Steven D. Targum, MD

The onset of some fatigue symptoms may suggest an emerging illness and often occurs as part of a medical and/or psychiatric disorder. Here are 5 key questions to ask as part of a comprehensive differential assessment of fatigue and depression.

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5 key questions to ask as part of a comprehensive differential assessment of fatigue and depression.

Which Came First: Fatigue or Depression?

This activity offers CE credits for:
1. Physicians (CME)
2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

To understand the connection between fatigue and depression and the extent to which residual symptoms of fatigue can lead to worsened outcomes.

At the end of this CE activity, participants should be able to:

• Understand the many causes of fatigue and its connection to MDD

• Identify and categorize fatigue symptoms associated with depressive episodes

• Differentiate fatigue symptoms related to MDD from those that are related to another psychiatric disorder or a medical condition, or those that result from medication adverse effects

• Describe the primary tools available to measure fatigue in depression

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Steven D. Targum, MD, reports that he is a grant recipient from Johnson and Johnson PRD, Sunovion, Pfizer Inc, Acadia Pharmaceuticals, Alkermes Inc, and Intracellular Therapeutics Inc; he has received research support from Bracket Global LLC; he is a consultant for Neurim Pharmaceuticals, Methylation Sciences Inc, and Resilience Therapeutics; and he is a shareholder in Bracket LLC, Prana Biotechnology Ltd, Methylation Sciences Inc, and Functional Neuromodulation Inc.

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Nearly everyone complains of fatigue at some point. Generally, these complaints reflect a transient lack of energy or motivation or are simply a reflection of a busy life. Most of the time, fatigue is not caused by an underlying disease. However, the onset of some fatigue symptoms may portend an emerging illness and often occurs as part of a medical and/or psychiatric disorder.

The term “fatigue” is generic and connotes many different meanings about symptoms across a wide range of physical, emotional, and cognitive domains. Consequently, a clinician needs more specific clinical information to address the possibility of an underlying disease that might warrant treatment.

Fatigue symptoms include a mix of lethargy, lassitude, muscular weakness or heaviness, daytime sleepiness, reduced motivation, and/or the inability to focus or concentrate. The subjective experience and perceived intensity of fatigue symptoms are influenced by social and cultural conventions as well as by an individual’s physical and emotional state. The perceived intensity of specific fatigue symptoms may be compounded by concurrent physiological, medical, or psychiatric conditions. In a general population survey of 18,000 people, more than 50% attributed their fatigue symptoms to psychological or nonmedical causes.

The etiology of fatigue can be as diverse as the range of symptoms. Among patients with MDD, symptoms of fatigue can present as part of the underlying depressive disorder. In fact, fatigue is one of the 9 component items that comprise the conventional diagnostic criteria for MDD. Thus, slowed speech, movement, and thinking; apathy; muscular weakness; lethargy; and lack of initiative are all specific fatigue symptoms that are commonly endorsed by patients during an acute depressive episode. In a survey of nearly 2000 depressed patients, 73% reported feeling tired, having no energy, and/or being listless during an acute major depressive episode.

Fatigue symptoms in depressed patients may also result from a comorbid disease or disorder (eg, obstructive sleep apnea [OSA], fibromyalgia, chronic obstructive pulmonary disease); a transient condition that is not related to any disease (eg, stress, lack of sleep); or an adverse effect of medication used to treat a medical condition or a depressive episode.

Regardless of the cause, fatigue symptoms can affect function, can exacerbate other symptoms of depression, and can contribute to the social or occupational difficulties experienced by many depressed patients. Effective treatment of fatigue symptoms may help ameliorate some of the depressive symptoms and thereby facilitate recovery.

Effective antidepressant treatment does not always resolve fatigue symptoms. Fatigue is a prominent residual symptom of recovering depression and is often associated with concentration difficulties, irritability, and reduced productivity. Patients recovering from depression who have residual symptoms of fatigue have more work and interpersonal difficulties and are at higher risk for relapse than patients without residual fatigue symptoms.

Mr. B, a 49-year-old college professor, has had recurrent MDD over the past 20 years with 4 distinct acute depressive episodes followed by periods of relative stability. Between episodes, he has been able to lead a productive personal and professional life. During each episode, he has had difficulty working and often withdraws from friends and family. Other acute depressive symptoms have included pervasive sadness, hopelessness, helplessness, pessimism, lethargy, physical and emotional fatigue, loss of interest in most activities, concentration difficulties, loss of appetite, and sleep problems (difficulty staying asleep and early morning awakening).

Mr. B has responded to antidepressant medications during each previous episode and has been able to return to his usual life. However, following the last episode, he had some residual symptoms that included concentration difficulties affecting his work performance and persistent sleep difficulties (intermittent awakening) that led to lethargy and sleepiness during the day. These residual fatigue symptoms have persisted despite antidepressant medication dose adjustments, medication changes, and drug-free periods. Given his lack of improvement, a more comprehensive assessment of the fatigue symptoms is indicated.

Each fatigue symptom needs to be identified and categorized, if possible, as either part of or distinct from the current, acute depressive episode. Therefore, the clinician needs to determine the timelines for the onset of fatigue symptoms relative to the onset of the current episode, the trajectory of response of specific fatigue symptoms to the treatment invention, and the persistence of fatigue symptoms following resolution of the depressive episode. The 

 suggests key questions to ask as part of a comprehensive differential assessment of fatigue.

Independent sleep disorders may overlap with depression and complicate assessment. The differentiation between sleep disturbances that are part of the core disorder of MDD (early morning awakening) and independent sleep disorders (eg, OSA) is essential in the assessment of fatigue. Moreover, hypnotic medications used to facilitate sleep at night (including antihistamines) may also exacerbate daytime fatigue or sleepiness.

Mr. B has had 4 documented acute major depressive episodes over the past 20 years, but there may have been other episodes that were not documented. Many things can happen over 20 years, including the emergence of other personal or medical issues that can generate symptoms of fatigue other than MDD. Hence, a comprehensive assessment of Mr. B’s residual symptoms of fatigue requires further inquiry about his personal and medical history. Besides his age, is anything different about this current acute depressive episode that distinguishes it from the others? Are there problems in his work or social life? Are there problems at home? Is he drinking too much alcohol? Is he drinking too much coffee? Has he gained a lot of weight? Does he have OSA or any other medical problems? Were any of these issues present before this current episode?

Mr. B had gained some weight over the past 20 years, but he was not considered overweight (his BMI was 25 mg/kg). However, he noted that he felt most tired in the morning, often had headaches, and was no longer the athletic man of his youth. Furthermore, his wife said that she occasionally was awakened by his gasping sounds while he slept, although she did not think his snoring patterns had changed. He was referred to a sleep specialist.

The objective of measurement is to reduce the ambiguity around the description of various fatigue symptoms and to provide a practical, standardized means to systematically measure clinical change over time. Numerous rating instruments have been developed to assess the presence and severity of fatigue symptoms in different clinical populations. The conventional, validated depression rating instruments used to assess MDD include questions about fatigue that represent only a part of the total assessment. In a busy clinical setting, it may be more practical to use a more concise global impression of the impact of fatigue symptoms on behavior and function that can be used visit to visit.

The clinician-rated clinical global impression of severity for fatigue scale (CGI-F) documents and assesses the impact of “targeted” relevant fatigue symptoms on a scale of 1 to 7 (with increasing severity) to yield a meaningful determination of the impact of fatigue symptoms on behavior and function (

 The CGI-F is not a diagnostic tool but can help gauge the effects of fatigue on function over time. The patient self-rated global impression of severity of fatigue scale lists an array of fatigue symptoms that allows patients to identify the relevant symptoms and score themselves accordingly.

A multimodal treatment plan is always a sensible strategy for patients with fatigue. Given that most fatigue symptoms are not caused by an underlying disease, it is best to start with non-invasive, health-promoting strategies such as better nutrition, exercise programs, reduced caffeine and alcohol intake, hydration, and better sleep hygiene. Some patients benefit from cognitive-behavioral techniques within the context of these other recommendations. It may seem a bit presumptuous for a busy clinician to prescribe rest and relaxation to his or her busy and stressed patient, but it is always worth an attempt. An exploration of current life stressors and schedules might lead to a more realistic reorganization of time and priorities.

Exercise in particular may improve depressed mood by reducing fatigue and increasing energy levels. Moderate exercise such as walking, yoga, or even dancing may be helpful if done with adequate intensity and often enough. However, most clinical studies that evaluated the effects of exercise on depression lacked methodological rigor, and more controlled, double-blind designs that include measurable but concealed exercise regimens are needed. Nonetheless, in their study of patients with MDD, Blumenthal and colleagues

 reported that exercise programs were almost as effective as antidepressant medications and that both were significantly better than placebo. Similarly, Trivedi and colleagues

 found that both high and low exercise regimens were useful adjuncts to SSRI treatment. In their study, it appeared that the higher-dose (more strenuous) exercise program was best for men but that the low-dose exercise group might have better long-term compliance.

Medical treatment for comorbid disorders and pharmacotherapy for specific fatigue symptoms may be appropriate depending on the findings of the clinical assessment. When indicated, pharmacotherapy needs to be introduced cautiously to avoid masking other sources of fatigue. Many fatigue symptoms respond to effective antidepressant treatment along with corresponding improvements in mood. Serotonin and dopamine are often implicated as part of the underlying central mechanisms that contribute to the experience of fatigue symptoms.

There are some practical recommendations to consider for pharmacotherapy for fatigue symptoms in MDD patients who are already taking antidepressant medications. First, it might be helpful to adjust the timing of the antidepressant doses to minimize adverse effects of the medication. Two secondary steps are to reduce the antidepressant dose (although the efficacy may be lost) or to switch to a different antidepressant with a lower likelihood to cause fatigue. Finally, the addition of adjunctive medications to restore energy and improve sleep must be considered.

Several adjunctive agents have been proposed to treat residual fatigue in patients with MDD. Some adjunctive treatment possibilities include psychostimulants, such as methylphenidate

; the dopamine transporter inhibitors modafinil or armodafinil

; norepinephrine reuptake inhibitors such as reboxetine9; as well as protriptyline and amantadine.

 reported that atomoxetine was also effective in reducing the residual fatigue symptoms associated with MDD. In their study, open-label atomoxetine added to SSRI therapy in patients with MDD led to a significant decrease on the fatigue item of the Hamilton Depression Rating Scale (

A polysomnogram revealed that Mr. B had OSA that may have exacerbated his fatigue, contributed to his mood disorder, and precluded his treatment response. Although OSA is often associated with obesity, it can occur in normal-weight individuals as well. An epidemiologic study of more than 9000 adults found that snorting, gasping, or loss of breathing while asleep was associated with feelings of failure and of hopelessness, as well as decreased energy and fatigue.15 In fact, this study found that people who snorted or stopped breathing at least 5 nights per week were 3 times more likely to have MDD than people who said they never snorted or stopped breathing during sleep.

Obviously, a comorbid medical disorder does not explain every case of inadequate treatment response. The key point is that each depressed individual has unique conditions that contribute to the illness. This case illustrates that the moderating and mediating factors that contribute to depressive episodes may change from episode to episode and must always be re-evaluated as part of the treatment plan.

Fatigue symptoms are common in everyday life but are also associated with psychiatric disorders, particularly MDD. Some of a patient’s identified fatigue symptoms may be part of the core illness of MDD, but others may be distinct from the disorder and require identification and separate treatment. The multiple causes of fatigue symptoms and the potential adverse effects of the drugs used to treat depression must also be considered in the assessment of symptoms and subsequent treatment.

Given the socio-economic consequences of persistent fatigue in patients with depression, targeting these symptoms regardless of their etiology must be part of the assessment and treatment plan. Serial measurement of fatigue symptoms can be as simple and practical as a single-item patient self-rated global severity score. A multimodal treatment strategy that starts with the least invasive methods (nutrition, rest, exercise) and leads to pharmacotherapeutic interventions as needed is generally the most sensible.

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Dr. Targum is Scientific Director of Bracket Global LLC in Boston, MA.

 Walker EA, Katon WJ, Jemelka RP. Psychiatric disorders and medical care utilization among people in the general population who report fatigue. 

 Regier DA, Myers JK, Kramer M, et al. The NIMH Epidemiologic Catchment Area program. Historical context, major objectives, and study population characteristics. 

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 Blumenthal JA, Babyak MA, Doraiswamy PM, et al. Exercise and pharmacotherapy in the treatment of major depressive disorder. 

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 DeBattista, Doghramji K, Menza MA, et al. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind placebo controlled study. 

 Fava M, Thase ME, DeBattista C, et al. Modanifil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. 

 Lam JY, Freeman MK, Cates ME. Modanifil augmentation for residual symptoms of fatigue in patients with a partial response to antidepressants. 

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 What's the connection between fatigue and depression, and to what extent can residual symptoms of fatigue lead to worsened outcomes? Insights here. 

Author | Steven D. Targum, MD

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