Special Article

Sympathoadrenal Hyperactivity and the Etiology

of Neuroleptic Malignant Syndrome
Ronald J. Gurrera, M.D.

Objective: The authors goal was to develop a pathophysiological model for neuroleptic
malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant). Method: Published clinical findings on neuroleptic malignant syndrome
were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function. Results: The data show that the sympathetic nervous systems latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic
inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic
hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant
syndrome. Conclusions: There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress
may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled
with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a
more comprehensive explanation for existing clinical data than do the current alternatives.
(Am J Psychiatry 1999; 156:169180)

t is widely believed that dopamine D2 (D2) receptor

antagonism causes hyperthermia in neuroleptic malignant syndrome by blocking heat-loss pathways in
the anterior hypothalamus, by increasing heat production secondary to extrapyramidal rigidity (1), or
both, but this model has been criticized as inadequate
(2, 3) and lacking sufficient evidence (4). An alternative hypothesis is that neuroleptics are directly toxic
Presented in part at the 53rd Annual Scientific Convention of the
Society of Biological Psychiatry, Toronto, May 2731, 1998.
Received March 2, 1998; revision received July 30, 1998;
accepted Aug. 25, 1998. From the Department of Psychiatry, Harvard Medical School, Brockton-West Roxbury DVA Medical Center. Address reprint requests to Dr. Gurrera, Brockton DVAMC
(116A), 940 Belmont St., Brockton, MA 02301; rgurrera@worldnet.att.net (e-mail).
Supported by DVA Medical Research Funds.

Am J Psychiatry 156:2, February 1999

to muscle tissue, as volatile anesthetics are in malignant hyperthermia (5), but neuroleptic malignant
syndrome and malignant hyperthermia likely have
distinct mechanisms (6, 7). Neither model enables clinicians to identify specific patients at greater risk for
neuroleptic malignant syndrome or to make reliable
treatment choices (810).
Autonomic dysfunction is a core component of neuroleptic malignant syndrome (11, 12, DSM-IV), and
peripheral catecholamines are typically elevated (13
16), but a pathophysiological role for excess catecholamines in neuroleptic malignant syndrome has been relatively overlooked. This paper provides an overview of
the sympathetic nervous system and its regulatory role
in body temperature, muscle function, and other organ
systems that are affected in neuroleptic malignant syndrome. These data are then integrated with published
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NEUROLEPTIC MALIGNANT SYNDROME

FIGURE 1. Pathophysiology Cascade in Neuroleptic Malignant Syndrome

clinical observations in support of the hypothesis that

dysregulated sympathetic nervous system hyperactivity
is the pathophysiological basis of neuroleptic malignant syndrome. The central premises of this hypothesis
are the intrinsic capacity of the sympathetic nervous
system for autonomous, fragmented function and its
ubiquitous involvement in all of the physiological processes relevant to neuroleptic malignant syndrome.
Figure 1 summarizes this thesis schematically, and the
reader will find it helpful to consult it frequently.

THE SYMPATHETIC NERVOUS SYSTEM:

AN OVERVIEW

Anatomy of the Autonomic Nervous System

Most organs are innervated by sympathetic and parasympathetic divisions of the autonomic nervous system,
but the adrenal medulla, sweat glands, and somatic
blood vessels are regulated exclusively by the sympathetic nervous system (17). Preganglionic sympathetic
nervous system fibers synapse within the adrenal medulla (17) and promote catecholamine secretion (18).
Sympathetic nervous system and adrenomedullary responses are often dissociated (19) and can be comple170

mentary (20, 21). The relative independence of the sympathetic nervous system from central nervous system
(CNS) regulation (17), its more permeable blood-nerve
barrier (22), and the ability of its end-organs to continue
functioning when autonomic nerves are interrupted (17)
all contribute to its capacity for autonomous function.
The sympathetic nervous system is regulated by the
frontal cortex and hypothalamus. The sulcal prefrontal cortex tonically influences the hypothalamus to
lower body temperature (23). Sympathetic nervous
system hyperactivity ensues when the hypothalamus is
released from cortical control (24), and systems lower
in the neuraxis operate independently following hypothalamic lesion (25). Sweating is tonically inhibited by
the frontal cortex (26), and a similar hierarchical inhibitory relationship exists between spinal cervicothoracic and thoracolumbar sudomotor (sweat gland) regulatory centers (27).
The sympathetic nervous system is regulated by the
lateral and posterior hypothalamus, whereas the parasympathetic division is controlled by the anterior and
medial hypothalamus (17, 24). Stimulation of the lateral hypothalamus increases adrenal nerve activity
(18), and the lateral hypothalamic area provides organ- or site-specific regulation of sympathetic nervous
system activity (28). Most dorsal hypothalamic spinal
Am J Psychiatry 156:2, February 1999

RONALD J. GURRERA

projection neurons are dopaminergic and appear to be

involved in autonomic function (29). Dopamine terminal axon density is highest in the intermediolateral cell
columns of the spinal cord, where preganglionic sympathetic nervous system neurons originate, and microelectrophoretic dopamine application there inhibits
sympathetic preganglionic neurons (30). Retrograde
labeling has identified caudal lateral hypothalamic
area neurons as likely sympathetic nervous system
central command neurons (31).
Autopsy findings have implicated only the posterior
hypothalamus in neuroleptic malignant syndrome (32).
Other autopsy results are inconclusive (33) or negative
(15, 34, 35) with respect to hypothalamic pathology.
Functional Neuropharmacology of the Sympathetic
Nervous System

Preganglionic sympathetic nervous system neurons

release acetylcholine, but postganglionic sympathetic
nervous system neurons release norepinephrine. Exceptions are sudomotor neurons and vasodilator neurons
in the muscle, whose postganglionic neurons release
acetylcholine, and the adrenal medulla, whose preganglionic neurons release norepinephrine (17, 36). Norepinephrine acts only within the neuroeffector junction
into which it is released (37). Plasma norepinephrine
levels reflect overflow from sympathetic nervous system
neuroeffector junctions, and there is good correlation
between muscle sympathetic nerve activity and plasma
norepinephrine levels (38). Norepinephrine promotes
its own release by means of prejunctional -adrenoceptors; at higher concentrations it inhibits its own release
by means of prejunctional -adrenoceptors (39). Trains
of high frequency action potentials may cause norepinephrine to accumulate, potentiating its functional effects (40). Symptoms of norepinephrine toxicity include
anxiety, pallor, and intense diaphoresis (41).
Epinephrine is the major catecholamine produced by
the adrenal medulla; in contrast to norepinephrine, it is
released into the circulation and acts at distant receptor sites (37). Symptoms of epinephrine toxicity include fear, anxiety, tenseness, restlessness, tremor,
weakness, dizziness, pallor, respiratory difficulty, and
palpitations (41). Norepinephrine constitutes no more
than 20% of the catecholamine content of the adrenal
medulla (41), and epinephrine has no significant activity at sympathetic nerve endings (36).
Norepinephrine activates predominantly - and 1adrenoceptors (42) and is more potent at 1 than 2 receptors (43). Epinephrine is active primarily at -adrenoceptors (42) and is much more potent than norepinephrine at 2 receptors, where norepinephrine has minimal
activity (44). Second messengers for adrenoceptors are
adenylate cyclase (activated by , inhibited by 2) and intracellular Ca2+ (increased by 1) (45). Adrenoceptors in
smooth muscle and glands are predominantly 1 (19),
whereas vasodilator 2-adrenoceptors in skeletal muscle
normally predominate over vasoconstrictor -adrenoceptors (44). Skeletal muscle contractility is increased by
Am J Psychiatry 156:2, February 1999

2-adrenoceptors (44), and cardiac rate and contraction

strength are both increased by -adrenoceptors (36). A
newly identified -adrenoceptor subtype, 3, promotes
lipolysis and plays a functional role in sympathetically
induced thermogenesis (43, 46).
High levels of D2 receptor mRNA are expressed in
the normal adrenal gland (47) and increased in human
pheochromocytoma tissue (48). In animals, D2 agonists
inhibit catecholamine release from adrenal glands, and
D2 presynaptic receptors located on norepinephrine
nerve terminals inhibit norepinephrine release if activated during nerve stimulation (49). In humans, D2 agonists cause inhibition of sympathetic output that is
abolished by D2 antagonists, but only at higher degrees
of sympathetic stimulation (49). These data are consistent with previously discussed anatomical evidence for
dopaminergic inhibition of sympathetic nervous system function and indicate that state-dependent factors
mediate D2 antagonist effects.
Hierarchical and Regional Organization of the Sympathetic
Nervous System

The functional components of the sympathetic nervous system exhibit considerable autonomy. For example, sympathetic vasoconstrictor pathways are distinct
from pilomotor and visceromotor pathways and can
be activated differentially (50). In cats, vasoconstrictor
pathways for skin and muscle are independent of one
another (51) and exercise-induced sympathetic discharge is regulated differently in the kidney and muscle
(52). Individual peripheral sympathetic nerves exhibit
a high degree of coherence at rest but respond uniquely
to experimentally induced cerebral ischemia, indicating that sympathetic nervous system circuits can convert a generalized excitatory stimulus into specific and
desynchronized discharge patterns (53).
Sympathoadrenomedullary responses also vary according to stressor: some stressors increase sympathetic nervous system activity but not adrenomedullary
secretion, and others have the opposite effect (54).
Moreover, sympathetic nervous system outflows to
different organs vary depending on the nature and intensity of the stressor (54). Autonomous and uncoordinated activity of sympathetic nervous system functional components following disruption of regulatory
(hierarchical) inputs, coupled with varying affinities of
norepinephrine and epinephrine for diverse and widely
distributed adrenoceptor subtypes, could account for
many of the clinical features of neuroleptic malignant
syndrome, including its fluctuating course.

MAMMALIAN THERMOREGULATION: AN OVERVIEW

The Biochemistry of Mammalian Thermogenesis

The two principal sources of thermogenesis in mammals are uncoupled oxidative phosphorylation in mitochondria and the contractile apparatus of skeletal muscle.
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NEUROLEPTIC MALIGNANT SYNDROME

Brown adipose tissue is specialized to generate large

amounts of heat rapidly, a process referred to as nonshivering thermogenesis. Brown adipose tissue is rich
in mitochondria containing uncoupling protein, which
permits respiratory chain oxidation to liberate energy
in the form of heat (55). Norepinephrine is a major
regulator of uncoupling protein synthesis (56, 57) but
may also have a direct thermogenic effect on brown
adipose tissue (57). Hypertrophy of brown adipose tissue and increased uncoupling protein synthesis have
been induced in the skeletal muscle of mice following 2
weeks of treatment with a 3 agonist (58).
The contraction-relaxation cycle of skeletal muscle
tissue is another important thermal energy source in
mammals; the term for heat generated by the contractile
apparatus is shivering thermogenesis. Contraction is
initiated when Ca2+ is released from its intracellular
storage site in the sarcoplasmic reticulum and binds to
contractile proteins (mainly troponin) in the sarcoplasm. Relaxation begins when intracellular [Ca 2+]
reaches a critical level, terminating further Ca2+ release
and activating Ca2+ reuptake pumps in the sarcoplasmic
reticulum membrane to move Ca2+ from sarcoplasm to
sarcoplasmic reticulum against a steep gradient.
Ca2+ release from the sarcoplasmic reticulum, Ca2+
binding to troponin, Ca2+ reuptake by the sarcoplasmic reticulum, and the oxidative chemical reactions of
the postcontraction recovery phase all produce heat
(59), and intracellular Ca2+ transport plays a role in
normal thermogenesis (60). Intracellular free [Ca 2+]
regulates contraction-relaxation (61), and agents that
lead to sustained elevation of sarcoplasmic [Ca2+] can
induce persistent contraction in the absence of an action potential (59). Creatine phosphokinase participates in regenerating high-energy cellular stores during
the relaxation phase (61) and is an integral component
of intracellular energy metabolism.
The Hierarchical Organization of Normal Mammalian
Thermoregulation

Homeothermy evolved as existing physiological reflexes were recruited for thermoregulatory functions,
gradually creating a hierarchically organized collection
of parallel subsystems, each of which regulates its phylogenetic predecessor. The neutral zone, defined as the
body temperature range within which no thermoeffectors (heating or cooling reflexes) are activated, narrows progressively at each level of this hierarchy, so
there is an illusion of a single fixed set point (in humans, about 98.6F) (62). However, homeothermy
represents the interaction of two separate groups of
neuronswarm-sensitive and cold-sensitive (63).
Warm sensitivity is mediated primarily by temperature-sensitive membrane ion conductances (64),
whereas cold sensitivity requires intact local synaptic
networks (64, 65). Warm-sensitive neurons activate
cold effectors (e.g., sweat glands) to lower body temperature, and cold-sensitive neurons activate warm
effectors (e.g., brown adipose tissue) to raise body
172

temperature. Warm and cold effectors are never activated simultaneously by an intact thermoregulatory
system (63).
Thermoregulation can be dissociated in a variety of
ways. The neurotoxin capsaicin disables heat-defense
responses but leaves cold-defense responses intact (23).
Shivering and nonshivering thermogenesis are modulated separately following CNS lesion, and stimulation
of the hypothalamus and spinal cord by opposing temperatures produces mutually independent and antagonistic thermoeffector (heating and cooling) responses
(62). Almost all thermoeffectors also serve nonthermoregulatory functions, so competition between thermal and nonthermal drives is likely (23, 66). Thermosensitive neurons in the hypothalamus are very
sensitive to emotional and behavioral inputs, and their
response is determined by perturbation magnitude
rather than hedonic attributes (23). Sympathetic nervous system activity in human skin is increased by
mental stress as well as thermal inputs (67), and many
dorsal horn spinal neurons are excited by both mechanical and thermal stimuli (68). Emotional fever is
provoked by restraint or novel stimuli in some species,
and anticipation can elevate body temperature in humans. These are true fevers in that they result from coordinated thermoeffector function (heat effectors
turned on, cold effectors turned off) (69, 70).
Stimulation of the preoptic hypothalamus can induce fever, but this structure is not essential because fever is under the control of multiple CNS structures
(69). The mammalian spinal cord has thermosensory
and thermoregulatory properties (51), but only extreme changes in body temperature elicit thermoregulatory responses in the absence of the hypothalamus
(62). Humans with spinal cord transections have wider
core temperature fluctuations (70), and subjects with
complete cervical cord transections have increased
core temperatures despite preserved regional heat-induced sweating (27). Some capacity for thermoregulation is preserved when hypothalamic regulatory inputs
are interrupted, so hypothalamic dysfunction alone
cannot explain the extreme hyperthermia sometimes
encountered in neuroleptic malignant syndrome.
CNS Dopamine and Mammalian Thermoregulation

It is widely believed that central dopamine receptor

antagonism within the hypothalamus is necessary for
neuroleptic malignant syndrome to occur, but the thermoregulatory role of dopamine is more complex. dAmphetamine (an indirect dopamine agonist) produces hypothermia or hyperthermia in rats, depending
on the ambient temperature, apparently by way of independent pathways (71, 72). Acutely and chronically
reserpinized rats demonstrate a reciprocal and statedependent D1-D2 receptor interaction in their thermoregulatory responses (73). Neuroleptic malignant
syndrome has followed neuroleptic dose reduction
(74), discontinuation (75), and long-term stable dosing
(76). Also, there is a report of severe extrapyramidal
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RONALD J. GURRERA

symptoms and hypothermia with fluphenazine, followed by rebound hyperthermia when this drug was
discontinued (77). Body temperature is highly correlated with plasma prolactin in thermally stressed men
(78), suggesting that normal heat defense is associated
with decreased central dopamine, and intraventricular
haloperidol produces a coordinated heat-defense response (79). These reports refute a unique or essential
role for central dopamine antagonism in neuroleptic
malignant syndrome hyperthermia and provide additional evidence that state-dependent factors are important mediators of dopamine antagonist effects.

THE SYMPATHETIC NERVOUS SYSTEM:

NORMAL PHYSIOLOGICAL FUNCTION

The Role of the Sympathetic Nervous System in Normal

Muscle Function

The sympathetic nervous system plays an integral

role in normal muscle function. Force is potentiated by
-adrenoceptor agonists in mammalian skeletal muscle, and adrenoceptors on skeletal myocyte membranes
are predominantly 2 (80), indicating that epinephrine
normally is directly involved in regulating skeletal
muscle contraction. In skeletal and heart muscle fibers,
-adrenoceptor agonists promote phosphorylation of
Ca2+ channels, increasing the probability of their being
open (81). Epinephrine increases contraction strength
by way of this altered Ca2+ influx (81), apparently by
increasing the amount of Ca2+ released from the sarcoplasmic reticulum into sarcoplasm during activation
(82). Epinephrine-induced Ca2+ influx by way of myocyte membrane channels also increases intracellular
[Ca2+], and the same effect is seen with the 1-adrenoceptor agonist phenylephrine (82). Liver Ca2+ homeostasis and muscle Ca2+ homeostasis are similar, and
norepinephrine induces a sustained rise in hepatocellular [Ca2+] (60). In rabbits, 1-adrenoceptor agonists
cause dose-dependent increases in peak skeletal muscle
tension (83). Thus, norepinephrine and epinephrine
are both potent activators of skeletal muscle and exert
this effect by altering intracellular [Ca2+].
Norepinephrine has similar effects on smooth muscle. In rabbits, norepinephrine triggers Ca2+-induced
Ca2+ release (84), a process whereby a large amount of
Ca2+ is released from the sarcoplasmic reticulum in response to a much smaller amount of Ca2+ outside the
sarcoplasmic reticulum (85). Norepinephrine-induced
Ca2+ release can activate smooth muscle contraction
fully (86), and in guinea pig myocytes, norepinephrine
produces spontaneous Ca2+-induced transmembrane
electrical transients that can cause depolarization (87).
Ca2+-induced Ca2+ release is responsible for caffeineinduced contractures in skeletal muscle (88).
Am J Psychiatry 156:2, February 1999

The Role of the Sympathetic Nervous System in Normal

Mammalian Thermoregulation

All thermoeffector activity is regulated by the sympathetic nervous system. Both the sympathetic nervous
system and the adrenal medulla are capable of preventing fatal hypothermia when the other is incapacitated
(89). Norepinephrine is the primary regulator of
brown adipose tissue metabolic activity and growth
(25), and norepinephrine also stimulates hormone-sensitive lipase, the principal lipolytic enzyme in white adipose tissue (89). Persistent -adrenergic stimulation
induces brown adipose tissue hypertrophy and accelerated uncoupling protein gene transcription in rats (58),
and although brown adipose tissue is probably not a
major thermogenic tissue in man (89), it does persist
throughout adulthood (90) and can be reactivated following intense sympathetic stimulation (e.g., in cold
acclimation or by a pheochromocytoma) (25). Repeated norepinephrine infusions potentiate thermogenesis in humans (91).
Uncoupling protein synthesis can be induced in rat
skeletal muscle following persistent adrenergic stimulation (58), and skeletal muscle is the primary site of
sympathomimetic-induced thermogenesis in humans
(90). Catecholamine-induced increases in intracellular
[Ca 2+ ] generate heat because chemical-mechanical
transduction efficiency is low (92). Salbutamol, a selective 2-adrenergic agonist, is thermogenic in humans
(93). Ephedrine, a mixed - and -adrenoceptor agonist, has a potent thermogenic effect in humans (90)
that is mediated by norepinephrine and probably involves 3-adrenoceptors (46). Isoproterenol, a nonselective -adrenoceptor agonist, substantially increases
the metabolic rate in humans, apparently through 1and 3-adrenoceptors (94). In one mammal, norepinephrine substantially increases skeletal muscle thermogenesis through 1-adrenoceptors, independent of
uncoupling protein (95).
Nonsteroidal anti-inflammatory agents are ineffective against the hyperthermia of neuroleptic malignant
syndrome, and dantrolene provides only inconsistent
benefit, so it is worth noting that both indomethacin
and dantrolene fail to inhibit phenylephrine-stimulated
thermogenesis in small mammals (95). These treatments would not be expected to reverse hyperthermia
caused by a hyperadrenergic state in which unregulated thermogenesis, due to uncoupled phosphorylation and/or disrupted intracellular Ca2+ homeostasis,
predominates.
The following general principles should now be evident:
1. Hierarchically organized thermoregulatory centers are located at all levels of the CNS.
2. The sympathetic nervous system is intimately involved in all aspects of thermoregulation.
3. The sympathetic nervous system consists of potentially autonomous components whose functions are
normally coordinated and integrated by the hypothal173

NEUROLEPTIC MALIGNANT SYNDROME

amus, but which function independently when these

regulatory inputs are disrupted.
4. Dopamine antagonists interrupt tonic inhibitory
modulation of sympathetic nervous system function at
the spinal cord level, an effect that is most evident
when the sympathetic nervous system is hyperactive.
5. Sympathetic nervous system hyperactivity is associated with intense emotional stress and frontal cortical dysfunction.
6. The sympathetic nervous system can augment or
initiate skeletal muscle contractile activity by means of
adrenoceptor-mediated increases in intracellular Ca2+
levels.
The following sections explore the role of sympathetic nervous system hyperactivity in the clinical presentation of neuroleptic malignant syndrome. Again,
the reader will find figure 1 helpful in following the
discussion.
SYMPATHETIC NERVOUS SYSTEM DYSREGULATION
AND THE PATHOPHYSIOLOGY OF NEUROLEPTIC
MALIGNANT SYNDROME

Neuroleptic Malignant Syndrome Risk Factors

Organic brain disease is a risk factor for neuroleptic

malignant syndrome (8, 9698) and for increased morbidity and mortality from this disorder (97, 99). Mental retardation is relatively frequent among cases of
neuroleptic malignant syndrome (8, 33, 100), and in
one small series the most severe syndrome was associated with bilateral frontal lesions (101). Catatonia,
considered a harbinger of neuroleptic malignant syndrome by some (102), is likely a frontal lobe syndrome
(103, 104).
Affective illness is another risk factor for neuroleptic
malignant syndrome (98, 99, 105, 106). Sympathetic
nervous system activity is increased in major depression (107); the relative contributions of the sympathetic nervous system and adrenomedullary components vary by depression subtype (108). In manic
patients, adrenomedullary activity is associated with
affective and behavioral symptoms but sympathetic
nervous system activity is correlated more strongly
with agitation (20). Rhabdomyolysis has been observed in mania (109). Plasma catecholamines and
their metabolites are elevated in periodic catatonia
(110, 111), which may be a variant of bipolar disorder
(103) and bears a strong clinical resemblance to neuroleptic malignant syndrome.
Illness Onset and Course

The temporal pattern in which specific features of

neuroleptic malignant syndrome emerge is inconsistent
across cases (99, 101, 112), but autonomic hyperactivity is often the earliest clinical finding. Although fulminant neuroleptic malignant syndrome may present
suddenly, more often the course is indolent, with unex174

plained episodic tachycardia and blood pressure fluctuations observed early on (112). In particular, elevated diastolic blood pressure may be antecedent
(113). In the prodrome that frequently precedes a fullblown syndrome (114), dysautonomic features typically predominate (99, 115, 116). Dysautonomia can
appear without hyperthermia (117) or precede hyperthermia (75, 113, 116, 118), which sometimes emerges
relatively late (101, 112). Individual differences in the
rates of catecholamine release and clearance, which are
the primary determinants of their physiological effect
(119), may contribute to the variability of the clinical
course. Opposing effects of - and -adrenoceptor
stimulation, as well as differing affinities of epinephrine and norepinephrine for these receptors, provide
additional sources of variability in clinical presentation
over time.
Major Clinical Features

Altered mental status. Altered consciousness is considered by some (120) to be a sine qua non for the diagnosis of neuroleptic malignant syndrome. In one relatively large series (98), a striking, frightened facial
expression was observed in all cases, accompanied by
a sense of doom and overwhelming anxiety (p.
719). Tollefson (6) described a mute and akinetic patient with neuroleptic malignant syndrome as having
an exaggerated startle response. Catatonic patients
retrospectively report intense, uncontrollable anxieties
(104). Healthy volunteers viewing a frightening film
have increased plasma norepinephrine, but their other
catecholamine and endocrine levels are normal (121).
Psychological stress is positively correlated with plasma
vanillylmandelic acid but not 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, or 5-hydroxyindoleacetic acid, suggesting that the sympathetic nervous system is activated more by transient emotional
stress than by persistent emotional conditions (122).
Acute, but not subacute or chronic, psychosis and
Brief Psychiatric Rating Scale scores indicating global
psychopathology and anxiety are positively correlated
with serum creatine phosphokinase levels (123). Catatonic excitement has been promoted as a highly reliable risk factor for neuroleptic malignant syndrome
(102), and labile mood and insomnia consistently precede lethal catatonia (124). Emotional disturbance
can trigger hyperthermia and many of the clinical features usually associated with neuroleptic malignant
syndrome (125), as can acute phencyclidine-induced
psychosis (126). Intense emotional or psychological
disturbance, with altered frontal cortical function,
could be a pathophysiological link between these syndromes and neuroleptic malignant syndrome.
Dysautonomia. Diaphoresis is common in neuroleptic malignant syndrome (124), with rates from 50%
to 100% (98, 99, 105), and is due to direct sympathetic nervous system stimulation rather than circulating catecholamines (17, 36). In contrast to its role in
true fever, diaphoresis in neuroleptic malignant synAm J Psychiatry 156:2, February 1999

RONALD J. GURRERA

drome is not part of a coordinated effort to lower body

temperature (127). Eccrine sweat glands are the only
mammalian organs with a purely thermoregulatory
function (23) and have the capacity to dissipate heat
faster than it can be generated (128), so hyperthermia
in neuroleptic malignant syndrome implicates a defective heat-loss mechanism in addition to any increase in
thermogenesis. Excessive sweat gland activity is probably responsible for neuroleptic-malignant-syndromeassociated dehydration in some cases (129), and dehydration may contribute to hyperthermia.
Tachypnea and tachycardia in neuroleptic malignant
syndrome reflect a hyperadrenergic state, but increased
metabolism makes additional demands on the cardiopulmonary system. In one drug-induced syndrome
similar to neuroleptic malignant syndrome, body temperature increased in tandem with blood pressure and
heart rate (130), and body temperature accounts for as
much as 16% of the respiratory rate variance in neuroleptic malignant syndrome (127).
Urinary incontinence is another clinical manifestation of autonomic dysfunction in neuroleptic malignant syndrome. The bladder base and internal sphincter consist of smooth muscle innervated exclusively by
predominantly -adrenergic sympathetic nervous system fibers. Voluntary restraint of micturition requires
the frontal lobes, and lesions in either hemisphere can
cause bladder incontinence (17, 67). In spinal cord patients, diaphoresis and bladder incontinence are associated with flexor spasms of the lower extremities, suggesting an intrinsic relationship among these motor
responses (27).
Catecholamine excess alone can produce a syndrome
similar to neuroleptic malignant syndrome, as illustrated by the case of a 34-year-old woman who experienced the sudden onset of palpitations, inability to
move or speak, and labile postural tachycardia and hypertension (111). Mutism, increased muscle tone, hyperactive tendon reflexes, and catalepsy were reproduced reliably by physical activity and anxietyprovoking situations and were always associated with
hypertension and tachycardia. Plasma epinephrine and
norepinephrine were markedly elevated and correlated
with amount of time upright, but urine 24-hour catecholamine and monoamine metabolite levels were
normal. She was found to have a hyperactive sympathetic response and peripheral 1-adrenoceptor subsensitivity (111).
Hyperthermia. Hyperthermia can occur when the
heat-loss apparatus is defective or when intact thermoeffectors are poorly coordinated. The ineffectiveness of
diaphoresis, normally a potent cold effector, in neuroleptic malignant syndrome has already been discussed.
The simultaneous activation of both warm and cold effectors in neuroleptic malignant syndrome indicates
that although thermoeffectors remain operational,
their activities are not coordinated (76, 127, 131). This
condition alone would be sufficient for hyperthermia
to supervene, but in addition there are two likely
sources of excess thermogenesis in neuroleptic maligAm J Psychiatry 156:2, February 1999

nant syndrome: accelerated brown-adipose-tissue-like

metabolism (uncoupled phosphorylation) and excessive catecholamine-induced Ca2+ release from the sarcoplasmic reticulum.
Persistent stimulation of sarcoplasmic reticulum
Ca2+ release would lead to continuous activation of
Ca2+ reuptake mechanisms, releasing heat as a byproduct. This could account for the observation that
serum creatine phosphokinase levels are positively
correlated with 24-hour urinary catecholamine metabolite excretion in neuroleptic malignant syndrome
(16). The appearance of elevated muscle enzyme levels in neuroleptic malignant syndrome before clinical
signs of autonomic instability are evident indicates
that hypermetabolism may precede the full syndrome
(132). Hypermetabolism related to hyperthyroidism,
in the absence of central dopamine blockade, can produce a syndrome similar to neuroleptic malignant
syndrome (133).
Peripheral catecholamines also directly stimulate uncoupled phosphorylation in mitochondria, as occurs in
some cases of pheochromocytoma, cold exposure, and
treatment with sympathomimetic agents. As in these
other examples, prolonged elevation of peripheral catecholamine levels in neuroleptic malignant syndrome
may even lead to induction of uncoupling protein
mRNA and increased thermogenic tissue mass, suggesting a possible physiological basis for persistent hyperthermia during recovery from neuroleptic malignant syndrome. This thermogenic mechanism is
distinct from that related to intracellular Ca2+ homeostasis. Hyperthermia in neuroleptic malignant syndrome can be dissociated from muscle rigidity (33,
134) and creatine phosphokinase levels (135), precede
extrapyramidal signs (115), and persist despite curarization-induced flaccidity (33). The lack of glycogen
and lipid stores in muscle biopsies strongly suggests
that uncoupled phosphorylation contributes to hyperthermia in neuroleptic malignant syndrome (136).
Rigidity, elevated creatine phosphokinase, and rhabdomyolysis. Asymptomatic creatine phosphokinase
elevations occur in patients with psychotic disorders,
whether clinically stable or acutely ill, following oral
treatment with typical or atypical neuroleptics (137
139). Clozapine is associated with more frequent and
higher creatine phosphokinase elevations than are typical neuroleptics (139); this is noteworthy because
clozapine has significantly greater 2-adrenoceptor
activity (140), which is probably the cause of de novo
diabetes mellitus in clozapine-treated patients (141).
Substantial creatine phosphokinase elevations accompanied only by tachycardia and elevated blood pressure
may follow neuroleptic treatment (142), suggesting a
hypermetabolic effect mediated by the sympathetic nervous system.
Cardiac lesions caused by elevated catecholamines
are indistinguishable from atherosclerotic lesions
(143). Short-term hypoxia permits creatine phosphokinase-MB to escape without necrosis (144), and intravenous isoproterenol causes elevated creatine phospho175

NEUROLEPTIC MALIGNANT SYNDROME

kinase-MB in childhood asthmatics (145). Elevated

creatine phosphokinase and focal skeletal myositis occur in pheochromocytoma (146), which releases
mainly norepinephrine (119). Ischemia mediated by
catecholamine-induced vasoconstriction in skeletal
muscle is probably the cause of muscle injury in pheochromocytoma (147). Creatine phosphokinase elevations and myoglobinuria in neuroleptic malignant syndrome may exist without rigidity or tremor (148), and
haloperidol-induced rhabdomyolysis is associated with
autonomic dysfunction but not rigidity (149).
Urinary catecholamines and catecholamine metabolites are positively correlated with blood creatine phosphokinase levels in acute neuroleptic malignant syndrome, but other clinical features are not (16). In
patients with neuroleptic malignant syndrome, serum
creatine phosphokinase covaries nonlinearly with other
muscle enzymes and exceeds by as much as 15-fold the
normal extracellular-intracellular gradient, indicating
that muscle necrosis alone cannot account for elevated
creatine phosphokinase levels (150). Experimental tissue injury models suggest that increased enzyme synthesis represents a reparative response to a noxious agent
(151). The noxious event in neuroleptic malignant syndrome could be a relative hypoxia created by a metabolism-perfusion mismatch caused by a hyperactive and
unregulated sympathetic nervous system.
Catecholamine-induced Ca2+ release from the sarcoplasmic reticulum may also cause cell death (152). Focal myocardial necrosis occurs in patients with pheochromocytoma (153), in rats infused with epinephrine
and norepinephrine (143), and in dogs infused with inotropic amines (154). Muscle necrosis in these settings
is apparently due to a direct effect of catecholamines
on Ca2+ influx (81, 153). Oxidation of excess catecholamines to catecholamine-O-quinones, with subsequent formation of superoxide radicals that attack cellular membrane and protein constituents essential to
energy metabolism, is another mechanism by which
excess catecholamines can damage myocytes (155).
Muscle biopsy findings in patients with neuroleptic
malignant syndrome have yielded minimal or inconsistent results (compare references 6 and 156 with references 34, 120, 136, and 157). Muscle abnormalities
that have been detected in neuroleptic malignant syndrome resemble those found in malignant hyperthermia (157) or consist of endomysial edema with a striking absence of both glycogen and lipid substrate stores
(136). Profound depletion of intracellular energy
stores strongly implicates uncoupled phosphorylation
as the source of hyperpyrexia (136), and the resemblance to malignant hyperthermia in these cases implicates Ca2+ overload as a common etiological factor. A
majority of patients with severe neuroleptic malignant
syndrome have documented serum hypocalcemia (98),
which could reflect a sudden net influx of Ca2+ into
myocytes that coincides with a malignant phase of
the syndrome.
176

Extrapyramidal signs associated with neuroleptic

malignant syndrome include rigidity, tremor, cogwheeling, dystonia, chorea, dyskinesia, opisthotonos,
opsoclonus, and posturing (3, 5, DSM-IV). As the data
presented here indicate, rigidity in neuroleptic malignant syndrome could be caused by catecholamine-induced changes in intracellular [Ca2+], and tremors
could also reflect elevated peripheral catecholamines.
Increased muscle tone caused by sympathetic nervous
system hyperactivity is independent of, but may coexist with, effects of neuroleptics on the extrapyramidal
system, and the presence of more complex motor signs
implicates concomitant basal ganglia involvement in
some cases of neuroleptic malignant syndrome.
Associated Clinical Findings

Granulocytosis is a feature of neuroleptic malignant

syndrome (3, 97), and sympathetic nervous system fibers innervate lymphoid tissue (158). Catecholamines
stimulate lymphocytes at low concentrations, but at
high concentrations they are inhibitory (158). Lymphocyte circulation is mediated mainly by plasma
membrane 2-adrenoceptors, whereas granulocyte circulation increases are mediated by -adrenoceptor
stimulation (42). An injection of norepinephrine can
raise neutrophil levels to two to three times normal
(159), and increased peripheral norepinephrine turnover is associated with reduced lymphocyte proliferation (160). The net effect of sympathetic nervous system
stimulation is leukocytosis with a shift to the left.
Blood sugar homeostasis is regulated by the sympathetic nervous system and can be impaired in neuroleptic malignant syndrome. A 44-year-old man with no
previous history of diabetes mellitus developed neuroleptic malignant syndrome and fatal diabetic ketoacidosis precipitously following a test dose of zuclopenthixol decanoate (161). Under normal physiological
circumstances, the sympathetic nervous system tonically suppresses insulin release through -adrenoceptors (162); stimulation of the pancreatic sympathetic
nerve decreases insulin secretion and increases glucagon secretion (163).
Bilateral E coli anterior tibial fasciitis in one case of
neuroleptic malignant syndrome (164) may have resulted from ischemic muscle necrosis. Noncardiogenic
pulmonary edema in neuroleptic malignant syndrome
(165) could be caused by excess sympathetic nervous
system activity because pheochromocytomas can cause
pulmonary edema (147). Necrotizing colitis without
fever, possibly a result of sympathetic-nervous-systemmediated vasoconstriction, has been attributed to neuroleptic treatment (166), and ischemic bowel followed
respiratory failure in another case of neuroleptic malignant syndrome (114). Paralytic ileus in neuroleptic
malignant syndrome (167) may be the result of intense
sympathetic nervous system activation (44).
Am J Psychiatry 156:2, February 1999

RONALD J. GURRERA

DISCUSSION

The intrinsic capacity of the sympathetic nervous

system for fragmented, autonomous activity normally
is suppressed by inhibitory regulatory inputs originating in the frontal cortex and mediated by hypothalamic nuclei. The hypothalamus integrates afferent
thermosensory information and coordinates thermoeffector responses by means of dopaminergic modulation of preganglionic sympathetic nervous system neurons. Disruption of these inhibitory inputs leads to
dysregulated sympathetic nervous system hyperactivity
with uncoordinated, excessive stimulation of end-organs by autonomous functional components of the
sympathetic nervous systemvasomotor, sudomotor,
inotropic, thermogenic, and others. In particular, extreme psychic distress (altered frontal lobe function) or
acute dopamine antagonism (of hypothalamospinal
tracts) may alter sympathetic nervous system function
and lead to profound disturbances of homeostasis.
Manifestations of dysregulated sympathetic nervous
system hyperactivity include increased muscle metabolism and tone (due to increased intracellular [Ca2+]), of
which elevated creatine phosphokinase is one indicator; increased mitochondrial thermogenesis (caused by
uncoupled oxidative phosphorylation); ineffective heat
dissipation related to unregulated vasomotor and sudomotor activity; fluctuations in vasomotor tone leading to labile blood pressure, flushing, and pallor; granulocytosis; and urinary incontinence.
The inherent autonomy of these circuits permits
these effects to be produced independently of one another, but they may interact to destabilize homeothermic and hemodynamic systems, producing the clinical
syndrome of neuroleptic malignant syndrome. Figure 1
illustrates how such a pathophysiological cascade
might occur. The relative mutual independence of neural and adrenal segments of the sympathetic nervous
system, and the differential effects of norepinephrine
and epinephrine at adrenoceptors, contribute to the
unpredictable course and fluctuating clinical signs and
symptoms that characterize this disorder. Direct effects
of neuroleptics on extrapyramidal systems may interact with sympathetic nervous system dysfunction to
produce the final clinical picture.
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