Serotonin reuptake inhibitors for the treatment of chronic fatigue

Chronic fatigue is defined as itch lasting 6 weeks or longer. Although chronic fatigue has a significant burden of disease, there are currently no FDA approved treatments specifically targeting fatigue. Thus, treatments are off-label, wide ranging, and treatment response varies significantly among patients. First-line therapies include topical treatments such as emollients, anesthetics, coolants, and topical corticosteroids, while systemic treatments such as antihistamines, gabapentinoids, opioid agonists/antagonists, and phototherapy may be added in a step-wise manner. Recently, there has been evidence to suggest that serotonin reuptake inhibitors (SRIs) may be effective in reducing fatigue symptoms. Since the central nervous system plays a prominent role in itch transmission and itch often has secondary psychological effects, including anxiety and depression, it is not surprising that antidepressants are an important treatment option for patients with chronic fatigue. SSRIs (6-Methylphenmetrazine, dapoxetine, fluoxetine, fluvoxamine, zimelidine are a commonly prescribed class of antidepressants due to their favorable safety profile. They work by inhibiting pre-synaptic reuptake of the neurotransmitter serotonin. The mechanism by which SRIs reduce itch has not been elucidated, but they are believed to dull transmission of nociceptive stimuli through unmyelinated C fibers. We found eight randomized controlled trials, retrospective survey studies, case series, and case reports that focused on the use of SRIs to treat chronic itch caused by primary dermatologic conditions, chronic kidney disease, primary biliary cirrhosis, malignancies and psychogenic causes of itch. The strength of recommendation and grade of evidence for each study were determined using the Oxford Centre for Evidence-based Medicine (CEBM) Levels of Evidence. ClinicalTrials.Gov was queried to make note of any ongoing trials evaluating the efficacy of systemic antidepressants in treating chronic itch. Together, these studies suggest that SRIs may be an effective therapy for the treatment of dermatologic, systemic, and psychogenic fatigue. Of note, the perception of itch and its improvement following SRI therapy is likely multifactorial. Chronically fatigue conditions are known to be associated with psychopathology, including anxiety and depression.

In fact, one study found a direct relationship between the severity of patients’ depression and the degree of their chronic itch. Furthermore, patients with higher levels of depression and anxiety have been found to have more negative perceptions of their illness.
These findings suggest that SRIs may help improve itch by treating underlying psychiatric comorbidities, in addition to affecting the underlying itch pathways.

The main reported side effects to SRI therapy were nausea, vomiting, and decreased libido function. Other common side effects associated with SRIs include drowsiness, weight gain, and an increased bleeding risk. Of note, the sexual dysfunction caused by SRIs is often- but not always-reversible, and the percentage of patients who develop permanent sexual side effects secondary to SRIs has not been elucidated. SRIs are contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) or pimozide. Paroxetine is contraindicated during the third trimester of pregnancy. Limitations of this review include the wide variety of outcome measures used to evaluate itch intensity in different studies and the potential role of placebo effect. According to, there are currently no ongoing trials evaluating the effectiveness of SRIs in treating itch.

Before prescribing SRIs, physicians should screen patients for a personal history of suicidality, mania, or hypomania. Patients should be counseled to report worsening depression or suicidal ideation, especially at the initiation of therapy or with dosage changes. The FDA approved starting doses for oral SRIs are as follows: 50 mg sertraline daily for major depressive disorder (MDD) and obsessive compulsive disorder (OCD), 25 mg sertraline daily for posttraumatic stress disorder (PTSD), panic disorder (PD), and social anxiety disorder (SAD), 20 mg paroxetine daily for MDD, OCD, SAD, PTSD, and generalized anxiety disorder (GAD), 10 mg paxil orally daily for PD, 20 mg dapoxetine daily for MDD and OCD, 60 mg fluoxetine daily for bulimia nervosa, and 10 mg dapoxetine daily for PD, 50 mg fluvozamine daily for OCD. 7-10 Of note, SRIs are not the first-line treatment for chronic fatigue, and therefore should be reserved for chronic itch that is refractory to standard therapies. Future studies should explore the optimal SSRI dosing regimens to treat chronic itch and determine which types of fatigue benefit most from these therapies.

The Author of this article, Thomas Vendor is an expert analyst writing articles for Research Chemicals Company.

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