Serotonin syndrome is a potentially life-threatening adverse drug reaction that results from excess serotonin activity in the central nervous system. It most commonly occurs when two or more serotonergic drugs are taken together, such as a combination of antidepressants. Symptoms range from tremors and diarrhea in mild cases to delirium, muscle rigidity, and hyperthermia in more severe cases. Treatment involves discontinuing the precipitating drugs, providing supportive care, and administering drugs that block serotonin receptors like cyproheptadine to counteract excess serotonin activity. Prevention relies on awareness of potential drug interactions and avoiding unnecessary combinations of serotonergic medications.

1. Serotonin syndrome
R.Anusha
PharmD 5th Year
Roll No:07
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2. INTRODUCTION
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 Potentially life threatening adverse drug reaction
 It may result from therapeutic drug use, intentional self-
poisoning or inadvertent interactions between drugs
 It is a predictable consequence of excess serotonergic
agonism of central nervous system (CNS) receptors and
peripheral serotonergic receptors
 It has been reported to result from a single, therapeutic dose
of an SSRI
 The exact incidence of serotonin syndrome is not known
because of its varied manifestations, lack of awareness and
sensitive diagnostic criteria.

3. SEROTONIN
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 Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine
neurotransmitter biochemically derived from tryptophan
 Serotonin is primarily found in the gastrointestinal tract (GI
tract), blood platelets, and the central nervous system
 It is thought to be a contributor to feelings of well being
and happiness

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 Serotonergic neurons in the CNS are found primarily in the
midline raphe nuclei located in the brain stem from the
midbrain to the medulla.
 The rostral end of this system assists in the
 Regulation of wakefulness,
 Affective behavior,
 Food intake,
 Thermoregulation,
 Migraine,
 Emesis, and
 Sexual behavior.

5. PATHOPHYSIOLOGY
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 It is a predictable consequence of excess serotonergic
agonism of central nervous system (CNS) receptors and
peripheral serotonergic receptors
 Many cases of serotonin toxicity occur in patients who
have ingested drug combinations that synergistically
increase synaptic serotonin
 It may also occur as a symptom of overdose of a single
serotonergic agent
 Addition of drug that inhibit cytochrome P450 (e.g.,
Erythromycin) when added to the therapeutic regimen of
serotonergic drugs may precipitate serotonin syndrome

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 Agonism of 5-HT2a receptors contributes substantially to
the occurrence of serotonin syndrome
 Noradrenergic CNS hyperactivity may play a critical role
 Other neurotransmitters including NMDA , GABA and
dopamine may affect the development of the syndrome, but
the role of these agents is less clear

7. Medications that May Contribute to Serotonin Syndrome
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Amphetamines and derivatives :
 Dextroamphetamine , Methamphetamine
Analgesics:
 Fentanyl, Meperidine
Antidepressants/mood stabilizers:
 Buspirone
 Lithium
 Monoamine oxidase inhibitors(e.g., phenelzine )
 Selective serotonin reuptake inhibitors (e.g., fluoxetine)
 Serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine )
 Serotonin 2A receptor blockers (e.g., trazodone)
 St. John’s wort
 Tricyclic antidepressants (e.g., amitriptyline, nortriptyline )

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Antiemetics
 Metoclopramide
 Ondansetron
Antimigraine drugs
 Carbamazepine
 Ergot alkaloids
 Triptans
 Valproic acid
Miscellaneous
 Cocaine
 Dextromethorphan
 Linezolid
 L-tryptophan
 5-hydroxytryptophan

9. CLINICAL FEATURES
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 The serotonin syndrome is often described as a clinical
triad of mental-status changes, autonomic hyperactivity,
and neuromuscular abnormalities
 The triad is not consistently present in all the patients with
the disorder
 Signs of excess serotonin range from tremor and diarrhea in
mild cases to delirium, neuromuscular rigidity and
hyperthermia in life-threatening cases

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 The onset of symptoms is usually rapid, with clinical
findings often occurring within minutes after a change in
medication or self-poisoning
 Approximately 60 percent of patients with the serotonin
syndrome present within six hours after initial use of
medication, an overdose, or a change in dosing
 The serotonin syndrome is not believed to resolve
spontaneously as long as precipitating agents continue to be
administered

11. MANAGEMENT
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 Removal of the precipitating drug
 Administration of 5-HT2a antagonists
 Supportive care
 Correction of vital signs
 Administration of intravenous fluids
 The control of autonomic instability
 The control of hyperthermia
 Many cases of the serotonin syndrome typically resolve
within 24 hours after the initiation of therapy and the
discontinuation of serotonergic drugs, but symptoms may
persist in patients taking drugs with long elimination half
lives, active metabolites or a prolonged duration of action

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Benzodiazepines
 Control of agitation with benzodiazepines is essential
in the management of the serotonin syndrome
regardless of its severity.
 Benzodiazepines such as diazepam improve survival in
animal models and blunt the hyperadrenergic
component of the syndrome.
 The benzodiazepines have the added benefits of
helping lower blood pressure, heart rate, and
temperature, and they can decrease muscle activity.

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5HT2AAntagonists
 Cyproheptadine is the recommended therapy for the
serotonin syndrome
 Treatment of the serotonin syndrome in adults may require
12 to 32 mg of the drug during a 24-hour period, a dose that
binds 85 to 95 percent of serotonin receptors.
 An initial dose of 12 mg of cyproheptadine and then 2 mg
every two hours if symptoms continue. Maintenance dosing
involves the administration of 8 mg of cyproheptadine
every six hours

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 Control of autonomic instability involves stabilization of
fluctuating pulse and blood pressure
 Hypotension arising from MAOI interactions should be
treated with low doses of direct-acting sympathomimetic
amines (e.g., norepinephrine, phenylephrine and
epinephrine)
 Hypertension and tachycardia develop should be treated
with short-acting agents such as nitroprusside and esmolol

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 Control of hyperthermia involves eliminating excessive
muscle activity.
 Benzodiazepines have a beneficial effect in moderate cases,
in severely ill patients with hyperthermia (a temperature of
more than 41.1°C) immediate paralysis should be induced
with nondepolarizing agents and orotracheal intubation and
mechanical ventilation

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 There is no role for antipyretic agents in the management of
the serotonin syndrome.
 The increase in body temperature is due to muscular
activity, not an alteration in the hypothalamic temperature
set point

17. Prevention
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 Prevention of serotonin syndrome begins with awareness
by physicians and patients of the potential for toxicity from
serotonergic drugs.
 Avoiding the combined use of serotonin-augmenting drugs
is essential.
 Physicians should modify prescribing practices to minimize
co-prescription of drugs known to have a high probability
of inducing serotonin syndrome.
 A computerized ordering system and medical software can
check for possible interactions when multi-drug regimens
are required.

18.  BIO MEDICAL JOURNAL, Practice Pointer,Serotonin
Syndrome,Nicholas A Buckley,1 March 2014 ; Volume
348;Page no:33-35.
 Toxicology, Drug-Induced Serotonin Syndrome, Dana
Bartlett, Critical Care Nurse Vol 37, No. 1, FEBRUARY
2017,Page no:49-54.
 Prevention , Diagnosis, and Management of Serotonin
Syndrome;American Family Physician; Volume 81,
Number 9 ;May 1, 2010;Page no:1139-1142
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