Serotonin syndrome
Serotonin syndrome consists of a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild cases include high blood pressure and a fast heart rate, usually without a fever. Symptoms in moderate cases include high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, and diarrhea. In severe cases, body temperature can increase to greater than. Complications may include seizures and extensive muscle breakdown.
Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs. These may include selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, amphetamines, pethidine, tramadol, dextromethorphan, buspirone,,, St. John's wort, triptans, MDMA, metoclopramide, or cocaine. It occurs in about 15% of SSRI overdoses. It is a predictable consequence of excess serotonin on the central nervous system. Onset of symptoms is typically within a day of the extra serotonin.
Diagnosis is based on a person's symptoms and history of medication use. Other conditions that can produce similar symptoms such as neuroleptic malignant syndrome, malignant hyperthermia, anticholinergic toxicity, heat stroke, and meningitis should be ruled out. As of 2013, no laboratory tests exist that can confirm the diagnosis.
Initial treatment consists of discontinuing medications which may be contributing. In those who are agitated, benzodiazepines may be used. If this is not sufficient, a serotonin antagonist such as cyproheptadine may be used. In those with a high body temperature, active cooling measures may be needed. The number of cases of serotonin syndrome that occur each year is unclear. With appropriate medical intervention the risk of death is low, likely less than 1%. The high-profile case of Libby Zion, who is generally accepted to have died from serotonin syndrome, resulted in changes to graduate medical school education in New York State.
Signs and symptoms
Symptom onset is usually relatively rapid, and serotonin syndrome encompasses a wide range of clinical findings. Mild symptoms may consist of increased heart rate, shivering, sweating, dilated pupils, and myoclonus, as well as hyperreflexia. Many of these symptoms may be side effects of the drug or drug interaction causing excessive levels of serotonin rather than an effect of elevated serotonin itself.Tremor is a common side effect of MDMA's action on dopamine, whereas hyperreflexia is symptomatic of exposure to serotonin agonists. Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds, high blood pressure and hyperthermia; a temperature as high as. The overactive reflexes and clonus in moderate cases may be greater in the lower limbs than in the upper limbs. Mental changes include hypervigilance or insomnia and agitation. Severe symptoms include severe increases in heart rate and blood pressure. Temperature may rise to above in life-threatening cases. Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, kidney failure, and disseminated intravascular coagulation; these effects usually arising as a consequence of hyperthermia.
The symptoms are often present as a clinical triad of abnormalities and can be used to assess the severity of serotonin syndrome:
| Severity | Autonomic effects | Neurological signs | Mental status | Other symptoms |
| mild |
| |||
| moderate | ||||
| severe | as above |
Causes
Numerous medications and street drugs can cause serotonin syndrome when taken alone at high doses or in combination with other serotonergic agents. The table below lists some of these.| Class | Drugs that can induce serotonin syndrome |
| Antidepressants | Monoamine oxidase inhibitors, tricyclic antidepressants, SSRIs, SNRIs, nefazodone, trazodone |
| Opioids | Dextropropoxyphene, tramadol, tapentadol, pethidine, fentanyl, pentazocine, buprenorphine oxycodone, hydrocodone |
| Stimulants and entactogens | MDMA, MDA, AMT, caffeine, methamphetamine, lisdexamfetamine, amphetamine, phentermine, amfepramone, sibutramine, methylphenidate, cocaine |
| 5-HT1 agonists | Triptans |
| Psychedelics | NBOMes |
| Herbs | St John's wort, Syrian rue, Panax ginseng, nutmeg, yohimbe |
| Others | Tryptophan, L-DOPA, valproate, buspirone, lithium, linezolid, dextromethorphan,, chlorpheniramine, risperidone, olanzapine, ondansetron, granisetron, metoclopramide, ritonavir, metaxalone, methylene blue |
Many cases of serotonin toxicity occur in people who have ingested drug combinations that synergistically increase synaptic serotonin. It may also occur due to an overdose of a single serotonergic agent. The combination of monoamine oxidase inhibitors with precursors such as or pose a particularly acute risk of life-threatening serotonin syndrome. The case of combination of MAOIs with tryptamine agonists can present similar dangers as their combination with precursors, but this phenomenon has been described in general terms as the cheese effect. Many MAOIs irreversibly inhibit monoamine oxidase. It can take at least four weeks for this enzyme to be replaced by the body in the instance of irreversible inhibitors. With respect to tricyclic antidepressants, only clomipramine and imipramine have a risk of causing serotonin syndrome.
Many medications may have been incorrectly thought to cause serotonin syndrome. For example, some case reports have implicated atypical antipsychotics in serotonin syndrome, but it appears based on their pharmacology that they are unlikely to cause the syndrome. It has also been suggested that mirtazapine has no significant serotonergic effects and is therefore not a dual action drug. Bupropion has also been suggested to cause serotonin syndrome, although as there is no evidence that it has any significant serotonergic activity, it is thought unlikely to produce the syndrome. In 2006 the US Food and Drug Administration issued an alert suggesting that the combined use of either SSRIs or SNRIs with triptan medications or sibutramine could potentially lead to severe cases of serotonin syndrome. This has been disputed by other researchers, as none of the cases reported by the FDA met the Hunter criteria for serotonin syndrome. The condition has however occurred in surprising clinical situations, and because of phenotypic variations among individuals, it has been associated with unexpected drugs, including mirtazapine.
Despite acting as non-selective serotonin receptor agonists, major serotonergic psychedelics like lysergic acid diethylamide and psilocybin do not cause serotonin syndrome even in the context of extreme overdose. This is thought to be due to the fact that they act as partial agonists of serotonin receptors like the serotonin 5-HT2A receptor, in contrast to serotonin itself which is a full agonist. Combination of psychedelics like LSD and psilocybin with antidepressants such as SSRIs is also not thought to pose a risk of serotonin syndrome. A 2018 retrospective analysis of 3,554 LSD-only exposures reported to poison control centers in the United States between 2000 and 2016 found that serious toxicity was infrequent. On the other hand, NBOMe psychedelics like 25I-NBOMe are more efficacious at the serotonin 5-HT2A receptor and have been uniquely associated with serotonin syndrome-like toxicity. In addition, serotonergic psychedelics additionally acting as serotonin releasing agents like methylenedioxyamphetamine and α-methyltryptamine or additionally acting as MAOIs like ayahuasca or AMT can cause serotonin syndrome.
The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. Serotonin syndrome has been reported in patients of all ages, including the elderly, children, and even newborn infants due to in utero exposure. The serotonergic toxicity of SSRIs increases with dose, but even in overdose, it is insufficient to cause fatalities from serotonin syndrome in healthy adults. Elevations of central nervous system serotonin will typically only reach potentially fatal levels when drugs with different mechanisms of action are mixed together. Various drugs, other than SSRIs, also have clinically significant potency as serotonin reuptake inhibitors, and are associated with severe cases of the syndrome. Severe and life-threatening serotonin syndrome has been said to almost exclusively be due to a combination of antidepressants, for instance an MAOI with an SSRI. However, combination of an MAOI and a serotonin releasing agent like MDMA can also consistently result in severe and life-threatening serotonin syndrome.
Although the most significant health risk associated with opioid overdoses is respiratory depression, it is still possible for an individual to develop serotonin syndrome from certain opioids without the loss of consciousness. However, most cases of opioid-related serotonin syndrome involve the concurrent use of a serotergenic drug such as antidepressants. Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to the comorbidity of pain and depression. Cases where opioids alone are the cause of serotonin syndrome are typically seen with tramadol, because of its dual mechanism as a serotonin-norepinephrine reuptake inhibitor. Serotonin syndrome caused by tramadol can be particularly problematic if an individual taking the drug is unaware of the risks associated with it and attempts to self-medicate symptoms such as headache, agitation, and tremors with more opioids, further exacerbating the condition.