Serotonin Syndrome

Authored By

Patricia I. Rosebush, MD
McMaster University
Hamilton, Ontario, Canada

Dr. Rosebush is a Professor in the Department of Psychiatry & Behavioral Neurosciences at McMaster University where she is actively involved in research and teaching, particularly in the area of neuropsychiatry.  She graduated from the University of Toronto with a Master of Science in nursing, completed medical school at McMaster and her residency training and fellowship at Harvard Medical School.  She is widely published and has authored several book chapters.  From 1988 to 2007 she was the Director of acute inpatient psychiatry. 

Over the course of her career she has developed large data bases for a prospective study of first onset psychosis,  neuroleptic malignant syndrome (NMS), The neuropsychiatry of inherited metabolic disorderssuch as adult-onset Tay Sachs disease, metachromatic leukodystrophy and adrenoleukodystrophy, catatonia and late-onset delusional disorder.

Read More About Dr. Rosebush ⇒

Presented By

NMSIS
Neuroleptic Malignant Syndrome Information Service
Hotline for Medical Professionals
US: 888-667-8367
Out of the US: 315-464-4001

SEROTONIN:  Background

Serotonin (5HT) is an important brain monoamine neurotransmitter like dopamine (DA) and norepinephrine (NE).

It is also highly concentrated in the spinal cord, pineal gland, platelets, mast cells and the chromaffin cells of the gastrointestinal tract.

The serotonin syndrome

All brain and spinal cord 5HTis produced in a series of 9 nuclei clustered along the mid-line of the pons and brain stem.

These cell bodies project widely to all parts of the brain as well as to the spinal cord and cerebellum.

5HT is made from the amino acid precursor tryptophan and packaged into vesicles presynaptically for release into the synaptic cleft.

Once released, 5HT either stimulates post-synaptic receptors or is taken back up into the pre-synaptic cell by a serotonin transporter (SERT).

After re-uptake it is either metabolized by the enzyme MAO or re-packaged into vesicles for re-use.

There are many different serotonin receptors.

Autoreceptors which down regulate 5HT release, are of the 5HT, 1A type.

The complexity of the serotonergic system, involving autoreceptors, wide distribution through the CNS and many different types of post-synaptic receptors, makes it difficult to know exactly whether a particular agent affecting this system will increase or decrease serotonin function in any given region.

This complexity is reflected for example in the fact that triptans are used to treat migraines and yet many SSRIs can cause or worsen headaches.

Before reviewing SS, a toxic condition, we will review the more common side-effects associated with medications thought to produce a net increase in serotonin centrally, especially SSRIs and SNRIs.

Serotonin and selective serotonin uptake inhibitors (SSRIs)

All SSRIs interfere with the re-uptake of 5HT from the synaptic cleft by inhibiting the transporter (SERT), theoretically making more serotonin available for stimulation of post-synaptic receptors as well as autoreceptors.

There are genetically determined differences in the serotonin transporter, with 2 common alleles, long (L) and short (S). Individual allelic differences (L/L; L/S or S/S) may play a role in the predisposition to the development of illness and side-effects.

SSRIs:  Pharmacology

As a group, SSRIs and SNRIs have replaced tricyclics and MAOIs as first line treatments for depression.

This is because of their comparative efficacy, reduced mortality following overdose and a side-effect profile that is more tolerable for most patients.

Except for paroxetine, SSRIs have no anti-cholinergic properties.

What is serotonin syndrome(SS)?

SS is the most serious clinical manifestation of serotonergic agent use. It is presumed to reflect centrally increased serotonergic neurotransmission although this has not been proven.

It has been referred to as a toxidrome or toxic syndrome.

The diagnosis is made on clinical grounds in patients who have taken one or more agents that are presumed to ‘increase’ serotonin.

The incidence of SS is quite low during routine treatment but increases to approximately 15% in patients who overdose with serotonergic agents.

Common side-effects associated with SSRIs

• Headaches: new onset or worsening of a pre-existing problem.
• Gastrointestinal disturbances, particularly nausea, upper gastric discomfort and diarrhea
• Restlessness or akathisia, perhaps associated with suicidality in younger patients
• Tremor
• Sexual dysfunction
• Easy bruising

Other reported complications of SSRI use

• Increased risk of upper gastrointestinal bleeding, especially in conjunction with non-steroidal anti-inflammatory medications
• Increased risk of intra-operative bleeding
• Increased risk of developing osteoporosis
• Extrapyramidal side-effects
• Syndrome of inappropriate secretion of anti-diuretic hormone (SIADH), especially in the elderly

It is, therefore, important for the treating clinician to consider each patient’s medical and psychiatric history, with attention to the potential for SSRIs to complicate or worsen certain conditions such as migraines.

Patients appreciate physicians’ awareness of the side-effect profile of the medications they prescribe and usually welcome the opportunity to be appropriately educated. This enhances compliance, primary prevention and early detection as well as timely intervention when problems arise.

Serotonin Syndrome (SS)

There is ongoing debate about whether SS represents a unique and unpredictable type of reaction to serotonergic agents or whether it is on the extreme end of a spectrum of SSRI-related side-effects or toxicities.

Drugs or substances which affect central 5-HT
and carry the potential to precipitate serotonergic toxicity

1. Excessive use of one or more agents thought to result in a net increase in serotonergic neurotransmission. These include:
    
   • SSRI and SNRI antidepressants
   • serotonergic tricyclic antidepressants such as clomipramine
   • hypericum perforatum (St.John’s Wort)
   • lithium
   • tryptophan-the amino acid precursor of serotonin
   • meperidine
   • Tryptans such as Sumatriptan
   • Buspirone
2. Agents that stimulate the release of serotonin such as ecstasy (methylene dioxymethamphetamine: MDMA), cocaine and amphetamines
3. Agents that inhibit the breakdown of serotonin and thereby make more available for neurotransmission. The most important are the monoamine oxidase inhibitors (MAOI).

Monoamine Oxidase

Monoamine oxidase (MAO)is an enzyme located on the outer membrane of the intracellular organelles, the mitochondria.

When serotonin is taken back up into the pre-synaptic cell after release, it is either packaged for re-release or broken down by MAO. If MAO is inhibited, as happens with the MAOI antidepressants, more of the neurotransmitter is available for repackaging and release.

Monoamine oxidase inhibitors

The concurrent use of an MAOI with:

• SSRIs
• TCAs
• Meperidine
• dextromethorphan

can result in a very severe form of the SS.

MAOIs and SS

A recently described drug interaction, that might lead to development of SS, involves the new synthetic antimicrobial, Linezolid, an oxazolidinone antibiotic

Linezolid is a weak, reversible, non-selective inhibitor of MAO and, in conjunction with other agents that enhance serotonergic neurotransmission, has been reported to precipitate SS.

LINEZOLID AND SS

An SSRI wash-out period is recommended prior to beginning Linezolid.

The recommended wash-out period would be five weeks for fluoxetine and two weeks for other SSRIs.

Medication profiles in 18 cases of SS seen by Dr. Rosebush

Clomipramine	N=1
Venlafaxine	N=3
Nefazadone	N=3
Fluvoxamine	N=2
Paroxetine	N=1
Fluoxetine	N=1
Fluvoxamine	N=1
MAOI + SSRI	N=2
MAOI + TCA	N=2
MAOI alone	N=1
Venlafaxine/Trazadone/Lithium	N=1

Note: 10 cases occurred with monotherapy and included 3 overdoses; 7 involved recent increase in dosage; in 1 there had been no medication change.

SS:  Clinical features

1. Cognitive-behavioral:
    
   • insomnia
   • agitation
   • restlessness
   • confusion
2. Neuromuscular:
    
   • generalized muscular rigidity
   • “jerking” limbs or myoclonus
   • tremulousness
   • hyperreflexia ± Babinski responses
   • ankle clonus
   • ataxia » falling
3. Gastrointestinal:
    
   • nausea
   • vomiting
   • diarrhea
4. Autonomic:
    
   • fever: core body temperature is typically mildly elevated
   • tachycardia
   • hypotension
   • diaphoresis or sweating is uncommon
5. Other:
    
   • bruising
   • bleeding

Common laboratory findings in SS

CPK elevation can vary greatly in severity but SS may be associated with rhabdomyolysis (muscle breakdown) and myoglobinuria.

Other muscle enzymes such as ALT, AST and LDH may also be elevated.

White blood cell count (CBC) is often increased at presentation but then returns to normal quickly as long as there is no intercurrent infection.

Platelet levels tend to decrease and must be watched closely in severe cases for several days.

Other laboratory abnormalities that may be present in SS

• Elevated blood urea nitrogen (BUN) and creatinine(Cr) secondary to dehydration. In severe cases, rhabdomyolysis may cause an increase in Cr level because of the effect of myoglobin on the kidney.
• Myoglobinuria secondary to muscle breakdown (rhabdomyolysis)
• Decreased serum iron
• Decreased serum calcium
• Decreased magnesium

Investigations of patients suspected of having SS

• Blood work: CBC with attention to the platelet count, BUN, creatinine, CPK, ALT, AST, LDH,electrolytes, Fe, Ca, Mg
• Urine for myoglobin and drug screen
• EKG
• EEG (optional depending on presentation)
• Lumbar puncture to rule out a CNS infection as cause of presentation (optional depending on presentation)
• Neuroimaging if mental status changes are present

Course of illness and complications

Most cases of SS resolve within 72 hours following discontinuation of the responsible agents and good supportive care.

A minority, however, go on to develop complications.

In our experience, complications are likely to ensue when the core body temperature at presentation is 40°C [104°F] or greater

Complications of SS

• Marked delirium
• Rhabdomyolysis and myoglobinuria
• Seizures
• Difficult-to-treat hypotension
• Ventricular tachycardia
• Disseminated intravascular coagulation: heralded by a precipitous drop in platelet count

In severe cases of SS, transfer to the ICU, intubation and ventilation may be necessary

Treatment of SS

Discontinuation of all antidepressants, lithium, dopamine D2 receptor blocking agents and any other serotonergic substances

Supportive care

• Frequent monitoring of vital signs IV hydration
• Use of cooling blankets if temperature is high
• Antipyretic agents
• Benzodiazepines (BZPs) SL or by intravenous drip
• CPK twice daily for 72 hours or until first decrement
• Platelet count twice daily for 72 hours or until first increase
• Attention to skin breakdown

The effectiveness of cyproheptadine, a 5-HT_2A antagonist, has been reported in case studies

Benzodiazepines are recommended as they:

• quell agitation and restlessness
• have antiseizure properties
• are central muscle relaxants
• do not produce any symptoms or side-effects that clinically overlap with SS

Although the use of low potency anti-psychotic agents (APDs) such as chlorpromazine and olanzapine have been recommended as treatments of SS, this practice is to be discouraged given that all APDs have the potential to precipitate NMS.

Furthermore, benzodiazepine, which do not carry such a risk, are highly effective for many aspects of the syndrome.

SS:  Differential Diagnosis

• Neuroleptic malignant syndrome
• Anti-cholinergic toxicity
• Infection: in most non-geriatric patients, non-CNS infections are unlikely to cause confusion or delirium. A lumbar puncture is important in ruling out encephalitis or meningitis
• Alcohol, opiate and benzodiazepine withdrawal: history of use is important but may be impossible to obtain and should always be considered
• Lithium toxicity: is clinically remarkably similar to SS and can be easily determined by a blood test
• Stimulant/Ecstasy use

NMS AND SS: Comparative clinical features

	NMS	SS
Typical clinical features	• immobility • mutism • staring,frightened expression • rapid onset	• excessive movement and agitation • incoherent speech • easily startled • rapid onset
Mental status changes	• difficult to assess because of mutism • EEG usually indicates encephalopathy, with diffuse slowing	• mild confusion to frank delirium
Autonomic features	• high fever • tachycardia • BP instability • diaphoresis • dilated pupils	• typically mild to moderate fever • tachycardia • hypotension • diaphoresis less common • dilated pupils
Gastrointestinal features	• constipation • ileus	• diarrhea • nausea • vomiting
Neurological findings	• severe cogwheel rigidity • rigors • tremulousness • unable to ambulate • reflexes often appear decreased because of severe rigidity • seizures very rare	• rigidity usually mild-moderate • tremulousness • myoclonic jerking • ataxic gait • hyperreflexia • clonus • may elicit Babinski responses • seizures may develop
Common lab abnormalities	• elevation of muscle enzymes: CPK, ALT, AST, LDH • low serum Fe • leukocytosis • thrombocytosis may be noted • low Ca, P	• elevation of muscle enzymes: CPK, ALT, AST, LDH • thrombocytopenia; • leukocytosis • low Fe, Ca, P may be seen
Complications	• aspiration pneumonia • renal failure • DVT secondary to immobility • pulmonary emboli • contractures/skin breakdown • muscle weakness- post episode • mortality high but improving • renal failure secondary to rhabdomylosis	• falls resulting in fractures, bruising, subdural hematoma • seizures severe hypotension • ventricular tachycardia • disseminated intravascular coagulation causing bleeding • renal failure secondary to rhabdomylosis • mortality unknown
Risk factors	• dopamine D2 blocking agents • withdrawal of dopamine agonists • benzodiazepine withdrawal during neuroleptic treatment • rapid increase in APD dosage • concurrent use of lithium • dehydration • catatonia;both retarded and excited types	• use of any agents which enhance or increase serotonergic neurotransmission • polypharmacy • MAOI plus an SSRI, TCA, meperidine or dextromethorphan • concurrent use of serotonergic agents and lithium
Treatment	• immediate discontinuation of all dopamine D2 antagonists • IV hydration; alkalization of urine if myoglobinuria present • benzodiazepines for anxiety and muscle rigidity • cooling blankets • antipyretic agents • physiotherapy to prevent contractures • Some (anecdotal) evidence for DA agonists, dantrolene and ECT in some cases	• immediate discontinuation of all serotonergic and anti-dopaminergic agents • careful monitoring of vital signs, platelets, hydration status • benzodiazepine drip • Do not use chlorpromazine or olanzapine • use of propranolol may worsen hypotension • Some (anecdotal) evidence for cyproheptadine

Anticholinergic toxicity

Many psychotropic medications have anticholinergic properties.

Toxicity, which is characterized by flushed dry skin, agitation, restlessness, visual hallucinations, tachycardia and hypotension can be distinguished from SS by the following:

• dryness vs. diaphoresis: characteristic of NMS and often seen in SS
• temperature is only mildly elevated
• rigidity is absent
• muscle enzymes are typically not elevated (constipation or ileus and urinary retention, are often present)

Stimulant abuse

Many stimulants are very similar to the brain’s own neurotransmitters, including dopamine, norepinephrine and serotonin

Some (such as MDMA, methamphetamine) can block the reuptake transporters causing neurotransmitters to stay in the synapse for longer.

Psychostimulants can cause restlessness and agitation leading to increased heat production.

The possibility of stimulant use or abuse causing a patient’s presentation or contributing to the development of SS can often be discerned from corroborative history, previous records, or the results of urine drug screen.

SS:  Conclusions

Serotonin toxicity is unrecognized and often misdiagnosed.

Serotonin toxicity can occur in patients on monotherapy without an increase in dosage.

Polypharmacy will increase the risk of serotonin toxicity.

The clinical syndrome consists of confusion/delirium, tremulousness, myoclonus, ataxia, hyperreflexia, and autonomic instability in over 80% of cases.

Serotonin syndrome is usually self-limited, although 30% of patients require ICU admission, intubation and IV lorazepam.

A fever of >40°C [104°F] on day one may be a good prediction of complications.