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Neuroleptic Malignant Syndrome and Serotonin Syndrome

Neuroleptic Malignant Syndrome and Serotonin Syndrome. APM Resident Education Curriculum.

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Neuroleptic Malignant Syndrome and Serotonin Syndrome

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  1. 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

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

  3. 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

  4. 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.

  5. 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)

  6. 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

  7. 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

  8. NMS - Clinical Characteristics • Develops quickly over hours to days • Early signs • Change in mental status • Catatonia • Extrapyramidal symptoms unresponsive to antiparkinsonian agents • Autonomic dysfunction

  9. NMS - Clinical Characteristics • Signs and Symptoms • Hyperthermia • 98% • Muscle rigidity - “lead pipe rigidity” • 97% • Delirium and/or catatonia • 97%

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

  11. NMS - Clinical Characteristics • Laboratory findings • Rhabdomyolysis (↑ CPK) • Leukocytosis • Low serum iron • Metabolic acidosis • Electroencephalogram often consistent with delirium • Neuroimaging typically normal

  12. “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

  13. 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

  14. 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.

  15. 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

  16. 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

  17. 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]

  18. 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

  19. 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

  20. 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

  21. 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”

  22. 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)

  23. 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

  24. 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

  25. 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

  26. 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

  27. Treatment of NMS • Basics • Early recognition • Cessation of neuroleptics • Re-introduction of dopamine agonists if removed • Hydration • Temperature reduction • Intensive monitoring • Supportive care

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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.

  40. 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.

  41. 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 Serotonin toxicity Inducible or ocular clonus with agitation or diaphoresis are present No Yes Serotonin toxicity Inducible ocular clonus and increased muscle tone and temperature >38oC are present 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

  42. 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

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

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

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

  50. 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

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