Hiding in plain sight: Decoding the unrecognized yet prevalent "chronic" serotonin syndrome.

Chronic serotonin syndrome (SS) is an evolving concept. It may present with nonspecific symptoms such as generalized body pain, stiffness/rigidity, insomnia, restlessness, and tiredness. As misdiagnosis is common for typical cases of SS, a high level of clinical suspicion is required to identify patients with a chronic variant. A detailed drug history and thorough physical examinations are needed to detect a case of SS. Diagnosis of even mild SS is important as inadvertent use of another serotonergic agent may worsen the clinical symptoms, and sometimes it can be fatal.

In a recent study published by Prakash et al in the World Journal of Psychiatry, authors have explored the epidemiological, clinical, and other aspects of the insidious onset SS. They retrospectively evaluated 14 consecutive adult patients (> 18 years) who had complaints for more than 6 weeks at the time of consultation and met the Hunter criteria for SS.

Serotonin syndrome (SS) is a drug-induced clinical phenomenon characterized by a triad of altered mental activity, neuromuscular hyperactivity, and autonomic disturbances. It occurs due to increased intrasynaptic concentration of 5- hydroxytryptamine (5-HT) or serotonin. Misdiagnosis is very common and partly due to its protean manifestation and partly due to unfamiliarity about SS among physicians.

The onset of SS is typically described in the setting of recent administration of a pro-serotonergic agent. However, SS, including severe and fatal cases, may occur even with a stable dosage. The diagnosis of SS is typically made according to either the Hunter criteria or the Sternbach's criteria, and both the diagnostic criteria are primarily intended to detect acute and severe cases. The Hunter serotonin toxicity criteria require the presence of one of the following clinical features in the presence of serotonergic agent use: (1) Spontaneous clonus; (2) Inducible clonus/ocular clonus with diaphoresis or agitation or rigidity, with a temperature > 38.0 °C; and (3) Hyperreflexia and tremor.

Literature describes SS as mostly an acute presentation but in a review of 56 cases of fatal SS, seven patients (13%) were on a stable dosage, and there was no change in the dosage of the drugs in the recent past; and all of them had insidious onset so called "chronic serotonin syndrome". Authors used 6 weeks to define the time frame of chronic SS in this publication.

This study was conducted as a retrospective chart review of all consecutive adult patients (≥ 18) who had 'presenting complaints' for more than 6 weeks at the time of the first consultation and met the Hunter criteria for SS.

The mean age was 41.1 years with a male preponderance (64%). Although tremors were observed in all patients, this was a presenting complaint in only 43% of patients. Generalized body pain, insomnia, and restlessness were common presenting features. Other common clinical features were:

1. stiffness of the limbs (43%),

2. diaphoresis (43%)

3. gait disturbances (36%),

4. bowel disturbances (36%),

5. dizziness (29%), sexual dysfunctions (21%), incoordination (14%), and fatigue (14%)

The mean duration of symptoms before the diagnosis of SS was 13.5 ± 5.8 weeks (range: 6-24 wk). Amitriptyline was the most common drug followed by tramadol and sodium.

All patients received cyproheptadine, a 5- hydroxytryptamine2A antagonist, as treatment and noted an excellent response over the course of 4-14 days. As they included only chronic cases, fever and agitation were not the part of the symptom complex in our patients.

The study serves as an important reminder for psychiatrists to keep an eagle-eye approach for diagnosing chronic SS. SS typically presents within 24 h of initiation or change in the dose of serotonergic agents, and it may evolve very rapidly, leading to death within a few hours. However, mild cases of SS (tremor with hyperreflexia and hypertonia) may be ignored by patients and doctors, and patients can continue to take serotonergic drugs for a longer period. Such patients may represent the chronic variant of SS.

Generalized body pain, stiffness of the limbs, insomnia, dizziness, and irritability were the common presenting features. Such nonspecific symptoms are often ignored by patients, and even physicians do not take these symptoms seriously and attribute such symptoms to underlying primary disorders or associated somatic complaints or nonspecific drug-induced side effects.

A diagnosis of SS is important even in mild and indolent form, as it is not supposed to resolve spontaneously as long as serotonergic drugs are administered. Furthermore, it may progress rapidly to death by an inadvertent increase of the dose or addition of another serotonergic agent.

Take home message: The incidence of SS is increasing because of the widespread use of serotonergic drugs. There is a need to improve the awareness about SS among the physicians for early recognition and effective management.

Source: World Journal of Psychiatry: Prakash S, Rathore C, Rana K, Roychowdhury D, Lodha D. Chronic serotonin syndrome: A retrospective study. World J Psychiatr 2021; 11(4): 124-132