1. Neuroleptic Malignant Syndrome and Serotonin Syndrome
APM Resident Education Curriculum
Thomas W. Heinrich, M.D.
Associate Professor of Psychiatry & Family Medicine
Chief, Psychiatric Consult Service at Froedtert Hospital
Department of Psychiatry & Behavioral Medicine
Medical College of Wisconsin

2. Historical Background
Syndrome malin des neuroleptiques
Rapidly progressive neurovegatative state
Observed during early clinical trials of haloperidol
1960
Neuroleptic Malignant Syndrome
First appeared in English literature in 1967
Belated recognition in the U.S.
Delay in 1960 observed this syndrome of a rapidly progressive neurovegatative state that preceded cardio-vascular collapse and death during the early clinical trials of haloperidol and coined the term syndrome malin des neuroleptiques.
Prior to the 1960s, clinical descriptions resembling NMS associated with phenothiazines were not formally diagnosed as NMS.
Caroff in 1980 published the first review of the sixty cases reported in the world literature. He estimated that NMS occurs in as many as 1% of neuroleptic treated patients and may have a mortality rate of 20%.
Reference
Caroff SN. The neuroleptic malignant syndrome. J Clin Psychiatry (3):79-83.

3. Incidence Typical antipsychotics Atypical antipsychotics
Best estimate % (Caroff and Mann, 1996)
Wide variance in estimates %
Atypical antipsychotics
It remains unclear whether atypical antipsychotics are less likely to cause NMS compared to typical antipsychotics (Troller, et al., 2009)
This estimate is produced by pooling the results of studies reporting the occurrence of NMS among large numbers of patients treated with antipsychotics at a particular center.
The wide variance is thought secondary to variance in diagnostic criteria, survey techniques and clinical settings.
NMS can result from treatment with atypical antipsychotics, and that it often presents with the classic features and course of illness reported previously in associated with typical antipsychotics. Only 30%, however, met the strict criteria for NMS in a case review by Carloff and Mann in 2000 the rest presented with an incomplete picture
Reference
Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North AM 1993; 77(1):
Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs. 2009;23(6):
Sachdev P, Kruk J ,Kneebone M, et al. Clozapine-induced neuroleptic malignant syndrome: review and report of new cases. J Clin Psychopharmacol Oct;15(5):
Residual catatonic state following neuroleptic malignant syndrome.
Caroff SN, Mann SC, Keck PE Jr, Francis A.
J Clin Psychopharmacol Apr;20(2):257-9.

4. Pathogenesis Central dopamine hypoactivity Evidence
All antipsychotics implicated share dopamine receptor antagonism
Withdrawal of dopamine agonists or “freezing” episodes in Parkinson’s disease have induced NMS-like states
Dopamine agonists appear beneficial in treatment
Disruption of dopamine tracts produce NMS-like states
A case report utilizing SPECT revealed almost complete D2 receptor blockade in a patient with NMS
Reduction in CSF homovanillic acid (HVA) in NMS
Reduction persisted after recovery
These cases imply that NMS-like syndromes occur when a rapid decrease in dopaminergic activity occurs.
This decrement may be caused by the blockade of dopamine receptors, decrease in dopamine stores, or the elimination of a dopaminergic agent.
NMS may represent the final common pathway of a rapid and significant impairment of dopaminergic function in the striatum and hypothalamus.

5. Pathogenesis Central dopamine hypoactivity (continued)
Theory (Strawn et al, 2007, Fricchione 1985)
Patients susceptible to developing NMS may have a baseline central hypodopaminergia
Trait vulnerability
The hypodopaminergic state is further stressed with pharmacologic or stress-induced reductions in dopamine activity
State vulnerability
Fricchione GL. Neuroleptic catatonia and its relationship to psychogenic catatonia. Biol Psychiatry Mar;20(3):
Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry Jun;164(6):870-6.

6. Clinical Characteristics
Early signs
Change in mental status
Extrapyramidal symptoms unresponsive to antiparkinsonian agents
Autonomic dysfunction
Changes in mental status
Obtundation
New onset catatonia
Extrapyraminal symptoms
Dysarthria
Dysphagia
Myoclonus
Tremor
Rigidity
Autonomic system dysfunction
Episodic tachycardia
Hypertension
Study of the pattern of system development in 153 clinical case reports.
Mental status changes or rigidity constituted the initial signs of the disorder in 82.3% of the cases . (Velamoor et al. 1994)
References
Velamoor VR, Norman RM, Caroff SN, et al. Progression of symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis Mar;182(3):

7. Clinical Characteristics
Signs and Symptoms
Hyperthermia
98%
Muscle rigidity - “lead pipe rigidity”
97%
Mental status changes - delirium and catatonia
Hyperthermia
Hyperthermia and profuse sweating occurs in 98% of reported NMS cases
>38C in 87%
>40C in 40%
Usually develops as a late manifestation of the full blown syndrome
Most distinguishing feature of NMS
Sets it apart from other neuroleptic related conditions such as EPS.
Need to rule out other potential sources of hyperthermia such as febrile illness do to infection.
Possible sources of hyperthermia:
Neuroleptic induced inhibition of central dopaminergic thermoregulatory mechanisms
Increased heat production derived from neuroleptic effects on skeletal muscle tone
Increased heat production resulting from increased metabolism
Muscle rigidity
Unresponsive to antiparkinsonian medications
Generalized rigidity, described as “lead pipe” in its most severe form, is reported in 97%
Rigidity may be a less impressive sign when NMS is associated with atypical antipsychotics.
Mental status changes
Reported in 97% of the cases
Manifestations
delirium
catatonia

8. Clinical Characteristics
Signs and symptoms (continued)
Autonomic dysfunction
Tachycardia
88%
Profuse diaphoresis
Labile blood pressure
61%
Tachycardia or labile blood pressure
95%

9. Clinical Characteristics
Laboratory findings
Rhabdomyolysis
Leukocytosis
Low serum iron
Metabolic acidosis
Electroencephalogram
Neuroimaging
Several laboratory abnormalities are common in NMS but are either nonspecific or reflect complications of the syndrome.
Rhabdomyolysis
Results from myonecrosis from rigidity, hyperthermia, and ischemia
CPK elevations may occur in up to 95% of cases
Myoglobinuria may occur as a consequence in 67% of the cases.
Leukocytosis
Nonspecific
No left shift
Present in 98% of the cases
Low serum iron
Metabolic acidosis
Present in 75% of examined cases
Electroencephalogram
Abnormal EEG present in 50% of cases
Nonfocal, generalized, nonspecific slowing which is consistent with encephalopathy
Neuroimaging
Usually normal
If abnormal the findings usually represent pre-existing pathology (atrophy or trauma) not and acute change related to NMS

10. Clinical Characteristics
Is there an “atypical” presentation of NMS with atypical antipsychotics?
A majority of cases of NMS produced by atypical antipsychotics present with “typical” NMS signs and symptoms
However…
Clozapine, however, appears to present with a lower incidence of rigidity (at least early in the course of the syndrome) when compared to the other atypical antipsychotics
Case reports of aripiprazole-induced NMS suggest a lower proportion of patients presenting with delirium and elevated temperature
Troller JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs 2009; 23(6):

11. Diagnostic Criteria Caroff’s Criteria for NMS
Treatment with neuroleptics
Hyperthermia (>38C)
Muscle rigidity
Five of the following
Change in mental status
Tachycardia
Labile blood pressure
Diaphoresis
Tremor
Incontinence
CK elevation
Leukocytosis
Metabolic acidosis
Exclusion of other causes

12. Diagnostic Criteria DSM - IV TR
Severe muscle rigidity and elevated temperature associated with the use of neuroleptics
Two or more of the following
Diaphoresis
Dysphagia
Tremor
Incontinence
Change in consciousness
Mutism
Tachycardia
Labile blood pressure
Leukocytosis
Muscle injury
Not due to medical, substance or mental condition

13. Diagnostic Criteria Levenson’s Criteria
Major manifestations
Fever
Rigidity
Elevated creatinine phosphokinase (CK) level
Minor manifestations
Tachycardia
Abnormal blood pressure
Tachypnea
Altered consciousness
Diaphoresis
Leukocytosis
Presence of all three major, or two major and four minor, manifestations indicates a high probability of NMS.

14. Risk Factors Not risk factors Risk factors Age Sex
Environmental factors
Risk factors
Heredity
Neuropsychiatric diagnosis
NMS is not specific to any specific neuropsychiatric diagnosis, but……
Catatonia
Organic brain disorders
Not risk factors
Age
It has been reported in all age groups following administration of antipsychotics.
Mean age of patients experiencing NMS has been estimated to be 40 years old.
Sex
Not a meaningful risk factor.
Environmental factors
NMS occurs independent of climate and ambient temperatures.
High ambient temperatures and humidity may augment the risk of NMS;
Risk Factors
Heredity
There are a couple of case reports of familial occurrence of NMS (Deuschl et al.1991 and Otani et al. (1991)
Neuropsychiatric Diagnosis
NMS is not specific to any neuropsychiatric diagnosis. It has been reported to occur in patients receiving antipsychotics for diverse neuropsychiatric disorders, as well as in medical patients with normal brain function. Various authors, however, have proposed that certain disorders may be at risk:
Schizophrenia
Mood disorders
Organic brain disorders
Developmental disabilities
Pre-existing basal ganglia disorders
Catatonia
Patients with idiopathic or antipsychotic catatonia may be at risk of for developing NMS when treatment with antipsychotics is initiated or continued. This, NMS may be conceptualized as a more fulminate form of catatonia.
Substance abuse, dependence, or withdrawal
A particularly vulnerable time to develop NMS may be during acute withdrawal from alcohol or CNS depressant drugs when neurological status and thermoregulatory and autonomic mechanisms are already compromised.

15. Risk Factors Risk factors (continued) Physiological states
Agitation and dehydration
Hypodopaminergic trait
Pharmacological variables
History of NMS
30-33% of NMS patients when rechallenged
17% of NMS patients report similar past episodes
Physiological States
Agitation
Dehydration
Exhaustion
Decreased serum iron levels
Pre-existing abnormalities in the state of brain dopamine activity or receptor function may constitute a critical variable in the development of NMS.
Pharmacological and treatment variables
History of NMS
30-33% of NMS patients at risk when rechallenged with antipsychotics. (Caroff and Mann 1988 & Rosebush 1989)
17% NMS patients reported a similar past episode when questioned. (Caroff and Mann 1988)
References
Caroff SN, Mann SC. Neuroleptic malignant syndrome. Psychopharmacol Bull. 1988;24(1):25-9.
Rosebush PI, Stewart TD, Gelenberg AJ. Twenty neuroleptic rechallenges after neuroleptic malignant syndrome in 15 patients. J Clin Psychiatry Aug;50(8):295-8

16. Risk Factors Pharmacologic variables
Exposure to drugs that block dopamine D2 receptors
High potency
High dosage
Rapid dose escalation (Shalev & Munitz 1988)
Study of 56 NMS cases
1 episode with decreased dose
4 episodes with steady state dosing
51 cases with dose escalation
Range chlorpromazine equivalents/day
Average of mg chlorpromazine/day
Virtually all classes of D2 dopamine receptor antagonists have been associated with NMS. The adverse effects of drugs with neuroleptic properties used in non-psychiatric settings are often neglected and under-recognized by non-psychiatric clinicians.
Prochlorperazine  nausea
Metoclopramide  peristalsis
Droperidol  anesthesia
Promethazine  sedation
High-potency
Cases often complicated by patients receiving more than one antipsychotic, making it difficult to distinguish the effects of individual drugs.
Most cases of NMS, however, have been reported in patient’s receiving high-potency neuroleptics.
Atypical antipsychotics with reduced D2 receptor affinity may mitigate extrapyramidal dysfunction.
Available data suggest that the incidence of NMS with atypical drugs may be the same or less than with typical antipsychotics. However, reports of NMS may be elevated with atypicals because of the rush to publish reports and patients switched to atypical agents may be more susceptible to NMS.
High dosage
Rapid dose escalation
Loading rate rather than total dose appears to represent more of a risk factor (Shalev & Munitz 1988)
56 NMS Cases
1 episode with decreased neuroleptic dose
4 episodes with steady state dosing
51 cases with dose escalation
Range of increase 40 – 6000mg chlorpromazine per day
Without extreme schedules the average rate of change is mg per day
A possible explanation is that NMS is likely to occur as a reaction to the sudden and significant down regulation of dopamine transmission.
References
Shalev A, Hermesh H, Munitz H. The role of loading rate in neuroleptic malignant syndrome. Am J Psychiatry Aug;143(8):1059.
Shalev A, Munitz H. The neuroleptic malignant syndrome: agent and host interaction. Acta Psychiatr Scand Apr;73(4):

17. Risk Factors Pharmacologic variables Depot neuroleptics
Longer duration
Little evidence of increased mortality
Concomitant medications
33% have more than one antipsychotic
>50% on additional non-neuroleptic medications
Anticholinergics impair temperature regulation
Depot neuroleptics
Longer duration of NMS and associated morbidity
Concomitant medications
Greater than half the cases of NMS reported involve concomitant polypharmacy with medications other than neuroleptics.
Anticholinergic medications impair heat loss. Therefore, they may be contraindicated in patients with high temperature and NMS.

18. Differential Diagnosis
Most common disorders mistaken for NMS
Infections
Catatonia
Agitated delirium
“Benign” extrapyramidal side effects (EPS)
Serotonin Syndrome
Systemic disorders
EPS with fever
Hormonal disorders
Thyrotoxicosis
Pheochromocytoma
The differential diagnosis of NMS encompasses a broad range of disorders presenting with elevated temperature, necessitating a through medical and neurological evaluation.
The associated features of rigidity, mental status changes, and autonomic dysfunction narrow the differential diagnosis.

19. Differential Diagnosis
Systemic disorders (continued)
Heatstroke
Exertional heat stroke
Classical heat stroke
Drugs
Malignant hyperthermia
Serotonin syndrome
Dopaminergic withdrawal
Levodopa withdrawal
Freezing episodes in Parkinson’s disease
Exertional Heat Stroke
During hot weather agitated patients are at risk for exertional heatstroke.
Caused by excessive accumulation of metabolically produced heat due to environmentally induced feature of heat dissipation.
High temperatures
Sweating
Hypotension
Rhabdomyolysis
Classic Heat Stroke
Occurs in elderly, inactive persons, involves inadequate host heat-defense responses, and is most probably a consequence of impaired heat dissipation (SNS failure) with aging.
Exposure to neuroleptics and anticholinergic agents may impair thermoregulation and increase the risk of classical heatstroke.
Not related to exertion
Anhidrosis
Respiratory alkalosis

20. Differential Diagnosis
Central Nervous System Disorders
Infections
Structural pathology
Seizures
Malignant catatonia
Unchecked hyperactivity leading to exhaustion, stupor, hyperthermia, and death
Reported prior to the advent of neuroleptics
NMS may represent an iatrogenic form of malignant catatonia
Malignant Catatonia
The potentially lethal progression of catatonic states in psychotic disorders has been well described for over a century. In these cases, unchecked hyperactivity can lead to exhaustion, stupor, hyperthermia, and death.
Differential diagnosis of malignant catatonia from NMS in the stuporous patient treated with neuroleptics can be difficult.
NMS may represent an iatrogenic form of lethal catatonia.
NMS is to lethal catatonia what neuroleptic induced catatonia is to simple catatonia.

21. Clinical Course Onset Duration
Related to initiation of neuroleptic treatment
16% within one day
66% by one week
96% within 30 days
Duration
Self limited once neuroleptics are stopped
9.6 +/- 9.1 days average length
23% recovered in two days
63% recovered in one week
97% recovered in one month
Onset
Related to initiation of neuroleptic treatment (Caroff and Mann 1988)
16% within 24 hours
66% by one week
96% within 30 days
Duration/Resolution
Once the neuroleptics are stopped, unless complications develop, the syndrome is self-limited.
If untreated by dopamine agonists or muscle relaxants the mean recovery time was 9.6+/-9.1 days for non-depot neuroleptics
23% recovered in 48h
63% recovered in I week
97% recovered in I month
Depot medications may cause significant protraction of the syndrome
Case reports of prolonged residual catatonic states following resolution of NMS
References
Caroff SN, Mann SC. Neuroleptic malignant syndrome. Psychopharmacol Bull. 1988;24(1):25-9.

22. Outcomes Mortality Mortality is decreasing (Shalev et al. 1989)
25% before 1984
12% after 1984
Risks for increased mortality
Older age
Higher temperatures
Depot neuroleptics (?)
Pre-existing brain pathology
Development of renal failure
Mortality is decreasing (Shalev et al. (1989)
Mortality of 25% before 1984
Mortality of 11.6% after 1984
Trend likely represents a better awareness, early diagnosis, and quicker discontinuation of antipsychotic drugs.
References
Shalev A, Hermesh H, Munitz H. Mortality from neuroleptic malignant syndrome. J Clin Psychiatry Jan;50(1):18-25.

23. Outcomes Morbidity Renal insufficiency/failure Respiratory failure
16-25%
Respiratory failure
Cardiac morbidity
Cognitive sequelae (?)
Renal insufficiency/failure
myoglobinuric renal failure occurs on 16-25% of cases
Etiology of myoglobinuria in NMS:
Muscle necrosis due to severe rigidity
Direct drug myotoxicity (?)
Dehydration
Hyperthermia
Ischemia
Hypoxia
Catatonic posturing
Respiratory failure
In one study 19% of patients with NMS required ventilator support (Levenson 1985).
Etiology:
Aspiration pneumonia
Pulmonary emboli
Necrosis of respiratory muscles due to myonecrosis
Cardiac morbidity
Arrhythmias due to electrolyte abnormalities
Ischemia secondary to hypoxia or metabolic hyperactivity
Cognitive sequelae
Long term cognitive effects appear rare.
Prolonged hyperthermia
Extreme hyperthermia
Prolonged hypoxia

24. Treatment Basics Early recognition Cessation of neuroleptics Hydration
Temperature reduction
Intensive monitoring
Supportive care
Nonspecific treatment consists of supportive measures and prevention of complications.
Intensive monitoring (telemetry and pulse oximetry)
Supportive care
DVT prophylaxis
Medication discontinuation
Immediate discontinuation of antipsychotics are essential in managing NMS.
Lithium should be discontinued. It may be hazardous to continue lithium in dehydrated patient due to concerns of toxicity.
Anticholinergic medications should be discontinued do to their ability to impair heat loss and inhibit sweating, thereby exacerbating hyperthermia.
However, abrupt withdrawal of dopamine agonists may predispose or exacerbate NMS
Hydration
Prevent hypovolemia, hypotension, shock, and renal failure.
Correct electrolyte imbalance.
Temperature reduction
Higher temperatures are predictive of increased morbidity and mortality.

25. Treatments Specific treatments Benzodiazepines Dantrolene
NMS may represent an iatrogenic malignant catatonia
Dantrolene
Theory
81% of patients benefited
1-10mg/kg/day in divided doses
Optimal length of treatment not established
May cause hepatic and respiratory compromise
Benzodiazepines
Use of benzodiazepines may be effective in mild cases of NMS
Theory
NMS may represent a drug induced form of malignant catatonia.
GABA-A agonists could inhibit the pars reticulata inhibitory GABA-B neurons which may result in disinhibition of neighboring pars compacta DA cells with resulting striatal DA agonism.
Dosage
A trial of lorazepam 1-2 mg IV may be warranted in mild cases with close monitoring of the patient’s respiratory status.
Dantrolene
Inhibits contraction and heat production in muscle.
It acts by inhibiting the excitation-contraction mechanism in skeletal muscles through the sequestration of calcium in the sarcoplasmic reticulum. It is not specific for malignant hyperthermia (MH).
Maybe most helpful in cases of NMS with extreme temperature elevations (>40C), rhabdomyolysis and rigidity.
Side effects
May cause hepatic and respiratory compromise.
Cardiovascular collapse may occur when coadministered with calcium channel antagonists.
Sakkas and Davis (1991) 100 cases
81% of patients were helped
Benefit evident within a few hours
1mg-10mg/kg/day in divided doses
1mg/kg every 6 hours for 48 hours for MH
Duration of treatment is unclear

26. Treatments Specific treatments (continued) Dopaminergic medications
Theory
Amantadine
63% found benefit as monotherapy
mg/day
Bromocriptine
94% found benefit as monotherapy
Shortened time to clinical response
2,5mg tid - 15mg tid
Levodopa
Dopamine agonists
Theory
dopaminergic agents may reduce the probable acute hypo-dopaminergic state in NMS.
Amantadine
Sakkas and Davis et al(1991) 34 patients
63% of clinicians reported beneficial when amantadine used as monotherapy.
Symptoms worsened in 6 patients when discontinued.
Dosage
mg/day in divided doses
Bromocriptine
Sakkas (1991) 100 patients
94% of patients benefits from monotherapy.
24-18% of patients experienced a return of NMS symptoms when discontinued after initial effectiveness.
Mortality rate was decreased by 50% when added to supportive therapy alone.
Rosenberg & Green (1989) 67 published cases
Shortened time to clinical response (1.03 +/ days) compared with supportive treatment alone (6.80 +/ days).
2.5mg tid
May increase up to 45 mg/day if necessary
References
Sakkas P, Davis JM, Janicak PG, et al. Drug treatment of the neuroleptic malignant syndrome.
Psychopharmacol Bull. 1991;27(3):381-4.

27. Treatments Specific treatments (continued) ECT
May increase dopamine synthesis and release
ECT considered if…
Unresponsive to pharmacologic treatment
Catatonia cannot be ruled out
Residual catatonia develops
Psychosis develops following NMS
Mean time to response is / days
ECT
Theory
Effective in catatonia and Parkinson’s disease
ECT may increase dopamine synthesis and release
ECT should be considered if:
Patients unresponsive to pharmacological and supportive measures
Catatonia cannot be ruled out
Residual catatonic state develops following NMS
Psychosis develops following NMS
ECT offers the unique advantage of treating the NMS and potentially addressing the underlying psychiatric disorder.
Patients with NMS are not considered to be at an increased risk for MH during ECT.
Mean time to clinic response following ECT 1.46+/-2.38 days.
Most patients responded in three days

28. Rough Treatment Guidelines
Mild or early NMS
Supportive care and benzodiazepines
Moderate NMS (rigidity and temperatures 38-40)
Dopamine agonist
Severe NMS (rigidity, hypermetabolism, temperatures >40)
Dantrolene
Rough Guidelines
Mild or early NMS
Discontinuation of dopamine antagonists, supportive care and benzodiazepines
Moderate NMS (rigidity and temperatures 38-40)
Add dopamine agonist to above treatment
Severe NMS (rigidity, hypermetabolism, temperatures >40)
Add dantrolene to above treatments
Strawn JR, Keck PE Jr, Caroff SN. Am J Psychiatry Jun;164(6):870-6.

29. Antipsychotic Rechallenge
Guidelines for rechallenge
Reduce potential risk factors
Two weeks from resolution of NMS
Gradual titration of low starting doses
Low potency or atypical antipsychotics
Ideally rechallenge should occur in a hospital
Wells (1988)
Recurrence of symptoms doubled when neuroleptics were reintroduced within five days of recovery.
Susman and Addonizio (1988)
Retreatment before two weeks elapsed after recovery increased the risk of recurrence.
Reference
Wells AJ, Sommi RW, Crismon ML. Neuroleptic rechallenge after neuroleptic malignant syndrome: case report and literature review. Drug Intell Clin Pharm Jun;22(6):
Susman VL, Addonizio G. Recurrence of neuroleptic malignant syndrome. J Nerv Ment Dis Apr;176(4):

30. Serotonin Syndrome
Serotonin syndrome can be a serious complication of treatment with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and other serotonergic medications.
It usually occurs when 2 or more serotonin-modifying agents are used in combination.
Cases have been reported after single agent therapy.

31. Serotonin Syndrome History
The syndrome was first described in the 1950s (Mitchell, 1955).
The patient exhibited restlessness, excitation, tremors, and hyper-reflexia during simultaneous administration of iproniazid (and anti-TB drug and MAOI) and Meperidine
Sternbach (1991) conducted the first comprehensive clinical review of serotonin syndrome
References
Mitchell RS. Fatal toxic encephalitis occurring during iproniazid therapy in pulmonary tuberculosis. Ann Intern Med Feb;42(2):
Sternbach H. The serotonin syndrome. Am J Psychiatry Jun;148(6):

32. Serotonin Syndrome Incidence Unknown
The variable nature of its presentation makes it difficult to diagnose and has caused underreporting
Several barriers exist to limit the ability of clinicians to diagnose the condition
The syndrome may be missed because of its diverse manifestations.
A strict application of the diagnostic criteria potentially rules out mild, early, or subacute cases of the disorder.
Lack of awareness among clinicians

33. Serotonin Syndrome Pathophysiology
Enhanced central serotonergic activity
The excessive serotonergic activity may influence other parts of the CNS
Dopamine
Norepinephrine
Receptors
Hyperstimulation of the 5-HT1A receptors
Noradrenergic CNS hyperactivity may play a critical role in the pathophysiology of serotonin syndrome.
CNS norepinephrine concentrations are increased in the serotonin syndrome
may correlate with the clinical outcome.

34. Serotonin Syndrome Pathophysiology (continued)
Hyperstimulation of the 5-HT1A and/or 5-HT2A receptors
5-HT1A
This relationship has been demonstrated in animals by the use of 5-HT1A agonists and antagonists to produce and block the syndrome, respectively
5-HT2
Nonspecific 5-HT receptor antagonists used in the treatment of human serotonin syndrome) have significantly greater potency at the 5-HT2 receptor compared with the 5-HT1A receptor
No single receptor appears to be responsible for the development of the serotonin syndrome
Several lines of evidence converge to suggest that agonism of 5-HT2 receptors contributes substantially to the condition.
Additional subtypes of serotonin receptors, such as 5-HT1a , may also contribute to the development and progression of serotonin syndrome
References
Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol. 1997;17(3):
Gillman PK. Serotonin syndrome: history and risk. Fundam Clin Pharmacol. 1998;12(5):

35. Serotonin Syndrome Clinical characteristics (Physical) Clinical triad
Cognitive/behavioral alterations
Confusion  Delirium
Agitation
Lethargy  Coma
Autonomic instability
Hyperthermia
Tachycardia
Diaphoresis
Dilated pupils
Neuromuscular abnormalities
Myoclonus
Hyperreflexia
Rigidity
Cognitive
Confusion 41-77%
Agitation 37-43%
ANS
Hyperthermia 27-34%
Tachycardia 44%
Nausea/Vomitting 27%
Diaphoresis 49%
Neuromuscular
Myoclonus 49-63%
Hyperreflexia 41-44%
Restlessness 29%
Tremor 17-61%
Adapted from Mason et al XXXX
Reference
Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore). 2000;79(4):201-9.

36. Serotonin Syndrome Clinical characteristics (Laboratory)
There are no specific tests available for the diagnosis of serotonin syndrome.
Blood levels of serotonin do not correlate with clinical findings.
Nonspecific laboratory findings may include…
Elevated total white blood cell count, CPK levels, and transaminases,
Decreased serum bicarbonate level
Severe cases can evolve to include…
Disseminated intravascular coagulation, rhabdomyolysis, and metabolic acidosis
Renal failure and myoglobinuria
Adult respiratory distress syndrome
References
Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol Jun;17(3):
LoCurto MJ. The serotonin syndrome. Emerg Med Clin North Am Aug;15(3):

37. Serotonin Syndrome
Sternbach’s suggested diagnostic criteria for serotonin syndrome
A. Coincident with the addition of or increase in a known serotonergic agent to an established medication regimen, at least three of the following clinical features are present:
1. Mental status changes (confusion, hypomania),
2. Agitation,
3. Myoclonus,
4. Hyperreflexia,
5. Diaphoresis,
6. Shivering,
7. Tremor,
8. Diarrhea,
9. Lack of coordination,
10. Fever.
B. Other etiologies (e.g. infectious, metabolic, substance abuse, or withdrawal) have been ruled out.
C. A neuroleptic had not been started or increased in dosage prior to the onset of the signs and symptoms listed above.
Sternbach H. The serotonin syndrome. Am J Psychiatry 1991; 148(6):
Reference
Sternbach H. The serotonin syndrome. Am J Psychiatry Jun;148(6):705-13

38. Serotonin Syndrome Revised diagnostic criteria for serotonin syndrome
Addition of a serotonergic agent to an already established treatment (or increase in dosage) and manifestation of at least 4 major symptoms or 3 major symptoms plus 2 minor ones
Mental (cognitive and behavioral) symptoms
Major symptoms: confusion, elevated mood, coma or semicoma
Minor symptoms: agitation and nervousness, insomnia
Autonomic symptoms
Major symptoms: fever, hyperhidrosis
Minor symptoms: tachycardia, tachypnea and dyspnea, diarrhea, low or high blood pressure
Neurological symptoms
Major symptoms: myoclonus, tremors, chills, rigidity, hyperreflexia
Minor symptoms: impaired co-ordination, mydriasis, akathisia
These symptoms must not correspond to a psychiatric disorder, or its aggravation, that occurred before the patient took the serotonergic agent.
Infectious, metabolic, endocrine or toxic causes must be excluded.
A neuroleptic treatment must not have been introduced, nor its dose increased, before the symptoms appeared.
Reference
Birmes P, Coppin D, Schmitt L, et al. Serotonin syndrome: a brief review. CMAJ. 2003;168(11):

39. Serotonin Syndrome The Hunter Serotonin Toxicity Criteria
In the presence of a serotonergic agent, serotonin toxicity is diagnosed:
Yes
Serotonin toxicity
Spontaneous clonus is present No
Yes
Inducible or ocular clonus with agitation or diaphoresis are present
Serotonin toxicity No
Inducible ocular clonus and increased muscle tone and temperature >38oC are present
Yes
Serotonin toxicity
Spontaneous clonus = involuntary muscular contraction and relaxation in rapid succession
Inducible clonus = involuntary muscular contraction and relaxation in rapid succession
with rapid dorsiflexion of the ankle.
Ocular clonus = slow continuous lateral eye movements No
Yes
Serotonin toxicity
Tremor and hyperreflexia are present
Adapted from Ables AZ, Nagubilli R.. Am Fam Physician. 2010

40. Serotonin Syndrome Risk factors Prevention
Administration of 2 or more serotonergic medications
Rarely with monotherapy
Prevention
Awareness of risk when prescribing medications that may lead to increased levels of serotonin in the CNS
Pharmacodynamic interactions
Pharmacokinetic interactions
Avoidance of these interactions whenever possible

41. Serotonin Syndrome
Mechanisms that lead to overstimulation of serotonin
Increased precursors of serotonin or its agonists
Buspirone, L-dopa, lithium, LSD, L-tryptophan, trazodone
Decreased serotonin metabolism
MAOI – irreversible (phenelzine, tranylcypromine, selegiline)
MAOI – reversible (linezolid)
Increased serotonin release
Amphetamines, cocaine, MDMA (“ecstasy”), fenfluramine, reserpine
Inhibit serotonin reuptake
SSRI, SNRIs, TCAs, meperidine, tramadol
Drugs and Drug Interactions Associated with the Serotonin
Syndrome.
Drugs associated with the serotonin syndrome
Selective serotonin-reuptake inhibitors
sertraline, fluoxetine, fluvoxamine, paroxetine, and citalopram
Other antidepressant drugs
trazodone, nefazodone, buspirone, clomipramine, and venlafaxine
Monoamine oxidase inhibitors
phenelzine, moclobemide, clorgiline, and isocarboxazid
Anticonvulsants
valproate
Analgesics
meperidine, fentanyl, tramadol, and pentazocine
Antiemetic agents
ondansetron, granisetron, and metoclopramide
Antimigraine drugs
triptans
Bariatric medications
sibutramine
Antibiotics
linezolid (a monoamine oxidase inhibitor) and ritonavir (through inhibition of 3A4)
Over-the-counter cough and cold remedies
dextromethorphan
Drugs of abuse
methylenedioxymethamphetamine (MDMA, or “ecstasy”), LSD
Dietary supplements and herbal products
tryptophan, Hypericum perforatum (St. John’s wort), Panax ginseng (ginseng)
Other
lithium

42. Serotonin Syndrome
The most common drug combinations causing the serotonin syndrome
MAOIs and SSRIs,
MAOIs and TCAs
MAOIs and tryptophan
MAOIs and meperidine

43. Serotonin Syndrome
Most common disorders mistaken for Serotonin Syndrome
Infections
Toxic-metabolic delirium
Alcohol withdrawal delirium
Extrapyramidal side-effects
Adrenergic or anticholinergic toxicity
NMS
Systemic disorders
Pheochromocytoma
Carcinoid tumor

44. Serotonin Syndrome Clinical course and outcome Rapid onset
Serotonin syndrome is usually self-limited, with an uneventful resolution, once the offending agent has been discontinued.
The onset of symptoms is usually rapid
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.
Patients with mild manifestations may present with chronic subacute symptoms.
The serotonin syndrome is not believed to resolve spontaneously as long as precipitating agents continue to be administered.

45. Serotonin Syndrome Treatment
No standardized treatment of serotonin syndrome exists.
Management starts with early recognition of the syndrome, and supportive care.(Mason)
The basic treatment of serotonin syndrome consists of
Discontinuation of the causative drugs
Supportive therapy
Hydration
Cooling
Medications
Management of the serotonin syndrome involves several steps
The removal of the precipitating drugs
The provision of supportive care
The control of agitation
The administration of 5-HT 2a antagonists
The control of autonomic instability and hyperthermia.

46. Serotonin Syndrome Discontinuation of the causative drugs
Non-Pharmacologic Treatment
Discontinuation of the causative drugs
Supportive therapy
Hydration
Cooling
The discontinuation of punitive agents and the administration of intravenous fluids and correction of vital signs, remains a mainstay of therapy.
However, an abrupt deterioration in the condition of a patient who has been conservatively treated indicates the need for an immediate, aggressive response.

47. Serotonin Syndrome Pharmacologic Treatment
Several drugs have been used to treat serotonin syndrome.
Cyproheptadine
Propranolol
Chlorpromazine
As in NMS the intensity of therapy depends on the severity of illness.
Mild cases (e.g., with hyperreflexia and tremor but no fever) can usually be managed with supportive care, removal of the precipitating drugs, and treatment with benzodiazepines.
Moderately to severely ill patients should have all physiologic abnormalities (autonomic instability and hyperthermia) aggressively corrected and may benefit from the administration of 5-HT 2A antagonists in addition to the above measures.

48. Serotonin Syndrome Pharmacologic Treatment Benzodiazepines
Control of agitation
May blunt the hyperadrenergic component of the syndrome
Control of the agitation often present in serotonin syndrome with benzodiazepines is often necessary.
Benzodiazepines such as diazepam improve survival in animal models and blunt the hyperadrenergic component of serotonin syndrome.

49. Serotonin Syndrome Pharmacologic Treatment Cyproheptadine
First-generation antihistamine
Shown in animal studies to prevent the onset of experimentally induced serotonin syndrome.
While no randomized control trials have been conducted to evaluate fully the efficacy of cyproheptadine, its use in the treatment of serotonin syndrome has been documented.
Mechanism
5-HT1A and 5-HT2 receptor antagonists (McDaniel, 2001).
Dose (Boyer and Shannon, 2005)
May consider an initial dose of 12mg followed by 2mg every 2 hours if symptoms continue
Maintenance dosage is 8mg every 6 hours
Cyproheptadine is the recommended therapy for the serotonin syndrome, although its efficacy has not been rigorously established.
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.
References
Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med. 1998;16(4):615-9.
McDaniel WW. Serotonin syndrome: early management with cyproheptadine.
Ann Pharmacother. 2001;35(7-8):870-3.
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med Mar 17;352(11):

50. Serotonin Syndrome Pharmacologic Treatment (continued) Chlorpromazine
Shown to be effective in some cases in the treatment of serotonin syndrome (Graham, 1997; Gillman, 1999)
Mechanism
Fairly potent 5-HT2 and 5-HT1A receptor antagonist
Advantages
It can be administered via an intramuscular injection.
Disadvantages
It can cause hypotension, dystonic reactions, and NMS.
Clinicians desiring a parenteral agent should consider the intramuscular administration of 50 to 100 mg of chlorpromazine.
Must be used cautiously given concern of hypotension and the often present concern of NMS in the differential diagnosis of patients presenting with symptoms suggestive of serotonin syndrome.
Reference
Graham PM. Successful treatment of the toxic serotonin syndrome with chlorpromazine. Med J Aust. 1997;166(3):166-7.

51. Serotonin Syndrome Pharmacologic Treatment (continued) Propranolol
It has been reported to be effective against serotonin syndrome in humans (Gillman, 1999),
Efficiency of propranolol remains unclear.
Mechanism
5-HT1A receptor antagonist
Propranolol, a 5-HT1a antagonist with a long duration of action, may cause exacerbate hypotension and lead to shock in patients with autonomic instability.
Furthermore, propranolol can blunt the tachycardia that can be used to determine the duration and effectiveness of therapy.
Reference
Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol. 1999;13(1):100-9.

52. Neuroleptic Malignant Syndrome
NMS versus 5HT Syndrome
Neuroleptic Malignant Syndrome
Serotonin Syndrome
Precipitated by
Dopamine antagonists
Serotoninergic agents
Onset
Variable (1-3 days)
Variable (<1d)
Vital Signs
Hypertension, tachycardia, tachypnea
Temperature
Hyperthermia
Mucosa
Sialorrhea
Skin
Diaphoresis
Mental Status
Delirium
Muscles
“Lead pipe” rigidity
Increased tone
Reflexes
Hyporeflexia
Hyperreflexia, clonus
Pupils
Normal
Dilated
References
Birmes P, Coppin D, Schmitt L, et al. Serotonin syndrome: a brief review. CMAJ. 2003;168(11):
Adapted from Birmes et al, CMAJ 2003

53. Selected References
Stephan C. Mann, M.D., Stanley N. Caroff, M.D., Paul E. Keck, Jr., M.D., and Arthur Lazarus, M.D., M.B.A. Neuroleptic Malignant Syndrome and Related Conditions, Second Edition, AAPI, 2003
Neuroleptic malignant syndrome. Strawn JR, Keck PE Jr, Caroff SN. Am J Psychiatry Jun;164(6):870-6.
Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med Mar 17;352(11):
Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: a brief review. CMAJ May 27;168(11):
Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81(9):