleep Medicine. Practice parameters for the dopaminergic treatment of restless legssyndrome and periodic limb movement disorder. Sleep. 2004;27:557-559.17. Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: anevidence-based review and implications for clinical practice. Mov Disord. 2008;23:2267-2302.18. Benes H, Kurella B, Kummer J, et al. Rapid onset of action of levodopa in restless legs syndrome:a double-blind, randomized, multicenter, crossover trial. Sleep. 1999;22:1073-1081.19. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep.1996;19:205-213.20. Ferini-Strambi L. Restless legs syndrome augmentation and pramipexole treatment. Sleep Med.2002;3(suppl):S23-S25.21. Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment ofrestless legs syndrome (RLS). Sleep Med. 2004;5:9-14.22. Winkelmann J, Schadrack J, Wetter TC, et al. Opioid and dopamine antagonist drug challenges inuntreated restless legs syndrome patients. Sleep Med. 2001;2:57-61.23. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al. Treatment of restless legs syndrome withgabapentin: a double-blind, cross-over study. Neurology. 2002;59:1573-1579.24. Telstad W, Sorensen O, Larsen S, et al. Treatment of the restless legs syndrome withcarbamazepine: a double blind study. Br Med J (Clin Res Ed). 1984;288:444-446.25. Eisensehr I, Ehrenberg BL, Rogge Solti S, Noachtar S. Treatment of idiopathic restless legssyndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid. JNeurol. 2004; 251:579-583.26. Winkelmann J, Prager M, Lieb R, et al. “Anxietas tibiarum.” Depression and anxiety disorders inpatients with restless legs syndrome. J Neurol. 2005;252:67-71.27. Lee HB, Hening WA, Allen RP, et al. Restless legs syndrome is associated with DSM-IV majordepressive disorder and panic disorder in the community. J Neuropsychiatry Clin Neurosci.2008;20:101-105.28. Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med.2004;5:385-391.29. Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch GenPsychiatry. 2007;64:327-337.30. Nierenberg AA, Dougherty D, Rosenbaum JF. Dopaminergic agents and stimulants asantidepressant augmentation strategies. J Clin Psychiatry. 1998;59(suppl 5):60-64.31. Wagner ML, Walters AS, Fisher BC. Symptoms of attention-deficit/hyperactivity disorder in adultswith restless legs syndrome. Sleep. 2004;27:1499-1504.32. Picchietti DL, Underwood DJ, Farris WA, et al. Further studies on periodic limb movement disorderand restless legs syndrome in children with attention-deficit hyperactivity disorder. Mov Disord.1999;14:1000-1007.33. Kang SG, Lee HJ, Jung SW, et al. Characteristics and clinical correlates of restless legs syndromein schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1078-1083.34. Aigner M, Prause W, Freidl M, et al. High prevalence of restless legs syndrome in somatoformpain disorder. Eur Arch Psychiatry Clin Neurosci. 2007;257:54-57.

Page 6 of 7

Diagnosis and Treatment of Restless Legs Syndrome in Psychiatric PracticePublished on Psychiatric Times(http://www.psychiatrictimes.com)

35. Montplaisir J, Lorrain D, Godbout R. Restless legs syndrome and periodic leg movements in sleep:the primary role of dopaminergic mechanism. Eur Neurol. 1991;31:41-43.36. Kraus T, Schuld A, Pollmächer T. Periodic leg movements in sleep and restless legs syndromeprobably caused by olanzapine. J Clin Psychopharmacol. 1999;19:478-479.37. Wetter TC, Brunner J, Bronisch T. Restless legs syndrome probably induced by risperidonetreatment. Pharmacopsychiatry. 2002;35:109-111.38. Garvey MJ, Tollefson GD. Occurrence of myoclonus in patients treated with cyclicantidepressants. Arch Gen Psychiatry. 1987;44:269-272.39. Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. BiolPsychiatry. 2005;58:510-514.40. Kim SW, Shin IS, Kim JM, et al. Bupropion may improve restless legs syndrome: a report of threecases. Clin Neuropharmacol. 2005;28:298-301.41. Rottach KG, Schaner BM, Kirch MH, et al. Restless legs syndrome as side effect of secondgeneration antidepressants. J Psychiatr Res. 2008;43:70-75.42. Terao T, Terao M, Yoshimura R, Abe K. Restless legs syndrome induced by lithium. BiolPsychiatry. 1991;30:1167-1170.43. Saletu M, Anderer P, Saletu-Zyhlarz G, et al. Restless legs syndrome (RLS) and periodic limbmovement disorder (PLMD): acute placebo-controlled sleep laboratory studies with clonazepam. EurNeuropsychopharmacol. 2001;11:153-161.44. Factor SA, Molho ES, Podskalny GD, Brown D. Parkinson’s disease: drug-induced psychiatricstates. Adv Neurol. 1995;65:115-138.45. Wolters EC. Dopaminomimetic psychosis in Parkinson’s disease patients: diagnosis andtreatment. Neurology. 1999;52(7, suppl 3):S10-S13.46. Dodd ML, Klos KJ, Bower JH, et al. Pathological gambling caused by drugs used to treat Parkinsondisease. Arch Neurol. 2005;62:1377-1381.47. Nirenberg MJ, Waters C. Compulsive eating and weight gain related to dopamine agonist use.Mov Disord. 2006;21:524-529.48. Klos KJ, Bower JH, Josephs KA, et al. Pathological hypersexuality predominantly linked to adjuvantdopamine agonist therapy in Parkinson’s disease and multiple system atrophy. Parkinsonism RelatDisord. 2005;11:381-386.49. Hobson DE, Lang AE, Martin WR, et al. Excessive daytime sleepiness and sudden-onset sleep inParkinson disease: a survey by the Canadian Movement Disorders Group. JAMA. 2002;287:455-463.50. Avorn J, Schneeweiss S, Sudarsky LR, et al. Sudden uncontrollable somnolence and medicationuse in Parkinson disease [published correction appears in Arch Neurol. 2006;63:468]. Arch Neurol.2005;62:1242-1248. Source URL: http://www.psychiatrictimes.com/printpdf/diagnosis-and-treatment-restless-legs-syndrome-psychiatric-practice/page/0/1

Links:[1] http://www.psychiatrictimes.com/sleep-disorders[2] http://www.psychiatrictimes.com/circadian-rhythm-sleep-disorders[3] http://www.psychiatrictimes.com/comorbidity-psychiatry[4] http://www.psychiatrictimes.com/major-depressive-disorder[5] http://www.psychiatrictimes.com/restless-legs-syndrome[6] http://www.psychiatrictimes.com/somatoform-disorder[7] http://www.psychiatrictimes.com/authors/hochang-benjamin-lee-md

Page 7 of 7