Hochang Benjamin Lee, MD

Mental illness accounts for a third of all years lived with disability and is associated with twice the relative risk of all-cause mortality. It also contributes to other leading causes of death such as heart disease, cancer, and cerebrovascular disease. An estimated 8 million deaths are attributable to mental disorders every year, with two-thirds due to comorbid medical illness.

Medical and psychiatric conditions are often interdependent with complex relationships between them. Medical conditions can cause mental illness by way of psychological and/or physiological effects; mental illness may make it difficult to engage in medical care due to barriers to access, poor motivation, functional impairment, and the like; and many medical and psychiatric conditions share common psychosocial determinants (eg, adverse childhood experiences).

A 56-year-old man with schizophrenia, hyperlipidemia, and hypertension who smokes a pack of cigarettes a day presents to the emergency department (ED) with chest pain. The diagnosis is acute coronary syndrome; he is admitted and scheduled for cardiac catheterization with possible angioplasty. On admission, blood pressure and cholesterol medications are continued. However, the primary team is unaware of his recent increase in risperidone dose from 2 mg qhs to 2 mg bid and starts him on 2 mg qhs. Nicotine replacement is not discussed.

The patient becomes distressed and increasingly paranoid about blood work and cardiac monitoring; he refuses cardiac catheterization for two days, saying, “I’ll think about it and let you know tomorrow.” On hospital day 3, he accuses his nurse of trying to poison him and refuses all medications. Agitated, he demands an against-medical-advice discharge and pushes the nurse, prompting security involvement, physical restraint, and sedation.

The medical team orders a constant companion (ie, sitter) and consults psychiatry. The patient is psychotic when evaluated by the consultation-liaison (C-L) psychiatrist the following day and found to lack capacity to refuse medical care. The patient’s cardiac enzymes normalize with medical treatment instead of cardiac catheterization while the hospital pursues temporary conservatorship. The patient waits another three days until a psychiatric hospital bed becomes available. He is in the psychiatric wing of the hospital for several days when he once again has chest pain at rest, and he is promptly transferred back to a medical wing.

A 46-year-old woman with chronic PTSD and a general mistrust of authority figures is admitted to the hospital with hematochezia, hypotension, and concern about a lower gastrointestinal bleed. On admission, the patient is identified on chart review by a proactive C-L service because she has a major psychiatric diagnosis and a documented history of psychiatric hospitalization.

During a brief evaluation by a psychiatric social worker the morning of hospital day 2, the patient is hypervigilant and ruminates about an anticipated colonoscopy; the social worker recommends that the primary team order a psychiatric consultation. A C-L psychiatrist sees the patient that day, begins to develop rapport with the patient, and helps to establish basic principles of trauma-informed care. Feeling more comfortable with her treatment team and the outlined plan of care, the patient undergoes colonoscopy without delay or incident; she is referred for mental health aftercare for treatment of PTSD.

These two cases contrast how major mental illness might be managed on a hospital medicine unit supported by traditional reactive C-L psychiatry versus by a proactive C-L model (

). The first case illustrates difficulties in communication and managing psychiatric illness. Ultimately, the patient’s care was compromised, the providers were exasperated, and the system incurred greater costs. The second case illustrates the potential value of meeting psychiatric needs from the time the patient arrives at the hospital. A multidisciplinary team identified patient-specific concerns and facilitated communication, which resulted in safe and efficient care.

Currently, more than a dozen sites around the country, including academic medical centers (eg, University of Rochester, Yale, University of Pennsylvania, Johns Hopkins, Northwestern) and community hospitals (eg, Sarasota Memorial Hospital), have fully established or pilot proactive C-L psychiatry services.

Psychiatric comorbidity among medicine and surgery inpatients is high, yet roughly half of these conditions go unrecognized. Based on claims data, 1 in 3 hospital patients has a psychiatric diagnosis;

 however, more than half of the patients admitted for non-psychiatric admission may have a diagnosis of mental illness.

 SimiCof hospital patients have a mentalN health concern deserving clinical attention.

 Patients with active psychiatric conditions undergo more procedures, receive more consultations of any kind, have longer durations of hospital stay, and are more likely to be discharged to a facility rather than home. They are also more likely to leave against medical advice and to have higher utilization of hospital care and other health care resources after discharge.

Although medical complexity may explain a portion of the poorer outcomes observed in patients with psychiatric comorbidity, other factors contribute as well. For example, patients with mental illness may receive substandard medical care because of a provider’s implicit bias or both patient and provider stigma associated with mental illness.

Psychiatric comorbidity in the hospital is overlooked by primary teams more than half the time, and only one in five medical inpatients with psychiatric comorbidity is in outpatient mental health treatment at the time of acute hospital care.

 Psychiatric consultation offers several benefits including enhanced medication and psychosocial interventions. Moreover, patients may be more likely to engage in care after speaking with a psychiatric consultant, especially where psychological issues contribute to care refusal.

Psychiatric consultation can lead to shorter duration of hospital stay and consequently to financial savings. This effect may be more pronounced when consultations occur earlier during hospitalization. Consultations also facilitate outpatient mental health referrals, which may include psychiatric admission or discharge to another level of mental health care and might also reduce 30-day readmission rates.

Proactive C-L psychiatry provides the benefits of traditional C-L psychiatry while simultaneously enriching the care (

). At Yale New Haven Hospital, the C-L service conducted a pilot study of embedded care, which led to shorter durations of hospital stay; in this program, a psychiatrist rounded daily with a hospital medicine team and provided real-time consultation and advice.

 Subsequently, the Behavioral Intervention Team (BIT) was started as a multidisciplinary form of embedded care. This team engaged the full complement of floor staff, not just the primary medical team.

 Its goals were to identify patients with behavioral issues that could compromise medical care delivery; ensure timely psychiatric treatment; and assist with psychiatric disposition, aftercare, and sitter use.

The 11-month pilot was shown to shorten the duration of stay among patients receiving BIT care compared with patients who had received non-BIT psychiatric consultation a year earlier (6.7 days versus 7.3 days). Moreover, the mean duration of stay for all patients was statistically lower than it was the preceding year. Based on the most conservative models, the BIT service is cost-neutral, but when the cost savings attributable to shorter hospital stays and increased revenue from backfill are considered, a net cost-benefit was shown with a return on investment of nearly 2 to 1.7 BIT was also rated favorably by roughly 9 out of 10 nurses. The financial benefits and staff satisfaction led to an expansion of BIT to serve all medicine units at Yale New Haven Hospital.

As adoption of this model continues to expand, several adaptations of proactive C-L psychiatry have been initiated. A recent systematic review identified two features of proactive C-L psychiatry consistently associated with reduced duration of stay

: a screening process aided by clinical expertise in mental health care and integration of mental health providers with primary services.

Team-based proactive C-L vis-Ã -vis traditional C-L

How does team-based proactive C-L differ from traditional C-L?

 Team-based proactive C-L differs in three ways that derive from modern advances in outpatient mental health care: it proactively identifies patients who might benefit from psychiatric care, employs a collaborative approach, and delivers care using a multidisciplinary team. The first of these seeks to prevent a cascade effect of medical and psychosocial complications that can accumulate in patients with psychiatric disorders.

 The second incorporates insights gleaned from outpatient models of integrated mental health care (eg, as in the IMPACT trial). The third draws on the value of the medical teamwork approach.

How does proactive C-L psychiatry identify mental health needs?

 Rather than providing universal consultation as in some earlier models, which yields a high false-negative rate, proactive C-L psychiatry uses a multi-step process.

The first step aims to achieve selective prevention by identifying patients with or at increased risk of active mental health issues that may interfere with medical care.

 A team member reviews the electronic health record (EHR) of each patient newly admitted to specific units, looking for evidence of psychiatric comorbidity.

Two chart-review approaches have been implemented to date. The original strategy is to have a mental health provider (eg, psychiatric nurse practitioner, clinical social worker) review the History & Physical, Problem List, and home Medications sections, supplemented by a review of notes pertaining to prior mental health care. A recently developed strategy involves an automated EHR reporting tool to screen large numbers of patients across a health care system.

 The result of either strategy is the creation of a daily screening list.

The second step aims to achieve the indicated prevention: a team member, drawing upon their mental health expertise, screens patients on the list by discussing each patient with the patient’s nurse and with the primary care team to identify active mental health concerns. The C-L team social worker also may briefly evaluate patients in person to supplement this process.

One of the following outcomes is chosen for each patient: no change in care is recommended; curbside advice to the primary team is provided without consultation; or full psychiatric consultation is requested. The C-L team member then writes a brief screening note for each patient reviewed and documents that the patient was screened, why the screen occurred (ie, what in the chart prompted the screen), and what the result of the screen was, including any care recommendations.

 The core members of the team are a C-L psychiatrist, a psychiatric nurse practitioner, and a clinical social worker. The psychiatrist is the team leader who oversees clinical care, provides consultations and, as often required in certain jurisdictions and by hospital policies, performs capacity assessments and completes medicolegal forms (eg, involuntary psychiatric commitment). The psychiatric nurse practitioner is the team quarterback who serves as the primary contact for primary teams, triages inquiries and new consultations, performs consultations, and assists with chart reviews and screens. The psychiatric social worker-ideally one with experience in acute psychiatric settings such as inpatient psychiatry or a psychiatric emergency department-is the team coordinator and collaborates with the medical social worker and care management, commonly sees patients with the psychiatrist or psychiatric nurse practitioner, arranges psychiatric aftercare, and performs chart reviews and screens.

How is proactive C-L psychiatry integrated with medicine?

 The overarching element of integration with this model is that it fosters personal relationships between floor staff and C-L team members. The team-based multidisciplinary nature of this model allows for unique collaboration with corresponding providers on the medical unit: physician to physician, nurse practitioner to advanced practice providers and nursing staff, and social worker to social worker and care manager. This kind of multi-level interdisciplinary collaboration overcomes many systemic, referrer, and patient-specific barriers to accessing psychiatric care.

More than a dozen US hospitals have adopted a proactive C-L model. Over the past several years, interest in piloting this model across the country has been growing across the US. We are routinely solicited for information about the model and are increasingly working with institutions who have laid the preliminary groundwork and developed business plans in preparation for launching a proactive C-L program.

Questions remain about several aspects of potential value offered by this model of care, including reduction in cost of sitters, staff turnover, and 30-day readmission rates. Likewise, we need to understand the scope of potential benefits related to patient experience and outcomes, staff satisfaction, unit-based teamwork, work-life quality of care providers, and the culture shift that embraces the interconnectedness of medical and mental health.

The ongoing HOME study in the UK is a randomized hospital-based trial currently looking at the efficacy of proactive C-L psychiatry among older adult inpatients.

 Similar trials in the US are needed and would do well to consider different age groups, hospital settings, and patient mixes.

Proactive C-L is uniquely suited to tackle the Quadruple Aim of patient care: enhancing care experience, improving population health, reducing health care costs, and improving work life of health care providers.

 This model reaches more patients and delivers a broader-base of care to patients. It also offers the promise of comprehensive vertical integration with outpatient services.

Early evidence suggests that proactive C-L psychiatry can shorten the duration of hospital stays, which more than offsets the cost of providing this enhanced care. Perhaps most immediately evident to those who have worked within this model of care, is the near-unanimous satisfaction from medical and nursing staff. Ultimately, in this era of value-based care, team-based proactive C-L psychiatry is poised to enhance the overall value to patient care in the general hospital.

Dr Oldham is Assistant Professor of Psychiatry, Dr Chahal is Fellow, Consultation-Liaison Psychiatry, and Dr Lee is Professor and Chair of Psychiatry, University of Rochester Medical Center. The authors report no conflicts of interest concerning the subject matter of this article.

 Bourgeois JA, Kremen WS, Servis ME, et al. The impact of psychiatric diagnosis on length of stay in a university medical center in the managed care era. 

 Finn CT, Thakur D, Shea KM, et al. Electronic medical record reporting enhances proactive psychiatric consultation. 

 Desan PH, Zimbrean PC, Weinstein AJ, et al. Proactive psychiatric consultation services reduce length of stay for admissions to an inpatient medical team. 

 Hansen MS, Fink P, Frydenberg M, et al. Mental disorders among internal medical inpatients: prevalence, detection, and treatment status. 

 Callaghan P, Eales S, Coates T, Bowers L. A review of research on the structure, process and outcome of liaison mental health services. 

 Sledge WH, Gueorguieva R, Desan P, et al. Multidisciplinary proactive psychiatric consultation service: impact on length of stay for medical inpatients. 

 Sledge WH, Bozzo JE, White-McCullum BA, Lee HB. The cost-benefit from the perspective of the hospital of a proactive psychiatric consultation service on inpatient general medicine services. 

 Oldham MA, Chahal K, Lee HB. A systematic review of proactive psychiatric consultation on hospital length of stay. 

 Sells D, Sledge WH, Wieland M, et al. Cascading crises, resilience and social support within the onset and development of multiple chronic conditions. 

 Rosen MA, DiazGranados D, Dietz AS, et al. Teamwork in healthcare: key discoveries enabling safer, high-quality care. 

 Desan P, Zimbrean P, Lee H, Sledge W. Proactive psychiatric consultation services for the general hospital of the future. Summergrad P, Kathol R, Eds. 

Integrated Care in Psychiatry: Redefining the Role of Mental Health Professionals in the Medical Setting

Reducing Risks for Mental Disorders: Frontiers for Preventive Intervention Research

. Washington, DC: National Academy Press; 1994.

 ISRCTN Registry. The HOME Study: A Study Comparing Two Different Ways of Looking After Older People in Hospitals to See if We Can Improve How Quickly They Go Home. 2018. 

 Bodenheimer T, Sinsky C. From triple to quadruple aim: care of the patient requires care of the provider. 

Articles

Mental illness accounts for a third of all years lived with disability and is associated with twice the relative risk of all-cause mortality. An estimated 8 million deaths are attributable to mental disorders every year, with two-thirds due to comorbid medical illness.

Collaborative Care Meets Hospital Medicine: Proactive Consultation-Liaison Psychiatry

Depression is a frequent psychiatric comorbidity among patients with restless leg syndrome (RLS). When reading the case below, consider the following question: If an untreated RLS patient presents with depressive symptoms, what would you treat first?

Lisa is a 45-year-old married woman who came to see a psychiatrist initially for depressive symptoms. During the initial evaluation, she complained of difficulty in falling asleep and other depressive symptoms such as low mood, difficulty with concentration, poor appetite, and low energy along with daytime fatigue. Depression was diagnosed. An SSRI was prescribed on an as-needed basis, and the patient was advised to take a nightly dose of diphenhydramine to help her sleep.

Three days later-after staying up nearly all night-Lisa called her doctor in despair and complained of worsening insomnia. On more detailed questioning about the insomnia, Lisa revealed that for the past 2 years, she has experienced leg discomfort when she gets into bed. She is so uncomfortable that she needs to walk or ride on her exercise bike past 2 or 3 am until the discomfort subsides. While not painful, this leg discomfort sometimes prevents her from relaxing and watching television because she just “has to move” her legs.

Lisa describes a deep uncomfortable sensation that feels like “bugs crawling in her legs.” She also reveals that her mother used to suffer from similar nighttime leg restlessness. For the past 3 nights, Lisa’s leg discomfort has been more intense and has lasted most of the night.

After secondary causes of RLS, such as iron deficiency anemia, pregnancy, uremia, and neuropathy, were ruled out, a diagnosis of RLS was made. SSRI and diphenhydramine therapy were stopped. Low-dose dopamine agonist therapy was started, after which the symptoms subsided. However, despite resolution of the RLS symptoms, her depressive symptoms continued. Titrated bupropion was given until the depressive symptoms fully resolved.

The case vignette illustrates the importance of evaluating for RLS symptoms in patients with major depressive disorder who complain of insomnia.

The diagnosis of RLS is made after identifying the presence of 4 cardinal features and excluding other causes:

1. An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs

2. The urge to move or unpleasant sensations that begin or worsen during periods of rest or inactivity, such as lying or sitting

3. The urge to move or unpleasant sensations that are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues

4. The urge to move or unpleasant sensations that are worse in the evening or night than during the day or only occur in the evening or night

Symptoms that mimic RLS include leg cramps, positional discomfort, neuroleptic-induced akathisia, peripheral neuropathy, arthritis, anxiety, claudication of the legs, and peripheral vascular disease.

 Because a diagnostic biological marker for RLS is not available, the standard for diagnosis remains a clinical one based on the patient’s subjective complaints and history.

 Case adapted from an article by Hochang Benjamin Lee, MD: 

Diagnosis and Treatment of Restless Legs Syndrome in Psychiatric Practice

. It is posted here with permission and input from the author.

National Institute of Neurological Disorders and Stroke, Restless Legs Syndrome Fact Sheet 

Dr Lee is Director of the Psychological Medicine Service at Yale New Haven Hospital and Associate Professor of Psychiatry at Yale University School of Medicine in New Haven, Conn.

1. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. 

 2003;4:101-119.
2. Buchfuhrer MJ.Strategies for the treatment of restless legs syndrome. 

 Earley CJ. Clinical practice. Restless legs syndrome. 

Depression is a frequent psychiatric comorbidity among patients with restless leg syndrome. The case presented here illustrates the importance of evaluating for RLS symptoms in patients with major depressive disorder who complain of insomnia.

Depression and Restless Legs Syndrome

The number of coronary artery bypass graft (CABG) surgery patients affected by depression ranges between 

 discusses the Neuropsychiatric Outcomes After Heart Surgery (NOAHS) study and implications for treatment and research of post-CABG depression. Dr Lee is Director of the Psychological Medicine Service at Yale New Haven Hospital and Associate Professor of Psychiatry at Yale University School of Medicine in New Haven, Conn.

(1) Depression is associated with higher morbidity and mortality among CABG surgery patients

(2) Screening and treatment of depression among CABG surgery patients could lead to improved quality of life and reduction of depression-related morbidity.

(3) Symptoms and course and post-CABG depression share several features with late-onset, vascular depression

(4) A NIH-funded study based on Vascular Depression Hypothesis is under way to identify patients at high risk for depression after CABG surgery to develop prevention strategies for post-CABG depression

Depression, anxiety, and cardiac morbidity outcomes after coronary artery bypass surgery: a contemporary and practical review

Discussing the Neuropsychiatric Outcomes After Heart Surgery study, testing the vascular hypothesis of post-coronary artery bypass graft depression.

NOAHS Study: Testing Vascular Hypothesis of Post-CABG depression

After reading this article, you will be familiar with:



• Pathogenesis of restless legs syndrome (RLS)
• Comorbidity of RLS and psychiatric disorders
• Treatment options for RLS in patients with psychiatric disorders



Who will benefit from reading this article?


Psychiatrists, geriatric psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals. To determine whether this article meets the continuing education requirements of your specialty, please contact your state licensing and certification boards.

Restless legs syndrome (RLS) is a neurosensory disorder first described by Sir Thomas Willis in 1672. As early as the 19th century, Theodor Wittmaack

 observed the comorbidity of RLS with depression and anxiety. He termed this condition “anxietas tibiarum” and believed it to be a form of hysteria.

Once thought to be rare, data now suggest that RLS is relatively common but underrecognized and undertreated.

 Several clinical and population-based studies have reported a high prevalence of psychiatric comorbidities-particularly depression and anxiety-in patients with RLS.

 Thus, for psychiatrists, understanding the clinical features and treatment of RLS has become critical in their daily practice. The symptomatic overlap between RLS and mood disorders and the potential impact of psychiatric medications on RLS symptoms make RLS a diagnostic and treatment challenge.

This article provides an overview of the clinical features of and treatment strategies for RLS. It also offers a survey of the current literature on issues in the diagnosis and treatment of RLS among psychiatric patients.

The case vignette illustrates the importance of evaluating for RLS symptoms in patients with major depressive disorder (MDD) who complain of insomnia.

The RLS diagnosis and epidemiology workshop at the NIH established 4 criteria for diagnosis of RLS

1. An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs

2. The urge to move or unpleasant sensations that begin or worsen during periods of rest or inactivity, such as lying or sitting

3. The urge to move or unpleasant sensations that are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues

4. The urge to move or unpleasant sensations that are worse in the evening or night than during the day or only occur in the evening or night

A diagnostically supportive but not essential feature of RLS includes a history of the disorder in first-degree relatives. A polygenetic disorder with its phenotype contributed by a number of variants, RLS is a highly familial trait with heritability estimates of about 50%.

 Recent linkage studies in families with RLS revealed several loci but have not led to the identification of disease-causing sequence variants.

Another supportive diagnostic feature is a history of positive response to dopaminergic therapy, such as levodopa (L-dopa) or a dopamine receptor agonist.

 Periodic limb movements during sleep (PLMS), although not specific to RLS, occur in at least 80% of RLS patients and correlate with clinical ratings of RLS severity.

 While polysomnography or actigraphy evidence of PLMS is not necessary for diagnosis, PLMS supports the diagnosis of RLS and provides an objective, indirect measure of RLS severity.

 In more severe cases, symptoms of RLS occur during the daytime, disrupting restful activities such as sitting or trying to nap. Ascertaining the degree of interference with daytime activities may provide a measure of RLS severity.

The diagnosis of RLS is made after identifying the presence of the above-mentioned 4 cardinal features and excluding other causes of symptoms that mimic RLS, such as leg cramps, positional discomfort, neuroleptic-induced akathisia, peripheral neuropathy, arthritis, anxiety, claudication of the legs, and peripheral vascular disease.

Nocturnal leg cramps (“charley horse”) are often mistaken for RLS; the former is usually the result of the painful contraction of a single muscle in the leg that can be relieved through stretching. During muscle cramps, the muscle bulk is prominent and the associated sharp pain is easily distinguished from RLS sensations.

Patients with peripheral neuropathy commonly report numbness, burning, and pain that are superficially felt in the skin. Although these sensory symptoms can increase at night, they are usually present throughout the day, and complete relief is not obtained by sustained movement or walking. Peripheral vascular disease or claudication is generally associated with pain during walking and relieved when sitting or lying down. Arthritis pain is centered in joints and is relieved by rest. Nei-ther peripheral vascular disease nor arthritis is associated with the circadian pattern characteristic of RLS.

Once thought to be rare, data now suggest that RLS is relatively common but under­recognized and undertreated. Several studies have reported a high prevalence of depression and anxiety in patients with RLS. 

Neuroleptic-induced akathisia is a whole-body sensation; there is no pronounced circadian pattern and no insomnia. Usually, movement provides no relief, and prior exposure to neuroleptic medication is easily established. Hypotensive akathisia is a feeling of restlessness, which may be localized in the legs when an individual with orthostatic hypotension sits still; the restless feeling should not occur when the patient is supine and it does not have a circadian pattern, unlike RLS.

Positional discomfort occurs after prolonged sitting (but not lying) in the same position and is usually relieved by a simple change in position. For some people who fidget, movements of their feet are volitional-especially when they are bored or anxious. Their movements are not associated with discomfort or an urge to move as in RLS, and their volitional movements lack a circadian pattern.

RLS is usually idiopathic. As noted, however, RLS can be secondary to other medical conditions.

 A high prevalence (greater than 20%) of RLS has been reported in studies based on clinical populations with a variety of medical conditions, such as iron deficiency, pregnancy (particularly during the third trimester), rheumatoid arthritis, and uremia secondary to end-stage renal disease.

 In secondary RLS, the initial treatment strategy should focus on addressing the underlying medical condition.

Several neurological disorders have also been reported to be associated with RLS. RLS may be common among patients with Parkinson disease and both disorders respond to dopamine therapy.

 Studies have also demonstrated that subtle nerve damage (eg, peripheral neuropathy) is more common among patients with late-onset RLS.

 RLS is frequently comorbid with other neurological conditions, such as multiple sclerosis, Charcot-Marie-Tooth disease type 2, cryoglobulinemic neuropathy, and spinocerebellar ataxia. Lower back pain, myelopathy, and arthropathy have been reported to be associated with RLS as well.

After secondary causes of RLS are ruled out, the initial treatment strategy should focus on sleep hygiene measures.

Exercise and hot baths around bedtime are frequently effective in treatment of mild RLS. If medication is necessary, the American Academy of Sleep Medicine evidence-based practice parameter guidelines list dopaminergic agents as the first line of treatment.

Second-line treatment options are opioids, benzodiazepines, and specific anticonvulsants (such as gabapentin and carbamazepine).

Nonergot dopamine agonists such as pramipexole, ropinirole, and rotigotine have been found effective in double-blind studies.

 In fact, 2 dopamine agonists, pramipexole and ropinirole, are the only medications that are approved by the FDA for treatment of moderate to severe RLS. The maker of rotigotine-another dopamine agonist delivered through a transdermal patch-filed for approval to market the drug for RLS. However, rotigotine was recently recalled in the United States and some European countries because of problems with the delivery mechanism.

Ergot-derived agonists, such as bromocriptine, pergolide, and cabergoline, have also been found to be effective in treating RLS.

 However, potentially serious adverse effects, such as heart valve abnormality, limit their use. Generally, treatment with dopamine agonists should start with the lowest dose possible followed by slow titration. Adverse effects-including nausea, orthostatic hypotension, dizziness, and daytime somnolence-should be monitored carefully.

(L-dopa) is also effective in treating RLS.

 Until nonergot dopamine agonists were available, (L-dopa) was the most popular pharmacological agent, particularly for intermittent symptoms, because of its rapid onset of action. However, long-term treatment of RLS with (L-dopa) is frequently associated with augmentation and rebound. Augmentation refers to the clinical phenomenon of earlier onset, increased severity, or involvement of other parts of the body with RLS symptoms.

Unlike long-term complications of (L-dopa)–induced dyskinesia in patients with Parkinson disease, augmentation usually resolves with cessation of (L-dopa) in patients with RLS. The rebound effect causes increased restlessness at night or in the morning as the dose wears off, or as tolerance to the drug builds up. While the risk may be less with dopamine agonists than with (L-dopa), augmentation has been associated with dopamine agonists.

Opiates, particularly oxycodone, are considered second-line agents for patients with moderate to severe RLS.

Because of concerns about the risk of opioid dependency, sedation, and exacerbation of sleep apnea, opiates have been primarily prescribed for RLS patients who cannot tolerate dopaminergic agents. Among opiates, codeine is considered to have the least abuse or dependency potential and has been reported to be effective in treating RLS.

The efficacy of the anticonvulsant gabapentin has also been demonstrated in controlled studies, and a prodrug of gabapentin-gabapentin enacarbil-is in the FDA pipeline with an indication for RLS treatment.

In controlled trials, efficacy has also been reported for other anticonvulsants, such as carbamazepine and valproic acid, but these are rarely prescribed.

Previous clinic-based studies reported a high prevalence of comorbidity between RLS and depression or anxiety disorders.

 used a structured psychiatric measure, the Munich–Composite International Diagnostic Interview for 

, to assess psychopathology among 130 RLS patients. Compared with 2265 community residents, those with RLS had an increased risk of having panic disorder (odds ratio [OR], 4.7; 95% confidence interval [CI], 2.1 to 10.1), generalized anxiety disorder (OR, 3.5; 95% CI, 1.7 to 7.1), and MDD (OR, 2.6; 95% CI, 1.5 to 4.4) over a 12-month period.

Several population-based studies have reported increased rates of anxiety and depression in patients with RLS.

 Data from the Baltimore Epidemiologic Catchment Area study showed strong associations between RLS and MDD (OR, 4.7; 95% CI, 1.6 to 14.5) and panic disorder (OR, 12.9; 95% CI, 3.6 to 46.0) among 1024 community residents over 12 months.

The underlying cause for the high prevalence of comorbidities between RLS and depression is unclear. Certainly, symptomatic overlap exists between MDD and RLS because RLS can trigger or exacerbate at least 4 of the 9 depressive symptoms listed in 

 Dysphoria, insomnia or excessive sleepiness (particularly during the day), decreased concentration, fatigue or loss of energy, and psychomotor retardation are common among RLS patients. Alternatively, an underlying shared pathophysiological mechanism between RLS and MDD might be responsible for the comorbidity.

Many studies have established the role of dopaminergic pathology in RLS.

A recent systematic review supported a role for diminished dopaminergic neurotransmission in major depression based on the following evidence

• Diminished dopamine release from presynaptic neurons or impaired signal transduction has been implicated.

• Animal models of depression have shown considerable responsiveness to dopamine neurotransmission.

• Several studies have shown reduced concentration of dopamine metabolites in cerebrospinal fluid and in brain regions that mediate mood and motivation.

• Neuroimaging studies have shown reduced dopamine transmission and compensatory up-regulation of D2 receptors.

In fact, bupropion, which has proven efficacy in the treatment of depression, acts, at least in part, by promoting dopaminergic function. Several clinical trials recently reported a potential role for dopamine agonists-the first-line agents for RLS-in managing treatment-resistant depression or bipolar depression.

Potential associations between other psychiatric disorders and RLS have been reported recently. Several studies found that RLS and PLMS are common among children or adults with attention-deficit/hyperactivity disorder (ADHD).

 It is still unclear whether sleep disruption from RLS rather than RLS itself is associated with ADHD-like symptoms of restlessness, overactivity, and inattention. High rates of RLS-like symptoms in patients with schizophrenia

Because RLS and psychiatric disorders are frequently comorbid, give careful consideration when choosing a medication for RLS in a patient with a psychiatric disorder. Many psychiatric medications can affect RLS symptoms. However, other than a number of case series or anecdotal reports, few studies have examined the direct effects of psychiatric medications on RLS symptoms, although several have examined the effect of these medications on the severity of PLMS. While PLMS occur in at least 80% of RLS patients and correlate with RLS severity, it is unclear whether medication effects on PLMS can be used to infer the effect of psychiatric medicine on RLS.

Predictably, all typical antipsychotics with dopamine receptor blocking properties exacerbate PLMS.

 Commonly used antiemetics, such as metoclopramide, promethazine, and prochlorperazine, also exacerbate RLS symptoms because of their dopamine receptor blocking properties. With their lower binding affinity for the dopamine D2 receptor, newer atypical antipsychotics are less likely to exacerbate PLMS. However, exacerbation of RLS-like symptoms with olanzapine

 has been reported. Insufficient data are available about effects of clozapine, quetiapine, and ziprasidone on RLS or PLMS. Aripiprazole, a partial dopamine agonist, theoretically might have a favorable effect on RLS symptoms, but a systematic study is needed.

Although it has been suggested that various tricyclic antidepressants (TCAs) and SSRIs exacerbate RLS or PLMS, the specific mechanisms are unknown.

 In contrast, bupropion, a dopamine agonist, might alleviate RLS symptoms.

 The effect of trazodone and mirtazapine on RLS symptoms is unclear.

Given the effects of these medications on RLS symptoms, it is important to screen for RLS symptoms before starting antidepressant therapy. For a patient with severe RLS and mild depressive symptoms, it is reasonable to treat RLS first to see whether improvements in sleep and energy lead to resolution of depressive symptoms. When treating depression in patients with severe RLS, consider trying a non-SSRI or non-TCA (eg, bupropion) first. Keep in mind that there are no comparative studies of the efficacy and safety of bupropion and SSRIs in comorbid depression and RLS.

In the treatment of mood disorders, especially bipolar disorder, anticonvulsants (eg, valproic acid) are commonly prescribed to stabilize mood. In general, anticonvulsants that are associated with pain relief ameliorate RLS symptoms. Gabapentin and carbamazepine are second-line agents in the treatment of RLS, and valproic acid might also be helpful in reducing RLS symptoms.

While anecdotal reports of RLS induced by lithium exist, no systematic study has tested the effect of this agent on PLMS or RLS symptoms.

Benzodiazepines and hypnotics are often prescribed to treat insomnia related to psychiatric disorders; these medications have not been shown to exacerbate PLMS. Among them, clonazepam is preferred over short-acting benzodiazepines for the treatment of anxiety and insomnia in patients with RLS because of its longer half-life. However, studies that examined the effect of clonazepam on PLMS and RLS did not find a consistent reduction in PLMS; patients instead reported a more restful sleep.

Antihistamines are commonly taken for sleep problems. However, certain drugs in this class, including diphenhydramine, can exacerbate PLMS and RLS and should be avoided.

Dopamine agonists and psychiatric symptoms

In randomized, double-blind, placebo-controlled trials of pramipexole or ropinirole for RLS treatment, none of the participants treated with dopamine agonists experienced neuropsychiatric symptoms. Use caution when interpreting the clinical safety data because the RLS treatment studies have systematically excluded patients with psychiatric comorbidity. Therefore, clear data do not exist on the potential neuropsychiatric adverse effects of dopamine agonist treatment of RLS in patients with comorbid psychiatric disorders.

Dopamine agonist treatment of Parkinson disease has been associated with hallucinations, delusions, confusion, and mania.

 Lower recommended doses of dopamine agonists seem less likely to induce psychotic symptoms in RLS patients without psychiatric comorbidity. However, the potential for inducing or exacerbating behavioral symptoms in RLS patients with psychiatric disorders from dopamine agonist therapy cannot be ignored.

 have also been associated with dopamine agonist treatment of Parkinson disease and, to a lesser degree, RLS. Therefore, those clinicians who treat RLS in patients with impulse-control disorder or affective disorders (eg, bipolar disorder) should be aware of the potential for initiating or exacerbating impulsive behavior or mood symptoms.

Another problematic adverse effect of dopamine agonist treatment of Parkinson disease is daytime somnolence. Sleep attacks (ie, sudden and overwhelming sleepiness without awareness of falling asleep), particularly while driving, have been described in patients taking dopamine agonists and represent a serious public safety issue.

 Therefore, dopamine agonists should be prescribed and titrated with caution, especially for older patients who have RLS, to reduce the adverse effect of daytime somnolence.

RLS is a common treatable disorder, closely associated with depression and anxiety in both clinical populations and the community. Given the potential impact of various psychiatric drugs on RLS symptoms, medications need to be chosen judiciously to avoid exacerbating RLS symptoms. As more patients with psychiatric disorders receive a diagnosis of RLS and are treated with dopamine agonists, uncommon, yet problematic psychiatric adverse effects related to pharmacotherapy for RLS may develop. Future systematic studies are warranted to guide the optimum treatment of RLS in patients with psychiatric conditions, particularly depression and/or anxiety.

[Note: The above artice is an expired CME and is here for informational purposes.]

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Restless legs syndrome (RLS) is a neurosensory disorder first described by Sir Thomas Willis in 1672. As early as the 19th century, Theodor Wittmaack observed the comorbidity of RLS with depression and anxiety. He termed this condition “anxietas tibiarum” and believed it to be a form of hysteria.

Author | Hochang Benjamin Lee, MD

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