Serotonin syndrome

Serotonin Syndrome: description

Serotonin syndrome is a combination of various symptoms caused by an excess of the neurotransmitter serotonin in the central nervous system. It is also called serotoninergic or serotonergic syndrome or central serotonin syndrome.

The cause of the serotonin excess is in drugs for depression (antidepressants), which affect the serotonergic system of the body. The serotonin syndrome thus arises in the broadest sense by side or interactions of various antidepressant (but also other) drugs.

What is serotonin?

Serotonin (chemically: 5-hydroxy-tryptamine) is an important messenger substance of the nervous system (neurotransmitter). It occurs both in the central (brain and spinal cord) and in the peripheral nervous system. In the central nervous system (CNS), serotonin is involved in the control of the sleep-wake cycle, emotions, temperature or pain, as well as in learning and memory formation.

In the rest of the body, for example, serotonin promotes gastrointestinal movements or dilates vessels in the skin and skeletal muscles, but narrows them in the heart. Serotonin is also involved in blood coagulation (it promotes platelet aggregation).

Depression before serotonin syndrome

Serotonin, together with another messenger called norepinephrine, controls several processes in the brain. These include, above all, emotional processes and the control of attention and pain inhibition. Experts believe that a deficiency of these messengers leads to depressive symptoms such as sadness, listlessness and loss of interest. Therefore, doctors treat depression with drugs that increase about the serotonin in the body. As a result, and for example, too high a drug dose can lead to serotonin excess and ultimately the serotonin syndrome.

Serotonin syndrome: symptoms

Serotonin affects many recipient structures (receptors) in the body. A serotonin excess can therefore also cause many different signs of disease. They usually occur within the first 24 hours after drug delivery. Sometimes the elevated serotonin level is initially seen as a mild influenza infection. More severe symptoms can then develop within minutes.

According to descriptions by US psychiatrist Sternbach, experts today divide serotonin syndrome symptoms into three groups:

Vegetative complaints

The patients suffer from fever and chills, so they often feel very ill (feeling flu). Other vegetative symptoms that commonly occur with serotonin syndrome are:

• Increased heart rate and blood pressure (tachycardia and hypertension)
• Fast breathing (hyperventilation)
• Heavy sweating (hyperhidrosis)
• Nausea, vomiting and diarrhea
• a headache

Disturbed interaction between muscles and nerves

Further symptoms of serotonin syndrome result from the fact that the interaction between nerves and muscles is disturbed (neuromuscular symptoms):

The patients tremble (tremor), have easily triggered and exaggerated reflexes (hyperreflexia), involuntary muscle twitching (myoclonus) and can move due to increased muscle tension only under exertion (hyperrigidity, rigor). Also muscle spasms are possible.

Psychic effects

In addition, patients suffer from symptoms caused by serotonin syndrome in the central nervous system. The serotonin excess leads here to an increased excitement. As a result, the following psychic abnormalities can occur in serotonin syndrome:

• Restlessness, nervousness, urge to move
• hallucinations
• Awareness and attention disorders
• Improved mood
• Problems with the fine-tuning of movements (coordination disorders)

Life-threatening serotonin syndrome

Ultimately, serotonin syndrome can be life-threatening. Serious consequences or complications occur, for example, by persistent cardiac arrhythmias. Patients usually feel a squeezing sensation in the chest, a fast and irregular heartbeat and heart stumbling.

Even epileptic seizures, including coma, can be the result of serotonin syndrome.

Since serotonin also acts on blood coagulation, a serotonergic syndrome leads in some cases to so-called consumption coagulopathy. The coagulation system (including the platelets) in the blood vessels is activated. As a result, blood clots form in various organs, which then can no longer fulfill their function. In addition, it comes in the later course to a lack of coagulation factors (by increased consumption) and thus spontaneous bleeding.

Death by a serotonin syndrome usually occurs through a multi-organ failure.

Serotonin syndrome: causes and risk factors

The serotonin syndrome is caused by the intake of certain medications. These are drugs that influence serotonergic processes in the body. Doctors usually prescribe it for the treatment of depression. Because researchers assume that a lack of serotonin (and norepinephrine) is responsible for the development of depression. With said drugs, the amount of messenger substance is increased by different mechanisms, such as by increasing the release of serotonin or inhibiting its degradation.

In some cases, the first signs of serotonin syndrome appear after the first antidepressant. In other patients, it develops only after a dose increase. However, in most cases, serotonin syndrome develops when two or more of the medications involved are combined. Because of interactions between the drugs, there is a significant excess of serotonin.

In addition to antidepressants, some other drugs as well as some illicit drugs can trigger a serotonin syndrome by interfering with the serotonergic system.

Among these drugs, as well as the drugs that can cause a serotonin syndrome, especially when combined count according to their effects:

Effect in the serotoninergic system	drugs
increased formation of serotonin	tryptophan
increased release of serotonin	Amphetamine, cocaine, mirtazapine, methadone, ecstasy, the Parkinson’s drug L-Dopa
Inhibition of reuptake from the synaptic cleft between two neurons	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
	Tramadol, pethidine (both analgesics), trazodone, St. John’s wort, cocaine, amphethamine, ecstasy, 5-HT3 receptor antagonist for nausea and vomiting such as ondansetron, granisetron
Inhibition of serotonin degradation	Monoamine oxidase (MAO) inhibitors such as moclobemide, tranylcypromid or the antibiotic linezolid
stimulating effect on serotonin receptor structures (5-HT receptors)	5-HT1 agonists such as buspirone or triptans (e.g., sumatriptan, almotriptan) prescribed for migraine
enhanced serotonin effect	lithium

Influence of other drugs

Also, medicines are broken down in the body. However, there are certain drugs that interfere with the breakdown of the above-mentioned drugs, mostly because they are metabolized in the same way. These include, for example, the heart medicines amiodarone or beta-blockers, anti-epileptic drugs such as carbamazepine, but also HIV therapeutics such as ritonavir or efavirenz. The gastric protective agent cimetidine also inhibits the degrading protein complexes. As a result, the serotonergic substances accumulate in the body. As a result, they affect the serotonin system even more. In this way even a smaller dose of medication can lead to a serotonin syndrome.

Serotonin syndrome: diagnosis and examination

The diagnosis of serotonin syndrome is difficult. On the one hand sufferers show different signs of a serotonergic syndrome. On the other hand, there are syndromes similar to those of serotonin syndrome, especially malignant neuroleptic syndrome (MNS).

In addition, an excess of serotonin develops relatively quickly. As a result, there is often only little time for extensive examinations in the case of severe processes. The diagnosis is made more difficult by the fact that there are no significant laboratory tests to determine the serotonin syndrome as the cause of the symptoms.

Anyone who is afraid of suffering from a serotonin syndrome should go to the doctor immediately, for example to the treating psychiatrist.

Medical history (anamnesis)

The cornerstone of the serotonin syndrome diagnosis is the history of the medical history (medical history). Because patients with serotonin syndrome are confused in some cases or suffer from a diminished consciousness, they can only answer some questions inadequately. Therefore, the external history is crucial. Here, the doctor does not ask the patient himself, but relatives, friends or other escorts. For example, the doctor asks the following questions:

• Which symptoms do you suffer from?
• Do you have a fever, nausea with vomiting and diarrhea? Do you sweat noticeably?
• Do you find movements difficult? Do you have muscle cramps or twitching?
• Are you having trouble sitting still?
• Since when do the complaints exist? Have you gained weight in the last few hours?
• Which pre-existing conditions are known to you?
• Do you suffer from depression against which you take tablets?
• Which medications do you take? Please name all medicines, including supplements and herbal ingredients!
• Has your medication been recently changed or extended?
• Do you consume drugs on a regular basis?

Physical examination

After the detailed questioning, the doctor carefully examines the body of the person concerned. He pays attention to typical symptoms of serotonin syndrome. These together with the medical history are crucial for the correct diagnosis of “serotonergic syndrome”. The doctor checks, for example, if the pupils are dilated. Muscle twitching or trembling of the patient is often already visible to the naked eye as well as accelerated breathing. In addition, the doctor measures blood pressure, heart rate and body temperature.

Furthermore, the doctor controls the neurological condition of the person affected. He pays special attention to the reflex check. For this he beats with a so-called reflex hammer, for example, on the femoral vision below the kneecap (patellar tendon reflex). If the patient suffers from a serotonin syndrome, the reflex, ie the “fasting” of the lower leg, takes place with excessive force and often with only slight tapping of the tendon.

Further investigations in serotonin syndrome

There are no specific laboratory tests that unambiguously demonstrate serotonin syndrome. Nevertheless, some laboratory values ​​may change due to the serotonin excess, for example, the inflammatory parameter C-reactive protein (CRP) increases. The serotonin syndrome can also affect the blood picture, recognizable for example by a low level of platelets (thrombocytes). Musculosine creatine kinase and myoglobin also rise in the blood in strong cramps.

With fast breathing, a so-called blood gas analysis can provide information about the exchange of oxygen and carbon dioxide in the lungs.

In addition, the doctor carries out toxicological tests. By means of a urine sample is often already in rapid tests (so-called toxicological bedside tests) a possible drug use or abuse. Laboratories can also detect elevated blood concentrations of a certain drug substance (determination of the drug level) by using sometimes complex screening methods.

In addition, depending on the symptoms, the doctor initiates further examinations. By means of electrocardiogram (ECG), for example, he reveals cardiac arrhythmias. After epileptic seizures, an imaging procedure such as computed tomography (CT) helps to rule out other causes of the symptoms.

differential diagnoses

Serotonin syndrome is sometimes difficult to differentiate from other diseases. Another conceivable diagnosis (differential diagnosis) is malignant neuroleptic syndrome, or MNS for short. The symptoms of the MNS can after taking especially strong effective (highly potent) drugs against psychosis (antipsychotics, neuroleptics) arise. As in the case of serotonin syndrome, patients also suffer from disorders of consciousness, fever, palpitations, blood pressure fluctuations and / or increased muscle tension.

However, in contrast to the serotonergic syndrome, the symptoms of MNS develop significantly more slowly over several days and generally only about two weeks after the start of therapy. In addition, MNS patients are less mobile (bradykinetic to akinetic) and have reduced reflexes (hyporeflexia). In addition, the muscle protein creatine kinase is greatly increased here. The same applies to white blood cells (leukocytes) and often also to liver values ​​(transaminase high).

Other diseases, some of which have symptoms similar to serotonin syndrome, include:

• Malignant hyperthermia
• Anticholinergic syndrome / delirium

Serotonin Syndrome: Treatment

Serotonin syndrome is considered a psychiatric and neurological emergency because it can become life threatening. As a first step, doctors stop taking medications that can cause serotonin syndrome. For mild symptoms, this procedure is usually sufficient (in about 90 percent of cases). If symptoms persist, doctors take additional measures. Serious serotonin syndrome requires intensive care monitoring and care.

Intensive care in serotonin syndrome

In the intensive care unit, blood pressure, heart rate, heart rate, oxygen saturation, body temperature and urine excretion are continuously monitored. The patients get enough fluid through an infusion (through the fever patients lose a lot of fluid). Under certain circumstances, they must also be put into an artificial coma and mechanically ventilated. In this way, far-reaching therapeutic steps such as a large-scale cooling (in very high fever) can be done.

drugs

Antipyretic drugs can additionally reduce the high body temperature.

If necessary, doctors also administer medications for muscle relaxation (muscle relaxants). As a result, they reduce the fever, which arises in a serotonin syndrome mainly due to the increased muscle tension. The muscle relaxants should also prevent severe muscle damage (breakdown of the muscle fibers = rhabdomyolysis). This protects the kidneys at the same time. After all, rhabdomyolysis releases the oxygen-binding muscle protein myoglobin in large quantities. This can be deposited in the kidney tissue and lead to kidney failure.

Benzodiazepines (such as lorazepam, diazepam) can also be given in serotonin syndrome. You can suppress seizures.

If symptoms persist, doctors also administer cyproheptadine or methysergide. Both drugs bind and, inter alia, inhibit serotonin receptor structures and thus reduce the deleterious effect of the hormone surplus of a serotonin syndrome. Guard patients swallow tablets, getting the active ingredients through a nasogastric tube.

Serotonin syndrome: disease course and prognosis

With fast and proper treatment, the serotonin syndrome overall has a good prognosis. In some cases, however, it can lead to death, for example, through a multi-organ failure.

Serotonin syndrome duration

Serotonin syndrome duration is primarily dependent on the triggering drugs. Depending on the active ingredient, the body takes different amounts of time to break down the drug. Experts speak of the so-called half-life (HWZ). It indicates the time after which half of the drug has left the body.

For example, fluoxetine has a relatively long HWZ. The active substance norfluoxetine is produced in the body with a HWZ of about four to 16 days. This means that this drug is metabolized and degraded only slowly. Consequently, serotonin syndrome symptoms last longer after taking fluoxetine than, for example, other antidepressants.

Beware of new drugs

This fact must also be taken into account when the medication of a patient changes. For example, if the person is given a new antidepressant drug or new medicines (such as strong painkillers or migraine medications), it may still develop after two weeks of interactions and ultimately a serotonin syndrome.

Prevent serotonin syndrome

As a rule, physicians pay attention to the various side effects and interactions of the prescribed drugs. Important information can be found in the respective technical information of the manufacturer. For example, serotonin reuptake inhibitors (SSRIs) should not be combined with MAO inhibitors (to prevent serotonin degradation) because of the risk of serotonin syndrome.

Herbal medicines such as St. John’s wort also carry the risk of serotonergic syndrome when taken in parallel with antidepressants (such as tricyclic antidepressants and SSRIs). Therefore, pay close attention to your doctor’s instructions and consult him promptly in case of complaints Serotonin syndrome submissions.