Sympathoadrenal Hyperactivity and the Etiology of Neuroleptic Malignant Syndrome

It 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 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 (8–10).

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 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 complementary (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 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 β-adrenoceptors; at higher concentrations it inhibits its own release by means of prejunctional α-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 α- and β₁-adrenoceptors (42) and is more potent at α₁ than α₂ receptors (43). Epinephrine is active primarily at β-adrenoceptors (42) and is much more potent than norepinephrine at β₂ receptors, where norepinephrine has minimal activity (44). Second messengers for adrenoceptors are adenylate cyclase (activated by β, inhibited by α₂) and intracellular Ca²⁺ (increased by α₁) (45). Adrenoceptors in smooth muscle and glands are predominantly α₁(19), whereas vasodilator β₂-adrenoceptors in skeletal muscle normally predominate over vasoconstrictor α-adrenoceptors (44). Skeletal muscle contractility is increased by β₂-adrenoceptors (44), and cardiac rate and contraction strength are both increased by β-adrenoceptors (36). A newly identified β-adrenoceptor subtype, β₃, 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.

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 β₃ 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 [Ca²⁺] 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 [Ca²⁺] 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 98.6˚F) (62). However, homeothermy represents the interaction of two separate groups of neurons—warm-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 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. d-Amphetamine (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 state-dependent 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 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 β-adrenoceptor agonists in mammalian skeletal muscle, and adrenoceptors on skeletal myocyte membranes are predominantly β₂(80), indicating that epinephrine normally is directly involved in regulating skeletal muscle contraction. In skeletal and heart muscle fibers, β-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 α₁-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, α₁-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 caffeine-induced contractures in skeletal muscle (88).

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 β-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 [Ca²⁺] generate heat because chemical-mechanical transduction efficiency is low (92). Salbutamol, a selective β₂-adrenergic agonist, is thermogenic in humans (93). Ephedrine, a mixed α- and β-adrenoceptor agonist, has a potent thermogenic effect in humans (90) that is mediated by norepinephrine and probably involves β₃-adrenoceptors (46). Isoproterenol, a nonselective β-adrenoceptor agonist, substantially increases the metabolic rate in humans, apparently through β₁- and β₃-adrenoceptors (94). In one mammal, norepinephrine substantially increases skeletal muscle thermogenesis through α₁-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:

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, 96– 98) 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 unexplained 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 full-blown 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 α- and β-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 syndrome 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-syndrome-associated 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 α-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 anxiety-pro­voking 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 α₁-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 malignant 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 by-product. 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 α₂-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 phospho­kinase-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.

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 β₂-adrenoceptors, whereas granulocyte circulation increases are mediated by α-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 α-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-system-mediated 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).

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 system—vasomotor, 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.

Presented in part at the 53rd Annual Scientific Convention of the Society of Biological Psychiatry, Toronto, May 27–31, 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; [email protected] (e-mail). Supported by DVA Medical Research Funds.