55: Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome

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CHAPTER 55 Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome



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 derangements, 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 first named and defined in 1847 by Karl Kahlbaum, who published a monograph that described 21 patients with a severe psychiatric disorder.1 This was among the first 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 flexibility and posturing), a second stage of stupor or melancholy, a third stage of mania (with pressured speech, hyperactivity, and hyperthymic behavior), and finally, after repeated cycles of stupor and excitement, a stage of dementia.1

Kraepelin,2 who was influenced by Kahlbaum, included catatonia in the group of deteriorating psychotic disorders named “dementia praecox.” Bleuler3 adopted Kraepelin’s 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 five features: motoric immobility (as evidenced by catalepsy [including waxy flexibility] or stupor); excessive motor activity (that is apparently purposeless and not influenced 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 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 nonspecific 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.


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 identified 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 afflicted.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 mesolim-bic 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. Afflicted 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 co-workers’11 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.

Table 55-1 Modified Bush-Francis Catatonia Rating Scale

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

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

Extreme hypoactivity, immobility, and minimal response to stimuli. Verbal unresponsiveness or minimal responsiveness. Fixed gaze, little or no visual scanning of environment, and decreased blinking. Spontaneous maintenance of posture(s), including mundane (e.g., sitting/standing for long periods without reacting). Maintenance of odd facial expressions. Mimicking of an examiner’s movements/speech. Repetitive, non–goal-directed motor activity (e.g., finger-play, or repeatedly touching, patting, or rubbing oneself); the act is not inherently abnormal but is repeated frequently. 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. Repetition of phrases (like a scratched record). Maintenance of a rigid position despite efforts to be moved; exclude if cogwheeling or tremor is present. Apparently motiveless resistance to instructions or attempts to move/examine the patient. Contrary behavior; one does the exact opposite of the instruction. During reposturing of the patient, the patient offers initial resistance before allowing repositioning, similar to that of a bending candle. Refusal to eat, drink, or make eye contact. Sudden inappropriate behaviors (e.g., running down a hallway, screaming, or taking off clothes) without provocation. Afterward, gives no or only facile explanations. Exaggerated cooperation with the examiner’s request or spontaneous continuation of the movement requested. “Anglepoise lamp” arm raising in response to light pressure of finger, despite instructions to the contrary. Resistance to passive movement that is proportional to strength of the stimulus; appears automatic rather than willful. The appearance of being “stuck” in indecisive, hesitant movement. Per neurologic examination. Repeatedly returns to the same topic or persistence with movement. Usually aggressive in an undirected manner, with no or only facile explanation afterward. Abnormal temperature, blood pressure, pulse, or respiratory rate, and diaphoresis.

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 first 14 signs combine to form the Bush-Francis Catatonia Screening Instrument (BFCSI). The BFCSI measures only the presence or absence of the first 14 signs, and it is used for case detection. Item definitions on the two scales are the same.

From Bush G, Fink M, Petrides G, et al: Catatonia I. Rating scale and standardized examination, Acta Psychiatr Scand 93:129-136, 1996.

Table 55-2 Potential Etiologies of the Catatonic Syndrome

Primary Psychiatric
Acute psychoses
Conversion disorder
Dissociative disorders
Mood disorders
Obsessive-compulsive disorder
Personality disorders
Secondary Neuromedical
Other Central Nervous System Causes
Akinetic mutism
Alcoholic degeneration and Wernicke’s encephalopathy
Cerebellar degeneration
Cerebral anoxia
Cerebromacular degeneration
Closed head trauma
Frontal lobe atrophy
Lesions of thalamus and globus pallidus
Postencephalitic states
Seizure disorders
Surgical interventions
Tuberous sclerosis
Frontal lobe tumors
Langerhans’ carcinoma
Paraneoplastic encephalopathy
Periventricular diffuse pinealoma
Coal gas
Organic fluorides
Tetraethyl lead poisoning
Acquired immunodeficiency syndrome
Bacterial meningoencephalitis
Bacterial sepsis
General paresis
Subacute sclerosing panencephalitis
Tertiary syphilis
Typhoid fever
Viral encephalitides (especially herpes)
Viral hepatitis
Metabolic and Other Medical Causes
Acute intermittent porphyria
Addison’s disease
Cushing’s disease
Diabetic ketoacidosis
Hepatic dysfunction
Hereditary coproporphyria
Idiopathic hyperadrenergic state
Multiple sclerosis
Systemic lupus erythematosus
Thrombocytopenic purpura
Neuroleptics (typical and atypical); clozapine and risperidone (all neuroleptics have been associated)
Antidepressants (tricyclics, monoamine oxidase inhibitors, and others)
Anticonvulsants (e.g., carbamazepine, primidone)
Dopamine depleters (e.g., tetrabenazine)
Dopamine withdrawal (e.g., levodopa)
Hallucinogens (e.g., mescaline, phencyclidine, and lysergic acid diethylamide)
Lithium carbonate
Sedative-hypnotic withdrawal
Amphetamines, methylphenidate, and possibly cocaine

Most common medical conditions associated with catatonic disorder from literature review done by Carroll BT, Anfinson TJ, Kennedy JC, et al: Catatonic disorder due to general medical conditions, J Neuropsychiatry Clin Neurosci 6:122-133, 1994.

From Philbrick KL, Rummans TA: Malignant catatonia, J Neuropsychiatry Clin Neurosci 6:1-13, 1994.

Fortunately, while no one test can confirm 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 flow 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 specific 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 confidence (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 sufficient 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 identified all of their patients with catatonia. Their standardized examination method is consistent with the DSM-IV criteria for catatonia (Table 55-3).

Table 55-3 Standardized Examination for Catatonia

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