sign in sign up
<<
Home , Clonus, Dolasetron, Myoclonus, Palonosetron, Safinamide, Serotonin syndrome

Med/Psych Update SYNDROME OR NMS?

Differentiating and neuroleptic malignant syndrome

Symptoms can overlap, but accurate diagnosis is critical because treatments are distinct

erotonin syndrome (SS) and neuroleptic malignant syn- drome (NMS) are each rare psychiatric emergencies Sthat can lead to fatal outcomes. Their clinical presenta- tions can overlap, which can make it difficult to differentiate between the 2 syndromes; however, their treatments are dis- tinct, and it is imperative to know how to identify symptoms and accurately diagnose each of them to provide appropriate intervention. This article summarizes the 2 syndromes and their treatments, with a focus on how clinicians can distinguish them, provide prompt intervention, and prevent occurrence.

Serotonin syndrome Mechanism. The decarboxylation and hydroxylation of tryp- IKON IMAGES tophan forms serotonin, also known as 5-hydroxytryptamine Andia H. Turner, MD Charles T. Nguyen, MD PGY-3 Resident Clinical Professor (5-HT), which can then be metabolized by monoamine Department of Psychiatry Department of Psychiatry oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid (5-HIAA).1 University of California Irvine University of California Irvine Irvine, California Irvine, California can disrupt this pathway of serotonin production Chief, MHICM Program or its , and result in excessive levels of serotonin, Jessica J. Kim, MD Department of Mental Health PGY-3 Psychiatry Resident Veterans Affairs Long Beach which subsequently leads to an overactivation of central and Department of Psychiatry Long Beach, California 1 University of California Irvine peripheral serotonin receptors. Increased receptor activation Irvine, California leads to further upregulation, and ultimately more serotonin Robert M. McCarron, DO transmission. This can be caused by monotherapy or use of Professor and Vice Chair of multiple agents, polypharmacy with a combina- Education and Integrated Care Residency Program Director tion of classes, drug interactions, or overdose. The Co-Director, Train New Trainers wide variety of medications often prescribed by different clini- Primary Care Psychiatry Fellowship Department of Psychiatry cians can make identification of excessive serotonergic activity University of California Irvine difficult, especially because mood stabilizers such as ,2 Irvine, California Section Editor, Consultation-Liaison and non-psychiatric medications such as and Psychiatry, Current Psychiatry Disclosures Current Psychiatry The authors report no financial relationships with any companies whose products are mentioned 30 February 2019 in this article, or with manufacturers of competing products. Table 1 Medications that can cause serotonin syndrome

Action Medications MDedge.com/psychiatry Increases serotonin formation Increases release of serotonin and derivatives MDMA Impairs serotonin reuptake Cocaine, MDMA, meperidine, , SSRIs (, , , , , ) SNRIs (, , , , ) - reuptake inhibitors () Serotonin modulators (, , , ) TCAs (, , , , ) Clinical Point St. John’s wort 5-HT3 antagonists (, , , Serotonergic agents ) can cause SS, , , , , whereas dopamine , Inhibits serotonin metabolism MAOIs (, , , , blockers cause NMS , , , , tedizolid, , ) Direct serotonin , , ergot derivatives, , LSD Increases sensitivity of Lithium postsynaptic receptor LSD: lysergic acid diethylamide; MAOIs: inhibitors; MDMA: 3,4-methylenedioxymethamphetamine; SNRIs: serotonin-norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic Source: Reference 3

Table 2 fluconazole, can also contribute. Table 13 lists Sternbach’s diagnostic criteria medications that can cause SS. The pathways for serotonin syndrome that increase serotonin transmission, poten- A. Coincident with the addition of or increase in tially causing SS, include: a known serotonergic agent to an established • inhibition of serotonin uptake (seen medication regimen, at least 3 of the following clinical features are present: with selective serotonin reuptake inhibitors • mental status changes (, [SSRIs], serotonin-norepinephrine reuptake ) inhibitors [SNRIs], and tricyclic antidepres- • agitation sants [TCAs]) • • inhibition of serotonin metabolism • (seen with monoamine oxidase inhibitors • diaphoresis [MAOIs]) • • increased serotonin synthesis (seen • • with ) Discuss this article at • incoordination • increased serotonin release (seen with www.facebook.com/ • MDedgePsychiatry stimulants and ) B. Other etiologies (eg, infectious, metabolic, • activation of serotonin receptors (seen substance abuse, or withdrawal) with lithium) C. A neuroleptic had not been started or • inhibition of certain increased in dosage prior to the onset of the listed above (CYP450) enzymes (seen with ciprofloxa- Source: Reference 5 Current Psychiatry cin, fluconazole, etc.). Vol. 18, No. 2 31 continued Figure Hunter serotonin criteria

Yes Spontaneous Serotonin toxicity

No Serotonin Yes syndrome or NMS? Inducible clonus with Serotonin toxicity agitation or diaphoresis

No Yes Ocular clonus with Serotonin toxicity agitation or diaphoresis

Clinical Point No Symptoms of SS Yes Tremor and hyperreflexia Serotonin toxicity present within 24 hours of starting or No changing therapy Yes Hypertonia, temperature above 100.4°F Serotonin toxicity (38°C), and ocular or inducible clonus

No

No serotonin toxicity

Source: Reference 6

It is important to recognize that various (altered mental status [AMS]), autonomic serotonergic agents are involved in the instability, and abnormalities of neuro- CYP450 system. Inhibition of the CYP450 muscular tone. Examples of AMS include pathway by common antibiotics such as agitation, , disorientation, and rest- ciprofloxacin, or antifungals such as fluco- lessness. Symptoms of autonomic instability nazole, may result in an accumulation of include , , tachy- serotonergic agents and place patients at pnea, , diaphoresis, flushed increased risk for developing SS. skin, , diarrhea, and arrhythmias. Symptoms stemming from changes in Clinical presentation. The clinical presen- neuromuscular­ tone include , clo- tation of SS can range from mild to fatal. nus, hyperreflexia, and muscle rigidity.1 The There is no specific laboratory test for diag- multiple possible clinical presentations, as nosis, although an elevation of the total well as symptoms that overlap with those creatine kinase (CK) and leukocyte count, of other syndromes, can make SS difficult to as well as increased transaminase levels recognize quickly in a clinical setting. or lower bicarbonate levels, have been reported in the literature.4 Diagnostic criteria. Sternbach’s diagnostic Symptoms of SS generally present within criteria for SS are defined as the presence of 24 hours of starting/changing therapy and 3 or more of the 10 most common clinical Current Psychiatry 32 February 2019 include a triad of mental status changes features (Table 2,5 page 31). Due to concerns Table 3 Medications that can cause neuroleptic malignant syndrome

Class Medications MDedge.com/psychiatry Neuroleptic agents , , , , , , , , , , , , , agents , , metoclopramide, , Source: Reference 1

Table 4 Differentiating neuroleptic malignant syndrome and serotonin syndrome Factor Serotonin syndrome Neuroleptic malignant syndrome Causative medications Serotonergic agents Dopamine antagonists Physical exam findings Hyperreflexia, myoclonus, ocular Severe rigidity (lead pipe), hyporeflexia clonus Laboratory findings More commonly no lab findings More commonly increased creatine Clinical Point kinase, leukocytosis, low serum iron SS treatment ranges Course of illness Symptoms seen within 24 hours Slower in onset (1 to 2 weeks after of starting/changing therapy and starting/changing therapy) and from supportive resolves within a few days of resolves within 9 to 14 days of care to use of a treatment treatment Source: Reference 17 serotonergic antagonist, neuromuscular sedation, and that Sternbach’s diagnostic criteria overem- Management pitfalls include misdiag- intubation phasized an abnormal mental state (leading nosis of SS, failure to recognize its rapid to possible confusion of SS with other AMS rate of progression, and adverse effects of syndromes), the Hunter serotonin toxicity pharmacologic therapy.3 The most effective criteria6 (Figure,6 page 32) were developed in treatment for SS is prevention. SS can be 2003, and were found to be more sensitive prevented by astute pharmacologic under- and specific than Sternbach’s criteria. Both standing, avoidance of polypharmacy, and tools are often used in clinical practice. physician education.3

Treatment. Treatment of SS begins with prompt discontinuation of all sero­tonergic Neuroleptic malignant syndrome agents. The intensity of treatment depends Possible mechanisms. Neuromuscular on the severity of the symptoms. Mild malignant syndrome is thought to result symptoms can be managed with sup- from antagonism lead- portive care,3 and in such cases, the syn- ing to a hypodopaminergic state in the drome generally resolves within 24 hours.7 striatum and .8 The patho- Clinicians may use supportive care to nor- physiology behind NMS has not fully been malize vital signs (oxygenation to maintain elucidated; however, several hypotheses SpO2 >94%, IV fluids for volume depletion, attempt to explain this life-threatening reac- cooling agents, antihypertensives, benzodi- tion. The first focuses on dopamine D2 azepines for sedation or control of agitation, receptor antagonism, because many of the etc.). Patients who are more ill may require neuroleptic () medications more aggressive treatment, such as the use that can precipitate NMS are involved in of a serotonergic antagonist (ie, cyprohep- dopamine blockade. In this theory, blocking tadine) and those who are severely hyper- dopamine D2 receptors in the anterior hypo- thermic (temperature >41.1ºC) may require thalamus explains the hyperthermia seen in neuromuscular sedation, paralysis, and NMS, while blockade in the corpus striatum Current Psychiatry possibly endotracheal intubation.3 is believed to lead to muscle rigidity.9 Vol. 18, No. 2 33 continued Table 5 Treatment for neuroleptic malignant syndrome vs serotonin syndrome Serotonin syndrome Neuroleptic malignant syndrome Stop serotonergic agent Stop causative agents Supportive care Supportive care (possible ICU admission) Serotonin (aim to normalize vital signs) syndrome or NMS? Sedation with Medical therapy (dantrolene, , ) Medical therapy () Consider ECT (unclear efficacy) ECT: electroconvulsive therapy Source: Reference 17

The second hypothesis suggests that “lead pipe rigidity” and may be accom- neuroleptics may have a direct toxic effect panied by tremor, , or dyskine- Clinical Point to muscle cells. Neuroleptics influence sias. Laboratory findings include elevated NMS can occur after calcium transport across the sarcoplasmic serum CK (from severe rigidity), often reticulum and can lead to increased cal- >1,000 U/L, although normal levels can be a single dose, after cium release, which may contribute to the observed if rigidity has not yet developed.13 a dose adjustment, muscle rigidity and hyperthermia seen or after years of in NMS.9 Treatment. The first step for treatment is treatment with the The third hypothesis involves hyperac- to discontinue the causative medication.14 tivity of the sympathetic ; it Initiate supportive therapy immediately same medication is thought that psychologic stressors alter to restrict the progression of symptoms. frontal lobe function, with neuroleptics dis- Interventions include cooling blankets, fluid rupting the inhibitory pathways of the sym- resuscitation, and antihypertensives to main- pathetic nervous system. The autonomic tain autonomic stability15 or benzodiazepines nervous system innervates multiple organ to control agitation. In severe cases, muscu- systems, so this excessively dysregulated lar rigidity may extend to the airways and sympathetic nervous system may be respon- intubation may be required. The severity of sible for multiple NMS symptoms (hyper- these symptoms may warrant admission to thermia, muscle rigidity, hypertension, the ICU for close monitoring. Pharmacologic diaphoresis, tachycardia, elevated CK.10 treatment with dantrolene (a muscle relaxant NMS can be caused by neuroleptic agents that blocks calcium efflux from the sarcoplas- (both first- and second-generation anti­ mic reticulum) and bromocriptine (a dopa- psychotics) as well as (Table 3,1 mine agonist) have been utilized.14 In case page 33). The time between use of these med- reports, electroconvulsive therapy (ECT) has ications and onset of symptoms is highly been used to treat NMS15,16; however, pro- variable. NMS can occur after a single dose, spective research comparing ECT with tra- after a dose adjustment, or possibly after ditional treatment has not been conducted. years of treatment with the same medication. It is also worth mentioning that if a clinician It is not dose-dependent.11 In certain individ- wishes to restart the neuroleptic medication, uals, NMS may occur at therapeutic doses. a 2-week washout period will minimize the risk of NMS recurrence.17 Clinical presentation. Patients with NMS typically present with a tetrad of symp- toms: mental status changes, muscular Differentiating between rigidity, hyperthermia, and autonomic SS and NMS instability.12 Mental status changes can Differentiating between these 2 syndromes include confusion and agitation, as well (Table 4,17 page 33) is critical to direct appro- as catatonic signs and mutism. The mus- priate intervention. Table 517 outlines the Current Psychiatry 34 February 2019 cular rigidity of NMS is characterized by treatment overview for SS and NMS. Detailed history. A detailed history is imperative in making accurate diagnoses. Related Resources Useful components of the history include • Kimmel R. Serotonin syndrome or NMS? Clues to diagnosis. Current Psychiatry. 2010;9(2):92. MDedge.com/psychiatry a patient’s duration of symptoms and • Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant medication history (prescription medica- syndrome: Answers to 6 tough questions. Current Psychiatry. tions as well as over-the-counter medica- 2008;7(1):95-101. tions, supplements, and illicit drugs). Also Drug Brand Names assess for medical comorbidities, because Amantadine • Symmetrel Linezolid • Zyvox Amitriptyline • Elavil, Endep Lithium • Eskalith, Lithobid certain medical diagnoses may alert the cli- Aripiprazole • Abilify Meperidone • Demerol nician that it is likely the patient had been Bromocriptine • Cycloset, Metoclopramide • Reglan Parlodel Milnacipran • Savella prescribed serotonergic agents or neuro- Bupropion • Wellbutrin, Nefazodone • Serzone leptics, and renal or impairment may Zyban Olanzapine • Zyprexa alert the clinician of decreased metabolism Buspirone • BuSpar Ondansetron • Zofran Carbamazepine • Carbatrol, Paliperidone • Invega rates. Medication history is arguably the Tegretol Palonosetron • Aloxi most useful piece of the interview, because Chlorpromazine • Thorazine Paroxetine • Paxil Ciprofloxacin • Cipro Pentazocine • Talwin, serotonergic agents can cause SS, whereas Citalopram • Celexa Talacen dopamine blockers cause NMS. It should Clomipramine • Anafranil Perphenazine • Trilafon Clinical Point Clozapine • Clozaril Phenelzine • Nardil be noted that excess serotonin acts as a true Cyclobenzaprine • Amrix, Procarbazine • Matulane Although both SS and is concentration-dependent Flexeril Prochlorperazine • Cyproheptadine • Periactin Compazine and NMS can result in in causing SS, whereas NMS is an idiosyn- Dantrolene • Dantrium Promethazine • Phenergan cratic reaction to a drug. Desipramine • Norpramin Quetiapine • Seroquel leukocytosis, elevated Desvenlafaxine • Pristiq Rasagiline • Azilect Dextromethorphan • Risperidone • Risperdal CK, and low serum Physical exam. Although there are many Benylin, Dexalone Safinamide • Xadago iron levels, these overlapping clinical manifestations, SS Dolasetron • Anzemet Selegiline • Eldepryl, Zelapar Doxepin • Silenor Sertraline • Zoloft findings are more produces neuromuscular hyperactivity (ie, Droperidol • Inapsine Sibutramine • Meridia clonus, hyperreflexia), whereas NMS is Duloxetine • Cymbalt Tedizolid • Sivextro common in NMS Escitalopram • Lexapro Thioridazine • Mellaril characterized by more sluggish responses Fentanyl • Actiq, Duragesic Tranylcypromine • Parnate (ie, rigidity, bradyreflexia).18 Fluconazole • Diflucan Tramadol • Ultram Fluoxetine • Prozac Trazodone • Desyrel, Oleptro Fluphenazine • Prolixin Venlafaxine • Effexor Laboratory findings. Overlap between Fluvoxamine • Luvox Vilazodone • Viibryd NMS and SS also occurs with lab findings; Granisetron • Kytril Vortioxetine • Trintellix Haloperidol • Haldol Valproate • Depacon both syndromes can result in leukocytosis, Isocarboxazid • Marplan Ziprasidone • Geodon elevated CK from muscle damage, and low Levomilnacipran • Fetzima serum iron levels. However, these findings are more commonly associated with NMS and are seen in 75% of cases.17,19 symptoms can be present for days to weeks. Resolution of symptoms may also be help- Course of illness. Duration of symptoms ful in differentiation because SS typically can also help differentiate the 2 syndromes. resolves within a few days of initiating SS typically develops within 24 hours of treatment, whereas NMS resolves within starting/changing therapy, whereas NMS 9 to 14 days of starting treatment.19 continued on page 42

Bottom Line The clinical presentations of serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) overlap, which can make them difficult to differentiate; however, they each have distinct approaches to treatment. Features in SS that are distinct from NMS include a history of serotonergic agents, rapid onset of symptoms, hyperreflexia, and clonus. NMS is slower in onset and can be found in patients who are prescribed Current Psychiatry dopamine antagonists, with distinct symptoms of rigidity and hyporeflexia. Vol. 18, No. 2 35 Serotonin syndrome or NMS? continued from page 35

References 11. Pope HG Jr, Aizley HG, Keck PE Jr, et al. Neuroleptic 1. Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. malignant syndrome: long-term follow-up of 20 cases. J Clin Ochsner J. 2013;13(4):533-540. Psychiatry. 1991;52(5):208-212. 2. Werneke U, Jamshidi F, Taylor D, et al. Conundrums in 12. Velamoor VR, Norman RM, Caroff SN, et al. Progression of : diagnosing serotonin syndrome – a meta- symptoms in neuroleptic malignant syndrome. J Nerv Ment analysis of cases. BMC Neurol. 2016;16:97. Dis. 1994;182(3):168-173. 3. Boyer EW, Shannon M. The serotonin syndrome. N Engl J 13. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med. 2005;352(11):1112-1120. Med Clin North Am. 1993;77(1):185-202. 4. Birmes P, Coppin D, Schmitt L, et al. Serotonin syndrome: a 14. Pileggi DJ, Cook AM. Neuroleptic malignant syndrome. brief review. CMAJ. 2003;168(11):1439-1442. Ann Pharmacother. 2016;50(11):973-981. 5. Sternbach H. The serotonin syndrome. Am J Psychiatry. 15. San Gabriel MC, Eddula-Changala B, Tan Y, et al. 1991;148:705-713. Electroconvulsive in a schizophrenic patient with 6. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter serotonin neuroleptic malignant syndrome and . J toxicity criteria: simple and accurate diagnostic decision rules ECT. 2015;31(3):197-200. for serotonin toxicity. QJM. 2003; 96(9):635-642. 16. Buggenhout S, Vandenberghe J, Sienaert P. Electroconvulsion 7. Lappin RI, Auchincloss EL. Treatment of the serotonin therapy for neuroleptic malignant syndrome. Tijdschr syndrome with cyproheptadine. N Engl J Med. Psychiatr. 2014;56(9):612-615. 1994;331(15):1021-1022. 17. Perry PJ, Wilborn CA. Serotonin syndrome vs neuroleptic 8. Nisijima K. Serotonin syndrome overlapping with malignant syndrome: a contrast of causes, diagnoses, neuroleptic malignant syndrome: A case report and and management. Ann Clin Psychiatry. 2012;24(2): approaches for differentially diagnosing the two syndromes. 155-162. Asian J Psychiatr. 2015;18:100-101. 18. Mills KC. Serotonin syndrome. A clinical update. Crit Care 9. Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic Clin. 1997;13(4):763-783. malignant syndrome. Br J Anaesth. 2000;85(1):129-135. 19. Dosi R, Ambaliya A, Joshi H, et al. Serotonin syndrome 10. Gurrera R. Sympathoadrenal hyperactivity and the etiology versus neuroleptic malignant syndrome: a challenge clinical of neuroleptic malignant syndrome. Am J Psychiatry. quandary. BMJ Case Rep. 2014;2014:bcr201404154. 1999;156:169-180. doi:10.1136/bcr-2014-204154.