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.
Restless Legs Syndrome and Attention-Deficit/Hyperactivity Disorder
There has been much interest in a potential association between attention-deficit/hyperactivity disorder (ADHD) and RLS as well.30 RLS and PLMS may be common in children or adults with ADHD (see also Chapter 23).31,32 However, it remains to be determined whether ADHD-like symptoms of restlessness, overactivity, and inattention are caused by the sleep disruption of RLS, like other daytime sequelae of RLS,33 or by a more direct link. One study compared ADHD symptoms among adults with RLS, normal control subjects, and control subjects with insomnia and reported that ADHD symptoms are more common in patients with RLS than in either control group.34 Specific tests of attention have not been applied to RLS subjects, although a frontal lobe dysfunction—which may also be due to sleep deprivation—has been reported.35 However, when normal subjects were sleep deprived to the same degree as RLS patients, they performed even less well on the same tests.36 This suggests that, even though sleep deprivation impacts RLS patients, they may have partially adapted to its effects.
Effects of Psychiatric Medications on Restless Legs Syndrome Symptoms
Because RLS and psychiatric disorders co-occur frequently, a clinician should give careful consideration when choosing a medication for a psychiatric patient with comorbid RLS. Many psychiatric medications have the potential to affect RLS symptoms (see Chapter 30). However, other than some case series or anecdotal reports, few studies have examined the direct effects of psychiatric medications on RLS symptoms, although several have examined the effects of these medications on the severity of PLMS. Because PLMS occur in at least 80% of RLS patients and correlate with RLS severity, effects on PLMS could be used to infer the effect of psychiatric medicine on RLS in general.37
Predictably, all typical antipsychotics with dopamine receptor–blocking properties exacerbate PLMS.38,39 In fact, common antiemetics such as metoclopromide, promethazine, and procholorperazine also exacerbate RLS symptoms due to their dopamine receptor–blocking property. Newer, atypical antipsychotics are less likely to exacerbate PLMS due to lower binding affinity for the dopamine D2 receptor, but two reports of initiation or exacerbation of RLS-like symptoms by risperidone and olanzapine exist.37,39 Few data are available about the effects of clozapine, quetiapine, and ziprasidone on RLS or PLMS. Aripiprazole, a partial dopamine agonist, theoretically might have a favorable effect on RLS symptoms, but no systematic study is available on this issue (see Table 28-2 for psychoactive drugs that may be more compatible with RLS).
TABLE 28-2 Psychoactive Medications That are More Compatible With Restless Legs Syndrome
| Comments | |
|---|---|
| Alternative for Neuroleptics | |
| Aripiprazole | Aripiprazole functions as a partial agonist at the dopamine D2 receptor. There have been some anecdotal claims that this drug may help RLS, but studies are necessary to confirm this benefit. |
| Alternatives for Antidepressants | |
| Buproprion | This drug is a weak dopamine reuptake inhibitor that may possibly help RLS symptoms* but rarely worsens RLS.† |
| Trazodone | This drug does not seem to affect RLS and may help sleep. |
| Desipramine | Although tricyclic antidepressants tend to worsen RLS, the secondary amines, desipramine, protriptyline, and nortriptyline have less serotonergic effects and may be safer for RLS sufferers.† |
| Reboxetine | Although widely available, this drug is not approved in the United States. It is a selective noradrenergic drug that is believed to be neutral for RLS.† |
| Nefazodone | This SNRI drug appears to have less serotonin effect than the others. It is not used very often due to its rare (1:300,000) side effect of liver failure. |
* Kim SW, Shin IS, Kim JM, et al. Bupropion may improve restless legs syndrome: A report of three cases. Clin Neuropharmacol 2005;28:298-301.
† Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep 2005;28:891-898.
Other than suspected dopamine antagonism, it is unknown what specific mechanisms exacerbate PLMS, although antidepressants, including both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have been implicated.15 Several reports have found increased PLMS associated with TCAs, SSRIs, and venlafaxine.40–42 Anecdotal reports also indicate that SSRIs and venlafaxine might exacerbate RLS.43–45 In contrast, bupropion might alleviate RLS symptoms with its dopamine agonist mechanism15,46,47 (see Table 28-2). Trazadone also might have beneficial effect on RLS.15,48 The effect of mirtazapine on RLS symptoms is unclear, because conflicting reports exist.49 Several anecdotal reports have reported that lithium can exacerbate PLMS or RLS symptoms.50,51
Another class of medications commonly prescribed by psychiatrists for sleep problems is antihistamines; however, centrally acting sedating antihistamines such as diphenhydramine could exacerbate PLMS and RLS and should be avoided.52
Treatment of Comorbid Restless Legs Syndrome and Psychiatric Disorders
Sometimes, alternate pharmacological classes can be used to avoid possible aggravation of RLS. In the treatment of mood disorders, especially for bipolar disorder, use of anticonvulsants (e.g., valproic acid) to stabilize mood is common. In general, anticonvulsants associated with pain relief ameliorate RLS symptoms. Gabapentin and carbamazepine are recommended second-line agents for the treatment of RLS53–56 (see Chapter 33). Valproic acid might also be helpful in reducing RLS symptoms.57
Often, psychiatrists will prescribe benzodiazepines and hypnotics to treat insomnia related to psychiatric disorders, because these medications have not shown to exacerbate PLMS. Studies that examined the effect of clonazepam on PLMS and RLS have not found a consistent reduction in PLMS58–62; patients instead reported a more restful sleep.63 Indeed, clonazepam has received only modest approval for treatment of RLS in evidentiary reviews55,56 and treatment algorithms.64 It may be more useful for milder RLS cases with disturbed sleep or as an adjunctive medication to dopaminergic treatment.64
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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
