Which antidepressive agent is associated with the lowest risk of developing restless legs syndrome?

Fråga: Which antidepressive agent is associated with the lowest risk of developing restless legs syndrome?

Sammanfattning: There are many reports in the literature asserting serotonergic antidepressants induce RLS; but the evidence is limited and the quality of the available evidence varies.

In a small study, bupropion was shown to improve RLS symptoms. Bupropion may thus be useful for the treatment of patients with both depression and RLS.

Svar: Restless legs syndrome (RLS) refers to symptoms characterized by complaints of a strong urge to move the legs during periods of rest. The symptoms are relieved by movement. Terms that patients use to describe the symptoms include crawling, creeping, itching, or stretching, all localized to deep structures rather than the skin. RLS may be a primary or a secondary condition. Causes of secondary RLS include iron deficiency, chronic kidney disease, pregnancy, and various medications including certain antidepressants, antipsychotics, dopamine-blocking antiemetics, and centrally-acting antihistamines. Alcohol, tobacco, excessive caffeine intake and sleep deprivation also may aggravate or trigger symptoms in some individuals (1).

Dopamine deficiency or dopamine dysfunction has been implicated as one of the factors involved in the pathophysiology of RLS. This is supported by an observed improved condition after treatment with levodopa and dopaminergic agents such as pergolide, pramipexole, and ropinirole (2).

Various antidepressants particularly those that affect serotonergic systems, have been reported to exacerbate symptoms of RLS (3,4,5). A large epidemiologic study (19000 patients) on the prevalence of RLS and associated factors showed a threefold increased risk of RLS for persons taking SSRI, but not for other types of antidepressants (5).

The possible biological explanation is an effect on dopamine levels. Antidepressants that block serotonin transporters block the reuptake of serotonin into serotonin neurons. This excess serotonin can be carried by dopamine transporters into dopamine neurons in the brain striatum, thus decreasing the amount of dopamine released. The decrease in dopamine could lead to increased RLS symptoms (6).

In a prospective naturalistic study of 271patients, RLS was recorded as treatment emergent adverse event during antidepressants therapy. The frequency was 2-10% among patients treated with selective serotonin-reuptake inhibitors, SSRIs (citalopram, escitalopram, sertraline, paroxetine, and fluoxetine) and serotonin- and noradrenaline-reuptake inhibitors, SNRIs (duloxetine and venlafaxine). Twenty eight percent (15/53) of patients treated with mirtazapin reported RLS symptoms. Interestingly the symptoms abated in half of the patients during continuous antidepressant treatment. In contrast, no case occurred during the use of the selective noradrenaline-reuptake inhibitor, NARI, reboxetine (n=25). This made the authors suggest the use of reboxetin as being safe (4). The non-randomized design and the small size of the study prohibited any causative conclusions.

On the other hand, the norepinephrinedopamine reuptake inhibitor NDRI, bupropion is an antidepressant that modulates dopaminergic systems and has been reported to have neutral to beneficial effects on RLS.

In one small case series, a low dose of bupropion (150 mg sustained-release) improved RLS symptoms in 3 depressed patients within a few days of the initiation of treatment (8).

Furthermore, one study concluded that at least bupropion does not exacerbate the symptoms of RLS and could be a reasonable choice if an antidepressant is needed in individuals with RLS. This was a double-blind randomized controlled trial in patients with depression which compared the effect of 150 mg sustained-release bupropion daily (n=29) with placebo (n=31) on the symptoms of RLS. Participants who took bupropion had significant symptom improvement at 3 weeks compared with those who received placebo (9). However, the study failed to show a statistically significant difference between the two study groups at 6 weeks since the placebo group reported some additional improvement in RLS symptoms at 6 weeks.

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