Neuroleptic Malignant Syndrome and Serotonin Syndrome Overview
This educational material provides an in-depth understanding of Neuroleptic Malignant Syndrome (NMS) and Serotonin Syndrome (SS) including their background, pathophysiology, clinical characteristics, differential diagnosis, risk factors, and treatment approaches. It also explores the historical background, incidence, and overlap between NMS and SS for comprehensive knowledge on these serious psychiatric conditions.
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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 ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY Psychiatrists Providing Collaborative Care Bridging Physical and Mental Health
Outline Neuroleptic Malignant Syndrome (NMS) Background Pathophysiology Phenomenology Risk Factors Treatment Serotonin Syndrome (SSS) Background Pathophysiology Phenomenology Risk Factors Treatment Academy of Consultation-Liaison Psychiatry 2
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 Academy of Consultation-Liaison Psychiatry 3
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. Academy of Consultation-Liaison Psychiatry 4
NMS - Incidence Typical antipsychotics Best estimate 0.02-0.03% (Pileggi & Cook, 2016) Wide variance in estimates 0.01-3.0% Atypical antipsychotics It remains unclear whether atypical antipsychotics are less likely to cause NMS compared to typical antipsychotics (Troller, 2009) Academy of Consultation-Liaison Psychiatry 5
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 Academy of Consultation-Liaison Psychiatry 6
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 Academy of Consultation-Liaison Psychiatry 7
NMS - Clinical Characteristics Develops quickly over hours to days Early signs Change in mental status Catatonia Extrapyramidal symptoms unresponsive to antiparkinsonian agents Autonomic dysfunction Academy of Consultation-Liaison Psychiatry 8
NMS - Clinical Characteristics Signs and Symptoms Hyperthermia 98% Muscle rigidity - lead pipe rigidity 97% Delirium and/or catatonia 97% Academy of Consultation-Liaison Psychiatry 9
NMS - Clinical Characteristics Signs and symptoms (continued) Autonomic dysfunction Tachycardia 88% Profuse diaphoresis Labile blood pressure 61% Tachycardia or labile blood pressure 95% Academy of Consultation-Liaison Psychiatry 10
NMS - Clinical Characteristics Laboratory findings Rhabdomyolysis ( CPK) Leukocytosis Low serum iron Metabolic acidosis Electroencephalogram often consistent with delirium Neuroimaging typically normal Academy of Consultation-Liaison Psychiatry 11
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 Academy of Consultation-Liaison Psychiatry 12
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 Academy of Consultation-Liaison Psychiatry 13
NMS - Past 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. Academy of Consultation-Liaison Psychiatry 14
NMS - Past Diagnostic Criteria 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 Academy of Consultation-Liaison Psychiatry 15
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 Academy of Consultation-Liaison Psychiatry 16
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] Academy of Consultation-Liaison Psychiatry 17
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 Academy of Consultation-Liaison Psychiatry 18
NMS - Risk Factors Physiological states 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 Academy of Consultation-Liaison Psychiatry 19
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 40-6000 chlorpromazine equivalents/day Average of 500-700mg chlorpromazine/day ? Intramuscular route Unclear if IM injections convey extra risk or simply contribute to elevated CK Academy of Consultation-Liaison Psychiatry 20
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 Academy of Consultation-Liaison Psychiatry 21
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) Academy of Consultation-Liaison Psychiatry 22
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 Academy of Consultation-Liaison Psychiatry 23
NMS - Clinical Course Onset 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 Academy of Consultation-Liaison Psychiatry 24
NMS - Outcomes Mortality Mortality is decreasing 25% before 1984 12% 1984-2015 6% as of 2015 Risks for increased mortality Older age Higher temperatures Depot neuroleptics (?) Pre-existing brain pathology Development of renal failure Academy of Consultation-Liaison Psychiatry 25
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 Academy of Consultation-Liaison Psychiatry 26
Treatment of NMS Basics Early recognition Cessation of neuroleptics Re-introduction of dopamine agonists if removed Hydration Temperature reduction Intensive monitoring Supportive care Academy of Consultation-Liaison Psychiatry 27
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 Academy of Consultation-Liaison Psychiatry 28
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 Academy of Consultation-Liaison Psychiatry 29
Treatment of NMS Dopaminergic medications Amantadine 63% found benefit as monotherapy 200-400 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 Academy of Consultation-Liaison Psychiatry 30
Treatment of NMS ECT Definitive treatment May increase dopamine synthesis and release ECT considered if Unresponsive to pharmacologic treatment in first 24-48 hours Prominent features of catatonia or severe rigidity Psychosis develops following NMS Mean time to response is 1.46 2.38 days Academy of Consultation-Liaison Psychiatry 31
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 Academy of Consultation-Liaison Psychiatry 32
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 Academy of Consultation-Liaison Psychiatry 33
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 Academy of Consultation-Liaison Psychiatry 34
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 Academy of Consultation-Liaison Psychiatry 35
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 Academy of Consultation-Liaison Psychiatry 36
SS - Clinical Characteristics Clinical triad 1. Cognitive/behavioral alterations Delirium Catatonia Agitation Lethargy Coma Autonomic instability Hyperthermia Tachycardia Diaphoresis Dilated pupils Neuromuscular abnormalities Myoclonus Hyperreflexia Rigidity 2. 3. Academy of Consultation-Liaison Psychiatry 37
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 Academy of Consultation-Liaison Psychiatry 38
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. Academy of Consultation-Liaison Psychiatry 39
SS Diagnostic Criteria 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. Academy of Consultation-Liaison Psychiatry 40
SS Diagnostic Criteria 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 Yes Inducible ocular clonus and increased muscle tone and temperature >38oC are present Serotonin toxicity 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 Academy of Consultation-Liaison Psychiatry 41
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 Academy of Consultation-Liaison Psychiatry 42
SS Risk Factors Risk factors Administration of 2 or more serotonergic medications Overdose Use of lithium? Rarely with monotherapy Pharmacodynamic interactions Pharmacokinetic interactions Academy of Consultation-Liaison Psychiatry 43
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 Academy of Consultation-Liaison Psychiatry 44
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 Academy of Consultation-Liaison Psychiatry 45
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 Academy of Consultation-Liaison Psychiatry 46
SS Clinical Course and Outcomes Clinical course and outcome 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 Academy of Consultation-Liaison Psychiatry 47
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 Academy of Consultation-Liaison Psychiatry 48
Treatment of SS Benzodiazepines May blunt the hyperadrenergic component of the syndrome Help with catatonic features Act as muscle relaxants Help with agitation Academy of Consultation-Liaison Psychiatry 49
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 Academy of Consultation-Liaison Psychiatry 50
