CHA PTER

55

Catatonia, Neuroleptic Malignant Syndrome,

and Serotonin Syndrome
Gregory L. Fricchione, MD, Jeff C. Huffman, MD, George Bush, MD, MMSc, and Theodore A. Stern, MD

KEY POINTS
Catatonia, neuroleptic malignant syndrome, and
serotonin syndrome are neuropsychiatric conditions
with prominent motor, behavioral, and systemic
manifestations.
Catatonia is a syndrome with multiple medical,
neurological, and psychiatric etiologies that requires a
systematic approach for diagnosis.
Neuroleptic malignant syndrome is a form of
malignant catatonia.
Lorazepam and electroconvulsive therapy are
important therapies for catatonic states.
Serotonin syndrome is usually self-limiting once the
offending serotonergic medications are discontinued
and supportive measures are initiated.

OVERVIEW
The syndromes described in this chapter each involve a
complex mixture of motor, behavioral, and systemic manifestations that are derived from unclear mechanisms. What
is clear is that neurotransmitters, such as dopamine (DA),
gamma-aminobutyric acid (GABA), and glutamate (GLU),
are of major importance in catatonia and neuroleptic malignant syndrome (NMS), and serotonin (5-hydroxytryptamine
[5-HT]) is crucial to the development of serotonin syndrome
(SS).
As medications with potent effects on modulation of
monoamines proliferate, the diagnosis and management of
these complex disorders become even more important;
without question, these syndromes have signs, symptoms,
and treatments that overlap.

CATATONIA
Denition
The catatonic syndrome comprises a constellation of motor
and behavioral signs and symptoms that often occurs in
relation to neuromedical insults. Structural brain disease,
intrinsic brain disorders (e.g., epilepsy, toxic-metabolic deran-

gements, infectious diseases), a variety of systemic disorders

that affect the brain, and idiopathic psychiatric disorders
(such as affective and schizophrenic psychoses) have each
been associated with catatonia. Catatonia was rst named and
dened in 1847 by Karl Kahlbaum, who published a monograph that described 21 patients with a severe psychiatric
disorder.1 This was among the rst studies in the area of mental
illness to use the symptom-based approach of Sydenham to
diagnose disorders without a known etiopathogenesis.
Kahlbaum believed that patients with catatonia passed
through several phases of illness: a short stage of immobility
(with waxy exibility and posturing), a second stage of
stupor or melancholy, a third stage of mania (with pressured
speech, hyperactivity, and hyperthymic behavior), and nally,
after repeated cycles of stupor and excitement, a stage of
dementia.1
Kraepelin,2 who was inuenced by Kahlbaum, included
catatonia in the group of deteriorating psychotic disorders
named dementia praecox. Bleuler3 adopted Kraepelins view
that catatonia was subsumed under severe idiopathic deteriorating psychoses, which he renamed the schizophrenias.
Kraepelin and Bleuler both believed that catatonic symptoms could emerge as part of a mood disorder (either mania or
depression) or could result from neurologic, toxic-metabolic,
and infectious etiologies. These states were considered phenomenologically indistinguishable from primary psychogenic
catatonias.
Nevertheless, catatonia was strongly linked with schizophrenia until the 1990s, and until fairly recently catatonia
could only be diagnosed as a schizophrenia in an obvious
nosological error. Thanks in large part to the work of Fink
and Taylor,4 the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV), now includes new
criteria for mood disorders with catatonic features and for
catatonic disorder secondary to a general medical condition,
as well as for the catatonic type of schizophrenia.5 Catatonia,
whether a consequence of medical illness, major depression,
mania, a mixed affective disorder, or schizophrenia, is diagnosed when the clinical picture includes at least two of the
following ve features: motoric immobility (as evidenced by
catalepsy [including waxy exibility] or stupor); excessive
motor activity (that is apparently purposeless and not inuenced by external stimuli); extreme mutism or negativism
(that is characterized by an apparently motiveless resistance
to all instructions or by the maintenance of a rigid posture

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against attempts to be moved); peculiarities of voluntary

movement (such as the voluntary assumption of an inappropriate or bizarre posture, stereotyped movement, prominent
mannerism, or grimace); or echolalia (or echopraxia).

Epidemiology and Risk Factors

The rate of catatonia in the general psychiatric population
varies according to study design and diagnostic criteria. Nevertheless, prospective studies on patients hospitalized with
acute psychotic episodes place the incidence of catatonia in
the 7% to 17% range.6 In patients who suffer from mood
disorders, rates have ranged from 13% to 31% over the last
century. Catatonia appears commonly in those with bipolar
disorder.7 Others at particular risk include patients with
mixed manic episodes and those with severe mood disorders.6 Some have contended that the incidence of catatonia
has diminished in schizophrenia, but here too diagnostic and
study design variations make this interpretation problematic.
Catatonia is a nonspecic syndrome associated with a
variety of etiologies.6 Neuromedical organic etiologies
account for 4% to 46% of cases in various series. This underscores the need for a thorough neuromedical workup when
catatonic signs are present. Personality disorders or conversion disorder is cited as etiologic in from 4% to 11% of
catatonia cases. Catatonia is idiopathic in 4% to 46% of cases
in various case series.

Subtypes

762

Several subtypes of catatonia have been described. Catatonic

withdrawal is characterized by psychomotor hypoactivity,
whereas catatonic excitement is characterized by psychomotor hyperactivity. These presentations may alternate during
the course of a catatonic episode. Kraepelin identied a periodic catatonia (with an onset in adolescence) characterized
by intermittent excited states, followed by catatonic stupor
and a remitting and relapsing course.8 In the 1930s this disorder was further described as lethal catatonia, distinguished
by the rapid onset of a manic delirium, high temperatures,
catatonic stupor, and a mortality rate in excess of 50%.
A dominant gene effect in families with periodic catatonia
has been noted, with more parents than siblings aficted.9
The disease locus maps onto chromosome 15q15 in families
with periodic catatonia.9 However, in one family the locus
was on chromosome 22q13, with WKL1 as the associated
gene.10 This gene codes for a cation channel protein found
in limbic and dorsal striatal tissue, suggesting that mesolimbic and nigrostriatal changes may be involved in periodic
catatonia.
Mann and co-workers11 reviewed the literature on lethal
catatonia and found that cases from the preneuroleptic era
classically began with 8 days of intense, uninterrupted motor
excitement; it was fatal in more than three out of four cases.
Aficted patients were often bizarre and violent, refused to
eat, and manifested intermittent mutism, posturing, catalepsy, and rigidity that alternated with excitement. Thought
was disorganized, speech was incoherent, and delusions and
hallucinations were present. When hyperactive they were
febrile, diaphoretic, and tachycardic. This stage would be

followed by exhaustion, characterized by stupor and by high

temperatures.
For Kraepelin, lethal catatonia was a syndrome with various
neuromedical and psychiatric etiologies; Mann and coworkers11 review of 292 cases since 1960 supports this
concept. Sixty percent of patients who received neuroleptics
died. The classic hyperactive form of catatonia was found
in two-thirds of the cases. High fever, altered consciousness,
autonomic instability, anorexia, electrolyte imbalance, cyanosis, and associated catatonic signs (e.g., posturing, stereotypies, and mutism) were present from the early stages; stupor
typically followed, but it was the initial manifestation in
nearly one-third of patients. Once stupor and rigidity emerged,
patients were clinically indistinguishable from those with
NMS.12

Clinical Features and Diagnosis

Signs and symptoms of the catatonic syndrome are outlined
in Table 55-1 (the Bush-Francis Catatonia Rating Scale).
Catatonia may be caused by a host of syndromes (Table
55-2).13 Efforts should of course be made to identify the
etiology of catatonia and to treat it if possible.
Fortunately, while no one test can conrm the diagnosis
of catatonia, some studies (e.g., the electroencephalogram
[EEG], neuroimaging of the brain, optokinetic and caloric
testing) may help identify the etiology. A personal and family
history of psychiatric illness is important although not diagnostic. Research on regional cerebral blood ow has shown
basal ganglia asymmetry (with left-sided hyperperfusion),
hypoperfusion in the left medial temporal area, and decreased
perfusion in the right parietal cortex. During working memory
tasks and with emotional-motor activation, the orbitofrontal
cortex appears to be altered in several cases studied with
functional magnetic resonance imaging (fMRI).14
The specic number and nature of the signs and symptoms
required to make a diagnosis of catatonia remains controversial. Lohr and Wisniewski15 proposed that one or more cardinal features (including catalepsy, positivism [such as seen
in automatic obedience], and negativism), and two of the
other features should be present to diagnose catatonia. Rosebush and colleagues16 suggested that catatonia was present
when three cardinal features (e.g., immobility, mutism, and
withdrawal [with refusal to eat or drink]) or when two
cardinal features and two secondary characteristics were
present.
Taylor17 contended that even one cardinal characteristic
conveys as much clinical condence (in the diagnosis and
treatment) as the presence of seven or eight characteristics.
The evidence does not support a relationship among the
number of catatonic features, the diagnosis, and response to
treatment. Fink and Taylor4 later considered that a minimum
of two classic symptoms was sufcient to diagnose the syndrome, and more recently, Bush and colleagues18 developed
a rating scale and guidelines for the diagnosis of catatonia.
They found that two or more signs identied all of their
patients with catatonia. Their standardized examination
method is consistent with the DSM-IV criteria for catatonia
(Table 55-3).

Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome

Table 55-1 Modied Bush-Francis Catatonia Rating Scale

Catatonia can be diagnosed by the presence of 2 or more of the rst 14 signs listed below.
1. Excitement

Extreme hyperactivity, and constant motor unrest, which is apparently nonpurposeful. Not to be
attributed to akathisia or goal-directed agitation.

2. Immobility/stupor

Extreme hypoactivity, immobility, and minimal response to stimuli.

3. Mutism

Verbal unresponsiveness or minimal responsiveness.

4. Staring

Fixed gaze, little or no visual scanning of environment, and decreased blinking.

5. Posturing/catalepsy

Spontaneous maintenance of posture(s), including mundane (e.g., sitting/standing for long periods
without reacting).

6. Grimacing

Maintenance of odd facial expressions.

7. Echopraxia/echolalia

Mimicking of an examiners movements/speech.

8. Stereotypy

Repetitive, nongoal-directed motor activity (e.g., nger-play, or repeatedly touching, patting, or rubbing
oneself); the act is not inherently abnormal but is repeated frequently.

9. Mannerisms

Odd, purposeful movements (e.g., hopping or walking on tiptoe, saluting those passing by, or
exaggerating caricatures of mundane movements); the act itself is inherently abnormal.

10. Verbigeration

Repetition of phrases (like a scratched record).

11. Rigidity

Maintenance of a rigid position despite efforts to be moved; exclude if cogwheeling or tremor is

present.

12. Negativism

Apparently motiveless resistance to instructions or attempts to move/examine the patient. Contrary

behavior; one does the exact opposite of the instruction.

13. Waxy exibility

During reposturing of the patient, the patient offers initial resistance before allowing repositioning,
similar to that of a bending candle.

14. Withdrawal

Refusal to eat, drink, or make eye contact.

15. Impulsivity

Sudden inappropriate behaviors (e.g., running down a hallway, screaming, or taking off clothes) without
provocation. Afterward, gives no or only facile explanations.

16. Automatic obedience

Exaggerated cooperation with the examiners request or spontaneous continuation of the movement
requested.

17. Mitgehen

Anglepoise lamp arm raising in response to light pressure of nger, despite instructions to the
contrary.

18. Gegenhalten

Resistance to passive movement that is proportional to strength of the stimulus; appears automatic
rather than willful.

19. Ambitendency

The appearance of being stuck in indecisive, hesitant movement.

20. Grasp reex

Per neurologic examination.

21. Perseveration

Repeatedly returns to the same topic or persistence with movement.

22. Combativeness

Usually aggressive in an undirected manner, with no or only facile explanation afterward.

23. Autonomic abnormality

Abnormal temperature, blood pressure, pulse, or respiratory rate, and diaphoresis.

From Bush G, Fink M, Petrides G, et al: Catatonia I. Rating scale and standardized examination, Acta Psychiatr Scand 93:129-136, 1996.
The full 23-item Bush-Francis Catatonia Rating Scale (BFCRS) measures the severity of 23 signs on a 0-3 continuum for each sign. The rst 14 signs combine
to form the Bush-Francis Catatonia Screening Instrument (BFCSI). The BFCSI measures only the presence or absence of the rst 14 signs, and it is used for
case detection. Item denitions on the two scales are the same.

Pathophysiology
Catatonia is thought to reect a disruption in basal ganglia
thalamocortical tracts (including the motor circuit [rigidity],
the anterior cingulate/medial orbitofrontal circuit [akinetic
mutism and perhaps through lateral hypothalamic connections hyperthermia and dysautonomia], and the lateral
orbitofrontal circuit [imitative and repetitive behaviors])
(Figure 55-1).19 Such disruption may lead to a relative
state of hypodopaminergia in these circuits through reduced
ow in the medial forebrain bundle, the nigrostriatal tract,
and the tuberoinfundibular tract. DA activity in the dorsal
striatum and in the ventral striatum and paralimbic cortex
is thus reduced perhaps secondary to reduced GABAA

inhibition of GABAB substantia nigra (SN) and ventral tegmentum (VTA) interneurons. This would lead to a dampening of DA outow, whereas activation at GABAA through
use of agonists, such as lorazepam, would indirectly disinhibit DA cell activity.20,21 Another possible site of pathophysiology involves reduced GABAA inhibition of frontal
corticostriatal tracts leading to NMDA changes in the dorsal
striatum and indirectly in the SN and VTA.20 Multiple etiologies, if they affect the basal ganglia, thalamus, or paralimbic or frontal cortices, will have the potential to cause these
neurotransmitter alterations that will disrupt basal ganglia
thalamocortical circuits, leading to the phenomenology of
catatonia.

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Table 55-2 Potential Etiologies of the Catatonic Syndrome

Primary Psychiatric
Acute psychoses
Conversion disorder
Dissociative disorders
Mood disorders
Obsessive-compulsive disorder
Personality disorders
Schizophrenia
Secondary Neuromedical
Cerebrovascular
Arterial aneurysms
Arteriovenous malformations
Arterial and venous thrombosis
Bilateral parietal infarcts
Temporal lobe infarct
Subarachnoid hemorrhage
Subdural hematoma
Third ventricle hemorrhage
Hemorrhagic infarcts
Other Central Nervous System Causes
Akinetic mutism
Alcoholic degeneration and Wernickes encephalopathy
Cerebellar degeneration
Cerebral anoxia
Cerebromacular degeneration
Closed head trauma
Frontal lobe atrophy
Hydrocephalus
Lesions of thalamus and globus pallidus
Narcolepsy
Parkinsonism
Postencephalitic states
Seizure disorders
Surgical interventions
Tuberous sclerosis
Neoplasm
Angioma
Frontal lobe tumors
Gliomas
Langerhans carcinoma
Paraneoplastic encephalopathy
Periventricular diffuse pinealoma
Poisoning
Coal gas
Organic uorides
Tetraethyl lead poisoning
Infections
Acquired immunodeciency syndrome
Bacterial meningoencephalitis

Infections (contd)
Bacterial sepsis
General paresis
Malaria
Mononucleosis
Subacute sclerosing panencephalitis
Tertiary syphilis
Tuberculosis
Typhoid fever
Viral encephalitides (especially herpes)
Viral hepatitis
Metabolic and Other Medical Causes
Acute intermittent porphyria
Addisons disease
Cushings disease
Diabetic ketoacidosis
Glomerulonephritis
Hepatic dysfunction
Hereditary coproporphyria
Homocystinuria
Hyperparathyroidism
Idiopathic hyperadrenergic state
Multiple sclerosis
Pellagra
Idiopathic
Peripuerperal
Systemic lupus erythematosus
Thrombocytopenic purpura
Uremia
Drug-Related
Neuroleptics (typical and atypical); clozapine and risperidone (all
neuroleptics have been associated)
Nonneuroleptic
Alcohol
Antidepressants (tricyclics, monoamine oxidase inhibitors, and others)
Anticonvulsants (e.g., carbamazepine, primidone)
Aspirin
Disulram
Metoclopramide
Dopamine depleters (e.g., tetrabenazine)
Dopamine withdrawal (e.g., levodopa)
Hallucinogens (e.g., mescaline, phencyclidine, and lysergic acid
diethylamide)
Lithium carbonate
Morphine
Sedative-hypnotic withdrawal
Steroids
Stimulants
Amphetamines, methylphenidate, and possibly cocaine

From Philbrick KL, Rummans TA: Malignant catatonia, J Neuropsychiatry Clin Neurosci 6:1-13, 1994.
Most common medical conditions associated with catatonic disorder from literature review done by Carroll BT, Annson TJ, Kennedy JC, et al: Catatonic
disorder due to general medical conditions, J Neuropsychiatry Clin Neurosci 6:122-133, 1994.

Management and Treatment

764

Whatever its etiology, catatonia is accompanied by signicant

morbidity and mortality rates from systemic complications.
In addition, many of the physical illnesses responsible for
catatonia can be hazardous, causing many complications

(Table 55-4). Thus, timely diagnosis and treatment are essential. If a neurological or medical condition is found, treatment
for that specic illness is indicated. Occasionally psychiatric
therapies will be used to treat catatonia as a secondary
behavioral manifestation of a medical illness. For example,

Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome

Table 55-3 Standardized Examination for Catatonia

The method described here is used to complete the 23-item
Bush-Francis Catatonia Rating Scale (BFCRS) and the 14-item
Bush-Francis Catatonia Screening Instrument (BFCSI). Item
denitions on the two scales are the same. The BFCSI
measures only the presence or absence of the rst 14 signs.
Ratings are based solely on observed behaviors during the
examination, with the exception of completing the items for
withdrawal and autonomic abnormality, which may be
based on directly observed behavior or chart documentation.
As a general rule, only items that are clearly present should be
rated. If the examiner is uncertain as to the presence of an
item, rate the item as 0.
Procedure
1. Observe the patient while trying to engage in a conversation.
2. The examiner should scratch his or her head in an
exaggerated manner.
3. The arm should be examined for cogwheeling. Attempt to
reposture and instruct the patient to keep your arm loose.
Move the arm with alternating lighter and heavier force.
4. Ask the patient to extend his or her arm. Place one nger
beneath his or her hand and try to raise it slowly after
stating, Do not let me raise your arm.
5. Extend the hand stating, Do not shake my hand.
6. Reach into your pocket and state, Stick out your tongue.
I want to stick a pin in it.
7. Check for grasp reex.
8. Check the chart for reports from the previous 24-hour
period. Check for oral intake, vital signs, and any incidents.
9. Observe the patient indirectly, at least for a brief period
each day, regarding the following:
Activity level

Waxy exibility

Abnormal movements

Gegenhalten

Abnormal speech

Mitgehen

Echopraxia

Ambitendency

Rigidity

Automatic obedience

Negativism

Grasp reex

From Fricchione G, Bush G, Fozdar M, et al: Recognition and treatment of

the catatonic syndrome, J Intensive Care Med 12:135-147, 1997.

lorazepam has been found to be effective in certain cases of

catatonia secondary to medical illness, and it has become the
rst-line treatment for catatonia regardless of etiology, as
discussed later.16 Electroconvulsive therapy (ECT) has been
used to treat lupus patients with catatonia22 and other secondary catatonias and remains the most effective treatment
for catatonia.23 Two or three ECT treatments are usually sufcient to lyse the catatonic state in routine cases, though a
course of four to six treatments is usually given to prevent
relapse, and ten to twenty treatments are sometimes needed
in difcult cases. Fatality rates of 50% or more were the rule
before the introduction of ECT.24
Intravenous (IV) amobarbital also leads to rapid resolution
in some patients with catatonic stupor.25 However, these
effects tend to be short-lived.
Neuroleptics have been frequently used to treat catatonia.
In addition to the variable response of catatonia to these

Table 55-4 Some Medical Complications Associated

with Catatonia
Simple Nonmalignant Catatonia
Aspiration
Burns
Cachexia
Dehydration and its sequelae
Pneumonia
Pulmonary emboli
Thrombophlebitis
Urinary incontinence
Urinary retention and its sequelae
Malignant Catatonia
Acute renal failure
Adult respiratory distress syndrome
Cardiac arrest
Cheyne-Stokes respirations
Death
Dysphagia due to muscle spasm
Disseminated intravascular coagulation
Electrocardiographic abnormalities
Gait abnormalities
Gastrointestinal bleeding
Hepatocellular damage
Hypoglycemia (sudden and profound)
Intestinal pseudo-obstruction
Laryngospasm
Myocardial infarction
Myocardial stunning
Necrotizing enterocolitis
Respiratory arrest
Rhabdomyolysis and sequelae
Seizures
Sepsis
Unresponsiveness to pain
Modied from Philbrick KL, Rummans TA: Malignant catatonia, J Neuropsychiatry Clin Neurosci 6:1-13, 1994.

drugs, neuroleptics may complicate matters; their use also

has precipitated catatonic reactions and NMS.12 At times
higher doses of antipsychotics are used to treat psychosis and
agitation, but it may worsen catatonia. Moreover, among the
292 patients with malignant catatonia reviewed by Mann and
colleagues,11 78% of those solely treated with a neuroleptic
died, compared with an overall mortality rate of 60%.
In 1983, both Lew and Tollefson26 (reporting on the usefulness of IV diazepam) and Fricchione and colleagues27
(reporting on the benet of IV lorazepam given to patients
in neuroleptic-induced catatonic states [including NMS])
suggested the use of IV benzodiazepines in primary psychiatric catatonia.
Bush and colleagues28 studied the use of lorazepam and
ECT in the treatment of catatonia. With a drug distribution
that is less rapid and less extensive, a relatively high plasma
level can be maintained, thus prolonging the clinical benet
of IV lorazepam.29 A switch to regular doses of lorazepam or
diazepam maintains the therapeutic effect. Lorazepam given
orally or via nasogastric tube in a daily dose of 6 to 20 mg
has also been used effectively. Diazepam (10 to 50 mg/day)

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Lorazepam
Dorsolateral prefrontal
Anterior cingulate/
medial orbitofrontal
(akinetic mutism and
dysautonomia)
Lateral orbitofrontal
(imitative and
repetitive behaviors)

GABAA

Cortex

GLU

Mesocorticolimbic
terminal zones

Supplementary
motor/motor/posterior
parietal cortex (rigidity,
initiation and termination
of movement)
Memantine
Amantadine

GABA: gamma
aminobutyric acid

GABA

Striatum

Pallidum
GPE

GPI
GABA

GABA

GLU

Figure 55-1 Basal ganglia thalamocortical

circuits and catatonia: a candidate loop.

Thalamus

GLU: glutamate
DA: dopamine
SN: substantia negra

VTA: ventral tegmental

area
GPI: globus pallidus interna
GPE: globus pallidus
externa

GABAA
SN/VTA
DA

Lorazepam

GABAB

GLU
Subthalamic
nucleus

Amantadine
Bromocriptine
Levodopa

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and clonazepam (1 to 5 mg/day) also have been used successfully, as has midazolam.29 If lorazepam is unsuccessful, ECT
should be considered.29
In a study of lorazepam treatment for NMS, rigidity and
fever abated in 24 to 48 hours, whereas secondary features
of NMS dissipated within 64 hours (without adverse
effects).30
Philbrick and Rummans13 reviewed 18 cases of malignant
catatonia; 11 out of 13 patients treated with ECT survived,
whereas only 1 out of 5 not treated with ECT survived. In
terms of NMS, 39 cases of ECT treatment have been reported;
34 of them improved. The message is clearwhen a patient
has malignant catatonia of any type, ECT should be used
expeditiously. Muscle relaxants, calcium channel-blockers,
carbamazepine, anticholinergics, lithium, thyroid medication,
stimulants, and corticosteroids have each been anecdotally
associated with resolution of catatonia.13 Adrenocorticotropic
hormone and corticosteroids also have been reported to work
in cases of lethal catatonia.11 Dopaminergic agents, such as
bromocriptine and amantadine, have been used successfully
in NMS.31 In a retrospective review of 734 cases, Sakkas and
colleagues32 concluded that these agents and the muscle
relaxant dantrolene led to improvement; bromocriptine and
dantrolene also were associated with a signicant reduction
in the mortality rate. However, in a prospective study of 20
patients, Rosebush and colleagues33 found that bromocriptine
and dantrolene were not efcacious.
In 1985, when it was suggested that psychogenic catatonia
and neuroleptic-induced catatonia (including NMS) shared a
common pathophysiology, use of specic dopaminergic or

GABA-ergic drugs in psychogenic catatonia untreated by neuroleptic medication also was suggested.21 Accordingly, it is of
interest that oral bromocriptine was used successfully for
catatonia that preceded neuroleptic exposure.34
Catatonia secondary to schizophrenia may be less responsive to lorazepam. In these patients, IV amantadine (available
in Europe) and more recently memantine have shown some
effectiveness in isolated cases, suggesting NMDA antagonist
therapeutics in this condition.35,36
Even if lorazepam has been helpful in lysing the catatonic
state, the patient will often still be left with psychotic symptoms and may eventually need antipsychotic medications. A
reasonable approach is to try an atypical neuroleptic while
maintaining the patient on lorazepam as a buffer against
reemergence of catatonia. If the catatonia has been malignant
as in NMS, a waiting period of approximately 2 weeks is
justied, although there are no systematic studies conrming
this. Indeed, rechallenging a patient who has had NMS with
an antipsychotic is controversial. Most investigators suggest
that antipsychotics should not be given until at least 2 weeks
after an episode of NMS has resolved and that rechallenge
should be with an atypical or with a typical neuroleptic of a
lower potency. Table 55-5 reviews management principles of
catatonia.

Prognosis and Complications

In patients with catatonia, the long-term prognosis is fairly
good in almost half the cases.37 Those with an acute onset,
depression, or a family history of depression have a better
prognosis.38 Periodic catatonias have good short- and long-

Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome

Table 55-5 Principles of Management of Catatonia

1. Early recognition is important; once catatonia has been
diagnosed, the patient must be closely observed and vital
signs taken frequently.
2. Supportive care is essential. Such care involves hydration,
nutrition, mobilization, anticoagulation (to prevent
thrombophlebitis), and precautions against aspiration.
3. Discontinue antipsychotics or other drugs, such as
metoclopramide, which can cause or worsen catatonia.
4. Restart recently withdrawn dopamine agonists, especially in
patients with parkinsonism.
5. Institute supportive measures (e.g., a cooling blanket if
hyperthermia is present or parenteral uids and
antihypertensives or pressors if autonomic instability
emerges and if malignant catatonia is suspected).
6. Maintain a high index of suspicion for the development of
medical complications and for new medical problems.
Modied from Philbrick KL, Rummans TA: Malignant catatonia, J Neuropsychiatry Clin Neurosci 6:1-13, 1994.

term prognoses. Neuromedically-induced catatonias vary in

prognosis in relation to their particular etiologies. Treatment
with ECT offers a good short-term prognosis for most catatonias, and maintenance ECT may often improve long-term
prognosis.
See Table 55-4 for medical complications associated with
simple and malignant catatonias.

NEUROLEPTIC MALIGNANT SYNDROME

Epidemiology and Risk Factors
Estimates of the risk for NMS have varied widely (from
0.02% to more than 3%). Different diagnostic criteria, survey
techniques, population susceptibilities, prescribing habits,
and treatment settings all contribute to the variance. In one
center with a large number of patients treated with antipsychotics, 1 out of every 500 to 1,000 patients was thought to
develop NMS.39 Age and gender do not appear to be reliable
risk factors, though young adult males may be more prone to
extrapyramidal symptoms (EPS). The fact that NMS occurs
around the world suggests that environmental factors are not
signicant predictors. While NMS can occur in association
with any disorder treated with a neuroleptic, certain conditions may elevate the risk of NMS. A history of catatonia is
a major risk for progression to the malignant catatonia of
NMS. Schizophrenia, mood disorders, neuromedical organic
brain disorders, alcoholism, and substance abuse disorders
have each been associated with NMS. The period of withdrawal from alcohol or sedative-hypnotics may increase the
risk of NMS due to aberrant thermoregulation and autonomic
dysfunction. Agitation, dehydration, and exhaustion may also
increase the risk for NMS. Basal ganglia disorders (e.g.,
Parkinsons disease, Wilsons disease, Huntingtons disease,
and tardive dystonia) are thought to place patients at increased
risk. Low serum iron appears to be a state-specic nding in
NMS, and patients with low serum iron in the context of
catatonia may be at greater risk for NMS if placed on neuro-

leptic medications. A history of NMS conveys the risk of

recurrence, with up to one-third of patients having a subsequent episode when rechallenged. High-potency neuroleptics
have been thought to produce an elevated risk and more
intense cases of NMS. Clozapine, for example, may cause
NMS with signicantly less rigidity. Nevertheless, use of
atypicals does cause NMS. It should be noted that withdrawal from antiparkinsonian agents or lorazepam has been
reported to cause NMS-like states. Studies have not supported any particular genetic predisposition, although case
reports have implicated an association with CYP2D6.39

Clinical Features and Diagnosis

Philbrick and Rummans13 suggested using the term malignant
catatonia rather than lethal catatonia (since not all cases are
lethal) to describe critically ill cases marked by autonomic
instability or hyperthermia (in contradistinction to cases of
simple, nonmalignant catatonia). The causes of malignant
catatonia are the same as those of simple catatonia. Pernicious
catatonia has also been used to describe this catatonic
variant.40
Neuroleptics have been viewed as potential causes because
NMS is considered a severe form of neuroleptic-induced
catatonia. NMS is a syndrome associated with the use of
neuroleptics and characterized by autonomic dysfunction
(with tachycardia and elevated blood pressure), rigidity,
mutism, stupor, and hyperthermia (associated with diaphoresis), sometimes in excess of 42 C. Hyperthermia is
reported in 98% of cases.39 The rigidity can become leadpipe in nature. Parkinsonian features, including cogwheel
rigidity, may be present. NMS (most often in the setting of
atypical antipsychotic use) may occur without rigidity or
other EPS or creatine phosphokinase (CPK) elevation. Mental
status changes occur in 97% of cases.39 Most often the NMS
patient will be in a catatonic state akin to akinetic mutism;
such patients may be alert, delirious, stuporous, or comatose.
Diagnostic criteria for NMS are found in Table 55-6,41 and
their overlap with features of catatonia are displayed in
Table 55-7.
EEGs are abnormal in roughly half of cases, most often
with generalized slowing that is consistent with encephalopathy.39 In contrast, computed tomography (CT) of the
brain and cerebrospinal uid (CSF) studies are normal in 95%
of NMS cases.39
In 1991 Rosebush and Mazurek22 found decreased levels
of serum iron in NMS and suggested a role for lowered iron
stores in the reduction of DA-receptor function.
Most commonly NMS develops over a few days, often
beginning with rigidity and mental status changes followed
by signs of hypermetabolism. The course is usually selflimited, lasting from 2 days to 1 month (once neuroleptics
are stopped and supportive measures are begun).39 Persistent
cases are usually secondary to use of depot neuroleptics
and ECT is highly effective in these cases. Although the
mortality rate has been reduced through better recognition
and management, there is still an approximately 10% risk of
death.39 Myoglobinuric renal failure may have long-term
consequences.

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MASSACHUSETTS GENERAL HOSPITAL COMPREHENSIVE CLINICAL PSYCHIATRY

Table 55-6 Diagnostic Criteria for Neuroleptic

Malignant Syndrome
Treatment with neuroleptics within 7 days of onset (2-4 weeks
for depot neuroleptics)
Hyperthermia ( 38 C)
Muscle rigidity
Five of the following:
1. Change in mental status
2. Tachycardia
3. Hypertension or hypotension
4. Tachypnea or hypoxia
5. Diaphoresis or sialorrhea
6. Tremor
7. Incontinence
8. Creatine phosphokinase elevation or myoglobinuria
9. Leukocytosis
10. Metabolic acidosis
Exclusion of other drug-induced, systemic, or neuropsychiatric
illness
Adapted from Caroff SN, Mann SC, Lazarus A, et al: Neuroleptic malignant
syndrome: diagnostic issues, Psychiatr Ann 21:130-147, 1991.

Table 55-7 Catatonia and Neuroleptic Malignant

Syndrome: Associated Features
NMS

Catatonia

Clinical Signs
Hyperthermia

Yes

Often

Motor rigidity

Yes

Yes

Mutism

Yes

Yes

Negativism

Often

Yes

Altered consciousness
Stupor or coma

Yes
Yes

Yes
Yes

Autonomic dysfunction
Tachypnea
Tachycardia
Abnormal BP
Diaphoresis

Yes
Yes
Yes
Yes
Yes

Often
Often
Often
Yes
Yes

Laboratory Results
CPK elevated

Yes

Often

Serum iron reduced

Yes

Probable

Leukocytosis

Yes

Often

BP, Blood pressure; CPK, creatine phosphokinase; NMS, neuroleptic malignant syndrome.

SEROTONIN SYNDROME
Denition

768

Serotonin is a neurotransmitter involved in many psychiatric

disorders. As serotonin levels increase, adverse central nervous
system (CNS) effects and toxicity may arise. Heightened
clinical awareness is necessary to prevent and to intervene
when a toxic syndrome secondary to serotonin excess emerges.
Serotonin syndrome (SS), as it is called, most commonly

occurs as a result of an interaction between serotonergic

agents and monoamine oxidase inhibitors (MAOIs). Signs of
SS include mental status changes (e.g., confusion, anxiety,
irritability, euphoria, and dysphoria), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea, and incontinence),
behavioral manifestations (e.g., restlessness and agitation),
neurological ndings (e.g., ataxia or incoordination, tremor,
myoclonus, hyperreexia, ankle clonus, and muscle rigidity),
and autonomic nervous system abnormalities (e.g., hypertension, hypotension, tachycardia, diaphoresis, shivering, sialorrhea, mydriasis, tachypnea, and hyperthermia).42-44

Epidemiology
The incidence of SS is unknown. There are no data to suggest
that gender differences confer any particular vulnerability to
the syndrome. Given the overlap of symptoms with NMS,
SS is often mistaken for it and thus may be underreported.
The existence of the syndrome in varying degrees also may
confound its recognition, as can unawareness on the part of
the majority of physicians.44 SS most often occurs in individuals being treated with psychotropics for a psychiatric
disorder. It occurs in about 14% to 16% of selective serotonin
reuptake inhibitor (SSRI) overdose patients.45
Most often SS involves some combination of an SSRI, an
MAOI, an antiparkinsonian agent, and lithium. At the outset,
patients will develop a peripheral tremor, confusion, and
ataxia; these features are followed by systemic signs (e.g.,
hyperreexia, diaphoresis, shivering, and agitation). If the
condition becomes more severe, fever, myoclonic jerking, and
diarrhea may develop. The syndrome can last from hours to
days after the offending agents have been stopped and supportive treatment has been initiated.

Clinical Features and Diagnosis

As with NMS, taking a detailed history is crucial. Use of two
or more serotonergic agents confers a greater risk of developing SS. Obtaining a history of neuroleptic use can be especially important because NMS shares many clinical features
with SS, as do other toxic syndromes.
Based on his review of 38 cases, Sternbach46 proposed
the rst operational denition of the syndrome in humans.
According to this schema, diagnosis requires the following
three criteria: an increase in, or addition of, a serotonergic
agent to an established medication regimen (in addition to
least three of the following features: mental status changes,
agitation, myoclonus, hyperreexia, diaphoresis, shivering,
tremor, diarrhea, and incoordination); other etiologies need
to be ruled out; and a neuroleptic must not have been started
or increased in dosage before the onset of the signs and
symptoms previously listed.
Based on a review of other diagnostic criteria, Keck and
Arnold42 modied Sternbachs criteria to include mental
status changes, agitation, restlessness, myoclonus, hyperreexia, diaphoresis, tremor, shivering, incoordination, autonomic nervous system dysfunction, hyperthermia, and muscle
rigidity. Most recently the so-called Hunter Serotonin Toxicity Criteria were proposed.47 If a patient has been exposed
to a serotonergic drug within the past 5 weeks and spontane-

Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome

ous clonus emerges, the patient has SS. If there is inducible

clonus or ocular clonus plus either agitation or diaphoresis,
SS is present. If there are tremor and hyperreexia, SS can
be diagnosed. If there are hypertonicity and temperature
greater than 38 C and either ocular or inducible clonus, SS
is present. This approach to SS diagnosis is hoped to be more
sensitive to serotonin toxicity and less prone to produce falsepositive cases.
A temporal relationship between the start of pharmacotherapy and the development of the syndrome exists. The
syndrome ranges from mild to severe, with a mildly affected
patient showing restlessness, tremor, tachycardia, shivering,
diaphoresis, and the start of hyperreexia. Moderate cases
will show tachycardia, hypertension, and fever, sometimes as
high as 40 C. There will also be mydriasis, strong bowel
sounds, hyperreexia, and clonus (greater in the lower
extremities than in the upper ones). Horizontal ocular clonus
will also be seen in moderate cases, and there will be mental
status changes of agitation, pressured speech, and autonomic
hyperactivity. Head rotation movement with neck extension
has also been reported. In severe cases, there will be severe
autonomic hyperactivity and severe hyperthermia with temperatures sometimes over 41.1 C. There is an agitated delirium accompanied by severe muscular rigidity, again greater
in the lower extremities. This severe hypertonicity may
obscure the appearance of clonus and hyperreexia and
thereby confound the diagnosis.
Laboratory abnormalities are mostly nonspecic or are
secondary to the medical complications of the syndrome. A
complete laboratory evaluation is nevertheless essential to
rule out other etiologies (for the signs and symptoms that are
shared with SS). Leukocytosis, rhabdomyolysis, and liver
function test abnormalities have all been reported in SS,
along with hyponatremia, hypomagnesemia, and hypocalcemia. It is thought that these latter disturbances are related
to uid and electrolyte abnormalities.
It is interesting to note that certain secreting tumors
(e.g., carcinoid and oat cell carcinoma) have been associated
with SS. Therefore, x-ray examinations and imaging of the
abdomen and lung may sometimes be helpful in working
up SS. An EEG and neuroimaging of the brain are often
useful in uncovering a seizure disorder or another neurological condition.
The most common drug interactions associated with SS
include MAOI-SSRI, MAOItricyclic antidepressant, and
MAOI-venlafaxine combinations. In general, when an SSRI
is used in combination with an MAOI, an SS is more
likely to occur. Drugs associated with SS are included in
Table 55-8.
Overdoses of MAOIs also have caused SS. Because of
the potential problems of using an MAOI and any medicine
with serotonergic properties, caution on the part of the prescribing physician is required. With this in mind, a 2-week
washout interval is required following discontinuation of
an MAOI before starting any serotonergic medications. In
the case of uoxetine discontinuation, there should be a
minimum 5-week washout period before an MAOI is
initiated.

Table 55-8 Central Nervous System Serotonergic

Agents
Enhanced Serotonin Synthesis
L-Tryptophan
Increased Serotonin Release
Cocaine
Amphetamines
Fenuramine
Dextromethorphan
Meperidine
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy)
Sibutramine
Serotonin Agonists
Buspirone
Dihydroergotamine (DHE)
Lithium
Meta-chlorophenylpiperazine (mCPP)
Sumatriptan
Trazodone
Inhibited Serotonin Catabolism
Isocarboxazid
Moclobemide
Phenelzine
Selegiline
Tranylcypromine
Inhibited Serotonin Reuptake
Amitriptyline
Bromocriptine
Clomipramine
Desipramine
Dextromethorphan
Fenuramine
Fluoxetine
Fluvoxamine
Imipramine
Meperidine
Mirtazapine
Nefazodone
Nortriptyline
Paroxetine
Pethidine
Sertraline
Tramadol
Trazodone
Venlafaxine
Modied from Keck PE, Arnold LM: The serotonin syndrome, Psychiatr Ann
30:333-343, 2000, p 336.

Pathophysiology
From both animal and human studies, the role of 5-HT has
been implicated in the pathogenesis of SS. Nucleus raphe
serotonin nuclei (located in the midbrain and arrayed in the
midline down to the medulla) are involved in mediating
thermoregulation, appetite, nausea, vomiting, wakefulness,
migraine, sexual activity, and affective behavior. Ascending
serotonergic projections are likely to play a role in the presentation of SS, particularly in the development of hyperthermia, mental status, and autonomic changes. The 5-HT2A45

769

MASSACHUSETTS GENERAL HOSPITAL COMPREHENSIVE CLINICAL PSYCHIATRY

and 5-HT1A receptors appear to be overactive in this condition, which has led some to use 5-HT1A antagonists in the
management of the SS. There also appears to be CNS norepinephrine overactivity. This is clinically signicant since
clinical outcomes may be associated with hypersympathetic
tone.44 The roles of catecholamines and 5-HT2 and 5-HT3
receptor interactions are unclear, as are the contributions of
glutamate, GABA, and DA.

Management and Treatment

No prospective studies have looked at treatment of SS. Recommendations for treatment are based solely on anecdotes.
SS is often self-limited, and removal of the offending agents
will frequently result in resolution of symptoms within 24
hours. Therefore, the initial step in managing SS is to discontinue the suspected offending agent or agents. The next
step is to provide supportive measures to prevent potential
medical complications. These supportive measures include
the use of antipyretics and cooling blankets to reduce hyperthermia, monitoring and support of the respiratory and
cardiovascular systems, IV hydration to prevent renal failure,
use of benzodiazepines for myoclonic jerking, use of anticonvulsants if seizures arise, and use of antihypertensive
agents for signicantly elevated blood pressures. In severe
cases with very high temperatures, patients should be intubated, sedated, and paralyzed. The syndrome rarely leads to
respiratory failure. When it does, it usually is because of
aspiration, and articial ventilation may then be required.
Benzodiazepine management of agitation, even when mild,
is essential in the SS. This is because benzodiazepines, such
as diazepam and lorazepam, can reduce autonomic tone and

temperature and thus may have positive effects on survival.44

Physical restraints should be avoided if at all possible because
muscular stress can lead to lactic acidosis and to elevated
temperature.
Specic 5-HT receptor antagonism has occasionally been
advocated for the treatment or prevention of the symptoms
associated with SS. Cyproheptadine, a 5-HT2A antagonist, has
been recommended.44 Mirtazapine, a 5-HT3 and 5-HT2
antagonist, has also been used in a small number of cases. For
hypertension, nitroprusside and nifedipine, and for tachycardia, esmolol, have been advocated.44 Since the rise in temperature is muscular in origin, antipyretics are of no use in
SS, and paralytics are required when fever is high.

Prognosis and Complications

Serotonin syndrome is relatively uncommon, though it is
thought to be underdiagnosed. Once begun, usually within
hours of medication initiation or dose increase or overdose,
the SS will continue as long as the serotonergic agents
continue to be taken. When mild, the symptoms may
become subacute or chronic. When severe, the SS can lead
to death from medical complications. Discontinuation of the
offending agents along with supportive care usually leads to
improvement.
In SS, rhabdomyolysis is the most common and serious
complication; it occurs in roughly one-fourth of cases.39 Generalized seizures occurred in approximately 10%, with 39%
of these patients dying. Myoglobinuric renal failure accounted
for roughly 5% of medical complications, as did diffuse intravascular coagulation (DIC). In those with DIC, nearly twothirds died.

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psychopathology to neurobiology, Washington, DC, 2004, American
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Mann SC, Caroff SN, Keck PE, Lazarus A: Neuroleptic malignant

syndrome and related conditions, ed 2, Washington, DC, 2003,
American Psychiatric Publishing.
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Sternbach H: The serotonin syndrome, Am J Psychiatry 148:705-713,
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Taylor MA: Catatonia: a review of a behavioral neurologic syndrome,
Neuropsychiatry Neuropsychol Behav Neurol 3:48-72, 1990.

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