Selective Serotonin Reuptake Inhibitor Toxicity

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Continuing Education Activity

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants. Other clinical indications for SSRI use include anxiety disorders, obsessive-compulsive disorder, panic disorders, and eating disorders. Compared to their predecessors, the monoamine oxidase inhibitors and tricyclic antidepressants, SSRIs are associated with fewer toxic effects. This activity describes the uses, mode of action and adverse effects of SSRIs and highlights the role of the interprofessional team in the management of these patients.


  • Identify the mode of action of the SSRIs.
  • Review the toxic effects of SSRIs.
  • Summarize the treatment options of SSRI toxicity.
  • Outline interprofessional team strategies for improving care coordination and outcomes in patients with SSRI toxicity.


Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants. Other clinical indications for SSRI use include anxiety disorders, obsessive-compulsive disorder, panic disorders, and eating disorders. Compared to their predecessors, the monoamine oxidase inhibitors and tricyclic antidepressants, SSRIs are associated with fewer toxic effects.[1] 

Individual SSRIs differ from each other regarding structure and pharmacokinetics but, as a group, they act by potentiating the action of serotonin. SSRIs are less cardiotoxic than many first-generation antidepressants, but there is still evidence that they inhibit sodium, calcium, and potassium ion channels at concentrations near therapeutic levels.[2] Citalopram and escitalopram are known to cause QTc prolongation.[3][4] There also have been reports of atrial fibrillation and bradycardia related to fluoxetine use.[5]

Adverse effects of SSRIs are vague and nonspecific but include hyponatremia, anorgasmia, sedation, stimulation, and gastric irritation.[6][7] Seizures are uncommon but have been reported; Isbister et al.[8] reported a seizure incidence of 1.9%. They may also inhibit platelet secretion, aggregation, and plug formation.[9]

Patients with adverse effects from SSRIs will present with a range of symptoms, and some researchers have advocated for the term “serotonin toxicity” rather than “serotonin syndrome” to highlight that this condition is a spectrum of symptoms rather than a single clinical entity. [10][11] In patients with mild symptoms, the benefit they receive from the prescribed SSRI may outweigh the negative side effects.


Serotonin toxicity is the most serious drug reaction from inadvertent or intentional SSRI overdose and can be iatrogenic, caused by the introduction of a serotonergic agent, increased dosing of an established serotonergic agent or after coadministration with another agent that increases serotonin activity.[12] The most severe cases are caused by combinations of drugs that enhance serotonin levels by acting through separate mechanisms, for example, a monoamine oxidase inhibitor and a serotonin reuptake inhibitor.[13]

Many medications affect serotonin levels by different overlapping mechanisms. In addition to SSRIs, ondansetron, methadone, clomipramine, amitriptyline, dextromethorphan, fentanyl, meperidine, tramadol, trazodone, venlafaxine, and pentazocine increase serotonin levels by blocking reuptake. Medications that can increase serotonin levels by inhibiting serotonin metabolism include linezolid, methylene blue, St. John's wort, or monoamine oxidase inhibitors like phenelzine, selegiline, and isocarboxazid. Methylenedioxymethamphetamine (MDMA) and mirtazapine enhance serotonin release. Tryptophan is a serotonin precursor. Cocaine increases serotonin synthesis. Buspirone, fentanyl, dihydroergotamine, lithium, lysergic acid diethylamide (LSD), metoclopramide and triptans stimulate serotonin receptors.[12][14][15][16] Research is still ongoing on the subject of opioid safety with concomitant SSRI.[17][18][19]Studies have shown that synthetic opioids can inhibit SERT (serotonin transporter) but fentanyl and oxycodone, which have not shown inhibitory effects on SERT, have been reported anecdotally in cases of serotonin toxicity.[20][21]


The American Association of Poison Control Centers reported over 50,000 overdose cases in 2016 where SSRIs were mentioned; of these reported cases, 102 were fatal, but in all but one of these fatalities co-ingestants were involved.[22] Sertraline and fluoxetine were the SSRIs most commonly taken in excess.[22] One study analyzing 469 SSRI overdoses reported serotonin toxicity in 14% of cases.[8]

History and Physical

Serotonin toxicity is a clinical diagnosis initially defined by the Sternbach criteria. Generally, these symptoms include neuromuscular excitation, autonomic stimulation and altered level of consciousness. The presence of generalized clonus indicates serotonin toxicity.[13] Neuromuscular symptoms are usually more prominent in the lower extremities.[15]

Due to the nonspecific nature of the Sternbach criteria, the Hunt serotonin toxicity criteria were developed. The Hunt serotonin toxicity criteria decision rule describes 5 constellations of symptoms that define serotonin toxicity[10]:

  1. Spontaneous clonus
  2. Inducible clonus and agitation or diaphoresis
  3. Ocular clonus with agitation or diaphoresis
  4. Tremor and hyperreflexia
  5. Ocular clonus, hypertonicity, and temperature greater than 38 C

Besides signs and symptoms, a history suggestive of serotonin exposure or overdose is required to diagnose serotonin toxicity.

Minor symptoms of serotonin toxicity include vomiting, somnolence, mydriasis, or diaphoresis. Someone can see severe symptoms (decreased level of consciousness, ECG changes, and seizures with overdoses greater than 75 times the recommended daily dose.[23] The concentration of the different serotonin receptors is highest in the neuromuscular, autonomic nervous, and gastrointestinal (GI) systems, accounting for the variety of common adverse effects of serotonin excess.[14]


Initial evaluation and treatment of a patient with serotonin toxicity are similar to any overdose, altered mental status, or poisoning patient with the establishment of intravenous access, initiation of cardiac monitoring, stabilization of vital signs, and fluid resuscitation. Diagnosis of serotonin toxicity is not only clinical but also a diagnosis of exclusion, therefore, even though diagnosis does not rely on any specific laboratory value, thorough testing to rule out other causes of altered mental status is essential.[12]

Treatment / Management

Nelson et al.[24] established guidelines for out-of-hospital management of isolated SSRI overdose and recommended at-home observation of patients who were experiencing minor symptoms and had ingested less than 5 times their own prescribed dose or less than 5 times the initial adult dose in an SSRI-naive patient. This should only be done in close conjunction with a regional poison control center.

Treatment is largely supportive and involves discontinuation of all serotonergic therapies, control of agitation with benzodiazepines and defervescence.[25][12] Droperidol and haloperidol should not be used to control agitation as these medications can worsen hyperthermia by inhibiting sweating through their anticholinergic properties.[26]

In severe cases of serotonin toxicity where patients required endotracheal intubation and ventilatory support, hypertonicity, rigidity, and high-grade fever were evident.[12]

Muscular rigidity is thought to be the primary cause of hyperthermia and death so patients with severe symptoms should be rapidly cooled. If benzodiazepines do not sufficiently control muscle spasm or temperature is greater than 41.1 C, intubation with neuromuscular blockade and paralysis can be considered.[12] In cases refractory to supportive care, cyproheptadine or chlorpromazine, which have anti-serotonergic properties, can be administered; although, it is unclear if these medications alter patient outcome.[27][28] Cyproheptadine does not have an IV formulation and must, therefore, be administered via a nasogastric or orogastric tube.[29] There is no role for acetaminophen, NSAIDs, or aspirin in control of hyperthermia as the increased temperature is not caused by a change in the hypothalamic temperature set point.[27]

Differential Diagnosis

Serotonin toxicity should not be confused with the neuroleptic malignant syndrome (NMS) which usually has an insidious onset of bradykinesia, "lead pipe" rigidity and other extrapyramidal symptoms.[13] Duration of NMS is on the order of weeks, significantly longer than serotonin toxicity, which usually resolves within 24 hours of discontinuation of serotonergic therapies [29]


Prognosis is good, and full recovery is expected.[29] The median length of stay for these SSRI overdose admissions was 15.3 hours in one study.[8] Mild cases can be observed in the emergency department for at least 6 hours before being discharged safely home.[12] Pharmacokinetics of the specific drug involved appear to affect duration; fluoxetine has a longer half-life than other SSRIs at 4 to 6 days.[7][29]

Patients with severe symptoms should be dispositioned to the intensive care unit.

Enhancing Healthcare Team Outcomes

SSRIs are prescribed by many healthcare workers including the primary care provider, psychiatrist, pain specialist, and the nurse practitioner. Unlike their predecessors, the monoamine oxidase inhibitors and tricyclic antidepressants, SSRIs are much safer in overdose.[1]  However, at the same time SSRIs are also associated with several serious adverse effects that need close monitoring. All clinicians who prescribe these drugs should educate the patient on the potential adverse effects. Nursing staff can also counsel the patients, monitor treatment effectiveness, watch for adverse drug reactions, and alert the prescriber regarding any issues that arise. In addition, the pharmacist has to make sure that the patient is not on any other medication that may lead to a drug-drug interaction with the SSRI.  More important the pharmacist should ensure that multiple clinicians do not prescribe similar agents leading to polypharmacy and report concerns to the clinical team. An interprofessional approach between clinicians and pharmacists working together will result in the best outcomes. [Level 5]

Clear, closed-loop communication between pre-hospital, regional poison control center, emergency department, and intensive care staff is essential to make sure that patients prescribed SSRI receive the appropriate level of care while safely allocating resources.[30]



Carla S. O'Day


7/4/2023 12:22:20 AM



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