[Academic Presentation] Advances in the Use of Antidepressants for the Treatment of Chronic Pruritus

Article reprinted from: Chinese Journal of Dermatology and Venereology

Authors: Wang Ying, Liu Liping, Huang Jianling, Chen Zhiqiang, Li Yumei

Pruritus is a skin‑related discomfort that triggers the urge to scratch; when it persists for more than six weeks, it is classified as chronic pruritus. Surveys indicate that the lifetime prevalence of chronic pruritus can be as high as 22%, and its impact may be comparable to that of chronic pain. As one of the most common symptoms in dermatology, chronic pruritus is observed in a wide range of skin disorders, including eczema, chronic urticaria, psoriasis, and atopic dermatitis. It also occurs in systemic conditions such as end‑stage chronic kidney disease, cholestasis, polycythemia, and lymphoma. Moreover, psychoneurogenic factors may contribute to chronic pruritus. Currently, treatment for chronic pruritus is broadly divided into topical and systemic approaches. Topical therapies typically include cooling agents, corticosteroids, and capsaicin, while systemic treatments often involve antihistamines, opioid receptor antagonists, immunosuppressants, and calcium channel modulators. In addition, physical modalities such as phototherapy and starch baths, as well as traditional Chinese medicine, are frequently employed. Nevertheless, conventional anti‑pruritic regimens prove ineffective in a substantial proportion of patients, particularly those with refractory pruritus of complex or unknown etiology, or with pruritus secondary to systemic diseases, posing significant therapeutic challenges.

1. Depressive Mood and Chronic Pruritus

Emotional disturbances can exacerbate pruritus, while persistent, intractable itch often worsens the patient’s mood, creating a vicious cycle. Depressive symptoms are commonly observed in various skin conditions, including chronic simple lichen, psoriasis, chronic urticaria, and atopic dermatitis. The discomfort of itch directly prompts patients to scratch, which temporarily relieves the sensation and produces feelings of pleasure or relief. In healthy individuals, scratching can provide some degree of itch relief; however, in patients with chronic itch, it fails to alleviate the symptom and may even intensify it. For instance, in patients with atopic dermatitis, scratching—whether on lesional or non-lesional skin—does not relieve itch but instead aggravates it. This “itch–scratch–worsening itch” vicious cycle is a key factor in the chronification of pruritus, and depressive mood further drives scratching behavior. Antidepressants, by improving depressive symptoms, also help suppress scratching and break the “itch–scratch–worsening itch” cycle. Accordingly, inhibiting scratching may represent a therapeutic target for antidepressants in the management of chronic itch.

2. Antidepressant Treatment for Chronic Pruritus

Among antidepressants, tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), norepinephrine–specific serotoninergic antidepressants (NaSSAs), and other agents are frequently used to treat chronic pruritus. These medications are indicated for a variety of skin conditions, including chronic urticaria, localized neurodermatitis, atopic dermatitis, and lichen simplex chronicus, as well as pruritus associated with systemic diseases such as chronic renal failure and primary biliary cirrhosis.

2.  1 Tricyclic antidepressants (TCAs)

Tricyclic antidepressants are nonselective monoamine reuptake inhibitors that exert their antidepressant effects by inhibiting the reuptake of norepinephrine (NE) and serotonin (5-HT), thereby increasing their synaptic concentrations; they also antagonize α1-adrenergic and H1 receptors. 2.1.1 Amitriptyline Topical amitriptyline is commonly formulated as a cream for the treatment of pruritus. For example, a 2% amitriptyline–0.5% ketamine compound gel has been shown to be effective for severe postherpetic pruritus. Amitriptyline is also highly efficacious in refractory chronic pruritus of unknown etiology. Poterucha et al. reported a patient with severe brachioradial pruritus lasting five years who achieved significant relief by applying a 1% amitriptyline hydrochloride–0.5% ketamine hydrochloride compound cream two to three times daily.

In addition to topical use, oral amitriptyline can also be used to treat pruritus. For example, in cases of refractory pruritus associated with lichenoid amyloidosis, conventional anti‑pruritic therapies—including oral antihistamines and topical corticosteroids—often prove ineffective. In such instances, oral amitriptyline was initiated at 10 mg nightly, with the dose gradually increased to 25 mg based on the patient’s response; once the condition stabilized, a maintenance dose of 10 mg was prescribed. Long-term follow-up confirmed that pruritus was effectively controlled. Because amitriptyline is primarily metabolized by the liver and places minimal burden on the kidneys, it is particularly suitable for patients with impaired renal function. Yong et al. treated two patients with pruritus due to chronic renal failure with amitriptyline, administering 25 mg and 10 mg nightly, respectively; within 2–3 weeks, pruritus scores decreased significantly in both cases.

2.1.2 Doxepin

Doxepin exhibits potent H1‑receptor antagonism and also inhibits acetylcholine, substance P, and other mediators, thereby alleviating local inflammation. Compared with immunomodulators, it has fewer adverse effects; and in contrast to biologic agents, it is considerably more affordable, offering distinct advantages. In 2014, the American Academy of Allergy, Asthma & Immunology’s guidelines for the diagnosis and management of acute and chronic urticaria recommended that, for refractory chronic urticaria, doxepin may be tried prior to initiating immunomodulatory therapy. Moreover, doxepin demonstrates favorable efficacy in pruritus associated with systemic diseases. Ruger et al. randomly assigned 56 patients with uremic pruritus into a control group and an experimental group, with 28 patients in each. All participants discontinued antipruritic medications for at least seven days before treatment. The experimental group received doxepin 25 mg twice daily, while the control group received a placebo. After seven consecutive days of observation, skin pruritus scores were recorded. The results showed that the response rate was significantly higher in the treatment group than in the control group. Based on these findings, low‑dose oral doxepin can effectively relieve uremic pruritus. Pourrezagholi et al. further suggested that even lower doses of doxepin may achieve good antipruritic effects in uremic pruritus; in clinical practice, administering doxepin 10 mg orally twice daily for one week typically yields noticeable improvement.

2.2 Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRI This class of antidepressants exhibits high selectivity for serotonin (5-HT) while exerting minimal effects on other neurotransmitters, and it is associated with no significant orthostatic hypotension, cognitive impairment, anticholinergic, or cardiovascular adverse effects, making it a widely used novel class of antidepressants.

2.2.1 Sertraline

Sertraline is commonly used to treat depression and obsessive–compulsive disorder, with an initial dose of 50 mg per day and a maximum dose that may reach 200 mg per day. Clinical studies have shown that sertraline can be effective for chronic pruritus secondary to systemic conditions such as renal‑origin pruritus and cholestatic pruritus. Shakiba et al. administered sertraline 50 mg once daily by mouth to end‑stage renal disease patients undergoing hemodialysis for a duration of four months; pooled analyses indicated a significant therapeutic effect. Chan et al. treated uremic patients with renal‑origin pruritus using sertraline, starting at 25 mg daily orally and titrating in 25‑mg increments based on clinical response, with a maximum dose of 200 mg when necessary. The results demonstrated that sertraline effectively alleviates renal‑origin pruritus, often achieving efficacy at lower doses. In addition, sertraline has been used to manage skin pruritus in patients with primary biliary cirrhosis; Wu et al. prescribed sertraline 50 mg daily for two consecutive weeks, and clinical trials confirmed its modest efficacy for this type of pruritus, with good tolerability. During treatment, only one patient experienced mild somnolence, which did not interfere with daily activities. Accordingly, it is recommended that, when other therapies prove ineffective, oral sertraline may be considered for skin pruritus associated with primary biliary cirrhosis.

2.2.2 Paroxetine

Paroxetine, a first-line clinical treatment for depression, has also been used to manage refractory pruritus associated with advanced malignancies. Animal studies have demonstrated that oral administration of paroxetine can attenuate the exacerbation of atopic dermatitis–like skin inflammation in NC/Nga mice and reduce scratching behavior; based on these findings, it is hypothesized that paroxetine may be clinically applicable, particularly in patients with comorbid mood disorders. Relevant clinical studies in patients with atopic dermatitis support this conclusion. Unotoro et al. administered paroxetine to patients with advanced gastrointestinal malignancies suffering from cholestatic pruritus; a daily oral dose of 10 mg effectively suppressed itching, with effects lasting anywhere from several hours to two days, suggesting promising therapeutic potential. In cases of refractory pruritus, a substantial proportion remain without identifiable somatic abnormalities, raising the possibility of psychogenic pruritus, which is especially amenable to antidepressant therapy. Heisig et al. reported a case of psychogenic pruritus treated with paroxetine: a elderly male with mild dementia who had experienced persistent pruritus for an extended period, unresponsive to antihistamines. On examination, he exhibited skin lesions resulting from scratching, while laboratory tests revealed no significant abnormalities, meeting the diagnostic criteria for psychogenic pruritus. Following paroxetine therapy, his pruritus improved, and both scratching behavior and the associated skin damage were markedly reduced.

2.2.3 Escitalopram

Reports on the use of escitalopram for treating chronic pruritus have been predominantly focused on psoriasis. D’Erme et al. reported that, after six months of escitalopram treatment, patients with moderate-to-severe psoriasis exhibited significant reductions in the Psoriasis Area and Severity Index, visual analog scale scores, and scores on the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale, with improvements in both itch severity and emotional distress. In addition to directly alleviating pruritus, escitalopram can also mitigate anxiety, reduce scratching behavior, break the vicious cycle between itch and scratching, and further help to relieve itching.

2.2.4 Fluvoxamine

Stnder et al. used fluvoxamine and paroxetine, both SSRIs, to treat chronic pruritus, with the greatest efficacy observed in cases attributable to lymphoma and solid malignancies. The effective doses were lower than the recommended daily doses of 100–200 mg used for treating depression. The specific treatment regimens were as follows: a starting dose of 10 mg paroxetine or 25 mg fluvoxamine for 3 days, followed by gradual dose escalation based on clinical response, with maximum doses of 60 mg and 150 mg, respectively; maintenance doses were 20 mg paroxetine or 50 mg fluvoxamine.

2.3 NE and specific serotonergic antidepressants (NaSSAs)

NaSSA antidepressants share a similar mechanism of action with TCAs and are dual‑action agents, yet they exhibit greater selectivity than TCAs, thereby reducing adverse effects while maintaining efficacy and improving tolerability. Mirtazapine exerts its antidepressant effects by modulating serotonergic and noradrenergic transmission through secondary mechanisms; recent clinical reports have demonstrated that mirtazapine can significantly alleviate refractory pruritus associated with malignant tumors, making it a valuable option for intractable itching unresponsive to conventional therapies. TNishi et al. described a 56‑year‑old female patient with peritoneal metastases from pancreatic head cancer, who presented with markedly elevated total bilirubin (9.9 mg/dL) and widespread, persistent pruritus unresponsive to antihistamines. Following the second day of oral mirtazapine, her pruritus was markedly relieved. Araki et al. reported an elderly patient with advanced lymphoma and refractory pruritus; after initiating mirtazapine 15 mg daily, significant improvement was observed within seven days, and continued treatment led to complete resolution of symptoms. Lee et al. described a case of advanced breast cancer accompanied by severe, intractable pruritus, for whom pregabalin and hydroxyzine had provided only minimal relief. Addition of mirtazapine 7.5 mg once nightly resulted in noticeable improvement after 12 hours, and increasing the dose to 15 mg after 48 hours reduced the subjective pruritus score from “200+” to “2.” At one‑month follow‑up, no recurrence was noted.

3. Conclusion

At present, the mechanisms by which antidepressants treat chronic pruritus remain to be further elucidated. However, for refractory chronic pruritus—particularly in patients with severe mood disorders or comorbid depression—the use of these antidepressants can yield dual benefits, reduce the cumulative burden of drug-related side effects, and lighten the patient’s medication load, thereby facilitating personalized treatment. In cases of severe systemic diseases such as chronic kidney disease or malignancies accompanied by pruritus, where conventional antipruritic agents fail to provide adequate relief or organ dysfunction limits their use, antidepressants often deliver unexpectedly favorable outcomes. For patients undergoing palliative care, antidepressants not only alleviate pruritus but also mitigate negative emotions, thereby improving quality of life. As medical research increasingly adopts a biopsychosocial model, we anticipate that additional psychologic and psychotherapeutic interventions—such as cognitive‑behavioral therapy and behavioral habit‑modification training—will be integrated into the management of chronic pruritus, offering patients more diverse and individualized therapeutic options.

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