In this prospective study, we observed that women with RLS had a higher risk of developing both clinical depression and clinically relevant depressive symptoms. This association appeared to be independent of age, smoking status, physical activity, body mass index, history of several chronic conditions, sleep duration, and snoring.
There are several potential mechanisms that may underlie the association between RLS and risk of depression. Firstly, dopaminergic hypofunction is a common pathophysiologic thread linking RLS and depression, as well as the more severe hypodopaminergic condition of Parkinson's disease. RLS may be related to postsynaptic desensitization that overcompensates during the circadian low point of dopaminergic activity in the evening and night (1
). Dopaminergic mesolimbic and mesocortical systems are involved in anhedonia and lack of motivation, two core symptoms of depression (37
). In addition, RLS may increase risk of Parkinson's disease (38
), and depression is a common nonmotor Parkinson's disease symptom that can antedate the diagnosis of Parkinson's disease (39
); thus, a subset of participants with RLS and incident depression may be on an ultimate path toward Parkinson's disease. However, the hypothesized role of the dopaminergic system in the observed RLS-depression relation is complex and remains to be elucidated. Secondly, a common genetic cause for both RLS and depression could be a potential reason. In one recent study, Puschmann et al. (40
) observed a family of 5 generations; the 43 individuals displayed signs and symptoms of Parkinson's disease, RLS, essential tremor, or depression, and a considerable number of the affected persons had features of more than 1 of these disorders, implying a potential genetic cause within the family.
The third potential mechanistic link between RLS and depression may be the presence of clinical or subclinical vascular disease: RLS has been related to increased cardiovascular disease risk (11, 41
), and vascular factors are associated with clinical presentations of depression in older persons (43
). However, our results were unaffected by adjustment for these conditions, making this explanation unlikely. The fourth potential explanation is that because RLS is a bothersome chronic condition (44
), persons with RLS may have a distinctly impaired quality of life (1
). For example, it is common for persons with RLS to complain of fatigue, disturbed sleep, diminished concentration, and psychomotor agitation (4
). Thus, symptoms accompanying RLS may in turn lead to depressive symptoms and/or clinical depression in RLS sufferers. Furthermore, insomnia itself has been well established as a risk factor for incident depression (45
), and the sleep disruption common in RLS may predispose RLS patients to depression. In our study, adjustment for sleep duration and frequent snoring did attenuate the association between RLS and depression, implying that the RLS-depression association could be partly explained by the sleep disturbance. We cannot exclude the possibility that women who have been diagnosed with RLS may visit physicians more frequently than others and thus are more likely to have their depression ascertained. Persons with RLS may also be more likely to be diagnosed with depression by physicians attentive to the mental health consequences of chronic illnesses. However, we observed a similar significant association between RLS and increased depression risk in secondary analyses in which different diagnostic criteria for depression were used. Further, when we used the self-reported CESD-10 or GDS-15 score as the outcome, a similar result was seen. The similar significant results obtained using different definitions of depression suggest that our findings were robust. In order to reduce the bias of possible reverse causation, we reexamined the association between RLS and depression after excluding the incident cases occurring between 2002 and 2004, and found similar results.
Our findings are consistent with previous retrospective and cross-sectional observations (5
). However, the magnitude of the association between RLS and risk of depression observed in the current prospective analysis was smaller than the concurrent odds ratios in previous cross-sectional or retrospective studies, as was shown in the meta-analysis (relative risk = 1.5 vs. odds ratio = 2.3). This is consistent with the notion that retrospective studies and cross-sectional observations could lead to overestimation of the association (46
). It has been suggested that depression or antidepressant medication use may increase the risk of RLS (22, 47
). Using the prospective study design, we minimized the potential for reverse causation, although we cannot dismiss its existence altogether.
To our knowledge, this was the first prospective study to investigate the association between RLS and risk of incident depression. A key strength of our prospective approach is the ability to avoid recall and selection biases. Another strength is that we collected detailed information on lifestyle and chronic conditions using validated questionnaires, which enabled us to control for the potential confounders that may be associated with both RLS and depression, such as obesity, physical activity, and chronic diseases. However, because of the observational nature of our study design, we cannot exclude the possibility of residual confounding. Thus, we support interventional studies to assess whether treated RLS patients develop less depression than placebo-treated controls.
One limitation is that the RLS assessment in the current study was based on established physician diagnoses. The prevalence of RLS in US women ranges from 6.4% to 11.2%, based on the International RLS Study Group criteria (10, 11, 48
). Thus, the RLS prevalence in this study (2.4% before excluding women with depression or depression symptoms at baseline and 1.7% in the current sample) demonstrates the underdiagnosis of RLS. In a large-scale US study published in 2005 that included 16,202 adults aged ≥18 years, only 6.2% of the RLS sufferers (n
= 337) reported having received a diagnosis of RLS (49
). Similar results were seen in another survey conducted among 6 Western European countries: Only 9% of RLS cases (n
= 365) had been diagnosed previously (50
). Thus, although RLS was probably underreported in the present study, we could not interview individual patients, because that approach would have been unrealistic given our sample size. Misclassification of depression is another concern because of the possibility of low recognition of depression by physicians, undertreatment of depression, and use of antidepressant medication for indications other than depression. We tried to maximize the specificity of the case definition, accepting as incident cases of depression only women who reported both a diagnosis of depression and the use of antidepressants. This approach increased the specificity of diagnoses but decreased the sensitivity, which would have been more likely to weaken the observed associations. However, as long as the probability of correctly classifying women with an incident case of depression is independent of their diagnosis of RLS (nondifferential misclassification of outcome between women with RLS and women without RLS), the low sensitivity of this strict case definition should not bias relative risk estimates (51
In conclusion, in this large-scale prospective study, we found that the presence of physician-diagnosed RLS was associated with a higher risk of developing depression in women during 6 years of follow-up. Further studies using more precise diagnostic strategies for identifying RLS and depression in the community are warranted.