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 and Radoms- ki criteria. Systematic review and meta-analysis Mechanism have been conducted, and the results have shown Serotonin (5-hydroxytryptamine [5-HT]) that the Hunter criteria did not perform better is a monoamine neurotransmitter. It is formed than the Sternbach and Radomski criteria. from the decarboxylation and hydroxylation of Therefore, clinicians should keep an open mind the amino acid L-tryptophan. The serotonin is about the diagnosis, even if HSTC are not met stored in vesicles and released into the synaptic [10]. cleft when there is stimulation. 5-HT is metabo- The primary differential diagnosis of SS lized by monoamine oxidase-A (MAO-A) into includes neuroleptic malignant syndrome 5-hydroxyindoleacetic acid, which is then (NMS), anticholinergic syndrome and malignant excreted in the urine. Serotonin receptors are hyperthermia. Other potential diagnoses may divided into seven families (5-HT1 to 5-HT7), include: serotonergic discontinuation syndrome, several of which have multiple members. No overdose of sympathomimetic drugs, meningitis, single receptor is responsible for the develop- encephalitis or heat stroke. Some diagnoses may ment of SS. However, several studies provide be distinguished from the SS by the clinical evidence that the 5-HT2A receptors mediate the Antidepressants-induced serotonin syndrome... PHARMACIA, vol. 65, No. 1/2018 67 most important consequences of SS [1, 3, 14]. Imipramine, Clomipramine, Desipramine, Dox- Serotonin has both central and peripheral epin, Amitriptyline, Amoxapine, Maprotiline, effects. In the central nervous system (CNS), Nortriptyline, Protriptyline, Trimipramine serotonergic neurons are found in the midline ▪ Bupropion, Nefazodone, Trazodone raphe nuclei of the brainstem from the midbrain 4. Activate serotonin receptors: Mirtazapine, to the medulla. In the CNS serotonin plays a role Trazodone in numerous functions: regulation of wakeful- 5. Inhibit CYP2D6 enzyme (pharmacokinetic ness, food intake, thermoregulation, affective mechanism): behavior (anxiety and depression), sexual behav- ▪ Inhibitors: Fluoxetine, Sertraline ior, nociception and motor tone. Outside of the ▪ Substrates: Dextromethorphan, Oxyco- CNS, the serotonin is synthesized in the enter- done, Tramadol, Phentermine, Risperidone ochromaffin cells of the gastrointestinal (GI) Although numerous antidepressants can tract. Peripheral 5-HT is involved in stimulation precipitate SS, most of the cases tend to occur of vasoconstriction, GI motility, bronchocon- when antidepressants are combined with other striction, uterine contraction and platelet aggre- serotonergic medications. The reported drug gation [1, 3, 14]. interactions that have caused SS continue to SS is a result of increased intrasynaptic increase and include interactions on both phar- levels of serotonin, caused by overstimulation of macodynamic and pharmacokinetic level. Some both the central and peripheral 5-HT receptors. of the reported drug combinations include [3, 7, Several animal studies show that other neurome- 14, 15, 16, 17, 18]: diators, such as noradrenaline, N-Methyl-D-as- ▪ MAOIs: alone or with SSRIs; SNRIs; partate (NMDA), gamma aminobutyric acid TCAs; opiates; Amphetamine or Ecstasy (GABA), and dopamine may also play a role in (3,4-methylenedioxymethamphetamine) SS, but their impact is still unclear [1, 3]. ▪ SSRIs: alone or with MAOIs; SNRIs; Drugs, which raise the intrasynaptic TCAs; opiates; triptans; Dextromethorphan; serotonin, are known as serotonergic drugs. The Linezolid or L-tryptophan complete list of the serotonergic drugs is long ▪ Citalopram with: Fluconazole or Olan- but is important to note that it includes zapine and Lithium over-the-counter drugs, illicit substances, and ▪ Fluoxetine with: Risperidone; Carba- diet supplements. However, as major representa- mazepine; Phentermine or Fentanyl tives, antidepressants take a central place. ▪ Sertraline with Fentanyl Antidepressants that have been reported ▪ Paroxetine with: Risperidone or Methy- to cause SS and the mechanism of each are as lene blue follows [3, 14]: ▪ Clomipramine with Methylene blue 1. Inhibit serotonin metabolism: ▪ Amitriptyline with: Dextromethorphan ▪ MAOIs: Tranylcypromine, Phenelzine, or Dextromethorphan and Risperidone Isocarboxazid, Nialamid, Iproniazid, Pargyline, ▪ SNRIs with: MAOIs; TCAs or opiates Clorgiline, Moclobemide, Toloxatone ▪ Venlafaxine with: Lithium or calci- 2. Increase serotonin release: Mirtazapine neurin inhibitors; Mirtazapine and Tramadol; 3. Inhibit serotonin reuptake: Amitriptyline and Meperidine; Mirtazapine or ▪ Selective serotonin reuptake inhibi- Tranylcypromine; Methadone and Fluoxetine; tors (SSRIs): Paroxetine, Sertraline, Fluoxe- Methadone and Sertraline; Tramadol; Trazodone tine, Fluvoxamine, Citalopram, Escitalopram and Quetiapine; Ciprofloxacin and Methadone; ▪ Serotonin and noradrenaline Co-amoxiclav reuptake inhibitors (SNRIs): Venlafaxine, ▪ Mirtazapine with SSRIs or Tramadol Desvenlafaxine, Duloxetine, Milnacipran and Olanzapine ▪ Tricyclic antidepressants (TCAs): ▪ Trazodone with Amitriptyline 68 PHARMACIA, vol. 65, No. 1/2018 K. Koleva, R. Nikolov and Lithium Some authors suggest that critical value of serotonin is necessary for the development of As demonstrated above, antidepressants SS [3, 4, 17]. Despite that, several case reports can lead to SS when they are combined with show that the critical value is likely different for each other or when they are combined with other each patient. The possible mechanisms of indi- medications from different groups. Such groups vidual variability include genetic differences in include opiates (Tramadol, Fentanyl), triptans, the SERT gene (a serotonin transporter), poly- atypical antipsychotics (Olanzapine, Risperi- morphisms of CYP2D6 or of the 5HT2A and done), antibiotics (Ciprofloxacin, Co-amoxi- 5HT3B receptors [3, 6]. clav), some illicit substances (Amphetamine, Ecstasy) and over-the-counter drugs (Dextro- Management methorphan). When SS is recognized promptly and Some of these interactions occur on a treated appropriately, the prognosis is generally pharmacokinetic level [3, 7, 14, 15, 16, 17]. The favorable [19]. First-line management involves inhibition of CYP 450 enzymes results in the discontinuing the offending drugs and providing accumulation of certain serotonergic drugs that supportive care via stabilizing vital signs. The are usually metabolized by these enzymes. Anti- intensity of treatment depends on the severity of depressants can play the role of both inhibitors the symptoms. Treatment for mild cases includes and substrates. As inhibitors of CYP2D6, SSRIs removal of the causative drugs, sedation with increase the concentration of Dextromethorphan benzodiazepines, and observation for at least 6 which is a substrate of the same enzyme. In other hours [1, 2, 3]. Most patients with mild cases do cases, the inhibition of CYP2C19 by Fluco- not require hospitalization [19]. nazole results in the accumulation of its substrate Patients with moderate to severe cases Citalopram [3]. require hospital admission. These patients The most well-known combination asso- should be treated as above with addition of sero- ciated with the SS is an SSRI with an MAOI. tonergic antagonist [3]. Cyproheptadine, a selec- However, life-threatening cases tend to occur tive serotonin 2A antagonist, is usually recom- with the use of an irreversible MAOI or with mended. Body et al. reported a sublingual use of combinations of serotonergic drugs rather than 5-HT2 receptor antagonist - Olanzapine in the with just the use of an SSRI alone [1, 3, 4, 6, 7]. treatment of serotonin syndrome [20]. Of all SNRIs, Venlafaxine has been asso- The managing of the hyperthermia and ciated with SS the most, even more than SSRIs. the muscle rigidity in severe cases requires Evidence suggests that it may act other than as a neuromuscular paralysis with nondepolarizing re-uptake inhibitor, possibly as a serotonin agent such as Vecuronium, sedation, and possi- releaser [14]. Furthermore, it has been suggested ble intubation [3, 19]. that the risk of inducing SS might be higher with Although, SS usually resolves within 24 SNRIs rather than with SSRIs, especially when hours, in some cases symptoms may persist for a these are combined with a 5-HT1A antagonist. longer period of time. Usually, these cases It is important to note that Fluoxetine involve drugs with long duration of action or interactions have been reported up to 6 weeks active metabolites with long half-lives [1, 3, 14]. after discontinuation of the antidepressant. Fluoxetine and its metabolite Norfluoxetine Conclusion have longer half-lives (1 week and 2.5 weeks, The SS is an underreported, underdiag- respectively) than the other SSRIs [3]. There- nosed and potentially life-threatening condition fore, clinicians should be cautious when which requires heightened clinical awareness. prescribing another serotonergic agent to the The early recognition and prompt treatment are same patient. vital for the favorable prognosis of the Antidepressants-induced serotonin syndrome... PHARMACIA, vol. 65, No. 1/2018 69 syndrome. Therefore, physicians should main- 7. Isbister G K, Bowe SJ, Dawson A, tain a heightened clinical scrutiny for the SS, Whyte IM. Relative toxicity of selective sero- especially in the mild cases, which often remain tonin reuptake inhibitors (SSRIs) in overdose. J not diagnosed. If SS is recognized, treatment Toxicol Clin Toxicol 2004; 42(3): 277-285. should start with a prompt cessation of the 8. Oates JA, Sjoerdsma A. Neurologic offending drug. effects of tryptophan in patients receiving a However, SS prevention takes a central monoamine oxidase inhibitor. Neurology 1960; place in reducing the morbidity and mortality 10(12): 1076-1076. associated with this condition. The avoidance of 9. Mason PJ, Morris VA, Balcezak TJ. multidrug regimens is critical to the prevention Serotonin syndrome presentation of 2 cases and of the syndrome, because of the widespread use review of the literature. Medicine 2000; 79(4): of antidepressants and numerous drug combina- 201-209. tions implicated with it. 10. Werneke U, Jamshidi F, Taylor, DM, Increased patient awareness may also Ott M. Conundrums in neurology: diagnosing reduce the incidence of the SS. Patients should serotonin syndrome – a meta-analysis of cases. be educated on the early signs and symptoms of BMC Neurology 2016; 16(1). the syndrome. They should also be warned about 11. Chander WP, Singh N, Mukhiya GK. the usage of some over-the-counter medications Serotonin syndrome in maintenance haemodial- and illicit substances associated with the sero- ysis patients following sertraline treatment for tonin syndrome. depression. J Indian Med Assoc 2011; 109(1):36-37. References 12. Radomski J, Dursun S, Reveley M, 1. Boyer EW, Shannon M. The Serotonin Kutcher S. An exploratory approach to the sero- Syndrome. NEJM 2005; 352(11): 1112-1120. tonin syndrome: an update of clinical phenome- 2. Boyer EW, Traub SJ, Grayzel J. Sero- nology and revised diagnostic criteria. Med tonin syndrome. In: UpToDate. Waltham, MA: Hypotheses 2000; 55(3): 218-224. UpToDate; 2010. Accessed 28 September 2011. 13. Sternbach H. The serotonin 3. Volpi-Abadie J, Kaye AM, Kaye AD. syndrome. Am J Psychiatry 1991;148:705-13. Serotonin Syndrome. The Ochsner J 2013; 14. Sun-Edelstein C, Tepper SJ, Shapiro 13(4): 533–540. RE. Drug-induced serotonin syndrome: a 4. Dunkley E, Isbister G, Sibbritt D, review. Expert Opin Drug Saf 2008; 7(5): Dawson A, Whyte I. The Hunter Serotonin Tox- 587-596. icity Criteria: simple and accurate diagnostic 15. Shakoor MT, Ayub S, Ahad A, Ayub decision rules for serotonin toxicity. QJM 2003; Z. Transient serotonin syndrome caused by 96(9): 635-642. concurrent use of tramadol and selective sero- 5. Bronstein AC, Spyker DA, Cantilena tonin reuptake inhibitor. Am J Case Rep 2014; LR, Rumack BH, Dart RC. 2011 Annual report 15: 562–564. of the American Association of Poison Control 16. Connor H. Serotonin syndrome Centers’ National Poison Data System (NPDS): after single doses of co-amoxiclav during treat- 29th Annual Report. Clin Toxicol 2012; 50(10): ment with venlafaxine. J R Soc Med 2003; 911-1164. 96(5): 233–234. 6. Stanford S, Stanford B, Gillman P. 17. Houlihan DJ. Serotonin syndrome Risk of severe serotonin toxicity following resulting from co-administration of tramadol, co-administration of methylene blue and sero- venlafaxine, and mirtazapine. Ann Pharmacoth- tonin reuptake inhibitors: an update on a case er 2004; 38(3): 411-413. report of post-operative delirium. J Psychophar- 18. Alkhatib AA, Peterson KA, macol 2009; 24(10): 1433-1438. Tuteja AK. Serotonin syndrome as 70 PHARMACIA, vol. 65, No. 1/2018 K. Koleva, R. Nikolov a complication of fentanyl sedation during syndrome. Am Fam Physician 2010; 81(9): esophagogastroduodenoscopy. Dig Dis Sci 1139-1142. 2010; 55(1): 215-216. 20. Boddy R, Ali R, Dowsett R. The use 19. Ables AZ, Nagubilli R. Prevention, of sublingual olanzapine in serotonin syndrome. recognition, and management of serotonin J Toxicol Clin Toxicol 2004; 42: 725.

Corresponding author: Dr. Kalina Koleva Department of Pharmacology and Toxicology Faculty of Medicine, Medical University – Sofia 2 Zdrave str. 1431 Sofia, Bulgaria Phone: + 359 893660366 e-mail: [email protected]