Serotonin Syndrome (Toxicity)

What is serotonin syndrome?

Serotonin syndrome is a condition where there is an abnormally high concentration of a brain hormone (neurotransmitter) known as serotonin. The nerve cells of the brain produce various chemicals called neurotransmitters, which are used to communicate with other cells, including other nerve cells or muscle cells. Serotonin is one such chemical that plays an important role in the transmission of nerve impulses between nerve cells (neurons). However, an abnormally increased concentration of serotonin in the brain can disrupt normal nerve communication and function and even lead to death.

Serotonin syndrome 5-HT receptors

Serotonin is known to be involved in the regulation of various mental states like mood, happiness, appetite, and sleep. Changes in serotonin levels are reported in aggression, pain, anxiety, migraine, depression, and nausea. Therapeutic doses and over-doses of serotonin can increase the serotonin concentration in the central nervous system, resulting in serotonin syndrome.

  • Serotonin is produced by serotonin-producing nerve cells called serotonergic neurons in the brain.
  • It is then released into the space between two neurons (known as the synaptic cleft), where it binds to and activates serotonin receptors (called 5-HT receptors) on adjacent neurons.
  • Excess serotonin release causes over-stimulation of these 5-HT receptors in the nervous system leads to serotonin syndrome.

Serotonin syndrome symptoms

The symptoms of serotonin syndrome can be categorized as follows:

Changes in mental state

Cognitive-behavioral changes like :

  • heightened anxiety
  • hallucinations
  • headache
  • restlessness

Overactivation of involuntary movements

Changes in autonomic functions like :

  • rapid heartbeat
  • hypertension and other changes in blood pressure
  • high body temperature
  • excessive sweating
  • vomiting
  • shivering
  • diarrhea

Overactivation of neuromuscular system

  • Shivering
  • Muscle rigidity
  • Twitching of muscles
  • Hyperresponsive reflexes
  • Repetitive contraction
  • Relaxation of muscles

Death from excess serotonin

Serotonin syndrome can happen at all ages. The symptoms tend to resolve once serotonin levels are return to normal. However, if left untreated, the condition can become severe and potentially fatal. High fever with seizures, irregular heartbeat, and unconsciousness are the symptoms seen in cases of severe serotonin syndrome.

Serotonin syndrome causes

Excess serotonin in the central nervous system can occur intentionally with the use of certain drugs to increase the serotonin levels for treating some mental health conditions. Alternatively, it can arise with unintended drug interactions between two serotonergic drugs. For example, anti-depressant drugs manage depression by increasing the serotonin concentration in the brain. Administration of another drug can unintentionally have synergistic effect on serotonin concentration leading to serotonin toxicity. Initiating a treatment or changing the treatment constituents can lead to this condition.

Medication that increases serotonin

The compounds that modulate serotonin levels in the brain are categorized as :

  • Selective serotonin reuptake inhibitors (SSRIs)
    – Citalopram
    – Fluoxetine
    – Fluvoxamine
    – Paroxetine
    – Sertraline
  • Selective serotonin/nor-epinephrine-reuptake inhibitors (SNRIs)
    – Razodone
    – Venlafaxine
  • Monoamine oxidase inhibitors (MAOIs)
    – Isocarboxazid
    – Phenelzine
  • Atypical- and tricyclic antidepressants (TCAs)
    – Amitriptyline
    – Nortriptyline

Other medication and substances

  • Compounds like lithium, cough suppressant and certain medication prescribed for migraine, pain, and nausea can also affect serotonin levels.
  • Antimicrobial agents like antibiotics such as Linezolid, and anti-retroviral drugs like Ritonavir can also lead to serotonin syndrome.
  • Illegal drugs like LSD, amphetamine and cocaine can substantially increase serotonin release suddenly.
  • Dietary supplements like ginseng and St. John’s wort may also contribute to serotonin syndrome especially if used in conjunction with anti-depressants or other drugs.

Serotonin syndrome risk factors

Serotonin syndrome can affect any individual of any age. The risk of developing serotonin syndrome increases upon starting or raising the dose of drugs that modulate serotonin levels. Though a single drug can lead to serotonin syndrome, the condition is usually precipitated when more than one drug is taken simultaneously to increase serotonin levels. The use of illicit drugs or herbal supplements also increases the risk for serotonin syndrome.

The most common drug combinations known to cause serotonin syndrome are :

  • irreversible MAOIs and SSRIs
  • irreversible MAOIs and TCAs
  • irreversible MAOIs and tryptophan
  • irreversible MAOIs and pain-relieving medication like pethidine

Certain medical conditions also increase the risk for serotonin syndrome. This may include :

  • atherosclerosis – hardened and narrow blood vessels with damaged inner lining
  • hypertension – high blood pressure
  • hypercholesterolemia – high blood cholesterol
  • stress

Serotonin is normally broken down and affected by certain enzymes and other substances. Nerve, hormone and other diseases where these substances, like MAO-A and nitric oxide are abnormal can therefore affect serotonin metabolism.

About serotonin syndrome video

Serotonin syndrome diagnosis

No single clinical test is available to diagnose serotonin syndrome. A physical exam coupled with a thorough medical history is often sufficient to diagnose serotonin toxicity. The patient is almost always using one of the medications mentioned above that affects serotonin levels. The physical exam includes checking for the presence of :

  • stiffened muscles
  • spontaneous twitching
  • tremors
  • hyper-responsive reflexes
  • agitation
  • excessive sweating
  • high body temperature

Differential diagnosis

Various other conditions may present with similar symptoms. The rapid onset of serotonin syndrome differentiates it from other similar neurological conditions like neuroleptic malignant syndrome (NMS) where the development of symptoms progresses slowly. Systemic infections, drug abuse or alcohol withdrawal symptoms are also considered in the differential diagnosis.

Serotonin syndrome complications

Complications associated with severe serotonin syndrome include :

  • increased plasma acidity (metabolic acidosis)
  • rapid break-down of skeletal muscles (rhabdomyolysis)
  • seizures
  • loss of kidney function
  • uncontrolled blood clotting coupled with abnormal bleeding.

Serotonin syndrome treatment

The treatment options for serotonin syndrome includes supportive measures and medication. The supportive measures are usually sufficient for mild-to-moderate cases of serotonin syndrome but the severe cases often require immediate attention and medical treatment. Some serotonergic medications persist longer in the body than others and hence, require extended hospitalization, monitoring and follow-up.

Mild serotonin syndrome

Mild cases of serotonin syndrome only require stopping the serotonin-enhancing medications and the symptoms usually go away within 24 hours. Sedatives or muscle relaxants are given to relieve mild symptoms like agitation and seizures.

Severe serotonin syndrome

Severe cases of serotonin syndrome require intensive medical care. The treatment is largely symptom-based. Cooling is effective in treating high body temperature, whereas sedation is effective in blocking neuromuscular activities. Intravenous fluids are administered to keep dehydration and fever under control. Drugs like esmolol or nitroprusside are helpful in managing high heart rate and/or high blood pressure. In severe cases, a serotonin blocker like cyproheptadine is used, which stops serotonin production.

References :

  1. http://www.mayoclinic.com/health/serotonin-syndrome/DS00860
  2. http://www.patient.co.uk/doctor/Serotonin-Syndrome.htm
  3. http://www.webmd.com/depression/guide/serotonin-syndrome-causes-symptoms-treatments

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