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Neuroleptic Malignant Syndrome and Serotonin Syndrome

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

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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 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.

  3. Incidence • Typical antipsychotics • Best estimate 0.1-0.2% (Caroff and Mann, 1996) • Wide variance in estimates 0.1-3.0% • Atypical antipsychotics • It remains unclear whether atypical antipsychotics are less likely to cause NMS compared to typical antipsychotics (Troller, et al., 2009)

  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 • Acase 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

  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

  6. Clinical Characteristics • Early signs • Change in mental status • Extrapyramidal symptoms unresponsive to antiparkinsonian agents • Autonomic dysfunction

  7. Clinical Characteristics • Signs and Symptoms • Hyperthermia • 98% • Muscle rigidity - “lead pipe rigidity” • 97% • Mental status changes - delirium and catatonia • 97%

  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

  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

  11. Diagnostic CriteriaCaroff’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 CriteriaDSM - 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 CriteriaLevenson’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 • Age • Sex • Environmental factors • Risk factors • Heredity • Neuropsychiatric diagnosis • NMS is not specific to any specific neuropsychiatric diagnosis, but…… • Catatonia • Organic brain disorders

  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

  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 40-6000 chlorpromazine equivalents/day • Average of 500-700mg chlorpromazine/day

  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

  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

  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

  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

  21. 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

  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

  23. Outcomes • Morbidity • Renal insufficiency/failure • 16-25% • Respiratory failure • Cardiac morbidity • Cognitive sequelae (?)

  24. Treatment • Basics • Early recognition • Cessation of neuroleptics • Hydration • Temperature reduction • Intensive monitoring • Supportive care

  25. Treatments • Specific treatments • Benzodiazepines • 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

  26. Treatments • Specific treatments (continued) • Dopaminergic medications • Theory • 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

  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 1.46 +/- 2.38 days

  28. Rough Treatment Guidelines Strawn JR, Keck PE Jr, Caroff SN. Am J Psychiatry. 2007 Jun;164(6):870-6. • Mild or early NMS • Supportive care and benzodiazepines • Moderate NMS (rigidity and temperatures 38-40) • Dopamine agonist • Severe NMS (rigidity, hypermetabolism, temperatures >40) • Dantrolene

  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

  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

  32. Serotonin Syndrome • Incidence • Unknown • The variable nature of its presentation makes it difficult to diagnose and has caused underreporting

  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

  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

  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

  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

  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): 705-713.

  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.

  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 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 Adapted from Ables AZ, Nagubilli R.. Am Fam Physician. 2010

  40. Serotonin Syndrome • Risk factors • 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

  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.

  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

  46. Serotonin Syndrome • Non-Pharmacologic Treatment • Discontinuation of the causative drugs • Supportive therapy • Hydration • Cooling

  47. Serotonin Syndrome • Pharmacologic Treatment • Several drugs have been used to treat serotonin syndrome. • Cyproheptadine • Propranolol • Chlorpromazine

  48. Serotonin Syndrome • Pharmacologic Treatment • Benzodiazepines • Control of agitation • May blunt the hyperadrenergic component of the 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

  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.

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