Evidence-Based Reviews

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

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A sufficient base of evidence is often lacking to guide pharmacotherapy for fatigue



Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.1 For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.6 Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis

Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.5 Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.10 Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.11

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.12 The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.13

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.14 Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.15

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion16 and cognitive abilities in patients exhibiting symptoms of fatigue.17 These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation18 and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.2

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being associated with fatigue.14 For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.19 Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.20

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.21 Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.22 Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.23

Clinical considerations: A role for rating scales?

Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale24 and the Montgomery-Åsberg Depression Rating Scale,25 have limited sensitivity for measuring fatigue.26 The Fatigue Associated with Depression (FAsD)27 questionnaire, designed according to FDA guidelines,28 is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

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