RLS (DSM-5 criteria)
Psychotropic-induced Akathisia
Location
Legs principally or exclusively involved (A)
Generalized, including upper extremities as well
Dysesthesias
Very common (A)
Rare
Relation to movement
Worse during inactivity or rest (A1)
Typically continuous
Response to movement
Partially or totally relieved by rest (A2)
Unaffected by movement
Diurnal variation
Worse in evening or night (A3)
Limited circadian variation
Psychotropic exposure
Independent of psychotropic exposure
Neuroleptics most common though also described with various antidepressants
Numerous cases of neuroleptics causing RLS symptoms have been reported including those for haloperidol [103], risperidone [104], and olanzapine [105–107]. Even the two neuroleptics with least D2 receptor antagonism and, consequently, the least risk of causing akathisia or other movement disorders—quetiapine [77, 80, 108–111] and clozapine [112]—have been reported to induce RLS symptoms. Although ropinirole was effective in managing a case of quetiapine-induced RLS, this practice cannot be uniformly recommended [109] given the potential for dopamine agonists to precipitate psychiatric destabilization (e.g., psychosis among patients with psychotic illness or mood elevation and impulsivity among patients with bipolar disorder). Studies suggest that certain dopamine receptor and monoamine oxidase alleles may increase a person’s vulnerability to neuroleptic-induced RLS [113–116] though the clinical utility of genotyping in the clinic remains limited.
The absence of randomized clinical trials supporting an association between neuroleptics and RLS notwithstanding, the fact that neuroleptics cause akathisia and other movement disorders makes their propensity to cause RLS not only plausible but quite likely. In general, one may expect atypical neuroleptics to be more benign than typicals with regard to RLS, and quetiapine and clozapine may be the safest options in RLS based on their preferential use in Parkinson’s disease and other alpha synucleinopathies. Aripiprazole, given its unique pharmacodynamics as a partial agonist/antagonist of D2 receptors, may offer a more favorable profile regarding RLS. Most reports suggest that aripiprazole does not cause RLS and may improve these symptoms [117–120], but a case report of aripiprazole-related RLS has been reported [121]. Clinicians, however, should note that roughly a third of patients on aripiprazole will experience akathisia. In many clinical situations, no adequate alternative to neuroleptics exists, and it may safest to treat RLS with an adjunctive α2δ ligand such as gabapentin [122] or gabapentin enacarbil.
Mood Stabilizers
Bipolar disorder and, at times, major depression are managed with mood stabilizers, which include lithium and several anticonvulsants (e.g., valproic acid, carbamazepine, lamotrigine, or oxcarbazepine). Anticonvulsants that improve neuropathic pain may improve RLS symptoms, and in particular carbamazepine and gabapentin (which is not a traditional mood stabilizer) have long been considered second-line agents for RLS on the basis of randomized clinical trials supporting their efficacy in RLS [123, 124]. Valproic acid [125] and lamotrigine [126] may also improve RLS symptoms. Lithium, however, may worsen RLS symptoms in select patients based on a few case reports [127–129]. Therefore, anticonvulsants may be preferred over lithium in the management of mood disorders with comorbid RLS. Clinicians should be extremely cautious in discontinuing lithium in patients who are euthymic even if RLS symptoms emerge. Lithium remains the gold-standard mood stabilizer and is highly effective. Discontinuation of lithium risks destabilizing bipolar disorder and should not be undertaken lightly.
Psychiatric Considerations of RLS Treatment
The two medication classes approved for RLS—dopamine agonists and α2δ ligands—have psychoactive properties that must be considered as well. Although uncommon, dopaminergics are well-documented to cause impulse-control syndromes in a minority of patients. Examples of impulse-control syndromes include pathological gambling [130–132], hypersexuality [130], hoarding [133] and other compulsive [134] behavior, punding [135], and nocturnal eating syndrome [136]. Patients should be monitored closely for these destructive behavioral consequences of treatment, and in virtually all cases the offending agent should be discontinued as rapidly as feasible. Although rare, abrupt discontinuation of dopamine agonists can precipitate a potentially lethal syndrome known as parkinsonism-hyperpyrexia syndrome, which is thought to be akin to neuroleptic malignant syndrome [137]. Agonists of α2δ may cause sedation and are often accompanied by anxiolysis. Although not approved for psychiatric use in the US pregabalin is efficacious for the management of general anxiety disorder [138, 139] and approved internationally for this purpose. Also, the potential for misuse of pregabalin and other agents should not be overlooked [140].
Treatment Implications
Balancing the management of psychiatric disorders with RLS and the potential for psychotropics to induce or worsen RLS presents many clinical challenges. Patients with RLS should be screened for major depression and anxiety disorders. Patients on dopamine agonists should be monitored closely for impulse-control syndromes and patients on α2δ ligands for medication misuse. On the other hand, patients with psychiatric illness should be actively screened for RLS given the high comorbidity. In either case, the comorbidity of RLS and mental illness may influence pharmacological selection.
In patients with RLS and comorbid depression, dopamine agonists are first-line as recommended by the International RLS Task Force [141]. If RLS is prominent and depression is mild, dopamine agonists may be preferable for RLS, which may improve depression as well [142–144]. The use of dopaminergics on depressive symptoms melds biological plausibility (dopamine activity is disrupted in depression) with the knowledge that enhancing sleep also improves mood (mitigating RLS symptoms is likely to improve sleep quality) [145]. If major depression is moderate to severe, bupropion may be considered before pro-serotonergic agents provided it is not contraindicated due to seizures or eating disorders that involve purging. If pro-serotonergic agents are considered, agents with a more balanced serotonin-to-norepinephrine reuptake profile may be less likely to worsen RLS. It should also be kept in mind that mild to moderate major depression may be adequately treated with cognitive behavioral therapy, interpersonal therapy, or psychodynamic psychotherapy per the American Psychiatric Association’s treatment guidelines for MDD. For severe major depression, electroconvulsive therapy also remains a viable clinical option.
For patients with RLS and comorbid GAD, α2δ ligands are preferred over dopamine agonists for the management of RLS symptoms [141]. As noted above, several randomized, controlled trials have demonstrated efficacy of pregabalin for GAD. Although it is approved in several countries throughout Europe for GAD [139], its use for GAD in the US remains off-label. Benzodiazepines may also be considered for the management of GAD in patients with comorbid RLS. Similarly, the pharmacological management of PD may involve benzodiazepines, but attempts at starting a pro-serotonergic agent could still be considered given their efficacy in preventing future panic attacks. The first-line pharmacological treatment of OCD and PTSD include pro-serotonergic agents, which may make clinical management with comorbid RLS particularly difficult. Psychotherapy should be given strong consideration for OCD or PTSD when comorbid with RLS because data on comparative efficacy of medications versus CBT in these disorders remain equivocal.
Anticonvulsants should be considered for managing bipolar disorder in the context of RLS as they may actually improve RLS symptoms as well. In general, valproic acid may be a reasonable first-line agent with consideration of carbamazepine as well. The use of lamotrigine for bipolar disorder is generally limited to managing bipolar II disorder given its dearth of anti-manic activity. Lithium may worsen RLS symptoms; though, again, clinicians should be well-advised not to discontinue this without compelling reason in patients who are affectively stable. Treating RLS in bipolar disorder is critical particularly because insomnia may precipitate mood episodes in bipolar disorder. It seems reasonable to consider α2δ ligands over dopaminergic agents. The fact that two patients with bipolar disorder tolerated ropinirole without manic switch [109] does not outweigh the potential for this disastrous clinical outcome [146].
For patients with comorbid RLS and schizophrenia, α2δ ligands are preferred to dopamine agonists due to the concern that dopamine agonism could pharmacologically work against antipsychotics. The data in support of pramipexole [147] or ropinirole [148] as adjuncts to neuroleptics in schizophrenia is far too meager to support their use in this population. No adequate alternative to neuroleptic agents exists for psychotic disorders. Therefore, patients with schizophrenia and RLS should be treated with antipsychotics with very few exceptions. Atypical neuroleptics are less likely to affect RLS symptoms than typicals, and quetiapine and clozapine may pose the least risk of neuroleptic-induced RLS symptoms based on their comparatively limited D2 receptor binding at therapeutic doses. Nevertheless, the emergence of RLS during neuroleptic use should be treated symptomatically unless these symptoms are severe or threaten patient non-adherence. Additionally, benzodiazepines such as clonazepam are commonly used as adjuncts in schizophrenia and could be considered as second line for RLS symptoms in this population.
Psychiatrists who diagnosis RLS should be well-aware of RLS mimics and consider a broad differential for symptoms consistent with RLS, particularly because such symptoms may be a harbinger of serious medical illness [149, 150]. For instance, misdiagnosis of peripheral neuropathy could risk overlooking type 2 diabetes mellitus. Claudication or pseudoclaudication should alert the clinician to heart disease or spinal cord compression, respectively. Uremia may present with RLS symptoms as may iron deficiency anemia, which could be the presenting symptom of colon cancer. In the same way that psychiatrists diagnose major depression after medical conditions such as hypothyroidism have been ruled out, RLS remains a clinical diagnosis of exclusion. Moreover, clinicians should not rely on the core clinical features of RLS (i.e., DSM-5 Criterion A or the IRLSSG essential criteria 1–4) to rule out conditions other than “true” RLS given the potential for false positives [149].
A differential diagnosis of RLS should be broad, and mental health professionals considering a diagnosis should familiarize themselves with other conditions that may present with RLS symptoms. A differential diagnosis for RLS should include metabolic (iron deficiency anemia, uremia, dehydration), obstetric (pregnancy), behavioral (positional discomfort or volitional movements [“foot tapping” or “leg rocking”]), sleep–wake-disorder-related (sleep starts, periodic movements in sleep disorder), musculoskeletal/nociceptive (muscle cramping, pain, myalgia, positional discomfort, arthritis, myxedema), vascular (claudication/peripheral vascular disease, peripheral venous insufficiency, hypotensive akathisia, congestive heart failure/peripheral edema), neurological (sciatica, peripheral neuropathy/radiculopathy/myelopathy, pseudoclaudication, painful [or painless] legs-moving toes, reflex sympathetic dystrophy), or medication-induced (akathisia) conditions [151, 152].
Conclusions
RLS is a common disorder that may share a bidirectional association with depression and anxiety. It was elevated to a unique diagnosis in DSM-5 because it is operationally valid, significantly impairs quality of life, and may be effectively treated with a several pharmacologic agents. Patients with RLS or with mental illness should be screened for the other in an ongoing fashion. The treatment of mental illness in RLS patients demands careful consideration of treatment planning including the decision to pursue medication versus therapy and, if using psychotropics, which psychotropic to use. Often, medications will need to be used and RLS symptoms managed in parallel with ongoing psychotropics. Prospective, randomized, controlled studies are needed to define the role of psychotropics in patients with RLS as well as the effects of RLS pharmacology on mental illness.
References
1.
Wittmaack T. Pathologie und Therapie der Sensibilitäs Neurosens. Leipzig: E Schäfer; 1861.
2.
Oppenheim H. Lehrbuch der Nervenkrankheiten. 7th ed. Berlin: Karger; 1923.
4.
Ekbom K. The pre-senile delusion of infestation (classic text no. 54). Hist Psychiatry. 2003;14:229–56.PubMed
5.
Ekbom K. Restless legs: a clinical study. Acta Med Scand. 1945;158:1–123.
6.
Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep. 2005;28(7):891–8.PubMed
7.
American Psychiatric Association. Diagnostic and statistical manual for mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing, Inc.; 2013.
8.
Scholz H, Benes H, Happe S, Bengel J, Kohnen R, Hornyak M. Psychological distress of patients suffering from restless legs syndrome: a cross-sectional study. Health Qual Life Outcomes. 2011;9:73.PubMedPubMedCentral
9.
Salas RE, Kwan AB. The real burden of restless legs syndrome: clinical and economic outcomes. Am J Managed Care. 2012;18(9 Suppl):S207–12.
10.
Abetz L, Allen R, Follet A, Washburn T, Earley C, Kirsch J, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. 2004;26(6):925–35.PubMed
11.
Kim JB, Koo YS, Eun MY, Park KW, Jung KY. Psychosomatic symptom profiles in patients with restless legs syndrome. Sleep Breathing = Schlaf & Atmung. 2013;17(3):1055–61.
12.
Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005;165(11):1286–92.PubMed
13.
Ohayon MM, O’Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012;16(4):283–95.PubMed
14.
Hasin DS, Goodwin RD, Stinson FS, Grant BF. Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry. 2005;62(10):1097–106.PubMed
15.
Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4(2):101–19.PubMed
16.
Robins LN, Helzer JE, Weissman MM, Orvaschel H, Gruenberg E, Burke JD Jr, et al. Lifetime prevalence of specific psychiatric disorders in three sites. Arch Gen Psychiatry. 1984;41(10):949–58.PubMed
17.
Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. 2004;164(2):196–202.PubMed
18.
Winkelmann J, Muller-Myhsok B, Wittchen HU, Hock B, Prager M, Pfister H, et al. Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families. Ann Neurol. 2002;52(3):297–302.PubMed
19.
Kendler KS. The dappled nature of causes of psychiatric illness: replacing the organic-functional/hardware-software dichotomy with empirically based pluralism. Mol Psychiatry. 2012;17(4):377–88.PubMedPubMedCentral
20.
Brand S, Lehtinen A, Hatzinger M, Holsboer-Trachsler E. Comparison of sleep EEG profiles of patients suffering from restless legs syndrome, restless legs syndrome and depressive symptoms, and major depressive disorders. Neuropsychobiology. 2010;61(1):41–8.PubMed
21.
Broman JE, Mallon L, Hetta J. Restless legs syndrome and its relationship with insomnia symptoms and daytime distress: epidemiological survey in Sweden. Psychiatry Clin Neurosci. 2008;62(4):472–5.PubMed
22.
Cuellar NG, Strumpf NE, Ratcliffe SJ. Symptoms of restless legs syndrome in older adults: outcomes on sleep quality, sleepiness, fatigue, depression, and quality of life. J Am Geriatr Soc. 2007;55(9):1387–92.PubMed
23.
Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res. 2002;53(1):547–54.PubMed
24.
Phillips B, Young T, Finn L, Asher K, Hening WA, Purvis C. Epidemiology of restless legs symptoms in adults. Arch Intern Med. 2000;160(14):2137–41.PubMed
25.
Winkelman JW, Finn L, Young T. Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med. 2006;7(7):545–52.PubMed
26.
Ulfberg J, Bjorvatn B, Leissner L, Gyring J, Karlsborg M, Regeur L, et al. Comorbidity in restless legs syndrome among a sample of Swedish adults. Sleep Med. 2007;8(7–8):768–72.PubMed
27.
Ulfberg J, Nystrom B, Carter N, Edling C. Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord (Official Journal Movement Disorder Society). 2001;16(6):1159–63.
28.
Wesstrom J, Nilsson S, Sundstrom-Poromaa I, Ulfberg J. Restless legs syndrome among women: prevalence, co-morbidity and possible relationship to menopause. Climacteric: J Int Menopause Soc. 2008;11(5):422–8.
29.
Bjorvatn B, Leissner L, Ulfberg J, Gyring J, Karlsborg M, Regeur L, et al. Prevalence, severity and risk factors of restless legs syndrome in the general adult population in two Scandinavian countries. Sleep Med. 2005;6(4):307–12.PubMed