Evidence-Based Reviews

Fatigue after depression responds to therapy. What are the next steps?

Current Psychiatry. 2015 June;14(6):16-17, 28-32

References

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The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clinically meaningful.²⁷ The measurement properties of the questionnaire showed internal consistency, reliability, and validity in testing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physical and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depression can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relationship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symptom of MDD can be complicated because symptoms of fatigue might be:
• a discrete symptom of MDD
• a prodromal symptom of another disorder
• an adverse effect of an antidepressant.^2,30

It is a major clinical problem, therefore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying antidepressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neurotransmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists potential treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been associated with a low probability of achieving remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepressants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospective and did not analyze the efficacy of a noradrenergic agent as an adjunct for alleviating symptoms of fatigue.³⁹

Bupropion. This commonly used medication for fatigue is believed to cause a significantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupropion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statistically significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be efficacious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from placebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associated with depression.⁴³

Adjunctive therapy with CNS stimulants, such as amphetamine/dextroamphetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacotherapeutic modality that targets the underlying physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symptoms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recommend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Fatigue after depression responds to therapy. What are the next steps?

References

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