Serotonergic effects of chlorpheniramine: An unexplored advantage of the first-generation antihistamine

INTRODUCTION

Pruritus is a complex and multidimensional symptom with dermatologic, neurologic, and psychogenic components. In chronic and refractory cases – such as in urticaria unresponsive to standard H₁-antihistamines or senile pruritus – the burden extends beyond somatic discomfort to include disrupted sleep, emotional distress, and reduced quality of life. Psychiatric comorbidities, especially depression and anxiety, are frequently under-recognized in this population. There is increasing recognition that neurotransmitters such as serotonin play a central role in both pruritus and mood regulation. Chlorpheniramine, although traditionally categorized as an H1-antagonist, exhibits serotonergic activity through serotonin transporter (SERT) inhibition. This review explores the dual-action potential of chlorpheniramine as both an antipruritic and mild mood-modulating agent.

UNDERSTANDING REFRACTORY PRURITUS

Refractory pruritus is defined as pruritus that persists despite standard treatment, including optimized use of antihistamines. In such cases, mechanisms beyond histamine – particularly neurogenic and psychogenic pathways – play a significant role. Serotonin (5-hydroxytryptamine or 5-HT) has emerged as a key mediator in non-histaminergic pruritus, with multiple receptor subtypes (5-HT2A, 5-HT3) implicated in the itch pathway.^[1,2]

Furthermore, chronic itch syndromes are often associated with psychiatric symptoms. In one large meta-analysis, the prevalence of anxiety and depression among patients with chronic urticaria reached 30.6% and 29.4%, respectively.^[3] In the elderly, senile pruritus is commonly linked to insomnia, irritability, and depressive syndromes.^[4]

CHLORPHENIRAMINE: A PHARMACOLOGICAL PROFILE

Chlorpheniramine is a first-generation antihistamine with significant lipophilicity, allowing it to cross the blood–brain barrier and exert central nervous system effects. In addition to H₁ receptor antagonism (Ki~2.5 nM), it demonstrates moderate affinity for the SERT with a Ki of approximately 15.2 nM.^[5] This positions chlorpheniramine as a weak selective serotonin reuptake inhibitor (SSRI) like agent, potentially capable of increasing synaptic serotonin.

Preclinical studies have shown that chlorpheniramine induces anxiolytic-like behaviors in mice, suggesting serotonergic activation of prefrontal pathways.^[6] Clinically, its central effects – sedation, mild mood elevation, and anxiolysis – have been noted in multiple studies but seldom explored in dermatologic settings.

SEROTONERGIC MODULATION OF ITCH AND MOOD

Serotonin plays a dual role in itch: certain receptor subtypes are pruritogenic (e.g., 5-HT2A, 5-HT3), while others may inhibit itch signaling. Drugs such as paroxetine, fluvoxamine, and mirtazapine have shown efficacy in neuropathic, uremic, cholestatic, and psychogenic pruritus, highlighting the relevance of central serotonin modulation.^[7,8]

SSRIs also relieve the psychiatric burden associated with chronic itch [Table 1]. In a study, paroxetine reduced pruritus severity by >50% in 68% of patients with chronic itch.^[9] Mirtazapine has similarly shown benefit in nocturnal pruritus and itch associated with depression and cancer.^[10] Amytriptyline, a tricyclic anti-depressant has a strong serotonergic potential along with sedative effects and is used for intractable itching.^[11] Pregabalin and Gabapentin, amino-acid derived anticonvulsive drugs are used to relieve psychogenic pruritus and have moderate sedative effects.^[12,13]

PSYCHIATRIC COMORBIDITIES IN PRURITIC DISORDERS

Several pruritic disorders demonstrate substantial overlap with mood and anxiety disorders:

• Chronic urticaria: >30% of patients experience depression/anxiety^[3]

• Senile pruritus: Linked to insomnia, loneliness, and subclinical depression^[4]

• Chronic idiopathic pruritus: Often overlaps with somatoform disorders.

In these populations, addressing psychiatric symptoms is essential for breaking the itch-scratch cycle. Chlorpheniramine, by acting as a central H₁-antagonist and weak SSRI, may provide benefit by the following mechanisms:

1. Reducing peripheral itch sensation

2. Improving mood

3. Promoting sleep

4. Calming hyperactive cortical itch processing.

CLINICAL EVIDENCE SUPPORTING CHLORPHENIRAMINE IN PRURITUS

Although trials comparing chlorpheniramine with classical SSRIs are limited, several studies and observational reports suggest efficacy.

Chlorpheniramine was found to be efficacious in lichen simplex chronicus, a condition involving an itch-scratch cycle as the essential pathology and characterized by habitual itching, elucidating a central role.^[14] In chloroquine-induced pruritus, chlorpheniramine prevented itch in 74% versus 24% in placebo (P < 0.001), supporting central modulation.^[15] A study on patients undergoing cesarean section showed the efficacy of chlorpheniramine in opioid-induced pruritus.^[16] An expert consensus review pointed out the role of chlorpheniramine in the management of chronic and idiopathic pruritus through histamine receptor blockade and centrally acting sedative effects.^[17]

CONCLUSION

Chlorpheniramine, traditionally used as a low-cost antihistamine, may offer under-recognized benefits in the treatment of refractory pruritus, particularly in patients with psychiatric comorbidities. Its moderate serotonergic activity, central sedative effects, and established safety profile position it as a potentially valuable adjunct or bridge therapy, especially in polypharmacy-prone populations where standard SSRIs or mirtazapine may be less feasible. Further clinical trials are needed to evaluate chlorpheniramine’s SSRI-like effects and to define its role in a neuroimmunological and psychodermatologic approach to pruritus.