Brief overview
- Symptoms: Profuse sweating, reddened skin, dry mucous membranes, high pulse and blood pressure, nausea and vomiting, disturbances between muscles and nerves (tremors, muscle rigidity, excessive reflexes), psychological disturbances (restlessness, agitation, impaired consciousness) as well as cardiac arrhythmias, epileptic seizures and organ failure
- Treatment: discontinuation of causative medications, extensive cooling if fever is high, fever-reducing and muscle-relaxing medications, serotonin-inhibiting medications
- Causes and risk factors: medications for depression, breakdown agents of medications used to treat heart disease and epilepsy, and drugs that act on the serotonin system
- Diagnosis and investigations: Medical interview (medical history) and physical as well as neurological examination (doctors test reflexes, for example), psychiatric examinations, blood tests, magnetic resonance imaging (MRI), computed tomography (CT), electrocardiogram (ECG).
- Course of disease and prognosis: The course is usually mild and the prognosis is good. It depends on the level of serotonin and the time it takes for the body to break down the causative drug or medication. Only in isolated cases does serotonin syndrome lead to death.
What is serotonin syndrome?
Serotonin syndrome results from an excess of the nerve messenger (neurotransmitter) serotonin in the central nervous system. Other names include serotoninergic or serotonergic syndrome and central serotonin syndrome.
The cause of serotonin excess is mostly due to medications for depression (antidepressants) that affect the body’s serotonergic system. Serotonin syndrome is thus caused in the broadest sense by side effects or interactions of various antidepressant (but also other) drugs. Doctors also speak of an adverse drug reaction.
It is not known exactly how often it occurs. It is usually mild, or atypical symptoms occur. Therefore, serotonin syndrome often cannot be detected.
What is serotonin?
Serotonin (chemical: 5-hydroxy-tryptamine) is an important messenger of the nervous system (neurotransmitter). It is found in both the central (brain and spinal cord) and peripheral nervous systems. In the central nervous system (CNS), serotonin is involved in the control of the sleep-wake rhythm, emotions, temperature or pain, but also in learning processes and memory formation.
Depression and serotonin syndrome
Serotonin, together with another neurotransmitter called norepinephrine, controls various processes in the brain. These include, above all, emotional processes and the control of attention and pain inhibition.
Experts assume that a deficiency of these messenger substances leads to depressive symptoms such as sadness, listlessness and loss of interest. For this reason, doctors treat depression with drugs that increase serotonin levels in the body. As a result, and for example due to too high a dose of medication, serotonin may be in excess and ultimately lead to serotonin syndrome.
What are the symptoms?
Sometimes the increased serotonin level initially manifests as a mild flu-like infection. More severe symptoms then develop within minutes.
Experts currently divide serotonin syndrome symptoms into three groups:
Vegetative symptoms.
Those affected suffer from fever and chills, so they often feel very ill (flu-like feeling). Other vegetative symptoms that often occur in serotonin syndrome are:
- Increased pulse and blood pressure (tachycardia and hypertension).
- Rapid breathing (hyperventilation)
- Profuse sweating (hyperhidrosis)
- Nausea, vomiting, and diarrhea
- Headache
Disturbed interaction between muscles and nerves
Sufferers tremble (tremor), have easily triggered and exaggerated reflexes (hyperreflexia), involuntary muscle twitching (myoclonia), and are only able to move with effort due to increased muscle tension (hyperrigidity, rigor). Muscle cramps are also possible.
Psychological effects
Furthermore, affected individuals suffer from symptoms triggered by a serotonin syndrome in the central nervous system. The serotonin excess here leads to increased arousal. As a result, the following mental abnormalities often occur in serotonin syndrome:
- restlessness, nervousness, urge to move around
- @ Hallucinations
- Disturbances of consciousness and attention
- Increased mood
- Problems with fine-tuning of movements (coordination disorders)
How is serotonin syndrome treated?
Serotonin syndrome is considered a psychiatric and neurological emergency because it is sometimes life-threatening. As a first measure, doctors discontinue the medications that cause serotonin syndrome. For mild symptoms, this approach is usually sufficient (in about 90 percent of cases). If symptoms persist, doctors take additional measures. Severe serotonin syndrome requires intensive medical monitoring and care.
Intensive care for serotonin syndrome
Medication
Antipyretic drugs further reduce the high body temperature.
If necessary, doctors administer drugs to relax the muscles (muscle relaxants). In this way, they lower the fever, for example, which occurs in serotonin syndrome mainly due to increased muscle tension. The muscle relaxants are also intended to prevent severe muscle damage, for example the dissolution of muscle fibers (rhabdomyolysis). This protects the kidneys at the same time. This is because rhabdomyolysis releases large quantities of the oxygen-binding muscle protein myoglobin. This is sometimes deposited in kidney tissue and leads to kidney failure.
Benzodiazepines such as lorazepam and diazepam are also administered for serotonin syndrome. They suppress seizures.
If symptoms persist, doctors also administer cyproheptadine or methysergide. Both drugs bind to and inhibit serotonin receptor structures, among other things, and thus reduce the harmful influence of the hormone excess of a serotonin syndrome. Awake persons swallow tablets, sedated persons receive the active substances via a stomach tube.
What are the causes and risk factors?
In some cases, the first signs of serotonin syndrome occur after the first dose of an antidepressant. In other sufferers, it develops only after an increase in dose. In most cases, however, serotonin syndrome develops when two or more of the drugs in question are combined. This is because interactions between the drugs result in a significant serotonin excess.
In addition to antidepressants, some other drugs and some illegal drugs also cause serotonin syndrome by interfering with the serotonergic system.
These drugs, as well as the medications that cause serotonin syndrome, especially in combination, include, subdivided according to their effect:
|
Effect in the serotoninergic system |
Active ingredients |
|
increased formation of serotonin |
|
|
increased release of serotonin |
amphetamines, cocaine, mirtazapine, methadone, ecstasy, the Parkinson’s drug L-dopa |
|
inhibition of reuptake from the synaptic cleft between two nerve cells |
Selective serotonin reuptake inhibitors (SSRIs), such as citalopram, sertraline, fluoxetine, paroxetine |
|
Selective serotonin-norepinephrine reuptake inhibitors (SSNRIs), such as venlafaxine, duloxetine |
|
|
Tricyclic antidepressants, such as amitriptyline, doxepin, desipramine, nortriptyline, clomipramine, imipramine |
|
|
Inhibition of serotonin degradation |
Monoamine oxidase (MAO) inhibitors such as moclobemide, tranylcypromide, or the antibiotic linezolid |
|
stimulatory effect at serotonin receptor structures (5-HT receptors) |
5-HT1 agonists such as buspirone or triptans (e.g., sumatriptan, almotriptan) prescribed for migraines |
|
enhanced serotonin effect |
Lithium |
Influence of other drugs
Drugs are also broken down in the body. However, there are certain drugs that interfere with the breakdown of the drugs mentioned above, mostly because they are metabolized in the same way. These include, for example, the heart medications amiodarone or beta blockers, drugs for epilepsy such as carbamazepine, and also HIV therapeutics such as ritonavir or efavirenz.
The gastroprotective drug cimetidine also inhibits the degrading protein complexes. As a result, the serotonergically active substances accumulate in the body. As a result, they influence the serotonin system even more strongly. In this way, even a small dose of medication can sometimes lead to serotonin syndrome.
How is serotonin syndrome diagnosed and investigated?
In addition, serotonin excess develops relatively quickly. This often leaves little time for extensive investigations in severe cases. The diagnosis is further complicated by the fact that there are no significant laboratory tests to determine serotonin syndrome as the cause of the symptoms.
Anyone who suspects that they are suffering from serotonin syndrome should see a doctor immediately, such as the psychiatrist treating them.
Medical history (anamnesis)
The cornerstone in serotonin syndrome diagnosis is taking a medical history (anamnesis). For example, the doctor asks the following questions:
- What symptoms are you suffering from?
- Do you have fever, nausea with vomiting and diarrhea? Do you sweat noticeably?
- Do you find it difficult to move? Do you have muscle cramps or twitching?
- Do you have problems sitting still?
- How long have the symptoms been present? Have they increased in the last few hours?
- What previous illnesses do you have?
- Do you suffer from depression for which you take tablets?
- What medications are you taking? Please list all medications, including dietary supplements and herbal agents!
- Has your medication been changed or extended recently?
- Do you use drugs at regular intervals?
Physical examination
After the detailed questioning, the doctor examines the body of the patient in detail. In doing so, he looks for typical serotonin syndrome symptoms. These, together with the medical history, are decisive for the diagnosis of “serotonergic syndrome”. The physician checks, for example, whether the pupils are dilated. Muscle twitching or trembling of the affected person is often already visible to the naked eye, as is accelerated breathing. The doctor also measures blood pressure, pulse and body temperature.
Furthermore, the doctor checks the neurological condition of the patient. He pays particular attention to reflex testing. To do this, he strikes the thigh tendons below the kneecap with a so-called reflex hammer (patellar tendon reflex), for example. If the patient suffers from a serotonin syndrome, the reflex, i.e., the “advancing” of the lower leg, occurs excessively strongly and often even with only a light tapping of the tendon.
Further examinations in serotonin syndrome
In the case of rapid breathing, a so-called blood gas analysis often provides information about the exchange of oxygen and carbon dioxide in the lungs.
The physician also performs toxicological tests. A urine sample often reveals possible drug use or abuse in rapid tests (so-called toxicological bedside tests). Using sometimes complex screening procedures, laboratory technicians also detect elevated blood concentrations of a certain active drug substance (determination of the drug level).
In addition, depending on the symptoms, the doctor will arrange for further examinations. For example, he uses an electrocardiogram (ECG) to detect cardiac arrhythmias. After epileptic seizures, an imaging procedure such as computer tomography (CT) helps to rule out other causes of the symptoms.
Differential diagnoses
Serotonin syndrome is sometimes difficult to distinguish from other disorders. Another conceivable diagnosis (differential diagnosis) is malignant neuroleptic syndrome, or MNS. The symptoms of MNS occur, for example, after the intake of, above all, strongly effective (highly potent) drugs against psychoses (antipsychotics, neuroleptics). As in the case of serotonin syndrome, those affected suffer from disorders of consciousness, fever, rapid heartbeat, fluctuations in blood pressure and/or increased muscle tension.
Other conditions, some of which have symptoms similar to serotonin syndrome, include:
- Malignant hyperthermia
- Anticholinergic syndrome/delir
Course of the disease and prognosis in serotonin syndrome
With prompt and proper treatment, serotonin syndrome has a good prognosis overall. In individual cases, however, it leads to death, for example, via multiple organ failure.
Serotonin Syndrome: Duration
Serotonin syndrome duration depends primarily on the triggering medication. Depending on the active ingredient, the body needs different amounts of time to break down the drug. Experts refer to this as the half-life (HWZ). This indicates the time after which half of the drug taken has left the body again.
Fluoxetine, for example, has a relatively long half-life. In the body, the active substance norfluoxetine is formed from it with an HRT of about four to 16 days. This means that the body metabolizes and breaks down the active substance only slowly. Serotonin syndrome symptoms consequently last longer after fluoxetine intake than with other antidepressants, for example.
Caution with new drugs
Life-threatening serotonin syndrome
Serotonin syndrome can sometimes be life-threatening. Serious consequences or complications occur, for example, due to persistent cardiac arrhythmias. Affected persons usually experience a pressing feeling in the chest, a fast and irregular heartbeat, and heart stuttering.
Epileptic seizures and even coma are also possible consequences of serotonin syndrome.
Since serotonin also affects blood clotting, a serotonergic syndrome in some cases leads to so-called consumption coagulopathy. In this case, the coagulation system (including platelets) in the blood vessels is activated. As a result, blood clots form in various organs, which are then impaired in their function. In addition, a deficiency of clotting factors (due to increased consumption) occurs later in the course of the disease, resulting in spontaneous bleeding.
A consequence of these hemorrhages and clots is multi-organ failure, which in severe cases of serotonin syndrome leads to death.
How can serotonin syndrome be prevented?
Herbal medicines such as St. John’s wort also carry the risk of serotonergic syndrome when taken with antidepressants (such as tricyclic antidepressants and SSRIs). Therefore, pay attention to your doctor’s orders and be sure to consult him or her if you have any complaints in order to prevent serotonin syndrome.
