Chapter 28 Restless Legs Syndrome and Psychiatric Disorders
There has always been a close relationship between RLS and psychiatric disorders. As early as the 19th century, Wittmaack observed the co-occurrence of restless legs syndrome (RLS) with depression and anxiety, which he termed “anxietus tibiarum,” and believed it to be a form of hysteria.1 More recently, several different strands of association have linked RLS to the psychiatric disorders. First, a number of studies have found that psychiatric disorders, especially anxiety and depression, can be linked to RLS.2,3 Second, there is some evidence that both dopamine-blocking neuroleptics and antidepressants can initiate or aggravate RLS. Moreover, there is some overlap in the key symptoms of RLS and depression or anxiety, which may at times bring about a spurious association. Even an alternate name for RLS, Ekbom’s syndrome, suggests a relationship to psychiatric disorders. Although most neurologists think that Ekbom’s syndrome refers to RLS, psychiatrists are more familiar with Ekbom’s syndrome as delusional parasitosis, a condition in which a person holds a belief that parasites have infested him or her.4 This confusion is due to the fact that Karl Ekbom, a Swedish neurologist, described both conditions, delusional parasitosis in 19375 and RLS in 19456 separately, and thus both conditions are named after him. This duplication of labels illustrates how the clinical entity of RLS lies in the boundary between psychiatry and neurology.
Epidemiology of the Psychiatric Comorbidity of Restless Legs Syndrome: Depression and Anxiety Disorders
Epidemiologically, there are several striking similarities between RLS and mood disorders, especially depression. Approximately 5% to 10% of the community has RLS of varying severity,7 whereas the lifetime prevalence of major depressive disorder in the community is between 5% and 10%.8 Median age at onset in both conditions is in the fourth decade.9,10 In both disorders women predominate,8,11 whereas the familial clustering of both conditions underlines their important genetic risk factors.12–14
In clinical populations, there is a high frequency of comorbidity between RLS and depression or anxiety disorders. Most studies have relied on simple depression or anxiety rating scales with limited validity and lacked a suitable control group, but their findings have consistently found a high level of comorbidity.15 In the best controlled study, Winkelmann and colleagues used a structured psychiatric interview, the Munich-Composite International Diagnostic Interview for DSM-IV, to assess psychopathology among 130 RLS patients and compared the prevalence of major depressive disorder and panic disorder with 2265 community residents with somatic disorders (excluding diabetes, which might cause RLS).2 The results from this study revealed an increased risk of having 12-month anxiety and depressive disorders with particularly strong associations for panic disorder, generalized anxiety disorder, and major depression (Table 28-1), confirming the high prevalence of depression and anxiety symptoms among RLS patients.
TABLE 28-1 Increased Risk of Psychiatric Disorders in Restless Legs Syndrome
| Population/Disorder | Odds Ratio (OR) | 95% Confidence Interval |
|---|---|---|
| German clinical population* | ||
| Panic disorder | 4.7 | 2.1 to 10.1 |
| Generalized anxiety disorder | 3.5 | 1.7 to 7.1 |
| Major depression | 2.6 | 1.5 to 4.4 |
| American biracial population sample† | ||
| Panic disorder | 12.9‡ | 3.6 to 46.0 |
| Major depressive disorder | 4.7‡ | 1.6 to 14.5 |
From *Lee et al.3 and †Winkelmann et al.2
‡ These are adjusted ORs to account for possible confounds.
Several population-based studies have also reported increased rates of anxiety and depression among subjects with RLS.15 Unlike clinic-based studies, population-based studies do not have a referral bias and have a comparison group drawn from the same population. Among the previous studies, the more recent RLS in Baltimore Epidemiologic Catchment Area (RiBECA) study provides strong evidence of the association between RLS and depression and/or anxiety disorder.3 In this study, Lee and colleagues examined the association between RLS and DSM-IV major depressive disorder (MDD) and panic disorder based on 1071 participants who completed the seven-item RLS Questionnaire and Diagnostic Interview Schedule. The study found highly elevated odds ratios in those endorsing RLS symptoms for both diagnosis of DSM-IV major depressive disorder (MDD) and panic disorder in the past 12 months, suggesting a strong association between RLS and MDD and/or panic disorder (see Table 28-1).
Sources of the Association Between Restless Legs Syndrome and Depression or Anxiety Disorders
Whether the close association found between RLS and depressive symptoms is a byproduct of symptomatic overlap remains an unresolved question. Of the nine symptoms listed for the diagnostic criteria for major depressive disorder in DSM-IV, RLS could trigger or exacerbate at least four of these depressive symptoms15 (Box 28-1). On the other hand, according to the RiBECA study, MDD symptoms supposedly unrelated to RLS (Box 28-1) are just as common among those with a comorbidity of RLS and MDD.3 In other words, the association between RLS and MDD seems likely to be more than simple diagnostic overlap. This leads to considering whether there is an underlying shared pathophysiologic mechanism responsible for the co-occurrence of RLS and MDD. RLS is very sensitive to dopaminergic medication16 and it is generally agreed that there must be a dopamine-related abnormality in RLS.17–19 Multiple studies also support a role for diminished dopaminergic neurotransmission in major depression.20 The following evidence favors such a role for dopamine: (1) diminished dopamine release from presynaptic neurons or impaired signal transduction in depression, (2) animal models of depression respond to enhanced dopamine neurotransmission, (3) there are reduced concentrations of dopamine metabolites in the cerebrospinal fluid and in brain regions that mediate mood and motivation, (4) neuroimaging studies have found upregulation of D2 receptors, consistent with decreased dopamine release. In fact, bupropion, which has proven efficacy in the treatment of depression, acts, at least in part, via promoting dopaminergic function.21 Several clinical trials recently reported a potential role for dopamine agonists, the first-line agent for RLS, for managing treatment-resistant depression or bipolar depression.22
BOX 28-1 Overlapping and Distinctive Criteria for Depression With Restless Legs Syndrome (RLS)
Adapted from Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep 2005;28:891-898.
The high prevalence of panic disorder among subjects with RLS is even more intriguing, because little symptomatic overlap exists between the two conditions. Similarly, the high rate of comorbidity with panic disorder and MDD is observable among patients with Parkinson’s disease (PD), a neurodegenerative disorder primarily involving central dopaminergic tracts.23 Psychiatric comorbidities of PD can be attributable to the dopaminergic deficits or to interactions between the dopaminergic deficits and variable deficits in norepinephrine and serotonin that occur in PD.24,25 Little is known about the role of noradrenergic or serotonergic neurotransmission in the pathophysiology of RLS, although serotonin uptake blockers have been implicated as possibly provoking or aggravating RLS26–28 (see later) and clonidine, an α2-adrenergic agonist, has been used to treat RLS.29 Future investigations should examine the symptomatic and pathophysiological overlap between RLS and MDD or panic disorder that frequently co-occur in the clinic and in the community.
Related posts:
Clinical Science of Restless Legs Syndrome
Introduction: Comorbid Disorders and Special Populations
Restless Legs Syndrome as a Movement Disorder
Restless Legs Syndrome in Neurological Disorders
Spinal Cord, Dopamine, Opiates, and Restless Legs Syndrome
Restless Legs Syndrome Morbidity: Sleep and Quality of Life
