Overview of serotonin syndrome
Auburn Mental Health Unit, Central New York Psychiatric Center, Marcy, NY, USA, Department of Psychiatry, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
School of Medicine and Biomedical Sciences, SUNY Buffalo, Buffalo, NY, USA
Central New York Psychiatric Center, Marcy, NY, USAMD Touhid Iqbal, BA
Central New York Master of Public Health Program, SUNY Upstate Medical University, Syracuse, NY, USA, Syracuse University, Syracuse, NY, USA
BACKGROUND: Serotonin syndrome (SS) is a rare and potentially life-threatening toxic state caused by an adverse drug reaction that leads to excessive central and peripheral serotonergic activity. This excessive serotonin hyperstimulation may be secondary to 1 standard therapeutic dose of a single agent, inadvertent interactions between various drugs, intentionally or unintentionally excessive use of particular drugs, deliberate self-harm, or recreational use of certain drugs. This review article serves as an overview of the epidemiology, pathophysiology, clinical features, diagnosis, differential diagnosis, management, and prevention of SS.
METHODS: The authors conducted a MEDLINE search for the period covering 1955 to 2011.
RESULTS: SS commonly occurs after the use of serotonergic agents alone or in combination with monoamine oxidase inhibitors. SS classically consists of a triad of signs and symptoms broadly characterized as alteration of mental status, abnormalities of neuromuscular tone, and autonomic hyperactivity. However, all 3 triads of SS may not occur simultaneously. Clinical manifestations are diverse and nonspecific, which may lead to misdiagnosis. SS can range in severity from mild to life-threatening. Most cases of SS are mild and resolve with prompt recognition and supportive care. Management of SS involves withdrawal of the offending agent(s), aggressive supportive care to treat hyperthermia and autonomic dysfunction, and occasionally the administration of serotonin antagonists—cyproheptadine or chlorpromazine. Patients with moderate and severe cases of SS require inpatient hospitalization.
CONCLUSIONs: Psychiatrists, clinicians, and general practitioners must develop increased awareness of SS due to the current increase in the use of serotonergic agents in clinical practice. As SS is a manifestation of adverse pharmacology, it is not considered an idiosyncratic drug reaction, making it predictable and highly preventable. Most cases of SS are mild and easily managed. With prompt recognition and supportive care, more severe cases of SS have a favorable prognosis.
KEYWORDS: serotonin syndrome, antidepressants, serotonergic agents, 5-hydroxytryptamine, selective serotonin reuptake inhibitors, neuroleptic malignant syndrome
ANNALS OF CLINICAL PSYCHIATRY 2012;24(4):310-318
Serotonin syndrome (SS), previously known as serotonin toxicity,1,2 has become an increasingly common and important clinical problem with the introduction of many new antidepressants.
Typically, SS develops soon after initiation or dosage increase of the offending serotomimetic/serotonergic agents. A striking number of drugs and drug combinations have been associated with SS.1,3-9 These include monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), opiate analgesics/pain medications, over-the-counter (OTC) cough medications, muscle relaxants, antimigraine medications, weight-reducing drugs, antiemetics, street drugs/drugs of abuse, herbal products, certain foods—cheese and red wine are known for their serotonergic activity because they contain the serotonin (5-hydroxytryptamine, 5-HT) precursor tryptophan—mood-stabilizing drugs, antiviral drugs, antibiotics, and antihypertensive agents1,3-16 (TABLE 1).1,3-12,14-17
Drug combinations associated with SS
||MAO-A irreversible: Isocarboxazid, phenelzine, tranylcypromine
MAO-A reversible: Moclobemide
SNRIs: Duloxetine, venlafaxine
SSRIs: Citalopram, escitalopram, fluoxetine, paroxetine, sertraline
TCAs: Amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline
Other: Bupropion, mirtazapine, nefazodone, trazodone
|Opiate analgesics/pain medications
||Buprenorphine, cyclobenzaprine, fentanyl, hydrocodone, meperidine, morphine, oxycodone, pentazocine, tramadol
|OTC cough medication
|Antimigraine agents/triptans (5-HT1 agonists)
||Triptans: Almotriptan, dihydroergotamine, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan
Others: Carbamazepine, valproic acid
||Amphetamine, cocaine, LSD, MDA, MDMA (“ecstasy”), 5-MeO-DiPT (“foxy methoxy”), Syrian rue (Peganum harmala) seeds
||Ginseng, nutmeg, Panax, St John’s wort, Syrian rue (Peganum harmala) seeds, yohimbe
||Droperidol, granisetron, metoclopramide, ondansetron
||5-HTP, buspirone, certain foods (eg, cheese, red wine), dextromethorphan, L-dopa, lithium, valproate
||Amphetamine, cocaine, diethylpropion, methamphetamine, methylphenidate, phentermine, sibutramine
||Carbamazepine, valproic acid
||Chlorpheniramine, olanzapine, reserpine
Norepinephrine-dopamine reuptake inhibitors (NDRIs), such as bupropion, and other antidepressant drugs such as trazodone, nefazodone, and mirtazapine also have been associated with SS in some cases.1,4-9,18 There have been several case reports showing that a single therapeutic dose of an SSRI caused SS.19
Severe cases of SS have been documented from use of dextromethorphan, meperidine, tramadol, SSRIs (fluoxetine, citalopram), ecstasy, imipramine, and MAOIs10,20 and typically result from the combined use of antidepressants of the MAOI, SSRI, or SNRI classes.21 Other medications also may induce less severe forms of SS when compared with the extremely severe forms associated with MAOIs in combination with selective and nonselective SSRIs.
Newer antidepressants, including SSRIs, SNRIs such as venlafaxine and duloxetine, and NDRIs such as bupropion, have shown far fewer side effects than their precursors, the MAOIs and TCAs. This is due to their narrower range of targets within the CNS. This added safety and efficacy have allowed these newer drugs to be used widely.22
Symptom onset typically develops within hours or days after the addition of new serotonergic agents to a medication regimen that already includes serotonin-enhancing drugs.10-12,23-29 Increasing the dosage of current serotonergic therapy, either after overdose or premature initiation of serotonergic agents, also can precipitate symptoms, with up to 60% of patients presenting to a hospital within 6 hours.3,17,27,30-32
Epidemiology/the discovery of SS
SS was first described in 1959 in a patient with tuberculosis who received meperidine along with iproniazid and died of a “fatal toxic encephalitis.”14,33-36 Oates and Sjoerdsma37 first recognized SS, also known as indoleamine syndrome, in 1960 as a result of medication interactions in depressed patients with tuberculosis. The signs and symptoms—changes in mental status, ataxia, restlessness, lower extremity hyperreflexia, and diaphoresis—were attributed to excess 5-HT levels in the CNS following the administration of a high dose of tryptophan in combination with MAOIs.
Since 1959, many similar reports have been published in various psychiatric and pharmacologic journals.11,12,17,23-32 Insel et al30 first described the constellation of symptoms observed with administration of ≥2 proserotonergic medications, coining the term serotonin syndrome.35
Despite being a widespread and important clinical problem, most epidemiologic research suggests that up to 85% of general practitioners are unaware of SS.38 Boyer and Shannon3 cited a report showing that in 2002 there were 7,349 cases of SS, resulting in 93 deaths. It is estimated that 14% to 16% of those who overdose with SSRIs display symptoms of SS.39 These numbers strongly indicate how important it is for physicians, especially psychiatrists, to gain greater insight and knowledge into this potentially dangerous adverse response.
SS came to national attention after the 1984 death of Libby Zion, age 18, the daughter of a lawyer and New York Times writer. Ms. Zion had presented with fever, agitation, and confusion and died within 8 hours of her emergency admission.35,40,41 Her untimely death was attributed to serotonin toxicity, resulting from the coadministration of meperidine, prescribed by an intern for agitation, and the MAOI phenelzine, which she had already been taking for depressive symptoms.35,40
Serotonin is a neurotransmitter responsible for various roles in the body. Serotonin is unable to cross the blood-brain barrier and therefore is synthesized both peripherally and centrally by decarboxylation and hydroxylation of the dietary amino acid L-tryptophan.42 Once formed, it is stored or rapidly inactivated by monoamine oxidase (MAO). Serotonin is 1 of 3 monoamine neurotransmitters most often associated with depressive symptoms. Although serotonin generally is associated with clinical depression, there are >7 known serotonin receptor (5-HT1A to 5-HT7A) subtypes found throughout the body in many organ systems other than the CNS.
Centrally, serotonin acts as a neurotransmitter with influences on mood, personality, sleep, nausea, vomiting, pain perception, cognition, sexual behavior, temperature regulation, hormone regulation, wakefulness, affective behavior, food intake (appetite), and emesis. While correct serotonin concentrations can greatly improve quality of life, excessive amounts can have deleterious effects, which are manifested as SS.
Serotonin is produced in presynaptic neurons within the CNS, primarily in the pons and the upper brain stem,43 and released into the synapse. Once bound to postsynaptic serotonin receptors, it remains viable until removed from the synapse by reuptake pumps or degraded by the enzyme MAO-A.44-46 The cause of SS is thought to be overstimulation of postsynaptic serotonin receptors in the CNS, mainly of the 5-HT1A—associated with overstimulation, which may cause hyperactivity, hyperreflexia, and anxiety—and the 5-HT2A type—associated with hyperthermia, incoordination, and neuromuscular excitement.3,14,42,47-50
Overstimulation of 5-HT1A receptors in the central gray nuclei and the medulla are thought to be primarily responsible for major SS symptoms.42 Monoaminergic neurotransmitters, N-methyl-d-aspartate receptor antagonists, and γ-aminobutyric acid also have been suggested as affecting SS development, providing evidence that other neurotransmitters also may play a role.3,6
There are at least 4 separate ways proserotonergic drugs can interact and cause excessive serotonin activation at 5-HT1A and 5-HT2A receptors:
Decreasing serotonin breakdown (eg, MAOIs, linezolid)
Decreasing serotonin reuptake (eg, SSRIs, SNRIs, TCAs, tramadol, fentanyl, cocaine, methadone, 3,4-methylenedioxymethamphetamine [MDMA, “ecstasy”], meperidine, St John’s wort, amphetamine, dextromethorphan)
Increasing serotonin precursors or agonists (eg, L-tryptophan, antimigraine medications, lysergic acid diethylamide, buspirone)
Increasing serotonin release (eg, amphetamine, methylphenidate, MDMA, cocaine, reserpine, buspirone, lithium).3,16,44,51
Clinical features and diagnosis of SS
SS classically is characterized by a triad of neuroexcitatory features, including altered mental status, neuromuscular hyperactivity, and autonomic instability.3,6,15,16,44,51-56
Alteration of mental status—ranging from agitation, excitement, irritability, hyperactivity, restlessness, anxiety, hypomania, confusion, lethargy, disorientation, delirium, hallucinations, and drowsiness to coma—is present in about 40% of patients with SS.52
One-half of patients with SS have evidence of neuromuscular hyperactivity, including rigidity; hyperreflexia and hypertonia (greater in legs); teeth grinding; myoclonus; clonus—inducible, ocular, or spontaneous (especially in ankles); ataxia and tremor—greater in legs; and advanced stages, nystagmus and pyramidal rigidity, which may affect truncal muscles.52,53
Autonomic instability occurs in approximately 40% of patients with SS and includes dilated and unreactive pupils, tachycardia, tachypnea, fever, diarrhea, abdominal pain, flushing, profuse sweating, hypertension, or hypotension.6,52-55 Symptom onset is rapid, usually developing within 6 hours of an increase or addition of a serotonergic agent,1,3,44,57,58 and typically resolves within 24 hours.35,55 Administration of serotonergic agents within 5 weeks after discontinuation of SSRIs also has produced SS.18
SS encompasses a wide range of clinical findings, ranging from barely perceptible to fatal.57,59,60 Classically, symptoms of SS have been classified into 3 major types based on their severity: mild, moderate, and severe—the full-blown form.57 Mild toxicity may or may not worsen the patient’s condition and may occur with therapeutic use of many serotonergic drugs. Mild forms of toxicity may show intermittent tremor or twitching, myoclonus, diaphoresis, restlessness, shivering, mydriasis, no fever, tachycardia, and hyperreflexia.57
In moderate toxicity, symptoms cause the patient significant distress and require symptomatic treatment. Moderate cases may show tachycardia; hypertension; hyperthermia—up to 40°C/104°F; hyperactive bowel sounds; diaphoresis; hyperreflexia/clonus—both greater in lower extremities than upper; horizontal ocular clonus; sweaty skin; tremor—greater in lower extremities than upper; and altered mental status—mild agitation, restlessness, irritability, slight pressured speech, hypervigilance; and peculiar head turning—repetitive rotation of head with neck hold in moderate extension.
In contrast, a patient with a severe serotonin toxicity or serotonin crisis—full blown or toxic—may manifest as a medical emergency, with symptoms such as the following: elevated mood; shivering; generalized tonic-clonic seizures; shock; unstable blood pressure—either marked hypertension or hypotension; tachycardia; tachypnea; hypertonicity; increase rigidity and muscle tone—greater in lower extremities; multiple organ failure; and mental status changes, such as confusion and agitated delirium that may ultimately lead to coma.10,47,57
Other findings include rapid onset of severe hyperthermia secondary to increased muscular hyperactivity that can exceed 40°C/104°F; rhabdomyolysis; seizures; elevated creatine phosphokinase (CPK) and transaminase activity; metabolic acidosis; renal failure; and rarely, disseminated intravascular coagulopathy (DIC).57 However, many of these abnormalities, such as metabolic acidosis, rhabdomyolysis, seizures, renal failure, and DIC, arise as a consequence of poorly treated hyperthermia.
The presence of muscular hypertonicity, sustained clonus, and hyperthermia—which may rise as high as 41°C/106°F—indicate severe, life-threatening, or full-blown SS, and if not treated within hours, can progress to multiple organ failure. This is a medical emergency and is almost exclusively associated with a combination of drugs acting at different sites, most commonly including an MAOI and an SSRI.10
There is no laboratory test for diagnosing SS; therefore, diagnosis is purely clinical and relies on patient presentation, symptom observation, medication history, physical examination, patient history, and the ruling out of other neurologic disorders such as meningoencephalitis, severe sepsis, delirium tremens, heat stroke, neuroleptic malignant syndrome (NMS), malignant hyperthermia, sympathomimetic toxicity, and anticholinergic poisoning.61,62 The diagnosis should not be made without identifying a cause. Before an SS diagnosis can be made, other toxidromes that may mimic SS must be excluded.
Although specific tests for SS have not been developed, diagnostic decision tools designed to aid physicians exist. In 1991, Harvey Sternbach, a psychiatry professor at the University of California, Los Angeles first defined SS in his published article, inciting heightened clinical awareness and research interest in this syndrome.1,3,63 Since then, Sternbach’s criteria have been used to define the majority of subsequent human cases of serotonin toxicity in the literature (TABLE 2).1,52,64,65 As of 2007, Sternbach’s criteria were still the most commonly used.64
Sternbach’s clinical criteria for SS diagnosis
Recent addition or increase in dosage of all agents that increases serotonin activity or are available in the central nervous system
The presence of ≥3 of the following clinical signs or symptoms:
Absence of other possible etiologies (eg, infection, metabolic disorder, endocrine disorder, substance abuse, withdrawal, etc.)
No recent addition or increase in the dose of a neuroleptic drug
Subsequently, several other diagnostic criteria have been developed to aid diagnosis, such as the Hunter Serotonin Toxicity Criteria (TABLE 3)3,52,65-67 and the Serotonin Syndrome Scale1,52 to assist with the difficulties surrounding SS diagnosis.1,58,65 Although Sternbach’s criteria exist, the gold standard of diagnosis is examination by a medical toxicologist.52
Hunter serotonin toxicity criteria
No specific laboratory abnormalities have been identified in association with SS. Those that have been reported have been either nonspecific (eg, leukocytosis) or secondary to complications of the syndrome (eg, azotemia). However, a thorough laboratory evaluation is often needed to rule out other causes of the clinical features associated with SS, especially in moderate to severe cases. These evaluations may include CPK, transaminase, myoglobin, and electrolyte levels—mainly sodium, magnesium, and calcium—and also may include drug screens.
Increases in CPK found in rhabdomyolysis, myoglobin secondary to muscle breakdown from muscular activity or rigidity, and decreases in sodium, magnesium, and calcium also have been reported in isolated cases secondary to fluid and electrolyte disturbances resulting from severe SS. Measurement of serum serotonin levels has not been shown to be helpful.35
The differential diagnosis of SS is extensive and should include cognitive, behavioral, neuromuscular, and autonomic nervous system dysfunction with or without hyperthermia.62,68,69 Other toxidromes to be considered are anticholinergic syndrome, sympathomimetic syndrome/toxicity from poisoning with OTC cold remedies containing ephedrine, illegal drug use, dietary supplement use, malignant hyperthermia, NMS from the use of antipsychotic agents, abrupt discontinuation of neuroleptic or antiparkinsonian agents, and the use of dopamine-depleting agents.70
Patients with anticholinergic syndrome or anticholinergic toxicity have normal reflexes; hot, red, dry, blotchy, and flushed skin; decreased mucus production resulting in dry mouth, nose, and throat; sore throat; urinary retention; dilated pupils with photophobia; altered consciousness—agitation, confusion, disorientation, delirium, and loss of coordination; auditory or sensory hallucination; increased vital signs—tachycardia, tachypnea, and hyperthermia; shaking; and a decrease or absence of bowel sounds. Patients with anticholinergic syndrome do not develop neuromuscular abnormalities. Treatment involves symptomatic and supportive care with the use of physostigmine as an antidote.
Patients with sympathomimetic syndrome or toxicity present signs and symptoms that include tachycardia, hypertension, diaphoresis, hyperthermia, and altered consciousness. Treatment involves physical, and more importantly, pharmacologic control of their agitation and combativeness.
Malignant hyperthermia (MH), also known as malignant hyperthermia syndrome or malignant hyperpyrexia,71 is a rare, life-threatening condition usually triggered by exposure to certain volatile drugs (eg, halothane, desflurane, sevoflurane) and neuromuscular blocking agents (succinylcholine) used for general anesthesia.72
Patients with MH present signs and symptoms including sweaty and mottled skin, generalized rigor mortis like rigidity and stiffness of the extremities, hyporeflexia, decreased bowel sounds, fluctuation of blood pressure, and increased vital signs—most importantly, very high body temperature: up to 46°C/114.8°F.
Patients with MH also present with metabolic and respiratory acidosis, hyperkalemia, and rhabdomyolysis; and dark, bloody urine, which if left untreated can lead to circulatory collapse and death. Symptoms usually develop within 1 hour after exposure to trigger substances, but may even occur several hours later in rare instances. Treatment involves reduction of temperature by using cooling blankets as well as supportive care with administration of IV dantrolene, lidocaine, or a beta blocker.
The development of NMS appears to be an idiosyncratic adverse drug reaction73,74 that has a more gradual onset.62 All antipsychotic medications are D2 dopamine receptor antagonists, which may cause many of the symptoms associated with NMS.73,74 Patients with NMS may have extremely high fever; diffuse “lead-type” rigidity throughout all extremities (catatonia); pale, sweaty skin; bradyreflexia; difficulty swallowing and speaking; sialorrhea; profuse sweating; incontinence; seizure; tremor; autonomic dysfunction—tachycardia, rapid heart beat, rapid breathing, or fluctuation of blood pressure; normal or dilated pupils; altered mental status; hypoxia with respiratory failure; metabolic acidosis; and acute renal failure.
Patients with NMS also have abnormal laboratory findings—myoglobin in urine and increased levels of serum transaminase, CPK, and white blood cells.62 Signs and symptoms of NMS usually resolve within 5 to 14 days after discontinuation of causative agents. Treatment involves symptomatic and supportive care (hydration, nutrition, and reduction of fever) with administration of dantrolene or bromocriptine to decrease muscular rigidity and body temperature.
There have been no gastrointestinal abnormalities, muscular rigidity, or hyperreflexia observed with NMS compared with SS. Catatonia, transaminase and CPK elevation, and leukocytosis are all abnormalities reported in both SS and NMS, although frequently noticed in NMS.75 In sum, there are many overlapping aspects in the clinical presentation of SS and NMS.
Management of SS
There are no prospective, randomized controlled trials for the management of SS.1 Management principles are largely based on case series, and include supportive measures, such as the control of agitation, autonomic instability, and hyperthermia, and specific antiserotonergic therapies and therapies directed toward neuromuscular excitability.76 Additionally, those who ingest large doses of serotonergic agents may benefit from gastrointestinal decontamination with activated charcoal if it can be administered within 1 hour of overdose.64
The initial management and treatment for all forms of SS is supportive care and cessation of any serotonergic medications. Initiation of supportive measures in the emergency department is imperative. Initial management must focus on the removal of the offending agents; focus on airway, breathing, circulation, and supportive care, including passive and active cooling of the patient; sedation, intubation; and controlling agitation, hyperthermia, muscle paralysis, and autonomic instability.77
Mild SS cases may not require hospital admission and may only require cessation of offending agents and supportive care. Supportive care can prevent secondary complications, such as rhabdomyolysis, renal failure, and DIC. Patients should be observed for at least 6 to 12 hours to monitor vital signs, electrolytes, and kidney function. Most patients will improve within 24 to 36 hours with treatment focused on decreasing muscle rigidity and controlling hyperthermia.58
Patients with moderate SS may show progressively increasing toxicity a number of hours after ingestion of serotonergic drugs and should be observed for 6 hours. However, if a slow-release formulation has been ingested, observation should be continued for 12 hours.64
Patients presenting with severe SS should be admitted on an urgent basis and referred to the intensive care unit, where neuromuscular complications can be treated with pharmacotherapy and artificial ventilation. Means to control muscular rigidity and possible hyperthermia also should be used and include benzodiazepine sedation, external cooling, and other methods seen in the treatment of MH.3,64,78
Aggressive fluid replacement is a mainstay of therapy. Therefore, it is recommended to rapidly correct any fluid deficits with crystalloids to maintain a high urine output (200 to 300 mL/h).79,80 Numerous studies indicate there may be a role for specific serotonin antagonists in serotonin toxicity, and animal studies provide data that nonspecific 5-HT2 antagonists and more selective 5-HT2A receptor antagonists reverse the lethal effects of serotonin toxicity.50,56 There are numerous case reports of patients improving after being given 5-HT2A receptor antagonists—cyproheptadine and chlorpromazine3,41,81,82—in the treatment of moderate to severe SS.3,9
The use of cyproheptadine, the most widely prescribed 5-HT antagonist, for the treatment of SS in humans is limited. Because cyproheptadine may only be administered nasogastrically, it is unlikely to be effective in patients administered activated charcoal and has limited use in severe cases.64 In less severe cases, cyproheptadine may produce rapid resolution of symptoms within 1 hour.81 The doses of cyproheptadine used in managing SS are an initial dose of 4 mg to 8 mg every 6 hours because of recurrence of symptoms. The main side effect of cyproheptadine is sedation, which usually is beneficial for controlling agitation.
Chlorpromazine has been reported to be effective in management of SS.3,83 Unlike cyproheptadine, chlorpromazine can be administered intramuscularly or intravenously, allowing for the treatment of severe cases of SS. Chlorpromazine should not be routinely used to manage SS, especially if the patient is hypotensive and/or NMS cannot be excluded.42
SS is highly preventable at the primary level, and increased awareness of this adverse drug reaction can reduce the various autonomic, somatic, and cognitive symptoms related to SS.3
Prevention should start with increased education for and awareness by both physicians and patients regarding the possibility of toxicity from serotonergic drugs. Physicians should be up to date on the patient’s current medications as well as previous medication history. Interactions between drugs are complex, and the risk of serotonin toxicity rises with the use of ≥2 serotonergic agents. Physicians should carefully monitor patients at increased risk of SS for its related symptoms, since there is currently no laboratory test to confirm a diagnosis.64 Physicians also should limit polypharmacy whenever possible to further decrease the risk of SS. Along with increased awareness, physicians should also be knowledgeable about what drugs and combinations of drugs may manifest as a possible source of serotonin toxicity. This will allow physicians to minimize prescribing drugs known to have a high probability of inducing SS, as well as creating the possibility of alternative drug options. Physicians as well as pharmacists can use medical software to check for possible adverse interactions when multiple drug regimens are necessary.67
Also important for primary prevention is to understand that serotonin levels can be affected by various agents, including OTC drugs, illicit drugs, and dietary supplements as well as general lifestyle. Patients must be forthcoming with their physicians regarding their health, diet, and lifestyle to avoid drug treatments that may disrupt proper serotonin activity. Physicians should encourage patients who have a history of depression or related diseases to seek natural ways, such as exercise and stress management, to promote healthy serotonin levels.
Although an uncommon adverse effect of combinations or high dosages of serotonergic medications, SS is potentially life-threatening and warrants further attention because the prescribing of inciting agents like SSRIs and serotonergic agents continues to increase among psychiatrists and general practitioners. Because diagnosing SS is based solely on patient presentation and medication history, greater awareness of the drug combinations commonly associated with the syndrome, attention to medication history, and patient presentation, combined with greater awareness of signs and symptoms, should enhance early recognition and treatment. SS is a complex but easily preventable and recognizable condition. Management varies depending on the severity of symptoms and consists of multiple treatment options. Such strategies include discontinuation of responsible medications, supportive care, administration of 5-HT2A receptor antagonists (eg, cyproheptadine or chlorpromazine), control of agitation with benzodiazepines (eg, lorazepam), and treatment of autonomic dysfunction and hyperthermia.
The manufacturer’s advice about washout periods should be considered carefully when switching or prescribing >1 antidepressant. By limiting drug combinations, improving compliance with “medication holidays,” and educating patients about possible drug interactions, avoiding self-medication (including OTC and herbal medications), and symptoms of serotonin toxicity and SS, its incidence may be reduced and early diagnosis facilitated.
DISCLOSURE: The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
- Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148:705–713.
- Buck ML. Serotonin syndrome: pediatric and neonatal considerations. Pediatric Pharmacotherapy. 2006;12:1–5.
- Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112–1120.
- Jones D, Story DA. Serotonin syndrome and the anaesthetist. Anaesth Intensive Care. 2005;33:181–187.
- Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy. 2006;26:1784–1793.
- Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs. Anesth Analg. 2006;103:1466–1468.
- D’Esposito M. Serotonin neurotoxicity: implications for cognitive neuroscience and neurology. Neurology. 1998;51:1529–1530.
- Parker V, Wong AH, Boon HS, et al. Adverse reactions to St John’s Wort. Can J Psychiatry. 2001;46:77–79.
- Strouse TB, Kerrihard TN, Forscher CA, et al. Serotonin syndrome precipitated by linezolid in a medically ill patient on duloxetine. J Clin Psychopharmacol. 2006;26:681–683.
- Isbister GK, Hackett LP, Dawson AH, et al. Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. Br J Clin Pharmacol. 2003;56:441–450.
- Sovner R, Wolfe J. Interaction between dextromethorphan and monoamine oxidase inhibitor therapy with isocarboxazid. N Engl J Med. 1988;319:1671.
- Bhatara VS, Bandettini FC. Possible interaction between sertraline and tranylcypromine. Clin Pharm. 1993;12:222–225.
- Marley E, Wozniak KM. Interactions of non-selective monoamine oxidase inhibitors tranylcypromine and nialamide, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake. J Psychiatr Res. 1984;18:191–203.
- Hall M, Buckley N. Serotonin syndrome. Australian Prescriber. 2003;26:62–63.
- Keck PE Jr, Arnold LM. Serotonin syndrome. Psychiatr Ann. 2000;30:333–343.
- Wooltorton E. Triptan migraine treatments and antidepressants: risk of serotonin syndrome. CMAJ. 2006;175:874.
- Westphal RJ. Serotonin syndrome. J Am Psychiatr Nurses Assoc. 1999;5:97–102.
- Gill M, LoVecchio F, Selden B. Serotonin syndrome in a child after a single dose of fluvoxamine. Ann Emerg Med. 1999;33:457–459.
- Demirkiran M, Jankovic J, Dean JM. Ecstasy intoxication: an overlap between serotonin syndrome and neuroleptic malignant syndrome. Clin Neuropharmacol. 1996;19:157–164.
- Milnacipran (savella) for fibromyalgia. Med Lett Drugs Ther. 2009;51:45–46.
- Rajapakse S, Abeynaike L, Wickramarathne T. Venlafaxine-associated serotonin syndrome causing severe rhabdomyolysis and acute renal failure in a patient with idiopathic Parkinson disease. J Clin Psychopharmacol. 2010;30:620–622.
- Thomas JM, Rubin EH. Case report of a toxic reaction from a combination of tryptophan and phenelzine. Am J Psychiatry. 1984;141:281–283.
- Guzé BH, Baxter LR Jr. The serotonin syndrome: case responsive to propranolol. J Clin Psychopharmacol. 1986;6:119–120.
- Smilkstein MJ, Smolinske SC, Rumack BH. A case of MAO inhibitor/MDMA interaction: agony after ecstasy. J Toxicol Clin Toxicol. 1987;25:149–159.
- Pearson HJ. Interaction of fluoxetine with carbamazepine. J Clin Psychiatry. 1990;51:126.
- Iruela LM, Minguez L, Merino J, et al. Toxic interaction of S-adenosylmethionine and clomipramine. Am J Psychiatry. 1993;150:522.
- Goldberg RJ, Huk M. Serotonin syndrome from trazodone and buspirone. Psychosomatics. 1992;33:235–236.
- Neuvonen PJ, Pohjola-Sintonen S, Tacke U, et al. Five fatal cases of serotonin syndrome after moclobemide-citalopram or moclobemide-clomipramine overdoses. Lancet. 1993;342:1419.
- Insel TR, Roy BF, Cohen RM, et al. Possible development of the serotonin syndrome in man. Am J Psychiatry. 1982;139:954–955.
- Ooi TK. The serotonin syndrome. Anaesthesia. 1991;46:507–508.
- Brannan SK, Talley BJ, Bowden CL. Sertraline and isocarboxazid cause a serotonin syndrome. J Clin Psychopharmacol. 1994;14:144–145.
- Sandyk R. L-dopa induced “serotonin syndrome” in a parkinsonian patient on bromocriptine. J Clin Psychopharmacol. 1986;6:194–195.
- Mitchell RS. Fatal toxic encephalitis occurring during iproniazid therapy in pulmonary tuberculosis. Ann Intern Med. 1955;42:417–424.
- Gillman PK. Serotonin syndrome: history and risk. Fundam Clin Pharmacol. 1998;12:482–491.
- Arora B, Kannikeswaran N. The serotonin syndrome—the need for physician’s awareness. Int J Emerg Med. 2010;3:373–377.
- Sorenson S. Serotonin syndrome. Utox Update. 2002;4:1–2.
- Oates JA, Sjoerdsma A. Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor. Neurology. 1960;10:1076–1078.
- Mackay FJ, Dunn NR, Mann RD. Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract. 1999;49:871–874.
- Isbister GK, Bowe SJ, Dawson A, et al. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277–285.
- Asch DA, Parker RM. The Libby Zion case. One step forward or two steps backward? N Engl J Med. 1988;318:771–775.
- Graham PM. Successful treatment of the toxic serotonin syndrome with chlorpromazine. Med J Aust. 1997;166:166–167.
- Hall RCW, Hall RCW, Chapman MJ. Central serotonin syndrome: Part II—Pathophysiology drug interactions, and treatment. Clin Geriatr. 2008;16:24–28.
- Mills KC. Serotonin syndrome. Am Fam Physician. 1995;52:1475–1482.
- Birmes P, Coppin D, Schmitt L, et al. Serotonin syndrome: a brief review. CMAJ. 2003;168:1439–1442.
- Mills KC. Serotonin syndrome. A clinical update. Crit Care Clin. 1997;13:763–783.
- Glennon RA, Dukat M, Westkaemper RB. Serotonin receptor subtypes and ligands. In: Bloom FE Kupfer DJ, eds. Psychopharmacology: the fourth generation of progress. New York, NY: Raven Press, Ltd; 1995.
- Bishop JR, Bishop DL. How to prevent serotonin syndrome from drug-drug interactions. Current Psychiatry. 2011;10:81–83.
- Nelson LS, Erdman AR, Booze LL, et al. Selective serotonin reuptake inhibitor poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007;45:315–332.
- Glennon RA. Serotonin receptors: clinical implications. Neurosci Biobehav Rev. 1990;14:35–47.
- Nisijima K, Yoshino T, Yui K, et al. Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res. 2001;890:23–31.
- Bodner RA, Lynch T, Lewis L, et al. Serotonin syndrome. Neurology. 1995;45:219–223.
- Walsh J. Serotonin syndrome. Anaesthesia Tutorial of the Week. 2010;1–5.
- Dvir Y, Smallwood P. Serotonin syndrome: a complex but easily avoidable condition. Gen Hosp Psychiatry. 2008;30:284–287.
- Thanacoody RHK. Serotonin syndrome. Adverse Drug React Bull. 2007;243:931–934.
- Gelener P, Gorgulu U, Kutlu G, et al. Serotonin syndrome due to duloxetine. Clin Neuropharmacol. 2011;34:127–128.
- Isbister GK, Buckley NA. The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clin Neuropharmacol. 2005;28:205–214.
- Radomski JW, Dursun SM, Reveley MA, et al. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses. 2000;55:218–224.
- Martin TG. Serotonin syndrome. Ann Emerg Med. 1996;28:520–526.
- Kaneda Y, Ishimoto Y, Ohmori T. Mild serotonin syndrome on fluvoxamine. Int J Neurosci. 2001;109:165–172.
- Lantz MS. Serotonin syndrome. A common but often unrecognized psychiatric condition. Geriatrics. 2001;56:52–53.
- Garside S, Rosebush PI. Serotonin syndrome: not a benign toxidrome. CMAJ. 2003;169:543.
- Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth. 2000;85:129–135.
- Hegerl U, Bottlender R, Gallinat J, et al. The serotonin syndrome scale: first results on validity. Eur Arch Psychiatry Clin Neurosci. 1998;248:96–103.
- Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust. 2007;187:361–365.
- Jacobs BL. An animal behavior model for studying central serotonergic synapses. Life Sci. 1976;19:777–785.
- Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96:635–642.
- Ables AZ, Nagubilli R. Prevention recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81:1139–1142.
- Wappler F. Malignant hyperthermia. Eur J Anaesthesiol. 2001;18:632–652.
- Frommer DA, Kulig KW, Marx JA, et al. Tricyclic antidepressant overdose. A review. JAMA. 1987;257:521–526.
- Hasan S, Buckley P. Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique. Am J Psychiatry. 1998;155:1113–1116.
- Rosenberg H, Davis M, James D, et al. Malignant hyperthermia. Orphanet J Rare Dis. 2007;2:21.
- Gronert GA, Pessah IN, Muldoon SM, et al. Malignant hyperthermia. In: Miller RD, ed. Miller’s anesthesia. 6th ed. Philadelphia, PA: Elsevier Churchill Livingston; 2005:1169–1190.
- Odagaki Y. Atypical neuroleptic malignant syndrome or serotonin toxicity associated with atypical antipsychotics? Curr Drug Saf. 2009;4:84–93.
- Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin. 2004;22:389–411.
- Keltner NL, Folks DG. Psychotropic drugs. 4th ed. St. Louis MO: Elsevier; 2005.
- Sporer KA. The serotonin syndrome. Implicated drugs pathophysiology and management. Drug Saf. 1995;13:94–104.
- Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol. 1999;13:100–109.
- Mir S, Taylor D. Serotonin syndrome. Psychiatric Bulletin. 1999;23:742–747.
- Bagley WH, Yang H, Shah KH. Rhabdomyolysis. Intern Emerg Med. 2007;2:210–218.
- Criddle LM. Rhabdomyolysis. Pathophysiology recognition, and management. Crit Care Nurse. 2003;23:14–22, 24–26, 28.
- Lappin RI, Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med. 1994;331:1021–1022.
- Chan BS, Graudins A, Whyte IM, et al. Serotonin syndrome resulting from drug interactions. Med J Aust. 1998;169:523–525.
- Gillman PK. Successful treatment of serotonin syndrome with chlorpromazine. Med J Aust. 1996;165:345–346.
CORRESPONDENCE: Mohammad M. Iqbal, MD, MPH, MSPH, Auburn Mental Health Unit, Central New York Psychiatric Center, PO Box 300, Marcy, NY 13403 USA E-MAIL: email@example.com
Annals of Clinical Psychiatry ©2012 Frontline Medical Communications.