Depressive symptoms are common in RLS/WED [35]. Frequently, the patients receive antidepressant treatment even before they receive treatment for RLS. Comorbidity between depressive disorders and RLS is common. However, the effect of antidepressants on RLS/WED symptoms is not clear. A prospective multi-center study involving different antidepressants resulted in 9% of the patients having RLS as a side effect [36]. Conversely, a chart review on 200 patients treated with a variety of antidepressants found no correlation between RLS and any of the antidepressant classes [37]. In another study 243 patients were interviewed before and after 6 months of treatment. The results indicated that antidepressant medications (tricyclic antidepressants and selective serotonin reuptake inhibitors) had no effect on the development of RLS symptoms [28]. However, when variables such as caffeine drinking and treatment with non-opioid analgesics were added, the patients who drank 5 or more cups of coffee a day and were on non-opioid analgesics did have an increase rate of RLS symptoms. A handful of studies suggest that antidepressants may affect RLS patients variably and the difference could be gender dependent [38, 39].

Even though the data on RLS is inconclusive at best, the data on periodic limb movements of sleep (PLMS) points toward a more definite effect. Several studies reported the occurrence of antidepressant dependent myoclonus [40–42].

Antidepressants can be divided into several groups that include tricyclic antidepressants, tetracyclic antidepressants, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxydase inhibitors, and others.

Tricyclic Antidepressants (TCA) are compounds with a typical three rings of atoms structure that increase the availability of serotonin and norepinephrine by inhibiting their uptake and may have minimal dopamine affinity. RLS/WED patients are frequently cautioned against the use of TCA, but the evidence-backed data relates to PLMS. The development of clinically significant myoclonus was reported in almost 10% (9 of 98) of patients receiving different TCA’s. Almost a third of the patients developed clinically insignificant myoclonus. The myoclonus persisted when the medications were not changed, but was reversed when TCA’s were discontinued [42].

Amitriptyline (Elavil, Endep, Tryptomer, Tryptizol, Laroxyl, Saroten, Sarotex, Lentizol) is a tricyclic antidepressant (TCA) that acts as a serotonin-norepinephrine reuptake inhibitor (SNRI), but does not affect dopamine reuptake. Amitriptyline was associated with RLS in men, but not in women [38]. It also increased PLMS when given to healthy males [39] However, another study found no increase in RLS symptoms with amitriptyline [28].

Nortrityline HCl (Pamelor, Aventyl, Sensoval, Norpress, Allegron, Noritrn, Nortrilen) is a TCA, the active metabolite of amitriptyline with adrenergic, anticholinergic, and antihistamine properties. There is one case reported on myoclonus induced by nortriptyline [43].

Imipramine HCl (Tofranil, Melipramine) is a TCA, a strong serotonin and norepinephrine reuptake inhibitor with dopaminergic and anticholinergic properties and a H1 antagonist. At therapeutic doses, there was one report of severe imipramine-induced myoclonus [44].

Desipramine (Norpramine, Pertofane) is a TCA that inhibits the reuptake of norepinephrine and to a lesser degree, serotonin. There is one case reported on desipramine-induced jaw myoclonus [45].

Clomipramine (Anafranil) is a potent serotonin and norepinephrine reuptake inhibitor. It is used to treat depression and obsessive-compulsive disorder (OCD). Increased PLMS was noted in two out of 21 patients with narcolepsy who were treated with clomipramine [46]. In another study, myoclonic movements have been observed in depressed patients receiving therapeutic doses of clomipramine [47].

Trimipramine (Surmontil, Rhotrimine, Stangyl) is a TCA, a weak norepinephrine, serotonin, and dopamine reuptake inhibitor and a strong histamine H1, serotonin 5-HT2, acetylcholine, and alpha1-adrenergic receptor antagonist; also a weak to moderate serotonin 5-HT1, alpha2 adrenergic and dopamine2 receptor agonist. It is used for its antidepressant, anxiolytic, antipsychotic, sedative, and analgesic effects. Patients who had PLMS before being treated with either imipramine or trimipramine had increased periodic limb movements index (PLMI) [48].

Maprotiline (Ludiomil, Deprilept, Psymion) is a TeCA, a strong norepinephrine reuptake inhibitor with weak serotonin and dopamine effects. It is used as antidepressant, anxiolytic, and sedative. Maprotiline was reported to induce myoclonus [49, 50].

Mianserin (Bolvidon, Depnon, Norval, Tolvon, Lerivon) is a TeCA, a norepinephrine reuptake inhibitor with serotonergic and antihistamine properties. It is used as an antidepressant, anxiolytic, hypnotic, antiemetic, antihistamine, and as an appetite stimulator. Mianserin-induced RLS was reported in two small case series [51, 52].

Mirtazapine (Remeron) is a TeCA with serotonergic and noradrenergic properties, is an antagonist or inverse agonist of the serotonin, adrenaline, dopamine, histamine, and acetylcholine receptors and is used as antidepressant, anxiolytic, hypnotic, antiemetic, and appetite stimulant. Mirtazapine has been consistently reported to provoke or deteriorate RLS in peer-reviewed data and on social websites. In a study looking at the effects of antidepressant medications, mirtazapine was recorded as provoking or deteriorating RLS symptoms in 28% of the patients, while other antidepressants affected only 5–10% of the patients [36]. Several studies and case reports noted mirtazapine-induced RLS symptoms [53–57] and some noted a worsening in RLS symptoms following treatment with mirtazapine [58, 59]. The mirtazapine-related RLS effects were improved or completely resolved with the discontinuation of mirtazapine, with a switch to a different antidepressant, such as bupropion, which seems to be “RLS protective” and with the addition of a dopaminergic in one study. In a well-controlled study, de novo mirtazapine at 30 mg (double the regular starting dose) was shown to result in increased PLMS in eight out of 12 young, healthy men. The distribution of the PLMS was similar to the distribution in RLS patients, but only three of the eight subjects reported any RLS-related symptoms. The presence of PLMS was attenuated on the second night and thereafter, suggesting rapid tolerance [60].

Monoamine oxydase inhibitors (MAOI) are preventing the breakdown of monoamine transmitters, increasing the availability of serotonin, melatonin, norepinephrine, and dopamine and are used for depression, panic disorder, posttraumatic stress disorder (PTSD), borderline personality disorder, and Parkinson’s disease.

Phenelzine (Nardil, Nardelzine) is a nonselective, irreversible MAOI affecting the breakdown of serotonin, melatonin, norepinephrine, and dopamine, and used as an antidepressant and anxiolytic. Several case reports noted phenelzine induced, sleep-associated limb movements that improved or resolved with reduction or cessation of treatment [61–63]. In a report of two cases, the limb movements started 6 weeks after treatment initiation [64].

Selegeline (Anipryl, l–deprenyl, Eldepryl, Emsam, Zelapar) is a selective irreversible MAO-B inhibitor used for PD, depression, and senile dementia. Selegeline is reported to decrease periodic limb movements in sleep [65]. The authors reviewed pre and posttreatment polysomnograms on 31 patients receiving selegiline for PLMS and reported a significant decrease in PLMI with no evidence of alerting effect on sleep efficiency or sleep onset latency.

Selective Serotonin Reuptake Inhibitors (SSRI’s) are compounds that inhibit the reuptake of serotonin, thus increasing the level of serotonin in the synaptic cleft, while having limited affinity for other receptors. SSRI’s are used to treat depression, anxiety, and personality disorders. They have slow onset of action and some of the side effects can take weeks to manifest. The SSRI’s have been associated with the serotonin syndrome, a life threatening drug reaction characterized by changes in mental status, hypertension, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, and tremor [66]. In addition, tremors, akathisia, and paresthesia are common side effects and it is important to differentiate these from RLS symptoms with or without PLM’s. One study reported that SSRI’s might have different effects on RLS symptoms [67]. In that report on 66 patients treated with SSRI, 43 patients who had a prior RLS history, claimed their RLS symptoms resolved, improved, or not changed, while among the 23 patients with no prior RLS history, two developed RLS. On social websites, only 0.3–0.4% report RLS symptoms as part of the side effects while on various SSRI’s. However, these symptoms tend to appear in the first 6 months and up to 10 years after treatment initiation, are more frequent in the 50 year and older group, tend to be within the severe range and tend to persist.

Fluoxetine (Depex, Prozac, Fontex, Seromex, Seronil, Sarfem, Ladose, Motivest, Flutop, Fluctin, Fluox, Depress, Lovan, Prodep) is one of the first SSRI’s to be approved for the treatment of major depression and remains a popular option. It can also increase plasma levels and half-life of antipsychotics, such as perphenazine. One case report noted fluoxetine-related RLS that was relieved 6 weeks after the drug was discontinued [68]. In a case series clinically significant periodic limb movement disorder (PLMD) was noted in four out of nine patients treated with fluoxetine [69]. In one case report, severe myoclonus developed 1-year after the initiation of treatment with fluoxetine and resolved with drug discontinuation [70]. In another case, myoclonus secondary to the use of trazodone and fluoxetine resolved when both medications were discontinued [71].

Paroxetine (Paxil, Aropax, Pexeva, Seroxat, Sereupin, Brisdelle) is one of the most potent and most selective SSRI used to treat depression, panic attacks, anxiety disorders, PTSD, and OCD. In one case report, RLS symptoms worsened by paroxetine [72] and in another were induced by it [73].

Sertraline (Zoloft, Lustral) is a SSRI and a dopamine reuptake inhibitor used for depression, OCD, panic attacks, and social anxiety disorders. Severe sleep-related movement disorder induced by sertraline was reported [74]. PLM and arousal indices seem to increase with sertraline, an increase that is dose dependent, but not associated with clinical symptoms [75]. One case reported on RLS worsened by sertraline [76]. In another case myoclonus developed 6 years after treatment with sertraline and methylphenidate and did not resolve by discontinuing sertraline [77].

Citalopram (Celexa, Cipramil) is a SSRI with minimal effect on norepinephrine or dopamine uptake and used to treat depression. One case reported on RLS being severely worsened by citalopram and relieved by bupropion [78].

Escitalopram (Lexapro, Cipralex, Citalin, Esitalo, Esto, Lexamil, Selectra, Sipralexa) is a highly selective SSRI used for the treatment of depression and anxiety disorder. One case report noted severe escitalopram-induced RLS that was relieved with discontinuation of the drug [79].

Duloxetine (Cymbalta) is a serotonin-norepinephrine reuptake inhibitor (SNRI) used for the treatment of depression and anxiety disorder as well as pain-associated disorders, such as osteoarthritis, neuropathies, and fibromyalgia. A review of patients treated with duloxetine among other second generation antidepressants in four neurology clinics showed increased reports of RLS symptoms as side effects [33].

Assessment of PLMS among 274 patients on antidepressants and 69 controls showed that patients on venlafaxine and on SSRI had significantly higher mean PLMI than control or bupropion groups [80]. De novo development of PLMS occurred in six out of eight volunteers on venflaxine [81]. In a case report, venaflaxine-induced RLS symptoms in a 44-year-old woman and the symptoms resolved after drug discontinuation [82].

Lithium (Eskalith, Lithobid, Cibralith, Lithane, Lithium Citrate) is a chemical element belonging to the alkali metal group. In a salt form it is used as a mood stabilizer by increasing serotonin, inhibition of inositol monophosphatase and interaction with nitric oxide and glutamate. Several case reports and a case series addressed the provocation or worsening of leg movements with or without RLS by lithium. In a case report of RLS induced by lithium, symptoms persisted even when lithium was discontinued [83]. However, in another case report, aggravated nocturnal myoclonus and RLS subsided when lithium was withdrawn [84]. A five case series and a case report noted the disappearance of lithium-induced nocturnal myoclonus with discontinuation of therapy [85] only to reoccur when lithium was reinstated [84].

Bupropion (Welbutrin, Budeprion, Prexaton, Elontril, Aplenzin, Zyban, Voxra) is an atypical antidepressant, dopamine, and norepinephrine reuptake inhibitor used in the treatment of depression and smoke cessation with possible effect on neuropathic pain. A double-blinded randomized controlled trial examined the effect of bupropion on RLS symptoms in 60 patients [86]. The results showed a decrease in the International Restless Legs Syndrome Study Group severity scale (IRLS Rating Scale) with bupropion that was significant at 3 weeks after treatment, but not at 6 weeks. A small case series showed that bupropion improved RLS symptoms in three depressed patients [87] A case report noted quick (3 days) resolution of RLS symptoms in a 45-year-old female presenting with chronic insomnia [88]. In a case series, bupropion SR treatment was associated with a reduction in measures of PLMD and an improvement in depression [89].

Trazodone (Desyrel, Oleptro, Beneficat, Deprax, Desirel, Molipaxin, Thombran, Trazorel, Trialodine, Trittico, Mesyrel) is an antidepressant, serotonin antagonist and reuptake inhibitor with anxiolytic and sedative effects. Trazodone was shown to improve polysomnographic parameters of sleep in patients with depression and increased PLMI [90].