Neuroleptic Malignant Syndrome and Serotonin Syndrome

Neuroleptic Malignant Syndrome and Serotonin Syndrome
APM Resident Education Curriculum Updated 2019: Scott R. Beach, MD, FACLP, Program Director, MGH/McLean Adult Psychiatry Residency, Assistant Professor of Psychiatry, Harvard Medical School, Department of Psychiatry, Massachusetts General Hospital Original version 2011: Thomas W. Heinrich, MD, Associate Professor of Psychiatry & Family Medicine, Chief, Psychiatric Consult Service at Froedtert Hospital, Department of Psychiatry & Behavioral Medicine, Medical College of Wisconsin Posted 3/15/2019

Outline Neuroleptic Malignant Syndrome (NMS) Serotonin Syndrome (SSS)
Background Pathophysiology Phenomenology Risk Factors Treatment Serotonin Syndrome (SSS)

Learning Objectives At the end of the talk, learners will:
1. Understand the approach to the patient with potential neuroleptic malignant syndrome (NMS), including clinical characteristics, differential diagnosis, and treatment approaches 2. Understand the approach to the patient with potential serotonin syndrome (SS), including clinical characteristics, differential diagnosis, and treatment approaches 3. Recognize the overlap between NMS and SS, as well as their overlap with the clinical syndrome of catatonia

NMS - Historical Background
Syndrome “malin des neuroleptiques” Rapidly progressive neurovegatative state Observed during early clinical trials of haloperidol in 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.

NMS - Incidence Typical antipsychotics Atypical antipsychotics
Best estimate % (Pileggi & Cook, 2016) Wide variance in estimates % Atypical antipsychotics It remains unclear whether atypical antipsychotics are less likely to cause NMS compared to typical antipsychotics (Troller, 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 Neuroleptic Malignant Syndrome. Pileggi DJ, Cook AM. Ann Pharmacother Nov;50(11): 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.

NMS - Pathophysiology 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.

NMS - Pathophysiology Central dopamine hypoactivity Theory (continued) (Strawn et al, 2007, Fricchione 1985) Patients susceptible to developing NMS may have a baseline central hypodopaminergia Trait vulnerability Evidence to support this includes the observation that patients with basal ganglia disorders are at greater risk for NMS 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.

NMS - Clinical Characteristics
Develops quickly over hours to days Early signs Change in mental status Catatonia Extrapyramidal symptoms unresponsive to antiparkinsonian agents Autonomic dysfunction Changes in mental status Obtundation Catatonia Extrapyramidal symptoms Dysarthria Dysphagia 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):

Signs and Symptoms Hyperthermia 98% Muscle rigidity - “lead pipe rigidity” 97% Delirium and/or 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

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

Laboratory findings Rhabdomyolysis (↑ CPK) Leukocytosis Low serum iron Metabolic acidosis Electroencephalogram often consistent with delirium Neuroimaging typically normal 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 Iron deficiency associated with catatonia and specifically with malignant catatonia 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

“Atypical NMS” 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 Many cases of so-called “atypical NMS” may represent non-malignant catatonia induced by antipsychotics Mortality of atypical NMS is 5.5% - nearly identical to that of NMS Troller JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs 2009; 23(6): Murri M, et al. Second-generation antipsychotics and neuroleptic malignant syndrome: systematic review and case report analysis. Drugs R D 2015; 15(1):

NMS - Past Diagnostic Criteria
Caroff’s Criteria 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

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.

Adityanjee’s Research Criteria 1. Altered sensorium 2. EPS (rigidity, dysphagia or dystonia) 3. Hyperpyrexia (>101.3 degrees for at least 48 hours) 4. Autonomic dysfunction (at least 2) Tachycardia Tachypnea BP fluctuations Diaphoresis New onset incontinence 5. Supportive features Elevated CPK Leukocytosis Low serum iron Elevated LFT’s Myoglobinuria Definite diagnosis: 1-4 present Possible diagnosis: 1, 3, 4 and any feature of 5 present

NMS - Debate about Diagnostic Criteria
DSM-5 does not list diagnostic criteria (descriptive text) Previous diagnostic criteria either had significant overlap with other syndromes or were too specific Levenson and Adityanjee allowed for diagnosis in the absence of rigidity Delirium emphasized in Adityanjee but not others Debate about whether fever or autonomic dysfunction are core criteria

NMS - Current Diagnostic Criteria
International Consensus Study Each criterion is assigned a priority score for a total of 100 (cutoff is [74] for NMS) Exposure to dopamine antagonist or dopamine agonist withdrawal in past 72 hours [20 points] Hyperthermia (>100.4 on at least 2 occasions, measured orally) [18] Rigidity [17] Mental status alteration [13] Elevated creatine phosphokinase (at least 4x upper limit of normal) [10] Sympathetic nervous system lability, defined as the presence of two or more of these features [10]: Elevated blood pressure (systolic or diastolic at least 25% above baseline) Blood pressure fluctuation (Change of 20mmHg diastolic or 25mmHg systolic in 24 hours) Diaphoresis Urinary incontinence. Tachycardia (at least 25% above baseline) and tachypnea (at least 50% above baseline) [5] Negative workup for infectious, toxic, metabolic and neurologic causes [7] Gurrera RJ, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry 2011; 72(9):

NMS - Risk Factors Heredity
Organic brain disease, particularly basal ganglia disorders Substance use disorders, particularly GABA-ergic drug withdrawal Low serum iron No great evidence to support the lore that young men are more predisposed to NMS Previously speculated to be related to muscle mass Actual average age of patients with NMS is 40 Not risk factors Age It has been reported in all age groups following administration of antipsychotics. 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 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. Environmental factors NMS occurs independent of climate and ambient temperatures. High ambient temperatures and humidity may augment the risk of NMS;

NMS - Risk Factors Physiological states Historical variables Agitation
Dehydration Historical variables History of NMS 30-33% of NMS patients when rechallenged 17% of NMS patients report similar past episodes History or current episode of catatonia Physiological States Agitation Dehydration Exhaustion Decreased serum iron levels 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) Catatonia Patients with idiopathic or antipsychotic catatonia may be at risk of for developing NMS when treatment with antipsychotics is initiated or continued. 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

NMS - 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 ? Intramuscular route Unclear if IM injections convey extra risk or simply contribute to elevated CK 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):

NMS - 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 Abrupt cessation of dopamine agonist Anti-parkinson’s medications Bupropion Abrupt cessation of antipsychotic “Withdrawal NMS” 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.

Differential Diagnosis of NMS
Most common disorders mistaken for NMS Malignant or non-malignant catatonia Delirious mania (aka Bell’s mania, manic delirium) Agitated delirium Serotonin Syndrome Malignant hyperthermia “Benign” extrapyramidal side effects (EPS) Infections Seizures Thyrotoxicosis Pheochromocytoma Heatstroke (Exertional or classic) 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. 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 is to malignant catatonia what neuroleptic induced catatonia is to simple catatonia. 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

NMS vs Catatonia Clinical features (stupor, rigidity, autonomic dysfunction, etc) overlap significantly with catatonia Many would consider NMS to be a subtype of malignant stuporous catatonia Not all catatonia resulting from the use of antipsychotic agents has malignant features or represents NMS

NMS - 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.

NMS - Outcomes Mortality Mortality is decreasing
25% before 1984 12% 6% as of 2015 Risks for increased mortality Older age Higher temperatures Depot neuroleptics (?) Pre-existing brain pathology Development of renal failure 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. Modi S, Dharaiya D, Schultz L, Varelas P: Neuroleptic malignant syndrome: Complications, outcomes, and mortality. Neurocrit Care:1-7, 2015

NMS - Outcomes Morbidity Renal insufficiency/failure
16-25% Respiratory failure Cardiac morbidity Some have suggested patients may experience cognitive sequelae, though long-term cognitive effects seem rare and may be the result of hypoxic injury in specific cases 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

Treatment of NMS Basics Early recognition Cessation of neuroleptics
Re-introduction of dopamine agonists if removed 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. Hydration Prevent hypovolemia, hypotension, shock, and renal failure. Correct electrolyte imbalance. Temperature reduction Higher temperatures are predictive of increased morbidity and mortality.

Treatment of NMS Benzodiazepines
NMS is thought to represent an iatrogenic malignant catatonia Benzodiazepines reduce rigidity and treat catatonia Intravenous lorazepam is preferred Easily administered Rapid onset of action Longer effective length of action Preference for GABA-B receptor High doses (18-24mg daily) often required and tolerated If IV route is not an option, IM>sublingual>PO Benzodiazepines Use of benzodiazepines may be effective in mild cases of NMS Theory 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 2 mg IV may be warranted in mild cases with close monitoring of the patient’s respiratory status.

Treatment of NMS Dantrolene Muscle relaxant
81% of patients benefit in some studies 1-10mg/kg/day in divided doses Optimal length of treatment not established May cause hepatic and respiratory compromise Dantrolene Theory 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 Dosage 1mg-10mg/kg/day in divided doses 1mg/kg every 6 hours for 48 hours for MH Duration of treatment is unclear

Treatment of NMS Dopaminergic medications Amantadine Bromocriptine
63% found benefit as monotherapy mg/day Bromocriptine 94% found benefit as monotherapy Shortened time to clinical response 2,5mg tid - 15mg tid Levodopa All dopaminergic medications carry risk of worsening underlying psychosis 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.

Treatment of NMS ECT Definitive treatment
May increase dopamine synthesis and release ECT considered if… Unresponsive to pharmacologic treatment in first hours Prominent features of catatonia or severe rigidity 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 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

Treatment Guidelines for NMS
Mild or early NMS Supportive care and benzodiazepines Moderate NMS (rigidity and temperatures 38-40) High-dose benzodiazepines; consider dopamine agonist Severe NMS (rigidity, hypermetabolism, temperatures >40°) High-dose benzodiazepines Early consideration of ECT 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) High-dose benzodiazepines Move to ECT more quickly Consider dantrolene

Antipsychotic Rechallenge following NMS
Recurrence rate may be as high as 30-50% Inversely related to time to rechallenge Guidelines for rechallenge Reduce potential risk factors Two weeks from resolution of NMS Gradual titration of low starting doses Use lower potency or atypical antipsychotics Ideally rechallenge should occur in a hospital Successful cases of clozapine rechallenge following clozapine-induced NMS, but some cases recur 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):

Serotonin Syndrome (SS)
Serotonin syndrome can be a serious complication of treatment with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and other serotonergic medications It usually occurs when 2 or more serotonin-modifying agents are used in combination or in overdose settings Cases have been reported after single agent therapy Incidence unknown Significantly underdiagnosed because of variable symptomatology

SS - History The syndrome was first described in the 1950s
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):

SS - 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.

SS - Clinical Characteristics
Clinical triad Cognitive/behavioral alterations Delirium Catatonia Agitation Lethargy  Coma Autonomic instability Hyperthermia Tachycardia Diaphoresis Dilated pupils Neuromuscular abnormalities Myoclonus Hyperreflexia Rigidity Prevalence of catatonia leads some to consider it a subtype of malignant catatonia with a specific etiology 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.

SS - Clinical Characteristics
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):

SS – Diagnostic Criteria
Sternbach’s Criteria 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. Reference Sternbach H. The serotonin syndrome. Am J Psychiatry Jun;148(6):705-13

Revised Criteria 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):

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 Inducible clonus = Involuntary muscular contraction and relaxation in rapid succession with rapid dorsiflexion of the ankle Ocular clonus = Slow continuous lateral eye movements

SS - Criticisms of Criteria
Criticisms of Sternbach’s Criteria Not specific to serotonin syndrome 5 of 10 symptoms are also included in the diagnostic criteria for SSRI discontinuation syndrome 8 of 10 symptoms can occur with catecholamine excess High overlap with anticholinergic toxodrome as well as alcohol and substance withdrawal states Criticisms of Hunter’s criteria Only capture moderate to severe case Many mild cases of serotonin syndrome would not meet criteria

SS – Risk Factors Risk factors
Administration of 2 or more serotonergic medications Overdose Use of lithium? Rarely with monotherapy Pharmacodynamic interactions Pharmacokinetic interactions

SS – Risk Factors 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

SS – Risk Factors The most common drug combinations causing the serotonin syndrome Classically MAOI and SSRI or other serotonergic agent Now much more commonly 3-6 serotonergic agents E.g. SSRI + trazodone + tramadol + buspar Overdose on SSRI, SNRI, atypical antipsychotic or combination

SS – Differential Diagnosis
Most common disorders mistaken for Serotonin Syndrome SSRI discontinuation syndrome Catecholamine excess Anticholinergic toxodrome Alcohol and substance withdrawal states Infections Toxic-metabolic delirium Extrapyramidal side-effects NMS Pheochromocytoma Carcinoid tumor

SS – Clinical Course and Outcomes
Rapid onset Usually self-limited, with an uneventful resolution, once the offending agent has been discontinued No data for rechallenge Clues to Serotonin Syndrome Look for it in every case of overdose Look for it in any patient on >4 psychiatric medications Consider it in all catatonic patients Keep an eye out for the twitchy patient 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.

Treatment of SS No standardized treatment of serotonin syndrome exists. Management starts with early recognition of the syndrome, and supportive care The basic treatment of serotonin syndrome consists of Discontinuation of the causative drugs Supportive therapy Hydration Cooling Medications Several drugs have been used to treat serotonin syndrome Benzodiazepines Cyproheptadine 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. 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.

Treatment of SS Benzodiazepines
May blunt the hyperadrenergic component of the syndrome Help with catatonic features Act as muscle relaxants Help with agitation

Treatment of SS Cyproheptadine
First-generation antihistamine with serotonin antagonist properties Shown in animal studies to prevent the onset of experimentally induced serotonin syndrome No randomized control trials; use documented in case reports and series Often not necessary 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):

Treatment of SS Chlorpromazine
Shown to be effective in some cases in the treatment of serotonin syndrome 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 increase risk for 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.

Neuroleptic Malignant Syndrome
NMS vs. SS 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

Selected References Ables AZ, Nagubilli R. Prevention, recognition, and management of serotonin syndrome. Am Fam Physician. 2010;81(9): Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: a brief review. CMAJ May 27;168(11): Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med Mar 17;352(11): Gurrera RJ, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using the Delphi method. J Clin Psychiatry 2011; 72(9): Modi S, et al. Neuroleptic Malignant Syndrome: Complications, Outcomes, and Mortality. Neurocrit Care 2015. Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry Jun;164(6):870-6. Trollor JN, et al. Neuroleptic malignant syndrome associated with atypical antipsychotic drugs. CNS Drugs 2009; 23 (6):

Neuroleptic Malignant Syndrome and Serotonin Syndrome

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Neuroleptic Malignant Syndrome and Serotonin Syndrome

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