How often are you faced with patients who come to you with “I’m exhausted,” “I have no energy,” “I’m dragging,” or “I can’t stay awake”? If you’re like most psychiatrists, you see this often, and at times simply giving a sleep aid is an unsatisfying or ineffective solution.

Up to one half of the general population, and one of every five patients seeking medical care, report fatigue (Walker EA et al, J Gen Intern Med 1993;8:436–440). Typically, fatigue is transient or self-limiting or can be explained by circumstances. In some cases, however, it can be persistent and debilitating. When faced with a patient presenting with fatigue, we must consider: Is this part of a larger medical problem? A psychiatric problem? A side effect of medication? Sleep deprivation? Or just part of regular life in the 21st century?

Fatigue and excessive sleepiness can affect the physical, psychological, social, and economic well-being of our patients. There can be negative effects on motivation, concentration, mood, memory, productivity, and even public safety (anyone remember Chernobyl or the Exxon Valdez?).

In this article, we’ll break down the best way to evaluate patients with fatigue and discuss the causes and treatments for this condition.

Initial Assessment
For starters, it’s important to distinguish between sleepiness and fatigue. Sleepiness is the decreased ability to stay awake or alert, while fatigue is a sustained exhaustion and decreased capacity for both physical and mental tasks. Although sleepiness usually is relieved completely by rest, fatigue may not be. Those with fatigue wake up tired even after a full night’s sleep and remain tired.

The first step in managing the patient with excessive fatigue or sleepiness is appropriate screening. Patients’ subjective complaints can be supplemented with objective measures like the Epworth Sleepiness Scale (ESS, which can be found at http://epworthsleepinessscale.com) and the Fatigue Severity Scale (FSS, which is available several places online, including: http://bit.ly/wgWePz), short questionnaires that can be self-administered in your waiting room. These tests measure daytime sleepiness and the impact of fatigue on daily activities, respectively.

Medical Causes of Fatigue and Sleepiness
As with much that we see in psychiatry, medical causes of fatigue must be ruled out. Fatigue can be caused by infections such as Epstein-Barr virus, HIV, Lyme disease, diabetes, anemia, iron deficiency (with or without anemia), malignancy, hypothyroidism, fibromyalgia, multiple sclerosis (MS), heart failure, chronic obstructive pulmonary disease (COPD), and renal or hepatic failure. Other causes include the still poorly understood chronic fatigue syndrome (CFS), which will likely be subsumed under the controversial Complex Somatic Symptom Disorder (CSSD) heading in the new DSM-5.

While fatigue may go away with the successful treatment of some of these underlying illnesses (eg, hypothyroidism), it may persist even with adequate treatment of many others—HIV, diabetes, Lyme disease, anemia, fibromyalgia, and malignancy to name a few. Lab work-up should include a complete blood count (CBC); metabolic panel; total iron-binding capacity (TIBC) and serum ferritin; sedimentation rate; thyroid function; and, with symptoms of mononucleosis, EBV titers. Screening for tuberculosis, HIV, or hepatitis may also be considered.

For excessive sleepiness, the most common cause is usually self-induced sleep deprivation: in a nutshell, going to bed too late and waking up too early. Many sleep experts recommend seven to nine hours of sleep for adults, although some experts have found lower mortality rates with six to seven hours a night (Kripke DF et al, Arch Gen Psychiatry 2002;59:131–136). Those who get less sleep than that should be educated on good sleep hygiene (http://bit.ly/ntoplM).

If the duration of sleep seems long enough and yet the patient complains of excessive sedation, one possible culprit is impaired sleep quality. Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness. OSA affects 2% to 5% of women and 3% to 7% of men, and an astonishing 41% of obese individuals (Park JG et al, Mayo Clin Proc 2011;86(6):549–555). Other causes of excessive daytime sleepiness are narcolepsy, shift work, jet lag, restless leg syndrome (RLS), or periodic leg movement disorder (PLMD), so a detailed history is essential.

Psychiatric Causes
Patients with depression commonly present with nonspecific aches and pains, sleep disturbances and fatigue. Although successful treatment of depression and other depressive disorders such as postpartum depression, dysthymia, and seasonal affective disorder may improve fatigue, some patients may continue to experience residual symptoms, including fatigue. Anxiety disorders, eating disorders and somatoform disorders can also cause fatigue.

Medication Effects
What some patients call “fatigue” may in fact be “sleepiness” as a medication side effect or the result of substance abuse. Alcohol, CNS depressants, marijuana, opioids (including Suboxone), as well as withdrawal from stimulants, can cause sleepiness and fatigue. A large number of other medications can cause sleepiness and fatigue. These include antihypertensives, statins, analgesics, antihistamines, and interferon. Changing medications should be considered, when possible, if medication is suspected as the cause for fatigue or sleepiness.

For psychotropic medications, strategies to consider include choosing less sedating agents such as bupropion (Wellbutrin) instead of mirtazapine (Remeron), or aripiprazole (Abilify) instead of quetiapine (Seroquel); or dosing sedating medications primarily at bedtime. Drug-drug interactions should also be considered. Multiple CNS depressants will have additive pharmacodynamic effects—think alcohol and benzodiazepines—and don’t forget about metabolic interactions, too. Be sure to watch out for medications from other prescribers, such as TCAs, gabapentin (Neurontin), or muscle relaxants.

Managing Fatigue and Sleepiness
Even after other causes have been identified and addressed, some patients will have persistent complaints. For these, stimulants such as dextroamphetamine and methylphenidate and other wakefulness promoting agents like modafinil (Provigil) and armodafinil (Nuvigil) may be considered, as well as some non-pharmacologic interventions.

Stimulants promote wakefulness, reduce fatigue and improve mood, at least acutely, by increasing synaptic dopamine. Methylphenidate and amphetamine have been used for decades in anergic patients with depression, and even longer to promote wakefulness (eg, in World War II). Use for depression is supported only by anecdotal experience, open label trials, and published case series. A systematic review of the only two published placebo-controlled studies failed to establish efficacy of stimulant augmentation in depression; however, fatigue and apathy were improved in the short term in those who received stimulants (Candy M et al, Cochrane Database Syst Rev 2008;16(2):CD006722). So when you consider using a stimulant to counter fatigue and apathy, don’t necessarily expect it to directly enhance overall mood. Side effects include appetite suppression, insomnia, irritability, as well as risk for dependence and abuse.

Modafinil (and its close cousin armodafinil) also promote wakefulness. Their mechanism of action is not entirely clear, but seems to involve the sleep/wake center in the hypothalamus rather than the dopamine reward pathway. These agents are approved for use in narcolepsy and other sleep disorders characterized by excessive daytime sleepiness, which include OSA and shift work sleep disorder. Modafinil’s potential benefits in patients with depression as well as fatigue and sleepiness were investigated in two randomized controlled trials (DeBattista C et al, J Clin Psychiatry 2003;64:1057–1064; Fava M et al, J Clin Psychiatry 2005;66–85–93). These studies showed that, when added to an SSRI, modafinil (100 mg/day to 400 mg/day) improved fatigue and alertness after two weeks, but was no better than placebo by studies’ end for improving depression or for reducing fatigue and sleepiness, except in those with the most extreme fatigue (Fava M et al, Ann Clin Psychiatry 2007;19:153–159). Another controlled study found no benefits of modafinil (200 mg/d and 400 mg/d) in non-depressed patients with chronic fatigue (Randall DC et al, J Psychopharmacol 2005;19(6):647– 660). Modafinil is generally well tolerated and it has relatively low abuse potential; however, its possible beneficial effects on fatigue and sleepiness may not be sustainable beyond a couple of weeks. And, it should be noted, this is a very expensive drug, coming in at $500 or more per month for the 200 mg daily dose. Longterm safety is also unknown. The most common side effects include headache, nervousness, irritability, and insomnia.

Non-pharmacologic interventions should always be considered when managing patients with persistent fatigue or sleepiness. Individualized patient education should be provided to target the specific cause, which could include sleep hygiene in sleep-deprived patients or compliance with CPAP use in patients with OSA.

Cognitive behavior therapy (CBT) should be considered in patients with chronic fatigue. In recent controlled trials, 70% of CFS patients who received 13 to 16 sessions of CBT improved their functioning compared to 20% to 27% of those assigned relaxation or usual care (Deale A et al, Am J Psychiatry 2001;158:2038–2042). Some have suggested dietary supplements, vitamin and mineral complexes (eg, essential fatty acids, magnesium, liver extract, B vitamins) to reduce fatigue in patients with fibromyalgia or CFS, but controlled studies have been negative or inconclusive. Alternatively, studies of physical interventions, particularly graded exercise therapy, and psychological interventions (especially CBT) suggest that these may be most effective. In fact, improvements from CBT appear to be sustained over six to 14 months of follow-up and even as long as five years.

TCPR’S VERDICT:
Fatigue and sleepiness are extremely common complaints and, in some patients, may be debilitating. Fatigue is most often a symptom of a medical or psychiatric disorder, or CFS, while sleepiness is more often a consequence of inadequate sleep, poor sleep quality or the effects of medication. Identifying and appropriately addressing the cause is key, but may or may not alleviate the patient’s fatigue or sleepiness. In persistent fatigue, there is limited evidence to support the short term use of stimulants or modafinil. For more chronic management, consider non-pharmacologic approaches including graded exercise therapy and CBT.