Which are common symptoms of serotonin syndrome select all that apply

Diagnosis

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SS is a clinical diagnosis. There are no specific laboratory tests for SS. A high index of suspicion along with a detailed medication history is the mainstay of diagnosis.

Diagnostic criteria: Most accurate is Hunter Serotonin Toxicity Criteria (sensitivity 84%, specificity 97%, confirmation by toxicologist). Sternbach diagnostic criteria (Table 1) are also commonly used.

Prognosis and Complications

Serotonin syndrome is relatively uncommon, though it is thought to be underdiagnosed. Once begun, usually within hours of medication initiation or dose increase or overdose, the SS will continue as long as the serotonergic agents continue to be taken. When mild, the symptoms may become subacute or chronic. When severe, the SS can lead to death from medical complications. Discontinuation of the offending agents along with supportive care usually leads to improvement.

In SS, rhabdomyolysis is the most common and serious complication; it occurs in roughly one-fourth of cases.39 Generalized seizures occurred in approximately 10%, with 39% of these patients dying. Myoglobinuric renal failure accounted for roughly 5% of medical complications, as did diffuse intravascular coagulation (DIC). In those with DIC, nearly two-thirds died.

Serotonin Syndrome

Serotonin syndrome (Chapter 404) is an adverse drug reaction primarily produced by excess serotonergic agonism of central nervous system and peripheral serotonin receptors by selected drugs (Table 406-5). In postmarketing surveillance studies of the newer antidepressants, the syndrome has an incidence of 4 cases per 10,000 patient-months in patients who start taking nefazodone, a drug that inhibits neuronal uptake of serotonin and norepinephrine and also acts as a 5-hydroxytryptamine type 2 (5-HT2) receptor antagonist. The syndrome also occurs in 15% of patients with intentional overdose of SSRIs. The serotonin syndrome is caused by overstimulation of 5-HT1A and possibly also 5-HT2 receptors through excess of serotonin precursors or agonists, increased serotonin release, reduced serotonin uptake, and decreased serotonin metabolism. Severe cases of the syndrome have been more frequently reported in patients treated with MAOIs who took over-the-counter dextromethorphan or the illegal methylenedioxymethamphetamine (Ecstasy) or who started treatment with serotonin reuptake inhibitors, meperidine, or atypical antipsychotics such as aripiprazole.

This potentially life-threatening syndrome is characterized by changes in mental status (ranging from agitation to confusion and coma), autonomic instability (tachycardia, labile or high blood pressure, diaphoresis, and diarrhea), neuromuscular abnormalities (myoclonus, mydriasis, ocular clonus, rigidity, hyperreflexia, tremors, and shivering), and hyperthermia. The symptoms occur within the first 24 hours and sometimes within minutes after the initial use of medication, a change in dose, addition of a new drug, or an overdose attempt. Death may occur as a consequence of rhabdomyolysis with renal failure, hyperkalemia, disseminated intravascular coagulation, and acute respiratory distress syndrome. The differential diagnosis includes neuroleptic malignant syndrome, viral or bacterial meningitis or encephalitis, heat stroke (Chapter 101), anticholinergic toxidrome (Chapter 102), and drug (Chapter 31) or alcohol (Chapter 30) withdrawal.

General management includes immediate discontinuation of serotonergic drugs, comprehensive supportive therapy, and benzodiazepines for control of agitation and myoclonus. Specific therapy relies on the use of cyproheptadine (an H1-receptor antagonist with antiserotonergic and anticholinergic properties) and chlorpromazine (a 5-HT1A and 5-HT2 receptor antagonist).

Pathophysiology of Serotonin Syndrome

Serotonin syndrome is caused by increased CNS 5-HT receptor activation. Usually, increased 5-HT receptor activation is due to significantly elevated CNS levels of 5-HT, which occurs as a result of proserotonergic agent activity. It is helpful to think of serotonin syndrome not as an on/off phenomenon, but as a continuous spectrum of toxicity caused by increased CNS 5-HT levels. This is similar to the spectrum of illness severity that exists for NMS. Unlike NMS, however, serotonin syndrome is not an idiosyncratic reaction but a dose-effect phenomenon caused by the combination of proserotonergic agents. Some investigators have advocated calling it serotonin toxicity, which is a more accurate description of the phenomenon. In many well-documented cases of serotonin syndrome, however, serum drug levels are often in the therapeutic range. Serum levels of proserotonergic drugs, however, may not correlate with end-organ concentrations or, more importantly, elevated CNS serotonergic activity.

There are several different groups of 5-HT receptors found in the CNS. Most of the symptoms seen in serotonin syndrome are believed to be caused by stimulation of the postsynaptic 5-HT2A receptor.29–32 This receptor is a G protein linked to phosphoinositide-specific phospholipase C as well as a K+ channel (causes depolarization).33 Although stimulation of the 5-HT1A receptor generates stereotypical behavior in mice once thought to be analogous to serotonin syndrome in humans, it is not believed to contribute significantly to the pathologic consequences of serotonin toxicity, and specific antagonists do not provide protection against serotonin syndrome lethality in a rat model.30,31

The stimulation of 5-HT2A receptors may occur in several different ways: increased 5-HT synthesis (e.g., l-tryptophan); increased 5-HT release (e.g., amphetamines); decreased 5-HT catabolism (e.g., MAOIs); decreased 5-HT reuptake (e.g., SSRIs); direct 5-HT receptor stimulation (e.g., 5-methoxy-N,N-dimethyltrypta-mine [DMT]); and increased postsynaptic 5-HT response by secondary messenger systems (e.g., lithium). Serotonin syndrome may also be precipitated following the withdrawal of an agent with 5-HT2A antagonist effects in a patient with 5-HT receptor up-regulation/hypersensitivity or in a patient on an SSRI.34

The propensity of an agent to cause serotonin syndrome is often directly correlated with its ability to increase brain serotonin levels or to directly stimulate 5-HT2A receptors. Usually a combination of pharmaceutical agents is required to elicit serotonin syndrome, but it has been reported following overdose of single agents.35,36 For instance, serotonin syndrome was noted to occur in 14% to 16% of patients who overdosed on SSRIs in one study. In addition, overdose of MAOIs produces a toxic syndrome that significantly overlaps with serotonin syndrome. It is much more common for serotonin syndrome to occur when two agents are combined that raise brain serotonergic tone by two different mechanisms. For example, many of the severe or fatal serotonin syndrome episodes have been due to an MAOI interaction with a selective serotonin uptake inhibitor.

Serotonin reuptake inhibition appears to be a very commonly encountered cause of serotonin syndrome. The SSRIs paroxetine, clomipramine (a tricyclic antidepressant [TCA]), sertraline, fluoxetine, and venlafaxine (a serotonin norepinephrine reuptake inhibitor [SNRI]) have all been implicated as causes of serotonin syndrome. Besides clomipramine, the other TCAs (e.g., imipramine, dothiepin, and amitriptyline) have a much lower affinity for the 5-HT reuptake transporter.37,38 These TCAs have rarely caused serotonin syndrome but do not usually cause significant morbidity unless combined with an MAOI. It has been hypothesized that chlorpheniramine and, possibly, brompheniramine can contribute to serotonin syndrome due to SSRI properties of these drugs.37,39 Duloxetine, a novel SSRI, is also likely capable of causing serotonin syndrome.

Certain synthetic opiates have SSRI activity and have been implicated as agents capable of precipitating serotonin syndrome when combined with other proserotonergic agents. These opiates include tramadol, meperidine, dextromethorphan, methadone, and pentazocine.40 Tramadol may have serotonin-releasing properties in addition to being an SSRI.41

Traditional, irreversible, nonselective MAOIs (e.g., tranylcypromine, phenelzine, and clorgyline) and the newer, reversible, nonselective MAOIs (e.g., moclobemide) are readily capable of precipitating serotonin syndrome when combined with other proserotonergic agents (see Chapter 29).40,42 Selegiline, a selective, irreversible MAOI-B inhibitor, may cause serotonin syndrome at higher doses since MAO selectivity is lost at supratherapeutic doses.43,44 Linezolid, a newer antibiotic that has reversible MAO activity, has the potential to cause a serotonin syndrome.

Several drugs of abuse (e.g., hallucinogenic amphetamines, alklytryptamines, and lysergamides) can potentiate 5-HT CNS activity and result in serotonin syndrome–like toxicity, either alone or in combination with other agents. The direct serotonin receptor agonists (e.g., lysergic acid diethylamide (LSD), 2,5 dimethoxy-4 methylamphetamine (DOM), DMT, and serotonin-releasing agents (e.g., cocaine and 3,4-methylenedioxymethamphetamine [MDMA]) may produce serotonin syndrome–like toxicity.45–47 L-tryptophan is converted to serotonin in the CNS and has caused serotonin syndrome when combined with an MAOI or SSRI.

Several substances have been implicated in causing serotonin syndrome whose contributing mechanism is not well understood. Lithium is believed to contribute to serotonin syndrome because it causes an inhibition of phosphatases, thus resulting in increased intracellular inositol phosphates and potentiating the secondary messenger effects of serotonin.33,48 Trazadone and nefazodone have been implicated in several cases of serotonin syndrome, even though they appear to have 5-HT2A antagonistic properties and are not particularly potent 5-HT uptake inhibitors.37,40,49 Buspirone is a direct 5-HT1A agonist and has been implicated in causing serotonin syndrome, although its effect appears weak.46,50 Sumatriptan (a 5-HT1D agonist) has been implicated as a cause of serotonin syndrome through uncertain mechanisms.39,51 It appears that 5-HT3 antagonists (e.g., ondansetron and similar antiemetics) are unlikely to cause serotonin syndrome, although this is controversial.52 Bromocriptine and L-dopa increase brain serotonin levels and can theoretically facilitate the development of serotonin syndrome.53

It is important to understand the pharmacokinetic and pharmacodynamic characteristics of certain proserotonergic agents. For example, fluoxetine and its active metabolite, norfluoxetine, have long elimination half-lives.40 This means that there will be significant serotonin uptake inhibition long after the agent is stopped. Thus, a “washout” period of 4 weeks is recommended after drug discontinuation. Another example is the use of irreversible MAOIs. Patients will require 4 to 5 weeks for the effect of these enzyme inhibitors to completely resolve. Significant P-450 interactions (and the effect of genetic polymorphisms) are observed with several of the psychiatric medications and can result in potentiation and prolongation of their effect. For example, paroxetine has significant CYP2D6 inhibition, which can increase serum levels of other medications metabolized by CYP2D6.

Serotonin Syndrome

Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur with therapeutic drug use, overdose, or interactions between serotoninergic drugs. A large number of drugs have been associated with serotonin syndrome. These include SSRIs, atypical and cyclic antidepressants, MAOIs, opiates, cough medicine, antibiotics, antiemetic drugs, antimigraine drugs, drugs of abuse (especially “Ecstasy”), and herbal products (Table 29.3).

Typical symptoms of serotonin syndrome include agitation, delirium, autonomic hyperactivity, hyperreflexia, clonus, and hyperthermia (Fig. 29.2). Additional syndromes to consider in the differential diagnosis of serotonin syndrome are listed inTable 29.4. Treatment includes supportive measures and control of autonomic instability, excess muscle activity, and hyperthermia. Cyproheptadine, a 5-hydroxytriptamine (serotonin)type 2A (5-HT2A) antagonist, can be used to compete for and bind to serotonin receptors. It is available only for oral use.

Presentation

Serotonin syndrome occurs in patients taking selective serotonin reuptake inhibitors (SSRIs), most commonly with increase in prior prescription dosage or in combination with other medications. Less commonly, serotonin syndrome can happen in patients taking SSRIs at regular therapeutic doses. In hospital setting, serotonin syndrome can occur if other medications are added to SSRIs, such as ondansetron or metoclopramide to treat nausea, trazodone to treat insomnia, and opioids such as tramadol or fentanyl to treat pain.1

Symptoms include pressured speech, confusion, agitation, ataxia (lack of coordination, gait abnormalities), headache, heavy sweating, nausea, vomiting, diarrhea, goose bumps, twitching muscles, shivering, resting tremors, and myoclonic jerks. On examination, patients may have hyperthermia, tachycardia, elevated blood pressure, dilated pupils, clonus, or hyperreflexia.2

Serotonin syndrome

Serotonin syndrome and neuroleptic malignant syndrome are adverse reactions to psychotropic medications that can be potentially life threatening. Given many patients are on multiple psychotropic medications of different classes, it can be difficult to differentiate these two syndromes. Laboratory testing can help make these diagnoses. However, it is imperative to remember that both are diagnoses of exclusion.

Serotonin syndrome is a clinical triad of sudden mental status change, autonomic hyperactivity (including fever), and neuromuscular abnormalities, for example, myoclonus [106–108]. The etiology is related to central nervous system intrasynaptic concentrations of serotonin [106]. Serotonin plays a role both in the central nervous system and the peripheral nervous syndrome. Centrally, serotonin is responsible for regulating temperature, behavior, and attention. Peripherally, it controls constriction of the vasculature and bronchioles, the motility of the gastrointestinal tract, and influences platelet aggregation [107]. The symptoms of serotonin syndrome can be directly linked to these functions. Excess serotonin typically is caused by serotonin agonist polypharmacy or drug–drug interactions that include a serotonin agonist. Illicit drugs such as cocaine and amphetamines can lead to increased release of serotonin. Some supplements can lead to increased production of serotonin. Antidepressants can inhibit reuptake or block metabolism of serotonin. Lithium can increase postsynaptic receptor responsivity. Several drugs including buspirone, triptans, and LSD can stimulate receptors directly [107].

Symptoms of serotonin syndrome have a rapid onset, typically within 6 to 24 h. Serotonin syndrome is characterized by behavioral changes, autonomic dysfunction, neuromuscular abnormalities, and hyperthermia [106–108]. Mental status changes can range from mood changes to agitated delirium and clouded sensorium and are seen in the majority of patients with serotonin syndrome. Tachycardia, diaphoresis, shivering, mydriasis, labile blood pressures, tachypnea, diarrhea, and sialorrhea represent autonomic dysfunction. Neuromuscular irritability, which typically manifests itself as spontaneous clonus, inducible clonus, or opsoclonus, is the most important diagnostic clue for serotonin syndrome [106,108].

Laboratory findings for serotonin syndrome are nonspecific but may include leukocytosis, increased creatine kinase, myoglobin, and creatinine (due to rhabdomyolysis and subsequent acute renal failure from myoglobinuria); metabolic acidosis; disseminated intravascular coagulopathy; and elevated serum hepatic enzymes. Mortality is estimated at 11% typically caused by inadequate management of hyperthermia leading to seizures, acute renal failure, or disseminated intravascular coagulopathy [107,108].

Treatment of serotonin syndrome is primarily supportive. Stopping the offending agent is the first step. Intravascular fluids, blood pressure medications, and antipyretics can be used for symptomatic control. Benzodiazepines can be used for agitation to help prevent rhabdomyolysis. Patients may need cooling measures to decrease hyperthermia. Dantrolene has been used for hyperthermia, but there is no evidence supporting its efficacy. If muscle rigidity or myoclonus is contributing to hyperthermia, nondepolarizing paralytics and mechanical ventilation may be necessary. Cyproheptadine, which is a serotonin antagonist, can be used in severe cases [106–108].

Clinical Manifestations

Serotonin syndrome is commonly identified by the presence of the triad of alteration of mental status, autonomic hyperactivity, and neuromuscular dysfunction. In 1991, Sternbach89 reviewed 38 reported patients with serotonin syndrome and used the observed clinical features to define his diagnostic criteria (see next section). The most common manifestations were, in decreasing order of frequency, restlessness, confusion, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, hypomania, diarrhea, and incoordination. A later review found that the most common reported manifestations were, in order of decreasing frequency, hyperreflexia, altered mental status, myoclonus, ataxia, diaphoresis, fever, shivering, and diarrhea.90 Mills conducted the most comprehensive analysis of reported cases and reported the signs and symptoms in 100 previously reported cases, dividing them into cognitive/behavioral, autonomic, and neuromuscular. The results of his analysis are shown in Table 29-3.

Serotonin Syndrome

Q35.9 Serotonin syndrome is a potentially life-threatening increase in serotonergic activity within the central nervous system (CNS) that may result from the therapeutic use of, drug interactions with, or intentional overdose using any serotonergic agent. It is a consequence of excessive serotonergic agonism. Interaction between SSRI and monoamine oxidase inhibitors (MAOI), some TCA, serotonin–norepinephrine reuptake inhibitors (SNRI), buspirone, trazodone, analgesics, and linezolid (an antibiotic) may lead to serotonin syndrome. Therefore, clinicians should avoid these drug combinations in clinical practice. Symptoms of serotonin syndrome include hyperthermia, tremor, autonomic instability, altered mental status, and agitated delirium. It differs from other types of agitated delirium because of the associated neuromuscular symptoms, especially in lower extremities, ocular clonus, and increased muscle tone. Early recognition is of paramount importance because serotonin syndrome may progress rapidly. Management may involve discontinuing all serotonergic agents, supportive care to stabilize vital signs, administration of a serotonin antagonist such as cyproheptadine, as well as sedation, neuromuscular paralysis, and intubation.15

Serotonin Syndrome

The serotonin syndrome is a closely related disorder that sometimes is difficult to distinguish from neuroleptic malignant syndrome and which can also be life-threatening in severe cases. It can occur after initiation, increase in dose, or overdose of one of the SSRI or SNRI antidepressants, or with combination therapy. Other drugs that have been implicated less frequently include other classes of antidepressants such as tricyclics, monoamine oxidase inhibitors, and bupropion; opioids, triptans, lithium, antinausea medications, and dextromethorphan-containing cough suppressants; as well as some herbal supplements (e.g., St John’s wort and ginseng) and recreational drugs (e.g., LSD, ecstasy, cocaine, and amphetamines).

The features of the serotonin syndrome include high fever, tachycardia, labile blood pressure and autonomic instability, confusion, agitation, tremor, myoclonus, shivering, seizures, piloerection, hyperreflexia, and incoordination. Muscular rigidity and hyperthermia tend to be less severe than in the neuroleptic malignant syndrome; some of the other typical features, such as prodromal nausea, vomiting, and diarrhea, and shivering, hyperreflexia, myoclonus, and ataxia are uncommon in neuroleptic malignant syndrome.

Cessation of the causative drug is critical if the diagnosis is suspected. Although mild cases may recover rapidly within a few days, patients with suspected serotonin syndrome should be hospitalized for observation and treatment. Key aspects of management include maintenance of hydration with intravenous fluids, sedation and control of seizures with benzodiazepines, and administration of cyproheptadine to block serotonin production.