Serotonin Syndrome – Risk Factors, Diagnosis and Treatment

Definition

Serotonin syndrome is a potentially life-threatening, medication-induced condition that occurs in individuals who are receiving serotonergic agents. These medications cause increased serotonergic activity in the peripheral and central nervous systems, which results in high levels of serotonin accumulating in the body. Serotonin is a chemical needed for your nerve cells and brain to function. Vomiting, sleep, temperature regulation, appetite, mood, regulation of BP, and the perception of pain are functions that involve brain serotonergic neurons. It may also be associated or involved in conditions such as migraine headaches and anxiety. The proper amount of serotonin helps improve our qulaity of life, but too much serotonin causes symptoms that range from mild, moderate, and potentially life-threatening symptoms.

It most often occurs when two drugs that affect the body’s level of serotonin are taken together at the same time. The drugs cause too much serotonin to be released or to remain in the brain area.

Types of Serotonin Syndrome

The severity levels are as follows:

Mild serotonin syndrome: In mild cases, individuals may experience symptoms such as restlessness, shivering, tremors, increased heart rate, dilated pupils, and gastrointestinal issues like diarrhea or nausea.

Moderate serotonin syndrome: Moderate cases involve more pronounced symptoms, including high fever, increased blood pressure, more intense muscle rigidity or twitching, excessive sweating, and worsening agitation.

Severe serotonin syndrome: Severe cases is a medical emergency that requires immediate attention. Symptoms may include extremely high fever, severe muscle stiffness, seizures, irregular heartbeat, rapid breathing, profound confusion, hallucinations, and even loss of consciousness.

It is important to note that the severity of can vary among individuals, and symptoms may progress rapidly. Prompt medical intervention is crucial to prevent complications and ensure appropriate management. If you suspect serotonin syndrome or experience any concerning symptoms while taking medications that affect serotonin, seek immediate medical assistance.

Epidemiology

Serotonin syndrome is seen in all age groups, from newborns to the elderly, and its incidence is increasing due to the growing use of serotonergic drugs. The use of antidepressants in adults in the United States has nearly doubled between 1999 and 2010. A surveillance system reported over 54,000 cases of exposure to selective serotonin reuptake inhibitors (SSRIs) in 2016, with an 18% increase in cases and 8% increase in deaths from 2002 to 2016. Moderate serotonin syndrome occurs in around 15% of SSRI poisonings. Surprisingly, close to half of the adverse event reports involving SSRIs were attributed to a single drug. The true incidence and severity of serotonin syndrome remain unknown due to its rarity, difficulty in detection during clinical trials, under-recognition, and under-reporting by physicians, with mild cases often being overlooked or self-resolving.

Pathophysiology of Serotonin Syndrome

Serotonin (5-hydroxytryptamine, 5-HT) is synthesised from the amino acid tryptophan. It has central and peripheral effects and there are at least seven different types of serotonin receptors. Centrally, serotonin acts as a neurotransmitter with influences on mood, sleep, vomiting and pain perception. Depression is often associated with low concentrations of serotonin. Peripherally, the primary effect of serotonin is on muscles and nerves. The majority of serotonin is synthesised and stored in the enterochromaffin cells of the gut where it causes contraction of gastrointestinal smooth muscle. Serotonin is also stored inplatelets and promotes platelet aggregation. It also acts as an inflammatory mediator.

The pathophysiology remains poorly understood. It is thought to result from stimulation of the 5-HT1A and5-HT2 receptors, and the drug classes implicated in serotonin syndrome reflect this theory. These include serotonin precursors, serotonin agonists, serotonin releasers, serotonin reuptake inhibitors, monoamineoxidase inhibitors (MAOIs) and some herbal medicines. Commonly used migraine medications such as sumatriptan and dihydroergotamine are also regarded as ‘serotonergic’ drugs. There are isolated case reports of mild/moderate serotonin syndrome associated with these drugs. Most cases will involve either an SSRI or an MAOI and at least one other medication. Generally, drugs with two different mechanisms of action on serotonin must be present for a severe serotonin syndrome to develop.

Some other drugs may cause this syndrome although how this happens remains unclear. Drugs with effects on catecholamines, tryptamine and dopamine may have secondary effects on serotonin release or reuptake.

Symptoms of Serotonin Syndrome

Symptoms vary depending on the severity of the condition. People with mild serotonin syndrome can experience:

• Sweating
• Tremor (mild shaking in the hands)
• Fast heart rate
• Trouble sleeping

People with severe serotonin syndrome have symptoms that are harder to ignore, such as:

• Confusion
• Agitation
• Diarrhea
• High fever
• Fast heart rate
• High blood pressure
• Lockjaw (trouble opening the mouth)
• Trouble turning around or getting up from a lying position
• Uncontrollable, spontaneous movements of their limbs (clonus, myoclonus)
• Unusual eye movements (ocular clonus)

Causes

It is also known as serotonin toxicity, happens as the result of taking serotonergic drugs, which are 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 an overdose is accidental or purposeful.

Taking two serotonergic medications together: The most common cause involves a person taking two (or more) serotonergic drugs at the same time, often without realizing it.

Which Medications Cause Serotonin Syndrome?

Drugs and supplements that if taken together or in high doses could lead to serotonin syndrome include:

• Selective serotonin reuptake inhibitors (SSRIs): antidepressants such as citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft)
• Serotonin and norepinephrine reuptake inhibitors (SNRIs), antidepressants such as trazodone, duloxetine (Cymbalta) and venlafaxine (Effexor)
• Tricyclic antidepressants, such as amitriptyline and nortriptyline (Pamelor)
• Anti-migraine medications
• Pain medications: opioid medications including codeine (Tylenol with codeine), fentanyl (Duragesic), hydrocodone meperidine (Demerol), oxycodone (Oxycontin, Percocet, Percodan) and tramadol (Ultram).
• Lithium
• Street drugs: LSD, cocaine, ecstasy, and amphetamines
• Anti-nausea medications
• Cough and cold medications
• Herbal supplements: St. John’s wort, ginseng, and nutmeg
• Cannabinoids may also influence serotonin

Complications associated with serotonin syndrome

In severe cases, serotonin syndrome can result in:

• Seizures
• Hyperthermia
• Shock
• Rhabdomylosis, in which muscle tissue breaks down, releasing myoglobin, a substance that can damage the kidneys
• Metabolic acidosis
• Kidney failure
• Respiratory failure
• Acute respiratory distress syndrome
• Blood clots

In some cases, it can be fatal. If this happens, it is usually within 24 hours of exposure.

Risk factors of Serotonin Syndrome

The risk factors include:

Medications: Certain medications that increase serotonin levels in the brain can raise the risk of serotonin syndrome.

Multiple medications: Taking multiple medications that affect serotonin can increase the chances of serotonin syndrome.

High doses: Taking high doses of medications that affect serotonin levels can increase the risk.

Drug interactions: Combining certain medications or recreational drugs can interact and increase serotonin levels, increasing the risk.

Individual susceptibility: Some people may be more susceptible to serotonin syndrome due to genetic factors or pre-existing medical conditions.

Rapid changes: Starting or increasing medication doses abruptly can raise the risk of serotonin syndrome.

Remember, it’s important to follow medication guidelines, talk to healthcare professionals, and be aware of the signs and symptoms of serotonin syndrome to seek immediate medical help if needed.

Diagnosis

There aren’t any tests to diagnose serotonin symptoms. Your healthcare provider usually makes the diagnosis based on the results of your physical exam, review of your symptoms and history of medications you take that affect serotonin levels.

You can assist your healthcare provider by telling them all the products you take, including prescription medicines, over-the-counter medicines, supplements, herbal products and illegal drugs.

Your healthcare provider may order:

• Blood and urine tests to measure the levels of drugs you’re taking.
• Tests to check how well your body is functioning.
• Tests to look for signs of infection, including a spinal tap.
• Other tests (including chest X-ray, CT scan), as needed, to rule out other disorders that may cause similar symptoms or to identify any complications.

Treatment

Treatment of serotonin syndrome depends on the severity of your symptoms.

• If your symptoms are minor, a visit to the doctor and stopping the medication causing the problem may be enough.
• If you have symptoms that concern your doctor, you may need to go to the hospital. Your doctor may have you stay in the hospital for several hours to make sure your symptoms are improving.
• If you have severe serotonin syndrome, you’ll need intensive treatment in a hospital.

Depending on your symptoms, you may receive the following treatments:

• Muscle relaxants. Benzodiazepines, such as diazepam (Valium, Diastat) or lorazepam (Ativan), can help control agitation, seizures and muscle stiffness.
• Serotonin-production blocking agents. If other treatments aren’t working, medications such as cyproheptadine can help by blocking serotonin production.
• Oxygen and intravenous (IV) fluids. Breathing oxygen through a mask helps maintain oxygen levels in your blood, and IV fluids are used to treat dehydration and fever.
• Drugs that control heart rate and blood pressure. These may include esmolol (Brevibloc) or nitroprusside (Nitropress) to reduce a high heart rate or high blood pressure.

If your blood pressure is too low, your doctor may give you phenylephrine (Vazculep) or epinephrine (Adrenalin, Epipen, others).

• A breathing tube and machine and medication to paralyze your muscles. You may need this treatment if you have a high fever.

Milder forms of serotonin syndrome usually go away within 24 to 72 hours of stopping medications that increase serotonin. You may need to take medications to block the effects of serotonin already in your system.

However, symptoms of serotonin syndrome caused by some antidepressants could take several weeks to go away completely. These medications remain in your system longer than do other medications that can cause serotonin syndrome.

Prevention of Serotonin Syndrome

To prevent serotonin syndrome, here are some measures you can take:

• Communication: Inform your healthcare provider about all the medications you are taking.
• Follow prescribed doses: Take medications as directed and avoid changing doses without guidance.
• Be cautious with combinations: Avoid mixing multiple medications that affect serotonin levels.
• Gradual changes: If dose adjustments are necessary, follow your healthcare provider’s instructions for gradual changes.
• Watch for interactions: Be aware of potential interactions between medications and discuss any concerns with your healthcare provider or pharmacist.
• Learn the symptoms: Be familiar with the signs of serotonin syndrome and promptly report any unusual symptoms.
• Monitor your well-being: Stay attentive to your body and mental health while taking medications.
• Seek professional guidance: Consult your healthcare provider if starting new medications or if you have concerns about serotonin syndrome.

By following these steps and maintaining communication with your healthcare provider, you can minimize the risk of serotonin syndrome.