Restless Legs Tied to Suicide Even in the Absence of Depression

Pauline Anderson

October 25, 2018

Restless leg syndrome (RLS) is strongly linked to suicidal thoughts and behavior, even in the absence of depression, new research shows.

"Restless leg syndrome is not just some annoying thing; it's a real disease that causes real suffering," Brian B. Koo, MD, associate professor of neurology, Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News.

"Restless leg should not be taken lightly," he said.

Data from previous studies show that RLS is associated with cardiovascular disease and depression. "Now, we know it's associated with suicide attempts and suicide ideation," said Koo.

The study was published online October 11 in Sleep Medicine.

Low Iron?

RLS is a chronic sensorimotor disorder characterized by an unrelenting urge to move the legs, most often at night. It's not clear what causes the condition. Some studies have indicated an association with low levels of iron in the brain, and others have suggested that dopamine may play a role, said Koo.

He is currently conducting research to see whether stress hormones are involved.

The condition occurs more often in women than men, at a ratio of about 2 to 1, said Koo.

The new analysis included 192 patients (mean age, 51 years) with mostly moderate to severe RLS and 158 matched control persons.

The investigators assessed suicidal risks using the Suicidal Behavior Questionnaire–Revised.

The researchers assessed depression history using the validated Brief Lifetime Depression Scale. Participants were asked whether they had ever felt down, depressed, or hopeless for a period longer than 2 weeks.

RLS patients were more likely than control persons to have a lifetime history of depression (65.6% vs 22.8%) and were significantly more likely to have a lifetime history of having a suicidal plan or making a suicide attempt (27.1% vs 7.1%; P < .00001).

The odds of ever having had a suicide plan or attempt were almost threefold greater in those with RLS compared to the control persons (odds ratio [OR], 2.80; confidence interval [CI], 1.29 - 6.11), even after adjusting for lifetime depression, as well as for age, sex, race, marital status, education, income, and a history of drug or alcohol abuse.

"Having depression certainly increases your likelihood of having suicidal thoughts or behavior, but even when we included the variable of depression in the model, having RLS still was significantly associated with suicidal thoughts and behavior," said Koo.

The researchers assessed sleep latency and sleep quality in study participants. Insomnia and difficulty sleeping are well-known independent risk factors for suicidal behavior and suicide itself.

Neither of these sleep characteristics was significantly associated with the odds of having suicidal thoughts or behavior.

Disrupted Sleep

But Koo pointed out that the study "wasn't really designed" to assess the impact of these sleep parameters. Having seen many RLS patients in his practice, Koo is convinced that their "very disrupted sleep" likely is a contributing factor.

"These people are in bed and very tired and want to go to sleep, but they have this unrelenting urge and need to get up and walk around, which has got to be torture," he said.

The investigators assessed the use of medication for RLS, including dopamine agonists, gabapentin and other alpha-2-delta ligands, benzodiazepines, and opiates, and did not find a link to suicidal thoughts or behavior.

There has been a suggestion that side effects of these drugs might include suicidal behavior. Koo noted that clinicians "are beginning to move away" from using some of these medications because of adverse events.

The link between RLS and suicidality may have something to do with socioeconomic status (SES). The study population was mostly made up of those in the middle to higher SES class and was highly educated.

"Although the study was not designed to look at this, even when we inserted income and education as variables, they were not associated with suicide," said Koo.

The relationship could have something to do with personality traits such as impulsive behavior. It's also possible that something about RLS itself affects the brain and drives sufferers to think about and in some cases attempt suicide, said Koo.

RLS severity was assessed using the International RLS Study Group Severity Scale. Those who rated their RLS symptoms as severe or very severe had almost 2.5 times the odds of having had a suicide plan or attempt in their lifetime compared to those with milder RLS (OR, 2.36; 95% CI, 1.03 - 5.40; P < .05)

Koo and his colleagues conducted an analysis of patients with milder cases of RLS and found a similar association. However, the study did not include many of these patients with mild RLS, said Koo.

Future studies should include patients with mild RLS "to see if the association stands for them," he added.

The new findings are particularly relevant, inasmuch as the suicide rate in the United States steadily increased from 1999 to 2014.

Physicians should ask patients with RLS, especially severe RLS, about depression, said Koo.

If clinicians are unfamiliar with treating RLS, he advises that they "refer patients to someone who knows how to treat it."

Getting the Word Out

Commenting on the study for Medscape Medical News, John W. Winkelman, MD, PhD, professor of psychiatry, Harvard Medical School, and associate physician in sleep medicine, Department of Psychiatry, Massachusetts General Hospital, Boston, raised an issue regarding the fact that many of the patients in the study were recruited through the RLS Foundation.

"These are people who are more affected, more invested in understanding treatment and the disease process. So they may not be absolutely representative of the RLS population as a whole in the US," he said.

Winkelman noted that almost 85% of the RLS study participants had a history of augmentation, in which symptoms worsen when taking dopamine agonists. Dopamine agonists are first-line therapy; drugs such as gabapentin are second-line treatments; and opiates are third line, said Winkelman.

A "very small percentage" of RLS patients in the study received a second- or third-line therapy, he noted.

Although RLS is now better recognized than ever and physicians are generally aware of it, "most doctors still will not be knowledgeable about how to treat it, or if they are knowledgeable, it's kind of the first level of knowledge," said Winkelman.

"They know dopamine agonists are effective, but they're unaware that dopamine agonists can make the condition worse," he said.

"Patients with RLS have this chronic disorder, a lifetime disorder, that is very distressing and interferes with sleep, and the healthcare community has provided them with a drug that makes them worse," said Winkelman

"How does that leave them feeling in terms of their hopefulness, without the ability to control this disorder?" he commented.

Experts in the field "need to get the word out" to neurologists "who are unfortunately too comfortable" prescribing dopamine agonists, sometimes in inappropriate doses, said Winkelman.

He has started a national registry of RLS patients who take opioids; the registry now includes 350 patients.

He will be following these patients for at least 5 years and collecting information on suicidal ideation before and after starting an opiate. Even at 6 months, there has been a "dramatic" drop among these patients in their level of "abstract" and "concrete" suicidal thoughts, said Winkelman.

The study received no funding. Dr Koo has disclosed no relevant financial relationships. Dr Winkelman has participated in a clinical trial of an IV iron formulation for RLS from Luitpold Pharmaceuticals and has received funding from the RLS Foundation.

Sleep Med. Published online October 11, 2018. Abstract

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