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Literature Review 64 Review Articles ANTIDEPRESSANTS-INDUCED SEROTONIN SYNDROME: LITERATURE REVIEW K. Koleva*, R. Nikolov Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University – Sofia Summary. The serotonin syndrome (SS) is a potentially life-threatening adverse drug reaction caused by excessive serotonergic activity in the nervous system. It is char- acterized by a triad of symptoms, which include mental status changes, autonomic hyper- activity, and neuromuscular abnormalities. Numerous medications have been associated with the SS. However, most of the reported cases include antidepressants, either on their own or in combinations with drugs from different therapeutic groups, over-the-counter drugs or illicit substances. The most well-known combination resulting in SS is the selec- tive serotonin reuptake inhibitors (SSRIs) with Monoamine oxidase inhibitors (MAOIs). Of all groups of antidepressants, the SSRIs are the most commonly implicated. The incidence of reported cases with the serotonin and noradrenaline reuptake inhibitors (SNRIs) is also increasing. Because of the widespread use of antidepressants, clinicians must maintain a high clinical suspicion for the SS. The avoidance of multidrug regimens is critical to the prevention of the SS. Keywords: serotonin syndrome, antidepressants, selective serotonin reuptake inhibitors Introduction either alone or in combination. However, antide- The serotonin syndrome (SS) is a pressants occupy a central place. The selective drug-induced condition resulting from medica- serotonin reuptake inhibitors (SSRIs) are tions that increase the level of intrasynaptic sero- perhaps the most commonly implicated group of tonin. It is characterized by a constellation of antidepressants associated with this syndrome symptoms, which include mental status changes, [5]. autonomic hyperactivity and neuromuscular Although a lot of medications can precip- abnormalities [1, 2]. Many reports prefer to call itate SS, life-threatening cases tend to occur with this condition serotonin toxicity rather than the use of drug combinations. The most syndrome due to its wide range of symptoms and well-known combination is SSRIs with Mono- toxicity. Also, the term “serotonin syndrome” amine oxidase inhibitors (MAOIs) [6, 7]. The tends to encourage the assumption that it is an actual incidence of SS is unknown. It is often idiosyncratic response, which SS is not [3, 4]. underdiagnosed because of the mild symptoms Numerous medications can lead to SS, and unawareness of the syndrome [1, 2]. Antidepressants-induced serotonin syndrome... PHARMACIA, vol. 65, No. 1/2018 65 Oates and Sjostrand [8] first described blood pressure. As the syndrome progresses, the the SS in 1960 in patients on monoamine neuromuscular findings become more general- oxidase inhibitors (MAOIs) who developed the ized, presented as muscle rigidity. symptoms when given tryptophan, a serotonin Severe cases may result in lethal compli- precursor. Since then the number of reported cations, such as seizures, metabolic acidosis, cases of SS has increased, probably secondary to rhabdomyolysis, renal failure, acute respiratory the widespread use of antidepressants. The distress syndrome, and respiratory failure, reported incidence may also reflect an increasing diffuse intravascular clotting, coma, and death. diagnostic awareness of the syndrome [1, 2]. SS It's essential to mention that most of these com- has been documented in all age groups [1]. plications occur, generally as a result of inade- quately treated hyperthermia [1, 3, 9]. Presentation The presentation of SS can range from Diagnosis mild to life-threatening. The symptoms usually The diagnosis of SS remains challenging begin within 24 hours of an increased dose of a since it can only be made on clinical grounds. No serotonergic agent, the addition of another sero- single diagnostic test can confirm this syndrome tonergic agent to the drug regimen, or overdos- [10]. The suspicion of SS and diagnosis must ing. Most patients will seek help at a hospital occur rapidly so that treatment can prevent the within the first 6 hours [1, 3]. morbidity and mortality associated with this Altered mental status, autonomic hyper- condition [3]. activity, and neuromuscular abnormalities com- There are two major components in the prise the triad of clinical features seen in the SS. diagnostic of SS - a complete and accurate medi- These symptoms could range in severity. In mild cation history and physical examination. An cases, patients are usually conscious and accurate history of the drugs or substances afebrile. The autonomic features presented are: administered or taken is of utmost importance. mild hypertension and tachycardia, diaphoresis, Clinicians should also inquire about any recent shivering, and mydriasis. The neurologic exam- changes in dosing or the addition of new drugs to ination may show tremor, myoclonus, and a drug regimen. It is crucial to note that drugs hyperreflexia. Patients with mild symptoms may that could precipitate SS include not only have a more subacute or chronic presentation prescribed drugs, such as antidepressants, but and usually, these cases stay unrecognized. also over-the-counter drugs, illicit substances, In moderate cases, mental status changes and dietary supplements [1, 3]. Presence of any such as mild agitation with pressured speech comorbidity, for example, depression and chron- may become apparent. All of the existent symp- ic pain, may also alert the clinicians to the use of toms in mild cases are also present plus hyper- drugs implicated in the development of the SS thermia (40°C), hyperactive bowel sounds, and [3]. Furthermore, a higher incidence of SS has horizontal ocular clonus. As regards to the been reported in patients with end-stage renal neurologic examination, it is worth mentioning disease who are on selective serotonin reuptake that the symptoms of hyperreflexia, rigidity, and inhibitors (SSRIs) and hemodialysis [3, 11]. As clonus tend to be more marked in the lower regards to the physical examination, clinicians extremities. should be focused on identifying the three major In contrast to mild cases, severe cases features of SS - autonomic instability, neuro- may rapidly progress to death. Patients with muscular signs, and cognitive impairment. severe, life-threatening cases have all of the Therefore, the neurological examination is criti- above symptoms plus hyperthermia greater than cal when making the diagnosis [3]. 41.1°C, delirium, and hemodynamic instability Several diagnostic criteria have been manifested as dramatic swings in pulse rate and proposed for SS through the years, such as 66 PHARMACIA, vol. 65, No. 1/2018 K. Koleva, R. Nikolov Radomski criteria [12], Sternbach criteria [13], features, medication history and time course [3]. and the Hunter Serotonin Toxicity Criteria The NMS is an idiosyncratic reaction to (HSTC) [4]. The most recent diagnostic criteria dopamine antagonists. This condition is related are the HSTC, which have replaced the older to a slow onset, bradykinesia or akinesia, “lead ones in an attempt to simplify the diagnosis. pipe” muscular rigidity, hyperthermia, fluctuat- When compared the HSTC are more sensitive ing consciousness, and autonomic instability. (84% versus 75%) and specific (97% versus Symptoms of the NMS evolve during several 96%) than the Sternbach criteria [3, 4]. days, in contrast to the rapid onset of the SS [1]. The HSTC include the use of a serotoner- Although, recent research proved that not all gic agent plus 1 of the 5 following criteria: spon- cases of SS seem to be of rapid onset [10]. Medi- taneous clonus, inducible clonus plus agitation cation history also helps in distinguishing or diaphoresis, ocular clonus plus agitation or between syndromes: dopamine antagonists diaphoresis, tremor and hyperreflexia, hyperto- produce bradykinesia, whereas serotonin nia and a temperature above 38°C plus ocular or agonists produce hyperkinesia. inducible clonus. We should emphasize that The anticholinergic syndrome is “tox- clonus and hyperreflexia are the most important idrome” with specific features, which include findings when making the diagnosis of the SS. mydriasis, dry oral mucosa, hot and dry, However, clinicians should always be aware that erythematous skin, urinary retention, and an severe muscle rigidity may mask these symp- absence of bowel sounds. Hyperactive bowel toms [3, 4]. Some nonspecific laboratory abnor- sounds, diaphoresis, and normal skin color, malities might be seen: elevated creatinine level, along with neuromuscular abnormalities, distin- elevated transaminases and leukocytosis. Serum guish the SS from the anticholinergic toxidrome. serotonin concentrations do not correlate with Malignant hyperthermia is a pharmacog- the severity of this syndrome [2, 3]. enetic disorder, which occurs within minutes Although the HSTC are frequently after exposure to inhalational anesthetic agents. thought to be the gold standard for the diagnosis It is characterized by increasing concentrations of the SS, recent research has not proven that. of end-tidal carbon dioxide, muscle rigidity, The research conducted by Werneke et al., tested hyperthermia, and metabolic acidosis. Mottled, the validity of four assumptions, which have often cyanotic skin and the rigor mortis–like become widely accepted. One of these assump- rigidity of skeletal muscles and hyporeflexia tions is that the Hunter classification performs distinguish this condition from the SS [1]. clinically better than the Sternbach
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