Serotonin Syndrome

• Serotonin regulates mood, cognition, and many other physiological processes. 
• Serotonin syndrome is an adverse drug reaction to SSRIs. 
• Some of the symptoms of serotonin syndrome are agitation and anxiety.  

The increased complexities within modern healthcare include therapeutics and the accompanying adverse drug reactions (ADRs) prescribed to an aging population with rising multi-morbidity.  

A handful of drugs drive ADR-related hospitalizations:  

• Antiplatelet 
• Anticoagulants 
• Cytotoxic drugs 
• Immunosuppressants 
• Diuretics 
• Antidiabetics 
• Antibiotics 

Unwanted drug reactions have significant economic and clinical costs contributing to: 

•  
• Hospital admissions 
• Extended hospital stays 
• Emergency department visits 

Serotonin syndrome or excessive serotonergic activity in the nervous system is a known adverse drug reaction associated with selective serotonin reuptake inhibitor (SSRI) antidepressants, including: 

• Citalopram 
• Escitalopram 
• Fluoxetine, 
• Fluvoxamine 
• Paroxetine 
• Sertraline 
• Dapoxetine 

Patients are at greater risk of serotonin syndrome when they are starting or increasing the dose of a serotonergic medicine, taking two serotonergic agents and in a drug overdose. 

Other common serotonergic drugs that may contribute to serotonin syndrome, including though not limited to amphetamines and derivatives such as: 

• Dextroamphetamine 
• Cyclobenzaprine (Flexeril) 
• Buspirone (Buspar) 
• Metoclopramide (Reglan) 
• Ondansetron (Zofran)  
• And many other medications 

When taken with antidepressants, Lysergic acid diethylamide (LSD), cocaine, St. John’s wort and ginseng, can cause serotonin syndrome. 

What Is Serotonin?

Serotonin is a neurotransmitter that modulates neural and complex biological functions, including:  

• Cardiovascular action 
• Bowel motility 
• Bladder control
  

 The 5-hydroxytryptamine molecule (monoamine) targets serotonin receptors and is a neurotransmitter modulating 

• Mood 
• Sleep 
• Cognition 
• Reward 
• Learning 
• Memory 
• and physiological processes including vomiting and vasoconstriction 

Disruptions to serotonin influence 

• the sleep cycle 
• melatonin 
• and the circadian rhythm 

 and dysfunction can include: 

• fatigue 
• the inability to fall asleep
  

Signs and Symptoms of Serotonin Syndrome

Serotonin syndrome produces many adverse effects, including changes in mental status such as  

• Agitation 
• Restlessness 
• Confusion 
• Anxiety 

The lack of serotonin plays a role in depression and the excess can lead to extreme nerve cell activity. 

Autonomic effects include: 

• Hypertension 
• Tachycardia 

• Hyperthermia 
• Tachypnea 
• Mydriasis (dilation of the pupil) 
• Diaphoresis 
• Shivering 

• Diarrhea 

 The neuromuscular effects of serotonin syndrome include: 

• Tremors 
• Clonus 
• Hyperreflexia
• Hypertonia
  

A Serotonin Syndrome Case Study

A 33-year-old female arrived at the hospital with a past medical history of generalized anxiety and depression. In triage, the patient expressed a recent history of unsteadiness and a mild headache for several weeks.  

Vital signs: tympanic temperature of 38.2 °C, pulse 127 beats/min and blood pressure of 153/94 mm Hg sitting, and oxygen saturations at 95% on room air with a respiratory rate of 21 per minute.  

The patient’s GCS (15) with bilateral 6 mm round and reactive pupils to light. The first look physician documented tachycardia, diaphoresis, and hyperreflexia in the patient’s electronic medical record (EMR).  

Along with a headache, the patient reported increased anxiety, insomnia, and constant twitching. She had seen her primary care MD one week prior and had a recent medication change. Her doctor discontinued her fluoxetine (Prozac) without taper and started her on Paroxetine (Paxil) 10 mg daily and hydroxyzine 50 mg as needed for anxiety. 

 The patient had no history of illicit drugs, alcohol use, or smoking. She had no known drug allergies or side effects experienced with fluoxetine. There was no history of drug overdose. She lived with her husband and three children.  

The physician diagnosed the patient with serotonin syndrome based on Hunter’s criteria. Hunter’s criteria include numerous parameters that equate to serotonin toxicity beyond spontaneous clonus.  

Additional diagnostic presentations include: 

• Inducible clonus, or ocular clonus plus agitation 
• Inducible clonus and diaphoresis 
• Tremors and hyperreflexia 
• Hypertonia and hyperthermia with ocular clonus 

The physician discontinued the paroxetine, and the patients’ physical symptoms improved. 

Serotonin Syndrome Treatment

The diagnosis of serotonin syndrome is a process of exclusion. In emergent presentations, the diagnosis is based on the history and physical and the patient’s use of a serotonergic drug, over-the-counter medications, dietary supplements, and illicit substance use. A medical toxicologist is the gold standard for diagnosis. 

The symptoms of serotonin syndrome can resolve within 24 hours of discontinuing the serotonergic agent, but medications with active metabolites or irreversible monoamine oxidase inhibitors (MAOIs) can persist for several days.  

Medications such as diazepam (Valium, Diastat) or lorazepam (Ativan), are useful in controlling agitation, seizure activity and muscle stiffness.  

If treatments are ineffective, serotonin-production blocking agents, such as cyproheptadine, can block serotonin production. Other treatment options include prompt discontinuation or lowering the dose of causative medication, avoiding two high-dose, serotonin-affecting medications and changing existing medications that do not affect serotonin.

The Bottom Line

Serotonin syndrome is caused when high levels of serotonin is built up in the body and is considered a serious drug reaction. 

The symptoms are usually alleviated when the medication causing the symptoms is no longer being administered. 

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