Evidence-based consensus guidelines for the management of catatonia: Recommendations from the British Association for Psychopharmacology

1Introduction 2

2Guideline rationale 2

3Guideline method 2

4Strength of evidence and recommendations 3

5Background 3

6History 3

7Definition 3

8Aetiology 5

9Catatonia due to a medical condition 5

10Catatonia due to another psychiatric disorder 6

11Clinical features 6

12Descriptive epidemiology 8

13Clinical assessment 8

14History and physical examination 8

15Rating instruments 9

16Investigations 10

17Challenge tests 12

18Lorazepam and other benzodiazepines 12

19Zolpidem 13

20Other drugs 13

21Differential diagnosis 13

22Treatment 16

23General approach 16

24First-line treatment 16

25Non-response 17

26Underlying condition 17

27Complications 17

28GABA-ergic pharmacotherapies 17

29Electroconvulsive therapy 18

30Other therapies 19

31NMDA receptor antagonists 19

32Dopamine precursors, agonists and reuptake inhibitors 20

33Dopamine receptor antagonists and partial agonists 20

34Anticonvulsants 21

35Anticholinergic agents 21

36Miscellaneous treatments 21

37Repetitive transcranial magnetic stimulation and transcranial direct-current stimulation as alternatives to ECT 21

38Subtypes of catatonia and related conditions 21

39Periodic catatonia 21

40Malignant catatonia 22

41Neuroleptic malignant syndrome 23

42Antipsychotic-induced catatonia 25

43Considerations in special groups and situations 25

44Children and adolescents 25

45Older adults 26

46The perinatal period 26

47The reproductive safety of lorazepam in the perinatal period 26

48The use of ECT in the perinatal period 27

49Autism spectrum disorder 28

50Medical conditions 28

51Considerations in kidney disease 28

52Considerations in liver disease 28

53Considerations in lung disease 29

54Research priorities 29

55Acknowledgement 30

56Declaration of conflicting interests 30

57Funding 30

58Supplemental material 30

59References 30

60Catatonia is a severe neuropsychiatric disorder affecting movement, speech and complex behaviour, often involving autonomic and affective disturbances. It has been associated with excess morbidity and, sometimes, mortality compared to other serious mental illnesses. For much of the 20th century, catatonia was considered a subtype of schizophrenia, but, in recent decades, emerging evidence has shown that catatonia can occur in a range of psychiatric, neurological and general medical conditions. This is now reflected in both the International Classification of Diseases, Eleventh Edition (ICD-11) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), which acknowledge the existence of catatonia in a range of conditions. However, recognition of catatonia is often poor, and knowledge about the condition and its distinctive treatments is frequently limited among clinicians. There are no national UK guidelines that adequately cover the management of catatonia. The only UK guidance that mentions catatonia is the 2003 National Institute for Health and Care Excellence (NICE) Technology Appraisal (TA59) on the use of electroconvulsive therapy (ECT), which recognises catatonia as an indication for ECT, but there is no consideration of pharmacological treatment for catatonia. From an international perspective, the European Association of Psychosomatic Medicine and the US Academy of Consultation-Liaison Psychiatry have produced guidelines for the management of the subpopulation of patients with catatonia that occurs in medically ill patients. The schizophrenia guidelines from the World Federation of Societies of Biological Psychiatry, the American Psychiatric Association (APA) and the German Association for Psychiatry, Psychotherapy and Psychosomatics briefly mention catatonia and suggest treatment with benzodiazepines, glutamate antagonists (amantadine and memantine) or ECT. There is a clear gap in the literature for a multidisciplinary consensus guideline that comprehensively reviews the current evidence and offers treatment recommendations.

61To address this need for a guideline, the British Association for Psychopharmacology (BAP) convened a group of experts with representation from general adult psychiatry, neuropsychiatry, child and adolescent psychiatry, liaison (consultation-liaison) psychiatry, perinatal psychiatry, autoimmune neurology, movement disorder neurology, pharmacy and primary care. Group members spanned the UK, USA, Canada, India and Germany, and were a mixture of disease experts and those with expertise in psychopharmacology, neuroimaging, epidemiology and clinical trials. There was patient representation on the group from its inception.

62A virtual meeting was convened in June 2022, where group members presented proposals for separate sections of the guideline, which were discussed by the overall group. Following the meeting, certain group members drafted sections of the guideline, which were edited and synthesised into a first draft. This draft was then disseminated to all authors for further amendments before a second draft was made for further review.

63The recommendations are summarised in an algorithm in Figure 1. A list of the recommendations apart from the rest of the manuscript is provided in Supplemental Material 1. Supplemental Material 2 provides a plain language summary of the guidelines for patients and carers. Example slides, which may be used for presentations of the guidelines, are available in Supplemental Material 3.

64To assess the strength of evidence and recommendations, the guideline group adopted the schema developed by. This system provides categories of evidence for the purposes of assessing causal relationships as well as a classification of the strength of recommendations. To grade the strength of evidence for non-causal relationships, we used the classification employed for the British Association for Pharmacology guidelines for the pharmacological treatment of schizophrenia, as shown in Table 1.

65Descriptions of what was likely catatonia date back to antiquity. However, major interest in motor manifestations of psychiatric disorders began only in the mid-19th century. At that time, Griesinger drew a distinction between abnormal movements that were the product of agency and those that were unconscious processes. The term ‘catatonia’ was coined by Karl Ludwig Kahlbaum in 1874, who described an early phase of alternation between excitement and stupor, followed by a phase of qualitatively abnormal movements, though other 19th-century authors had described similar phenomena.

66By the end of the 19th century, Kraepelin’s diagnostic classifications of psychiatric disorders incorporated catatonia into an enlarged concept of dementia praecox where motor signs were the result of psychological processes, and therefore catatonia was subsumed under the diagnosis of schizophrenia by Eugen Bleuler. This differed from Kahlbaum, who had conceived of catatonia as an independent disorder with motor, behavioural and affective signs as primary manifestations of the disorder. Moreover, Kahlbaum emphasised the strong occurrence of affective symptoms in combination with motor and behavioural abnormalities.

67Catatonia as a subtype of schizophrenia went on to be the conceptual model used by earlier editions of the ICD and DSM. However, two papers published in 1976 challenged this assumption, arguing that catatonia appears in a range of psychiatric and medical disorders, not exclusively (or even mainly) in schizophrenia. The current major diagnostic manuals (ICD-11 and DSM-5-TR) have since endorsed a broader concept of catatonia and permit diagnosis in the context of other mental and physical disorders, as well as providing an ‘unspecified’ category.

68Unlike many psychiatric disorders, where there is an emphasis on symptoms, the clinical features of catatonia largely consist of observed or elicited signs. More than 50 such signs have been identified. These signs cover focal motor activity (e.g. catalepsy, posturing, mannerisms, stereotypies, grimacing and echopraxia), generalised motor activity (stupor and agitation), speech (mutism, verbigeration and echolalia), affect (affective blunting, anxiety and ambivalence), complex behaviour (negativism, reduced oral intake and withdrawal) and autonomic activity (tachycardia and hypertension). They concern failures in initiation of activity (stupor, mutism and reduced oral intake) and in cessation of activity (perseveration, catalepsy and posturing).

69With such a wide range of clinical signs, there is a need to identify which may be specific to catatonia. Those that have little specificity (e.g. tachycardia and anxiety) are unlikely to be very useful diagnostically, although they may be helpful in gauging severity and treatment response. In terms of sensitivity, studies have failed to identify any catatonic feature that is invariably present in catatonia, which is the case for many psychiatric disorders.

70If there are no clinical signs that are pathognomonic of catatonia, it is reasonable to use a combination of clinical signs. The question then is how many signs should be used. Between two and four signs have been proposed as an appropriate threshold. One important study had an a priori threshold of two catatonic signs and found that there was a high response rate to a lorazepam challenge, but ultimately all included patients had at least three signs. Others propose the presence of at least one motor, one behavioural and one affective sign. Such a definition of catatonia conforms to the psychomotor concept introduced by, and it does not regard any of the catatonic signs as pathognomonic for catatonia.

71Without a gold-standard biomarker, there can only be moderate confidence around the validity of diagnostic criteria. There is also a certain circularity to defining a syndrome based on response to benzodiazepines, then testing the same drugs as treatments. However, benzodiazepine response can perhaps be considered as a surrogate marker for some form of as yet not fully characterised pathophysiological process, although the response to benzodiazepines is not universal.

72One of the more compelling pieces of evidence for a requirement of three catatonic signs derives from a cluster analysis of potential catatonic features, which distinguished patients with and without catatonia. Using this as a gold standard, the authors ascertained that a combination of at least three signs best fitted the cluster-derived catatonic syndrome. A threshold of four catatonic signs is highly specific but may miss some cases and thus have poorer sensitivity.

73Definitions of different forms of catatonia are shown in Table 2.

74Recommendation on the definition of catatonia

75Catatonia should be diagnosed based on the presence of three or more catatonic signs, as in DSM-5-TR or ICD-11. (B)

76Catatonic signs are not uncommon and can occur in many psychiatric and medical disorders. The lingering nosological legacy of catatonic schizophrenia, whereby catatonia necessarily implied schizophrenia, has been laid to rest by ICD-11 and DSM-5-TR, where catatonia can now be diagnosed in the context of many different conditions. The terms ‘organic’ or ‘secondary’ catatonia have been used in the past to signify underlying medical or neurological aetiological conditions. However, the distinction between ‘organic’ and ‘functional’ is perhaps best avoided due to their differing connotations in disparate clinical settings.

77Our consideration of the medical and psychiatric conditions underlying catatonia is largely based on clinical judgements in the published literature about what is likely to have led to catatonia, rather than on robust epidemiological associations. Often there is a close temporal relationship and sometimes a concomitant response to treatment. However, the literature largely rests on heterogeneous case reports and series, sometimes lacking standardised assessment. Many reports do not fulfil the Bradford Hill criteria for causation. Moreover, as prolonged or severe catatonia can, in turn, result in medical complications, it can be difficult to elucidate the cause-and-effect dilemma in some cases. However, it is hard to design studies to test for aetiological links, as there is under-detection and a lack of comprehensive investigations in many cases with catatonia. This may lead to a publication bias at both ends, with many cases going under-reported but the more dramatic ones finding favour for publication.

78There is evidence to suggest that in about 20% of patients with catatonia in unselected populations and more than 50% of patients with catatonia in acute medical and surgical settings there is an associated medical disorder that may be contributing to their presentation; this percentage rises to almost 80% in older patients. These figures exclude catatonic signs seen in neuroleptic malignant syndrome (NMS). There are several clinical features that suggest a higher likelihood of ‘medical catatonia’, and these include comorbid delirium, clinically significant autonomic disturbances, catatonic excitement, presence of the grasp reflex, pneumonia, known history of a neurological condition and history of seizures.

79describes the common underlying medical disorders associated with catatonia in a systematic review of 11 studies, with inflammatory brain disorders contributing 28.8% out of a total of 302 patients. These disorders include encephalitis (most common) and systemic lupus erythematosus (SLE), followed by neural injury (19.2%; with vascular and degenerative conditions the most common causes of injury), toxins or medications (11.6%; such as benzodiazepine withdrawal), structural brain pathology (9.6%; such as space occupying lesions) and epilepsy (9.3%), with miscellaneous disorders and states (such as hyponatremia, postpartum, renal failure and sepsis) contributing 19.5%. Unlike delirium, where metabolic and systemic disorders predominate, 68.9% of medical disorders underlying catatonia were secondary to a central nervous system (CNS)-specific disease.

80The medical disorders underlying catatonia listed in this guideline are not a comprehensive list, as such a compilation is out of the scope of this guidance. In Table 3, we provide a selection of the most important underlying disorders.

81In terms of focal neurological lesions in catatonia, there are case reports of catatonia associated with lesions to the frontal, parietal and temporal lobes, basal ganglia, diencephalon and cerebellum and lesions around the third ventricle. However, larger studies have found that most of the structural neuroimaging abnormalities in catatonia consist of generalised atrophy or non-specific white matter abnormalities.

82In terms of functional neuroimaging, decreased activation in the contralateral motor cortex, decreased regional cerebral blood flow (r-CBF) in right fronto-parietal cortex and decreased density of γ-aminobutyric acid (GABA)-A receptors in the left sensorimotor cortex and right parietal cortex have all been found.

83In DSM-5-TR, catatonic signs represent a specifier for autism spectrum disorder, mood disorders (major depressive disorder, bipolar I disorder and bipolar II disorder), psychotic disorders (schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder and substance-induced psychotic disorder) and another medical condition. The DSM-5-TR also includes a category for unspecified catatonia. The DSM-IV Handbook of Differential Diagnosis provided a helpful hierarchy of diagnosis for catatonia, with medical aetiology first, followed by antipsychotic-induced catatonia, then substance intoxication or withdrawal, and then bipolar disorder and major depression, and then other psychiatric disorders including schizophrenia. This remains a useful hierarchy for clinical use.

84Among primary psychiatric disorders, observational studies have reported catatonia in association with depression, mania, schizophrenia, autism spectrum disorder, anxiety disorders and postpartum psychosis. Other psychiatric disorders with evidence from case reports or case series include obsessive-compulsive disorder and post-traumatic stress disorder (; Dhossche et al., 2010b;; ).

85Given that catatonic signs can fluctuate over time, catatonic signs should be examined both cross-sectionally and longitudinally using the diagnostic systems ICD-11 and DSM-5-TR or one of the available clinical rating scales (for details, see sections ‘History and physical examination’ and ‘Rating instruments’). The characteristic motor signs include mannerisms, stereotypy, festination, athetotic movements, dyskinesias, Gegenhalten, posturing, catalepsy, waxy flexibility (flexibilitas cerea), rigidity, muscular hypotonus, sudden muscular tone alterations and akinesia. The characteristic affective features include compulsive emotions, emotional lability, impulsivity, aggression, excitement, affect-related behaviour, flat affect, affective latency, anxiety, ambivalence, staring and agitation. The cognitive-behavioural catatonic features include grimacing, verbigeration, perseveration, aprosodic speech, abnormal speech, automatic obedience, echolalia/echopraxia, Mitgehen/Mitmachen, compulsive behaviour, negativism, autism/withdrawal, mutism, stupor, loss of initiative and vegetative abnormalities. From a longitudinal perspective, catatonic signs often fluctuate and patients can show different forms of catatonia at different points in their illness.

86The courses and outcomes of catatonia vary. A rare form of catatonia is ‘periodic’ catatonia (see Table 2 for overview of different forms of catatonia), characterised by a cyclic pattern of akinesia (stupor) and hyperkinesia (excitement), with intervals of remission (see section ‘Periodic catatonia’ for more details). Acute catatonic states can be rapidly relieved due to early therapy or may become a residual state. The clinical profile of catatonia observed in patients with chronic psychotic disorders appears to be different from that seen in acutely emerging mostly stuporous catatonic states (see e.g.).

87Many estimates of catatonia prevalence in various populations of patients seen in mental health services are available. provided a synthesis of these results and the headline figure is that about 9% (95% confidence interval (CI): 6.9–11.7%) of mental health patients have features of catatonia. However, there are some important considerations to keep in mind. First, there is considerable variation across the studies that is not explained by sampling variation alone. For example, the larger studies reported much lower prevalence. For studies where n was greater than 1000, the prevalence was 2.3% (95% CI: 1.3–3.9%). Some of these studies also estimated prevalence within a series of patients with schizophrenia, which might be expected to have a higher prevalence than in individuals with some other mental disorders. There did not appear to be a consistent relationship between catatonia prevalence and whether the study was conducted in high-income or low- and middle-income countries. Second, many of these studies relied upon clinical diagnoses. It is probable that catatonia is under-diagnosed clinically and the smaller studies were far more likely to have used a systematic means of identifying catatonia, thereby explaining higher reported prevalence.

88estimated an incidence of catatonia in the general population, in London, UK, finding that catatonia occurred in 10.6 (95% CI: 10.0–11.1) per 100,000 person-years, but this also relied upon the mention of catatonia in the healthcare notes. In a large recent study in US non-federal general hospitals, a discharge diagnosis with an ICD-10 catatonia code occurred in 0.05% of hospital admissions.

89Some reports indicate a temporal decline in the diagnosis of catatonia in routinely collected data. described a drop in incidence of catatonic schizophrenia between the 1950s and 1970s in Finnish registry data, especially in the age group of 25–40 years. However, it is possible that this apparent decline is a result of changes in diagnostic practice rather than a true change in incidence. reported that the apparent decline in catatonia between 1980 and 2000 in routine diagnostic data from the Netherlands could be explained by a change in diagnostic habits. A sample of patients with more detailed clinical data illustrated a high frequency of catatonic presentations from 2001 to 2003. reported an increase in incidence between 2007 and 2016. The varying interest in catatonia and changes in diagnostic practice over time make the interpretation of time trend data very difficult.

90Several studies conducted in Western nations have found that catatonia was more common among individuals from ethnic minorities, often by a large margin.

91Studies commonly identify at least three factors or principal components of catatonia, which include hyperkinetic, hypokinetic and parakinetic (i.e. abnormal movements) phenotypes. Therefore, as a rule, catatonia should be considered as a differential diagnosis whenever a patient exhibits substantially altered levels of motor activity or abnormal behaviour, especially where it is grossly inappropriate to context.

92The diagnosis of catatonia can typically be made on clinical assessment alone, even though patients with catatonia are often unable to provide a clear narrative history. Collateral sources of information should be sought to clarify potential explanations for the presenting syndrome and time course. The clinician should seek detailed information regarding the patient’s medical, neurological and psychiatric history, along with exposure to or withdrawal from medications (plasma concentration measurement may be used to ascertain concordance where available), recreational substances and blood-borne or sexually transmitted infections (Table 4). It is also important to obtain a detailed family medical, neurological and psychiatric history to identify potentially specific biological vulnerability. Physical examination is also essential (Table 5).

93The overwhelming majority of patients with catatonia are assessed within secondary care, which seems appropriate given the complexities of management and the risks to the patient. Every patient presenting with a first lifetime episode of catatonia should receive a thorough evaluation for potential underlying medical disorders with a focus on relevant neurological conditions (see section ‘Aetiology’). When a patient presents with a recurrent episode of catatonia, the assessing clinician should not presume that an adequate workup was completed previously; instead, the adequacy of prior medical evaluation should be confirmed. In addition, every time a patient presents with catatonia, a medical evaluation is important to address potential complications of catatonia, as well as for care planning.

94Patients who do not participate in clinical evaluation should be assessed for the capacity to refuse evaluation and care. This is particularly important whenever catatonia is considered because several features (e.g. stupor, mutism, negativism or withdrawal) can be hard to distinguish from volitional acts. The fluctuating nature of catatonic signs can also reinforce the misinterpretation of wilful non-engagement. It is also important to keep in mind that patients with catatonia often understand what others are saying yet are unaware of their inability to respond. As such, clinicians should speak to patients with catatonia as though they comprehend what is being told to them because they may; in fact, once catatonia resolves, patients may have vivid recall of what they experience while in a catatonic state.

95Reliable identification of catatonia requires deliberate assessment (Table 6). Three primary means of assessment include clinical observation, elicitation and physical examination. The clinician should observe the patient before evaluation, often casually without drawing attention to the fact, while no one is interacting with them to evaluate for spontaneous expression of catatonic features. Observation should continue throughout and then after direct evaluation. Next, several features of catatonia must be elicited by environmental stimuli. For instance, demonstration of negativism requires that an instruction or prompt be given, and echophenomena require speech or behaviours to be mimicked. Assessment for catalepsy, rigidity and waxy flexibility (variously defined, see Table 8) requires physical examination. Collateral information is needed to assess the extent and duration of withdrawal, and evaluation for autonomic abnormality involves assessment of vital signs, either by chart review or by obtaining them directly.

96Recommendations on the assessment of catatonia

97Initial assessment and treatment of catatonia should be conducted within secondary care. (S)

98Catatonia should be considered as a differential diagnosis whenever a patient exhibits a substantially altered level of activity or abnormal behaviour, especially where it is grossly inappropriate to the context. (D)

99A collateral history should be sought wherever possible. (S)

100The history should include identification of possible medical and psychiatric disorders underlying catatonia, as well as prior response to treatment. (S)

101Physical examination should include assessment for catatonic signs, signs of medical conditions that may have led to the catatonia and signs of medical complications of catatonia. (D)

102When assessing a patient with catatonia, clinicians should interact with the person as if they are able to understand what is being said to them. (S)

103In an individual who is suspected to have catatonia, non-engagement with clinical assessment should not automatically be assumed to be wilful. Mental capacity to engage in an assessment should be assessed and, if found lacking, consideration should be given to acting in an individual’s best interests within the appropriate legal framework. (S)

104Most catatonia rating instruments approach catatonia scoring in a polythetic fashion (i.e. any combination of a diverse range of clinical features can contribute towards reaching a threshold for caseness), with the Northoff Catatonia Rating Scale (NCRS) a notable exception (Table 7).

105The Rogers Catatonia Scale was designed to differentiate catatonic depression from non-depressed patients with Parkinson’s disease. Its exclusive focus on motoric features of catatonia means that it has uncertain generalisability to other populations. It also omits several diagnostic criteria included in the ICD-11. The Kanner scale also has a significant weakness in that it has yet to be validated in a clinical cohort. As such, both the Rogers and Kanner scales should be disfavoured from routine clinical use at this time.

106The Bräunig Catatonia Rating Scale has good psychometric properties and has been validated against the criteria for catatonia in DSM-III-R, although DSM-III-R is somewhat different from DSM-5-TR in this regard. The Bräunig scale was scored using a robust 45-min semi-structured interview, which is likely infeasible in routine clinical practice. It also has some idiosyncratic definitions of its motor signs (Table 8).

107The two leading catatonia instruments are the Bush-Francis Catatonia Rating Scale (BFCRS) and NCRS, each with its unique strengths and weaknesses. The BFCRS is the most widely cited and clinically used scale worldwide. It has good psychometric properties and is the only scale to be validated by a lorazepam challenge. Its primary limitation is its idiosyncratic definition of waxy flexibility (Table 8); however, with slight adaptation, it assesses all DSM-5-TR criteria in its screening instrument alone, which makes for an efficient clinical evaluation. The full 23-item scale evaluates all ICD-11 catatonia criteria. The BFCRS scale was originally validated using a standardised clinical exam against other clinical criteria. It has been found to be sensitive to change in clinical status in response to treatment. The exam has been further refined in a Training Manual for the BFCRS and depicted in videographic educational resources, all freely available online at https://bfcrs.urmc.edu.

108The NCRS has good psychometric properties and offers the most comprehensive evaluation of catatonic signs. It divides its 40 items into three categories: behaviour (15 items), motor (13 items) and affective (12 items). The NCRS assesses for all diagnostic criteria of catatonia in the DSM-5-TR and ICD-11, and its definitions of motoric findings are consistent with their definitions in these diagnostic systems as well. Among catatonia scales, the NCRS uniquely emphasises affective features. Notably, the NCRS differs from other scales by requiring the presence at least one feature in each of its three domains (i.e. motor, affective and behavioural). Although such an approach is supported by Kahlbaum’s original description and some studies on subjective reports of catatonia, it is not supported by DSM-5-TR or ICD-11. With such a broad range of clinical features evaluated, the NCRS’s lack of a standardised clinical assessment is a significant limitation to its reliability.

109Although most scales report high interrater reliability in published studies (see for a detailed overview), this finding does not necessarily translate to the accurate use of a scale in clinical practice. There is evidence that training using videographic resources can improve use of the BFCRS. The results of a catatonia rating scale should be converted to diagnostic criteria for clinical diagnosis.

110Recommendation on the use of rating instruments

111When assessing for the presence of catatonia or its response to treatment, a validated instrument such as the BFCRS or the NCRS should be used. (C)

112Research on catatonia should report how individual items have been defined, including thresholds. (S)

113The diagnosis of catatonia is made through clinical observation, interview and physical examination of the patient, as well as from collateral information from carers and review of the medical record, and in general is not established through clinical investigations (e.g. laboratory tests, brain imaging, EEG, cerebrospinal fluid (CSF) analysis, urine drug screen). Clinical investigations should be ordered based on history and clinical examination findings, taking into consideration the overall severity of illness as well as medical and psychiatric comorbid illnesses. Medical investigations are typically performed to rule out catatonia-like conditions or to understand the underlying aetiology of catatonia as this informs treatment and prognosis.

114Although catatonia is not diagnosed through neuroimaging, given the large number of neurological conditions associated with catatonia (see Table 3), brain imaging is often requested as part of the medical evaluation of a patient with catatonia. A systematic review of structural and functional brain imaging in catatonia, which identified 137 case reports and 18 studies with multiple patients (pooled n = 186), found that more than 75% of cases of catatonia were associated with non-focal brain imaging abnormalities affecting several brain regions, and associated with a variety of underlying conditions, including neuroinflammatory conditions (SLE, encephalitis). The most common abnormalities in catatonia are generalised atrophy and non-specific white matter abnormalities.

115Even less is known about laboratory abnormalities present in patients experiencing catatonia. In a case–control study of 1456 patients with catatonia and 24,956 psychiatric inpatient controls, serum iron was reduced in catatonia cases (11.6 vs 14.2 μmol/L, odds ratio (OR): 0.65; 95% CI: 0.45–0.95), creatine kinase (CK) was raised (2545 vs 459 IU/L, OR: 1.53; 95% CI: 1.29–1.81), but there was no difference in C-reactive protein or white blood cell count, though analysis relied on a small subset of the patients with laboratory results. N-methyl-D-aspartate (NMDA) receptor antibodies were significantly associated with catatonia, but there were only a small number of cases. However, it should be noted that there is a strong association between anti-NMDA receptor encephalitis and catatonia, with most patients with this form of autoimmune encephalitis experiencing catatonia at some point in their illness. Other autoantibodies have also been identified in association with catatonia including anti-Hu antibodies, anti-myelin oligodendrocyte glycoprotein antibodies, antinuclear antibodies (ANA), antiphospholipid antibodies, anti-ribosomal P antibodies, anti-Ro antibodies, anti-Smith antibodies, double-stranded DNA antibodies, GABA-A receptor antibodies, GAD-65 antibodies, leucine-rich glioma-inactivated 1 antibodies, ribonucleoprotein antibodies and septin-7 antibodies. However, the prevalence and pathogenicity of these antibodies in catatonia is unclear, although it is a rapidly expanding field.

116In terms of neurophysiology, there is a clear case for an electroencephalogram (EEG) in the context of possible non-convulsive status epilepticus (NCSE), which can present as catatonia. Red flags for NCSE include subtle ictal phenomena (such as twitching of the face or extremities), comorbid neurological disease and a change in medications that affect seizure threshold. Another quite specific EEG finding of relevance to catatonia is the extreme delta brush, which occurs in some patients with anti-NMDA receptor encephalitis. The literature on the value of ‘encephalopathic’ findings on EEGs suggests that this is not entirely specific for a medical disorder underlying catatonia.

117Any hospital work-up must weigh the potential risks and benefits of detailed investigation. Hospital investigations may contribute to anxiety. Given that several studies have associated catatonia with intense anxiety, prolonged uncertainty amid medical testing may be expected to worsen this in some patients. In addition, the costs and potential harms of investigation (e.g. radiation exposure with computed tomography (CT) imaging, or magnetic resonance imaging (MRI) scans in patients who are unable to communicate whether they have any metallic implants) must be considered.

118Recommendations on the use of investigations in catatonia

119Investigations, such as blood tests, urine drug screen, lumbar puncture, electroencephalography and neuroimaging, should be considered based on history and examination findings, taking into account the possible diagnoses that may mimic catatonia and the possible underlying aetiology of the catatonia. (D)

120In patients experiencing a first episode of catatonia or where the diagnosis underlying catatonia is unclear, consider a CT or MRI scan of the brain. (C)

121In patients experiencing a first episode of catatonia or where the diagnosis underlying catatonia is unclear, consider assessing for the presence of antibodies to the NMDA receptor and other relevant autoantibodies in serum and CSF. (D)

122In patients with risk factors for seizures, possible evidence of a seizure or possible encephalitis, consider performing an EEG (with continuous monitoring if available). (C)

123DSM-5-TR has included a diagnosis of unspecified catatonia to encourage early treatment while a search for an underlying disorder can continue. Challenge tests may provide support in clarifying diagnosis and appropriate treatment. This section is limited to the use of benzodiazepines and zolpidem as a diagnostic and therapeutic ‘challenge test’. These agents are discussed in greater detail in section ‘GABA-ergic pharmacotherapies’.

124In 1930, Bleckwenn described the use of short-acting barbiturates to ‘render catatonic patients responsive’. Lorazepam (and to a limited extent, other benzodiazepines, such as diazepam, midazolam, clonazepam and oxazepam) have now replaced the use of barbiturates (such as amobarbital and sodium thiopental) as a diagnostic challenge (sometimes called the lorazepam test or the diazepam test) for confirming the diagnosis of catatonia.

125Lorazepam is an effective and clinically useful diagnostic challenge test for catatonia. It is available in oral, liquid, intramuscular (IM) and intravenous (IV) forms, and is available in a variety of clinical settings. Lorazepam is a non-selective positive allosteric modulator of GABA-A receptors. Possible therapeutic mechanisms in catatonia are discussed in section ‘GABA-ergic pharmacotherapies’.

126The recommended dose for a lorazepam challenge is 1–2 mg IV, IM or 2 mg oral. The response to an oral challenge is often slower than for parenteral administration and oral formulations can be harder to administer to both hyperkinetic and hypokinetic patients. A positive response to a lorazepam challenge, commonly defined as a 50% reduction in catatonic signs on a standardised scale, makes a diagnosis of catatonia more likely, but it is not 100% specific. A good response on the first day appears predictive of overall response to lorazepam. Low serum iron has been reported as a predictor of poor response with benzodiazepines. An example protocol is provided in Table 9.

127Based on their clinical effectiveness in these conditions, benzodiazepines may also be considered as a therapeutic test in antipsychotic-induced catatonia, NMS and malignant catatonia.

128described a serendipitous dramatic response to oral zolpidem 10 mg in a woman with a subcortical stroke whose catatonia was largely unresponsive to lorazepam or ECT. This was followed by other positive reports. The response is transitory, as with benzodiazepines, and is usually observed for 3–6 h, which is consistent with zolpidem’s short elimination half-life of 1–4 h. Catatonia has also been reported in zolpidem withdrawal.

129Several reports have been published of zolpidem’s effectiveness following neurological injury due to a variety of different brain insults. It is not clear whether some of these cases following brain injury had undiagnosed catatonia. It appears that the positive effect of zolpidem in post-brain injury states occurs at a sub-sedative dose, and there is a suggestion of a differential response in patients with traumatic or anoxic brain injury.

130Zolpidem is an imidazopyridine that is a selective positive modulator of the GABA-A alpha-1 subunit and this action appears to be important for its clinical efficacy. It seems selective for the gamma-2 subunit of the GABA-A receptor (alpha1-beta2-gamma2 GABA-A receptor) in animal experiments, but the implications of this in zolpidem’s efficacy as a diagnostic challenge tool are not entirely clear.

131The recommended dose of zolpidem is usually 10 mg orally for a diagnostic and/or therapeutic test, but 5 mg has sometimes been used in older patients. Zolpidem is available in oral formulation (and as a sublingual preparation in some countries), with no parenteral preparation available, which somewhat limits its use. A therapeutic plasma concentration of 80–150 ng/L has been suggested, with an onset of action within 10–30 min of ingestion of 10 mg zolpidem.

132showed that mutism is not a good prognostic sign for lorazepam response, so it is interesting that zolpidem may differentially help improve impairment of verbal fluency in patients with catatonia.

133In contrast to reports of ketamine causing catatonic signs, there is at least one report of slow IV injection of sub-anaesthetic doses of ketamine (12.5 mg) producing dramatic improvement in catatonic signs. More studies, including randomised controlled trials (RCTs), are needed before this translates into clinical practice as a diagnostic test.

134Recommendations on the use of challenge test

135When a diagnosis of catatonia is uncertain, a diagnostic challenge using lorazepam should be considered. (B)

136When a diagnosis of catatonia is uncertain, a diagnostic challenge using zolpidem may be considered. (C)

137In suspected or confirmed cases of catatonia, a lorazepam challenge may be used to predict future response to benzodiazepines. (B)

138There is some overlap between the differential diagnosis of catatonia (i.e. mimics of catatonia) and the conditions that may underlie catatonia. For example, NMS is sometimes listed in both categories, probably because of diverging views as to what extent it represents a form of catatonia (see section ‘Neuroleptic malignant syndrome’). For some conditions, their status is subject to debate. In Table 10, we provide a list of some of the more important conditions that may mimic catatonia, what the similarities are and how they can be differentiated.

139As general principles, the positive features of catatonia (such as echophenomena, catalepsy and posturing) may have greater discriminatory value than some of the negative features (such as mutism and stupor). Challenge tests are useful in many situations (see section ‘Challenge tests’), but their sensitivity and specificity are imperfect; importantly, stiff person syndrome and NCSE are likely to improve with a lorazepam challenge.

140Although it has been asserted that serotonin syndrome (SS) is a form of catatonia, there is currently insufficient systematic evidence to support this claim. Furthermore, although ECT, a core intervention for catatonia, has been advocated for the treatment of SS, recent reports suggest that it is ineffective and, in fact, may exacerbate SS.

141The evidence base for the treatment of catatonia is not extensive. Several RCTs have been conducted, but they have usually been at high risk of bias, inadequately reported, using outdated treatments or applicable to only a small subset of patients with catatonia. One systematic review found only four studies that had more than 50 participants. Nonetheless, where there is converging evidence from multiple sources, some clinically relevant inferences can be made.

142Many treatments for catatonia are unlicensed applications for licensed medicines. Relevant guidance on this issue has been produced by the General Medical Council, the Royal College of Psychiatrists in association with the BAP, and the Royal College of Paediatrics and Child Health. While this guidance recommends that prescribing should usually be within a product’s licence, it is recognised that there are situations in which prescribing off-licence is appropriate. Beyond the common standards for good prescribing, it is advised to use licensed medications in preference where appropriate, to be familiar and satisfied with evidence for safety and efficacy, to seek advice where necessary, giving sufficient information to patients, to inform patients that a medicine is being used outside its licence, to take consent or to document where this is not possible, to start at a low dose and to inform other professionals that the medicine is being used off-licence.

143There are two distinct aspects to treating catatonia: specific treatments for catatonia per se and treatments for the disorder(s) underlying catatonia, where identified. While employing either one of these approaches may be effective in some cases, there are many cases where using either one of these strategies alone fails but using the other or a combination of the two is successful. In addition, consideration must be given to the prevention and management of the medical complications of catatonia.

144Several studies have found that response to catatonia treatment is more likely or more rapid in patients with a shorter duration of illness, although this has not universally been the case. Given this preponderance of evidence and the likely explanation that catatonia becomes less treatment-responsive with time, we recommend treating catatonia as soon as possible after its identification.

145In terms of first-line treatments, there is most evidence for benzodiazepines and ECT. We provide more detail about these treatments in sections ‘GABA-ergic pharmacotherapies’ and ‘Electroconvulsive therapy’, but here we consider the question of which to use as first-line therapy. Response rates are similar: 59–100% for ECT and 66–100% in Western studies of benzodiazepines (although some Asian studies found lower response rates). If one treatment is contraindicated, this makes the decision simpler. Beyond this, consideration should be given to the potential of ECT to ameliorate a disorder underlying the catatonia (NICE recommends ECT for severe depression and prolonged or severe mania in certain circumstances;, ), balancing the side effects of ECT (particularly the small risk associated with a general anaesthetic, risk of status epilepticus, post-ictal confusion and autobiographical memory loss) and the side effects of benzodiazepines (particularly respiratory depression, sedation and amnesia). Other considerations more specific to ECT include often limited availability, delays in accessing care, legal issues obtaining consent and patient preferences. There are several studies of ECT after benzodiazepines have been ineffective, reporting high response rates. There is a case series and uncontrolled cohort study suggesting that the combination of benzodiazepines and ECT may be effective.

146There are several special cases to these recommendations about first-line treatment, which are as follows:

147Clozapine-withdrawal catatonia: a systematic review of case reports found that restarting clozapine or using ECT were the most effective treatment strategies, while benzodiazepines were less effective.

148Benzodiazepine-withdrawal catatonia: a systematic review of case reports found that reinstating benzodiazepines was generally effective.

149Catatonia in autism spectrum disorder: see section ‘Autism spectrum disorder’.

150Chronic, milder catatonia in the context of schizophrenia: there is some evidence that this tends not to respond to benzodiazepines or ECT. There is some evidence based on observational data that these patients may respond to clozapine. There have been rare cases of cardiorespiratory arrest associated with the concomitant use of clozapine and benzodiazepines, so caution should be exercised if there is co-administration.

151Malignant catatonia: see section ‘Periodic catatonia’.

152NMS: see section ‘Neuroleptic malignant syndrome’.

153Antipsychotic-induced catatonia: see section ‘Antipsychotic-induced catatonia’.

154Women in the perinatal period: see section ‘The perinatal period’.

155Where benzodiazepines or ECT do not succeed in achieving remission of catatonia, it is important to re-evaluate the diagnosis. In one study of 21 patients who entered an RCT for catatonia, 2 of the non-responders were subsequently diagnosed with Parkinson’s disease. For alternative treatment approaches, see section ‘Other therapies’.

156Alongside treating the catatonia, it is important to treat any underlying disorder. This may involve psychotropic medications (e.g. antidepressants), other medical therapies (e.g. antibiotics, immunosuppressants) or even occasionally surgical treatments (e.g. tumour resection in the case of a paraneoplastic syndrome). Guidelines for treating relevant psychiatric disorders are available from the BAP. There is some controversy over the use of antipsychotic medications in catatonia, which is discussed in section ‘Dopamine receptor antagonists and partial agonists’.

157Some, though not all, studies have associated catatonia with an increased mortality. There is an extensive case report literature on the medical complications of catatonia and a large cohort study of patients with schizophrenia found that those with catatonic stupor had an increased risk of various infections (pneumonia, urinary tract infection and sepsis), disseminated intravascular coagulation, rhabdomyolysis, dehydration, deep vein thrombosis, pulmonary embolus, urinary retention, decubitus ulcers, cardiac arrhythmia, renal failure, NMS, hypernatraemia and liver dysfunction. Guidance has been developed for averting such complications, which include recommendations such as pharmacological thromboprophylaxis, frequent assessment of pressure areas, stretching to avoid muscle contractures and consideration of artificial feeding.

158Recommendations on the general approach to treating catatonia

159Treatment for catatonia should be instituted quickly after identification of catatonia and it is not always necessary to await results of all investigations before commencing treatment. (D)

160Prescribing outside of a product licence is often justified in catatonia, but where a prescriber does this, they should take particular care to provide information to the patient or carer and obtain consent, where possible, taking advice where necessary. (S)

161Catatonia treatment should consist of specific treatment for the catatonia, treatment of any underlying disorder and prevention and management of complications of catatonia. (S)

162First-line treatment for catatonia should usually consist of a trial of benzodiazepines and/or ECT, (C) but see references to special cases in ‘First-line treatment’ and below.

163ECT should be available in any settings where catatonia may be treated, including in psychiatric and general hospitals. (S)

164When deciding between benzodiazepines and ECT as a first-line treatment, consider the following factors: side effect profile, whether there is an underlying disorder that is likely to be responsive to ECT (such as depression or mania) and availability of ECT. (S)

165Where benzodiazepines have not resulted in remission, ECT should be used. (B) For details of what an adequate trial of benzodiazepines consists of, see section ‘GABA-ergic pharmacotherapies’.

166Where catatonia has resulted from clozapine withdrawal, restart clozapine if possible and, if necessary, use ECT. (D)

167Where catatonia has resulted from benzodiazepine withdrawal, restart a benzodiazepine. (D)

168If catatonia is chronic and mild in the context of schizophrenia, consider a trial of clozapine. (C)

169If clozapine and benzodiazepines are administered concomitantly, titrate slowly and closely monitor vital signs. (S)

170Where catatonia does not respond to first-line therapy, re-evaluate the diagnosis. (D)

171Evidence for pharmacotherapies for catatonia that augment GABA-ergic signalling pathways is supported by neuroimaging studies. conducted an iomazenil GABA-SPECT study and found that patients with catatonia (in a post-acute state) showed significantly lower iomazenil binding in the sensorimotor cortex as well as in the parietal cortex and prefrontal cortex (PFC). The same group was followed up in post-acute catatonia with a subsequent functional MRI (fMRI) study where emotional stimulation was applied before and after lorazepam administration: the orbitofrontal-ventromedial PFC was particularly responsive to a lorazepam challenge, normalising its activity.

172The involvement of the orbitofrontal-ventromedial PFC was further supported by a separate fMRI study where post-acute catatonia patients showed significantly lower emotion-induced activity in this region compared to psychiatric patients without catatonia with the same underlying diagnosis and healthy controls. Given that the orbitofrontal-ventromedial PFC is strongly involved in emotion processing, which is mediated by GABA activity, these findings provide further evidence for GABA-ergic mechanisms in catatonia including both GABA-A and GABA-B receptors.

173In terms of clinical findings, a double-blind RCT investigated the effect of the barbiturate derivative amobarbital in 1992, finding that of 10 patients randomised to the drug, 6 responded, compared to none of the 10 randomised to a saline infusion. However, barbiturate use has largely been abandoned since due to safety concerns.

174Acute catatonia often shows a rapid and dramatic response to benzodiazepines in case series and observational studies, although a Cochrane review found no placebo-controlled RCTs evaluating benzodiazepines in catatonia. reported 17 studies describing benzodiazepine use in patients with catatonia. Most used lorazepam 1–4 mg per day, with some using up to 16 mg per day. Some sources recommend a maximum dose of 24 mg and there are cases of such doses being helpful. Some studies have used other benzodiazepines, such as oxazepam, diazepam, clonazepam or flurazepam and a small RCT found no difference in outcome between lorazepam and oxazepam treatment. However, lorazepam is the most commonly used benzodiazepine for catatonia, it is available in several formulations and its use has a large amount of clinical experience, including at high doses.

175Administration can be oral, IM or IV. Parenteral administration can be particularly useful if oral administration is not possible, for example due to negativism. Lorazepam is usually administered in 2–4 divided doses each day.

176Reported response ranges from 66% up to 100%. These studies were mainly conducted in Western countries. Studies conducted in India and Asia show more variable response, ranging from 0% to 100%. The reason for these differences remains unclear, but it is possible that – given that lorazepam is unstable at room temperature – storage conditions may play a role. Usually, administration of lorazepam is well tolerated, and major side effects are rare. Even a dose as high as 16 mg of lorazepam is often well tolerated without sedation.

177Therapeutic response may entail partial or complete remission within hours, though it may sometimes take several days. The therapeutic response seems to be strongest in acute catatonia where the patient presents with a rapid-onset catatonic state. This is especially the case in patients suffering from bipolar disorder and major depressive disorder. In contrast, patients with chronic catatonia, especially in the context of schizophrenia, show a less strong response to lorazepam and are more likely to receive ECT.

178One important issue is the weaning of benzodiazepines. There is a need to balance the therapeutic benefits and the risks of withdrawal effects against dependence and the various risks of long-term benzodiazepine use. Withdrawal schedules for benzodiazepines exist, but these are generally designed for individuals who have been treated with benzodiazepines for months or years, whereas benzodiazepines in catatonia are often used for days or weeks. Nonetheless, such withdrawal schedules are associated with higher retention in treatment and better tolerability than abrupt discontinuation and the latter risks potentially fatal withdrawal seizures. In one case series of seven patients who had a relapse of their catatonia on withdrawal of lorazepam (the speed of withdrawal ranging from abrupt discontinuation to dose reduction by 1 mg per week), all had resolution of catatonia once lorazepam was restored to its previous dose and four were able to successfully wean off more slowly over 6 weeks, although three received long-term lorazepam treatment to prevent relapse. There are other reports of long-term benzodiazepines being used to prevent re-emergence of catatonia. Therefore, some form of taper seems reasonable and, in the event that catatonia re-emerges following benzodiazepine withdrawal, it is sensible to ensure that an underlying condition has been appropriately treated as well as undertaking a slower taper.

179Recommendations on the use of GABA-ergic medications in catatonia

180Where benzodiazepines are used for catatonia, available routes of administration may include oral, sublingual, IM and IV. The choice of route should be decided based on clinical appropriateness, rapidity of the required response, patient preference, local experience and availability. (S)

181Where benzodiazepines are used for catatonia, lorazepam is generally the preferred agent. (S)

182Where lorazepam is used for catatonia, high doses above the licensed maximum may be necessary to achieve maximal effect. An adequate trial may be considered complete when catatonia is adequately treated, titration has been stopped due to side effects or dose has reached at least 16 mg per day. (C)

183Benzodiazepines for catatonia should not be stopped abruptly but rather tapered down. The speed of the taper depends on a balance of the therapeutic benefits and the risks of withdrawal effects against the possibility of dependence and the risks of long-term harm from benzodiazepines. (S)

184If catatonia relapses on withdrawal of benzodiazepines, a clinician should ensure that any underlying condition has been adequately treated and a slower taper may be tried. (S)

185The first patients treated with convulsive therapy, both for chemically induced seizures by Meduna in 1934 and for electrically induced seizures by Cerletti and Bini in 1938, had catatonic illnesses. Since then, governmental authorities, authors of textbooks on ECT or catatonia, and most publications discussing treatment options for catatonia endorse ECT, usually as the most effective treatment even where medications or other interventions have failed. For example, the United States FDA panel endorsed ECT for catatonia under a less restrictive Class 2 safety/efficacy designation and in the UK NICE recommends ECT for catatonia. In the UK and many other countries, there are specific legal requirements for administering ECT in a patient who is unable to consent.

186Despite this extensive clinical recognition in common practice, a rigorous base of high-quality published evidence is lacking. This deficiency of RCTs arises principally from practical difficulties in conducting sham or placebo treatment arms in people who are usually severely ill with catatonia and often lack an ability to participate in informed-consent processes for such clinical trials.

187Among several reviews of existing evidence on ECT for catatonia, the most recent comprehensive one was a meta-analysis. Three RCTs involving ECT for patients with catatonia have been conducted, all of which were in patients with primary psychotic disorders. Comparisons were between ECT and risperidone; ECT, sham ECT and sodium thiopental; and bifrontal ECT and bitemporal ECT. Two of the trials were conducted specifically in patients with catatonia, while one had a catatonic subgroup. Unfortunately, none of these contained both standardised ratings for outcome and quantitative results that would allow for statistical determinations of effect size. The review did, however, identify 10 studies with such data on quantitative outcomes, but they lacked control groups. Bilateral forms of ECT were the typical treatment modality. From these 10 studies, a meta-analysis showed a standardised mean difference between pre-post severity scores of −3.14, which represents a highly effective treatment. Reported side effects were similar to those seen generally in the use of ECT for depression.

188Since Leroy et al.’s review, four additional studies of ECT with pre/post-quantitative outcomes have been published. All were naturalistic case series or retrospective analyses, using Clinical Global Impression (CGI) or BFCRS quantitative outcomes. Results ranged from decreases in scores of 40% to 82%, and of response (final CGI ⩽2) rates from 83% to 90%. Pierson et al. studied adolescents ⩽18 years, reporting 90% met the CGI criteria for response.

189Most published reports describing ECT for catatonia have used bilateral forms of ECT, which are generally recommended for severe, medication-resistant or malignant forms of catatonia. No studies were found comparing bilateral versus unilateral ECT for catatonia.

190In terms of ECT sessions, most studies captured by Leroy et al.’s review that reported ECT frequency described ECT as taking place three times weekly, although this ranged between daily and twice weekly. Number of sessions ranged from 3 to 35 sessions with a mean of 9 sessions. There is a lack of data on the superiority of these differing protocols.

191Recommendations for the use of ECT in catatonia

192Where ECT is administered, bilateral ECT should be considered. (S)

193Where ECT is administered in acute catatonia, it should be given at least two times weekly. (S)

194Number of ECT sessions should be decided on the basis of treatment response, risks and side effects. (S)

195While the majority of patients with catatonia respond robustly to benzodiazepines or ECT, some patients have a partial or non-response. Catatonia associated with schizophrenia may be less likely to respond to benzodiazepines. In addition, benzodiazepines and ECT are cautioned in some circumstances. There are also barriers to ECT use such as legal restrictions and stigma.

196These factors have prompted the trialling of several alternative agents, either as monotherapies or as augmentation strategies. The studies examining adjunctive medications for catatonia have consisted of prospective cohort studies, open prospective studies, prospective open label studies, retrospective chart review studies, case series and an open label double blind trial.

197The NMDA receptor may be allosterically more available to glutamate in catatonia leading to dysfunction in cortico-striato-thalamo-cortical (CSTC) circuits. The NMDA receptor antagonists, amantadine and memantine, may reset the problems related to reduced dopamine and GABA in the CSTC circuitries by balancing NMDA receptor effects on PFC GABA-A parvalbumin interneurons that inhibit PFC pyramidal corticostriatal glutamatergic projections to the striatum while also reducing NMDA action in the striatum itself. Medications such as amantadine and memantine serve as uncompetitive antagonists of the NMDA receptor and thus may be helpful in patients with catatonia. Amantadine has the added theoretical benefit of enhancing central dopamine release and delaying dopamine reuptake from the synapse and since catatonia is hypothesised to be to some degree a disorder of hypodopaminergic tone, this profile may also benefit patients with catatonia.

198In their systematic review, reported on 11 articles that described the use of amantadine in 18 cases. Most patients had schizophrenia spectrum disorders, and some had medical comorbidities. Amantadine as monotherapy often abolished catatonia after a few doses. Five cases involved IV use and the others involved oral dosing. Oral doses ranged from 100 to 600 mg daily, with most patients receiving 200 mg daily. Daily IV doses ranged in 400–600 mg. In 2018, updated the cases and reported three more amantadine cases that used a mean oral dose of 306 (standard deviation (SD): 189) mg a day. In two of these cases, ECT was also used and in another one the results were equivocal. In a review by, seven further cases of catatonia, six of whom were diagnosed with schizophrenia, were treated successfully with oral amantadine 200 mg a day. Another patient with atypical psychosis with catatonia showed no improvement with amantadine, though upon removal of amantadine the condition worsened.

199In a clinical study of catatonia in neurologic and psychiatric patients in a tertiary neurological centre, 23 of 42 patients with catatonia related to a neurological disorder received adjunctive amantadine (mean dose 243 (SD: 57) mg/day) most often in addition to first-line oral lorazepam (mean dose 7.3 (SD: 2.8) mg/day) treatment. All patients achieved remission of their catatonia except for two patients who died of encephalitis or encephalomyelitis.

200In Beach et al.’s (2017) review, nine papers reported memantine treatment in nine cases. Again schizophrenia-spectrum illnesses were predominantly represented in this sample. Memantine was commonly prescribed as an adjunctive treatment in combination with benzodiazepines. added three unpublished memantine cases and reported the mean daily dose used for all 12 cases was 12.5 (SD: 6.2) mg.

201A few additional articles cite the benefits for catatonia of other medications that may act as glutamate antagonists. These include four cases of minocycline use and one case of dextromethorphan–quinidine use.

202In summary, reviews show that in 58 published cases plus other additional reports of amantadine and memantine use in catatonia of various aetiologies, substantial improvement was reported. This improvement usually occurred within a 7-day window. A bias towards the non-reporting of negative results must be considered, making the lack of RCTs and controlled studies an important shortcoming.

203The dopamine system modulates motivation and movement by informing the anterior cingulate cortex/mid-cingulate cortex when a task is associated with high predictive value (tonic dopamine) as well as when circumstances abruptly change to better or worse than predicted (phasic dopamine). proposes that the dopamine system in the midbrain ventral tegmental area/substantia nigra functions as a manager of sorts for the CSTC circuits thought to be implicated in catatonia. The dopamine agonists and precursors can be hypothesised to treat catatonia by increasing dopamine modulation and by favouring the striosomal direct pathway as they do in akinetic mutism, leading to opening of the thalamic filter with feedforward activation of cortical regions including the supplementary motor area and primary motor cortex.

204Levodopa is a dopamine precursor that is often used in combination with a peripheral DOPA decarboxylase inhibitor (e.g. carbidopa and benserazide) in the treatment of Parkinson’s disease. A case report and small case series found marked improvement after treatment with levodopa, although the case series reported worsening of psychosis. Bromocriptine, a dopamine D2 receptor agonist was used successfully in a 16-year-old girl with catatonia. There is also a literature on the use of dopamine agonists in the related conditions of NMS (see section ‘Neuroleptic malignant syndrome’) and akinetic mutism, a neurological condition associated with lesions to frontal-subcortical circuits.

205Methylphenidate is a noradrenaline and dopamine reuptake inhibitor. There have been five case reports of successful use of methylphenidate for catatonia. Most of these cases were due to mood disorders, and most used methylphenidate as monotherapy.

206The use of antipsychotics is one of the most controversial areas in catatonia management. Antipsychotic medications can induce catatonia (see section ‘Antipsychotic-induced catatonia’) and worsen it. Catatonia is also a risk factor for NMS, a severe antipsychotic-induced movement disorder. Moreover, in some studies of catatonia, the use of antipsychotics has been associated with poor outcomes.

207Nevertheless, dopamine receptor antagonists and partial agonists have been reported in some cases as beneficial in catatonia. This may particularly be the case in catatonic schizophrenia. There have been reports of the use of olanzapine, risperidone, ziprasidone, quetiapine and aripiprazole.

208Second-generation antipsychotics (SGAs) theoretically would be less likely to strongly antagonise dopamine receptors making them potentially less dangerous adjunctive treatments than first-generation antipsychotics (FGAs) in terms of NMS risk. Aripiprazole’s partial agonism might balance the dopaminergic effects and be of some benefit for catatonia. A recent Cochrane review found only one RCT of antipsychotics for schizophrenia spectrum disorders with catatonic features, and considered the evidence to be of very low quality due to a small sample size, short duration, risk of bias and other methodological issues. This RCT compared risperidone to ECT, finding greater improvement in the ECT-treated group.

209Given that D2 receptor antagonists can worsen catatonia and trigger NMS in an at-risk group, some reviews have urged caution, especially in malignant catatonia. It has also been suggested that SGAs – or an FGA with weaker dopamine receptor affinity – should be preferred. Some sources suggest that antipsychotics should only be given in catatonia if co-administered with a benzodiazepine. One review concluded that there does not seem to be evidence to support the use of SGAs in patients with catatonia without an underlying psychosis. Two small studies have suggested that low serum iron in catatonia is associated with the development of NMS, leading some to suggest that serum iron may be used in catatonia to predict those who may develop NMS, but the evidence is not of a high quality.

210Regarding clozapine, a systematic review found there is some evidence from case reports and small uncontrolled observational studies that clozapine may be effective in catatonic schizophrenia. In the largest identified study, 55 patients with catatonic schizophrenia received clozapine, resulting in 2 cases of complete remission, 48 cases of partial remission and 5 cases of no remission. Where catatonia occurs in the context of clozapine withdrawal, a systematic review of case reports found that re-initiation of clozapine or the use of ECT was usually effective, while benzodiazepines were less reliable.

211Leaving aside the cases where catatonia is a presentation of NCSE, catatonia has occasionally been treated with anticonvulsant medications. Evidence consists of case series and case reports.

212Three articles have reported using carbamazepine to treat catatonia in seven cases. Most cases were associated with a mood disorder, and carbamazepine was found to be effective without the need for benzodiazepines. Doses ranged from 100 to 1000 mg daily, with six cases receiving 600 mg daily or greater.

213Valproic acid use in catatonia has been reported in four papers in which five patients were suffering with psychoses, mostly schizophrenia spectrum in nature. In three instances, excited catatonia was noted as part of the presentation. These patients were treated successfully with valproic acid. Doses ranged from 600 to 4000 mg daily.

214Another case series involving four cases highlighted the benefits of topiramate in the treatment of catatonia. Here too most of these patients had been diagnosed with schizophrenia-like illnesses. Topiramate was used as an adjunctive treatment along with a benzodiazepine. All four cases improved on 200 mg daily.

215Phenytoin has been reported to be effective in cases where catatonia has appeared in the context of bacterial meningoencephalitis, NCSE and frontal lobe seizures. Levetiracetam and zonisamide have each been used in one case along with aripiprazole.

216Two case reports described using benztropine IV as monotherapy to treat catatonia in two cases. In another case, trihexyphenidyl was used in combination with clozapine to treat catatonia. All patients had a schizophrenia-spectrum illness. And in a fourth case, several medications including trihexyphenidyl were used to treat catatonia in a young woman with Wilson’s disease.

217Muscle relaxants, calcium channel blockers and corticosteroids have all anecdotally been associated with improvement in isolated patients with catatonia. Lithium and other treatments for prophylaxis in periodic catatonia warrant particular attention and are considered in section ‘Periodic catatonia’.

218There are conditions and situations that discourage the use of ECT after non-response to benzodiazepines and second-line agents, and when maintenance ECT is required that offers a potential niche for newer neuromodulatory treatments such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS) for the treatment of catatonia. Two systematic reviews have covered this topic and found that the majority of case reports and case series in the literature reported a positive response. rTMS over the bilateral dorsolateral PFC has been particularly emphasised. Adverse effects appear to be minimal.

219Recommendations on the use of other therapies

220Where first-line therapies for catatonia are unavailable, cautioned, ineffective or only partially effective, consider a trial of an NMDA receptor antagonist, either amantadine or memantine. (C)

221Where first-line therapies and NMDA receptor antagonists are unavailable, cautioned, ineffective or only partially effective, consider a trial of levodopa, a dopamine agonist, carbamazepine, valproate, topiramate or a SGA. (D)

222Antipsychotic medications should be avoided where there is no underlying psychotic disorder. (C)

223Where catatonia exists in the context of an underlying psychotic disorder, if antipsychotic medications are used, they should be prescribed with caution after an evaluation of the potential benefits and risks, including the risk of NMS. Additional caution should be exercised if there is low serum iron or a prior history of NMS. If antipsychotic medications are used, a SGA should be used with gradual titration, and co-administration of a benzodiazepine should be considered. (S)

224Where ECT is indicated but unavailable, consider treatment with rTMS or tDCS. (D)

225Periodic catatonia is a rare form of catatonia characterised by rapid-onset, brief, recurring episodes of hypokinetic or hyperkinetic catatonia. The typical episode may last 4–10 days, with an interepisodic period lasting weeks to years. Kraepelin first described it in the context of schizophrenia. Gjessing extensively studied this entity and published data mainly in German. His work has been summarised by. Leonhard considered periodic catatonia to be a form of unsystematic schizophrenia (i.e. genetically determined schizophrenia) compared to the systematic (nonperiodic and nonfamilial) form of schizophrenia. Based on this conceptualisation, subsequent research showed that periodic catatonia has an autosomal dominant pattern of transmission.

226Classically periodic catatonia has been reported to occur in association with schizophrenia, but it has also been reported in patients with affective disorders and occasionally in patients with substance use disorders, underlying medical illnesses and in association with menstrual cycles. It has also been reported in adolescents and the geriatric population. Studies that have focused on the clinical profile of patients with periodic catatonia during the different episodes in the same patients suggest consistency of clinical features across the various episodes.

227There is great uncertainty in the treatment of periodic catatonia, though several sources advise treatment in acute catatonic episodes along the lines of other cases of catatonia with benzodiazepines and ECT, and several reports support this. However, some cases do not respond to these treatments. There is also the important issue of maintenance treatment to prevent catatonic episodes. Lithium is the most frequently reported agent used in the maintenance of periodic catatonia, but even this evidence relies only on case reports and small case series. Case reports have reported success with mirtazapine and clomipramine in the maintenance treatment of periodic catatonia in patients with depressive disorder. In another case report, authors reported the effectiveness of fluoxetine (20 mg/day) and fluphenazine in the maintenance treatment of periodic catatonia in a patient with schizoaffective disorder. Case reports or series have reported the role of lamotrigine and carbamazepine in the maintenance treatment of periodic catatonia. Despite the potential risk of NMS when antipsychotics are used in catatonia, some have reported a beneficial role of olanzapine, ziprasidone and risperidone in the long-term treatment of periodic catatonia.

228Recommendation on periodic catatonia

229In the maintenance phase of periodic catatonia, consider prophylactic treatment with lithium. (D)

230Catatonia may be conceptualised as a continuum, with milder forms at one end (termed simple or benign) and more severe forms, involving hyperthermia and autonomic dysfunction (termed malignant), at the other. described ‘lethal catatonia’ as a fulminant psychotic disorder characterised by intense motor excitement, which progressed to stuporous exhaustion, cardiovascular collapse, coma and death. The entire course, passing through excitement into stupor, involved mounting hyperthermia, autonomic instability, delirium, muscle rigidity and prominent catatonic features. The paucity of findings on autopsy was difficult to explain and in sharp contrast to the catastrophic clinical manifestations. This disorder was the subject of numerous publications throughout the pre-antipsychotic drug era. Competing terminology included Bell’s mania, acute delirious mania, pernicious catatonia and delirium acutum, among numerous others. More recently, the term malignant catatonia has been proposed, since not all cases are fatal. Unlike Stauder, some authors have observed that muscle tone in malignant catatonia is flaccid.

231Although the incidence of malignant catatonia appears to have declined following the introduction of modern psychopharmacologic agents, it continues to be reported. Like non-malignant catatonia, malignant catatonia represents a syndrome rather than a specific disease, occurring in association with diverse neuromedical illnesses as well as with psychiatric disorders. Current data suggest that it is likely that a proportion of malignant catatonia cases previously attributed to schizophrenia were more likely the product of autoimmune disorders, particularly anti-NMDAR encephalitis. Mortality, which had exceeded 75% during the pre-antipsychotic drug era, has fallen to 10% in recent reports.

232Although some qualified support may exist for the use of SGAs in non-malignant catatonia (see section ‘Dopamine receptor antagonists and partial agonists’), the literature on antipsychotics for malignant catatonia is rather different. First, there is an issue that malignant catatonia is generally clinically indistinguishable from NMS, so antipsychotics seem injudicious. Second, in a review of 292 malignant catatonia cases, 78% of those treated with only an antipsychotic died, compared with an overall mortality of 60%. Moreover, this review found that many patients with catatonia developed malignant features only after treatment with antipsychotics. The evidence for the SGAs in malignant catatonia is minimal and mixed. Antipsychotic drugs should be withheld whenever malignant catatonia is suspected.

233Since RCTs are unavailable, treatment recommendations for malignant catatonia are based on case reports or case series. Five international guidelines for the management of schizophrenia specifically address the treatment of malignant catatonia, although they are based on low levels of evidence. Each of the guidelines recommends ECT either as the initial treatment or as second line after a failed benzodiazepine trial. Although the benefits of benzodiazepines in malignant catatonia are less consistent than in non-malignant catatonia, a review of 44 cases found that there was clear benefit in about a third, transient or partial improvement in a third and no benefit in the remainder, so a benzodiazepine trial seems reasonable. Doses as high as 24 mg of lorazepam per day may be required. However, if benzodiazepines are not rapidly effective, ECT should be started within 48–72 h following the onset of malignant catatonia.

234ECT appears to be a safe and effective treatment for malignant catatonia occurring in association with a psychiatric disorder. Among 68 patients reported in five series, 51 of 54 treated with ECT survived, whereas only 6 of 14 who received antipsychotics and supportive care recovered. Still, ECT appears effective only if initiated before severe progression of malignant catatonia. In another series, although 16 of 19 patients receiving ECT within 5 days of malignant catatonia onset survived, none of 14 patients starting ECT beyond that 5-day point recovered. In view of the life-threatening potential of malignant catatonia, bilateral treatments daily or twice daily for 3–5 days are often required to achieve a rapid result, followed by ECT at conventional frequencies until complete resolution. In addition, ECT has been effective as a symptomatic measure in malignant catatonia complicating a diversity of medical conditions, such as anti-NMDAR encephalitis, permitting resolution of the underlying condition.

235An older body of case series data had suggested that malignant catatonia could be successfully treated with adrenocorticotropic hormone and corticosteroids. However, the interpretation of these reports may be compromised by the simultaneous use of ECT in many cases. Other proposed treatments have included bromocriptine, amantadine, memantine and calcitonin. A single case report observed dramatic resolution of malignant catatonia with rTMS. Although one case report noted rapid improvement in malignant catatonia with tDCS, a second found no effect. Like non-malignant catatonia, rTMS and tDCS could prove promising in malignant catatonia where ECT is indicated but not possible. However, further investigation is necessary. Finally, a couple of case reports have reported benefit from propofol in malignant catatonia, which may possibly be useful if ECT is delayed.

236Recommendations for the treatment of malignant catatonia

237In malignant catatonia, discontinue all dopamine antagonists. (D)

238In malignant catatonia, commence a trial of lorazepam at 8 mg/day (PO, IM or IV), titrating up according to response and tolerability up to a maximum of 24 mg/day. (C)

239If there is partial or no response to lorazepam within 48–72 h in malignant catatonia, institute bilateral ECT once or twice daily for up to 5 days until malignant catatonia abates, followed by ECT three times per week until there is sustained improvement, usually 5–20 treatments in total. (D)

240NMS is a rare and potentially lethal idiosyncratic reaction to treatment with dopamine antagonists. Like malignant catatonia, NMS involves altered consciousness with catatonia, muscle rigidity, hyperthermia and autonomic dysfunction. Recent reports suggest a prevalence of 0.02–0.03%, much lower than the 1–3% reported in the 1980s. Mortality has declined over the years to an average of less than 10%. Virtually, all classes of drugs that induce dopamine receptor blockade have been implicated in causing NMS, with antipsychotics that have higher affinity for the D2 receptor posing the greatest risk. However, SGAs have also been associated with NMS, although they may result in an ‘atypical’ presentation with less severe or absent rigidity or hyperthermia. NMS may also occur with dopamine-blocking drugs used as antiemetics, with dopamine depleting drugs, and during dopamine agonist withdrawal. About two-thirds of cases develop within the first 1–2 weeks after drug initiation. Laboratory abnormalities are nonspecific but commonly include elevated serum CK, leucocytosis and low serum iron resembling malignant catatonia.

241Several authors have proposed that NMS represents an antipsychotic drug-induced toxic or iatrogenic subtype of malignant catatonia. Two retrospective studies of hospitalised patients meeting stringent criteria for NMS found that, in total, 42 out of 43 episodes also met DSM-IV criteria for catatonia. As mentioned in section ‘Dopamine receptor antagonists and partial agonists’, antipsychotic drugs can precipitate and worsen catatonia, while catatonia is a risk factor for NMS. Others, however, have asserted that malignant catatonia and NMS represent two distinct entities, suggesting that excited or agitated behaviour points to malignant catatonia. A prodromal phase involving agitation and affective disturbance is perhaps more common in malignant catatonia but is not universally present.. However, agitation is a common feature of the psychosis preceding NMS for which antipsychotics were originally used. Prominent muscle rigidity has also been proposed as a distinguishing feature. Nonetheless, since patients with hyperactivity or psychotic features usually receive medications early in treatment, it may be difficult to know if the presence of rigidity represents NMS or drug-induced extrapyramidal side effects superimposed on malignant catatonia. Furthermore, many malignant catatonia cases in the era prior to antipsychotic therapy did present with rigidity. At a minimum, differentiating between NMS and malignant catatonia where antipsychotic medications have been used is acknowledged to be very challenging.

242The most important factor in improving survival in NMS is discontinuation of dopamine-blocking medications. With cessation of dopamine-blocking drugs and supportive medical care, NMS is in most cases a self-limiting disorder with a mean recovery time of 7–10 days. Anticholinergic medications, which impair heat loss through reduction of sweating, should also be discontinued. Beyond these measures, there is limited consensus regarding the optimal therapeutic approach to NMS. It is difficult to compare specific treatments because NMS is rare, usually self-limiting, and heterogeneous in onset, progression and outcome, which renders RCTs challenging. Nevertheless, therapies that have been reported as successful in the treatment of NMS include benzodiazepines, dopamine agonists, dantrolene and ECT. The use of benzodiazepines for treating NMS is not surprising given the proposed overlap between NMS, catatonia and malignant catatonia. Several case reports and series have found that benzodiazepines have been associated with improvements in some individuals with NMS, though this response is sometimes transient. However, they are not effective in all patients and one prospective study of 14 episodes of NMS found that while seven out of nine patients with catatonic features responded to benzodiazepines, none of the five patients without catatonic features responded. Given that risks are small and benefits possibly marked, several sources suggest a trial of benzodiazepines.

243Some evidence suggests that NMS results from a reduction of dopaminergic activity in the brain, such that dopamine agonists may reduce that deficit and facilitate resolution of the syndrome. Systematic reviews of case reports have found that the dopaminergic medications, bromocriptine and amantadine, are associated with reduced mortality, and bromocriptine is associated with a reduced time to clinical response. Although levodopa has been used in only a limited number of reported NMS cases, it was thought to be effective in half the case reports and dramatic improvements were observed in some cases, even after failure to respond to dantrolene. Newer dopamine agonists developed for transdermal delivery may facilitate administration of dopamine drugs under extreme circumstances (e.g. rotigotine).

244Temperature elevation in NMS is theorised to result from antipsychotic drug-induced impairment of central heat loss mechanisms in combination with excess heat production secondary to peripheral hypermetabolism and rigidity of skeletal muscle. Dantrolene, which inhibits contraction and heat production in muscle, may benefit those cases of NMS with extreme temperature elevations, severe rigidity and true hypermetabolism. In one systematic review, where dantrolene was used in 101 NMS patients and was the only medication used in 50%, improvement was reported in 81%. Furthermore, mortality was decreased by nearly half compared with supportive care alone. reported a positive response to dantrolene in 105 (74.5%) of 141 NMS patients. Intravenous dantrolene should not be co-administered with calcium channel blockers (particularly verapamil and diltiazem; amlodipine and nifedipine may be safer alternatives), as hyperkalaemia and cardiovascular collapse can occur.

245The pharmacological agents discussed above are generally effective within the first several days of NMS. If, despite adequate dosing, a response has not been achieved by 2–3 days, a delayed response is unlikely and ECT should be considered. A review of 40 cases where ECT was used as a treatment primarily for NMS found that there was complete recovery in 25 cases (63%) and partial recovery in a further 11 (28%), although reporting bias is a significant concern. Response often occurs during the first few treatments, although some cases have required multiple ECTs in a single day. Furthermore, ECT has the advantages of treating some underlying conditions during acute NMS when antipsychotics must be avoided and in treating a prolonged, residual catatonic or parkinsonian state, which has been observed following NMS. conducted a literature review that found the mortality of 48 NMS patients treated with ECT was 10% compared with 21% for patients treated with supportive care alone. retrospectively identified 15 NMS patients treated with ECT at their centre over a 17-year period and reported a mortality rate of 6.7%. ECT should therefore be considered as an initial therapy when NMS is severe and the risk of complications is high. Patients with NMS are not considered at risk for malignant hyperthermia during ECT. However, succinylcholine can cause hyperkalaemia and arrhythmias in patients with severe rhabdomyolysis, which may explain instances of cardiac complications in NMS patients treated with ECT. Alternative muscle relaxants should be considered in patients at risk.

246Treatment recommendations for NMS are not uniform and – in the absence of RCTs – any recommendations should be made with caution. In a prospective study of 20 NMS patients, observed that those receiving dantrolene (two patients), bromocriptine (two patients) or both (four patients) had a more prolonged course and more sequalae than those treated only with supportive care, leading the authors to question the efficacy of either agent. More recently, conducted a systematic review of 405 NMS cases comparing patients treated with dantrolene, bromocriptine and ECT with those receiving supportive care alone. Cases were defined as mild, moderate or severe using the criteria. Across the entire sample, independent of severity levels, differences in mortality rates with specific therapies compared to supportive care alone were not statistically significant. However, in severe NMS, mortality rates proved significantly lower with each of dantrolene, bromocriptine and ECT compared to supportive care. The authors concluded that supportive care alone could be sufficient for the treatment of mild to moderate NMS, but that specific therapies were indicated for severe NMS.

247A series of international guidelines for the management of schizophrenia contain certain specific recommendations for the treatment of NMS, but these are based on weak levels of evidence and do not consider all relevant treatment options. contend that expert-based treatment algorithms derived from clinical experience, numerous clinical reports and rational theories are of greater value than recommendations provided by the guidelines. These algorithms stress that the specific treatment of NMS be individualised and based on the character, duration and severity or stage of clinical features. In general, the first steps include supportive care and discontinuing dopamine blocking agents and anticholinergics. Benzodiazepines are also widely recommended as an initial intervention for patients with mild NMS characterised by mild rigidity, catatonia or confusion, temperature < 38°C, HR < 100. Trials of bromocriptine, amantadine or other dopamine agonists may be a reasonable next step in patients with moderate NMS involving prominent parkinsonian signs and temperatures in the range of 38–40°C. Dantrolene appears beneficial primarily when extreme hyperthermia (>40°C) and severe rigidity develop. Although many patients respond to pharmacotherapy, none of the above medications have been reliably effective in all reported cases of NMS. As reviewed above, ECT may remain effective even late during treatment, as opposed to pharmacotherapies, and after pharmacotherapies have failed.

248Among patients who recover from NMS, there may be a 30% risk of recurrent episodes following antipsychotic rechallenge. However, most patients who require antipsychotics can be safely treated provided measures to reduce risk are followed. Strategies suggested are minimising other risk factors for NMS (such as agitation, medical illness and dehydration), allowing at least 2 weeks from recovery before rechallenge, using a low dose of a SGA with gradual titration and careful monitoring for early signs of NMS.

249Recommendations for the treatment of NMS

250In NMS, discontinue all dopamine antagonists. (C)

251In NMS, discontinue anticholinergic drugs. (S)

252In NMS, supportive care should be provided. This consists of assessment and appropriate management of airway, ventilation, temperature and swallow. Fluid input/output should be monitored, and aggressive fluid resuscitation should be used where required. There should be assessment for hyperkalaemia, renal failure and rhabdomyolysis. There should be careful monitoring for complications such as cardiorespiratory failure, aspiration pneumonia, thromboembolism and renal failure, alongside early consideration of high-dependency care. (S)

253For mild, early NMS, characterised by mild rigidity, catatonia or confusion, temperature < 38°C and HR < 100, consider a trial of lorazepam. (C)

254For moderate NMS, characterised by moderate rigidity, catatonia or confusion, temperature = 38°C–40°C and HR = 100–120, consider a trial of lorazepam. Consider a trial of bromocriptine or amantadine. Consider ECT. (C)

255For severe NMS, characterised by severe rigidity, catatonia or coma, temperature > 40°C and HR > 120, consider a trial of lorazepam and consider dantrolene. Consider bromocriptine or amantadine. Consider ECT. (C).

256If clinical features persist, consider bilateral ECT three times weekly or, in severe cases, once or twice daily, until NMS abates. Continue ECT three times per week until there is sustained improvement to a total of 5–20 treatments. (C)

257Delay restarting antipsychotics by at least 2 weeks after resolution of an NMS episode to reduce the risk of recurrence. (C)

258Antipsychotics with strong dopamine receptor affinity in particular can lead to the development of antipsychotic-induced catatonia. Antipsychotic-induced catatonia can occur in association with FGAs and probably less frequently with SGAs, and may develop within hours after the first administration of an antipsychotic agent. Diagnosis is often complicated by a question over whether the catatonia is intrinsic to the psychiatric illness or induced by its treatment, the so-called ‘catatonic dilemma’.

259The incidence of and risk factors for antipsychotic-induced catatonia are currently unclear. The catatonic signs of akinesia, stupor and mutism are more often associated with antipsychotics whereas catalepsy and waxy flexibility are less common in antipsychotic-induced catatonia. More complex catatonic behavioural abnormalities, such as echolalia, echopraxia, verbigeration or Mitgehen, are not generally reported in association with antipsychotic treatment.

260The primary intervention for antipsychotic-induced catatonia is discontinuation of the antipsychotic agent. In some cases, this is sufficient on its own. Other possible options are reducing the dose or switching to an antipsychotic with lower affinity for the dopamine receptors. Benzodiazepines may also be helpful. In one prospective cohort study including 18 patients with antipsychotic-induced catatonia, all were administered lorazepam, of whom 14 had complete remission and 4 had some partial response. Of the partial responders, three were administered amantadine, which was associated with a prompt recovery. Anticholinergics were ineffective in six patients before they were administered benzodiazepines. Good response to lorazepam has also been reported in other case series. Amantadine has also been reported to be helpful in a case series.

261There is a lack of data on the prophylaxis of antipsychotic-induced catatonia.

262Recommendations for antipsychotic-induced catatonia

263When catatonia is attributed to antipsychotic administration, consider discontinuing the antipsychotic. (C)

264In more severe cases or cases that do not resolve with antipsychotic discontinuation, consider a trial of a benzodiazepine. (C)

265Once catatonia is treated, if an antipsychotic is still necessary, commence at a low dose and titrate gradually, closely monitoring for side effects. (S)

266The prevalence of catatonia in modern child psychiatry has a wide range from 0.6% to 17%; the lowest prevalence being reported in a French study of adolescents, and the highest in a UK study of young people with autism. An Indian study reported an inpatient paediatric prevalence of 5.5%. Most cases appear to occur in adolescence: the 119 paediatric cases in a large cohort study had a mean age of 14.6 (SD: 2.7) years, although age ranged from 5 to 17 years. The potential aetiologies of catatonia in youth span the same psychiatric and medical categories as adults, and while affective and psychotic processes are most commonly found, appropriate assessment of other potential aetiologies, as detailed in section ‘Clinical assessment’, are indicated based on clinical history, evaluation and examination. In recent years, paediatric catatonia has been increasingly recognised in anti-NMDA receptor encephalitis, being found in over a third of affected children in one study. The Pediatric Catatonia Rating Scale (PCRS) is modified from the BFCRS and has been shown to be applicable in young people.

267Given the paucity of evidence in children and adolescents, current treatment paradigms are based on those recommended for adults, combined with case reports, case series and international clinical experience. This seems reasonable, particularly where cases occur among adolescents. In terms of benzodiazepines, in a case series of 66 children and adolescents who were hospitalised for catatonia, 51 received benzodiazepines, which were associated with improvement in 33 (65%). The mean dose of lorazepam was 5.4 (SD 3.6) mg/day. A smaller case series of six adolescents with catatonia found IV lorazepam was associated with improvement in all cases.

268With regard to ECT, a retrospective study of 39 adolescents who received ECT, of whom 17 had catatonia, found that 92% of those with catatonia responded. In literature reviews, the underlying evidence base is largely case reports and series. In one such review of 59 cases with a range of underlying disorders, at least 45 out of 59 (76%) improved after ECT. Another review identified 24 patients with catatonia who had outcome data after ECT, of whom 18 (75%) showed remission or marked improvement. The evidence suggests that side effects of ECT are similar to the adult population and serious complications are very rare.

269Since 2008, several reviews have proposed paediatric catatonia management along the lines of objective catatonia rating scales, medical work-up, removal of offending drugs and lorazepam challenge, followed by lorazepam treatment (sometimes at high doses) and or ECT (Dhossche et al., 2010a;;;;; ).

270Recommendations for catatonia in the children and adolescents

271Catatonia is known to occur in children as young as 5 years and clinicians should screen for catatonia whenever clinical suspicion exists. (S)

272Evaluation of catatonia aetiologies in children and adolescents should include the same range of disorders as found in adults. (S)

273When assessing for the presence of paediatric catatonia, the PCRS should be used. (C)

274First-line management for paediatric catatonia includes a lorazepam challenge test, lorazepam in increasing doses and bilateral ECT. (D)

275The literature on catatonia in the older adult population is limited compared to that in the working-age adult population. As with adult patients, it can be transient or long lasting, varying from weeks to months or years. The studies that have assessed the epidemiology of catatonia among older adults have focused on the acute psychiatric hospital setting, liaison psychiatry setting and intensive care setting. The prevalence has varied widely by the study setting and the assessment instruments used.

276The phenotype of catatonia among older adults shows a high prevalence of hypokinetic signs, such as immobility/stupor, staring, rigidity, mutism, withdrawal, posturing and negativism, although one study listed excitement among the commonly identified clinical features. Catatonia among older adults is often multifactorial in aetiology and a wide range of medical conditions has been implicated, though the outcome is still usually good if it is treated promptly.

277Differential diagnosis can be challenging and misdiagnosis of catatonia as delirium, psychosis, stroke, dementia or coma have been reported. This may result in inappropriate ‘do not resuscitate’ orders. Reports suggest that medical complications of catatonia, such as deep vein thrombosis, pulmonary embolism and pneumonia may be particular risks in older adults. One small study found that 4 out of 10 older adult patients with catatonia in a liaison psychiatry setting had medical complications and 2 died.

278Benzodiazepines remain the cornerstone of the treatment of catatonia among older adults, although they may respond to lower doses.

279ECT remains the treatment of choice among those not responding to benzodiazepines. Case reports suggest that methylphenidate and zolpidem may also be effective in managing catatonia in older adults. Case reports further suggest a possible beneficial effect of medications including amantadine, memantine, valproate, carbamazepine, topiramate, bromocriptine, propofol, biperiden, bupropion, olanzapine, lithium and tramadol. However, reports are mixed for amantadine, valproate or carbamazepine. Case reports have also reported the beneficial effect of rTMS and tDCS in the management of catatonia.

280Recommendations for catatonia in older adults

281In older adults, care should be taken to identify medical disorders underlying catatonia. (S)

282Catatonia should be considered in the differential diagnosis for an apparent rapidly progressive dementia or ‘failure to thrive’ clinical presentations in older adults. (S)

283First-line treatment of catatonia in the older adults consists of benzodiazepines, often at lower doses than among younger adults, and ECT. (D)

284The only systematic study of catatonia in the perinatal period is a retrospective chart review of 200 women consecutively admitted to hospital with postpartum psychosis, which suggests that the condition may be prevalent in women with severe mental illness in the postnatal period: 40 women (20%) were assessed as having catatonic signs. The literature in other perinatal groups with psychiatric or medical illnesses does not allow prevalence estimates.

285In pregnancy, many potential complications of persistent catatonia place the mother and child at exceptionally high risk. These include venous thrombosis and thromboembolism, dehydration, malnutrition, incontinence, infections, communication difficulties, impaired co-operation with assessments and investigations, and impairment of capacity. Postnatally, the mother’s ability to breastfeed and to care and bond with her infant are key concerns.

286The sections that follow describe the risks that the two main treatments for catatonia, lorazepam and ECT, may pose to the mother and the child. More details about the general principles of use of psychotropic medications in the perinatal period may be found in the BAP guidance on this topic

287Research on the reproductive safety of benzodiazepines remains at an early stage, and studies more typically evaluate benzodiazepines as a group, rather than individual agents. In a meta-analysis of cohort studies of exposure to benzodiazepines, found a trend towards increased risks for total (n = 5195) and cardiovascular (n = 4414) malformations with the lower end of the 95% CI nearly achieving significance. reported in a nationwide cohort study of 3.1 million pregnancies with a larger sample of benzodiazepine exposures (n = 40,846), using propensity scores to account for a large number of potential confounders and several sensitivity analyses, that first trimester exposure to benzodiazepines was associated with a very small increased risk of overall congenital malformations (adjusted relative risk (aRR): 1.09; 95% CI: 1.05–1.13) and specifically, heart defects (adjusted RR: 1.15; 95% CI: 1.10–1.21). A risk of oral clefts, reported by several previous studies, was not confirmed. There were differences between compounds and lorazepam was not associated with significant effects (aRR for overall congenital malformations 1.00, CI: 0.85–1.18; aRR for cardiovascular malformations 1.14, CI: 0.93–1.40).

288A systematic review and meta-analysis of prospective studies found that benzodiazepine exposure in pregnancy was associated with increased risks of spontaneous abortion, preterm birth, low birthweight and low Apgar scores with odds ratios of approximately two, a value generally regarded as the threshold for clinical significance. These outcomes are determined by other risk factors, many of them associated with mental disorders and difficult to capture from obstetric databases. Therefore, research findings in this area are known to be difficult to interpret and prone to overestimates. The authors highlight this risk of confounding as well as significant heterogeneity in the populations across the included studies. However, the risk of neonatal intensive care unit admission (2.61; CI: 1.64–4.14) was consistently increased and is likely to be related to neonatal benzodiazepine withdrawal.

289Cohort studies of neurodevelopmental outcomes following foetal benzodiazepine exposure have been inconclusive.

290A small number of studies suggest that a fully breastfed infant ingests very small amounts of the maternal lorazepam dose (Drugs and Lactation Database (LactMed), 2022; ), 2022). Clinical observations of infants are scarce but do not report infant sedation or other serious adverse effects following maternal doses within the licensed range (Drugs and Lactation Database (LactMed), 2022; ), but there is a lack of data regarding the effects of the high doses of lorazepam sometimes used in catatonia.

291In systematic reviews of the case literature on ECT in the perinatal period, summarised by, the most common adverse effects attributed to the treatment were foetal bradyarrhythmia, abdominal pain, uterine contractions, premature birth, vaginal bleeding, placental abruption and threatened abortion. In many cases, symptoms were mild and transient. No maternal deaths were reported.

292Among 339 cases summarised by, 11 foetal or neonatal deaths were reported, one of which was attributed to the treatment: it occurred in the context of maternal status epilepticus following three successive stimuli administered during ECT. found a high rate of complications in their systematic review of case reports and series, including 12 foetal and neonatal deaths among 169 cases. However, the authors did not state whether these outcomes were caused or thought to be caused by ECT. This review included all adverse maternal and foetal outcomes among complications of ECT even if they were highly unlikely to be related to the treatment, such as, for example, anencephaly and other congenital anomalies. This approach led the authors to call for great caution when considering the use of ECT in pregnancy. The authors of the other four systematic reviews – while acknowledging the difficulties with interpreting case literature – concluded that ECT is an effective treatment for severe mental illness during pregnancy and that the risks to mother and foetus are relatively low. This view is shared by publications of the Royal College of Psychiatrists, the APA, and the Royal Australian and New Zealand College of Psychiatrists.

293To achieve the optimal outcomes for mother and child, it is important that professionals with expertise in ECT, perinatal psychiatry and obstetrics are involved in a decision to deliver ECT during pregnancy. It is essential that clinicians identify pre-existing risk factors for poor outcomes, appropriately monitor maternal and foetal well-being before, during and after the procedure, and utilise effective preventative interventions. The location and team composition for conducting the ECT and what measures should be taken before, during and after the procedure to prevent maternal and foetal complications depend on the stage of pregnancy.

294There is evidence from three observational studies that ECT is more effective for women with severe affective disorders after childbirth than for non-postnatal patients. The short half-lives of medication used for anaesthesia and muscle relaxation during ECT mean that women should not be prevented from resuming breastfeeding after treatments.

295Due to inherent methodological difficulties, considerable uncertainties exist in the evidence, and research findings should be interpreted with caution.

296Recommendations for catatonia in the perinatal period

297If catatonia is severe and the woman suffers from a mental illness, the psychiatric and obstetric team should make a joint decision as to which inpatient setting is most appropriate for treatment. Contact between the mother and baby should be encouraged as much as is possible and appropriate. Psychiatric care should be provided by a psychiatrist experienced in the management of perinatal mental illness. (S)

298If catatonia is severe and presents high risks to the physical health of the mother and child, and treatment of the underlying condition has been ineffective or would lead to an unacceptable delay, specific treatment for catatonia should be considered. (S)

299The risks of any specific treatment should be carefully weighed against the risks of other treatments or no treatments. (S)

300Recommendations for catatonia during pregnancy

301Screening and selection of patients for ECT should be conducted by a psychiatrist experienced in ECT, in consultation with both a psychiatrist with appropriate expertise in perinatal psychiatry and an obstetrician. (D)

302If delivery is expected within a few weeks, alternative options, such as induction of labour or Caesarean section should be considered by the obstetrician, anaesthetist, paediatrician and psychiatrist. (S)

303If specific treatment for catatonia is required, lorazepam at doses up to 4 mg/day should be considered initially. (S)

304If lorazepam is not effective at up to 4 mg/day, and the risks to the health of the mother and/or the child are high, the use of ECT can be considered (S)

305Recommendations for catatonia during breastfeeding

306If treatment with lorazepam at doses higher than 4 mg/day is used, the mother should not breastfeed because of a lack of evidence of its safety. If possible and appropriate, lactation can be maintained during the period of high lorazepam dosing by expressing and discarding milk. (S)

307Women can resume breastfeeding after ECT treatments. (C)

308International studies over the past two decades have documented a point prevalence of catatonia ranging from 12% to 20% in individuals with autism, with onset most commonly in adolescence and early adulthood. As the US Center for Disease Control estimated an incidence of autism as 1 in 44 children, it is likely that clinicians will care for individuals with autism and catatonia. It is theorised that shared neuronal circuitry and genetic susceptibility loci exist between autism and catatonia. Catatonia often encompasses the full range of psychomotor retarded and agitated clinical features in autism, and the latter may include dangerous repetitive self-injury with high risk for severe bodily harm.

309Diagnosis of catatonia in autism is complicated by the overlap in clinical features between the two conditions. Therefore, several authors have suggested that diagnosis of catatonia in autism should entail a marked change from baseline presentation. This is important because no pharmacological or neuromodulatory therapies are indicated for the core symptoms of autism.

310Treatment paradigms are based on case reports and series, as well as international clinical experience. The first blueprints for treatment of catatonia in autism were published by and begin with standardised assessment of catatonia, taking into consideration baseline autistic features that may mimic catatonia. emphasised that amotivation, prompt dependence, withdrawal and slowness often accompany classic DSM catatonia signs in autism, and consideration of catatonia is urged for any change in activity level, self-care or skill. After a catatonia diagnosis and evaluation for underlying medical disorders, clinical features are to be classified as mild, moderate or severe, drawing a clear distinction between impairments such as slowness throughout the day versus immobility, stupor and food refusal. Mild catatonic features may be addressed by the Shah–Wing approach of psychological and supportive interventions with a focus on prompting, structure and stress reduction, and possible lorazepam usage. More severe presentations should be treated with the standard biological anticatatonic regimens including bilateral ECT. Fink, Taylor and Ghaziuddin offered a medical treatment model in 2006 including catatonia diagnosis with standardised rating scales including the BFCRS, lorazepam trial and ongoing therapy, and bilateral ECT as needed. In a case series of 22 individuals with catatonia and autism, Wachtel further discussed limited response to benzodiazepines as well optimisation of ECT response, adequate hydration, pre-treatment hyperventilation and limited usage of anaesthetic agents that interfere with seizure threshold. A 2021 systematic review of 12 studies encompassing 969 individuals with autism and catatonia, also noted a lack of clear response to benzodiazepines, which often had to be discontinued due to side effects. This stands in contrast to the overall benefit of benzodiazepines in catatonia in general and is consistent with other reports where ECT was implemented after failed benzodiazepine trials. The authors also noted that antipsychotics were often used in individuals with catatonia and autism despite a lack of known benefit of such agents in catatonia in general, and urged caution given the risk of worsening catatonia or precipitating its malignant form. Finally, for those patients with autism who require ECT, multiple reports suggest that maintenance ECT may be necessary indefinitely after an index course.

311Recommendations for catatonia in autism spectrum disorder

312Clinical vigilance is warranted for the assessment of catatonia in autism spectrum disorder given its high prevalence. (C)

313Diagnosis of catatonia in autism spectrum disorder requires a marked change from baseline presentation. (S)

314First-line interventions in mild cases of catatonia are psychological interventions and/or lorazepam, but the standard treatments for catatonia (i.e. benzodiazepines in escalating dosages and/or bilateral ECT) should be considered in moderate to severe cases. (D)

315Catatonia, including malignant catatonia, has been described in the context of severe renal impairment, in patients receiving dialysis and in the post-transplantation period, often as a result of drug toxicities. Patients with renal impairment, even those on dialysis, may still be able to tolerate and benefit from benzodiazepines with consideration of the severity of renal impairment, route of administration of benzodiazepines, comorbidities (e.g. frailty), including the risk for delirium.

316Typically, no dose adjustments are required even in severe impairment for acute dosing of lorazepam in either oral or parenteral formulation; however, for high or repeated parenteral dosing, monitoring for propylene glycol toxicity and consideration of other therapies such as ECT and NMDA receptor antagonists may be indicated to lessen the impact of the potential side effects of treatment (e.g. falls, confusion, delirium).

317Malignant catatonia may be a rare cause of liver failure. Catatonia has been reported secondary to Wilson’s disease, after liver transplantation, including in post-transplantation delirium as well as secondary to post-transplantation drug toxicities. The early post-liver transplantation period may be a state of deficiency in GABA signalling, which may place the patient at increased risk for catatonia.

318Benzodiazepines may be an effective treatment for catatonia post-transplantation. In mild to moderate hepatic impairment, typically no dose adjustment for lorazepam is required (oral or parenteral formulations). In severe impairment or failure, use caution. Other treatments such as NMDA receptor antagonists or ECT may be required when benzodiazepine treatment is cautioned.

319Pulmonary complications of catatonia may include pulmonary embolism, aspiration pneumonia, pneumothorax, bronchorrhoea, central hypoventilation, respiratory failure and delayed weaning from mechanical ventilation (;;; ter; ).

320Catatonia has been described in the context of respiratory illnesses, including influenza and SARS-CoV-2, as well as in critical illnesses (e.g. sepsis, shock). Catatonia in the context of critical illness including respiratory failure may have high comorbidity with delirium. Respiratory failure due to malignant catatonia has been described and may be especially responsive to ECT (;;; ter; ), especially in those unable to tolerate a benzodiazepine.

321Recommendations for catatonia in kidney, liver and lung disease

322In renal impairment, lorazepam dosing does not usually need to be altered, but consider additional monitoring for side effects. (C)

323In mild or moderate hepatic impairment, lorazepam dosing does not usually need to be altered, but caution should be exercised when considering lorazepam in severe hepatic impairment. (B)

324In severe respiratory disease, consider giving ECT as a first-line treatment rather than benzodiazepines. (D)

325One general point for future research is that there is a need to harmonise definitions of catatonia and definitions of specific catatonic signs, as well as thresholds for making a diagnosis.

326As this guideline has highlighted, the most urgent research goal for catatonia is to develop a more robust evidence base for its treatment. Despite the wealth of small reports and observational data, a Cochrane systematic review of the use of benzodiazepines for catatonia found that no RCT met its inclusion criteria. Although some might consider an RCT infeasible in catatonia, the Cochrane review found several examples. Unfortunately, though, these studies had methodological issues, introducing questions of validity. Conducting clinical trials in catatonia is an important priority for psychiatric research in the next decade.

327In the meantime, there is substantial scope to improve the quality of evidence for the treatment of catatonia by using large databases of electronic healthcare records with prescribing data. Additional measures to improve the evidence base would include harmonising the outcomes used in research studies by developing a set of core outcomes. This would facilitate pooling of data across research centres, which is an important tool in researching less common conditions.

328We provide a list of priority research questions in Table 11.