Fatigue is a very common physical complaint. What therapeutic options are available?
TALES FROM THE CLINIC
In this installment of Tales From The Clinic: The Art of Psychiatry, we visit a very common physical complaint, fatigue, that often accompanies depressive disorders. The etiological aspects of fatigue, mental or physical, are difficult to disentangle and treatment remains elusive. In this article, Drs Khan and Ukrani walk us through therapeutic options and, most importantly, how to think of this ubiquitous presentation to best help our patients.
“Ms Riley” is a 35-year-old woman with diagnoses of systemic lupus erythematosus (SLE) and recurrent major depression. She began coming to our clinic to continue care after the retirement of her former psychiatrist, whom she had been seeing for several years. She has been treated with numerous antidepressants for her depression but continues to have persistent symptoms—particularly fatigue—with remission hard to obtain. Her previous psychiatrist added aripiprazole to help with these persistent symptoms. She reached her best period of stability with a combination of vilazodone, aripiprazole, and buspirone.
She is married with 2 young children and had postpartum depression after both of her pregnancies. Although her marriage is stable overall, she and her husband had some strain around finances and the chronicity of her symptoms, which had previously led to hospitalizations for suicidal ideation. She is employed as an accountant, but her fatigue makes it difficult to stay on top of her work and meet deadlines. Her depression is relatively well controlled from a mood standpoint but there was discussion between the patient and her various specialists as to whether this fatigue was related to her lupus or was a residual symptom of her depression.
Treatment of Fatigue in Depression
Although we can often achieve response in patients with major depressive disorder (MDD), remission is a more difficult target, and many patients continue to have residual symptoms. Fatigue, while being a ubiquitous symptom across a variety of illnesses, is one of the most common residual symptoms of depression and overlaps with anhedonia, decreased energy, and other depressive dimensions. It can impact physical, cognitive, and emotional functioning; impact school and work performance; disturb social and family relationships; and increase health care utilization. Patients with MDD who have persistent symptoms of fatigue are substantially more likely to develop active depressive symptoms again despite continued treatment. Therefore, it is essential to recognize these symptoms and intervene as soon as possible.1,2
An article by Baldwin and Papakostas describes strategies to address fatigue including using antidepressant medications that are less likely to induce or exacerbate fatigue symptoms; using antidepressant medications that are more likely to resolve the fatigue symptoms; and using adjunctive treatments to target residual fatigue and sleepiness in MDD patients specifically.3
For the first approach, this would mean avoiding medications with greater reported rates of fatigue or tiredness as an adverse effect (eg, tricyclic antidepressants, mirtazapine, duloxetine, and trazodone) in favor of those that are less sedating. Some options that may have better outcomes with fatigue include selective serotonin reuptake inhibitors (SSRIs), bupropion, alternate serotonin-norepinephrine reuptake inhibitors (SNRIs) and norepinephrine reuptake inhibitors (NRIs) like venlafaxine or reboxetine, agomelatine, tianeptine, and monoamine oxidase inhibitors (MAOIs). Although data is limited, some representative studies include those on fluoxetine, reboxetine (not available in the United States), and bupropion. Fluoxetine, in a study by Judge et al, showed greater efficacy than placebo in resolving retardation factor scores, and this was also shown in elderly patients with depression.4 In a pooled analysis, bupropion was more effective than placebo and SSRIs in resolving hypersomnia and fatigue. In this same analysis, SSRIs did not separate from placebo with regards to hypersomnia but did appear more effective in resolving fatigue.
Finally, pharmacologic augmentation strategies may be used to treat residual fatigue. Bupropion is also a viable augmentation strategy. Stimulants have been shown to be effective in a small case series by Masand et al,5 and atomoxetine has been shown to be helpful in improving remission rates and reducing fatigue. The evidence has been mixed for improvement with modafinil, specifically with hypersomnia and fatigue, but more consistent for improvement in overall depression remission.3,6
Treatment of Fatigue in SLE
SLE is an autoimmune disease that causes widespread inflammation and tissue damage in affected organs. Patients with SLE may experience various symptoms that include fatigue, skin rashes, fevers, and pain or swelling in the joints. Some patients will have flares of their symptoms interspersed with periods of remission, while others will have more persistent symptoms.7
Patients with SLE often report fatigue as a significant and debilitating symptom but the etiology remains poorly understood due to its likely multifactorial explanation. There have been conflicting findings about the link between disease activity and amount of fatigue, the dimensions of which include general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue; all of these are elevated in patients with SLE.8 In a multivariate analysis, disease activity, disease damage, and the presence of fibromyalgia significantly correlated with physical fatigue and were independent contributors.8 However, disease-related factors were not found to be significant predictors of mental fatigue. Investigators also found that 23% of their patients had clinically significant depressive symptoms and this depressed mood was associated with worse physical and mental fatigue. In the analysis, it was a stronger determinant of mental fatigue but correlated with both. They also found that impaired sleep and less exercise participation contributed to increased fatigue.
Yuen and Cunningham9 published a systematic review on the optimal management of fatigue in patients with SLE. They identified 9 strategies to reduce fatigue in patients with lupus: psychosocial intervention, exercise, diet changes, vitamin D, N-acetylcysteine (NAC), dehydroepiandrosterone (DHEA), belimumab, ultraviolet-AQ (UVA-1) phototherapy, and acupuncture.
For psychosocial interventions, they found that nearly half of patients with SLE report ongoing distress over time. There is an association between distress and fatigue, and thus patients may benefit from psychosocial interventions. These interventions include cognitive behavioral therapy, psychoeducation, counseling, psychotherapy, and biofeedback to decrease the disease's interference with daily activities, as well as to improve interpersonal relationships, social support, self-efficacy, and stress-coping skills. Yuen and Cunningham reviewed several studies related to exercise with the premise that, because physical inactivity is associated with fatigue, increasing activity would logically improve fatigue. The exercise programs' primary goals were to improve exercise tolerance, aerobic capacity, perceived physical function, and fatigue. Similarly, nearly half of adults with SLE are obese. Obesity is independently associated with impaired functional capacity and inflammation markers in patients with lupus. If patients lose weight, they may improve their functional capacity.10
Many of the treatments for SLE can impact vitamin D metabolism and place patients with SLE at risk of a vitamin D deficiency. However, the evidence for a correlation between vitamin D deficiency and fatigue is mixed. N-acetylcysteine (NAC) serves as an inhibitor of autoimmune inflammatory processes and is an amino acid precursor of glutathione. Some data suggests that patients with SLE have low levels of glutathione and may then benefit from NAC supplementation. In the studies reviewed by Yuen and Cunningham, doses of 2.4 and 4.8 g/day showed significant improvement in fatigue but the 4.8 g/day dose was not as well tolerated.9
Data also suggests that patients with SLE have lower mean serum levels of 5-dehydroepiandrosterone (DHEA), an androgen with immunomodulatory properties, which might relate to increased fatigue. Belimumab is a monoclonal antibody that modulates B-lymphocyte stimulator protein and inhibits its activity. Patients with SLE have high stimulator protein levels and are correlated with changes in disease activity. UVA-1 phototherapy has emerged as a potential adjuvant therapy for SLE, while acupuncture is a treatment option for SLE patients who have fatigue-related pain and do not want to rely on medications to control pain.
In sum, Yuen and Cunningham found weak evidence not meeting the minimal clinically important difference (MCID) threshold in the various studies for psychosocial interventions, dietary changes, vitamin D supplementation, and acupuncture; no effect from DHEA; and weak-to-moderate effect in 1 small pilot randomized controlled trial (RCT) with UVA-1 phototherapy. NAC was found to have moderate benefit in 1 small pilot study, which is promising. Aerobic exercise and belimumab appear to have the most substantial evidence for treatment efficacy for fatigue management in patients with SLE. Although the evidence for psychosocial interventions is weak, psychosocial interventions still do lead to improvement in pain and distress reduction and, thus, may be beneficial. Yuen and Cunningham concluded that optimal management of fatigue for patients with SLE should start with lifestyle changes including exercise and dietary changes to help with weight loss and physical activity. Vitamin D supplementation should be considered when there is vitamin D hypovitaminosis. As NAC has few adverse effects and is relatively affordable, it may be considered with its early promising data. Belimumab has better evidence, but its high cost and adverse effects may limit its use. UVA-1 has some early encouraging data but safety concerns and exacerbation of SLE remain, so caution should be exercised. Lastly, acupuncture may benefit those with significant pain associated with their SLE and those who do not want to rely on medication.
Fatigue remains a nonspecific symptom of numerous diseases and is likely multifactorial in etiology across this spectrum. In the case of our patient, her fatigue may arise as a residual symptom of her depression or as a symptom of her SLE. Further complicating this picture, her SLE may be contributing to her ongoing depression symptoms, as nearly a quarter of all patients with SLE also report clinically significant depression symptoms. Although this Gordian Knot of etiology may be impossible to disentangle, another question arises: Does this matter?
On the one hand, as we can see in the review of treating fatigue across our patient’s illnesses, some common factors arise. Exercise has been shown to help fatigue in patients with SLE and reduce symptoms of depression,11 and to benefit those with depression. Similarly, behavioral therapy and psychosocial interventions can benefit both. Acupuncture may result in a moderate reduction in depression symptoms, although the current quality of the evidence is very low,12 and may be of some benefit to those with SLE.
From a pharmacologic standpoint, some options for treating depression and/or the fatigue related to depression are bupropion, atomoxetine, modafinil, and psychostimulants. Additionally, there are case reports13 of improved lupus fatigue with modafinil. Although Mertz et al14 reported that the exact benefits of antidepressants on fatigue in SLE is difficult to assess due to the lack of studies, there is “no reason to believe that those treatments would not be appropriate” barring drug-drug interactions. NAC similarly has emerging evidence for SLE, as noted above, and in animal studies, as well as mixed evidence in humans for NAC in depression.15
On the other hand, when things are unclear in etiology, that can place patients and clinicians at risk of referring to other specialists and not addressing an issue, either because they did not recognize the issue or because they thought it was outside their scope of practice. Especially when mental health gets involved, there is the risk for patients to experience diagnostic overshadowing where physical illness symptoms are attributed to mental illness16; the term treatment overshadowing has been proposed to describe possible treatment biases in actual treatment decisions. Our patient had experienced this previously, with the thought that her fatigue must have been due to her depression, or that a stimulant was “only” for attention-deficit/hyperactivity disorder and therefore would need to be prescribed by a psychiatrist.
Case Study Continued
In our clinic, we see many medically complex patients with multifactorial symptoms that impact their daily life and functioning, like Ms Riley. Symptoms like fatigue can have far-reaching effects on quality of life, work and financial stability, family relationships, and self-image. In Ms Riley’s case, her marriage was strained by her fatigue and chronic symptoms, she struggled to keep up at work, she could not keep up with her children at home, and she often felt she was putting many house duties onto her spouse. These led to a chronic negative self-image and feeling too tired to do more.
With the belief that this fatigue was likely multifactorial, a stimulant was started. With titration of lisdexamfetamine, Ms Riley felt she was able to achieve a tenuous stability and worked in both individual and couples’ therapy to improve her self-esteem, increase her feelings of being “good enough,” and work with her spouse to have a better relationship.
While she continued along for several months, further complications arose when she became pregnant again. She was worried about the potential effects of her medication on pregnancy and breastfeeding and was concerned that discontinuing some of her medications could worsen her symptoms, make it difficult to function at work, or increase the risk of developing postpartum symptoms again. That discussion is worth a separate investigation into treating clinically complex patients through pregnancy, but we hope this case drives home the thoughtfulness needed to manage these complex patients and the reward for both patients and clinicians when there can be positive outcomes.
Dr Khan is medical director, associate program director for general psychiatry, and an assistant professor in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine in Houston, Texas. Dr Ukrani is a PGY-1 internal medicine resident at Mercy Fitzgerald Hospital.
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