Restless legs syndrome as side effect of second generation antidepressants
Introduction
Restless legs syndrome (RLS) is a common condition characterized by paresthesia and an urge to move. The lower limbs are primarily affected. Short-term alleviation is attained by moving the affected extremity or by walking. Predominantly, symptoms occur at rest and manifest themselves in the evening or at night. The diagnostic criteria for RLS were defined by the International RLS Study Group (Walters, 1995) in 1995 and modified in 2003 (Allen et al., 2003, Hening, 2004).
RLS as a side effect is ascribed to a number of drugs. The majority of publications focusing on this issue are case reports. There are reports on cimetidine (O’Sullivan and Greenberg, 1993), carbamazepine (Milne, 1992), lithium (Terao et al., 1991), zonisamide (Chen et al., 2003), caffeine (Lutz, 1978), olanzapine (Kraus et al., 1999), promethazine (Ekbom, 1960), pimozide (Akpinar, 1982), risperidone and haloperidol (Wetter et al., 2002), tricyclic AD (Yeragani et al., 1988; Ware et al., 1984), mianserin (Paik et al., 1989, and Markkula and Lauerma, 1997).
Several case reports are found in the literature on the provocation of RLS by “modern antidepressants (AD)” with specific receptor binding profile. One case was reported for each of the selective serotonin reuptake inhibitors (SSRIs) sertraline (Hargrave and Beckley, 1998), fluoxetine (Bakshi, 1996), paroxetine (Sanz-Fuentenebro et al., 1996), and citaloprame (Nader et al., 2007). A total of seven cases were documented for the noradrenergic-specific serotonergic AD (NASSA) mirtazapine (Agargün et al., 2002, Bonin et al., 2000, Teive et al., 2002, Bakh et al., 2002, Pae et al., 2004, Chang et al., 2006).
Some papers systematically focused on the relationship between AD and RLS. In a retrospective study (1998–2000), the possible association was investigated between AD and RLS in 200 patients with sleep onset disturbance (Brown et al., 2005). Of these 45% met the diagnostic criteria of RLS, 56% suffered from depression, and 38% were on AD. However, a statistically significant association between RLS and AD was not demonstrable.
Yang et al. (2005) studied the frequency of periodic limb movements (PLMs) in a prospective study of 274 patients referred to a diagnostic workup in a sleep laboratory and treated with AD. The patients included in this study were taking SSRIs, venlafaxine, or bupropion. Compared to the normal population, PLMs were markedly more frequently observed in the SSRI and venlafaxine groups, but not in the bupropion group.
A large epidemiologic study on the prevalence of RLS showed that SSRI intake is associated with an increased risk (odds ratio 3:1) of RLS (Ohayon and Roth, 2002).
Unlike all other studies, one paper (Dimmit and Riley, 2000) focused on the question of whether pre-existing RLS may be improved by SSRIs. Symptoms of RLS had existed before the start of the treatment in 65% of the participants. Of these, 70% experienced partial or complete relief of symptoms when treated with SSRIs. On the other hand, symptoms increased or new occurrence of RLS was observed in 21% of patients.
The literature review reveals a number of case reports suggesting that selective AD may trigger RLS. By contrast, the few systematic studies present contradictory results. Hence, the objective of this study was to determine by prospective observation whether and how often individual AD trigger or worsen pre-existing RLS. In addition, we were interested in the latency of RLS presenting as a side effect and whether the risk is affected by comedication such as benzodiazepines, antipsychotics, and tricyclic AD.
Section snippets
Patients and methods
Five psychiatrists working in four medical offices conducted the study in the course of 1 year. It was a prospective naturalistic trial focusing on the question of whether RLS developed as a side effect in patients initially treated with a “modern AD”. By definition, “initial treatment” meant that the patient had not received an AD for at least 3 months. All patients eligible with regard to inclusion and exclusion criteria were included in the study by the participating medical offices. Prior
Patients
Two hundred and seventy-one patients completed the study, 89 males (33%) and 182 females (67%). The dropout rate was 17% (excluding patients who discontinued treatment because of newly occurred RLS). The median age of the patients was 46 years; the youngest patient was 18 years of age, the oldest 87 years.
RLS as a side effect of AD
In 24 of 271 patients (9%) RLS appeared or worsened as a side effect of the AD treatment. RLS as a side effect occurred in all modern AD except for reboxetine. RLS was a common side effect
Discussion
The association between RLS, depression and AD is clinically relevant: frequently, patients with RLS suffer from depression or exhibit at least some depressive symptoms (Picchietti and Winkelman, 2005, Hornyak et al., 2005). Furthermore, RLS occurs more frequently among patients with depression or anxiety disorders (Picchietti and Winkelman, 2005, Winkelmann et al., 2005, Ohayon and Roth, 2002). Because RLS leads to sleep disturbances, it interferes with the severity and treatment of
Conflict of interest
There is no conflict of interest.
Contributors
There were no further contributors besides the authors.
Role of the funding source
There was no funding source.
Acknowledgement
We are grateful to R. John Leigh for critically reading the manuscript.
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