Serotonin toxicity (ST) (aka serotonin syndrome) is a cluster of symptoms that develops with very high serotonin levels or serotonergic activity from direct agonists at certain serotonin receptors. It is most often seen with a combination of drugs, such as a monoamine oxidase inhibitor (MAOI) with a serotonin reuptake inhibitor (SRI), but it can also occur with a single drug, usually when a substantial overdose is used.
The effects of overly high serotonin exist on a spectrum. The mildest cases often won’t meet the diagnostic criteria for serotonin toxicity even though the observed symptoms are technically the result of high serotonin. This means a threshold of sorts must be crossed for serotonin toxicity to be diagnosed. Classically the condition has been defined as including symptoms from three categories: neuromuscular (arguably the most important), autonomic, and mental.
It may be an underdiagnosed condition given how many other conditions can present similarly to it, especially with mild cases, and due to clinicians simply being unaware of it. One report found over 85% of clinicians are unaware of the diagnosis itself (Sun-Edelstein, 2008). At the same time, the literature contains many reports of alleged serotonin toxicity that may not actually be ST. Much of the time the potentially inaccurate reports are attributable to the use of the first diagnostic criteria for serotonin toxicity described by Sternbach. Those criteria allow for a diagnosis to be made with primarily mental symptoms and without some of the more serotonin-specific symptoms like neuromuscular changes, thereby making it easier for misdiagnosis.
The clearest reports of ST are those that have significant neuromuscular symptoms like clonus, hyperreflexia, or rigidity. When relying on other mental and physical symptoms it’s possible for different conditions (e.g. neuroleptic malignant syndrome, anticholinergic toxicity, malignant hyperthermia, and simple drug overdose/adverse drug effects) to be diagnosed as ST. While not perfect, the Hunter diagnostic criteria described by Dunkley (2003) may be preferable because they emphasize neuromuscular effects.
Historically the more common term has been serotonin syndrome, but because “syndrome” may imply an idiosyncratic reaction, as with neuroleptic malignant syndrome, the term “serotonin toxicity” is preferable.
Some psychedelics. There are few reports of this occurring with certain drugs, such as 2C-I and 25I-NBOMe. Overall it’s usually not a risk with psychedelics, especially LSD, psilocin, DMT, and other common ones.
Enzyme inhibitors that inhibit the metabolism of a serotonergic drug.
Mostly serotonergic substances are the primary causal drugs, including MAOIs, SSRIs, and SNRIs. Tricyclic antidepressants (TCAs) aren’t always a major concern due to them generally being less potent serotonergics, as is seen with amitriptyline, though some, like clomipramine and imipramine, carry a notable risk of ST.
SRIs alone (in overdose) or in combination have been associated with ST. This includes all SSRIs and SNRIs like venlafaxine, which may actually be more concerning than SSRIs on average.
SRIs (selective and nonselective): paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram/escitalopram, venlafaxine, milnacipram, duloxetine, sibutramine, tramadol, dextropropoxyphene, pentazocine, meperidine, fentanyl, methadone, dextromethorphan, clomimpramine, imipramine. ST occurs in 14-16% of patients who overdose on SSRIs, according to data from the UK’s National Health Service (Sun-Edelstein, 2008).
Older, irreversible MAOIs like tranylcypromine are some of the most concerning drugs and fatal ST can easily arise from those drugs being taken with SRIs or serotonin releasers. All nonselective MAOIs and selective MAO-A inhibitors come with some potential for ST, including moclobemide, despite some reviews claiming it can be used with other serotonergics without risk of ST (Sun-Edelstein, 2008). Moclobemide has been implicated in multiple cases of ST (Neuvonen, 1993) when used with an SSRI. When used alone, moclobemide is relatively safe even in overdose. It can take weeks for enzyme activity to return to baseline after an irreversible MAOI is used, so 4-6 weeks should be given between ending an irreversible MAOI and starting a new serotonergic drug.
Some opioids have enough serotonergic activity to be implicated in ST when combined with other drugs. This includes the phenylpiperidine opioids meperidine, tramadol, methadone, fentanyl, and propoxyphene. Fentanyl should be used cautiously but more evidence is needed to confirm it is problematic. Fentanyl derivatives like remifentanil appear to be safer due to having shorter half-lives and/or preferable pharmacodynamic properties.
Morphine and its analogs codeine, oxycodone, hydrocodone, and buprenorphine, among others, do not have known SRI properties and don’t appear to be associated with ST alone or in combination with serotonergics (Sun-Edelstein, 2008).
Serotonin releasers, particularly highly serotonergic releasers like the entactogens (e.g. MDMA, 6-APB, 5-MAPB, and MDA), can cause ST. Most often this occurs when combining them with other drugs, but overdoses can cause ST as well. When combined with SRIs the risk of ST is usually reduced due to the SRI blocking the releaser’s entrance to presynaptic terminals, thereby blocking the releaser’s activity.
Serotonin precursors carry some risk of ST, though essentially just in combination. Among the implicated precursors are 5-HTP and tryptophan. One of the earliest models of ST-like effects in animals used tryptophan combined with an MAOI, which has been shown to increase brain serotonin more than an MAOI used by itself (Sun-Edelstein, 2008). Tryptophan with MAOIs was also a cause of ST in humans when it used to be prescribed for depression.
Despite a warning from the FDA and other health agencies stating triptans can cause ST when combined with SRIs, there is little supporting evidence for this. The triptans are 5-HT1B, 5-HT1D, and 5-HT1F agonists; those receptors have not been implicated in the pathophysiology of ST. An alert about their connection to ST was issued by the FDA in 2006 based on 29 reports of apparent ST stemming from triptans combined with SSRIs, yet a subsequent analysis found the FDA-cited cases largely had questionable diagnoses and even if every FDA reported case was legitimate and 10% of all US cases of ST stemming from triptans/SSRIs were reported, the annual incidence of ST would be under 0.03% for patients exposed to both drugs, with an annual incidence of life-threatening events under 0.002% (Sun-Edelstein, 2008).
Other implicated drugs are chlorpheniramine and brompheniramine (due to SRI activity), dextromethorphan, tramadol, and lithium, which appears to potentiate serotonergics and ST (Goodwin, 1986). Because some of the causal drugs are found in cough/cold medications, the potential interaction with existing serotonergic drugs should be considered before taking those over-the-counter preparations. That being said, the normal use of an SSRI with an OTC preparation containing dextromethorphan, for example, typically won’t be dangerous.
Though rare, 5-HT2A agonists like psychedelics may cause serotonin toxicity on their own or in combination with other serotonergic drugs. A few case reports have shown this in humans, such as with 2C-I (Bosak, 2013) and animal studies have shown ST-like symptoms can be generated by LSD and 5-MeO-DMT (Goodwin, 1986 ; Lucki, 1982). If 5-HT2A is indeed the primary receptor responsible for ST it makes sense that 2A agonists can, at least in overdose, cause the condition.
Mirtazapine, triptans, ondansetron, olanzapine, buspirone, lithium (alone), trazodone, cyclobenzaprine, and olanzapine do not appear to cause ST (Foong, 2018). Rather than causing ST, mirtazapine has been shown in animals to inhibit hyperthermia and behavioral effects when rats are given an MAOI/SSRI combo (Shioda, 2010).
The three main effect categories are mental, autonomic, and neuromuscular and the most accurate diagnoses will come when a patient is showing symptoms from each category:
Neuromuscular: Hyperreflexia, clonus (e.g. myoclonus, ocular clonus, inducible clonus, or spontaneous clonus), hypertonia, tremor, shivering, and rigidity.
A lot of the same effects can be caused in a setting that is not concerning, such as the normal use of MDMA. Many recreational drug users become unnecessarily concerned about serotonergic drugs due to knowing too much serotonergic activity can be dangerous. In reality, it is a pretty uncommon occurrence when a single serotonergic is taken at a normal dose. And some combinations that are listed as having a risk of ST are actually not that concerning. As Buckley (2014) notes, a clinician searching drug interactions on a resource like Drugs.com may be warned of a thousand interacting drugs that are supposedly linked to “rare but serious” ST, yet ST is primarily linked to just a a couple dozen drugs from a few categories.
Lab findings include increases in white blood cell count (WBC) and creatine kinase (CK).
Someone experiencing ST will often initially be alert alongside less-risky symptoms like sweating, mydriasis, and increased heart rate. When neuromuscular symptoms do develop they are more pronounced in the lower limbs. In more severe instances the mental effects can deteriorate to agitated delirium (Sun-Edelstein, 2008).
The most common neuromuscular symptoms are tremor and hyperreflexia, followed by muscle rigidity and hyperetonia. Myoclonus is more common than clonus (Werneke, 2016). Ocular clonus can include a range of abnormal eye movements such as fine or coarse alterations of gaze in various directions. Those alterations can either be continuous or triggered by eye movement (Buckley, 2014).
While it has often been differentiated from neuroleptic malignant syndrome (NMS) based on it supposedly having an onset of a few hours after the initiation of a serotonergic drug or a dose increase, this doesn’t appear true. Symptoms can show up hours to days after a change in medication.
There’s little agreement between the three diagnostic criteria (Sternbach, Radomski, and Hunter), complicating diagnosis. Werneke (2016) demonstrated with a meta-analysis of cases published between 2004 and 2014 that only 48.8% of cases meet all three criteria and the Hunter criteria were found to identify fewer cases with overdose, rhabdomyolysis, and intensive care treatment compared to Sternbach and Radomski, making it useful for clinicians to consider all criteria when deciding if someone has ST, rather than exclusively using the Hunter criteria. 35.7% of rhabdomyolysis cases and 35.1% of cases requiring ICU treatment would not have been diagnosed as ST if strictly following the Hunter criteria and it’s unlikely all of those cases were misdiagnosed with the other criteria.
More severe cases, such as those requiring ICU treatment, produce significantly more clonus, rigidity, hypertonicity, hyperthermia, and tachypnea/dyspnea. Respiratory compromise may arise from rigidity affecting the truncal musculature and via separate serotonergic mechanisms.
Elevated temperature is very common, though a greater than 38°C temperature is only seen in 59.7% of cases and a temperature higher than 41.1°C is only seen in 9.2% (Werneke, 2016). Because of this, hyperthermia should not be relied on in diagnosis since diagnosing based on 38+°C temp will lead to missing ST in one-quarter of ICU cases and diagnosing based on 41.1+°C temperature will cause 4/5 of ICU cases to be missed. Hyperthermia is a primary cause of many of the worst effects of ST, including metabolic acidosis, rhabdomyolysis, and DIC.
There are many similarities between ST and NMS, which is why taking into account a patient’s medication/substance use history is vital during diagnosis. Altered mental state, autonomic instability, rigidity, increased temperature, and increased CK can occur in both. Though NMS can often be distinguished by the presence of lead-pipe rigidity rather than clonus/hyperreflexia, a lack of mydriasis, and exposure to neuroleptic agents or the withdrawal of dopamine agonists.
Diagnosis can be complicated by drugs having persistent activity (e.g. irreversible MAOIs) or long half-lives. Factors like those have sometimes led to drugs causing ST despite having been discontinued days to weeks prior. This also means it is best to discontinue serotonergic medications for at least a couple weeks before starting a new one.
Mild ST can be hard to differentiate from the mere non-toxic effects of a drug, Therapeutic SSRI use, for example, may cause altered mental status and some hyperreflexia or ankle clonus without toxicity (Buckley, 2014), so it’s easiest to diagnose the condition when a range of overt symptoms are present.
The original diagnostic criteria were outlined by Sternbach (1991) and those criteria are still the most widely used:
Recent addition or increase in dose of a known serotonergic drug.
Absence of other possible causes like infection, substance abuse, withdrawal, etc.
No recent addition or increase in dose of a neuroleptic drug.
At least 3 of these: mental status changes (confusion, hypomania), agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, ataxia, incoordination, and fever.
Because the Sternbach criteria allow for diagnosis with primarily mental symptoms there may be a higher than ideal risk of misdiagnosis. Certain symptoms, namely ataxia/incoordination, should also generally be left out of the diagnostic criteria given a lack of relevance to ST.
Radomski’s criteria also require the clinical features not be the result of a different acute condition or an underlying disorder and that a neuroleptic has not been recently initiated. Beyond that, there should be at least four minor or three major plus two minor symptoms from the following list associated with the recent addition or increase in dose of a serotonergic drug:
Major mental: Consciousness impairment, elevated mood, semicoma/coma
Minor mental: Restlessness, insomnia
Major neurological: Myoclonus, tremor, shivering, rigidity, hyperreflexia
Minor neurological: Incoordination, pupil dilation, akathisia
Major vegetative: Sweating, fever
Minor vegetative: Tachycardia, tachypnea/dyspnea, diarrhea, hyper/hypotension
The Hunter criteria published by Dunkley in 2003 place much greater emphasis on a handful of neuromuscular symptoms along with agitation and diaphoresis. In the presence of a serotonergic drug, if any of the following are present then ST can be diagnosed:
Inducible clonus and either agitation or diaphoresis
Ocular clonus and either agitation or diaphoresis
Tremor and hyperreflexia
Hypertonicity and hyperthermia (temp over 38°C) and ocular clonus or inducible clonus
Dunkley (2003) found severe cases had a temperature over 38.5°C and/or significxant hypertonia or rigidity (particularly truncal) and in those cases there was a high risk of respiratory compromise, necessitating fast treatment such as neuromuscular paralysis, intubation, and assisted ventilation.
Some of the conditions that overlap enough with ST to result in misdiagnosis are anticholinergic toxicity, malignant hyperthermia, NMS, drug overdose, benzodiazepine or alcohol withdrawal, and meningitis or encephalitis (Foong, 2018).
In animal models high serotonin is associated with a behavioral response featuring hyperactivity and reactivity, forepaw treading, head-weaving, hind-limb abduction, and the Straub or arched tail, sometimes along with tremor, rigidity, salivation, flushing, myoclonus, and seizure (Martin, 1996). This set of symptoms has been used to investigate the mechanisms of apparent ST in animals and the findings underlie much of what is known about ST in humans.
Animal models, though useful, are complicated by the fact that the generated symptoms aren’t identical to those in humans and there are also species differences, such as serotonin/5-HT2A agonists causing hyperthermia in rats and hypothermia in mice (Harberzettl, 2013).
Prognosis and Treatment
The prognosis is good when it’s recognized early, the causal drugs are stopped, and supportive or pharmacologic treatments are initiated.
ST has been fatal and in severe cases can easily be lethal if it’s not quickly treated; life-threatening ST occurs in up to 50% of those ingesting an adequate combo of an MAOI and SSRI, for example (Sun-Edelstein, 2008). With treatment, the condition usually resolves within a matter of days without lasting effects, though altered mental status and muscle pain can persist for a few days and occasionally longer.
When fatalities occur they’re usually associated with issues like renal failure, DIC, cardiac arrhythmia, hyperthermia, myoglobinuria, respiratory arrest, and rhabdomyolysis (Bodner, 1995).
The most common treatments include benzodiazepines, other forms of sedation (e.g. opioids and barbiturates), cooling measures, and 5-HT2A antagonists like cyproheptadine and chlorpromazine. 5-HT1A agonism has often been implicated as the primary causal mechanism in ST, but a lot of animal and human evidence supports a greater role of 5-HT2A, particularly in moderate to severe cases, making 5-HT2A antagonists more useful than 1A antagonists (Martin, 1996). For severe ST, intravenous use of chlorpromazine appears to be the most effective 2A antagonist (it should be given alongside IV fluids to prevent hypotension), while in moderate cases oral cyproheptadine can be used, though it’s unclear if its general sedating effects or specific 2A antagonist property is responsible for the benefits (Buckley, 2014).
Hyperthermia is a common finding in the condition and it’s an important source of toxicity. Despite this, dantrolene and antipyretics are not recommended as they target temperature increases stemming from mechanisms unrelated to those seen in ST.
Benzodiazepines are a nonspecific way to treat some of the core symptoms, including increased muscle tone and agitation due to a reduction in sympathetic activity. They have been very effective in a number of cases, but sometimes alternative treatments are required to yield any response.
Toxicity is greatest when hyperthermia and increased muscle tone/clonus/hyperreflexia go inadequately treated, making aggressive treatment important in severe cases that show signs of increased muscle tone, increased temperature, and/or rhabdomyolysis. Rhabdomyolysis is a fairly common complication in severe cases, though the majority of ST cases don’t lead to it. Occasionally other severe conditions like disseminated intravascular coagulation (DIC) can develop.
Non-depolarizing neuromuscular blockers (e.g. vecuronium) are recommended in instances where muscle tone is not adequately controlled by benzodiazepines.
Drugs to avoid include pancuronium, succinylcholine, and bromocriptine are not recommended (Katus, 2016). Succinylcholine should be avoided because of the risk of arrhythmia from hyperkalemia caused by rhabdomyolysis. Bromocriptine, which is dopaminergic and a 5-HT1A agonist, has been found to worsen symptoms when patients are accidentally treated as if they have NMS.
Serotonin is synthesized from the dietary amino acid tryptophan, which undergoes hydroxylation (the rate-limiting step) inside the cytoplasm of neurons and other cells. Then it is decarboxylated to form serotonin and it’s stored in vesicles for release upon depolarization. Because serotonin itself doesn’t cross the blood-brain barrier (BBB), it must be independently produced peripherally and centrally. In the periphery it’s mostly made by intestinal enterochromaffin cells and centrally it’s produced by nuclei in the lower pons and upper brain stem, regions that have axonal projections to almost every part of the CNS (Mills, 1997).
The level of serotonin within the CNS and outside the CNS is usually tightly regulated by cellular uptake via the serotonin transporter (SERT) and via metabolism to 5-HIAA by the enzyme monoamine oxidase (MAO), which is present on the mitochondrial membrane, but enough serotonin to cause toxicity can accumulate, most often when multiple drugs are used or a single serotonergic is overdosed. More specifically, serotonin is metabolized by MAO-A.
Seven types of serotonin receptors and many subtypes exist, though 5-HT2A is the primary receptor implicated in ST, with possible (though inadequately confirmed) contributions from 5-HT1A and 5-HT3. It’s been proposed 5-HT1A, a more abundant receptor, may be involved in the minor-to-moderate symptoms of ST while overactivation of 2A is vital for all or most of the truly toxic effects (Ellahi, 2015). This is potentially supported by the finding that the combination of 5-HTP and clorgyline, which is known to cause ST, yields hypothermia at low doses and hyperthermia at higher doses (Harberzettl, 2013). 1A is both more common and a much higher affinity site for serotonin than 2A, so high serotonin levels will initially cause more effects via 1A.
Indirectly from increases in serotonergic activity there may be a rise in glutamatergic, noradrenergic, and dopaminergic function, which could play important roles in the physiology of ST. Dopamine activity might be important since dopamine antagonists like haloperidol can treat ST in animals (Martin, 1996). Some of the autonomic symptoms (e.g. diaphoresis and tachycardia) point to a role for hyperactive noradrenergic activity.
Many of the symptoms are primarily mediated by central effects, but peripheral activity could be important in neuromuscular activity and vomiting and diarrhea (Harberzettl, 2013).
Hyperthermia appears to be caused in large part by excess muscular activity; a change in the hypothalamic temperature set point from a pyrogen isn’t involved, which is why antipyretic drugs are not used in treatment. Because physical restraints can increase muscle contractions (raising the risk of lactic acidosis, hyperthermia, and rhabdomyolysis), they should be avoided. Though not the result of pyrogen activity, some reports have noted hyperthermia may be partly coming from activity at hypothalamic 5-HT2A receptors, which could impair temperature regulation (Steele, 2010).
Some researchers have proposed ST shares some of the same pathophysiology as NMS because high serotonin levels could potentially depress dopamine activity in some regions, producing a relatively hypodopaminergic state and therefore extrapyramidal symptoms (Martin, 1996), though the two conditions still have significant mechanistic and symptomatic differences. When ST was less well known, some cases of obvious ST were actually described as neuroleptic malignant syndrome “without neuroleptics.”
Individuals could have different susceptibilities to ST due to genetic differences at SERT, serotonin receptors, enzymes involved in drug metabolism (e.g. CYP2D6), and P-glycoprotein.
In the musculature, serotonin can increase the frequency and duration of firings, leading to clinical symptoms like tremor, clonus, and hyperreflexia. Stimulation of central 5-HT2A is linked to hyperthermia, while 1A causes hypothermia, implicating the former in the generation of ST. Similarly, animal models have found 1A agonism decreases HR and BP, while 5-HT2 agonism does the opposite and indeed, increased HR and BP is much more common than low BP/HR in ST (Brown, 1996).
Metabolic analysis in rats with ST induced by 5-HTP and the MAOI clorgyline showed hyperthermia could be coming from an increase in the expression of the mitochondrial protein UCP-3 (Zaitsu, 2018). Many metabolic changes were found in muscles, the liver, and plasma in ST rats. Along with a rise in UCP-3 (in the gastrocnemius muscle but not the trapezius) there was a significant increase in urea cycle metabolites and signs of anaerobic respiration.
Downregulation of serotonin receptors may be protective against ST. Chronic MAOI administration has been shown to protect against ST-like symptoms in rats, while TCAs given for the same length of time (7 days) did not protect against ST (Lucki, 1992). The protection from chronic MAOI administration was associated with a decline in serotonin binding sites in the brain stem and spinal cord; the TCAs failed to downregulate serotonin receptors.
Serotonin availability is required for the presentation of ST, just as serotonin receptors must be adequately available. The effects can be blocked by para-chlorophenylalanine, which inhibits serotonin synthesis (Sternbach, 1991). Decreasing serotonin synthesis by decreasing tryptamine is also an effective way to attenuate the condition (Martin, 1996).
Diaz (2011) showed 5-HT2B is protective against ST in mice. When it’s absent, such as with 2B knockout mice or with a 2B antagonist, serotonin toxicity is significantly enhanced.
It’s possible the reports of “convulsive ergotism” stretching back to the 11th century may have involved serotonin toxicity (Ganetsky, 2005). The symptoms reported in those cases included distortion of trunk and limbs, ankle flexion or extension, drowsiness, mania, hallucinations, diarrhea, sweating, fever, muscle stiffness, twitching, and opisthotonus. Ergot alkaloids are known to stimulate 5-HT1 and 5-HT2 receptors, giving a potential route to ST.
The modern history of ST goes back to the 1950s. It was first reported in humans treated with MAOIs in the early 1950s to 1960s, sometimes with it being prescribed alongside tryptophan (Martin, 1996). A dose-response effect was found with tryptophan combined with MAOIs:
12-18 mg/kg with phenelzine 60 mg: No hypertensive effect (Sternbach, 1991)
20 mg/kg: Altered mental status and an inebriated state.
30 mg/kg: Hyperreflexia and clonus
50+ mg/kg: Diaphoresis and myoclonus.
70-90 mg/kg: May cause ST alone. Also causes euphoria, drowsiness, nystagmus, hyperreflexia, ankle clonus, and clumsiness (Sternbach, 1991).
A report in 1955 described a patient with severe muscle twitching, ankle clonus, and Babinski signs who was given iproniazid (an MAOI) with the opioid meperidine (Bodner, 1995). The condition was further described by Oates and Sjoerdsma who reported mental changes, restlessness, lower-extremity hyperreflexia, and diaphoresis in four patients in the early 1960s (Bodner, 1995). They attributed the symptoms to excess serotonin activity caused by the use of high tryptophan doses with MAOIs. Oates and Sjoederma also gave single doses of tryptophan (20-50 mg/kg) with the MAOI beta-phenylisopropylhydrazine and reported it caused dizziness, drunken-like effects, clonus, restlessness, hyperactive reflexes, and diaphoresis without significant cardiovascular changes.
Hodge et al. reported giving five hypertensive patients a decarboxylase inhibitor before they received the MAOIs pargyline or isocarboxazid and this was shown to block nystagmus, jaw tremor, hyperreflexia, clonus, sweating, and intoxication, implicating serotonin in the condition (Sternbach, 1991).
Between the mid-1950s and early 1980s there were many case reports of serotonin toxicity. Even by 1962 there were already at least 20 separate reports of apparent ST in dozens of patients: 18 involved MAOIs with imipramine (7 fatalities) and 10 involved MAOIs with meperidine (3 fatalities). Nearly all were reported without the authors connecting the observed effects to the ST-like condition that had been reported in animals, so it would take decades for ST to be well-understood and widely known (Gillman, 1998).
Interactions between MAOIs and TCAs leading to sweating, muscle twitches, restlessness, rigidity, hyperthermia, and loss of consciousness were reported by Beaumont in 1973. Some of those cases were fatalities. All fatalities involved patients who were already on an MAOI (tranylcypromine or mebanazine) at the time the TCA was added.
The term “serotonin syndrome” was first used in animal research in the late 1970s and then in a human case report in the early 1980s.
The first ST-related death to receive substantial attention was that of Libby Zion in 1984. It is believed she died from an interaction between the MAOI phenelzine and meperidine. Her death eventually led to nationwide regulations in the US to limit working hours among medical staff (Martin, 1996).
By the 1980s various drugs had been shown to counteract ST in humans and animals, including chlorpromazine, thiothixene, clozapine, pimozide, methysergide, and cyproheptadine. Given what was known about these drugs at the time, their efficacy appeared to be evidence of a substantial role of 5-HT2A in the disorder since those drugs are generally much more potent at 2A than 1A.
Sternbach laid our diagnostic criteria for ST in 1991 based on a review of 38 case reports in which the symptoms were: restlessness (45%), confusion (42%), myoclonus (34%), hyperreflexia (29%), and sweating, shivering, and tremor (26% each). Nearly all of those cases came from the use of antidepressants with other substances.
In 2001 Radomski published an updated diagnostic criteria based on a larger review of 62 cases (including Sternbach’s original 38) and differentiated between major and minor symptoms, along with adding rigidity to the list of neuromuscular symptoms.
Another set of criteria was published in 2003 by Dunkley using 2222 cases of SSRI overdose in order to more precisely identify serotonin-specific effects, leading to the conclusion that an excess specifically of serotonin will yield clonus as the most important diagnostic symptom. Dunkley’s Hunter criteria limited the role of mental symptoms in the diagnosis, which has often been considered a good way to increase precision. However, the fact that it only used SSRI overdose cases could make the outlined symptomatology less generalizable to other types of serotonergic drugs and to combinations of substances, so strictly using the Hunter criteria may lead to false negatives. Also, the criteria were validated partially using the same cases used to derive the symptoms, which could have produced an overestimation of the criteria’s precision. Regardless, the Hunter criteria do seem superior to the more common Sternbach criteria because of a lower risk of false positives.
Because so many case reports have been published utilizing either no formal diagnostic criteria or using Sternbach’s criteria, some of the case reports outlined here may not be demonstrating actual ST, even though the authors have reported the presence of ST.
(Martini, 2015) – Two cases of ST from metaxalone combined with other serotonergics.
Considering the structural similarity between metaxalone and linezolid, it could be suspected metaxalone is also an MAOI like linezolid, at least at supratherapeutic levels.
22-year-old female presented with altered mental status after feeling unwell earlier in the day and her mother described possible seizure activity. Medications: metaxalone 800 mg TID, medroxyprogesterone 150 mg/mL one injection every 3 months, diclofenac 50 mg BID, hydrocodone-paracetamol 5/325 mg PRN, norelgestromin/ethiynl estradiol path, clonazepam 0.5 mg QID, amitriptyline 25 mg/d. Also taking paroxetine that had not been prescribed.
Progressive decline in alertness. Cardiac rhythm showed supraventricular tachycadia; treated with adenosine 6 mg and electrical cardioversion.
Arrival at ED: BP 168/80, HR 208, RR 20, temp 41.6 deg C. Temp rose to 42.2 deg C within 15 min of arrival. Hot to the touch, flushed, diaphoretic. Dilated pupils and dry mucus membranes. Motor exam showed muscular rigidity more pronounced in lower extremities with hyperreflexia and sustained clonus at ankles.
Given lorazepam 2 mg and 20 mg midazolam without resolution of symptoms. Intubated after paralysis with succinylcholine and sedated with midazolam. Icepacks and cooling blanket used. Within 1 h: cooled to temp of 37.7 deg C. Vitals improved to BP 131/63 and HR 160.
Troponin I peaked at 2.13 ng/mL, CK at 2631 U/L, and INR at 1.67. She required two days of sedation for increased motor tone and agitation. Rigidity resolved on hospital day 2. Extubated on hospital day 3 and ultimately discharged.
Serum paroxetine was therapeutic at 23 ng/mL while metaxalone was 31 mcg/mL (peak level averages 0.9 mcg/mL after single oral dose of 400 mg).
27-year-old male presented with altered mental status after being found agitated and confused. Reported using three extra 800 mg metaxalone tablets 7 h earlier for back pain. Denied use of stimulants or any other drugs or medications.
Arrival at ED: BP 158/131, HR 126, RR 20, temp 37.2 deg C. Agitated, diaphoretic, and warm to the touch. Pupils 5 mm and reactive. Neurological exam showed ocular clonus, hyperreflexia of lower extremities with sustained clonus, and flaccidity of upper extremities.
Aggressive management with bolus diazepam; total of 80 mg diazepam. With sedation BP declined to 123/67. Hydrated with normal saline and admitted to ICU. Benzos continued as needed.
Hospital Day 3: Agitation and rigidity fully resolved. Discharged without neurologic deficits.
Escitalopram: 24 ng/mL (therapeutic: 21-64 ng/mL)
Metaxolone: 58 mcg/mL
(Malik, 2015) – Unusual case of ST involving phenelzine started two weeks after mirtazapine
27-year-old female presented with 1 day history of unsteadiness and feeling unwell. This was preceded by a short episode of dysarthria that spontaneously resolved without lasting deficit. She began having unsteadiness while on her feet several hours after.
At arrival to hospital: Felt well aside from a mild headache. Denied other symptoms.
Medication history: Folic acid 5 mg, phenelzine 15 mg TDC began 2 weeks prior to admission, propranolol 40 mg.
She was on mirtazapine before phenelzine and that had been stopped 2 weeks prior to commencing phenelzine.
On exam: Oriented to time, place, and person. 36.9 deg C, HR 80, BP 100/54 sitting, RR 18. Only positive finding was dilated pupils 5 mm and reactive.
20 min after first assessment: GCS dropped from 15 to 9. Temp rose to 40.4 deg C, diaphoretic, tachycardic at 164.
Neurologic exam showed increased tone with clonus and brisk reflexes, Babinski’s sign positive bilaterally. Pupils remained dilated and reactive, ocular oscillations apparent but fundoscopy was normal.
Labs: CK of 146 IU/L.
Given 15 mg diazepam rectally but clonus persisted. Intubated with propofol and alfentanil. Despite this, clonus remained and atracurium was started with good effect.
Next 24 h: Atracurium gradually weaned and extubated. Reviewed by psychiatry team and diagnosis of unusual presentation of ST was made. Antidepressant medications ceased.
Full recovery and discharged 2 days later.
(Prakash, 2014) – 4 cases in which headache was reported alongside ST
Serotonin at high concentrations binds to 5-HT2A and induces migraine attacks. An increase in the density of 2A has been seen in platelets of patients with analgesic-overuse headache and following drug withdrawal the receptor density declined, with declining headache frequency.
Activation of 2A may enhance nitric oxide production in the trigeminovascular pathway and then NO could trigger a headache attack.
Various observations have shown 2A antagonists can have a positive response in both ST and headache. Cyproheptadine,. Chlorpromazine, and olanzapine have good efficacy in both.
22-year-old male presented with a 2-week history of headache that was continuous since onset, nonthrobbing, holocephalic and mild for most of the time, though with occasional exacerbations to moderate to severe intensity for 2-6 hours. No nausea, vomiting, photophobia, phonophobia, auras or cranial autonomic features.
Was receiving tramadol/paracetamol 37.5/325 mg TID for two weeks for a right ankle sprain. Headache began 1-2 days after beginning treatment.
Exam showed 118 HR, mydriasis, mild postural tremor of both hands and generalized hyperreflexia. Fulfilled criteria for ST based on Hunter classification.
Tramadol discontinued and cyproheptadine began. Within 10 h of starting cyproheptadine the headache began to improve. After 72 h the headaches, tremor, and hyperreflexia resolved entirely. Cyproheptadine continued for another 3 days and in the next 3 months of follow-up the patient was symptom-free.
34-year-old male receiving paroxetine 25 mg/d and clonazepam 0.5 mg/d for 4-5 weeks. Reported to an outpatient clinic for near-daily headache lasting 2-3 weeks; described as holocephalic, pressing, and as mild to moderate much of the time. Denied nausea, vomiting, photophobia, phonophobia, or any cranial autonomic features.
Physical and neurological exam showed 122 HR, BP 156/94, and postural tremor of both hands. Both lower extremities were rigid and hyperreflexic, with five-beat, inducible ill-sustained ankle clonus.
Fulfilled Hunter criteria for ST. Paroxetine was stopped and cyproheptadine was started; within 24 h the headache began to improve and after 1 week of cyproheptadine the headaches, tremor, rigidity, and hyperreflexia resolved entirely. Cyproheptadine continued for another week. In the 3-month follow-up period there were no other symptoms.
36-year-old female presented with 4-day history of headache. Headache was holocephalic, pressing and continuous since onset. Headache fluctuated from moderate to severe in intensity. Occasionally felt nausea, photophobia, and phonophobia with the exacerbations of headache.
Had been taking tramadol/paracetamol 37.5/325 mg combo BID and fluoxetine 20 mg for the last 7 days. Clinical exam showed 118 HR, mydriasis, postural tremor, and hyperreflexia. Mildly elevated temp at 37.8 deg C.
Fulfilled both Hunter and Sternbach criteria for ST. All medications were stopped and cyproheptadine started; within 6 h the headache started to improve and fully subsided within 48 h. Mydriasis, tremor, and hyperreflexia returned to normal in 72 h and cyproheptadine was continued for another 72 h. In the next 2 months the patient was symptom-free.
46-year-old male receiving fluoxetine 40 mg and tramadol/paracetamol 37.5/325 mg combo for the previous 4 weeks. Ondansetron 8 mg BID was added five days earlier for nausea and vomiting.
Referred for evaluation of headache, restlessness, and disturbed sleep for 4 days duration. Headache had been continuous since onset and began gradually, then became severe in about 3-4 days. Described as holocephalic and throbbing.
HR 126, mildly elevated temp at 37.6 deg C, mydriasis, postural hand tremor, rigidity in both lower limbs and ill-sustained clonus.
Fulfilled both Sternbach and Hunter criteria for ST. All 3 drugs discontinued and cyproheptadine started. Symptoms began to improve after 36 h and subsided entirely within 3 days. Cyproheptadine continued for another 3 days. Remained headache-free after 10 weeks of followup.
(Fugate, 2014) – 3 cases involving therapeutic hypothermia using fentanyl
Postanoxic encephalopathy and ST could be related in that global brain ischemia has been shown in experimental models to increase extracellular serotonin release. Fentanyl promotes serotonergic transmission.
58-year-old male lost consciousness and was found with ventricular fibrillation. He was defibrillated. Due to persistent coma he was intubated and therapeutic hypothermia was used with a surface cooling device.
Sedated with IV fentanyl, midazolam, and paralyzed with atracurium while cooled to a target temp of 33°C for 24 h.
Extubated after rewarming but became febrile at 38.8°C and hypertensive at 188/75. Awake but agitated and unable to follow commands.
2 days later: Improved neurologically. Remained awake but not interactive. Appeared flushed, diffuse tremors, rigidity of all extremities (more prominent in lower extremities), fasciculations, and bilateral ankle clonus.
Clinical diagnosis of ST. His medications included sertraline 50 mg/d and he was on tramadol for analgesia. So those medications were discontinued, as was fentanyl.
Rigidity improved but was still present. Full recovery made over the ensuing weeks.
36-year-old male collapsed at home and was found in asystole, evolving into fine ventricular fibrillation after epinephrine was given. Defibrillated. Remained comatose and therapeutic hypothermia was initiated.
Sedated with fentanyl, midazolam, and paralyzed with atracurium, cooling to target temp of 33°C for 24 h.
2 h after reaching normothermia he became febrile at 38.5°C. Sedation switched to dexmedetomidine infusion and when that was temporarily held he opened his eyes to stimulation but was agitated, not following commands, tachycardic, and hypertensive. Severe rigidity in lower extremities associated with hyperreflexia and clonus at the ankles.
ST suspected, so fentanyl was discontinued and hydromorphone (the opioid with the least serotonergic activity) was given for analgesia. He’d been on paroxetine prior to admission.
Next several days: When off sedation he remained agitated with hypertension and tachycardia.
Day 9: Extubated after slow improvement in agitation.
53-year-old male lost consciousness and was found in asystole. Remained unconscious and therapeutic hypothermia was initiated, so he was given fentanyl, midazolam, and atracurium. Urine screen at admission was negative for metabolites of any opioids and antidepressants. Temp maintained at 33°C at 24 h.
When off sedation he opened his eyes and followed simple commands with upper extremities. Diffuse rigidity which was severe and more prominent in lower extremities with bilateral ankle clonus, hyperreflexia, and tremors. Tachycardic and febrile, requiring water temp of 9°C in the cooling device to maintain core body temp of 37°C.
Developed rhabdomyolysis shown by urine dark in color and increased serum CK to 2811 U/L.
Fentanyl discontinued and treated with enteral cyproheptadine 8 mg and IV diazepam 10 mg, both given every 6 h.
Continued to require light sedation with dexmedetomidine for agitation and gradually improved over the following days and he was extubated on Day 7. Alert and oriented, able to have a conversation, moved all extremities without focal weakness, and no rigidity or clonus.
(Shakoor, 2014) – ST from citalopram, and citalopram
44-year-old female presented to ED with altered mental status, random spontaneous jerky movements in extremities, generalized weakness, and vomiting. Medications included hydrocodone-paracetamol 5/300 mg every 6 h, citalopram 40 mg/d, clonazepam 1 mg BID, gabapentin 300 mg TID, lisinopril 5 mg/d, and tramadol 100 mg every 6 h as needed.
Tramadol was started a week prior and she reported using her pain medications excessively. She’d been on the same dose of citalopram for 2 years without adverse effects.
BP 86/76, HR 101, RR 27, temp 37 de C. Physical exam showed abdominal tenderness on deep palpitation, confusion, tremors, generalized weakness, hyperreflexia, and inducible and spontaneous myoclonus without focal neurological deficits.
All medications stopped. After initial fluid resuscitation, she became hypertensive and tachycardic. Renal function rapidly improved over next 2 days but hypertension, tachycardia, and neurological symptoms remained over 4 days.
(Davies, 2014) – Severe ST caused by a presumably high dose of MDMA.
23-year-old male brought to ED in a delirious state. He had been at a music concert where he used three MDMA pills and began behaving “weirdly’ a few hours later after.
Initial exam: GCS of 12, 171 HR, 84/75 BP, RR 25, hyperthermia with rectal temp of 42.7 deg C. Awake but combative and not obeying commands. Tremulous, hypertonic, and hyperreflexic. Pupils equal and reacting sluggishly to light. Given etomidate and rocuronium and intubated for airway protection.
Supportive measures included cooling and IVF. Temp dropped to 37.2 deg C within 2 h of presentation.
CK of 1356 U/L and he had hyperkalemia, for which he received sodium polystyrene and calcium gluconate.
Sedation continued with midazolam and propofol and other supportive measures were also used.
Within first 24 h: Rigidity reduced and HR declined.
ICU Day 2: Extubated without incident and neurologically intact without any gross memory impairments.
From ICU Day 2: Severe rhabdomyolysis, multi-organ failure, and mild disseminated intravascular coagulation. Given sodium bicarbonate to alkalinize the urine to aid myoglobin excretion but this was stopped after a few hours due to lack of change in urine pH. Peak lab abnormalities included CK of 130,350 U/L, AST 3011 U/L, ALT 314 U/L, albumin 1,6 g/dL, creatinine 9.6 md/dL, phosphate 8 mg/dL, platelet count 54 K/uL, INR 1.44, activated partial thromboplastin time 42.7, and D-dimer levels 1799 ng/mL
Hemodialysis was used beginning hospital Day 6 due to lack of improvement in renal function with worsening creatinine and metabolic acidosis; progressive rise in phosphate, potassium, and CK, and progressive al in ionized calcium; he developed anasarca.
Hospital Day 14: Discharged after five sessions of hemodialysis and he received two more sessions as an outpatient. Renal function fully recovered.
Hunter criteria for ST was met.
(Bosak, 2013) – ST from 2C-I use
19-year-old male insufflated a liquid called “liquid acid.” Shortly after he had a generalized tonic-clonic seizure and EMS was called. Upon arrival of EMS: comatose with HR of 143, oxygen saturation 80%, and skin that was cool and clammy. Given 2 mg IV naloxone without change in mental status.
During transport: Two more generalized tonic-clonic seizures prompting the use of 2.5 mg IV midazolam.
ED: BP 230/104, HR 135, temp 39.4 deg C, oxygen saturation 92%, GCS 6. Soon after arrival another generalized seizure occurred and he was given 2 mg IV lorazepam. Exam remarkable for spontaneous clonus and rigidity of lower extremities.
Intubated, sedated with propofol, and chemically paralyzed. Temp improved to 38.2 deg C.
Arrival to ICU: Remained agitated with weaning of sedation. Exam showed diffuse muscular rigidity along with spontaneous clonus in lower, but not upper, extremities. Due to concerns of persistent rigidity and inability to exclude ongoing seizures he was given phenobarbital 15 mg/kg and cyproheptadine 12 mg. Despite phenobarbital and propofol, agitation persisted prompting use of fentanyl and midazolam.
Hospital Day 2: When sedation was weaned he again became agitated, tachycardic, hypertensive, and febrile at 40.3 deg C. Sedated with resolution of vital sign abnormalities.
Hospital Day 3: Again he failed sedation weaning due to agitation and he required midazolam, propofol, and fentanyl.
Hospital Day 4: Extubated and reported visual hallucinations then developed hypertension, tachycardia, and 39.9 deg C temp 2 h post-extubation. These improved after IV lorazepam.
Hospital Day 5: Agitation and hallucinations resolved then he was discharged on Day 6.
Comprehensive testing of urine showed 2C-I and no other drugs
(John, 2013) – Two cases of apparent ST associated with catastrophic reversible cerebral vasoconstriction (RCVS)
RCVS involves the acute onset of severe headaches with or without neurological deficit. There is evidence of reversible cerebral vasoconstriction.
Serotonergic drugs are often implicated in the course of RCVS, there have not been reports of RCVS with concomitant ST.
Serotonergic vasoconstriction is mediated via the action of 5-HT1B and/or 2A, which are found on smooth muscle cells in peripheral and cerebral vessels.
Upregulation of 1B has been seen in cerebral blood vessels in subarachnoid hemorrhage and ischemia.
45-year-old female on escitalopram 10 mg/d. Presented after thunderclap headache and confusion.
History: 3 weeks earlier she sustained accidental head trauma; treated with hydrocodone.
History showed migraine and mechanical aortic and mitral valve replacements secondary to remote infectious endocarditis, for which she was maintained on anticoagulation therapy.
Hospitalized and treated with dihydroergotamine IV and multiple doses of hydromorphone. Initial neurological exam normal without focal deficits.
Initial brain MRI showed T2 hyperintensities in cerebellum, resembling posterior reversible encephalopathy syndrome, but didn’t demonstrate acute ischemia or hemorrhage.
Repeat brain MRI 2 days after symptom onset showed focal T2 hyperintensity in bilateral parietal subarachnoid space, consistent with a bleed.
Magnetic resonance venogram was normal. Magnetic resonance angiography showed narrowing in the proximal anterior and middle cerebral arteries.
14 days after symptom onset: Acute worsening with deterioriating mental status, fevers, tachycardia, rigidity, and hyperreflexia. Repeat brain MRI showed patchy bilateral acute infarcts predominantly in the parieto-occipital region.
Intubated. Escitalopram had presumably been stopped after the worsening as it was not being given when she was admitted to the newest facility. Comatose upon examination with decerebrate posturing but with maintenance of brainstem reflexes.
Extremely rigid and had clonus, along with significantly higher HR and BP.
CT of head showed large bihemispheric ischemic infarcts with mass effect and sulcal effacement.
Day 16: Cerebral angiogram showed severe segmental vessel narrowing in all vascular distributions.
Infusion of intra-arterial nicardipine into right and left internal carotid artery and the right vertebral artery resulted in moderate angiographic improvement.
Aggressive management to handle high intracranial pressure was unsuccessful. Repeat brain MRI showed large bihemispheric infarcts with significant edemic and midline shift.
Worsening examination and imaging led family to withdraw care and she died a few hours after extubation.
Urine toxicology was positive for THC, which is a known precipitant of RCVS.
57-year-old female on buprenorphine 8 mg TID, bupropion 200 mg BID, mirtazapine 15 mg/d, and citalopram (recent increase from 40 mg/d to 60 mg/d).
Presented with dizziness of 4 days duration.
Day after admission: Acute confusion, seizure, and unresponsiveness. Exam showed diaphoresis, febrile, tachycardic with markedly labile BP, rigidity, and hyperreflexia.
CT of head showed bilateral parieto-occipital hypodensities and MRI confirmed bilateral parietal infarcts.
Intubated. Exam at new facility was similar to prior exam but also showed decerebrate posturing and clonus, though she remained awake and intermittently was able to follow commands.
Day 8 after symptom onset: CT of head showed new areas of hypoattenuation in posterior frontal lobes. Cerebral angiogram confirmed severe vessel narrowing worse in the posterior circulation.
Given absence of structural lesions, the decerebrate posturing was hypothesized to be from brainstem hypoperfusion. Intra-arterial nicardipine was administered to right and left internal carotid artery and the right vertebral artery, improving the narrowing slightly.
Antidepressants stopped and cyproheptadine began given presumed ST. Also started on verapamil.
Day 12 after symptom onset: Worsening decerebrate posturing led to another cerebral angiogram, which revealed improvement in narrowing in all vascular territories.
In both cases extensive evaluation for an alternative cause of ischemic stroke was unrevealing. These cases showed severe diffuse vasospasm trigering large ischemic stroke.
Interestingly, headache was absent in both. Both cases met Sternbach criteria for ST and they also had clonus, the most significant factor in the Hunter criteria.
(Warrick, 2012) – Lethal apparent ST after the use of cathinones, namely butylone and methylone
24-year-old female presented to ED after using two “Ecstasy” capsules. Found unconscious with 132 HR, BP 80/60. EMS gave diazepam 10 mg IV for apparent seizure activity.
In ED: nonverbal and withdrew from pain. Temp 41.8°C oral, HR 158, RR 34, BP 101/61, pupils 6 mm and minimally reactive, mucus membranes moist and mild increase in secretions. Skin was hot and diaphoretic. Didn’t open her eyes but did make incomprehensible sounds. Tremors noted in upper extremities with increased tone and bilateral ankle clonus.
Fluid resuscitated, mechanically ventilated, and externally cooled with ice packs. Myoclonus first controlled via IV lorazepam 2 mg followed by 32 mg midazolam. Benzos decreased myoclonus but did not fully remove it. Non-depolarizing neuromuscular blockers were used to cease all muscle activity to control hyperthermia. 3 h after neuromuscular blockade core temp was down to 37.7 deg C.
4 h after arrival: BP 147/83, HR 130, and temp 37.1 deg C.
Shortly after control of hyperthermia: Developed posterior epistaxis and oozing from IV sites. Repeat coagulation tests were consistent with DIC. She was transfused with fresh frozen plasma, packed red blood cells, and platelets to obtain hemostasis.
10 h post-admission: Developed pulseless electrical activity arrest from unclear etiology. Spontaneous circulation returned within 90 s of CPR and 1 mg epinephrine but she needed multiple pressors: norepinephrine, vasopressin, and dopamine. Repeat exam showed clonus, hyperreflexia, and tremor had resolved. Coagulopathy didn’t respond to treatment. Repeat labs showed multiple organ failure.
Over next 24 h: Hemodynamics and coagulopathy improved. Developed ARDS and renal failure. Despite optimal ventilation, hypoxemia, and lactic acidosis she died 48 h after presentation.
Analysis of urine and a capsule in her possession confirmed methylone and butylone exposure. Powder in capsule was 422 mg methylone and 53 mg butylone.
Negative for other drugs of abuse.
(Tanaka, 2011) – An overdose on DPH that at least mimicked ST
DPH does have a moderate SRI property and the search for analogs to it is what led to the development of fluoxetine. It has a SERT Ki of 9050 nM compared to a histamine H1 Ki of 96.0 nM.
Agonism at 5-HT1A could be involved in the myoclonus and hyperreflexia of ST, while overstimulation at 2A could yield hyperthermia and overstimulation of 3A could yield diarrhea.
17-year-old female attempted suicide by using DPH 1800 mg. About 5 h later she became incoherent and had profuse diaphoresis, myoclonus, and muscular rigidity.
At admission: Disoriented and appeared to be having auditory and visual hallucinations. Seemed to be delirious and did not follow instructions. Neurologic exam showed potentiation of deep tendon reflexes in all limbs.
Temp of 37.9 deg C, HR 138, and BP 128/67, respectively.
WBC was elevated to 10700/uL and CK to 914 IU/L
IVF and oral lorazepam 3 mg/d initiated. On the first day her body temp, BP, WBC, and CK worsened but on Day 2 all vitals returned to normal and the myoclonus and hyperreflexia resolved, then on Day 3 her mental state returned to normal.
(Mugele, 2011) – ST linked to MDPV alone
41-year-old female presented with altered mental status after using “bath salts” for 2 days prior to admission. Presented with BP 99/64, HR 98, and temp 98.1°F. Alert and oriented but agitated. Spontaneous myoclonus, but neither nystagmus nor hypertonicity.
She had a history of alcohol abuse but denied recent alcohol abuse or coingestants. She’d been using Blue Magic bath salts bought from a gas station, leading to progressive agitation and confusion.
8 hours after arrival: Severely agitated, hallucinating, temp rose to 40.1°C, BP 152/85, HR 130.
Given 13 mg lorazepam and 5 mg diazepam without improvement.
Intubated after administration of etomidate and succinylcholine. Sedated with propofol and midazolam.
While sedated her vitals were stable at BP 119/57, HR 81, and temp 37.3°F. When sedation was stopped she became extremely agitated and couldn’t follow commands.
Neurological exam showed no focal deficits, clonus, or rigidity. ECG showed sinus rhythm with normal QTc. Lab findings only remarkable for mildly high WBC at 13900/cubic mm
Continued sedation and supportive care recommended given apparent sympathomimetic toxidrome and MDPV detection. So she received fentanyl infusion of at 100 μg/h for sedation and analgesia.
Hospital Day 2: Hyperreflexic with inducible clonus or dorsiflexion and she had increased tone in the lower extremities. Supportive care with propofol and benzos continued, while fentanyl was discontinued given the concern for ST.
Next 2 days: Continuing agitation and hypertonicity, though controlled by sedation. Acutely worsening clonus whenever sedation was weaned.
Hospital Day 4: Cyproheptadine initiated for ST treatment.
Hospital Day 7: Gradual improvement in responsiveness and absence of inducible clonus, so she was extubated.
Day 8: Cyproheptadine discontinued
Day 9: Demonstrated multiple beats of inducible clonus at ankles and bilateral patellar hyperreflexia. Cyproheptadine was restarted.
Day 11: Full resolution of symptoms and discontinuation of cyproheptadine.
MDPV: 3,100 ng/mL
No amphetamines, antidepressants, or other serotonergic agents.
She met the Hunter criteria for ST.
(Rajapakse, 2010) – Venlafaxine. Diaphoresis, hypertonicity, clonus, hyperthermia, cardiovascular stimulation. Leading to shock, acidosis, high CK, and other issues.
43-year-old male presented with fever, dysphagia, and progressive drowsiness of 2 days duration. At admission he was on l-dopa 25 mg with carbidopa 100 mg TID, amantadine 100 mg BID, benzhexol 2 mg/d, ropinirole 0.5 mg TID, and venlafaxine 75 mg/d that was started 2 weeks prior.
History of ICU admission due to probable NMS after the use of phenothiazine, which was given for sedation due to him being restless and agitated.
Altered mental status with agitated delirium. Diaphoretic and flushed, dilated pupils. Muscle hypertonicity and sustained clonus. Temp 41.2°C, HR 120, and BP 135/90.
Next few hours: BP dropped and he developed frank shock. Given 3 inotropic/pressor drugs (norepinephrine, DA, and dobutamine). Desaturated and was intubated, and ventilation started.
Labs showed metabolic acidosis, CK of 3600 U/L, WBC 18,600/uL, and myoglobinuria.
Venlafaxine discontinued and other medications continued. IV midazolam commenced.
CK continued to rise, reaching 65,330 U/L on Day 2, 148,970 on Day 3, and 170,800 U/L on Day 4. On the third day his urine output dropped and he had rising creatinine. Diagnosis of acute renal failure. Bicarbonate hemodialysis started.
Condition improved with regular hemodialysis and midazolam. Serum CK returned to normal within 2 weeks.
(Thorpe, 2010) – Bupropion alone causing ST symptoms
A few cases of ST involving bupropion have been reported but always with other drugs.
(Munhoz, 2004) – 62-year-old female developed ST from combo of bupropion, sertraline, piracetam, and venlafaxine. She had subtle symptoms after 3 weeks of bupropion and sertraline alone, then it acutely worsened with addition of venlafaxine and piracetam.
(Szakaly, 2008) – Possible ST in patient undergoing surgery who took his regular dose of bupropion along with a single dose of DXM.
(Dvir, 2008) – 53-year-old female was on fluoxetine and olanzapine daily, then developed ST after addition of bupropion.
Toxicity from bupropion overdose has been reported but ST largely has not been. Symptoms include tachycardia, dry skin, and seizures, but not hyperreflexia. Cases have essentially never reported lower extremity hyperreflexia or clonus.
Bupropion doesn’t have serotonergic activity according to some studies. But animal studies have shown it may have some serotonergic properties. (Foley, 2006) found a comparable rise in serotonin, NE, and DA in hippocampus in rats with bupropion. And other reports have postulated it could indirectly have serotonergic activity via upregulation of VMAT-2.
15-year-old male treated only with bupropion (he admitted to using 3000 mg of bupropion SR). He woke his family with incoherent shouting and reported hallucinations of people, then had 5 min of generalized tonic-clonic movements without incontinence or eye deviation.
EMS arrived: Patient was incoherent and agitated. He had a second episode of tonic-clonic movements on the way to the hospital; they resolved spontaneously.
Arrival at ED: Confused and restless. HR 170, RR 24, BP 170/130, temp 37.1°C, oxygen saturation 98%. Dilated but reactive pupils, normal conjunctiva, dry oral mucosa, tachycardia, flushed and dry skin, rigidity in legs, and +4 reflexes in ankles.
Given IV fluids and a total of 8 mg of lorazepam IV, which decreased agitation.
Total creatine phosphokinase was elevated at 991 IU/L and WBC was elevated at 19,900/cubic millimeter.
ECG showed HR of 170, QRS 100 ms, and QTc 434 ms.
Patient continued to be delirious and agitated with unchanging vitals. Repeat physical exam showed dry mucous membranes and mydriasis. No diaphoresis. Neurological exam showed hyperreflexia and clonus in lower extremities, while upper extremity reflexes were unchanged. Extremely rigid in lower extremities while upper extremities had normal tone.
Given 2 mg physostigmine IV with no effect.
Comprehensive urine drug screen with GC/MS only showed naproxen and bupropion.
Admitted to inpatient unit and treated supportively with IV fluids and lorazepam.
Within 24 h of admission he was awake with normal vitals and neurological exam.
Some stigmata of anticholinergic poisoning but no response to physostigmine or anticholinergics.
No exposure to neuroleptics, inhaled anesthetics, or succinylcholine — ruling out neuroleptic malignant syndrome or malignant hyperthermia
Not febrile and neck was supple, making CNS infection less likely.
Meets diagnostic criteria for SS based on Sternbach, but he did not develop hyperthermia, a classically reported finding in SS. Though (Radomski, 2000) reviewed 62 cases of SS reported to journals and found the incidence of hyperthermia was only 37.5% and diaphoresis was 33.3%.
In this case adequate sedation with benzos could have also prevented hyperthermia that’d have otherwise come from ongoing muscle hyperactivity. And dehydration could’ve contributed to lack of sweating.
COI: Not reported
(Schwartz, 2008) – Two cases of ST involving high-dose DXM mixed with other serotonergics at therapeutic levels.
20-year-old male found confused. He was given naloxone 2 mg and dextrose IV for low blood glucose (59 mg/dL) but without effect.
Later admitted to using a large dose of DXM-containing cough medications and denied supratherapeutic use of prescriptions: escitalopram, benztropine, and aripiprazole.
Transported to local ED: temp 38.9°C, confused, and tremulous. Head CT and lumbar puncture were normal. Given ceftriaxone.
Rectal temp 38.4°C, HR 168, RR 16, BP 150/80, oxygen saturation 94%. Warm, flushed, and generalized diaphoresis, pupils 6 mm and reactive. Tremulous and lethargic but easily aroused with incomprehensible speech. Lower extremities rigid and hyperreflexia, with seven beat clonus at both ankles. Upper extremities and remainder of neurologic exam normal.
EEG showed no epileptiform activity. Serum creatine phosphokinase elevated at 327 U/L and WBC elevated at 14,500/cubic mm. Remainder of blood screen was normal.
Treated with 6 mg IV lorazepam, 12 mg oral cyproheptadine, and IV fluids over a 90 min period. This led to resting without tremor and HR declined to 124. Generous IVFs and frequent lorazepam used to ensure urine output, control agitation, and prevent significant rhabdomyolysis.
Within 12 hr of admission: awake and neurologically normal with falling creatine kinase.
Toxicology (serum at admission)
DXM: 950 ng/mL
Citalopram/escitalopram: 23 ng/mL
Chlorpheniramine: 430 ng/mL
Undetectable aripiprazole and benztropine.
6-year-old male recently started on sertraline. Found lethargic and confused with an empty bottle of DXM elixir, with estimated exposure to DXM 40 mg/kg.
Brought to ED: 38.1°C temp, HR 118, RR 24, BP 140/69. Skin was warm and diaphoretic. Confused and irritable with rigidity and clonus in lower extremities only. Pupils were dilated.
Sedated with fentanyl and versed, intubated for airway support, and received IVFs.
CBC was normal. Total creatine kinase was 134 U/L.
Toxicology (serum at admission)
DXM: 2820 ng/mL
Sertraline: 12.5 ng/mL
Within 15 hr of admission: Extubated and neurologically intact.
COI: Not reported
(Bradley, 2008) – Methylene blue and paroxetine
7 published reports of adverse effects associated with methylene blue, with all patients experiencing symptoms consistent with ST: agitation, confusion, hypertonicity, and clonus. 5 patients were also on an SSRI/SRI. 1 was receiving clomipramine.
Methylene blue is a derivative of phenothiazine, which formed the base of the first gen of antipsychotics.
58-year-old female taking paroxetine 40 m/d for several years. Also on omeprazole 40 mg BID and simvastatin 20 mg QHS
Morning of surgery: Normal medications and methylene blue at 5 mg/kg over one hour. Anesthesia induced with midazolam 1 mg IV, fentanyl 100 mcg IV, propofol 100 mg IV, and rocuronium 40 mg IV. Anesthesia maintained with sevoflurane. Brief period of hypotension at 75/45 that responded to ephedrine and metaraminol.
End of procedure: Neuromuscular blockade reversed with neostigmine 2.5 mg and atropine 1.2 mg IV.
Soon noted to be deeply sedated and, although arousable, did not awaken for 25 min. Upon waking she was agitated, unresponsive, disoriented, and moving all limbs purposelessly. HR 100 and normal BP. Neurological exam showed increased tone in all limbs and normal reflexes. Treated with morphine 5 mg IV and midazolam 2 mg IV, without effect.
Dystonia and agitation resolved slowly over 5 hours.
Though atropine was used, anticholinergic toxicity was considered unlikely given she had tolerated atropine during a prior instance of anesthesia. However, methylene blue is also an anticholinergic and could have made anticholinergic syndrome more common, but common symptoms like mydriasis and dryness of mouth and skin were absent.
(Dvir, 2008) – Olanzapine and venlafaxine
53-year-old female presented to the ED with a complaint of gradually worsening tremor. She reported 2 weeks of progressive tremor, gait difficulties, diarrhea, diaphoresis, insomnia, and mental status changes that included visual hallucinations of a baby in her room.
Medications: olanzapine 5 mg/d, methadone 50 mg/d, venlafaxine XR 75 mg/d. The venlafaxine had been started in the past month.
In the ED: Low-amplitude tremor in her head, neck, and hands. Diaphoresis, slurred speech, right-sided lean and upper extremity myoclonic jerks. Significantly hypertensive at 182/107, tachycardic with HR up to 127.
Olanzapine and venlafaxine discontinued. Treated with diazepam and metoprolol.
Discharged 3 days later with full symptom resolution.
(Phan, 2008) – Therapeutic sertraline use causing ST in and male child
(Kaminski, 1994) – 9-year-old male with history of ADHD who presented with the syndrome two hours after ingesting an unknown number of 50 mg sertraline tablets. Serum level 9 hours after ingestion: 68 ng/mL
Admission to ED: BP 100/66, temp 38.5°C, irregular HR at 176, and RR of 38. Changed mental status with hallucinations. Treatment with activated charcoal, physostigmine, paracetamol, lorazepam, and chloral hydrate. After 4 days in the hospital he was discharged.
(Pao, 1997) – 5-year-old female ingested at least 400 mg sertraline with a serum level of 99 ng/mL 72 hours post-ingestion. Treated with gastric lavage and charcoal in ED and discharged 48 hours post-ingestion. But readmitted the next day because of increased irritability, tachycardia, insomnia, agitation, and combative behavior. She was then discharged a week later.
(Horowitz, 1999) – 24-month-old female accidentally ingested 500 mg sertraline. Asymptomatic for 3 hours while in the ED following gastric lavage and activated charcoal. Later developed the syndrome with hyperactivity, tremor, hyperreflexia, and unsteady ataxic gait 12 hours post-ingestion.
Readmitted to ED and then given schedule cyproheptadine. Symptoms subsided 40 min after starting cyproheptadine and she was discharged home with continued cyproheptadine for 2 additional days. Based on follow-up the patient remained asymptomatic.
(Gill, 1999) – 11-year-old male with history of ADHD-PI had a single fluvoxamine 50 mg dose. One hour later: increasing agitation, tremor, unresponsiveness to stimuli.
In ED (4 hours post-ingestion): BP up to 160/90, HR up to 190, jaw myoclonus and shivering.
Treated with benzodiazepines, IV thiamine, and sodium bicarbonate. Stabilized within 48 hrs and transferred to inpatient psychiatry service for continued care.
History: He’d been taking perphenazine and bentropine. And, a week prior to starting fluvoxamine he ended valproic acid.
(Mullins, 1999) – 16-year-old female had restlessness, tremor, and anxiety after sertraline 100 mg. ED 4 hours after ingestion: sinus tachycardia of 105-120 bpm, BP 154/80, tremors, and increased motor tone.
Treated with cyproheptadine 4 mg and paracetamol and was discharged 4 hours after arrival.
USA. 9-year-old male with chronic behavioral problems was prescribed sertraline 50 mg by his PCP. Within 30 min of use: stomach pain and increasingly delirious and combative over the next 2 hours. No fever, cough, headache, vomiting, diarrhea, or rash prior to the mental status change.
3 hours after ingestion EMS arrived. Patient had tremors, diaphoresis, and marked agitation.
36.4°C temp, HR 162, RR 15, BP 109/71.
Encephalopathic with a GCS of 10 and progressively severe agitation.
Within 4.5 hours after ingestion: rectal temp increased to 38.8°C. Pupils were 5 mm bilaterally and sluggishly reactive.
Treated with IV lorazepam and a dose of haloperidol for combativeness. Endotracheal intubation for airway protection.
Admitted to PICU (about 8.5 hours after ingestion) : 36.7°C, HR 135, BP 90/42. Hypertonicity in all extremities, with lower being worse. 4+ deep tenon reflexes in his legs, clonus bilaterally, and bilaterally dilated pupils at 5 mm which were sluggish. After coming out of sedation he could not follow commands and was intermittently agitated.
Consulted with tox service and decided to start cyproheptadine 8 mg via nasogastric tube + 2.5 mg every 8 hours.
Intermittent lorazepam was still used for agitation and spasticity.
Mental status improved through first PICU day and he was extubated that afternoon. Still hypertonicity, disorientation, and intermittent fevers. Symptoms managed with cyproheptadine therapy, intermittent lorazepam, and acetaminophen.
He had mild, transient diarrhea typical of serotonin syndrome.
It was well into Hospital Day 4 before the patient was consistently afebrile. Cyproheptadine was discontinued on the morning of Hospital Day 5 and he was discharged that day.
Naranjo score of 6 = probable.
24-year-old female presented to ED with fever, uncontrollable shaking, and severe leg pain of several hours duration.
Medications: escitalopram 30 mg/d (which had been increased 6 weeks earlier). Unknown doses of metaxolone, carisoprodol, dicyclomine, drospirenone/ethinyl estradiol, and ibuprofen.
Initial evaluation: 37.1°C temp, BP 151/82, HR 129, RR 24, and GCS of 15.
During ED stay: Temp rose to 38.9°C. Diaphoretic and tremulous. Shivering and noted to have sialorrhea, diarrhea, and muscle rigidity. Coordination problems, myoclonus, but normal deep tendon reflexes. Confused, agitated, anxious, irritable, and restless.
Only significant lab findings were mildly high magnesium at 1.4 mg/dL and elevated CK of 177 U/L.
While in ED: All outpatient medications discontinued. IV hydration and IV lorazepam for anxiety and agitation. Mental state deteriorated and she was confused and disoriented. Due to increasing respiratory difficulty and altered mental status, it was decided to intubate the patient and to use propofol for sedation. She was admitted to ICU with suspected ST.
In ICU: Given dantrolene 1 mg/kg once. And given (as needed) fentanyl 25 μg/hr and acetaminophen 650 mg/4 hours. Later that day she began receiving cyproheptadine 4 mg every 4 hours for a 24-hour period.
Condition improved overnight. By the next day her vitals were normal and labs were normal. Removed from ventilator and the propofol and fentanyl were stopped.
Afebrile, normal HR/BP/RR. No muscle pain. No tremor, diaphoresis, and her diarrhea and sialorrhea resolved. No myoclonus or muscle rigidity. Mental status exam was normal + resolution of confusion and agitation.
(Bonetto, 2007) – Possible ST from St. Johns wort, fluoxetine, and triptans
28-year-old female complained of frequent migraines. She was treated with eletriptan 3-4x per month and she’d been on fluoxetine 60 mg/d for 1 year.
Admitted to hospital for sudden head deviation and loss of consciousness. In the ED she had an epileptic fit with tonic-clonic seizures and tongue bite followed by mental confusion. Given lorazepam IV.
At admission she’d been on fluoxetine 60 mg/d for a year and self-prescribed St. Johns wort for 1 month. And in the previous 3 days she’d taken eletriptan 40 mg/d for recurrent migraine.
Clinical and neurological exam were normal aside from mental slowness and subtle postural tremor in fingers. Mildly high temp at 37.5°C and normal BP and HR, with no sign of autonomic dysfunction. Mild increase of myoglobin but normal CK and modest rise in D-dimer.
Daily fluoxetine reduced to 20 mg and hypericum withdrawn while continuing eletriptan 40 mg/d for persisting migraine
Complained of diffuse myalgias worsening a few days later. Signs of acute rhabdomyolysis with CK 13,600 U/L, myoglobin 965 ug/L, aldolase 80 U/L. Also increases in serum aminotransferase and D-dimer.
Hydration was immediately started but she had transient acute renal failure. Fluoxetine and eletriptan discontinued. EMG showed no signs of myopathy.
Discharged 10 days later
(Paruchuri, 2006) – Possible paroxetine-only ST in an elderly female
80-year-old female admitted for altered mental status. She was on paroxetine 25 mg/d for depression and anxiety. Confused, disoriented, and agitated with 38.6°C temp, though not tachycardic or tachypneic. Physical exam showed myoclonus of lower extremities. Lab results showed rhabdomyolysis and acute renal failure.
Paroxetine was ceased and she was aggressively hydrated with IVF and began on 16 mg/d cyproheptadine in four divided doses.
Within 48 h: Mental status improved and treatment was continued with cyproheptadine and IVF.
By Day 4: Function returned to baseline and labs were within normal limits. She was discharged.
(Karunatilake, 2006) – Oxycodone with stable serotonergic antidepressants probably produced ST
3 prior cases of probable syndrome due to oxycodone with a serotonergic (either sertraline or escitalopram) have been reported. Oxycodone is mostly a centrally acting opioid with effects mediated by MOR and KOR. Oxycodone differs from most opioids in having significant KOR affinity. Its potent minor metabolite oxymorphone is also active. Either drug may have serotonergic effects, potentially. Opioids transiently raise serotonin levels in animals after an initial dose to opioids.
70-year-old female presented to ED with acute confusion. She’d been on fluvoxamine 200 mg in the morning and doxepin 50 mg at night for depression for many months and was also receiving diclofenac 50 mg BID, raloxifene 60 mg/d, calcium carbonate 600 mg/d , diltiazem CD 240 mg/d, and simvastatin 40 mg/d.
3 days pre-admission: Fell and had a fracture. Started on oxycodone XR 40 mg BID then one day before admission short-acting oxycodone 10 mg was added to her treatment as needed. And ultimately she was reported to have taken 60 mg oxycodone in the 24 hrs prior to admission.
She became confused, had nausea, and was febrile and shivering. 38.8°C, restless, confused, and agitated, BP of 135/56 and HR of 113, with intermittent atrial fibrillation. Atrial fibrillation didn’t recur after the first 2 hours and HR declined to 80.
Mini-Mental State Score was 26/30; attention and registration were most impaired.
Sustained clonus, increased muscle tone but not rigidity, very brisk reflexes (more prominent in lower limbs).
Pupils large but reactive. Normal WBC and serum electrolytes. CK was 485 U/L
Fluvoxamine, doxepin, and oxycodone were discontinued. She was given paracetamol for pain and improved slowly over the next 48 hours: confusion, neurological issues, and temperature all resolved and the heart rhythm returned to sinus rhythm.
Doxepin 50 mg was restarted without issue and she was not challenged with oxycodone or fluvoxamine.
Possible PK interactions
Fluvoxamine strongly inhibits CYP1A2 and CYP2C19, while moderately inhibiting CYP3A4 and 2D6, and doxepin and oxycodone are both 2D6 and 3A4 substrates, so higher concentrations could have been achieved.
COI: Not reported
(Gnanadesigan, 2005) – Cases of suspected ST from serotonergic drugs and opioids although only some are truly likely ST and all would not likely meet Hunter criteria.
Rats given morphine SC pellets had a 50% rise in central serotonin. Although opioids do not directly stimulate serotonin release they do suppress GABA-mediated inhibition of serotonin release, which causes a disinhibition of serotonergic neurons and an excess release of central serotonin.
86-year-old female was on sertraline 150 mg/d and oxycodone 10 mg BID. Oxycodone was then increase to 20 mg BID during hospitalization.
Exam: alert, oriented to person and place, and could follow commands but she was agitated. Muscle tone in upper extremities was normal but markedly increased in her lower extremities. Truncal ataxia and she was unable to sit or stand without assistance. Coarse tremors along with myoclonic jerks in both feet.
ST was considered and sertraline was rapidly tapered along with reduction in oxycodone dose. Dramatic improvement within 2 days with no tremors, myoclonus, or rigidity.
88-year-old female evaluated for acute rise in BP to 200/90. On exam she had frequent myoclonic jerks of lower extremities. On escitalopram 10 mg/d and oxycodone XR 20 mg BID; ~5 weeks earlier her XR oxycodone had been doubled.
Given IV lorazepam and escitalopram and oxycodone were stopped. In under a day her myoclonus resolved and BP returned to baseline. Later oxycodone was restarted while escitalopram was not; neither myoclonus nor BP elevation returned.
90-year-old female on hydrocodone 10 mg and citalopram 10 mg daily. Antidepressant then changed to escitalopram 10 mg/d. When seen a few weeks later she complained of seeing strangers in her room, especially at night, which was frightening. Diagnosis of complex visual hallucinations was made after ruling out acute infectious and metabolic problem.
Hydrocodone was discontinued due to pain improvement.
Routine visit a month later: No longer having visual hallucinations.
85-year-old female seen for recurrent episodes of lethargy, confusion, hypotension, bronchospasm, and hypoxia. No associated motor symptoms.
On mirtazapine 22.5 mg/d and tramadol 100 mg TID. Mirtazapine current dose started 4 days prior (started entirely at 7.5 mg three weeks prior) to the episode while tramadol was ongoing for several months.
Within hours of ceasing mirtazapine and tramadol she was completely alert and lucid, with episodes of hypoxia and hypotension resolving and not reoccurring.
(Mittino, 2004) – Tramadol and sertraline
75-year-old female presented with sudden onset of confusion and myoclonic jerks. 3 days earlier she began tramadol 50 mg/d and symptoms occurred after her first dose of sertraline 50 mg.
EEG showed widespread slow waves and occasionally bitemporal triphasic waves. CSF serotonin was elevated at 38.5 ng/mL, compared to a normal level of under 10 pg/mL.
After discontinuation of sertraline the condition remitted within a few days and CSF serotonin returned to normal range and EEG improved.
(Karki, 2003) – 2 cases of ST involving risperidone and serotonergics
Sternbach criteria used for diagnosis.
86-year-old male admitted with increased confusion and generalized weakness over the past several days. Medical history showed hypertension, hyperlipidemia, depression, and dementia.
Medications: Quinipril 40 mg BID, simvastatin 20 mg at bedtime, paroxetine 10 mg at bedtime, and risperidone 0.25 mg/d.
BP 110/60, RR 20, HR 120.
CT on Day 2 of hospitalization showed moderate generalized atrophy, old lacunar infarctions within the basal ganglia bilaterally and probably the right cerebellar hemisphere.
Cardiac enzymes initially negative for troponin and with normal CK.
Began to have aggressive, agitated outbursts that required haloperidol 1 mg IM every 6 h as needed, which was then stopped at psychiatric consultation. Hydroxyzine and risperidone were also used at various times.
During the acute behavioral change he was diagnosed with acute exacerbation of underlying dementia.
Risperidone was increased to 0.5 mg/d and the patent’s confusion in the hospital worsened. He slapped another patient and attacked the nurses and aides when they tried to quiet him. Psychosis, agitation, and aggressive behaviors worsened; treated with risperidone increase to 0.5 mg BID with 0.5 mg every 6 h as needed.
Alternated between extreme agitation and unresponsiveness.
Died on Day 5 of admission at which time he was being treated with risperidone 2-3 mg/d.
ST symptoms included: muscle rigidity, myoclonus, tachycardia, diaphoresis.
78-year-old female on venlafaxine 37.5 mg BID for depression and risperidone 0.25 mg at bedtime for agitation for over 1 year.
Medical history: hypertension, angina, diabetes, depression, and dementia.
Began to experience frequent periods of extreme agitation. Medications switched to paroxetine 20 mg/d and risperidone 0.5 mg at bedtime.
Agitation and assaultive behaviors worsened, and risperidone was increased to 0.5 mg BID after 3 days.
2 days after the change in risperidone dosage: Didn’t react to verbal or tactile stimuli and transferred to ED. HR was irregular, skin warm and clammy, vitals of BP 170/102, RR 16, HR 92. Developed tremor, dizziness, and muscle incoordination.
Risperidone and paroxetine discontinued and agitation managed with minimum doses of lorazepam. She began responding to verbal commands within 24 h and was transferred back to nursing home in 2 days.
Paroxetine 20 mg and olanzapine 2.5 mg at bedtime at 6 months follow-up after the incident.
ST symptoms included: muscle rigidity, myoclonus, diaphoresis, tachycardia
NMS ruled out given the absence of lead pipe rigidity, obtundation, unstable BP, or elevated temp.
Cases satisfied all Sternbach criteria expect the one specifying no recent increase in neuroleptic dose.
Naranjo showed Case 1 was probable and Case 2 was definite.
Paoxetine, as the most potent inhibitor of serotonin reuptake, may have been involved. Metabolic reactions are also possible.
Venlafaxine is thought to have been uninvolved.
(Bernard, 2003) – Apparent ST from concomitant use of citalopram and the antimicrobial linezolid (TDC Note: Linezolid is also an MAOI)
81-year-old male underwent surgical debridement of ankle osteomyelitis due to MRSA. He was receiving citalopram 20 mg BID for 3 weeks pre-admission and was also on low doses of prednisone and methotrexate, digoxin, trinitras, torasemid, insulin, and oxazepam. Following surgery he began linezolid therapy at 600 mg BID.
After 1 week of linezolid: Mental changes
After 3 weeks of linezolid: Fever, BP increase, tachycardia, confusion, and tremors without localizable neurological signs. CK was 766 U/L.
During needle introduction for lumbar puncture he had cardiac arrest. Rapid intubation and ventilation, leading to resuscitation without drugs. Serum lactate rose to 29.1 uM and in addition to severe lactic acidosis, hepatic failure worsened. Cardiac ultrasonography showed major ventricular dysfunction. He died following 3 additional episodes of cardiac arrest. Autopsy showed drug encephalopathy and myocardial infarction, the latter probably after cardiac arrest since the cardiac isoenzyme and troponin were normal before arrest. Results of bacterial cultures were negative and no other abnormalities noted.
75-year-old male admitted with impaired consciousness. Medications included salbutamol 100 mcg QID, ipratropium bromide 0.02 mg QID, nimodipine 30 mg/d (had been used for a number of years), and 8 days of mirtazapine 15 mg/d.
3 days pre-admission: Developed agitation, confusion, incoordination, and gait disturbance because of progressive rigidity.
Admission: temp 37.5°C, HR 105, BP 170/90, diaphoresis, and neurological exam showed coma, bilateral cogwheel rigidity, hyperreflexia, tremor, and myoclonus.
Mirtazapine was discontinued on admission and supportive therapy was initiated. No medication therapy. 24 h later his neurologic status improved and he was discharged with mild rigidity remaining.
(Wong, 2002) – Sertraline and cyclosporin
53-year-old male admitted with dizziness, slurred speech, and right-sided weakness. BP 150/80, HR 80, afebrile. He had a right intranuclear ophthalmoplegia, a right facial nerve upper motor neuron type palsy, and grade 4/5 weakness on the right side.
Deteriorated over the next few days and became tetraplegic and aphasic. Medications were azathioprine 125 mg, ciclosporin 100 mg BID, prednisolone 5 mg, atorvastatin 5 mg, and aspirin 160 mg.
Upon becoming depressed and tearful, sertraline 50 mg/d was prescribed. 5 days after beginning sertraline he developed generalized tremor, profuse sweating, tachycardia, and fever of 42°C. RR 40, HR 180, BP fluctuated between 180/100 and 210/120. Neurological exam showed ankle clonus and generalized hyperreflexia.
Sertraline was discontinued. Treated with labetalol IV infusion, promethazine, paracetamol, and cooling measures. HR, BP, and temp returned to normal within 12 hours. Labetalol, promethazine, and paracetamol were discontinued 2 days later and he remained stable.
Two possible mechanisms of interaction with sertraline and cyclosporin. First, they’re both extensively protein-bound, so competition for protein binding could lead to increased level of free sertraline. Secondly, in mice ciclosporin enhances brain serotonergic neural activity with increased serotonin turnover in the brain resulting in increased irritability.
(Wigen, 2002) – ST with SSRI and linezolid (an MAOI) but symptoms could easily be non-ST and would not meet Hunter criteria.
56-year-old male admitted for elective laminectomy. Notably, abdominal CT showed hepatic cirrhosis. Preoperative medications: paroxetine, IFN-alpha, felodipine, terazosin, lisinopril, insulin, methocarbamol, morphine, and ibuprofen.
Postoperative course was uneventful until postoperative day 11 when she became oversedated. Administration of morphine and methocarbamol discontinued and paroxetine was tapered for 3 days. The last dose of paroxetine was on postoperative day 14, at which time mental status significantly improved.
Discovered she had a grossly infected surgical wound, so vancomycin was started. Despite antimicrobial therapy the patient was still febrile at 39.5°C. Because drug fever was suspected, IV linezolid replaced vancomycin on postoperative day 17.
Within 24 h: Delirium, hypertension, hostility, anger, tremors. Linezolid was discontinued and vancomycin was restarted, leading to baseline mental status within 48 hours.
(Haslett, 2002) – Possible case of ST with olanzapine
47-year-old female maintained on lithium, valproate, and haloperidol for many years. Then her treatment was switched to lithium 1600 mg and risperidone 6 mg. Five months later she had a depressive episode and was given citalopram 20 mg/d.
Over the following year, depression was reduced but she continued to have delusions, so olanzapine 15 mg was tried in place of risperidone.
3 months later: She became increasingly irritable. Because hypomanic switch was suspected, citalopram was stopped while olanzapine was increased to 20 mg. But over the next 4 days her irritability increased markedly.
Presented to ED with many symptoms (4 months after commencing the combo of citalopram, lithium, and olanzapine and 4 days after the olanzapine increase)
Severely agitated, shouting, refusing to give history or to allow full examination. She appeared confused and agitated, while sweating profusely. Motor reflexes were brisk bilaterally, generalized fine motor tremor, and 37.3°C temp. CK of 308 mmol/L and WBC of 17800/cubic meter. Serum lithium was in the normal range.
6 Sternbach criteria met: mental status changes (confusion, hypomania), hyperreflexia, agitation, diaphoresis, tremor, and fever. Myoclonus and coordination could not be tested because the patient didn’t tolerate complete examination.
All medications stopped and she was sedated with benzodiazepines. Symptoms of ST subsided.
(Avarello, 2002) – Fatality linked to SSRI and nortriptyline
72-year-old male receiving an SSRI and nortriptyline for a year and shortly before admission he was given L-dopa. He presented some days after the acute onset of limb stiffness, anxiety, trismus, and dysphagia. Unstable BP, tachycardia, tachypnea, and sweating. Poor concentration and moderate agitation. Tone heavily increased in trunk and legs. Clear evidence of limb hyperreflexia, without Babinkski’s sign.
Lab data was normal aside from serum CK and WBC.
Saline, diazepam, and antibiotics given for treatment. Neurological stratus worsened rapidly and he died a few days later.
(Dams, 2001) – Fatality associated with a significant overdose of moclobemide and citalopram
41-year-old male was found deceased at home from suicide. There were three empty medication containers for lormetazepam, moclobemide, and citalopram, along with an empty bottle of whiskey.
Moclobemide: 5.62 μg/mL compared to a therapeutic range of 0.36-3.00 μg/mL
Citalopram: 4.47 μg/mL compared to a therapeutic range of 0.03 – 0.20 μg/mL
(Turkel, 2001) – Two cases in which 5-HT3 antagonists were implicated, atypically.
Mirtazapine and other 5-HT3 antagonists have been put forth as potential serotonin syndrome treatments.
12-year-old male. Treated with mirtazapine 15 mg at bedtime to control depression. He was also given ondansetron, the routine nausea treatment during chemotherapy. Morphine was also continued at this time.
The following day: Confused, tremulous, myoclonus.
Both ondansetron and mirtazapine were stropped. Morphine continued.
Remained confused the following day with auditory and visual hallucinations, which resolved with a single dose of droperidol 0.25 mg IV.
Mirtazapine was resumed several days later without issue.
11-year-old female. Receiving continuous fentanyl as well as antibacterial, antifungal, and antiviral antibiotics, cyclosporine, and the 5-HT3 antagonist granisetron.
2 weeks later: She became irritable and dysphoric with restricted affect, poor eye contact, impaired attention consistent with early delirium, but treatment was kept the same.
5 days later: Acutely confused with visual hallucinations, marked anxiety, tremulousness, ataxia, and myoclonus.
Serotonin syndrome was suspected so granisetron was stopped and fentanyl was switched to hydromorphone.
By the next day, confusion was alleviated and myoclonus resolved.
(Demirkiran, 1996) – MDMA-related ST
19-year-old female found in acute confused state after using one tablet of Ecstasy. Within 15 min she became nauseated and vomited; disoriented and drowsy with a bout of diarrhea while heading to the hospital.
Local ED: Tachycardic, drowsy, but responsive to pain, and pupils were dilated.
Urine tox screen positive only for amphetamine
Low sodium of 120 mEq/L and phosphorus of 2.0 mg/dL. Lactate dehydrogenase elevated to 1,060 IU/L, and CK to 3,960 U/L.
She had a seizure and was admitted with BP 123/72, HR 100-120, RR 20-24. Temp was 37.1°C initially but then rose to 38.5°C. Drowsy and disoriented with sluggishly reactive dilated pupils. Skin had piloerection. Deep tendon reflexes were hyperactive in all extremities. No prominent rigidity observed during initial exam.
WBC was 13,100, CK was 6,357 U/L.
EEG showed grade III, diffuse, dysrhythmia, and very severe delta grade I slowing and disorganization of background activity, suggestive of severe and diffuse cortical dysfunction.
Blood and urine tox negative for all drugs other than MDMA and urinalysis was positive for amphetamine and MDA, a metabolite of MDMA. Subsequent analysis of a sample of the substance she used confirmed MDMA ingestion.
Diagnosed with possible NMS and rhabdomyolysis; given gastric lavage with charcoal and sorbitol and treated with IVF, bromocriptine, and dantrolene.
NMS improved gradually and she became oriented 4 days post-admission. Complained of diplopia, generalized weakness, and painful stiffness in limbs. During the hospital course of 11 days her liver and muscle enzymes remained high. The most significant lab value increase was with CK of 71,760 U/L.
After discharge she had residual blurry vision, positional vertigo, postural tremors in her hands, intermittently throbbing headaches sometimes associated with nausea. Evaluated 10 days after discharge and shown to have bilateral mild postural tremor. Labs were normal.
(Lee, 1999) – A potetial mild case of ST linked to sertraline and erythromycin
12-year-old male. He was on sertraline 12.5 mg every morning and then was gradually titrated to 37.5 mg/d over a 12 week period. That dosage was maintained without issue for 5 weeks. Due to a penicillin allergy he was prescribed erythromycin 200 mg BID.
Within 4 days of beginning erythromycin he was mildly nervous and over the next 10 days the nervousness increased, leading to panic, restlessness, irritability, intermittent agitation, parasthesias, tremulousness, decreased concentration, and confusion.
Erythromycin and sertraline were quickly stopped and 72 hr later the boy felt calmer and less irritable, with decreased confusion.
The temporal aspect of this case strongly implicates erythromycin, though the pharmacodynamic explanation is lacking.
Both are protein-bound drugs, though erythromycin binds to α1-glycoprotein, while sertraline binds to albumin and α1-glycoprotein. So it’s possible protein binding competition raised the concentration of sertraline, but this was not verified.
More likely this came from an impact on metabolism. Sertraline is metabolized via CYP3A. Erythromycin has been associated with higher serum levels of carbamazepine and cyclosporine due to CYP pathway inhibition.
Erythromycin induces CYP, is demethylated and oxidized, and then forms an inactive, reversible complex with CYP. This is associated with lower CYP3A4 activity in the liver and small intestine.
Also, a metabolite of erythromycin, anhydroerythromycin, is a potent inhibitor of CYP3A and could be playing a role.
Together, this means it’s conceivable a metabolic interaction led, effectively, to an acute overdose of sertraline and that is how mild ST symptoms were brought about.
(Gill, 1999) – Therapeutic use of fluvoxamine leading to ST
11-year-old male brought to ED for acute mental status change and unresponsiveness. Medications were perphenazine and benztropine, which had been taken for 2 years. Valproic acid was discontinued 7 days before presentation. Fluvoxamine 50 mg had been started the morning of presentation.
1 hour after his first fluvoxamine dose: Rapidly progressing agitation and unresponsiveness to any stimuli. He had uncontrolled shaking without bowel or urinary incontinence.
ED: Agitation required 5 security officers to control him. BP up to 160/90. HR fluctuating between 60 and 190. Temp 35.8°C and RR 22.
Jaw myoclonus and shivering. Markedly diaphoretic. Pupils 8 mm in diameter and equally reactive to light. Neurological exam showed a patient who didn’t respond to verbal or painful stimuli. Moved all extremities wildly and uncontrollably. Bilateral ankle clonus, upgoing bilateral Babinski reflexes, hyperreflexia with rigidity of the lower extremities greater than upper extremities. Fasciculation noted in all extremities.
10 mg diazepam and 21 mg lorazepam IV used over a 2 hour period after presentation without improvement in combativeness or rigidity.
Condition deteriorated. Temp rose to 39.7°C. Because of progressive hyperthermia and consequent rhabdomyolysis, he was paralyzed with rocuronium 50 mg and intubated. Cool mist and a cooling blanket used. Resolution of fasciculations, rigidity, and hyperthermia was noted within minutes of neuromuscular blockade.
Comprehensive urine drug screen showed fluvoxamine, perphenazine, benztropine, and benzodiazepines. Other initial lab data obtained in ICU showed normal CK and CBC
Peak CK was 6,500 U/L at 28 h after presentation.
Remained pharmacologically sedated and paralyzed for around 24 h because of ongoing muscle fasciculations and rigidity whenever neuromuscular blockade was stopped.
Extubated the next day. Physical exam was significant for mild lower extremity rigidity, ataxia, and diarrhea that persisted for an extra 12 hours.
48 h after presentation his physical exam was normal.
(Daniels, 1998) – Venlafaxine-only ST from a significant overdose
28-year-old male presented 1 hour after an overdose of 3,000 mg venlafaxine. Upon arrival he was conscious but unable to speak, with coarse tremor of upper limbs and rigid lower limbs with marked clonus present in ankles. He was not using any other prescribed or illicit drugs.
HR 160, BP 174/83, flushed, and diaphoretic. Temp 36.6°C. ECG showed sinus tachycardia.
Diagnosed with ST. Given saline and charcoal via nasogastric tube. Chlorpromazine 12.5 mg IV to control tremor. 15 min later his condition improved so he could answer questions via nodding or shaking his head; temp was 38.5°C.
30 min after chlorpromazine: seizure, treated with midazolam 2 mg IV. Second dose of chlorpromazine given 3 hours after the overdose upon return of rigidity. Pyrexia responded to cooling and chlorpromazine. CK peaked at 1307 U/L at 16 hr after overdose. Renal function was normal throughout.
Recovered completely and discharged after 48 h.
(Hodgman, 1997) – Tranylcypromine and venlafaxine
60-year-old female was being treated with tranylcypromine at 70 mg/d. She had been on it for 3 weeks for depression. Then she accidentally took one dose of venlafaxine and soon became weak, confused, and collapsed.
Presented to ED restless and didn’t respond meaningfully to verbal or painful stimuli. Generalized fine tremors noted. HR 118, BP 130/80, RR 24, temp 38.3°C. Skin was warm and moist with increased reflexes.
Treated with 5.5 mg diazepam over the first several hours for tremor and restlessness. She had profound diaphoresis.
BP and HR remained largely the same during ED stay. Routine labs, including CK and CBC, were normal.
6 hours post-presentation: 41.1°C, tachycardic, increasingly tremulous and unresponsive. pH of 7.31, pCO2 of 47, and pO2 of 141. Treated with cooling blanket, ice packs, dantrolene 80 mg IV, and sodium bicarbonate.
Within several hours her temp was down to 38°C.
Next morning: Afebrile and no tremor but she remained hyperreflexic. Mental status was a bit confused but was mostly as baseline. Modest rise in CK to 363 U/L.
Discharged in good condition after 4 days.
(Mason, 1997) – Possible ST from tramadol and sertraline
42-year-old female admitted to ICU with atypical chest pain that was sharp, substernal, and on the left side, radiating down both arms. ECG showed sinus tachycardia at 140 and questionable ST depression in leads V2-V4. BP 155/70 and temp 36.9°C, confusion, psychosis, sundowning, agitation, diaphoresis, and tremor.
She’d been receiving tramadol 300 mg/d for 3 weeks. Tramadol was increased from 150 mg/d in 50 mg increments every 2-3 days to reach current dose. She’d been receiving sertraline for over a year prior to tramadol.
Chest pain resolved 24 h after admission. Treated with rest, oxygen, and three doses of haloperidol IV.
Psychiatric consult: flight of ideas, ideas of reference, and confabulation with mental status which stopped 24-36 h after admission, when tramadol was discontinued and sertraline was decreased to 50 mg/d.
At discharge: Sertraline was 50 mg/d, alternating with 100 mg/d. 6 weeks later it was dropped further to 25 mg/d and tramadol was reinitiated at 25-50 mg BID. 8 weeks after admission sertraline was stopped due to resolution of depressive symptoms.
(Molaie, 1997) – Possible ST involving fluoxetine (discontinued) and abrupt start of clomipramine
30-year-old female presented with convulsion and altered mental status. She’d been receiving fluoxetine 100 mg/d for several months and then it was abruptly switched to clomipramine 200 mg/d 48 h before presentation.
Initial neurological exam: confused, combative patient who was unable to follow simple verbal commands. Both pupils were 4 mm and symmetrically reactive to light. Able to move all extremities only in response to painful stimuli, more vigorous on the right than the left. Hyperreflexia of the lower extremities with bilateral plantar extensor sign.
Next day: More awake and able to follow simple commands. Incoordination of both hands and truncal ataxia seen.
Hospital Day 2: MRI of head revealed abnormal signal intensity in the right tempoparietal and cerebellar hemispheres, suggestive of recent ischemic infarction. EEG revealed focal slow activity in the right temporal and occipital areas with isolated epileptiform discharges in those regions.
Subsequent days: Mental status improved somewhat but cognition remained impaired and she was left with constructional apraxia and right cerebellar ataxia at discharge.
5 years of follow-up: Slow, steady improvement but cognition remains moderately impaired and she’s had occasional complex partial seizures despite adequate levels of antiepileptic medication. Several follow-up MRIs have revealed no new lesions. Intermittent headaches associated with photophobia and nausea have persisted with less intensity.
49-year-old male treated for refractory depression. Appeared at hospital ED 6 hours after the acute onset of anxiety, impaired concentration, muscle twitches, limb stiffness, shortness of breath, and chest tightness.
Symptoms worsened overnight then gradually improved. No nausea, diarrhea, vertigo, palpitations, or lightheadedness noted.
Exam: BP 132/90 (supine) and 98/60 (sitting), HR 70 lying and HR 80 sitting, normal temp.
Muscle tone increased in legs, more so on the right. Mild proximal leg muscle weakness, with normal arm strength. Involuntary writhing bicycling movements were seen while lying supine. Leg hyperreflexia without Babinski signs.
Normal CBC, liver function, serum CK, serum calcium, and urinalysis. Magnesium was low at 1.5 mg/dL (ref range: 1.8 – 2.4 mg/dl).
Treatment: IV saline and magnesium. After several hours his neurological exam became completely normal and he was discharged.
4 months later
Readmitted 1 month following the slow introduction of carbamazepine 600 mg/d due to reporting depression and akathisia. Carbamazepine was reduced to 350 mg, with symptomatic relief though akathisia persisted when sertraline 25 mg/d was added.
His history indicates he was susceptible
Fluoxetine alone had previously caused right-hand “coordination” to be impaired. And after some dose increases while on isocarboxazid, trazodone, and methylphenidate he eventually decreased the isocarboxaid and trazodone due to feeling “peculiar” and having agitation and myoclonus.
(Skop, 1994) – Paroxetine and dextromethorphan
51-year-old male presented with a primary complaint of vomiting blood. 4 days pre-admission he developed fatigue, rhinnorhea, and nasal congestion and 2 days later he had shortness of breath, nausea, headache, and confusion. He was self-medicating with Nyquil. Medications: diltiazem, nitroglycerin, ticlopidine, piroxicam, ranitidine, diazepam, paroxetine, Nyquil.
Arrival at ED: Diaporetic, tremulous, confused. Abdominal pain in back and severe shortness of breath. Vitals were BP 202/110, HR 122, RR 26, temp 37.2°C. Pupils midrange and reactive, no papilledema or flame hemorrhages, no nystagmus.
SBP in lower extremities was 160. Oriented to person and place. Increased muscle tone, 10-beat clonus, frontal-release signs.
Initial ED treatment included oxygen and IV nitroglycerin for BP control.
Became rigid and more confused, but remained conscious. IV lorazepam to treat hyperautonomic signs and symptoms; 16 mg given over 1 hour. Intervention resolved tachycardia, hypertension, confusion, and increased motor activity. Transferred to ICU with normal vitals and clear mental status.
Toxicology screen positive for benzos, amphetamines, and paracetamol. Consistent with use of prescription meds and Nyquil. Paroxetine discontinued.
(Neuvonen, 1993) – Five moclobemide and SRI fatalities
(Dingemanse, 1993) suggested moclobemide does not interact adversely with SSRIs.
5 cases with fatal outcome apparently stemming from moclobemide, a selective MAOA inhibitor, and an SRI.
Patients 1 and 2 used 1000-1500 mg moclobemide with 225-500 mg clomipramine to get high. 2-3 h later they were euphoric but within the next 2 h both had extreme tremor followed by convulsions and loss of consciousness. Both died 9-10 h after administration, one following status epilepticus and one following hyperthermia after generalized epileptiform convulsions.
Toxicology showed only moderate overdose of the antidepressants.
Patients 3-5 died 3 to 16 h after overdoses of moclobemide and citalopram but showed a similar pattern of events to the deaths following clomipramine and moclobemide.
Patient 3: Blood level of moclobemide was 30-50x higher than therapeutic and citalopram was 5x higher than therapeutic.
Patient 4: Blood level of the moclobemide was 5x higher and the level of citalopram was 2x higher.
Patient 5: Blood level of moclobemide was 20-30x higher than therapeutic and the level of citalopram was therapeutic.
Patients 3 and 4 died despite immediate conventional treatment in the hospital.
Based on these cases it appears moclobemide with SRIs can be fatal, whereas an overdose on moclobemide alone is fairly benign.
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