Catatonia is a psychomotor syndrome that has been reported to occur in more than 10% of patients with acute psychiatric illnesses. Two subtypes of the syndrome have been identified. Catatonia of the retarded type is characterized by immobility, mutism, staring, rigidity, and a host of other clinical signs. Excited catatonia is a less common presentation in which patients develop prolonged periods of psychomotor agitation. Once thought to be a subtype of schizophrenia, catatonia is now recognized to occur with a broad spectrum of medical and psychiatric illnesses, particularly affective disorders. In many cases, the catatonia must be treated before any underlying conditions can be accurately diagnosed. Most patients with the syndrome respond rapidly to low-dose benzodiazepines, but electroconvulsive therapy is occasionally required. Patients with longstanding catatonia or a diagnosis of schizophrenia may be less likely to respond. The pathobiology of catatonia is poorly understood, although abnormalities in gamma-aminobutyric acid and glutamate signaling have been suggested as causative factors. Because catatonia is common, highly treatable, and associated with significant morbidity and mortality if left untreated, physicians should maintain a high level of suspicion for this complex clinical syndrome. Since 1989, we have systematically assessed patients presenting to our psychiatry service with signs of retarded catatonia. In this paper, we present a review of the current literature on catatonia along with findings from the 220 cases we have assessed and treated.

Catatonia is a clinical syndrome characterized by a distinct constellation of psychomotor disturbances. Two subtypes have been described: Retarded and excited. Catatonia of the retarded type is associated with signs reflecting a paucity of movement, including immobility, staring, mutism, rigidity, withdrawal and refusal to eat, along with more bizarre features such as posturing, grimacing, negativism, waxy flexibility, echolalia or echopraxia, stereotypy, verbigeration, and automatic obedience[1-3]. Excited catatonia, on the other hand, is characterized by severe psychomotor agitation[4], potentially leading to life-threatening complications such as hyperthermia, altered consciousness, and autonomic dysfunction. This so-called “malignant” or “lethal” catatonia can be rapidly fatal if not appropriately treated[5,6]. The relative prevalence and diagnostic significance of catatonic signs differ among studies and patient populations, but there is general agreement that catatonia occurs in 9%-17% of patients with acute psychiatric illnesses[1,2,7] and that retarded catatonia is the more frequently observed subtype[4,8-10].

The catatonic syndrome is associated with other disorders, underscoring the necessity of rapid diagnosis and treatment. In particular, catatonia appears to be a risk factor for the development of neuroleptic malignant syndrome[11-13], which has a mortality rate of approximately 10%[14] and may be clinically indistinguishable from malignant catatonia[15,16]. This has important implications for the treatment of catatonia in the context of psychosis, which will be discussed later in this review. Additionally, the immobility and refusal to eat or drink associated with catatonia can give rise to potentially serious medical complications, including dehydration[17], malnutrition[18,19], deep vein thrombosis and pulmonary embolism[20,21], pneumonia and other infections[17], pressure ulcers[19], and muscle contractures[18,19]. The very nature of catatonia can make it challenging, if not impossible, to carry out patient interviews and examinations, thereby interfering with the recognition of underlying diagnoses. These complications of catatonia highlight the importance of recognizing the syndrome and quickly initiating treatment.

Overall, it is clear that catatonia is a common and serious problem that often remains unrecognized. Despite a renewed interest in the disorder over the last several decades[22], a number of questions remain regarding its causes and treatment. In this paper, we review the current understanding of the diagnosis, treatment, and pathophysiology of catatonia, and we identify several areas of uncertainty where further research is required.

All patients suspected of having catatonia should have EEG testing as a screen for other neurological conditions. This will typically show epileptiform activity in nonconvulsive status epilepticus and slowing in cases of encephalopathy. The EEG in catatonia is typically normal unless there is a concurrent condition that may be causing the abnormality[1,9,46]. Given that catatonia can develop in the context of a wide array of neurological conditions, brain imaging, preferably by MRI, is recommended[1,47]. In cases of retarded catatonia, immobility generally allows these investigations to be conducted easily. Laboratory investigations should include a complete blood count, blood urea nitrogen, creatinine, muscle and hepatic enzymes, thyroid function tests, electrolytes, blood glucose, and urinalysis to assess for comorbid conditions, causes, or complications of catatonia. Marked dehydration is not uncommon in catatonic patients, and must be attended to. Vital signs should be assessed frequently, as hypertension and fever (often accompanied by elevated creatine phosphokinase, decreased serum iron, and leukocytosis) may herald the onset of malignant catatonia or neuroleptic malignant syndrome if the patient has received antipsychotic agents[35,48-50]. When possible, a careful review of the patient’s recent medications and any changes should be conducted. It is important to determine whether or not a patient has been receiving antipsychotic agents or benzodiazepines, as we have reported, and continue to see, the development of catatonia following abrupt discontinuation of benzodiazepines[51,52].

Unfortunately, the nature of catatonia makes some aspects of a physical and neurological exam impossible. Components of the neurological exam that can usually be assessed include the pupillary reaction, ocular movements, corneal reflex, reaction to pain, the presence of drooling, blink response to threat, reaction to light or sound, frontal release signs, assessment of tone, deep tendon reflexes, and the plantar response.

A characteristic feature of catatonia is its striking responsiveness to benzodiazepine treatment. We recommend an initial dose of 1-2 mg lorazepam, administered sublingually or intramuscularly. The ability to administer lorazepam intramuscularly is a major advantage, since many catatonic patients refuse to eat or take medication by mouth. A lower lorazepam dose is preferable in patients who are young, elderly, or medically compromised, especially when there is a diagnosis or high likelihood of sleep apnea. If the initial dose is ineffective, it should be repeated in 3 h and again after another 3 h. We have analyzed treatment response in 153 patients treated with lorazepam. In this group, we have observed a response in 132 (85.7%), 90 of whom experienced complete recovery within 3 h. This robust response to low-dose lorazepam has also been reported by others[46,53], but higher doses may be necessary in some cases[54,55]. If a patient responds adequately to benzodiazepine treatment, they should continue on the same dose (provided that this dose is not overly sedating or causing any other problematic side-effects) until treatment of any underlying disorder is underway. Relapse into a catatonic state can occur if benzodiazepines are discontinued before this. In our experience, a subset of patients may develop catatonia whenever attempts are made to discontinue lorazepam, and these patients may require long-term maintenance treatment[56]. This phenomenon has also been reported by others[57].

It should be noted that patients with long-standing catatonia may not respond as robustly or as rapidly to benzodiazepine treatment as those with acute catatonia[54,58]. We have reported the cases of two brothers, one of whom had been catatonic for 2 wk prior to treatment, while the other had been hospitalized with catatonia for 5 years[59]. The first brother recovered completely in 2 wk on a lorazepam dose of 3 mg/d. The second brother, on the other hand, showed only gradual improvement on lorazepam 4 mg/d before being discharged from hospital a year after treatment initiation.

An underlying diagnosis of schizophrenia may be associated with a less robust response to benzodiazepine treatment[53]. We have observed a response rate of only 59.1% in patients with schizophrenia, compared with a response rate of over 90% in patients with other psychiatric diagnoses (Table 2). The poorer treatment response in patients with schizophrenia may be related to the chronicity of symptomatology, or it may suggest a distinct underlying pathophysiology, perhaps reflecting the prominence of psychosis affecting their motor behaviour. Nevertheless, benzodiazepines can be effective for treating catatonia in many patients with schizophrenia, and a therapeutic trial is warranted. This is especially the case given the overall safety of benzodiazepine medication.

ECT is another highly effective option for the treatment of catatonia[9,60], and even patients who do not respond to benzodiazepines are likely to respond to ECT[61,62]. Despite its effectiveness, ECT has an important drawback: It requires clear consent. Catatonic patients are unable to discuss ECT or consent to its administration, and consent from a substitute decision maker is often difficult to obtain. Because of these problems, and because benzodiazepines are easily administered and have a high margin of safety, we recommend that benzodiazepines be used as the first line of treatment. ECT should be considered in patients who fail to respond to benzodiazepines after several days and surrogate consent should be sought. The exception to this strategy is the patient with malignant catatonia, for whom ECT should be administered early, since the condition has a high rate of mortality if it is not rapidly and effectively treated[6,49].

Of the catatonic patients we have assessed, 77.7% later reported having experienced psychotic symptoms during the catatonic episode. This raises a difficult problem in treatment, since antipsychotic medications may be associated with an increased risk of neuroleptic malignant syndrome in patients with catatonia. White et al[12] identified 17 consecutive patients with neuroleptic malignant syndrome, all of whom exhibited catatonic signs prior to antipsychotic exposure. In our own patients, we have observed that 3.6% of catatonic patients treated with antipsychotic medications developed neuroleptic malignant syndrome[63]. This is in contrast to an incidence of 0.07%-1.8% in all patients treated with antipsychotic drugs[64,65]. Raja et al[11] identified 3 cases of neuroleptic malignant syndrome in a series of consecutive patients presenting to the psychiatric emergency service, all 3 of whom demonstrated catatonic signs and low serum iron prior to the onset of neuroleptic malignant syndrome. The relationship between catatonia and neuroleptic malignant syndrome is not limited to patients treated with typical antipsychotics, as clozapine has also been reported to be a precipitating factor[13]. Although more research is required in order to identify which patients are most susceptible to neuroleptic malignant syndrome, we feel that the existing evidence is sufficient to recommend the avoidance of antipsychotic drugs in acutely catatonic patients. In our experience, once catatonic symptoms have been treated by benzodiazepines or ECT and patients are eating, drinking, and walking, antipsychotic treatment can be initiated safely.

Although lorazepam and ECT have long been recognized as effective treatments for patients with catatonia, other options have been suggested. Several case reports have described patients effectively treated with zolpidem[66,67], which, like typical benzodiazepines, may treat catatonia through interactions with GABA-A receptors[68]. As well, amantadine and memantine, which act as NMDA antagonists but also interact with a number of other neurotransmitter systems, have shown efficacy in a small number of patients[69,70]. It is not yet clear whether these options are likely to be helpful in the small fraction of patients who do not respond to either lorazepam or ECT.

While the pathophysiology of catatonia is still unclear, several theories have been proposed based on the available data. One possible interpretation of catatonia is that the syndrome is an outward manifestation of intense anxiety[22,71]. The majority of catatonic patients we have treated reported feeling extremely anxious before and during their catatonic episode, to the extent that some believed they were about to die, had already died, or that they needed to remain immobile in order to avoid threats from others. Benzodiazepines reduce anxiety by enhancing chloride conductance through GABA-A receptor ion channels, and may treat catatonia through this mechanism. However, a number of our patients - particularly those with schizophrenia - reported little anxiety during their catatonic episode. This observation does not exclude the possibility that anxiety is an important component of catatonia, but suggests that it is not an essential component for all patients with the syndrome.

A second interpretation of catatonia is that it is essentially a movement disorder similar to parkinsonism. As noted previously, the clinical features of catatonia overlap with those of parkinsonism, which is understood to be caused by dysfunction of the basal ganglia. Since most projection neurons in the basal ganglia are GABAergic, it is plausible that benzodiazepines could treat catatonia by influencing GABA signaling in the basal ganglia. Functional imaging studies have shown that catatonia is associated with altered activity in orbitofrontal, prefrontal, parietal, and motor cortical regions[72], suggesting that these cortical structures may also play a role in the pathophysiology of catatonia. This interpretation is reinforced by observations that GABA-A binding is reduced in cortical regions of catatonic patients, motor and affective symptoms are correlated with these abnormalities in GABA-A binding, and cortical abnormalities in catatonic patients are normalized following exposure to lorazepam[72].

Whatever the pathophysiology of catatonia may be, it is clear that a wide variety of underlying disorders can be associated with the emergence of catatonic signs. These include mood disorders, nonaffective psychotic disorders, a number of medical and neurological conditions, and genetic disorders[73]. How - or if - these diverse etiologies converge upon a final common pathway causing catatonia is unknown, and it is possible that variations in the clinical presentation of catatonia represent distinct underlying mechanisms that would respond preferentially to different treatments. For instance, future research may allow physicians to identify patients who are unlikely to respond to lorazepam treatment and should receive ECT or another pharmacological treatment as a first line option.

The syndrome of catatonia encompasses a wide range of psychomotor abnormalities, none of which are present in all patients. Immobility and mutism are especially common, and the presence of these signs should prompt physicians to actively assess other markers of catatonia. The differential diagnosis of catatonia is complex, and catatonia itself can arise from a diverse array of psychiatric and medical etiologies, complicating the investigation of these patients. Affective disorders are the most common underlying psychiatric diagnoses. Fortunately, most catatonic patients rapidly respond to low-dose lorazepam. Some patients, particularly those with long-standing catatonia or schizophrenia, may respond more gradually or not at all to lorazepam, and may require ECT or other pharmacological treatments. We feel that the use of antipsychotics should generally be avoided until the acute catatonic episode has resolved in order to avoid precipitating neuroleptic malignant syndrome. The pathophysiology of catatonia is still poorly understood, and it is unclear whether different constellations of clinical signs might represent distinct underlying mechanisms. Recognizing and treating catatonia usually results in rapid resolution of the syndrome, whereas failing to recognize it may lead to potentially fatal complications including infection, neuroleptic malignant syndrome, and pulmonary embolism. Because of this, physicians should maintain a high level of suspicion for the catatonic syndrome, especially in patients experiencing an acute psychiatric illness.