Restless Legs Syndrome Foundation Blog

Is Melatonin Right for You?

If you or a loved one are affected by restless legs syndrome (RLS), then you likely suffer from disrupted sleep. In fact, a person with moderate to severe RLS averages less than five hours of sleep per night, according to experts. Sleep deprivation is linked to many negative health effects, including depression, which can have a profound impact on a person’s day-to-day life.* Therefore, it makes sense to seek an intervention that may improve quality of life.

Many people who have difficulty sleeping turn to an over-the-counter supplement: melatonin. Melatonin is a naturally occurring hormone that is produced by the pineal gland in the brain to regulate the circadian rhythm, or the body’s internal clock. The release of melatonin is controlled by light. As daylight fades, usually one to three hours before bedtime, melatonin levels increase, which helps promote sleep. In the morning, the increase in daylight signals to the brain to halt melatonin production, aiding the transition to wakefulness.

More than 3 million adults take melatonin as a sleep aid, according to the National Center for Health Statistics. However, the effects of melatonin seem to vary; its effectiveness largely depends on the dose and timing of the supplement, as well as the sleep disorder being addressed.

Research on circadian rhythm sleep-wake disorders sheds light on the use of melatonin to improve sleep. According to the clinical guideline for treating these disorders (Auger, et al., 2015), studies have shown mixed results when administering melatonin to people whose circadian rhythm sleep-wake disorders stem from external alterations to their sleep cycles, such as shift work or jet lag. In one study, melatonin improved the length and quality of daytime sleep for people with shift work disorder in some, but not all participants. In another study of people with jet lag disorder, melatonin was more effective than the placebo for the first three days after traveling, but then lost its advantage. For circadian rhythm sleep-wake disorders that fall under the category of internal alterations in the timing of sleep, such as irregular sleep-wake rhythm, current data does not support the use of melatonin as a treatment. This may be relevant to RLS, since RLS follows a circadian pattern – that is, with most intense symptoms in the evening and nighttime hours. More research with a greater number of participants is necessary to determine the usefulness of melatonin across the board.

Nevertheless, melatonin may help one’s sleep schedule if taken at the right time and at the right dose. Typical doses of melatonin range from 0.5 mg to 5 mg. Higher doses should be avoided, even though there are many over-the-counter products available in doses as high as 10 mg. The best timing for most people is one to three hours before bedtime. It makes sense to consider melatonin as a potential option for a good night’s rest – but not necessarily for individuals with RLS; melatonin has been shown to trigger symptoms of RLS for some people. In a small study, researchers found a significant increase of sensory and motor symptoms of RLS when participants took melatonin compared to those who did not (Whittom, et al., 2010). Why is this?

Although RLS follows a circadian pattern, RLS is believed to be a sensorimotor disorder of the central nervous system. Research has shown that brain iron deficiency contributes to RLS, particularly within brain cells that contain the neurotransmitter dopamine. In terms of the sleep-wake cycle, dopamine is associated with wakefulness because it hinders the neurotransmitter norepinephrine, which then blocks melatonin release from the pineal gland. Because the human body operates under a system of checks and balances, melatonin also hinders release of dopamine in the central nervous system, thus creating a feedback loop. Since melatonin contributes to lower levels of dopamine, and lower levels of dopamine are associated with worsening RLS symptoms, some scientists suggest that melatonin may play a role in exacerbating RLS symptoms.

Another characteristic to note is that melatonin is serotonergic, which means that it is made from the same starting molecule (or building block) as serotonin – a neurotransmitter produced by the body that contributes to feelings of well-being and happiness. While serotonin’s role in regulating the sleep-wake cycle is complex, studies show that increases in serotonin reduce rapid eye movement sleep (REM sleep, the stage in sleep generally associated with dreaming) and can aggravate periodic leg movements of sleep. This is consistent with the fact that a common class of antidepressant medications that increase serotonin called selective serotonin reuptake inhibitors, or SSRIs, cause a worsening of RLS symptoms.

The bottom line is that melatonin may or may not help individuals sleep depending on many different factors. For people with RLS, it is important to know that taking melatonin comes at a risk of potentially aggravating symptoms. As always, you should to talk to your doctor before starting or stopping any treatment, even when they are marketed as naturally produced supplements.

*See Depression and RLS, available in the member portal at www.rls.org or by request.

Help, Hope and Treatment

By Brian B. Koo, MD

This is an excerpt from the fall 2018 edition of NightWalkers, the Foundation's quarterly magazine. To get your subscription to NightWalkers and to enjoy other benefits, become a member of the Restless Legs Syndrome Foundation today!

Individuals suspecting they may have RLS should consult a qualified healthcare provider. Literature posted by the RLS Foundation, including this blog post, is offered for informational purposes only and should not be considered a substitute for the advice of a healthcare provider. Prior to making any changes to your treatment plan, please discuss treatment options with your healthcare provider.

As anyone who has restless legs syndrome (RLS) knows, RLS can be incredibly disabling, especially when it is severe. Chronic sleeplessness and the recurring need to battle against RLS, night after night, can leave a person feeling helpless.

Helplessness and sentiments that the battle cannot be won, may then lead to hopelessness. Helplessness and hopelessness are both cardinal features of major depressive disorder, so it is no surprise that depression is quite common among those with RLS. In fact, between 40 and 60 percent of people with RLS suffer from a major depressive episode within their lifetime –more than three times the rate for people without RLS. Other anxiety and mood disorders are also common for people with RLS, including panic disorder, generalized anxiety disorder, and dysthymia, a type of near-constant, low-level depression.

If you are suffering from both RLS and depression, there is hope – both are treatable conditions. One possible key to treating your depression is to effectively treat your RLS. If your RLS symptoms are severe or uncontrolled, it is important to seek the care of a healthcare provider who is experienced in treating RLS. In short, this care includes:

• Eliminating factors that trigger RLS, such as alcohol, caffeine and certain over-the-counter and prescribed medications (for a comprehensive list, see the handout RLS Triggers, available at www.rls.org)
• Checking blood iron and ferritin levels, and offering iron therapy if appropriate
• Ensuring proper sleep hygiene
• Assessing for sleep apnea, which is critical if there are symptoms of snoring or breathing irregularities
• Treating RLS with medication

Of course, if depression is severe or persists even if RLS is controlled, it will be important to treat the depression with medication and/or psychotherapy. An experienced and qualified provider, preferably a psychiatrist, should provide this treatment. Simplistically, depression can be treated in three main paths: 1) healthy lifestyle, 2) psychotherapy and 3) pharmacotherapy (drug therapy).

A healthy lifestyle is essential for good mental health. This includes getting adequate aerobic exercise, eating a sensible diet, and engaging in regular social activity. Psychotherapy, whether from a psychiatrist, trained psychologist, social worker or simply someone with a good caring ear, is of utmost importance. Depression is very isolating, and sharing this experience with another person is an important step to ease the burden of isolation.

Finally, pharmacotherapy can also be extremely helpful. It should be noted, however, that pharmacotherapy will be most effective when combined with both psychotherapy and a healthy lifestyle. Medicine is by no means a silver bullet for treating depression, just as it is not a silver bullet for treating RLS.

Each of the potential therapies for depression requires active participation Brian B. Koo, MD from the patient. In addition to getting to the gym and out to social events, the patient should make the effort to find a psychotherapist, psychiatrist or someone with a good caring ear.

Choosing the right medicine to treat depression when one has RLS can be tricky, as many, if not most antidepressant medications can worsen RLS symptoms. This largely occurs through two different pharmacologic mechanisms: 1) by increasing serotonin levels and 2) by blocking histamine receptors.

Most antidepressant medications work by increasing availability of certain brain chemicals called neurotransmitters –particularly serotonin. Unfortunately, increasing serotonin worsens symptoms of RLS. One antidepressant, bupropion (Wellbutrin), works by increasing availability of the neurotransmitters dopamine and norepinephrine but not serotonin, so this antidepressant may be the first thing to try for treating depression in someone who has RLS. Of course, all medicines have side effects, and not all people with RLS will respond to bupropion or be free of side effects. It may be essential to try another antidepressant, even if it increases serotonin and has the potential to worsen RLS.

In general, histamine blockade medications, or antihistamines, are well known to make RLS worse. The prototypical medicine in this class is diphenhydramine (Benadryl). Many antidepressant medicines also have antihistamine-like qualities and should be avoided. These include mirtazapine (Remeron), doxepin (Silenor), amitriptyline (Elavil) and most other tricyclic antidepressants, with the exception of desipramine. These antidepressants are sedating; thus, a provider inexperienced in treating RLS may offer them unsuspectingly to the RLS patient, thinking that they will aid with sleep.

What I tell my patients is, if you are very depressed, even if a medicine may worsen your RLS symptoms, it is very important to treat your depression and try the medication if you’ve already explored nondrug treatments. You should not worry about whether or not the medicine will worsen your RLS. The selective serotonin reuptake inhibitors, or SSRIs, are commonly used antidepressants and can be very helpful, even for people who have RLS. The SSRIs sertraline (Zoloft) and citalopram (Celexa) may be a good start and are less activating, or stimulating, than fluoxetine (Prozac) or venlafaxine (Effexor), which may cause anxiety. In the end, individuals will have very different responses to different antidepressants, so you may need to try more than one medicine to find one that works for you.

When treating RLS with medications, another very important fact to keep in mind is that any medicine that blocks dopamine, particularly antipsychotic medications, should be avoided. Antipsychotic medications are often used by psychiatrists in addition to antidepressants, especially when a patient has insomnia, as antipsychotics are often sedating. These medications worsen RLS, so they should not be used to treat depression or sleeplessness when patients have RLS.

Both RLS and depression are treatable. Unfortunately for some, proper treatment steps are not taken because of problems with healthcare access or other issues. The most serious consequences of the undertreatment of depression are suicidal thoughts and of course, suicide itself. In a recent research study, “Suicidal Thought and Behavior in Individuals with Restless Legs Syndrome,” which was completed at Yale University and will be published in the journal Sleep Medicine, researchers found that 27.1 percent of people with RLS had either suicide plans or attempts over their lifetimes, compared to just 7.1 percent of age-, sex- and socioeconomically matched individuals without RLS (the control group).

The increased suicidal tendencies were not accounted for completely by the higher lifetime rate of depression, which was 65 percent in the RLS group and 23 percent in the control group. This suggests that there is likely something inherent to RLS that predisposes people to thoughts about and attempts at suicide. It should be noted that RLS was severe or very severe in about two-thirds of the RLS group, so this increase in suicidal thoughts and behavior may not apply to all people with RLS, especially if RLS is mild to moderate.

Most people in the RLS group who participated in the study are members of the RLS Foundation. I am very grateful to this community for your commitment to RLS research, and at the same time I have the utmost empathy for those of you who are indeed suffering with both depression and RLS.

Luckily, you have the RLS Foundation as a resource. If your RLS symptoms are not controlled, and especially if you are experiencing depression, please give real consideration to visiting the RLS Foundation Quality Care Center nearest to you. Controlling your RLS symptoms will go a long way toward improving mental health.

For those of you who are suffering with depression and suicidal thoughts, please seek psychiatric and psychotherapeutic care. If you are having thoughts of attempting suicide, please call the National Suicide Prevention Lifeline at 1-800-273-TALK (1-800-273-8255). You are not alone.

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No article written for general distribution can take into account individual differences or circumstances. Readers are encouraged to share this article with their health care providers and discuss any steps taking individual circumstances into account.

What You Need to Know

Depressive disorders are common in adults living with restless legs syndrome (RLS). In fact, the likelihood of developing depression with RLS is increased by 2-4 times when compared to other adults. While it is unclear exactly why this is, sleep disturbances and sleep deprivation are likely a contributing factor.

Indicators of depression include a low mood, diminished interests, feelings of worthlessness, weight gain or loss, fatigue or loss of energy, diminished concentration, insomnia or excessive sleepiness, mental/physical sluggishness or agitation, or thoughts of death. Many with RLS can feel totally alone in their struggle, especially during sleepless nights. If you are experiencing depression, you are not alone. There is help available.

The first step is to talk to your doctor about how you are feeling. (See our RLS Healthcare Provider Directory or Quality Care Center Network.) Fifty-eight percent of older adults think that "feeling blue" is a normal part of aging, but in fact it is not. These older adults often go untreated because they do not tell their healthcare providers about their symptoms, which can be triggered by chronic illnesses like RLS. It's important to assess the severity of the depression-related symptoms, and to consider whether poor sleep might be a significant factor. Treating the RLS before treating the depression can be beneficial, especially when depression-related symptoms are mild. However, patients with moderate to severe depression may need a different approach, which may include antidepressant medication.

It's important to note here that all antidepressants can worsen RLS symptoms. However, some RLS-safe alternatives include Desipramine (possibly), Nefazodone (may cause liver failure)*, Trazodone and Wellbutrin. Talk to your doctor about medication options to see what is best for you. Want to bring some RLS publications to your appointment? Email us and we will get you what you need.

In 2016, the RLS Foundation produced a webinar on RLS and depression featuring John Winkelman, MD, PhD, of Massachusetts General Hospital, a certified RLS Quality Care Center. Learn about the signs of depression, management strategies, and when to seek a professional opinion in this free webinar recording below.

While dealing with a chronic illness like RLS can sometimes seem fruitless, there are helpful and effective strategies for staying ahead of your depression. Talking about how you are feeling can be therapeutic and emotionally healing. RLS support groups are a safe environment that bring people together to share their experiences, coping strategies, and to build a community of care on which RLS patients and their families can depend. If there is not a support group in your area, all RLS Foundation volunteer support group leaders and remote contacts available via phone or email to provide support. Additionally, the Foundation's Discussion Board serves as a virtual support group, and is available 24/7 for those sleepless nights.

You have a treatable medical illness. There are resources available to you in every community including doctors, community agencies, clergy, and counseling centers. You are not alone.

If you are experiencing thoughts of suicide or self harm, call 911 immediately or visit your nearest emergency room.

*Note: The brand Serzone (nefazodone) has been discontinued but generic versions are still available. However, physicians must fully aware of side effects before prescribing.

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The Restless Legs Syndrome Foundation is a nonprofit 501(c)(3) agency that is dedicated to improving the lives of men, women, and children who live with this often-devastating disease. Founded in 1992, the Foundation’s goals are to increase awareness, improve treatments and through research, find a cure for RLS. The Foundation serves healthcare providers, researchers, 5,000 members and an estimated seven million individuals in the United States who have RLS. The Foundation has funded more than $1.6 million in RLS research.

An excerpt from the Summer 2016 edition of NightWalkers the Foundation's quarterly magazine. This piece is from the reoccurring column "In the News" by Lynn Marie Trotti, MD, MSc

Restless legs syndrome & depression: effect mediation by disturbed sleep and periodic limb movements.

Koo BB, et al. American Journal of Geriatric Psychiatry. April 2016.

Background:

Prior studies have shown that RLS and depression are associated, such that people with RLS are twice as likely as people without RLS to have depression at some point in their lives. The reason behind this relationship is not known, but a number of theories have been proposed (which are not mutually exclusive): 1) RLS and depression could share a common underlying cause; 2) depression medications may trigger RLS symptoms (which, in a cross-sectional study, could explain an association between depression and RLS); 3) sleep disruption from RLS could cause depression; or 4) periodic limb movements in sleep (PLMS) could cause depression. This study was designed to evaluate the latter three possibilities.

Research:

The researchers used data from the large Osteoporotic Fractures in Men (MrOS) study of elderly men, which has been used in multiple prior RLS studies. Included participants were evaluated for RLS and depression. Measures of PLMS and estimates of sleep quality were performed with in-home sleep studies and wrist actigraphy (a measure of activity), respectively. RLS was present in 17 percent of the 982 men. Those with moderate to severe RLS were most likely to be depressed, took the longest amount of time to fall asleep, had the most disrupted sleep, and had the greatest PLMS. The presence of moderate to severe RLS increased the likelihood of depression by about three times. Disrupted sleep accounted for some, but far from all, of the relationship between RLS and depression. Periodic limb movements moderated the depression-RLS relationship, such that people with RLS and PLMS had more depressive symptoms than those without RLS, but this effect was not seen in those with RLS without PLMS. People with RLS who were taking antidepressants had fewer depressive symptoms than people with RLS and depression who were not on medications.

Bottom Line:

The relationship between depression and RLS is mediated, in part but not exclusively, by the sleep disruption that accompanies RLS. The relationship between RLS and depression is apparent in those with PLMS, but not in those without PLMS. In people who are depressed, antidepressants are associated with fewer depression symptoms despite the presence of RLS (that is, having RLS does not appear to prevent an antidepressant benefit of medications).

New Questions:

Given that sleep disruption only partially explains the RLS depression relationship, what other factors are important?