Definition

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.

Subtypes

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

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 significant 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., Parkinson’s disease, Wilson’s disease, Huntington’s disease, and tardive dystonia) are thought to place patients at increased risk. Low serum iron appears to be a state-specific finding in NMS, and patients with low serum iron in the context of catatonia may be at greater risk for NMS if placed on neuroleptic 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 significantly 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 “lead-pipe” 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.

Table 55-6 Diagnostic Criteria for Neuroleptic Malignant Syndrome

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

Definition

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 findings (e.g., ataxia or incoordination, tremor, myoclonus, hyperreflexia, 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., hyperreflexia, 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 first operational definition 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, hyperreflexia, 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 modified Sternbach’s criteria to include mental status changes, agitation, restlessness, myoclonus, hyperreflexia, 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 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 hyperreflexia, 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 false-positive 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 hyperreflexia. Moderate cases will show tachycardia, hypertension, and fever, sometimes as high as 40° C. There will also be mydriasis, strong bowel sounds, hyperreflexia, 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 hyperreflexia and thereby confound the diagnosis.

Laboratory abnormalities are mostly nonspecific 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 fluid 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, MAOI–tricyclic 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.

Table 55-8 Central Nervous System Serotonergic Agents

Modified from Keck PE, Arnold LM: The serotonin syndrome, Psychiatr Ann 30:333-343, 2000, p 336.

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 fluoxetine discontinuation, there should be a minimum 5-week washout period before an MAOI is initiated.

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-HT_2A⁴⁵ and 5-HT_1A receptors appear to be overactive in this condition, which has led some to use 5-HT_1A antagonists in the management of the SS. There also appears to be CNS norepinephrine overactivity. This is clinically significant 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 significantly 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 artificial 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.

Specific 5-HT receptor antagonism has occasionally been advocated for the treatment or prevention of the symptoms associated with SS. Cyproheptadine, a 5-HT_2A 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 two-thirds died.