Serotonin Syndrome Causes, Symptoms, and Treatment

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Serotonin syndrome is a potentially life-threatening condition that's caused by elevated serotonin concentrations in your system from certain medications. Serotonin is a chemical called a neurotransmitter that communicates with nerve cells and has a wide variety of functions throughout your body, primarily in your central nervous system and intestines. In the right amounts, serotonin is necessary, but when your body builds up too much and your levels get too high, symptoms can range from unpleasant to severe. If it's left untreated, serotonin syndrome can potentially lead to death.

Causes

Serotonin syndrome, also known as serotonin toxicity, happens as the result of taking serotonergic drugs, medications that affect the level of serotonin in your body. It may be brought on by several different circumstances including:

  • Taking one serotonergic medication: It's unlikely that using one serotonergic medication by itself will cause serotonin syndrome, but it can happen in certain people who are sensitive to serotonin, especially when the dose is increased.
  • Overdosing: You can end up with serotonin syndrome if you ingest too much of your serotonergic medication(s), whether or not it's purposeful.
  • Taking two serotonergic medications together: The majority of cases involve a person taking two (or more) serotonergic drugs at the same time, often without realizing it.

The medications that are most often associated with serotonin syndrome are antidepressants such as:

There are other medications that are also considered serotonergic drugs, though they may not be as well-known. Some examples of these include:

  • Migraine medications called triptans such as Axert (almotriptan), Amerge (naratriptan), Imitrex (sumatriptan), and Maxalt (rizatriptan)
  • Anticonvulsants like Tegretol (carbamazepine) and Depakene (valproic acid), which are used for migraines, epilepsy, and bipolar disorder
  • Opioid pain medications such as Ultram (tramadol), codeine (Tylenol with codeine), Demerol (meperidine), Talwin (pentazocine), and Oxycontin (oxycodone)
  • 5-HT3 receptor antagonists, which treat nausea, like Anzemet (dolasetron), granisetron, Zofran (ondansetron), and Aloxi (palonosetron)
  • Reglan (metoclopramide), a prokinetic medication that's used to treat gastroesophageal reflux disease (GERD), diabetes, and sometimes to treat nausea in chemotherapy patients
  • Over-the-Counter cough and cold medications that contain dextromethorphan like Children's Robitussin Cough Long-Acting, Vicks DayQuil Cough, Vicks Formula 44 Custom Care Dry Cough, Zicam Cough MAX, and many others, including a combination cough and cold medications that have dextromethorphan in them
  • Ergot derivatives, including Ergomar (ergotamine) for migraines and Methergine (methylergonovine) for uterine bleeding after childbirth
  • A muscle relaxant called Amrix (cyclobenzaprine)
  • Buspirone, a medication that's prescribed for anxiety disorders

Other substances and supplements that can contribute to serotonin syndrome include:

  • St. John's Wort
  • Illegal/illicit drugs such as cocaine, amphetamines, ecstasy, and LSD
  • L-tryptophan, an over-the-counter amino acid supplement that people use to quit smoking, for mental health disorders, and to help athletic performance
  • Lithobid (lithium), a mood stabilizer that's often used to treat bipolar disorder

All of these drugs and substances affect serotonin in some way. Some block nerve receptors; some block reuptake; some slow the breakdown of serotonin; and some increase the release of serotonin.

Because so many medications can contribute to serotonin syndrome, it's essential that any doctors you see who prescribe you medication always know about all the over-the-counter and prescription medications and supplements you're currently taking.

Risk Factors

Your risk of developing serotonin syndrome goes up under these circumstances:

  • You just started taking a serotonergic medication like one of those mentioned above or you had your dose increased. Some people's bodies are naturally slower than others' are at metabolizing serotonin, and this isn't something you or your doctor will know until you are on a drug that boosts serotonin.

Most cases of serotonin syndrome start within 24 hours after starting or increasing a serotonergic medication and the majority of those start within six hours.

  • You're switching from an MAOI to another antidepressant or vice versa. Almost all antidepressants contain a warning that you should wait for at least two weeks, and sometimes more, when you switch antidepressant types. One of the main reasons for this is the danger that having both types of drugs in your system can lead to serotonin syndrome. Prozac (fluoxetine) in particular takes several weeks to be flushed out of your body.
  • You're taking more than one serotonergic medication, supplement, or substance at the same time. For instance, you're on Wellbutrin for depression and you take an Imitrex for a migraine or you're taking Zoloft (sertraline) and you treat a cold with DayQuil.

Symptoms

Symptoms of serotonin syndrome can be mild to severe indicating anything from a slight serotonin excess to a life-threatening syndrome. The most common symptoms include:

  • Sudden jerky or shock-like movements
  • Flushing or paleness
  • Slow or fast pulse
  • Fever
  • Headache
  • Anxiety
  • Muscle rigidity
  • Confusion
  • Restlessness
  • Profuse sweating
  • Tremor
  • Dilated pupils
  • Poor coordination
  • Rapid breathing
  • Irregular heartbeat
  • High blood pressure
  • Shivering

If your condition becomes severe, it can turn into a life-threatening situation and may include signs like:

  • High fever
  • Sudden swings in your blood pressure and/or pulse
  • Seizures
  • Losing consciousness

If you suspect you or a loved one is showing signs of serotonin syndrome, contact your doctor immediately. If your symptoms are getting worse or they're severe, head to the emergency room, or call 911. Quick treatment is important because you can become seriously ill and your condition can become fatal the longer you go untreated.

Diagnosis

Because the symptoms are similar to many other issues, you won't be diagnosed with serotonin syndrome until every other possible diagnosis has been ruled out. This is mainly because serotonin syndrome has to be diagnosed purely on your symptoms, history, and your physical and neurological exam.

Other conditions that you will likely have ruled out include:

  • Neuroleptic malignant syndrome (NMS), another drug-related disorder that has some of the same symptoms as serotonin syndrome but results from antipsychotics. The biggest difference is that serotonin syndrome generally comes on quickly after starting the trigger medication.
  • Infections like meningitis and encephalitis
  • An overdose of a substance like cocaine.
  • Withdrawal from alcohol or drugs
  • Intoxication
  • Reactions to other medications

The tests you may have to rule these conditions out include:

  • Blood tests such as a complete blood count (CBC), blood cultures to test for infection, and other blood tests that check your electrolytes, screen for drugs and alcohol, and check your kidney, thyroid, and liver function
  • Urine tests to screen for drugs and alcohol, as well as to look at your kidney function
  • Computed tomography (CT) scan of your brain
  • Electrocardiogram (ECT) to check your heart
  • Lumbar puncture (spinal tap) to evaluate your spinal fluid
  • Chest X-ray

Treatment

Once you've been diagnosed with serotonin syndrome, the first line of treatment is to discontinue all serotonergic drugs. Benzodiazepines like Valium (diazepam) or Ativan (lorazepam) may be helpful to relieve any muscular symptoms, and you may need supportive treatment like oxygen and intravenous (IV) fluids and stabilization of vital signs. Drugs that specifically act against serotonin, called serotonin antagonists, can potentially be useful.

For mild to moderate cases, your symptoms should subside within 24 to 72 hours once you've discontinued taking the serotonergic drug and you can expect to fully recover.

If your symptoms are worrisome, your doctor may have you hospitalized until you're stabilized. In cases where you're exhibiting signs of severe serotonin syndrome, you'll likely need to be hospitalized in the intensive care unit (ICU) until all your symptoms are gone. For high fever, you may need to be sedated and given a medication that keeps you still (paralytic) to avoid any more damage to your muscles. You'll also have a breathing tube and ventilator.

SSRI Discontinuation Syndrome

It should be noted that some of the same symptoms listed above may also occur when you abruptly stop taking an antidepressant or you taper it off too quickly, known as SSRI discontinuation syndrome. Agitation, headaches, shock-like sensations, poor coordination, chills, and impaired concentration are some of the characteristics common to both syndromes. Because of this risk, it's vital that you never stop taking your antidepressant abruptly without discussing with your doctor.

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Article Sources
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  1. Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin Syndrome. Ochsner J. 2013;13(4):533-540.

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Additional Reading
  • Boyer EW. Serotonin Syndrome (Serotonin Toxicity). UpToDate. Updated March 12, 2018. https://www.uptodate.com/contents/serotonin-syndrome-serotonin-toxicity

  • Mayo Clinic Staff. Serotonin Syndrome. Mayo Clinic. Updated January 20, 2017. https://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/symptoms-causes/syc-20354758

  • MedlinePlus. Serotonin Syndrome. The American Society of Health-System Pharmacists, Inc. National Institutes of Health. U.S. National Library of Medicine. Updated August 14, 2018. https://medlineplus.gov/ency/article/007272.htm

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