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Clinical Psychopharmacology Seminar

Serotonin Syndrome and Neuroleptic MalignantSyndrome

Original Author: Paul Perry, Ph.D, BCPPLatest Reviser: Vicki Ellingrod, Pharm.D., BCPP

Creation Date: 1996Last Revision Date: October 2002Peer Review Status: Internally Peer Reviewed

INTRODUCTION

Both Serotonin Syndrome (SS) and Neuroleptic Malignant Syndrome (NMS) are rare, but potentially life-threatening toxic effects of psychotropic drugs. SS is associated with an excessof serotonin (5HT) usually resulting from increasing the dose of a single serotonergic agonistdrug, polypharmacy of serotonic agents, or a pharmacodynamic drug interaction of amonoamine oxidase inhibitor (MAOI) with a serotonin reuptake inhibitor (SRI) (Ciraulo andShader, 1990).The SS was first reported in the 1950s, but it wasn't until the 1990s that the term serotoninsyndrome was used (Keck and Arnold 2000). NMS has been associated with antipsychotic (neuroleptic) drugs and other drugs that affectdopamine (DA) neurotransmission. NMS was first described during early studies of haloperidol in 1960 (Delay et al, 1960). The first report of NMS in English literature was in1968 (Delay and Deniker, 1968). Since NMS occurs very infrequently, it is extremelydifficult to characterize it objectively under controlled conditions. As a result, manyuncontrolled reports have been published, sometimes with misleading results. Numerousreviews have been published that provide comprehensive discussions of NMS (Caroff andMann, 1993; Dickey, 1991; Ebadi et al, 1990; Heiman-Patterson, 1993).This review will attempt to compare and contrast the well-established features of NMS andSS. Signs and symptoms common to the two syndromes include excitement, diaphoresis,rigidity, hyperthermia, tachycardia, and hypertension. Depending on the circumstances of thecase involved, the washout period between use of an MAOI and an SRI may range from oneto more than five weeks. It is during this washout period that a misdiagnosis of NMS would be most likely, particularly when a patient is seeing more than one physician and completerecords are not available.

PATHOGENESIS

Of the several mechanistic hypotheses proposed for SS, the most creditable is that thesyndrome results from an overabundance of serotonin in the CNS. Originally, Oates andSjoerdsma (1960) described an "indolamine syndrome" in several patients who wereadministered an MAOI and L-tryptophan concurrently. They suggested that elevations inserotonin and tryptamine were responsible for the clinical symptoms see with this syndrome.Similarly, the numerous pharmacologic mechanisms prosposed for NMS are described inseveral reviews (Caroff and Mann, 1993; Dickey, 1991; Ebadi et al, 1990; Heiman-Patterson,1993; Thornberg and Ereshefsky, 1993). However, none satisfactorily explain why NMS onlyoccurs in certain patients or why NMS does not always recur even if the patient is re-exposedto the same offending antipsychotic (Rosebush et al, 1989b). Despite these observations, mostof the signs and symptoms can be traced to dopamine blockade (Caroff and Mann, 1993;Dickey, 1991; Ebadi et al, 1990; Heiman-Patterson, 1993; Thornberg and Ereshefsky, 1993).Thus there is a natural assumption since dopamine antagonists cause NMS, dopamine agonistsare the obvious treatments of choice for NMS.The NMS-induced tremor and rigidity are linked to nigrostriatal dopamine blockade, anextension of the parkinsonian side effects seen at therapeutic doses of antipsychotics(Heiman-Patterson, 1993; Dickey, 1991). Extreme rigidity, in turn, contributes tohyperthermia, muscle breakdown, elevated CK, and rhabdomyolysis. Peripherally,antipsychotics also affect intracellular calcium transport resulting in an increased calciumconcentration and altered muscle fiber contractility. This effect is reversed by dantrolene, acalcium ion release antagonist (Dickey, 1991). However, there are cases of NMS in whichdantrolene administration eliminated fever but had no effect on rigidity (Dickey, 1991).Central dopamine blockade in the hypothalamus may result in impaired temperatureregulation. Dopamine blocking drugs may alter the body temperature "set point" in thehypothalamus such that the heat dissipating mechanisms of shivering, sweating, and peripheral vasoconstriction or vasodilatation are altered (Heiman-Patterson, 1993).Spivak et al (1999) conducted a prospective study of circulating levels of 5HT, DA, andepinephrine (E) in patients diagnosed with NMS. They found that in platelet poor plasma patients, the DA levels were lower and the E levels higher in contrast to the patients' remittedstate. 5HT concentrations trended higher (p = 0.078). Also, the 5HT/DA ratio wassignificantly higher in the acute NMS state. Thus, some of these results support the theory that NMS is due to depletion in DA, but they also support the theory that other neurotransmittersare involved.

ETIOLOGY

SS is associated with medications that effect 5HT. The majority of evidence supporting thisrelationship is based on case reports. Overall SS has been reported to occur when drugsincluding clonazepam, alprazolam, lithium, SSRIs, trazodone, nefazodone, thioridazine arecombined with tricyclic antidpressants. Additionally the SS has been reported to occur whenl-tryptophan, dextromethorphan, SSRIs, meperidine, or clonazepam have been used incombination with an MAOI. Combinations between SSRIs, and venlfaxine,dextromethorphan, buspirone, carbamazepine, mirtazapine, tramadol, nefazodone,sumatriptan, and DHE have been associated with SS. Lastly, there are have been case reports

of SS in patients receiving monotherapy of venlfaxine, clomipramine, SSRIs, moclobemide,sumatriptan, and other serotonergic agents such as "Ecstasy" (Keck and Arnold 2000, Parrott2001). NMS has been associated with all dopamine-blocking drugs (Caroff and Mann, 1993).Clozapine, an antipsychotic that does not exhibit significant antagonism of D2 dopaminereceptors in the nigrostriatal tracts, has been thought to be less likely to cause NMS. However,at least fourteen cases of NMS have been attributed to clozapine (Reddig et al, 1992; Sachdevet al, 1995; Thornberg and Ereshefsky, 1993). Likewise, three cases of NMS have also beenattributed to risperidone, another "atypical" antipsychotic (Webster P and Wijeratne C, 1994;Raitasuo V et al, 1994). Metoclopramide, prochlorperazine, promethazine, and droperidol areall dopamine antagonists frequently used as antiemetics and for other indications alsoassociated with NMS (Caroff and Mann, 1993). It is recommended that dopamine blockingantiemetics should only be used long-term in patients with a clear indication.The abrupt withdrawal of dopaminergic drugs has also produced an NMS-like condition in patients with Huntington's disease and Parkinson's disease (Ebadi et al, 1990). Implicateddrugs include levodopa, bromocriptine, and amantadine. Not surprisingly, dopaminergicdrugs have been studied to treat NMS (Caroff and Mann, 1993; Dickey, 1991; Ebadi et al,1990; Heiman-Patterson, 1993).There is one case report in the literature were the patient diagnosed with NMS was presumedto have taken > 300 mg of cyclobenzaprine (Flexeril®), a commonly prescribed musclerelaxant, as his only medication. The patient's presentation was similar to neuroleptic-induced NMS. The authors suggested that the reaction in the absence of a neuroleptic may be ahyperthermic reaction and should be classified as a "drug-induced central hyperthermicsyndrome" (Theoharides et al, 1995)

INCIDENCE

Based on the literature the incidence of the SS is relatively rare, however specificcombinations of 5HT agonists appear to account for the majority of cases which appear in theliterature. These cases were particularly severe and often had lethal outcomes (Keck andArnold 2000). NMS is very rare (Deng et al, 1990; Keck et al, 1991; Modestin et al, 1992). Estimates of thefrequency of NMS in prospective studies range from 0.07% (Gelenberg et al, 1988) to 2.2%(Hermesh et al, 1992; Keck et al, 1989a). Analysis of NMS across studies suggests afrequency of approximately 0.2% (Caroff and Mann, 1993). A number of factors may explainthis wide range of frequencies. Diagnostic criteria for NMS varies widely from center tocenter (Gurrera et al, 1992; Modestin et al, 1992). NMS at one site may be diagnosed assevere pseudoparkinsonism at another. Study duration and length of exposure toantipsychotics varies greatly among studies. Obviously, the prevalence rate will be higher asthe duration of exposure is increased. Likewise, antipsychotic dosing practices between sitesor over time are likely to affect the reported incidence of NMS. Subjects in studies usinghigher antipsychotic doses are more likely to identify more cases of NMS (Gelenberg et al,1988). In one study (Keck et al, 1991), the incidence of NMS declined significantly from1.1% during a 31 month survey period to 0.15% over a later 47 month period. The authorsattributed this decline primarily to enhanced awareness of NMS, earlier treatment, and areduction in risk factors.