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Serotonin Toxicity

Serotonin toxicity, or serotonin syndrome, is a serious and potentially fatal adverse drug reaction caused by excessive stimulation of the central nervous system (CNS) and peripheral serotonin receptors. It can result from high levels of serotonin agonists, serotonin releasing agents, serotonin reuptake inhibitors, MAOI's or in combination. This is an especially dangerous case when mixing sertonergic agents and MAOI's.

Introduction

Serotonin toxicity, or serotonin syndrome, is an adverse drug reaction to 5-HT (5-hydroxytryptamine or serotonin) agonists i.e. serotonergic agents, caused by excessive stimulation of the central nervous system (CNS) and peripheral serotonin receptors[1]. It was first described among depressed patients in 1960 as a consequence of the administration of high doses of tryptophan in combination with MAOIs [2].

It can occur as a consequence of normal therapeutic drug use, overdose (deliberate or accidental) or drug interactions [1].
Although usually the result of a combination of serotonergic drugs it may occur in patients following ingestion of a single serotonergic agent [3].

The illness can vary in severity from minor symptoms such as a barely noticeable tremor, to an acute life-threatening illness involving seizures, hyperthermia and coma[1].

Pathophysiology

Serotonin toxicity is caused by an increase in serotonin in the central nervous system. It is thought to be induced by combined activation of 5-HT1A and the 5-HT2 receptors. Stimulation of these receptors in the dorsal and median raphe nuclei of the brainstem and spinal cord may be important in the pathophysiology of the illness. The dopaminergic system may be involved. It has recently been proposed that this illness may be mediated by presynaptic inhibition of dopamine release or synthesis, somewhat similar to neuroleptic malignant syndrome[2].

The effects of the 5-HT receptor subtypes in relation to serotonin toxicity are:
  • 5-HT1A - Neuronal inhibition, regulation of sleep, feeding, thermoregulation, hyperactivity associated with anxiety, hypoactivity associated with depression
  • 5-HT1D - Locomotion, muscle tone
  • 5-HT2A - Neuronal excitation, learning, peripheral vasoconstriction, platelet aggregation
  • 5-HT2B - Stomach contraction
  • 5-HT3 - Nausea and vomiting, anxiety
  • 5-HT4 - Gastrointestinal motility
[1]

Epidemiology and Problems With Diagnosing Serotonin Toxicity

A post-marketing surveillance study of nefazodone suggested an incidence of 0.4 cases per 1000 patient-months of treatment [4].

Serotonin toxicity is displayed by 16 percent of people who take an overdose of SSRI medication [5].

However, incidence of serotonin toxicity is unclear due to the extent of under diagnosis. A survey carried out in 1998 discovered that 85% of UK general practitioners were unaware of the diagnosis [4]. There is also widespread under diagnosis because of the heterogeneity of its presentation, an evolving diagnostic criterion, a lack of awareness amongst prescribers, and the mistaking of the symptoms for features of other illnesses or a pre-existing psychiatric illness [6].

Due to this lack of knowledge and failure to recognize the illness, mild cases may be overlooked and the continuation of, or increasing the dosage of, the offending drug can cause progression to a more severe, life-threatening form [1].

Risk Factors and Causative Agents

The use of serotonergic agents is the risk factor for serotonin toxicity [6].

Many cases of serotonin toxicity occur in patients who have ingested drug combinations that synergistically increase synaptic 5-HT. Elevations of CNS serotonin will usually only reach potentially fatal levels when drugs with different mechanisms of action are taken concomitantly [7], therefore it is useful to consider these agents according to their mechanisms of action:

Direct 5-HT receptor stimulation:

Direct release of stored 5-HT:

Increased availability of 5-HT precursors:

Reduced 5-HT reuptake:

Decreased 5-HT degradation:

Other drugs:

  • 5-HT3 antagonist anti-emetics: ondansetron; tropisetron; metoclopramide; granisetron; dolasetron; palonosetron; ramosetron [6].
  • Pethidine - causality not established [1]
Recreational substances most often associated with serotonin toxicity (when combined with antidepressants) in reviewed literature:

Amphetamines; Cocaine; DXM; LSD; MDA; MDMA; Opioids - particularly Tramadol; Tryptamines.

Presentation and Symptoms

Serotonin excess is best thought of as a spectrum of toxicity, rather than a defined clinical syndrome with clear prognostic importance. This is because it is a concentration-dependent toxicity that can develop in any individual rather than an idiosyncratic reaction to a drug [21]

Typically the illness develops within 6-8 hours of taking a serotonergic agent, or an increase in dosage of an agent already being used [22]. .

It is characterized by the presence of a triad of; mental-status changes, autonomic disturbances and, neuromuscular dysfunction. Broken down into each individual area of the triad, the symptoms are:

Mental-status

Mild:
  • Restlessness
  • Anxiety
Moderate:
  • Easily startled
  • Increased confusion
  • Agitation
  • Hyper vigilance
  • Hypomania
Severe:
  • Hallucinations
  • Delusions
  • Delirium
  • Coma

Autonomic

Mild:
  • Afebrile or low-grade fever
  • Tachycardia
  • Mydriasis
  • Diaphoresis or shivering
  • Dilated pupils
  • Nausea
Moderate:
  • Hypertension
  • Excessive sweating
  • Increased tachycardia
  • Fever (up to 41°C)
  • Diarrhea with hyperactive bowel sounds
  • Diaphoresis with normal skin color
  • Excessive vomiting
Severe:
  • Temperature often more than 41°C (secondary to increased muscle tone)
  • Severe hypertension and tachycardia which may lead to shock

Neuromuscular

Mild:
  • Intermittent tremor
  • Akathisia
  • Myoclonus
  • Mild hyperreflexia
  • Tremor
Moderate:
  • Muscle rigidity
  • Hyperreflexia (may be masked if there is severe muscle rigidity)
  • Inducible clonus
  • Ocular clonus (slow continuous lateral eye movements)
  • Myoclonus
  • Hypertonicity
Severe:
  • Increased muscle tone
  • Spontaneous clonus
  • Substantial myoclonus or hyperreflexia

Other

In moderate – severe toxicity, usually associated with hyperthermia:
  • Rhabdomyolysis
  • Metabolic acidosis
  • Renal failure
  • Disseminated intravascular coagulopathy (secondary to hyperthermia)
  • Seizures
  • Death
[6][10]

Not all of these features are present in all cases. Signs and symptoms vary but always tend to include; agitation, confusion, disorientation, restlessness, myoclonus, rigidity, hyperreflexia, low grade fever, nausea, diarrhea, headache, tachycardia, tachypnea, blood pressure changes and shivering. It is, however, rare for all of them present at the same time. The presence of muscular hyper tonicity, sustained clonus and hyperthermia indicates a severe form of the illness[2].

Differential Diagnosis

  • Anticholinergic poisoning
  • Malignant hyperthermia
  • Neuroleptic malignant syndrome. Serotonin toxicity is most often confused with neuroleptic malignant syndrome as the two illnesses share very similar features [23]
  • Other poisoning
  • Catatonia
  • Dystonia
  • Recreational drug toxicity
  • Hyperthyroidism
  • Tetanus
  • Delirium tremens
  • Encephalitis
  • Rhabdomyolysis
  • Meningitis
  • Withdrawal syndromes
  • Wernicke's encephalopathy
[6]

Investigations

There are no specific confirmatory investigations.

A physical examination of the patient should include assessment of deep-tendon reflexes and muscle rigidity, the dryness of the oral mucosa, the size and reactivity of the pupils, the intensity of bowel sounds, skin color, and the presence or absence of sweating. The patient's history should also be assessed and inquiries should be made about the use of prescription medications , over-the-counter and recreational drugs, and dietary supplements; these agents have all been implicated in the development of serotonin toxicity[1].

Other investigations should include:
  • Check U&E's and creatine kinase to look for evidence of rhabdomyolysis and consequent renal impairment
  • Toxicology screen, particularly for agents likely to be responsible.
  • FBC and blood culture/microbiological samples can suggest alternative causes of fever.
  • Liver function tests.
  • CXR if there are respiratory complications.
  • CT scanning of head if there is trauma, seizures, hypertension or focal neurology.
  • Lumbar puncture if there is fever and altered mental state.
[6]

Treatment and Management

In all cases the most important step is the immediate cessation of the offending agent or interacting drugs. Mild to moderate cases usually resolve within 24-72 hours of discontinuation and may need supportive measures only. If the agent has been recently ingested or a large overdose recently taken, then activated charcoal may help to prevent absorption. Supportive measures such as IV fluids and control of agitation with benzodiazepines may also be used[6].

Recovery from drugs with long half-lives or active metabolic breakdown products (e.g. fluoxetine) may take longer, sometimes several weeks.
Treatment is based on severity and focuses on prompt cessation of the offending agents, treatment of hyperthermia, and the use of benzodiazepines to decrease hypertonicity and neurological excitability. The use of 5-HT antagonists should be considered in moderate and severe cases[10] and severe cases need aggressive treatment and intensive care with early sedation, neuromuscular paralysis and ventilator support [6].

Possible Complications

  • Hyperthermia can lead to metabolic acidosis, rhabdomyolysis, renal failure and disseminated intravascular coagulation.
  • Seizures.
  • Aspiration pneumonia.
  • Respiratory failure.
[6]

Prognosis

If the patient recovers from the acute episode and provoking agents are avoided/discontinued the outlook is good. Most deaths occur within the first 24 hours[6]. In a review of 41 cases it was found that only 1 death occurred, and most patients (57.5%) had complete resolution of their symptoms within 24 hours of presentation [24] .

Deaths due to overdose, particularly of SSRIs, are usually associated with combination of other medications or illicit substances [6]. In postmortem studies by Goeringer et al [25], toxicological and cause and manner of death data were examined in 60 deaths involving fluoxetine, 5 involving fluvoxamine, 75 involving sertraline, and 28 involving paroxetine. Deaths involving drug toxicity were generally a result of ingestion of multiple drugs, and in only a small number of the cases was death attributed principally to the SSRI involved[25].

If serotonin toxicity is diagnosed correctly and the appropriate medical treatment and management are undertaken, serotonin toxicity is rarely fatal and is associated with a favorable prognosis.[24].

Seretonin syndrome is frequently treated with Benzodiazepines in order to lower CNS hyperactivity and calm an individual.

Prevention

Caution should be exercised by the prescriber when prescribing serotonergic agents. All patients starting SSRIs should be counseled about:
  • Potential interactions (including over the counter and 'herbal' medication).
  • The symptoms of serotonin toxicity.
Improved knowledge amongst the medical community is essential - particular care should be taken when changing SSRIs or prescribing more than one antidepressant.

Improved pharmacogenetic understanding is needed in order to identify those at increased risk.

Adequate post-marketing surveillance of new serotonergic therapies to help identify epidemiology, persons at risk and improve knowledge of interactions[6].

For patients who partake in recreational drug use, knowledge of their mechanisms of action, the symptoms of serotonin toxicity and possible interactions can be invaluable – especially if the patient is taking antidepressant medication.

References

  1. ^ a b c d e f g h i j k l m n o p q r sBoyer EW, Shannon M: 2005: “The serotonin syndrome.” N Engl J Med; Mar 17; 352(11): 1112-20.
  2. ^ a b cAvarello TP, Cottone S: 2002. “Serotonin syndrome: a reported case.” Neurol Sci; 23: S55–S56.
  3. ^Fraser J, South M: 1999. “Life-threatening fluvoxamine overdose in a 4-year-old child.” Intensive Care Med; 25 (5): 548.
  4. ^ a bMackay FJ, Dunn NR, Mann RD: 1999. “Antidepressants and the serotonin syndrome in general practice.” Br J Gen Pract; Nov 49 (448): 871-4.
  5. ^Whyte IM, Dawson AH: 2002. “Redefining the serotonin syndrome.” J Toxicol Clin Toxicol; 40: 668–9.
  6. ^ a b c d e f g h i j k l m n o p q r s t u vDraper R: 2007. “Serotonin Syndrome.” Patient UK; http://www.patient.co.uk/doctor/Serotonin-Syndrome.htm
  7. ^ a bIsbister GK, Buckley NA, Whyte IM: 2007. “Serotonin toxicity: a practical approach to diagnosis and treatment.” Med. J. Aust; 187 (6): 361–5.
  8. ^Fryer J D, Lukas R J: 1999. “Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine.” J Pharmacol Exp Ther; 288 (6): 88–92.
  9. ^ a bNichols DE. 1997. “Role of serotonergic neurons and 5-HT receptors in the action of hallucinogens.” In: Baumgarten HG, Gothert M, eds. Serotonergic neurons and 5-HT receptors in the CNS; 563–585.
  10. ^ a b c d e f g h iFrank C: 2008. “Recognition and treatment of serotonin syndrome.” Canadian Family Physician; 54: 2008.
  11. ^Birmes P, Coppin D, Schmitt L, Lauque D: 2003. “Serotonin syndrome: a brief review.” CMAJ; 168 (11): 1439–42.
  12. ^Ener RA, Meglathery SB, Van Decker WA, Gallagher RM: 2003. “Serotonin syndrome and other serotonergic disorders.” Pain Med; 4 (1): 63–74.
  13. ^Carta M, Allan AM, Partridge LD, Valenzuela CF: 2003. “Cocaine inhibits 5-HT3 receptor function in neurons from transgenic mice over expressing the receptor.” Eur. J. Pharmacol; 459 (2-3): 167–9.
  14. ^Domino EF: 1999. “History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants.” Psychosomatic Medicine; 61: 591-598.
  15. ^Lavery S, Ravi H, McDaniel WW, Pushkin YR: 2001. “Linezolid and Serotonin Syndrome.” Psychosomatics; 42: 432-434.
  16. ^Vuori E, Henry J, Ojanperä I, Nieminen R, Savolainen T, Wahlsten P, Jäntti M: 2003. “Death following ingestion of MDMA (ecstasy) and moclobemide.” Addiction; 98 (3): 365–8.
  17. ^Chan BS, Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG: 1998. “Serotonin syndrome resulting from drug interactions.” Med.J.Aust; 169(10):523-5.
  18. ^ a bTatsumi M, Groshan K, Blakely RD, Richelson E: 1997. “Pharmacological profile of antidepressants and related compounds at human monoamine transporters.” Eur J Pharmacol; 340 (2-3): 249-258.
  19. ^Pan JJ, Shen WW: 2003. “Serotonin syndrome induced by low-dose venlafaxine.” Ann Pharmacother; Feb 37 (2): 209-11.
  20. ^Braun U, Kalbhen DA: 1973. "Evidence for the Biogenic Formation of Amphetamine Derivatives from Components of Nutmeg". Pharmacology; 9 (5): 312–16.
  21. ^Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM: 2003. "The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity". QJM; 96 (9): 635–42.
  22. ^Sternbach H: 1991. “The serotonin syndrome.” Am J Psychiatry; Jun 148 (6): 705-13
  23. ^Isbister GK, Dawson A, Whyte IM: 2001. "Citalopram overdose, serotonin toxicity, or neuroleptic malignant syndrome?" Can J Psychiatry; 46 (7): 657–9.
  24. ^ a bMason PJ, Morris VA, Balcezak TJ: 2000. "Serotonin syndrome. Presentation of 2 cases and review of the literature". Medicine (Baltimore); 79(4): 201–9.
  25. ^ a bGoeringer KE, Raymon L, Christian GD, Logan BK: 2000. “Postmortem forensic toxicology of selective serotonin reuptake inhibitors: a review of pharmacology and report of 168 cases.” J Forensic Sci; 45(3): 633-48.
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