Serotonin syndrome

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Chapter 4 Serotonin syndrome


Dimitrios A. Nacopoulos and Hubert H. Fernandez



Introduction


Serotonin syndrome, a medical condition that gained prominent attention with the death of Libby Zion, the 18-year-old daughter of Sydney Zion (a lawyer and writer for The New York Times), remains a serious, yet preventable condition. This potentially life-threatening syndrome, which results from excess levels of serotonin (5-Hydroxytryptimine or 5-HT) in the brain, is an important condition for clinicians to recognize. The serotonin syndrome itself has several features—including the classic triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.1 These symptoms may not all be present, and occur with varying degrees of severity, which contributes to the heterogeneity of its clinical presentation. The more severe end of the spectrum can result in toxicity that can be fatal. The challenge is not only for clinicians to recognize these symptoms (as the diagnosis remains clinical); but, in addition, because the condition is not an idiosyncratic drug reaction, to also understand the syndrome at its basic level to prevent inadvertent drug interactions.


This chapter will cover the serotonin syndrome in detail, assessing the background and epidemiology, pathophysiology, clinical manifestations, diagnosis with discussion of commonly used clinical criteria, treatment, and a discussion of prevention.



History


First described in 19598 as a “fatal toxic encephalitis” in a patient with tuberculosis receiving meperidine, it was only in 1982 that the term “serotonin syndrome” was coined by Insel and colleagues.9 Prior to this, studies beginning in the 1960s on the effects of L-tryptophan (a precursor to 5-HT) on the CNS observed signs such as hyperreflexia, clonus, ataxia, drowsiness, nystagmus, and restlessness. Subsequent studies demonstrated the interaction between antidepressants that produced these symptoms.5 Hodge, in 1964, described the reduction of the central nervous system effects of L-tryptophan after administering a decarboxylase inhibitor.5


In 1984, the condition became recognized from the news headline case of Libby Zion, who died in a New York City hospital after administration of pethidine (Demerol, an opioid analgesic) and phenelzine (a nonselective and irreversible monoamine oxidase inhibitor or MAOI).10 She presented with fever and agitation, and several hours later, suffered a cardiac arrest and could not be resuscitated. Spearheaded by efforts from her journalist father, the case became famous for its implications in restriction of duty hours for graduate medical residency programs (particularly the Accreditation Council on Graduate Medical Education or ACGME); but it also brought awareness of the serotonin syndrome to the medical community. In 1991, Sternbach published his report on serotonin syndrome, including his suggested diagnostic criteria.



Epidemiology


Although the syndrome has been reported in all age groups, due to the lack of specific laboratory tests to diagnose the condition, serotonin syndrome may be underrecognized in practice. With the increasing number of proserotonergic medications prescribed in the general population, the incidence of serotonin syndrome is believed to be following suit.2 The serotonin syndrome has been reported in patients with a variety of neurological and psychiatric conditions, including depression, bipolar disorder, obsessive compulsive disorder, Parkinson’s disease, eating disorders, and others.5 There have been no laborious epidemiological assessments to date. There have been postmarketing surveillance studies on some serotoninergic drugs, such as nefazodone, with an incidence of 0.4 cases per 1000 patient-months.3 Complicating future studies is the realization that because the diagnosis is clinical, identification among clinicians can vary greatly and thus may be a challenge. A 1998 English survey among general practitioners revealed that 85 percent of those prescribing the antidepressant nefazodone were not aware of “serotonin syndrome” as a clinical diagnosis!3 In primary care settings, patients presenting with very mild symptoms such as diarrhea may not have an assessment of other clinical findings such as hyperreflexia. Moreover, many clinicians may confuse serotonin syndrome with other diagnoses, such as neuroleptic malignant syndrome.5


Toxicity reports on the use of selective serotonin-reuptake inhibitors (SSRIs) from the 2002 Toxic Exposure Surveillance System (TESS), assessing case descriptions in a variety of clinical settings, reported an incidence of exposures at 26,733 to SSRIs that caused significant toxicity in 7,349 people and resulted in 93 deaths.4 A 2004 report from TESS reported nearly double the incidence of exposures to SSRIs at 48,204, resulting in significant toxicity in 8,187 patients and 103 deaths.7 Furthermore, patients may have only mild symptoms on presentation, which often are dismissed by the practitioner rather than associated with drug therapy. In the cases reviewed and subsequent criteria proposed by Sternbach in 1991 (reviewed in the section Diagnosis), mild or early cases of the disorder may not have been recognized.1,5 Among those overdosing on SSRIs, serotonin syndrome has been reported in approximately 15% of patients.4



Medications implicated


Recognizing drugs that are known to be associated with serotonin syndrome is also important for practitioners, and its underrecognition further contributes to the lack of proper epidemiological studies at this time. The syndrome may present after a single administration of a therapeutic serotonergic drug,6 an inadvertent combination of drugs with interaction, or after overdose or subsequent to recreational use of some drugs. Many drugs and combinations of drugs with proserotonergic effects have been implicated in serotonin syndrome. Many classes of medications have been associated with this condition, including MAOIs, SSRIs, tricyclic antidepressants (TCAs), opiates, analgesics, herbal products, cough medications, antibiotics, drugs of abuse, weight-loss supplements, antinausea medications, antimigraine medications, and anticonvulsant medications.1,5


Triptan medications (5-HT agonists) used in headache conditions such as migraines have been implicated recently, with the United States Food and Drug Administration (FDA) issuing a warning in 2006 against the use of triptans concomitantly with an SSRI or a selective serotonin/norepinephrine reuptake inhibitor (SNRI) in the development of serotonin syndrome.15 Subsequently, these suspected cases were reviewed and it was discovered that the majority did not meet either Sternbach’s criteria or Hunter’s criteria (both criteria are reviewed later in the section Diagnosis). Thus, the American Headache Society in a position paper in 2010 declared that there was not sufficient data to support limiting the use of triptans with SSRIs or SNRIs.16


Severe forms of the syndrome may be seen particularly after the administration of MAOIs, which are irreversible or nonselective, particularly those inhibiting monoamine oxidase subtype A, and notably when coadministered with meperidine, dextromethorphan, SSRIs, or methylenedioxymethamphetamine (MDMA, or the drug of abuse “ecstasy”).1,4 MAO inhibitors are subdivided into their selectivity for blocking two subtypes—type A and type B. Nonselective MAO inhibitors (MAOIs) can block both subtypes, and selective inhibitors block either type A or type B. Drug interactions associated with MAO inhibitors are largely related to inhibition of MAO-A and are therefore less likely with selective MAO-B inhibitors. Concomitant use of antidepressant medications or other serotonergic agents can potentially increase the risk for serotonin syndrome.


Most serious reactions have occurred with uses of MAO-A or nonselective MAO-B inhibitors, rather than with selective MAO-B inhibitors.27 However, the FDA has issued a warning on the packages of MAO-B inhibitors used in Parkinson’s disease (selegiline and rasagiline) 28, 29 that indicates this theoretical risk. As of yet, this is not a black-box contraindication for use of serotonergic agents with MAO-B inhibitors. The risk of serotonin syndrome with MAO-B inhibitors increases as the dose escalates above what is typically prescribed. The Parkinson Study Group found that of 4,568 PD patients treated with an antidepressant and selegiline, only 11 (0.24%) reported symptoms consistent with serotonin syndrome.30 Only two patients (0.04%) experienced serious symptoms, and no fatalities occurred. No cases of serotonin syndrome have been reported with the use of rasagiline, an MAO-B inhibitor.29 Use of meperidine, tramadol, methadone, propoxyphene, dextromethorphan, St. John’s wort, and other MAO inhibitors (selective or nonselective) concurrent with MAO-B inhibitors is contraindicated, however.27


The addition of drugs that inhibit cytochrome isoforms CYP2D6 and CYP3A4 to SSRI therapy has been implicated in the condition as well. Due to the long serum half-life of certain SSRIs such as fluoxetine, even after discontinuation of the drug for up to five weeks, serotonin syndrome may still occur. Withdrawal from any of the implicated medications may also result in the syndrome.1,6,10 Some patients may present with mild clinical features and after assessment of medication history, the use of a serotonergic medication is discovered (i.e., SSRIs). As will be discussed later in the Diagnosis section, less severe clinical features are sometimes difficult to associate with a diagnosis of mild serotonin syndrome, versus mild serotonergic adverse effect. In any case, discontinuation of the medication will lead to symptomatic improvement. Typically, mild serotonergic adverse effects encountered with therapeutic efficacy will not advance to severe toxicity and severe serotonin syndrome unless an additional medication is added that leads to interaction, or an increase in dose of the suspected agent occurs.14



Pathophysiology


Serotonin is the product of decarboxylation and hydroxylation of L-tryptophan in presynaptic neurons in the central nervous system (CNS). It is stored in presynaptic vesicles where it remains until a signal mediates its release for response in neurotransmission. Once the axon is stimulated, there is release of serotonin in the synaptic space, with 5-HT binding to postsynaptic receptors. There is a feedback system where presynaptic 5-HT receptors inhibit exocytosis of vesicles, and a reuptake mechanism allows for 5-HT to return to the presynaptic space, where it again is stored in vesicles for the following neurotransmission cycle. Finally, the enzyme monoamine oxidase subtype A metabolizes serotonin in the presynaptic cytoplasm to become hydroxyindoleacetic acid, which is released from the neuronal cytoplasm.1


Early studies by Smith and Prockop on the CNS effects of L-tryptophan in humans demonstrated findings of euphoria, drowsiness, nystagmus, signs of hyperreflexia, clonus, and imbalance.13 In animal models, treatments implicated in inducing the syndrome included L-tryptophan or SSRIs given with MAOIs in combination, and simulation of the 5-HT receptor directly with 5-HT agonists.5 In the CNS, serotonin is produced primarily in the midline raphe nuclei in the brainstem. The rostral end regulates wakefulness, behavior, food intake, thermoregulation, migraine, emesis, and sexual behavior.1 The peripheral effects of serotonin include regulation of vascular tone and gastrointestinal motility.1 Feedback systems and reuptake mechanisms control the quantity and actions of serotonin in the CNS (see Box 4.1). There are seven serotonin receptor families (5-HT1 to 5-HT7), with further subgroups in each (e.g., 5-HT1A, 5-HT1B, etc.). No single receptor appears to be solely responsible in the serotonin syndrome; however, stimulation of postsynaptic 5-HT1A and 5-HT1B receptors has been more commonly associated.7 The 5-HT2A receptor subtype has also been demonstrated to contribute to developing serotonin syndrome.1



Box 4.1 Agents associated with serotonin syndrome


Drugs implicated in serotonin syndrome



– Selective serotonin-reuptake inhibitors: sertraline, paroxetine, fluoxetine, fluvoxamine, and citalopram



– Other antidepressant drugs and antipsychotics: trazodone, nefazodone, buspirone, clomipramine, and venlafaxine



– Monoamine oxidase inhibitors: phenelzine, moclobemide, clorgiline, and isocarboxazid



– Anticonvulsants: valproic acid



– Analgesics: meperidine, fentanyl, tramadol, and pentazocine



– Antinausea medications: ondansetron, granisetron, and metoclopramide



– Migraine medications: triptans*



– Antibiotics: linezolid and ritonavir



– Cough suppressants: dextromethorphan



– Drugs of abuse: methylenedioxymethamphetamine (MDMA aka “ecstasy”), lysergic acid diethylamide (LSD)



– Supplements and herbal products: tryptophan, St. John’s wort, ginseng



* – see text for FDA warning and AHS statement regarding triptans

Other neurotransmitters that may be involved include N-methyl-D-aspartate (NMDA) receptor antagonists and γ-aminobutyric acid (GABA), but their mechanism and role remain unclear. Furthermore, CNS noradrenergic hyperactivity may be involved, as demonstrated with the degree of CNS noradrenergic concentration correlating with clinical outcome as levels increase.12



Clinical Manifestations


The serotonin syndrome encompasses a clinical spectrum. Patients may demonstrate very mild findings of tachycardia, with slight anxiety, and on physical exam shivering, diaphoresis, mydriasis, with neurologic exam significant for intermittent tremor or myoclonus, and increased deep-tendon reflexes. The classic triad clinical features—mental status changes, dysautonomia, and neuromuscular abnormalities—may not be simultaneously present. Symptoms will typically develop rapidly, within minutes to hours after intake of a suspected drug or agent.7 Mild symptoms may present as a subacute or chronic presentation.1


Moderate symptoms may include tachycardia, hypertension, and hyperthermia, with temperatures reaching as high as 40°C in some cases. Clinical features in moderate toxicity seen commonly are mydriasis, hyperactive bowel sounds, and sweating, with normal skin color. Reflexes are further increased in moderate intoxication, and lower extremity reflexes may be significantly greater in particular, with clonus seen in patellar deep-tendon reflexes. Other clonus may manifest, including ocular clonus. Ocular clonus represents a spectrum of abnormal eye movements that range from fine or slight oscillations of gaze in different directions, either triggered by rapid eye movements or spontaneously, to more obvious movements such as “ping-pong gaze” with short cycle, and alternating lateral gaze.14 Startle response and mild agitation or hypervigilance may be present on cognitive testing. A dystonic posture following startle, involving repetitive rotation of the head while the neck is moderately extended, may also be seen.1


Severe toxicity can result in marked hypertension and tachycardia, with autonomic instability resulting in shock. Clinically, patients may be agitated severely and encephalopathic. Neuromuscular abnormalities including myoclonus and rigidity, greater in the lower extremities, are characteristic. In a review by Dunkley and colleagues, life-threatening cases demonstrated progressive rigidity (particularly truncal) in serotonin toxicity resulting ultimately in intubation secondary to respiratory compromise.11 Hyperthermia may result, with severe and life-threatening cases exceeding 41.1°C. Muscle hyperactivity and hyperthermia can be so severe that significant abnormal laboratory findings can occur—including metabolic acidosis, elevated creatinine kinase (even rhabdomyolysis), elevated serum aminotransferase and creatinine, and disseminated intravascular coagulopathy.1


Neuromuscular abnormalities are the clinical findings that appear to be the most significant, as demonstrated in a study assessing 2222 consecutive cases of serotoninergic drug overdose.11 Hyperreflexia, clonus, myoclonus, ocular clonus, and other neuromuscular signs are typically encountered. Additional signs observed included dysautonomia, GI symptoms such as diarrhea, and signs of hyperactive bowel sounds. Mental status with agitation and encephalopathy were associated, but hyperthermia (temperature greater than 38°C) was only encountered in severe toxicity.1

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Apr 27, 2017 | Posted by in NEUROLOGY | Comments Off on Serotonin syndrome

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