https://doi.org/10.1177/02698811231158232
Journal of Psychopharmacology
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The Author(s) 2023
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DOI: 10.1177/02698811231158232
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Evidence-based consensus guidelines for the
management of catatonia: Recommendations
from the British Association for
Psychopharmacology
Jonathan P Rogers
1,2
, Mark A Oldham
3
, Gregory Fricchione
4,5
,
Georg Northoff
6
, Jo Ellen Wilson
7,8
, Stephan C Mann
9
, Andrew Francis
10
,
Angelika Wieck
11,12
, Lee Elizabeth Wachtel
13,14
, Glyn Lewis
1
,
Sandeep Grover
15
, Dusan Hirjak
16
, Niraj Ahuja
17
, Michael S Zandi
18,19
,
Allan H Young
20,2
, Kevin Fone
21
, Simon Andrews
22
, David Kessler
23
,
Tabish Saifee
19
, Siobhan Gee
24,25
, David S Baldwin
26
and Anthony S David
27
Abstract
The British Association for Psychopharmacology developed an evidence-based consensus guideline on the management of catatonia. A group of
international experts from a wide range of disciplines was assembled. Evidence was gathered from existing systematic reviews and the primary literature.
Recommendations were made on the basis of this evidence and were graded in terms of their strength. The guideline initially covers the diagnosis,
aetiology, clinical features and descriptive epidemiology of catatonia. Clinical assessments, including history, physical examination and investigations are
then considered. Treatment with benzodiazepines, electroconvulsive therapy and other pharmacological and neuromodulatory therapies is covered. Special
regard is given to periodic catatonia, malignant catatonia, neuroleptic malignant syndrome and antipsychotic-induced catatonia. There is attention to the
needs of particular groups, namely children and adolescents, older adults, women in the perinatal period, people with autism spectrum disorder and those
with certain medical conditions. Clinical trials were uncommon, and the recommendations in this guideline are mainly informed by small observational
studies, case series and case reports, which highlights the need for randomised controlled trials and prospective cohort studies in this area.
Keywords
Catatonia, catatonic schizophrenia, guideline, treatment, benzodiazepine, electroconvulsive therapy, neuroleptic malignant syndrome
1158232JOP0010.1177/02698811231158232Journal of PsychopharmacologyRogers et al.
research-article2023
BAP Guidelines
1
Division of Psychiatry, University College London, London, UK
2
South London and Maudsley NHS Foundation Trust, London, UK
3
Department of Psychiatry, University of Rochester Medical Center,
Rochester, NY, USA
4
Department of Psychiatry, Massachusetts General Hospital, Boston,
MA, USA
5
Harvard Medical School, Boston, MA, USA
6
Mind, Brain Imaging and Neuroethics Research Unit, The Royal’s
Institute of Mental Health Research, University of Ottawa, Ottawa,
ON, Canada
7
Veterans Affairs, Geriatric Research, Education and Clinical Center,
Tennessee Valley Healthcare System, Nashville, TN, USA
8
Department of Psychiatry and Behavioral Sciences, Vanderbilt
University Medical Center, Nashville, TN, USA
9
Private Practice, Harleysville, PA, USA
10
Penn State Medical School, Hershey Medical Center, PA, USA
11
Greater Manchester Mental Health NHS Foundation Trust, Manchester,
UK
12
Institute of Population Health, University of Manchester, Manchester, UK
13
Kennedy Krieger Institute, Baltimore, Maryland, USA
14
Department of Psychiatry, Johns Hopkins School of Medicine,
Baltimore, Maryland, USA
15
Department of Psychiatry, Postgraduate Institute of Medical
Education and Research, Chandigarh, CH, India
16
Department of Psychiatry and Psychotherapy, Central Institute of
Mental Health, Medical Faculty Mannheim, University of Heidelberg,
Mannheim, Germany
17
Regional Affective Disorders Service, Cumbria, Northumberland, Tyne
and Wear NHS Foundation Trust, Newcastle, UK
18
Queen Square Institute of Neurology, University College London,
London, UK
19
National Hospital for Neurology and Neurosurgery, London, UK
20
Department of Psychological Medicine, Institute of Psychiatry,
Psychology and Neuroscience, King’s College London, UK
21
School of Life Sciences, Queen’s Medical Centre, The University of
Nottingham, Nottingham, UK
22
Patient and Retired Physician, Liverpool, UK
23
Centre for Academic Mental Health, University of Bristol, Bristol, UK
24
Pharmacy Department, South London and Maudsley NHS Foundation
Trust, London, UK
25
F aculty of Life Sciences and Medicine, King’s College London,
London, UK
26
Clinical Neuroscience, Clinical and Experimental Sciences, Faculty of
Medicine, University of Southampton, Southampton, UK
27
Institute of Mental Health, University College London, London, UK
Corresponding author:
Jonathan P Rogers, UCL Division of Psychiatry, 6th Floor, Maple House,
149 Tottenham Court Road, Bloomsbury, London, W1T 7NF, UK.
Email: jonathan.rogers@ucl.ac.uk
2 Journal of Psychopharmacology 00(0)
Contents
Introduction 2
Guideline rationale 2
Guideline method 2
Strength of evidence and recommendations 3
Background 3
History 3
Definition 3
Aetiology 5
Catatonia due to a medical condition 5
Catatonia due to another psychiatric disorder 6
Clinical features 6
Descriptive epidemiology 8
Clinical assessment 8
History and physical examination 8
Rating instruments 9
Investigations 10
Challenge tests 12
Lorazepam and other benzodiazepines 12
Zolpidem 13
Other drugs 13
Differential diagnosis 13
Treatment 16
General approach 16
First-line treatment 16
Non-response 17
Underlying condition 17
Complications 17
GABA-ergic pharmacotherapies 17
Electroconvulsive therapy 18
Other therapies 19
NMDA receptor antagonists 19
Dopamine precursors, agonists and 20
reuptake inhibitors
Dopamine receptor antagonists and 20
partial agonists
Anticonvulsants 21
Anticholinergic agents 21
Miscellaneous treatments 21
Repetitive transcranial magnetic 21
stimulation and transcranial direct-current
stimulation as alternatives to ECT
Subtypes of catatonia and related conditions 21
Periodic catatonia 21
Malignant catatonia 22
Neuroleptic malignant syndrome 23
Antipsychotic-induced catatonia 25
Considerations in special groups and situations 25
Children and adolescents 25
Older adults 26
The perinatal period 26
The reproductive safety of lorazepam 26
in the perinatal period
The use of ECT in the perinatal period 27
Autism spectrum disorder 28
Medical conditions 28
Considerations in kidney disease 28
Considerations in liver disease 28
Considerations in lung disease 29
Research priorities 29
Acknowledgement 30
Declaration of conflicting interests 30
Funding 30
Supplemental material 30
References 30
Introduction
Guideline rationale
Catatonia is a severe neuropsychiatric disorder affecting move-
ment, 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 (Funayama et al., 2018; Niswander et al., 1963;
Rogers et al., 2021). 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
(Abrams and Taylor, 1976; Gelenberg, 1976). 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 (van
der Heijden et al., 2005), and knowledge about the condition
and its distinctive treatments is frequently limited among clini-
cians (Takács et al., 2021; Wortzel et al., 2021). 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 treat-
ment for catatonia (National Institute for Health and Care
Excellence, 2003). From an international perspective, the
European Association of Psychosomatic Medicine (Denysenko
et al., 2015) and the US Academy of Consultation-Liaison
Psychiatry (Denysenko et al., 2018) 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 benzodiaz-
epines, glutamate antagonists (amantadine and memantine) or
ECT (American Psychiatric Association, 2021; Deutsche
Gesellschaft für Psychiatrie und Psychotherapie, 2019; Hasan
et al., 2012). There is a clear gap in the literature for a multidisci-
plinary consensus guideline that comprehensively reviews the
current evidence and offers treatment recommendations.
Guideline method
To address this need for a guideline, the British Association for
Psychopharmacology (BAP) convened a group of experts with
representation from general adult psychiatry, neuropsychiatry,
Rogers et al. 3
child and adolescent psychiatry, liaison (consultation-liaison)
psychiatry, perinatal psychiatry, autoimmune neurology, move-
ment 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.
A virtual meeting was convened in June 2022, where group
members presented proposals for separate sections of the guide-
line, which were discussed by the overall group. Following the
meeting, certain group members drafted sections of the guide-
line, which were edited and synthesised into a first draft. This
draft was then disseminated to all authors for further amend-
ments before a second draft was made for further review.
The 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.
Strength of evidence and recommendations
To assess the strength of evidence and recommendations, the
guideline group adopted the schema developed by Shekelle et al.
(1999). This system provides categories of evidence for the pur-
poses of assessing causal relationships as well as a classification
of the strength of recommendations. To grade the strength of evi-
dence for non-causal relationships, we used the classification
employed for the British Association for Pharmacology guide-
lines for the pharmacological treatment of schizophrenia, as
shown in Table 1 (Barnes et al., 2020).
Background
History
Descriptions of what was likely catatonia date back to antiquity
(Berrios, 1981; Jeste et al., 1985). 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 (Berrios and Marková,
2018). 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 qualita-
tively abnormal movements (Kahlbaum, 1874; Kendler, 2019),
though other 19th-century authors had described similar phe-
nomena (Hirjak et al., 2022).
By the end of the 19th century, Kraepelin’s diagnostic classi-
fications of psychiatric disorders incorporated catatonia into an
enlarged concept of dementia praecox where motor signs were
the result of psychological processes (Foucher et al., 2022;
Shorter and Fink, 2018), and therefore catatonia was subsumed
under the diagnosis of schizophrenia by Eugen Bleuler. This dif-
fered from Kahlbaum, who had conceived of catatonia as an
independent disorder with motor, behavioural and affective signs
as primary manifestations of the disorder (Foucher et al., 2022;
Hirjak et al., 2022). Moreover, Kahlbaum emphasised the strong
occurrence of affective symptoms in combination with motor and
behavioural abnormalities (Hirjak et al., 2020, 2022; Hirjak
et al., 2021a; Northoff et al., 2021).
Catatonia as a subtype of schizophrenia went on to be the con-
ceptual model used by earlier editions of the ICD and DSM.
However, two papers published in 1976 challenged this assump-
tion, arguing that catatonia appears in a range of psychiatric and
medical disorders, not exclusively (or even mainly) in schizo-
phrenia (Abrams and Taylor, 1976; Gelenberg, 1976). The cur-
rent major diagnostic manuals (ICD-11 and DSM-5-TR) have
since endorsed a broader concept of catatonia and permit diagno-
sis in the context of other mental and physical disorders, as well
as providing an ‘unspecified’ category.
Definition
Unlike 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 (Sienaert et al., 2011). These signs cover focal motor
activity (e.g. catalepsy, posturing, mannerisms, stereotypies, gri-
macing and echopraxia), generalised motor activity (stupor and
agitation), speech (mutism, verbigeration and echolalia), affect
(affective blunting, anxiety and ambivalence), complex behav-
iour (negativism, reduced oral intake and withdrawal) and auto-
nomic 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).
With 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 pre-
sent in catatonia (Dawkins et al., 2022; Wilson et al., 2015),
which is the case for many psychiatric disorders.
If there are no clinical signs that are pathognomonic of catato-
nia, 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
(Rasmussen et al., 2016; Zingela et al., 2022). 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 (Bush
et al., 1996a, 1996b). Others propose the presence of at least one
motor, one behavioural and one affective sign (Northoff et al.,
1999a). Such a definition of catatonia conforms to the psychomo-
tor concept introduced by Kahlbaum (1874), and it does not
regard any of the catatonic signs as pathognomonic for catatonia
(Northoff et al., 1999a).
Without a gold-standard biomarker, there can only be moder-
ate 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 treat-
ments. However, benzodiazepine response can perhaps be con-
sidered as a surrogate marker for some form of as yet not fully
characterised pathophysiological process, although the response
to benzodiazepines is not universal.
4 Journal of Psychopharmacology 00(0)
Figure 1. Quick reference algorithm for the management of catatonia.
Rogers et al. 5
One of the more compelling pieces of evidence for a require-
ment 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 (Peralta and Cuesta,
2001). A threshold of four catatonic signs is highly specific but
may miss some cases and thus have poorer sensitivity (Peralta
et al., 2010).
Definitions of different forms of catatonia are shown in Table 2.
Recommendation on the definition of catatonia
? Catatonia should be diagnosed based on the presence
of three or more catatonic signs, as in DSM-5-TR or
ICD-11. (B)
Aetiology
Catatonic signs are not uncommon and can occur in many psy-
chiatric 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 (American Psychiatric Association,
2013; World Health Organization, 2018). The terms ‘organic’ or
‘secondary’ catatonia have been used in the past to signify under-
lying medical or neurological aetiological conditions (Ahuja,
2000). However, the distinction between ‘organic’ and ‘func-
tional’ is perhaps best avoided due to their differing connotations
in disparate clinical settings.
Our 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 catato-
nia, rather than on robust epidemiological associations. Often
there is a close temporal relationship and sometimes a concomi-
tant 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 (Hill, 1965). 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 aetio-
logical links, as there is under-detection and a lack of compre-
hensive 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.
Catatonia due to a medical condition. There 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 per-
centage rises to almost 80% in older patients (Oldham, 2018).
These figures exclude catatonic signs seen in neuroleptic malig-
nant syndrome (NMS). There are several clinical features that
suggest a higher likelihood of ‘medical catatonia’, and these
include comorbid delirium, clinically significant autonomic dis-
turbances, catatonic excitement, presence of the grasp reflex,
pneumonia, known history of a neurological condition and his-
tory of seizures (Oldham, 2018).
Oldham (2018) describes 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), fol-
lowed by neural injury (19.2%; with vascular and degenerative
conditions the most common causes of injury), toxins or medica-
tions (11.6%; such as benzodiazepine withdrawal), structural
brain pathology (9.6%; such as space occupying lesions) and epi-
lepsy (9.3%), with miscellaneous disorders and states (such as
hyponatremia, postpartum, renal failure and sepsis) contributing
Table 1. Categories for strength of evidence and recommendations (Barnes et?al., 2020; Shekelle et?al., 1999).
Categories of evidence for causal relationships and treatment
Ia: Evidence from meta-analysis of RCTs
Ib: Evidence from at least one RCT
IIa: Evidence from at least one controlled study without randomisation
IIb: Evidence from at least one other type of quasi-experimental study
III: Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and case–control studies
IV: Evidence from expert committee reports or opinions and/or clinical experience of respected authorities
Categories of evidence for non-causal relationships
I: Evidence from large representative population samples
IIa: Evidence from small, well-designed, but not necessarily representative samples
IIb: Evidence from pharmacovigilance studies
III: Evidence from non-representative surveys, case reports
IV: Evidence from expert committee reports or opinions and/or clinical experience of respected authorities
Strength of recommendations
A: Directly based on category I evidence
B: Directly based on category II evidence or extrapolated recommendation from category I evidence
C: Directly based on category III evidence or extrapolated recommendation from category I or II evidence
D: Directly based on category IV evidence or extrapolated recommendation from category I, II or III evidence
S: Derived from a consensus view in the absence of systematic evidence
RCT: randomised controlled trial.
6 Journal of Psychopharmacology 00(0)
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 dis-
ease (Oldham, 2018).
The 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 selec-
tion of the most important underlying disorders.
In 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 cer-
ebellum 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 (Jeyaventhan et al., 2022;
Magnat et al., 2022).
In terms of functional neuroimaging, decreased activation in
the contralateral motor cortex, decreased regional cerebral blood
flow (r-CBF) in right fronto-parietal cortex (Northoff et al.,
1999c) and decreased density of γ-aminobutyric acid (GABA)-A
receptors in the left sensorimotor cortex and right parietal cortex
(Northoff et al., 1999b) have all been found.
Catatonia due to another psychiatric disorder. In 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 (schizo-
phrenia, schizoaffective disorder, schizophreniform disorder,
brief psychotic disorder and substance-induced psychotic disor-
der) and another medical condition. The DSM-5-TR also includes
a category for unspecified catatonia (American Psychiatric Asso-
ciation, 2013). The DSM-IV Handbook of Differential Diagnosis
(First et al., 1995) provided a helpful hierarchy of diagnosis for
catatonia, with medical aetiology first, followed by antipsy-
chotic-induced catatonia, then substance intoxication or with-
drawal, and then bipolar disorder and major depression, and then
other psychiatric disorders including schizophrenia. This remains
a useful hierarchy for clinical use.
Among primary psychiatric disorders, observational studies
have reported catatonia in association with depression, mania,
schizophrenia, autism spectrum disorder, anxiety disorders and
postpartum psychosis (Abrams and Taylor, 1976; Babu et al.,
2013; Dutt et al., 2011; Kline et al., 2022; Krüger and Br?unig,
2000; Nahar et al., 2017; Starkstein et al., 1996; Stompe et al.,
2002; Vaquerizo-Serrano et al., 2021). Other psychiatric disor-
ders with evidence from case reports or case series include obses-
sive-compulsive disorder and post-traumatic stress disorder
(Ahmed et al., 2021; Dhossche et al., 2010b; Jaimes-Albornoz
et al., 2020; Shiloh et al., 1995).
Clinical features
Given 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 char-
acteristic motor signs include mannerisms, stereotypy, festina-
tion, athetotic movements, dyskinesias, Gegenhalten, posturing,
catalepsy, waxy flexibility (flexibilitas cerea), rigidity, muscular
Table 2. Key definitions.
Term Definition
Medication-induced catatonia Catatonia induced by administration or withdrawal of prescribed medications
Substance-induced catatonia Catatonia induced by administration or withdrawal of psychotropic substances
Malignant (pernicious/
febrile/lethal) catatonia
A life-threatening form of catatonia that, in addition to the usual signs of catatonia, is accompanied by
pronounced autonomic abnormalities. In some cases, this can lead to a life-threatening elevation in blood
pressure, heart rate and body temperature with a poor outcome. Malignant catatonia occurs in only a small
fraction of patients with catatonia
Catatonia in critical illness Catatonia in patients requiring medical ICUs (e.g. intubation, ventilation or vasopressors). Although current
diagnostic criteria for catatonia exclude delirium, some patients may meet syndromal criteria for both and
benefit from treatment for catatonia and delirium
Periodic catatonia A rare form of catatonia with relatively high heritability characterised by alternation between stupor and
excitement
Catatonic schizophrenia A historical subtype of schizophrenia (e.g. in ICD-10 and DSM-IV) in which psychomotor disorders predominate.
Other features of schizophrenia such as hallucinations, delusions and thought disorder can also be present
Organic catatonic disorder A diagnosis listed in ICD-10 that describes a catatonic syndrome due to a known physiological condition.
Catatonic schizophrenia, delirium and stupor (e.g. dissociative) according to ICD-10 must be excluded prior to
the diagnosis. In ICD-11, this is listed as ‘secondary catatonia syndrome’ and in DSM-5-TR as ‘catatonic disorder
due to another medical condition’
Psychomotor concept of
catatonia
A clinical/neurobiological concept that understands catatonia as a psychomotor syndrome (in the tradition of
Karl Ludwig Kahlbaum) and defines it by motor, affective and behavioural domains with their associated brain
networks
Motor concept of catatonia A clinical/neurobiological concept that understands catatonia as a primarily motor syndrome (in the tradition
of Emil Kraepelin and Eugen Bleuler) and defines it mainly by motor and behavioural features and their
associated brain networks
DSM: Diagnostic and Statistical Manual of Mental Disorders; ICD: International Classification of Diseases; ICU: intensive care unit; LSD: lysergic acid diethylamide; MDMA:
3,4-methylenedioxymethamphetamine.
‘Malignant catatonia’ is now the preferred term.
Rogers et al. 7
Table 3. Selected important medical conditions that may underlie catatonia.
Medical conditions associated with catatonia
CNS autoimmunity or inflammation Medication or drug withdrawal
?? Anti-NMDA receptor encephalitis ?? Alcohol
?? Multiple sclerosis ?? Benzodiazepines
?? ?Other causes of autoimmune encephalitis, including paraneoplastic
syndromes
?? Clozapine
?? Gabapentin
?? SLE ?? Zolpidem
CNS infection Metabolic disorders and states
?? Bacterial meningitis or encephalitis ?? Diabetic ketoacidosis
?? Cerebral malaria ?? Glucose-6-phosphate dehydrogenase deficiency
?? HIV encephalopathy ?? Hepatic encephalopathy
?? Prion disease ?? Homocystinuria
?? Subacute sclerosing panencephalitis ?? Hyperammonaemia
?? Syphilis ?? Hypercalcaemia
?? Viral meningitis or encephalitis ?? Hyponatraemia
Endocrine ?? Pellagra
?? Addison’s disease ?? Porphyria
?? Cushing’s disease ?? Uraemia or renal failure
?? Hyperthyroidism ?? Vitamin B12 deficiency or pernicious anaemia
?? Hypoparathyroidism ?? Wernicke’s encephalopathy
?? Hypothyroidism ?? Wilson’s disease
?? Panhypopituitarism Neurodegenerative
?? Phaeochromocytoma ?? Dementia with Lewy bodies
Focal neurological lesions ?? Frontotemporal dementia
?? ?Lesions of varying pathophysiology to the frontal lobes, temporal lobes,
parietal lobes, limbic regions, diencephalon, basal ganglia and cerebellum
?? Parkinson’s disease
?? Space-occupying lesion Seizure
?? Traumatic brain injury ?? NCSE
?? Tumour Toxins
?? Vascular injury ?? Bulbocapnine
Medication or drug administration or overdose ?? Carbon monoxide
?? Antiretroviral drugs ?? Coal gas
?? Azithromycin ?? Fluorinated hydrocarbons
?? Antipsychotics (see section ‘Antipsychotic-induced catatonia’) ?? Isopropanol
?? Baclofen Miscellaneous
?? Beta-lactam antibiotics ?? Burns
?? Cannabis and synthetic cannabinoids ?? Electrocution
?? Ciclosporin ?? Extrapontine myelinolysis
?? Corticosteroids ?? Narcolepsy
?? CNS stimulants ?? Posterior reversible encephalopathy syndrome
?? Disulfiram ?? Postoperative, including post-transplant
?? Fluoroquinolones ?? Respiratory failure
?? Inhalants ?? Systemic infection or sepsis
?? Ketamine ?? Toxic epidermal necrolysis
?? Levetiracetam ?? Tuberous sclerosis
?? Lithium
?? LSD
?? Methoxetamine
?? Opioids
?? Phencyclidine
?? Tacrolimus
Source: Ahuja (2000), Carroll and Goforth (2004), Denysenko et?al. (2018), Fink and Taylor (2003), Oldham (2018), Rogers et?al. (2019), Tatreau et?al. (2018), Yeoh
et?al. (2022).
CNS: central nervous system; HIV: human immunodeficiency virus; LSD: lysergic acid diethylamide; NCSE: Non-convulsive status epilepticus; NMDA: N-methyl-D-aspartate;
SLE: Systemic lupus erythematosus.
8 Journal of Psychopharmacology 00(0)
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, ambiva-
lence, staring and agitation. The cognitive-behavioural catatonic
features include grimacing, verbigeration, perseveration, apro-
sodic speech, abnormal speech, automatic obedience, echolalia/
echopraxia, Mitgehen/Mitmachen, compulsive behaviour, nega-
tivism, autism/withdrawal, mutism, stupor, loss of initiative and
vegetative abnormalities. From a longitudinal perspective, cata-
tonic signs often fluctuate and patients can show different forms
of catatonia at different points in their illness.
The courses and outcomes of catatonia vary. A rare form of
catatonia is ‘periodic’ catatonia (see Table 2 for overview of dif-
ferent 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. (Ungvari et al., 2005, 2010)).
Descriptive epidemiology
Many estimates of catatonia prevalence in various populations of
patients seen in mental health services are available. Solmi et al.
(2018) provided a synthesis of these results and the headline fig-
ure 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 dis-
orders. There did not appear to be a consistent relationship
between catatonia prevalence and whether the study was con-
ducted 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 (van der
Heijden et al., 2005) and the smaller studies were far more likely
to have used a systematic means of identifying catatonia, thereby
explaining higher reported prevalence.
Rogers et al. (2021) estimated 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 (Luccarelli et al., 2022).
Some reports indicate a temporal decline in the diagnosis of
catatonia in routinely collected data. Tanskanen (2021) 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. Van der Heijden et al. (2005) 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. Rogers et al. (2021) reported an
increase in incidence between 2007 and 2016. The varying inter-
est in catatonia and changes in diagnostic practice over time
make the interpretation of time trend data very difficult.
Several studies conducted in Western nations have found that
catatonia was more common among individuals from ethnic minor-
ities (Chandrasena, 1986; Dealberto, 2008; Hutchinson et al., 1999;
Lee et al., 2000; Rogers et al., 2021), often by a large margin.
Clinical assessment
History and physical examination
Studies commonly identify at least three (Cuevas-Esteban et al.,
2020; Grover et al., 2015; Krüger et al., 2003; McKenna et al.,
1991; Subramaniyam et al., 2020; Ungvari et al., 2007; Wilson
et al., 2015) 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 behav-
iour, especially where it is grossly inappropriate to context.
The 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, neuro-
logical and psychiatric history, along with exposure to or with-
drawal from medications (plasma concentration measurement
may be used to ascertain concordance where available), recrea-
tional substances and blood-borne or sexually transmitted infec-
tions (Table 4). It is also important to obtain a detailed family
medical, neurological and psychiatric history to identify poten-
tially specific biological vulnerability. Physical examination is
also essential (Table 5).
The overwhelming majority of patients with catatonia are
assessed within secondary care (Rogers et al., 2021), 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’) (Oldham,
2018). When a patient presents with a recurrent episode of cata-
tonia, 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 impor-
tant to address potential complications of catatonia (Clinebell
et al., 2014), as well as for care planning.
Patients 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
Rogers et al. 9
of wilful non-engagement. It is also important to keep in mind
that patients with catatonia often understand what others are say-
ing yet are unaware of their inability to respond (Northoff, 2002).
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.
Reliable identification of catatonia requires deliberate assess-
ment (Table 6). Three primary means of assessment include clini-
cal observation, elicitation and physical examination. The clinician
should observe the patient before evaluation, often casually with-
out 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 echophenom-
ena 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 evalu-
ation for autonomic abnormality involves assessment of vital
signs, either by chart review or by obtaining them directly.
Recommendations on the assessment of catatonia
? Initial assessment and treatment of catatonia should be
conducted within secondary care. (S)
? Catatonia 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)
? A collateral history should be sought wherever possible.
(S)
? The history should include identification of possible med-
ical and psychiatric disorders underlying catatonia, as
well as prior response to treatment. (S)
? Physical examination should include assessment for cata-
tonic signs, signs of medical conditions that may have led
to the catatonia and signs of medical complications of
catatonia. (D)
? When 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)
? In an individual who is suspected to have catatonia, non-
engagement with clinical assessment should not automat-
ically 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)
Rating instruments
Most 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) (Oldham, 2022).
The Rogers Catatonia Scale (Starkstein et al., 1996) 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 (Carroll et al., 2008)
also has a significant weakness in that it has yet to be vali-
dated in a clinical cohort. As such, both the Rogers and Kanner
scales should be disfavoured from routine clinical use at this
time.
Table 4. Selected salient points in a history from a person with catatonia.
Personal and family history Personal history
Psychiatric conditions Psychotropic drugs
Prior catatonia or NMS Serotonergics (including lithium)
Mood disorder D
2
antagonists (including antiemetics)
Psychotic disorder Clozapine discontinuation
Neurodevelopmental disorder Benzodiazepine or alcohol discontinuation
Prior ECT Other medications
Neuro-medical conditions Immune checkpoint inhibitors
Seizure disorder Recreational drugs
Known/risk for CNS pathology Cannabis/cannabinoids
Space-occupying lesions Stimulants
Neurodegenerative condition Exposures (e.g. HIV or syphilis)
Encephalitis (esp. autoimmune) Sexual history
Lupus or other vasculitis Intravenous drug use
ECT: electroconvulsive therapy; NMS: neuroleptic malignant syndrome; CNS: central nervous system; HIV: human immunodeficiency virus.
Table 5. Physical examination for patients with catatonia.
Volume/nutritional status
Temperature
Cardiovascular examination (especially if considering ECT)
Respiratory status (especially if on opioids, prior to benzodiazepine
administration)
Neurological examination for localising signs
Evidence of deep vein thrombosis
Pressure ulcers on all potential pressure points
ECT: electroconvulsive therapy.
10 Journal of Psychopharmacology 00(0)
The Br?unig Catatonia Rating Scale (Br?unig et al., 2000) has
good psychometric properties and has been validated against the
criteria for catatonia in DSM-III-R, although DSM-III-R is some-
what different from DSM-5-TR in this regard. The Br?unig 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).
The two leading catatonia instruments are the Bush-Francis
Catatonia Rating Scale (BFCRS) (Bush et al., 1996a) and NCRS
(Northoff et al., 1999a), each with its unique strengths and weak-
nesses. 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 (Bush et al.,
1996b). 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
(Wilson et al., 2017), which makes for an efficient clinical evalu-
ation. The full 23-item scale evaluates all ICD-11 catatonia crite-
ria. The BFCRS scale was originally validated using a
standardised clinical exam against other clinical criteria (Bush
et al., 1996a). It has been found to be sensitive to change in clini-
cal status in response to treatment (Bush et al., 1996b; Girish and
Gill, 2003). 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
(Oldham and Wortzel, 2022).
The 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 diag-
nostic criteria of catatonia in the DSM-5-TR and ICD-11, and its
definitions of motoric findings are consistent with their defini-
tions 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 (Hirjak et al., 2020; Northoff et al., 1996,
2021), 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.
Although most scales report high interrater reliability in pub-
lished studies (see Sienaert et al. (2011) 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 (Oldham
and Wortzel, 2022; Wortzel et al., 2021, 2022). The results of a
catatonia rating scale should be converted to diagnostic criteria
for clinical diagnosis (Oldham, 2022).
Recommendation on the use of rating instruments
? When 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)
? Research on catatonia should report how individual items
have been defined, including thresholds. (S)
Investigations
The 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 medi-
cal record, and in general is not established through clinical
investigations (e.g. laboratory tests, brain imaging, EEG, cere-
brospinal fluid (CSF) analysis, urine drug screen). Clinical inves-
tigations should be ordered based on history and clinical
examination findings, taking into consideration the overall sever-
ity of illness as well as medical and psychiatric comorbid ill-
nesses. Medical investigations are typically performed to rule out
catatonia-like conditions or to understand the underlying aetiol-
ogy of catatonia as this informs treatment and prognosis.
Although 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 sys-
tematic review of structural and functional brain imaging in cata-
tonia, 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) (Haroche et al., 2020). The most
common abnormalities in catatonia are generalised atrophy and
non-specific white matter abnormalities (Haroche et al., 2020;
Jeyaventhan et al., 2022; Magnat et al., 2022).
Even 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),
Table 6. Means of assessment of catatonia.
Means of assessment Examples
DSM-5-TR and ICD-11 ICD-11 only In neither
Observation Stupor, agitation, posturing, mannerism,
stereotypy, grimacing
Impulsivity, combativeness,
staring, verbigeration
(pre, during and post exam)
Elicitation Mutism, negativism, echolalia, echopraxia Ambitendency
Physical examination Catalepsy, waxy flexibility Rigidity
Collateral Withdrawal
Review of vital signs Autonomic abnormality
DSM: Diagnostic and Statistical Manual of Mental Disorders; ICD: International Classification of Diseases.
Rogers et al. 11
T
able 7.
A comparison o
f comm
only used catatoni
a r
atin
g scales
.
Rog
ers catatoni
a scale
(Starkstein et?al., 1996)
BFCRS (Bush et?al., 1996a)
NCRS
(N
orth
o
ff et?al., 1999a)
Br
?uni
g Catatoni
a Ratin
g
Scale (Br
?uni
g et?al., 2000)
K
ann
er Scale
(Carr
oll et?al., 2008)
Year
1996
1996
1999
2000
2008
Sample (
n
)
Depressed with catatonia (79)
Psychosis (3)
Schizophrenia (13)
Schizophrenia (34)
None
Mania (11)
Mania (17)
Depression (4)
Bipolar (15)
Depression (14)
Non-depressed with Parkinson disease (41)
Medical (6)
Unipolar (6)
Medical (6)
Other (4)
Reference standard
DSM-IV
Barnes
Lohr/Wisniewski
DSM-III-R
None
Lohr/Wisniewski
Rosebush
Rosebush
Items
22
14 (screening
?
)
40
21
18
23 (full scale)
Individual item scoring
0–2
0–3
0–2
0–4
0–8
Assessment
Based on motor examination
Standard 5- to 10-min assessment
Unspecified
Semi-structured 45-min exam
Standard assessment
Item description
MRS Appendix
1
On scale
On scale
On scale
Only in Part 2
Threshold
8 or more
2 or more (on 14 screening items
?
)
1 or more in each domain
At least 4 scored
?
2
2 or more on Part 1
All
DSM-5-TR
criteria?
Yes
?
Yes (all in screening instrument
?
)
?
Yes
Yes
?
Yes (8/12 in Part 1)
All
ICD-11
criteria?
Omits 7 features
Yes
?
Yes
Yes
?
Yes, but misinterprets verbigeration
§
Notes
Uncertain generalisability
Most widely used in clinical & research
Most comprehensive scale
Based on 45-min exam, though not described
Yet to be validated clinically
Incomplete assessment of
ICD-11
criteria
Predicts response to lorazepam
Motor features consistent with
DSM
/
ICD
?
Video references & Training Manual available
Assessment unspecified
Derived fr
om th
e M
odifi
ed Rog
ers Scale
, whi
ch was vali
d
ated in a schizophr
eni
a coh
ort.
?
Th
e first 14 item
s o
f th
e BFCRS comprise th
e Bush-Fr
an
cis Catatoni
a Scr
eenin
g In
strum
en
t (BFCSI).
?
Th
e d
efiniti
on
s o
f posturin
g, catalepsy
, waxy fle
xibility
, an
d ri
gi
dity differ am
on
g scales (see T
able 8 below). Only th
e NCRS d
efin
es th
ese con
sisten
tly with
DSM-5-TR
an
d
ICD-11
. Th
ese fin
din
gs can be d
erived fr
om th
e Bush-Fr
an
cis
with sli
gh
t m
odifi
cati
on. Derivin
g th
ese fr
om th
e Br
?uni
g would r
equir
e a m
or
e substan
ti
al scorin
g m
odifi
cati
on.
§
K
ann
er in
corr
ectly d
escribes verbi
g
er
ati
on as ‘gibberish’
.
BFCRS: Bush-Fr
an
cis Catatoni
a Ratin
g Scale; DSM: Di
agn
osti
c an
d Statisti
cal M
an
u
al o
f M
en
tal Disor
d
ers; I
CD: In
tern
ati
on
al Classifi
cati
on o
f Diseases; NCRS: N
orth
o
ff Catatoni
a Ratin
g Scale
.
12 Journal of Psychopharmacology 00(0)
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 (Rogers et al., 2021), 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 (Rogers et al., 2021). 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 catato-
nia at some point in their illness (Espinola-Nadurille et al.,
2016; Rogers et al., 2019). Other autoantibodies have also been
identified in association with catatonia including anti-Hu anti-
bodies, 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 recep-
tor antibodies, GAD-65 antibodies, leucine-rich glioma-inacti-
vated 1 antibodies, ribonucleoprotein antibodies and septin-7
antibodies (Boeke et al., 2018; Chuck et al., 2022; Endres et al.,
2020; Ferrafiat et al., 2021; Fujimori et al., 2021; Harmon et al.,
2022; Hinson et al., 2022; Inagaki et al., 2020; Kusztal et al.,
2014; Pettingill et al., 2015; Samra et al., 2020; Witek et al.,
2018). However, the prevalence and pathogenicity of these anti-
bodies in catatonia is unclear, although it is a rapidly expanding
field (Rogers et al., 2019).
In terms of neurophysiology, there is a clear case for an elec-
troencephalogram (EEG) in the context of possible non-convul-
sive status epilepticus (NCSE), which can present as catatonia
(Ogyu et al., 2021; Volle et al., 2021). 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 (Ogyu et al., 2021; Volle
et al., 2021). Another quite specific EEG finding of relevance to
catatonia is the extreme delta brush, which occurs in some
patients with anti-NMDA receptor encephalitis (Schmitt et al.,
2012). The literature on the value of ‘encephalopathic’ findings
on EEGs suggests that this is not entirely specific for a medical
disorder underlying catatonia (Carroll and Boutros, 1995; Smith
et al., 2012).
Any hospital work-up must weigh the potential risks and ben-
efits of detailed investigation. Hospital investigations may con-
tribute to anxiety (Carney et al., 2004; Lindholm et al., 1997;
Puglisi et al., 2005). Given that several studies have associated
catatonia with intense anxiety (Cuevas-Esteban et al., 2020;
Dawkins et al., 2022; Kline et al., 2022; Northoff et al., 1996),
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.
Recommendations on the use of investigations in catatonia
? Investigations, such as blood tests, urine drug screen,
lumbar puncture, electroencephalography and neuroim-
aging, should be considered based on history and exami-
nation findings, taking into account the possible diagnoses
that may mimic catatonia and the possible underlying
aetiology of the catatonia. (D)
? In patients experiencing a first episode of catatonia or
where the diagnosis underlying catatonia is unclear, con-
sider a CT or MRI scan of the brain. (C)
? In patients experiencing a first episode of catatonia or
where the diagnosis underlying catatonia is unclear, con-
sider assessing for the presence of antibodies to the
NMDA receptor and other relevant autoantibodies in
serum and CSF. (D)
? In patients with risk factors for seizures, possible evidence
of a seizure or possible encephalitis, consider performing
an EEG (with continuous monitoring if available). (C)
Challenge tests
DSM-5-TR has included a diagnosis of unspecified catatonia to
encourage early treatment while a search for an underlying disor-
der can continue. Challenge tests may provide support in clarify-
ing 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’.
In 1930, Bleckwenn described the use of short-acting barbi-
turates to ‘render catatonic patients responsive’ (Bleckwenn,
1932; Gershon and Shorter, 2019). Lorazepam (and to a limited
extent, other benzodiazepines, such as diazepam, midazolam,
clonazepam and oxazepam (Abrams et al., 1978; Benazzi, 1991;
Mustafa, 2017; Schmider et al., 1999)) 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
(Kavirajan, 1999).
Lorazepam and other benzodiazepines. Lorazepam is an effec-
tive and clinically useful diagnostic challenge test for catatonia. It
is available in oral, liquid, intramuscular (IM) and intravenous
Table 8. Representation of items on motor tone across diagnostic manuals and major rating scales.
DSM-5-TR ICD-11 Northoff Bush-Francis Br?unig
Posturing ‘Active maintenance of a posture against gravity’ Posturing with ‘limp’ tone
Catalepsy ‘Passive induction of a posture held against gravity’ Combined as ‘waxy flexibility’
Waxy flexibility ‘Slight, even resistance to positioning’ ‘Initial resistance before
allowing. . .to be repositioned’
Notes: ‘“waxy” muscular
resistance may be felt’
Rigidity Not included ‘Increased
muscle tone’
ICD-11 ICD-11 Posturing with ‘increased
muscle tone’
Include cogwheel Exclude cogwheel or tremor
Mild to severe Exclude tremor
DSM: Diagnostic and Statistical Manual of Mental Disorders; ICD: International Classification of Diseases.
Rogers et al. 13
(IV) forms, and is available in a variety of clinical settings. Loraz-
epam is a non-selective positive allosteric modulator of GABA-A
receptors. Possible therapeutic mechanisms in catatonia are dis-
cussed in section ‘GABA-ergic pharmacotherapies’.
The recommended dose for a lorazepam challenge is 1–2 mg
IV (Bush et al., 1996b; Suchandra et al., 2021), IM (Bush et al.,
1996b; Lin and Huang, 2013) or 2 mg oral (Ungvari et al., 1994).
The response to an oral challenge is often slower than for paren-
teral administration and oral formulations can be harder to
administer to both hyperkinetic and hypokinetic patients. A posi-
tive 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 (Bush et al., 1996b; Payee et al., 1999).
Low serum iron has been reported as a predictor of poor response
with benzodiazepines (Lee, 1998). An example protocol is pro-
vided in Table 9.
Based on their clinical effectiveness in these conditions, ben-
zodiazepines may also be considered as a therapeutic test in
antipsychotic-induced catatonia (Fricchione et al., 1983), NMS
(Kontaxakis et al., 1990) and malignant catatonia.
Zolpidem. Mastain et al. (1995) described a serendipitous dra-
matic response to oral zolpidem 10 mg in a woman with a subcor-
tical stroke whose catatonia was largely unresponsive to lorazepam
or ECT. This was followed by other positive reports (Amorim and
McDade, 2016; Baptista and Choucha, 2019; Bastiampillai et al.,
2016; Isomura et al., 2013; Javelot et al., 2015; Kumar and Kumar,
2020; Peglow et al., 2013; Sayadnasiri and Rezvani, 2019; Seeth-
aram and Akerman, 2006; Thomas et al., 1997; Zaw and Bates,
1997). The response is transitory, as with benzodiazepines, and is
usually observed for 3–6 h (Bastiampillai et al., 2016; Thomas
et al., 2007), which is consistent with zolpidem’s short elimination
half-life of 1–4 h (Hiemke et al., 2018). Catatonia has also been
reported in zolpidem withdrawal (Hsieh et al., 2011).
Several reports have been published of zolpidem’s effective-
ness following neurological injury due to a variety of different
brain insults (Sutton and Clauss, 2017). It is not clear whether
some of these cases following brain injury had undiagnosed cata-
tonia. It appears that the positive effect of zolpidem in post-brain
injury states occurs at a sub-sedative dose (Hall et al., 2010;
Sutton and Clauss, 2017), and there is a suggestion of a differen-
tial response in patients with traumatic or anoxic brain injury
(Zhang et al., 2021).
Zolpidem 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 (Hall et al., 2010).
It seems selective for the gamma-2 subunit of the GABA-A
receptor (alpha1-beta2-gamma2 GABA-A receptor) in animal
experiments (Richter et al., 2020), but the implications of this in
zolpidem’s efficacy as a diagnostic challenge tool are not entirely
clear.
The recommended dose of zolpidem is usually 10 mg orally
for a diagnostic and/or therapeutic test (Thomas et al., 2007), but
5 mg has sometimes been used in older patients (Amorim and
McDade, 2016; Isomura et al., 2013; Sayadnasiri and Rezvani,
2019). Zolpidem is available in oral formulation (and as a sublin-
gual preparation in some countries), with no parenteral prepara-
tion 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
(Thomas et al., 2007).
Narayanaswamy et al. (2012) showed 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 (Sayadnasiri and
Rezvani, 2019; Thomas et al., 2007).
Other drugs. In contrast to reports of ketamine causing cata-
tonic 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 (Iserson and Durga, 2020). More
studies, including randomised controlled trials (RCTs), are
needed before this translates into clinical practice as a diagnostic
test.
Recommendations on the use of challenge test
? When a diagnosis of catatonia is uncertain, a diagnostic
challenge using lorazepam should be considered. (B)
? When a diagnosis of catatonia is uncertain, a diagnostic
challenge using zolpidem may be considered. (C)
? In suspected or confirmed cases of catatonia, a lorazepam
challenge may be used to predict future response to ben-
zodiazepines. (B)
Differential diagnosis
There is some overlap between the differential diagnosis of cata-
tonia (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 malig-
nant syndrome’). For some conditions, their status is subject to
debate. In Table 10, we provide a list of some of the more impor-
tant conditions that may mimic catatonia, what the similarities
are and how they can be differentiated.
As general principles, the positive features of catatonia (such
as echophenomena, catalepsy and posturing) may have greater
Table 9. Example protocol for a lorazepam challenge for catatonia.
1. Assess baseline catatonic features using a standardised instrument such as the BFCRS
2. Administer lorazepam 1–2 mg IV, or 1–2 mg IM, or 2 mg oral.
3. Re-assess catatonic features after 5 min (following IV lorazepam), 15 min (following IM lorazepam) or 30 min (following oral lorazepam). A
positive response is considered a 50% reduction in score on a standardised catatonia instrument
4. If there is not a positive response, consider a further challenge (ideally parenterally), as in step 2, and re-assess
Source: Bush et?al. (1996b), Sienaert et?al. (2014).
BFCRS: Bush-Francis Catatonia Rating scale; IM: intramuscular; IV: intravenous.
14 Journal of Psychopharmacology 00(0)
T
able 10.
Differ
en
ti
al di
agn
osis o
f catatoni
a.
Categ
ory
Ex
ample differ
en
ti
al di
agn
oses
Similariti
es to catatoni
a
Distin
guishin
g featur
es fr
om catatoni
a
Neurological movement disorders
Stiff person syndrome
Muscle spasms and rigidity
Head retraction reflex
Progressive encephalomyelitis with rigidity and myoclonus
Immobility in severe cases
GAD-65, glycine or DPPX antibodies usually present
Associated with anxiety Emotional stimuli can trigger muscle spasms Respond to benzodiazepines
Causes of parkinsonism (e.g. Parkinson’s disease, drug-induced parkinsonism, cerebrovascular disease, juvenile Huntington’s disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration)
Poverty of movement, staring and rigidity
Patients usually interactive and cooperative
Freezing can resemble catatonic posturing
Tremor usually present Insidious onset
Dystonia
Can resemble catatonic posturing
Stupor absent Generally responds to anticholinergics
Akathisia
Hyperactivity can resemble catatonic excitement
Lack of other ‘positive’ signs of catatonia (e.g. echophenomena, posturing, verbigeration)
SS
Tachycardia Pyrexia Muscle rigidity
Triggered by serotonergic drugs Myoclonus and hyperreflexia Diarrhoea
NMS
See section ‘Neuroleptic malignant syndrome’
Speech disorders
Aphasia
Transcortical sensory aphasia can feature echolalia, as patient repeats back questions rather than answers them In severe cases, speech may be absent
Motor function intact
Anarthria
Absence of speech
Language preserved in written form
Selective mutism
Some variability
Communication completely comfortable in certain settings
Seizure
NCSE
Can be clinically indistinguishable May respond to benzodiazepines
Often history of epilepsy EEG usually helpful
(Con
t
inu
ed)
Rogers et al. 15
Categ
ory
Ex
ample differ
en
ti
al di
agn
oses
Similariti
es to catatoni
a
Distin
guishin
g featur
es fr
om catatoni
a
Locked-in syndrome
Locked-in syndrome
Near-complete absence of movement
Usually have preserved vertical gaze and blinking – generally keen to attempt to communicate using these MRI shows pontine lesions No response to benzodiazepines
Encephalopathy and disorders of consciousness
Delirium
Can coexist with catatonia
Tends to resolve with reversal of underlying medical condition (though may be delayed)
Coma
Unresponsiveness
No resistance to eye opening
Vegetative state
Unresponsiveness
No volitional responses and no visual tracking No resistance to eye opening
Disorders of motivation
Abulia
Reduction/absence of
spontaneous
activity
Respond to external stimuli
Autoactivation deficit syndrome Akinetic mutism
Flat affect Several disorders associated with both catatonia and akinetic mutism
Sometimes a ‘telephone effect’: sudden sensory stimulus causes return of movement and speech Lack of emotional disturbance Possibly no response to lorazepam
Psychiatric disorders
Mania
Can resemble catatonic excitement Can co-occur with catatonia
Irritable or expansive mood Absence of stuporous phases
Functional neurological disorder
Mutism and paralysis in severe cases
Usually progression from milder states of functional paralysis
Autism spectrum disorder
See section ‘Autism spectrum disorder’
Intellectual disability
Stereotypies and mannerisms Absence of speech
Chronic without sudden decompensation
Volitional uncooperativeness
Malingering
Mutism
Past benzodiazepine misuse
Lack of cooperation
Simulating clinical features (e.g. pouring water to simulate incontinence)
Factitious disorder
History of personality problems
Sour
ce: Arn
ts et?al. (2020), Cuevas-Esteban et?al. (2022), Den
ysenk
o et?al. (2018), H
arten et?al. (1999), I
shizuk
a et?al. (2022), M
orrison (2006), Oldham an
d Lee (2015), Rasm
ussen et?al. (2016), T
aylor an
d Fink (2003), W
an
g an
d
Rehm
an (2021), W
on
g (2010).
NCSE: n
on-convulsive status epilepti
cus; NM
S: n
eur
olepti
c m
ali
gn
an
t syn
d
r
om
e; SS: ser
otonin syn
d
r
om
e
.
T
ab
le 10.
(Contin
ued)
16 Journal of Psychopharmacology 00(0)
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 specific-
ity are imperfect; importantly, stiff person syndrome and NCSE
are likely to improve with a lorazepam challenge.
Although it has been asserted that serotonin syndrome (SS) is
a form of catatonia (Fink and Taylor, 2001), there is currently
insufficient systematic evidence to support this claim (Katus and
Frucht, 2016; Keck and Arnold, 2000; Mann et al., 2022; Rosebush
and Mazurek, 2010). Furthermore, although ECT, a core interven-
tion for catatonia, has been advocated for the treatment of SS
(Fink, 1996; Fink and Taylor, 2003, 2009), recent reports suggest
that it is ineffective and, in fact, may exacerbate SS (Cheng et al.,
2015; Katus and Frucht, 2016; Klysner et al., 2014).
Treatment
General approach
The 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 (Girish and Gill, 2003; McCall et al., 1992; Merlis,
1962; Miller et al., 1953; Phutane et al., 2013; Schmider et al.,
1999; Ungvari, 2010; Ungvari et al., 1999; Wetzel et al., 1997;
Zaman et al., 2019). One systematic review found only four
studies that had more than 50 participants (Pelzer et al., 2018).
Nonetheless, where there is converging evidence from multiple
sources, some clinically relevant inferences can be made.
Many 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 (General Medical Council,
2022; Royal College of Paediatrics and Child Health and
Neonatal & Paediatric Pharmacists Group, 2013; Royal College
of Psychiatrists Psychopharmacology Committee, 2017). While
this guidance recommends that prescribing should usually be
within a product’s licence, it is recognised that there are situa-
tions 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 pos-
sible, to start at a low dose and to inform other professionals that
the medicine is being used off-licence.
There 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
(Asnis, 2020; Bogdan et al., 2022; Ekici et al., 2021; Johnson
et al., 2022; Lee and House, 2017; Marques Macedo and Gama
Marques, 2019; Sundaram et al., 2021). In addition, considera-
tion must be given to the prevention and management of the
medical complications of catatonia.
First-line treatment. Several studies have found that response
to catatonia treatment is more likely or more rapid in patients
with a shorter duration of illness (Bush et al., 1996b; Raveendra-
nathan et al., 2012; Shukla et al., 2012; Swain et al., 2017),
although this has not universally been the case (Payee et al.,
1999). 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.
In terms of first-line treatments, there is most evidence for
benzodiazepines and ECT (Pelzer et al., 2018). We provide more
detail about these treatments in sections ‘GABA-ergic pharma-
cotherapies’ and ‘Electroconvulsive therapy’, but here we con-
sider 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) (Pelzer et al., 2018). If one treatment is
contraindicated, this makes the decision simpler. Beyond this,
consideration should be given to the potential of ECT to amelio-
rate a disorder underlying the catatonia (NICE recommends
ECT for severe depression and prolonged or severe mania in
certain circumstances; National Institute for Health and Care
Excellence, 2003, 2022), balancing the side effects of ECT (par-
ticularly 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 (particu-
larly 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 (Bush et al., 1996b; Dutt et al., 2011; Girish and
Gill, 2003; Medda et al., 2015). There is a case series and uncon-
trolled cohort study suggesting that the combination of benzodi-
azepines and ECT may be effective (Petrides et al., 1997; Unal
et al., 2013).
There are several special cases to these recommendations
about first-line treatment, which are as follows:
1. Clozapine-withdrawal catatonia: a systematic review of
case reports found that restarting clozapine or using ECT
were the most effective treatment strategies, while ben-
zodiazepines were less effective (Lander et al., 2018).
2. Benzodiazepine-withdrawal catatonia: a systematic
review of case reports found that reinstating benzodiaz-
epines was generally effective (Lander et al., 2018).
3. Catatonia in autism spectrum disorder: see section
‘Autism spectrum disorder’.
4. Chronic, milder catatonia in the context of schizophre-
nia: there is some evidence that this tends not to respond
to benzodiazepines (Ungvari et al., 1999) or ECT (Miller
et al., 1953). There is some evidence based on observa-
tional data that these patients may respond to clozapine
(Saini et al., 2022). There have been rare cases of cardi-
orespiratory arrest associated with the concomitant use
of clozapine and benzodiazepines (Faisal et al., 1997;
Saini et al., 2022), so caution should be exercised if there
is co-administration.
5. Malignant catatonia: see section ‘Periodic catatonia’.
6. NMS: see section ‘Neuroleptic malignant syndrome’.
Rogers et al. 17
7. Antipsychotic-induced catatonia: see section
‘Antipsychotic-induced catatonia’.
8. Women in the perinatal period: see section ‘The perinatal
period’.
Non-response. Where 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 (Schmider et al., 1999). For alternative
treatment approaches, see section ‘Other therapies’.
Underlying condition. Alongside treating the catatonia, it is
important to treat any underlying disorder. This may involve psy-
chotropic medications (e.g. antidepressants), other medical thera-
pies (e.g. antibiotics, immunosuppressants) or even occasionally
surgical treatments (e.g. tumour resection in the case of a para-
neoplastic syndrome). Guidelines for treating relevant psychiat-
ric disorders are available from the BAP (Baldwin et al., 2014;
Barnes et al., 2020; Cleare et al., 2015; Goodwin et al., 2016;
Howes et al., 2018; Lingford-Hughes et al., 2012; O’Brien et al.,
2017). There is some controversy over the use of antipsychotic
medications in catatonia, which is discussed in section ‘Dopa-
mine receptor antagonists and partial agonists’.
Complications. Some, though not all, studies have associated
catatonia with an increased mortality (Funayama et al., 2018;
Niswander et al., 1963; Rogers et al., 2021). 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 infec-
tions (pneumonia, urinary tract infection and sepsis), dissemi-
nated intravascular coagulation, rhabdomyolysis, dehydration,
deep vein thrombosis, pulmonary embolus, urinary retention,
decubitus ulcers, cardiac arrhythmia, renal failure, NMS, hyper-
natraemia and liver dysfunction (Funayama et al., 2018). Guid-
ance has been developed for averting such complications, which
include recommendations such as pharmacological thrombopro-
phylaxis, frequent assessment of pressure areas, stretching to
avoid muscle contractures and consideration of artificial feeding
(Clinebell et al., 2014; Connell et al., 2022).
Recommendations on the general approach to treating
catatonia
? Treatment 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)
? Prescribing 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)
? Catatonia treatment should consist of specific treatment
for the catatonia, treatment of any underlying disorder
and prevention and management of complications of cat-
atonia. (S)
? First-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.
? ECT should be available in any settings where catatonia
may be treated, including in psychiatric and general hos-
pitals. (S)
? When 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)
? Where 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’.
? Where catatonia has resulted from clozapine withdrawal,
restart clozapine if possible and, if necessary, use ECT.
(D)
? Where catatonia has resulted from benzodiazepine with-
drawal, restart a benzodiazepine. (D)
? If catatonia is chronic and mild in the context of schizo-
phrenia, consider a trial of clozapine. (C)
? If clozapine and benzodiazepines are administered con-
comitantly, titrate slowly and closely monitor vital signs.
(S)
? Where catatonia does not respond to first-line therapy,
re-evaluate the diagnosis. (D)
GABA-ergic pharmacotherapies
Evidence for pharmacotherapies for catatonia that augment
GABA-ergic signalling pathways is supported by neuroimaging
studies. Northoff et al. (1999b) 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 prefron-
tal 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 particu-
larly responsive to a lorazepam challenge, normalising its activ-
ity (Richter et al., 2010).
The 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 con-
trols (Northoff et al., 2004). Given that the orbitofrontal-ventro-
medial PFC is strongly involved in emotion processing, which is
mediated by GABA activity, these findings provide further evi-
dence for GABA-ergic mechanisms in catatonia including both
GABA-A and GABA-B receptors (Hirjak et al., 2021a; Northoff,
2002; Plevin et al., 2018).
In terms of clinical findings, a double-blind RCT investigated
the effect of the barbiturate derivative amobarbital in 1992, find-
ing that of 10 patients randomised to the drug, 6 responded, com-
pared to none of the 10 randomised to a saline infusion (McCall
et al., 1992). However, barbiturate use has largely been aban-
doned since due to safety concerns (López-Mu?oz et al., 2005).
Acute catatonia often shows a rapid and dramatic response to
benzodiazepines in case series and observational studies (Bush
18 Journal of Psychopharmacology 00(0)
et al., 1996b; Greenfeld et al., 1987; Northoff et al., 1995;
Rosebush et al., 1990; Schmider et al., 1999), although a Cochrane
review found no placebo-controlled RCTs evaluating benzodiaz-
epines in catatonia (Zaman et al., 2019). Pelzer et al. (2018)
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 (Taylor
et al., 2021; Weder et al., 2008). Some studies have used other
benzodiazepines, such as oxazepam, diazepam, clonazepam or
flurazepam (Pelzer et al., 2018) and a small RCT found no dif-
ference in outcome between lorazepam and oxazepam treat-
ment (Schmider et al., 1999). 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.
Administration can be oral, IM or IV (Bush et al., 1996b;
Girish and Gill, 2003; Pelzer et al., 2018). Parenteral administra-
tion can be particularly useful if oral administration is not possi-
ble, for example due to negativism. Lorazepam is usually
administered in 2–4 divided doses each day (Pelzer et al., 2018).
Reported response ranges from 66% up to 100% (Edinoff
et al., 2021; Northoff et al., 1995; Pelzer et al., 2018; Rasmussen
et al., 2016; Rosebush et al., 1990). These studies were mainly
conducted in Western countries. Studies conducted in India and
Asia show more variable response, ranging from 0% to 100%
(Pelzer et al., 2018). The reason for these differences remains
unclear, but it is possible that – given that lorazepam is unstable
at room temperature (De Winter et al., 2013; Gottwald et al.,
1999) – storage conditions may play a role. Usually, administra-
tion 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 (Pelzer et al., 2018).
Therapeutic response may entail partial or complete remis-
sion within hours, though it may sometimes take several days
(Lee et al., 2000; Rasmussen et al., 2016; Ungvari et al., 1994).
The therapeutic response seems to be strongest in acute catatonia
where the patient presents with a rapid-onset catatonic state
(Northoff et al., 1995; Northoff et al., 1999a; Pelzer et al., 2018;
Rasmussen et al., 2016; Rosebush et al., 1990). This is especially
the case in patients suffering from bipolar disorder and major
depressive disorder (Rasmussen et al., 2016). 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 (Pelzer et al., 2018; Rasmussen et al., 2016; Ungvari
et al., 1999).
One 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 (Baldwin et al., 2013).
Withdrawal schedules for benzodiazepines exist, but these are
generally designed for individuals who have been treated with
benzodiazepines for months or years (Lader and Kyriacou,
2016), whereas benzodiazepines in catatonia are often used for
days or weeks. Nonetheless, such withdrawal schedules are
associated with higher retention in treatment and better tolera-
bility than abrupt discontinuation (Denis et al., 2006) 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 loraze-
pam treatment to prevent relapse (Ali et al., 2017). There are
other reports of long-term benzodiazepines being used to pre-
vent re-emergence of catatonia (Grover and Aggarwal, 2011;
Mader et al., 2020; Saddichha et al., 2007). 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.
Recommendations on the use of GABA-ergic medications
in catatonia
? Where 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)
? Where benzodiazepines are used for catatonia, lorazepam
is generally the preferred agent. (S)
? Where lorazepam is used for catatonia, high doses above
the licensed maximum may be necessary to achieve max-
imal effect. An adequate trial may be considered com-
plete when catatonia is adequately treated, titration has
been stopped due to side effects or dose has reached at
least 16 mg per day. (C)
? Benzodiazepines 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 benzo-
diazepines. (S)
? If 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)
Electroconvulsive therapy
The first patients treated with convulsive therapy, both for chemi-
cally induced seizures by Meduna in 1934 and for electrically
induced seizures by Cerletti and Bini in 1938, had catatonic ill-
nesses (Fink et al., 2022). 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 (Food and Drug Administration,
HHS, 2018) and in the UK NICE recommends ECT for catatonia
(National Institute for Health and Care Excellence, 2003). In the
UK and many other countries, there are specific legal require-
ments for administering ECT in a patient who is unable to
consent.
Despite this extensive clinical recognition in common prac-
tice, a rigorous base of high-quality published evidence is lack-
ing. This deficiency of RCTs arises principally from practical
difficulties in conducting sham or placebo treatment arms in peo-
ple who are usually severely ill with catatonia and often lack an
Rogers et al. 19
ability to participate in informed-consent processes for such
clinical trials.
Among several reviews of existing evidence on ECT for cata-
tonia, the most recent comprehensive one was a meta-analysis
(Leroy et al., 2018). Three RCTs involving ECT for patients with
catatonia have been conducted, all of which were in patients with
primary psychotic disorders (Girish and Gill, 2003; Miller et al.,
1953; Phutane et al., 2013). Comparisons were between ECT and
risperidone (Girish and Gill, 2003); ECT, sham ECT and sodium
thiopental (Miller et al., 1953); and bifrontal ECT and bitemporal
ECT (Phutane et al., 2013). Two of the trials were conducted spe-
cifically in patients with catatonia (Girish and Gill, 2003; Miller
et al., 1953), while one had a catatonic subgroup (Phutane et al.,
2013). Unfortunately, none of these contained both standardised
ratings for outcome and quantitative results that would allow for
statistical determinations of effect size (Leroy et al., 2018). The
review did, however, identify 10 studies with such data on quan-
titative outcomes, but they lacked control groups. Bilateral forms
of ECT were the typical treatment modality. From these 10 stud-
ies, 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.
Since Leroy et al.’s review, four additional studies of ECT
with pre/post-quantitative outcomes have been published (Perugi
et al., 2017; Pierson et al., 2021; Tor et al., 2021; Tripodi et al.,
2021). 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 (Pierson et al., 2021).
Most published reports describing ECT for catatonia have
used bilateral forms of ECT (Leroy et al., 2018), which are gener-
ally recommended for severe, medication-resistant or malignant
forms of catatonia. No studies were found comparing bilateral
versus unilateral ECT for catatonia.
In 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 (Leroy et al., 2018). Number of sessions
ranged from 3 to 35 sessions with a mean of 9 sessions (Leroy
et al., 2018). There is a lack of data on the superiority of these
differing protocols.
Recommendations for the use of ECT in catatonia
? Where ECT is administered, bilateral ECT should be con-
sidered. (S)
? Where ECT is administered in acute catatonia, it should
be given at least two times weekly. (S)
? Number of ECT sessions should be decided on the basis
of treatment response, risks and side effects. (S)
Other therapies
While the majority of patients with catatonia respond robustly to
benzodiazepines or ECT, some patients have a partial or non-
response (Lee et al., 2000; Pelzer et al., 2018; Rosebush et al.,
1990; Unal et al., 2017). Catatonia associated with schizophrenia
may be less likely to respond to benzodiazepines (Rosebush and
Mazurek, 2010; Ungvari et al., 1999). In addition, benzodiaz-
epines and ECT are cautioned in some circumstances. There are
also barriers to ECT use such as legal restrictions and stigma.
These factors have prompted the trialling of several alterna-
tive agents, either as monotherapies or as augmentation strate-
gies. 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.
NMDA receptor antagonists. The NMDA receptor may be allo-
sterically more available to glutamate in catatonia leading to dys-
function 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 (Fricchione and
Beach, 2019). 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 (Carroll et al., 2007).
In their systematic review, Beach et al (2017) reported on 11
articles that described the use of amantadine in 18 cases
(Babington and Spiegel, 2007; Carroll et al., 2006, 2007; de
Lucena et al., 2012; Ellul et al., 2015; Ene-Stroescu et al., 2014a,
2014b; Hervey et al., 2012; Muneoka et al., 2010; Northoff et al.,
1997; Northoff et al., 1999d). 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, Theibert and Carroll (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 Carroll et al. (2007), seven further
cases of catatonia, six of whom were diagnosed with schizophre-
nia, 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 (Brown et al., 1986).
In 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 addi-
tion 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 encephalomy-
elitis (Espinola-Nadurille et al., 2016).
In Beach et al.’s (2017) review, nine papers reported meman-
tine treatment in nine cases (Brown et al., 2016; Carpenter et al.,
2006; Carroll et al., 2006; Caudron et al., 2016; Mukai et al.,
2011; Munoz et al., 2008; Obregon et al., 2011; Thomas, 2005;
20 Journal of Psychopharmacology 00(0)
Utumi et al., 2013). Again schizophrenia-spectrum illnesses were
predominantly represented in this sample. Memantine was com-
monly prescribed as an adjunctive treatment in combination with
benzodiazepines. Theibert and Carroll (2018) added three unpub-
lished memantine cases and reported the mean daily dose used
for all 12 cases was 12.5 (SD: 6.2) mg.
A 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 dex-
tromethorphan–quinidine use (Carroll et al., 2007; Miyaoka
et al., 2007; Theibert and Carroll, 2018; Turner et al., 2016).
In 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 win-
dow (Sienaert et al., 2014). A bias towards the non-reporting of
negative results must be considered, making the lack of RCTs
and controlled studies an important shortcoming.
Dopamine precursors, agonists and reuptake inhibitors. The
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 dopa-
mine) as well as when circumstances abruptly change to better or
worse than predicted (phasic dopamine) (Holroyd and Yeung,
2012). Hong (2013) 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 modula-
tion 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 supple-
mentary motor area and primary motor cortex.
Levodopa is a dopamine precursor that is often used in com-
bination with a peripheral DOPA decarboxylase inhibitor (e.g.
carbidopa and benserazide) in the treatment of Parkinson’s dis-
ease. A case report and small case series found marked improve-
ment after treatment with levodopa, although the case series
reported worsening of psychosis (Neppe, 1988; Rogers, 1991).
Bromocriptine, a dopamine D
2
receptor agonist was used suc-
cessfully in a 16-year-old girl with catatonia (Mahmood, 1991).
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 asso-
ciated with lesions to frontal-subcortical circuits (Arnts et al.,
2020).
Methylphenidate is a noradrenaline and dopamine reuptake
inhibitor. There have been five case reports of successful use of
methylphenidate for catatonia (Bajwa et al., 2015; Corchs and
Teng, 2010; Frost, 1989; Neuhut et al., 2012; Prowler et al.,
2010). Most of these cases were due to mood disorders, and most
used methylphenidate as monotherapy.
Dopamine receptor antagonists and partial agonists. The
use of antipsychotics is one of the most controversial areas in
catatonia management (Sienaert et al., 2014). Antipsychotic
medications can induce catatonia (see section ‘Antipsychotic-
induced catatonia’) and worsen it (Goetz et al., 2013; Lee, 2010;
Lewis and Kahn, 2009). Catatonia is also a risk factor for NMS
(Berardi et al., 1998; Funayama et al., 2018; Lee, 2010; Rose-
bush and Mazurek, 2010), a severe antipsychotic-induced move-
ment disorder. Moreover, in some studies of catatonia, the use of
antipsychotics has been associated with poor outcomes (Hawkins
et al., 1995; Zingela et al., 2022).
Nevertheless, dopamine receptor antagonists and partial ago-
nists have been reported in some cases as beneficial in catatonia
(Sienaert et al., 2014; Van den Eede et al., 2005). This may par-
ticularly be the case in catatonic schizophrenia (Gazdag and
Sienaert, 2013). There have been reports of the use of olanzapine
(Babington and Spiegel, 2007; Chang et al., 2009; Kumagai
et al., 2016; Nicolato et al., 2006; Numata et al., 2002; Spiegel
and Klaiber, 2013; Spiegel and Varnell, 2011; Ueda et al., 2012),
risperidone (Ahmed et al., 2009; Duggal, 2005; Girish and Gill,
2003; Grenier et al., 2011; Hesslinger et al., 2001; Serata et al.,
2015; Valevski et al., 2001), ziprasidone (Angelopoulos et al.,
2010; Levy and Nunez, 2004), quetiapine (Yoshimura et al.,
2013) and aripiprazole (Bastiampillai and Dhillon, 2008; Lin
et al., 2016; Nakagawa et al., 2012; Sasaki et al., 2012; Voros
et al., 2009).
Second-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 dopamin-
ergic effects and be of some benefit for catatonia (Huffman and
Fricchione, 2005). 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 (Huang et al., 2022). This RCT com-
pared risperidone to ECT, finding greater improvement in the
ECT-treated group (Girish and Gill, 2003).
Given that D
2
receptor antagonists can worsen catatonia and
trigger NMS in an at-risk group, some reviews have urged cau-
tion, especially in malignant catatonia (Edinoff et al., 2021;
Sienaert et al., 2014; Van den Eede et al., 2005). It has also been
suggested that SGAs – or an FGA with weaker dopamine recep-
tor affinity – should be preferred (Edinoff et al., 2021). Some
sources suggest that antipsychotics should only be given in cata-
tonia if co-administered with a benzodiazepine (Edinoff et al.,
2021). One review concluded that there does not seem to be evi-
dence to support the use of SGAs in patients with catatonia with-
out an underlying psychosis (Pelzer et al., 2018). Two small
studies have suggested that low serum iron in catatonia is associ-
ated 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 (Carroll
et al., 1995; Lee, 1998).
Regarding 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
(Saini et al., 2022). 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 (Naber et al., 1992). 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 (Lander et al., 2018).
Rogers et al. 21
Anticonvulsants. Leaving aside the cases where catatonia is a
presentation of NCSE (Silva Gadelho and Gama Marques,
2022), catatonia has occasionally been treated with anticonvul-
sant medications. Evidence consists of case series and case
reports.
Three articles have reported using carbamazepine to treat
catatonia in seven cases (Kritzinger and Jordaan, 2001; Rankel
and Rankel, 1988; Spear et al., 1997). Most cases were associ-
ated 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.
Valproic 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 cat-
atonia was noted as part of the presentation. These patients were
treated successfully with valproic acid (Bowers and Ajit, 2007;
Ene-Stroescu et al., 2014b; Krüger and Br?unig, 2001; Yoshida
et al., 2005). Doses ranged from 600 to 4000 mg daily.
Another case series involving four cases highlighted the ben-
efits of topiramate in the treatment of catatonia (McDaniel et al.,
2006). Here too most of these patients had been diagnosed with
schizophrenia-like illnesses. Topiramate was used as an adjunc-
tive treatment along with a benzodiazepine. All four cases
improved on 200 mg daily.
Phenytoin has been reported to be effective in cases where
catatonia has appeared in the context of bacterial meningoen-
cephalitis, NCSE and frontal lobe seizures (Coffey, 2013; Lim
et al., 1986; Orland and Daghestani, 1987). Levetiracetam and
zonisamide have each been used in one case along with aripipra-
zole (Muneer, 2014; Nakagawa et al., 2012).
Anticholinergic agents. Two case reports described using ben-
ztropine IV as monotherapy to treat catatonia in two cases (Albu-
cher et al., 1991; Panzer et al., 1990). In another case,
trihexyphenidyl was used in combination with clozapine to treat
catatonia (Yeh et al., 2004). 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 (Davis et al., 2021).
Miscellaneous treatments. Muscle relaxants, calcium channel
blockers and corticosteroids have all anecdotally been associated
with improvement in isolated patients with catatonia (Philbrick
and Rummans, 1994). Lithium and other treatments for prophy-
laxis in periodic catatonia warrant particular attention and are
considered in section ‘Periodic catatonia’.
Repetitive transcranial magnetic stimulation and transcra-
nial direct-current stimulation as alternatives to ECT. There
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 tran-
scranial 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 (Hansbauer et al., 2020; Stip et al., 2018).
rTMS over the bilateral dorsolateral PFC has been particularly
emphasised (Stip et al., 2018). Adverse effects appear to be mini-
mal (Hansbauer et al., 2020).
Recommendations on the use of other therapies
? Where first-line therapies for catatonia are unavailable,
cautioned, ineffective or only partially effective, consider
a trial of an NMDA receptor antagonist, either amanta-
dine or memantine. (C)
? Where first-line therapies and NMDA receptor antago-
nists are unavailable, cautioned, ineffective or only par-
tially effective, consider a trial of levodopa, a dopamine
agonist, carbamazepine, valproate, topiramate or a SGA.
(D)
? Antipsychotic medications should be avoided where
there is no underlying psychotic disorder. (C)
? Where 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)
? Where ECT is indicated but unavailable, consider treat-
ment with rTMS or tDCS. (D)
Subtypes of catatonia and related
conditions
Periodic catatonia
Periodic catatonia is a rare form of catatonia characterised by
rapid-onset, brief, recurring episodes of hypokinetic or hyperki-
netic catatonia (Hervey et al., 2013). 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 Minde
(1966). Leonhard considered periodic catatonia to be a form of
unsystematic schizophrenia (i.e. genetically determined schizo-
phrenia) compared to the systematic (nonperiodic and nonfamil-
ial) form of schizophrenia (Beckmann et al., 2000). Based on this
conceptualisation, subsequent research showed that periodic
catatonia has an autosomal dominant pattern of transmission
(St?ber et al., 2000).
Classically periodic catatonia has been reported to occur in
association with schizophrenia, but it has also been reported in
patients with affective disorders (Barroso Ca?izares et al., 1999;
Br?unig, 1991; Hervey et al., 2013; Yeh et al., 2010) and occasion-
ally in patients with substance use disorders (Bajaj et al., 2011),
underlying medical illnesses (Aragon et al., 2016; Boyce, 1958;
Leentjens and Pepplinkhuizen, 1998; Sengul et al., 2005; Sutar and
Rai, 2020) and in association with menstrual cycles (Zwiebel et al.,
2018). It has also been reported in adolescents (Kinrys and Logan,
2001; Sutar and Rai, 2020) and the geriatric population (Carroll
et al., 2011; Tang and Park, 2016). Studies that have focused on the
clinical profile of patients with periodic catatonia during the differ-
ent episodes in the same patients suggest consistency of clinical
features across the various episodes (Francis et al., 1997).
22 Journal of Psychopharmacology 00(0)
There is great uncertainty in the treatment of periodic catato-
nia, though several sources advise treatment in acute catatonic
episodes along the lines of other cases of catatonia with benzodi-
azepines and ECT (Fink and Taylor, 2001; Ghaffarinejad et al.,
2012; Hervey et al., 2013), and several reports support this (Chen
and Huang, 2017; Hervey et al., 2013; Saddichha et al., 2007).
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 evi-
dence relies only on case reports and small case series (Gjessing,
1967; Padhy et al., 2011; Petursson, 1976; Sato et al., 2020;
Sovner and McHugh, 1974; Wald and Lerner, 1978). Case reports
have reported success with mirtazapine (Yeh et al., 2010) and
clomipramine (Barroso Ca?izares et al., 1999) in the mainte-
nance treatment of periodic catatonia in patients with depressive
disorder (Yeh et al., 2010). In another case report, authors
reported the effectiveness of fluoxetine (20 mg/day) and fluphen-
azine in the maintenance treatment of periodic catatonia in a
patient with schizoaffective disorder (Bia?ek and Jarema, 1999).
Case reports or series have reported the role of lamotrigine
(Konstantinou et al., 2021) and carbamazepine (Padhy et al.,
2011) in the maintenance treatment of periodic catatonia. Despite
the potential risk of NMS when antipsychotics are used in catato-
nia, some have reported a beneficial role of olanzapine (Guzman
et al., 2007, 2008), ziprasidone (Levy and Nunez, 2004) and ris-
peridone (Duggal and Gandotra, 2005) in the long-term treatment
of periodic catatonia.
Recommendation on periodic catatonia
? In the maintenance phase of periodic catatonia, consider
prophylactic treatment with lithium. (D)
Malignant catatonia
Catatonia 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 (Philbrick and Rummans,
1994). Stauder (1934) described ‘lethal catatonia’ as a fulmi-
nant psychotic disorder characterised by intense motor excite-
ment, which progressed to stuporous exhaustion, cardiovascular
collapse, coma and death. The entire course, passing through
excitement into stupor, involved mounting hyperthermia, auto-
nomic instability, delirium, muscle rigidity and prominent cata-
tonic 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 pub-
lications throughout the pre-antipsychotic drug era. Competing
terminology included Bell’s mania, acute delirious mania, per-
nicious catatonia and delirium acutum, among numerous oth-
ers. More recently, the term malignant catatonia has been
proposed, since not all cases are fatal (Philbrick and Rummans,
1994). Unlike Stauder, some authors have observed that muscle
tone in malignant catatonia is flaccid (Mann et al., 1986).
Although the incidence of malignant catatonia appears to
have declined following the introduction of modern psychop-
harmacologic 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 disor-
ders. Current data suggest that it is likely that a proportion of
malignant catatonia cases previously attributed to schizophre-
nia were more likely the product of autoimmune disorders, par-
ticularly anti-NMDAR encephalitis (Mann et al., 2022; Rogers
et al., 2019). Mortality, which had exceeded 75% during the
pre-antipsychotic drug era, has fallen to 10% in recent reports
(Mann et al., 2022).
Although some qualified support may exist for the use of
SGAs in non-malignant catatonia (see section ‘Dopamine recep-
tor antagonists and partial agonists’), the literature on antipsy-
chotics for malignant catatonia is rather different. First, there is
an issue that malignant catatonia is generally clinically indis-
tinguishable from NMS, so antipsychotics seem injudicious
(Philbrick and Rummans, 1994). Second, in a review of 292
malignant catatonia cases (Mann et al., 1986), 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 (Mann et al., 1986). The evidence for the
SGAs in malignant catatonia is minimal and mixed (Van den
Eede et al., 2005). Antipsychotic drugs should be withheld when-
ever malignant catatonia is suspected.
Since 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
(Sch?nfeldt-Lecuona et al., 2020a), 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 ben-
zodiazepine 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 (Philbrick and Rummans, 1994), 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 (Fricchione et al.,
1997; Fricchione and Beach, 2019).
ECT appears to be a safe and effective treatment for malig-
nant catatonia occurring in association with a psychiatric disor-
der. Among 68 patients reported in five series (Mann et al., 2022;
Philbrick and Rummans, 1994), 51 of 54 treated with ECT sur-
vived, 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 (Arnold, 1952), although 16 of 19 patients receiv-
ing ECT within 5 days of malignant catatonia onset survived,
none of 14 patients starting ECT beyond that 5-day point recov-
ered. In view of the life-threatening potential of malignant cata-
tonia, bilateral treatments daily or twice daily for 3–5 days are
often required to achieve a rapid result, followed by ECT at con-
ventional frequencies until complete resolution (Fink and Taylor,
2003; Petrides et al., 2004). In addition, ECT has been effective
as a symptomatic measure in malignant catatonia complicating a
diversity of medical conditions, such as anti-NMDAR encephali-
tis, permitting resolution of the underlying condition.
An older body of case series data had suggested that malig-
nant catatonia could be successfully treated with adrenocortico-
tropic hormone and corticosteroids (Chrisstoffels and Thiel,
Rogers et al. 23
1970; Lingjaerde, 1964). However, the interpretation of these
reports may be compromised by the simultaneous use of ECT in
many cases. Other proposed treatments have included bromocrip-
tine, amantadine, memantine and calcitonin (Mann et al., 2022).
A single case report observed dramatic resolution of malignant
catatonia with rTMS (Kate et al., 2011). Although one case report
noted rapid improvement in malignant catatonia with tDCS
(Haroche et al., 2022), a second found no effect (Baldinger-
Melich, 2016). Like non-malignant catatonia, rTMS and tDCS
could prove promising in malignant catatonia where ECT is indi-
cated but not possible. However, further investigation is neces-
sary. Finally, a couple of case reports have reported benefit from
propofol in malignant catatonia (Alfson et al., 2013; Nomura
et al., 2021), which may possibly be useful if ECT is delayed
(Hirjak et al., 2019).
Recommendations for the treatment of malignant catatonia
? In malignant catatonia, discontinue all dopamine antago-
nists. (D)
? In 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)
? If 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 cata-
tonia abates, followed by ECT three times per week until
there is sustained improvement, usually 5–20 treatments
in total. (D)
Neuroleptic malignant syndrome
NMS 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 (Barnes et al., 2020). Mortality has declined
over the years to an average of less than 10% (Caroff et al., 2022).
Virtually, all classes of drugs that induce dopamine receptor
blockade have been implicated in causing NMS, with antipsy-
chotics that have higher affinity for the D
2
receptor posing the
greatest risk (Nielsen et al., 2012). However, SGAs have also
been associated with NMS, although they may result in an
‘atypical’ presentation with less severe or absent rigidity or
hyperthermia (Caroff et al., 2022). 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 com-
monly include elevated serum CK, leucocytosis and low serum
iron resembling malignant catatonia.
Several authors have proposed that NMS represents an
antipsychotic drug-induced toxic or iatrogenic subtype of
malignant catatonia (Fink and Taylor, 2009; Fricchione et al.,
1997; Goforth and Carroll, 1995; Koch et al., 2000; Mann et al.,
1986; White and Robins, 1991). 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 (Goforth and Carroll, 1995; Koch et al., 2000).
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, how-
ever, have asserted that malignant catatonia and NMS represent
two distinct entities, suggesting that excited or agitated behav-
iour points to malignant catatonia (Castillo et al., 1989;
Fleischhacker et al., 1990). A prodromal phase involving agita-
tion and affective disturbance is perhaps more common in
malignant catatonia but is not universally present. (Carroll and
Taylor, 1981; Fleischhacker et al., 1990; Mann et al., 1986).
However, agitation is a common feature of the psychosis pre-
ceding NMS for which antipsychotics were originally used.
Prominent muscle rigidity has also been proposed as a distin-
guishing feature (Castillo et al., 1989). 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 extrapy-
ramidal 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 (Fleischhacker et al., 1990).
The most important factor in improving survival in NMS is
discontinuation of dopamine-blocking medications (Guinart
et al., 2021). With cessation of dopamine-blocking drugs and
supportive medical care, NMS is in most cases a self-limiting
disorder (Mann et al., 2022; Strawn et al., 2007; Woodbury and
Woodbury, 1992) with a mean recovery time of 7–10 days.
Anticholinergic medications, which impair heat loss through
reduction of sweating, should also be discontinued (Mann et al.,
2022). Beyond these measures, there is limited consensus regard-
ing 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 (Caroff et al., 2022; Strawn
et al., 2007). Nevertheless, therapies that have been reported as
successful in the treatment of NMS include benzodiazepines,
dopamine agonists, dantrolene and ECT (Caroff et al., 2022). 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 benzo-
diazepines have been associated with improvements in some
individuals with NMS (Francis et al., 2000; Greenberg and
Gujavarty, 1985; Kontaxakis et al., 1990; Lee, 2007; Lew and
Tollefson, 1983; Miyaoka et al., 1997), though this response is
sometimes transient (Greenberg and Gujavarty, 1985; Lee, 2007;
Lew and Tollefson, 1983). 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 (Lee, 2007). Given that risks are
small and benefits possibly marked, several sources suggest a
trial of benzodiazepines (Adnet et al., 2000; Berman, 2011;
Caroff et al., 1998; Strawn et al., 2007).
Some 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
(Davis et al., 2000; Mann et al., 2000). Systematic reviews of
case reports have found that the dopaminergic medications,
bromocriptine and amantadine, are associated with reduced
mortality (Sakkas et al., 1991), and bromocriptine is associated
24 Journal of Psychopharmacology 00(0)
with a reduced time to clinical response (Rosenberg and Green,
1989). Although levodopa has been used in only a limited num-
ber of reported NMS cases, it was thought to be effective in half
the case reports (Sakkas et al., 1991) and dramatic improvements
were observed in some cases, even after failure to respond to
dantrolene (Nisijima et al., 1997). Newer dopamine agonists
developed for transdermal delivery may facilitate administration
of dopamine drugs under extreme circumstances (e.g. rotigotine)
(Caroff et al., 2022).
Temperature elevation in NMS is theorised to result from
antipsychotic drug-induced impairment of central heat loss
mechanisms in combination with excess heat production second-
ary to peripheral hypermetabolism and rigidity of skeletal mus-
cle. Dantrolene, which inhibits contraction and heat production
in muscle, may benefit those cases of NMS with extreme tem-
perature elevations, severe rigidity and true hypermetabolism
(Caroff et al., 2022). In one systematic review (Sakkas et al.,
1991), 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 com-
pared with supportive care alone (Sakkas et al., 1991). Yamawaki
et al. (1993) 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 (Baxter and Preston, 2022).
The pharmacological agents discussed above are generally
effective within the first several days of NMS (Davis et al.,
2000). 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 (Trollor
and Sachdev, 1999). Response often occurs during the first few
treatments, although some cases have required multiple ECTs
in a single day (McKinney and Kellner, 1997). 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 (Caroff et al., 2000).
Davis et al. (1991) conducted a literature review that found the
mortality of 48 NMS patients treated with ECT was 10% com-
pared with 21% for patients treated with supportive care alone.
Morcos et al. (2019) 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 con-
sidered 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 (Davis et al., 2000).
However, succinylcholine can cause hyperkalaemia and arrhyth-
mias in patients with severe rhabdomyolysis, which may explain
instances of cardiac complications in NMS patients treated with
ECT (Davis et al., 2000). Alternative muscle relaxants should be
considered in patients at risk.
Treatment recommendations for NMS are not uniform
(Sch?nfeldt-Lecuona et al., 2020b) and – in the absence of RCTs
– any recommendations should be made with caution. In a pro-
spective study of 20 NMS patients, Rosebush et al. (1991)
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, Kuhlwilm et al. (2020) 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 Woodbury and Woodbury (1992) 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 suffi-
cient for the treatment of mild to moderate NMS, but that specific
therapies were indicated for severe NMS.
A 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 evi-
dence and do not consider all relevant treatment options
(Sch?nfeldt-Lecuona et al., 2020a). Sch?nfeldt-Lecuona et al.
(2020a) 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 (Caroff et al., 2022;
Davis et al., 2000; Strawn et al., 2007; Woodbury and Woodbury,
1992). In general, the first steps include supportive care and dis-
continuing 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
(Barnes et al., 2020; Caroff et al., 2022; Strawn et al., 2007;
Woodbury and Woodbury, 1992). Trials of bromocriptine, aman-
tadine or other dopamine agonists may be a reasonable next step
in patients with moderate NMS involving prominent parkinso-
nian 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 (Caroff et al., 2022; Davis et al., 2000; Strawn et al., 2007).
Among patients who recover from NMS, there may be a 30%
risk of recurrent episodes following antipsychotic rechallenge
(Caroff et al., 2022). However, most patients who require antipsy-
chotics 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 (Rosebush and Stewart, 1989; Strawn et al., 2007).
Recommendations for the treatment of NMS
? In NMS, discontinue all dopamine antagonists. (C)
? In NMS, discontinue anticholinergic drugs. (S)
? In NMS, supportive care should be provided. This consists
of assessment and appropriate management of airway,
ventilation, temperature and swallow. Fluid input/output
Rogers et al. 25
should be monitored, and aggressive fluid resuscitation
should be used where required. There should be assess-
ment for hyperkalaemia, renal failure and rhabdomyoly-
sis. There should be careful monitoring for complications
such as cardiorespiratory failure, aspiration pneumonia,
thromboembolism and renal failure, alongside early con-
sideration of high-dependency care. (S)
? For mild, early NMS, characterised by mild rigidity, cata-
tonia or confusion, temperature < 38°C and HR < 100,
consider a trial of lorazepam. (C)
? For 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)
? For severe NMS, characterised by severe rigidity, catato-
nia or coma, temperature > 40°C and HR > 120, consider
a trial of lorazepam and consider dantrolene. Consider
bromocriptine or amantadine. Consider ECT. (C).
? If 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)
? Delay restarting antipsychotics by at least 2 weeks after
resolution of an NMS episode to reduce the risk of recur-
rence. (C)
Antipsychotic-induced catatonia
Antipsychotics with strong dopamine receptor affinity in particu-
lar can lead to the development of antipsychotic-induced catato-
nia (Fricchione et al., 1983; Hirjak, Sartorius, et al., 2021).
Antipsychotic-induced catatonia can occur in association with
FGAs (Gelenberg and Mandel, 1977; Gugger et al., 2012) and
probably less frequently with SGAs (McKeown et al., 2010; Tu
et al., 2016; Xiong et al., 2009), 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’ (Brenner and Rheuban, 1978).
The 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 antip-
sychotic-induced catatonia (Gelenberg and Mandel, 1977;
Lopez-Canino and Francis, 2007). More complex catatonic
behavioural abnormalities, such as echolalia, echopraxia, verbig-
eration or Mitgehen, are not generally reported in association
with antipsychotic treatment.
The primary intervention for antipsychotic-induced catatonia
is discontinuation of the antipsychotic agent. In some cases, this
is sufficient on its own (Gelenberg and Mandel, 1977; McKeown
et al., 2010). Other possible options are reducing the dose or
switching to an antipsychotic with lower affinity for the dopa-
mine receptors. Benzodiazepines may also be helpful. In one
prospective cohort study including 18 patients with antipsy-
chotic-induced catatonia, all were administered lorazepam, of
whom 14 had complete remission and 4 had some partial
response (Lee, 2010). 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
(Fricchione et al., 1983; Gugger et al., 2012). Amantadine has
also been reported to be helpful in a case series (Gelenberg and
Mandel, 1977).
There is a lack of data on the prophylaxis of antipsychotic-
induced catatonia.
Recommendations for antipsychotic-induced catatonia
? When catatonia is attributed to antipsychotic administra-
tion, consider discontinuing the antipsychotic. (C)
? In more severe cases or cases that do not resolve with
antipsychotic discontinuation, consider a trial of a benzo-
diazepine. (C)
? Once catatonia is treated, if an antipsychotic is still neces-
sary, commence at a low dose and titrate gradually,
closely monitoring for side effects. (S)
Considerations in special groups and
situations
Children and adolescents
The 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 (Cohen et al., 1999;
Wing and Shah, 2000). An Indian study reported an inpatient
paediatric prevalence of 5.5% (Thakur et al., 2003). 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 (Rogers et al., 2021). The
potential aetiologies of catatonia in youth span the same psychi-
atric 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 (Sarkis et al., 2019). The Pediatric Catatonia Rating
Scale (PCRS) is modified from the BFCRS and has been shown
to be applicable in young people (Benarous et al., 2016).
Given 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 associ-
ated with improvement in 33 (65%) (Raffin et al., 2015). 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 (Sorg et al., 2018).
With 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 (Grover et al., 2013). 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
(Consoli et al., 2010). Another review identified 24 patients with
catatonia who had outcome data after ECT, of whom 18 (75%)
showed remission or marked improvement (Rey and Walter,
26 Journal of Psychopharmacology 00(0)
1999). The evidence suggests that side effects of ECT are similar
to the adult population and serious complications are very rare
(Grover et al., 2013; Rey and Walter, 1999).
Since 2008, several reviews have proposed paediatric cat-
atonia management along the lines of objective catatonia rating
scales, medical work-up, removal of offending drugs and loraze-
pam challenge, followed by lorazepam treatment (sometimes at
high doses) and or ECT (Dhossche et al., 2010a; Dhossche and
Wachtel, 2013; Hauptman and Benjamin, 2016; Lahutte et al.,
2008; Raffin et al., 2015; Withane and Dhossche, 2019).
Recommendations for catatonia in the children and
adolescents
? Catatonia is known to occur in children as young as
5 years and clinicians should screen for catatonia when-
ever clinical suspicion exists. (S)
? Evaluation of catatonia aetiologies in children and ado-
lescents should include the same range of disorders as
found in adults. (S)
? When assessing for the presence of paediatric catatonia,
the PCRS should be used. (C)
? First-line management for paediatric catatonia includes a
lorazepam challenge test, lorazepam in increasing doses
and bilateral ECT. (D)
Older adults
The 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 (Jaimes-Albornoz et al., 2022). The
studies that have assessed the epidemiology of catatonia among
older adults have focused on the acute psychiatric hospital set-
ting, liaison psychiatry setting and intensive care setting (Cuevas-
Esteban et al., 2017; Grover et al., 2014; Jaimes-Albornoz et al.,
2022; Jaimes-Albornoz and Serra-Mestres, 2013; Kaelle et al.,
2016; Serra-Mestres and Jaimes-Albornoz, 2018; Sharma et al.,
2017; Takács et al., 2017). The prevalence has varied widely by
the study setting and the assessment instruments used.
The phenotype of catatonia among older adults shows a high
prevalence of hypokinetic signs, such as immobility/stupor, star-
ing, rigidity, mutism, withdrawal, posturing and negativism
(Jaimes-Albornoz et al., 2022), although one study listed excite-
ment among the commonly identified clinical features (Cuevas-
Esteban et al., 2017). Catatonia among older adults is often
multifactorial in aetiology and a wide range of medical condi-
tions has been implicated, though the outcome is still usually
good if it is treated promptly (Jaimes-Albornoz et al., 2022).
Differential diagnosis can be challenging and misdiagnosis of
catatonia as delirium, psychosis, stroke, dementia or coma have
been reported (Alisky, 2007; Meyen et al., 2018; Ratnakaran
et al., 2020). This may result in inappropriate ‘do not resuscitate’
orders (Swartz and Galang, 2001). Reports suggest that medical
complications of catatonia, such as deep vein thrombosis, pulmo-
nary embolism and pneumonia may be particular risks in older
adults (Hu and Chiu, 2013; Jaimes-Albornoz and Serra-Mestres,
2013; Swartz and Galang, 2001). One small study found that 4
out of 10 older adult patients with catatonia in a liaison psychia-
try setting had medical complications and 2 died (Jaimes-
Albornoz and Serra-Mestres, 2013).
Benzodiazepines remain the cornerstone of the treatment of
catatonia among older adults, although they may respond to
lower doses (Ungvari, 1994).
ECT remains the treatment of choice among those not
responding to benzodiazepines (Jaimes-Albornoz et al., 2022).
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, olan-
zapine, 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 manage-
ment of catatonia (Jaimes-Albornoz et al., 2022).
Recommendations for catatonia in older adults
? In older adults, care should be taken to identify medical
disorders underlying catatonia. (S)
? Catatonia should be considered in the differential diagno-
sis for an apparent rapidly progressive dementia or ‘fail-
ure to thrive’ clinical presentations in older adults. (S)
? First-line treatment of catatonia in the older adults con-
sists of benzodiazepines, often at lower doses than among
younger adults, and ECT. (D)
The perinatal period
The 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 (Nahar et al., 2017). The literature in other perina-
tal groups with psychiatric or medical illnesses does not allow
prevalence estimates (Csihi et al., 2022).
In pregnancy, many potential complications of persistent cat-
atonia place the mother and child at exceptionally high risk.
These include venous thrombosis and thromboembolism, dehy-
dration, malnutrition, incontinence, infections, communication
difficulties, impaired co-operation with assessments and investi-
gations, and impairment of capacity (Clinebell et al., 2014; Csihi
et al., 2022; Funayama et al., 2018). Postnatally, the mother’s
ability to breastfeed and to care and bond with her infant are key
concerns (Csihi et al., 2022).
The 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 (McAllister-Williams
et al., 2017)
The reproductive safety of lorazepam in the perinatal
period. Research 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,
Grigoriadis et al. (2019) 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. Noh
et al. (2022) reported in a nationwide cohort study of 3.1 million
Rogers et al. 27
pregnancies with a larger sample of benzodiazepine exposures
(n = 40,846), using propensity scores to account for a large num-
ber 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 spe-
cifically, heart defects (adjusted RR: 1.15; 95% CI: 1.10–1.21). A
risk of oral clefts, reported by several previous studies (Dolovich
et al., 1998), 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).
A 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 approxi-
mately two (Grigoriadis et al., 2020), a value generally regarded
as the threshold for clinical significance (Andrade, 2015). 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.
Cohort studies of neurodevelopmental outcomes following
foetal benzodiazepine exposure have been inconclusive (Wang
et al., 2022).
A 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; Nishimura
et al., 2021), 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; Kelly et al., 2012), but
there is a lack of data regarding the effects of the high doses of
lorazepam sometimes used in catatonia.
The use of ECT in the perinatal period. In systematic reviews
of the case literature on ECT in the perinatal period (Anderson
and Reti, 2009; Calaway et al., 2016; Miller, 1994; Pompili et al.,
2014), summarised by Coshal et al (2019), the most common
adverse effects attributed to the treatment were foetal bradyar-
rhythmia, abdominal pain, uterine contractions, premature birth,
vaginal bleeding, placental abruption and threatened abortion. In
many cases, symptoms were mild and transient (Anderson and
Reti, 2009; Miller, 1994). No maternal deaths were reported.
Among 339 cases summarised by Anderson and Reti (2009),
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 adminis-
tered during ECT. Leiknes et al. (2015) found a high rate of com-
plications 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 (Anderson and Reti,
2009; Calaway et al., 2016; Miller, 1994; Pompili et al., 2014) –
while acknowledging the difficulties with interpreting case litera-
ture – 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 (Gregoire and Spoors, 2019),
the APA (American Psychiatric Association Committee on
Electroconvulsive Therapy, 2001), and the Royal Australian and
New Zealand College of Psychiatrists (Weiss et al., 2019).
To achieve the optimal outcomes for mother and child, it is
important that professionals with expertise in ECT, perinatal psy-
chiatry and obstetrics are involved in a decision to deliver ECT
during pregnancy (Weiss et al., 2019). It is essential that clini-
cians identify pre-existing risk factors for poor outcomes, appro-
priately monitor maternal and foetal well-being before, during
and after the procedure, and utilise effective preventative inter-
ventions. 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 (Lakshmana et al., 2014).
There is evidence from three observational studies that ECT is
more effective for women with severe affective disorders after
childbirth than for non-postnatal patients (Haxton et al., 2016;
Reed et al., 1999; Rundgren et al., 2018). 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.
Due to inherent methodological difficulties, considerable
uncertainties exist in the evidence, and research findings should
be interpreted with caution.
Recommendations for catatonia in the perinatal period
? If catatonia is severe and the woman suffers from a men-
tal 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)
? If catatonia is severe and presents high risks to the physi-
cal 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)
? The risks of any specific treatment should be carefully
weighed against the risks of other treatments or no treat-
ments. (S)
Recommendations for catatonia during pregnancy
? Screening and selection of patients for ECT should be
conducted by a psychiatrist experienced in ECT, in con-
sultation with both a psychiatrist with appropriate exper-
tise in perinatal psychiatry and an obstetrician. (D)
? If delivery is expected within a few weeks, alternative
options, such as induction of labour or Caesarean section
28 Journal of Psychopharmacology 00(0)
should be considered by the obstetrician, anaesthetist,
paediatrician and psychiatrist. (S)
? If specific treatment for catatonia is required, lorazepam
at doses up to 4 mg/day should be considered initially. (S)
? If 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)
Recommendations for catatonia during breastfeeding
? If 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)
? Women can resume breastfeeding after ECT treatments. (C)
Autism spectrum disorder
International studies over the past two decades have documented
a point prevalence of catatonia ranging from 12% to 20% in indi-
viduals with autism, with onset most commonly in adolescence
and early adulthood (Billstedt et al., 2005; Breen and Hare, 2017;
Wing and Shah, 2000). As the US Center for Disease Control esti-
mated an incidence of autism as 1 in 44 children, it is likely that
clinicians will care for individuals with autism and catatonia
(Maenner et al., 2021). It is theorised that shared neuronal cir-
cuitry and genetic susceptibility loci exist between autism and
catatonia (Dhossche et al., 2006b; Dhossche et al., 2005).
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 (Dhossche and Wachtel, 2013; Wachtel, 2018, 2019).
Diagnosis of catatonia in autism is complicated by the overlap in
clinical features between the two conditions (Wing and Shah, 2006).
Therefore, several authors have suggested that diagnosis of catatonia
in autism should entail a marked change from baseline presentation
(Dhossche et al., 2006a; Kakooza-Mwesige et al., 2008; Mazzone
et al., 2014; Vaquerizo-Serrano et al., 2021). This is important
because no pharmacological or neuromodulatory therapies are indi-
cated for the core symptoms of autism (Howes et al., 2018).
Treatment 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 Dhossche et al.
(2006a) and begin with standardised assessment of catatonia, taking
into consideration baseline autistic features that may mimic catato-
nia (Dhossche et al., 2006a). Wing and Shah (2000) emphasised
that amotivation, prompt dependence, withdrawal and slowness
often accompany classic DSM catatonia signs in autism, and con-
sideration 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 immobil-
ity, stupor and food refusal. Mild catatonic features may be
addressed by the Shah–Wing approach of psychological and sup-
portive interventions with a focus on prompting, structure and stress
reduction, and possible lorazepam usage. More severe presenta-
tions should be treated with the standard biological anticatatonic
regimens including bilateral ECT (Dhossche et al., 2006a). Fink,
Taylor and Ghaziuddin offered a medical treatment model in 2006
including catatonia diagnosis with standardised rating scales includ-
ing the BFCRS, lorazepam trial and ongoing therapy, and bilateral
ECT as needed (Fink et al., 2006). 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
(Bailine et al., 1994; Wachtel, 2019). 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 (Bush et al., 1996b; Vaquerizo-Serrano
et al., 2021; Wachtel, 2019). The authors also noted that antipsy-
chotics were often used in individuals with catatonia and autism
despite a lack of known benefit of such agents in catatonia in gen-
eral, and urged caution given the risk of worsening catatonia or pre-
cipitating 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 (Ghaziuddin
et al., 2017; Wachtel, 2019; Wachtel et al., 2010).
Recommendations for catatonia in autism spectrum disorder
? Clinical vigilance is warranted for the assessment of cata-
tonia in autism spectrum disorder given its high preva-
lence. (C)
? Diagnosis of catatonia in autism spectrum disorder
requires a marked change from baseline presentation. (S)
? First-line interventions in mild cases of catatonia are psy-
chological interventions and/or lorazepam, but the stand-
ard treatments for catatonia (i.e. benzodiazepines in
escalating dosages and/or bilateral ECT) should be con-
sidered in moderate to severe cases. (D)
Medical conditions
Considerations in kidney disease. Catatonia, including malig-
nant catatonia (Nomura et al., 2021), has been described in the
context of severe renal impairment (Carroll et al., 1994; Desai
et al., 1984; Fekete, 2013), in patients receiving dialysis (Deny-
senko and Nicolson, 2011) and in the post-transplantation period,
often as a result of drug toxicities (Quinn et al., 2014; Sikavi
et al., 2019). Patients with renal impairment, even those on dialy-
sis, may still be able to tolerate and benefit from benzodiazepines
(Tsai and Huang, 2010) with consideration of the severity of
renal impairment, route of administration of benzodiazepines,
comorbidities (e.g. frailty), including the risk for delirium.
Typically, no dose adjustments are required even in severe
impairment for acute dosing of lorazepam in either oral or paren-
teral formulation; however, for high or repeated parenteral dosing
(Morrison et al., 1984; Verbeeck et al., 1976), monitoring for pro-
pylene glycol toxicity and consideration of other therapies such as
ECT and NMDA receptor antagonists may be indicated (Goforth,
2007; Quinn et al., 2014) to lessen the impact of the potential side
effects of treatment (e.g. falls, confusion, delirium).
Considerations in liver disease. Malignant catatonia may be a
rare cause of liver failure (Kiparizoska et al., 2021). Catatonia
has been reported secondary to Wilson’s disease (Davis et al.,
2021), after liver transplantation (Chung et al., 2013; Cottencin
Rogers et al. 29
et al., 2002; Huang et al., 2006; Kalivas and Bourgeois, 2009;
Tatreau et al., 2018), including in post-transplantation delirium
(Brown et al., 2016; Kahn, 2016) as well as secondary to post-
transplantation drug toxicities (Davis and Tripathi, 2020). The
early post-liver transplantation period may be a state of defi-
ciency in GABA signalling (Tatreau et al., 2018), which may
place the patient at increased risk for catatonia.
Benzodiazepines may be an effective treatment for catatonia
post-transplantation (O’Donnell et al., 2007; Seetharam and
Akerman, 2006). In mild to moderate hepatic impairment, typi-
cally no dose adjustment for lorazepam is required (oral or paren-
teral formulations). In severe impairment or failure, use caution
(Kraus et al., 1978; Peppers, 1996). Other treatments such as
NMDA receptor antagonists (Brown et al., 2016) or ECT may be
required when benzodiazepine treatment is cautioned.
Considerations in lung disease. Pulmonary complications of
catatonia may include pulmonary embolism, aspiration pneumo-
nia, pneumothorax, bronchorrhoea, central hypoventilation,
respiratory failure and delayed weaning from mechanical ventila-
tion (Funayama et al., 2018; Gupta et al., 2015; Hayashi et al.,
2006; ter Haar et al., 2006; Thomas et al., 1994).
Catatonia has been described in the context of respiratory ill-
nesses, including influenza (Coulonjou et al., 1958; Wender,
1979) and SARS-CoV-2 (Amouri et al., 2020; Brand?o et al.,
2021; Caan et al., 2020; Cooper and Ross, 2020; Ghaziuddin
et al., 2021; Gouse et al., 2020; Kaur et al., 2021; Kopishinskaia
et al., 2021; Kwon et al., 2021; Mulder et al., 2021; Naik et al.,
2021; Nikayin et al., 2022; Raidurg et al., 2021; Scheiner et al.,
2021; Torrico et al., 2021; Vazquez-Guevara et al., 2021; Zain
et al., 2021; Zandifar and Badrfam, 2020), 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 (Grover et al., 2014; Wilson et al., 2017).
Respiratory failure due to malignant catatonia has been described
and may be especially responsive to ECT (Barnardo et al., 2007;
Boyarsky et al., 1999; Hayashi et al., 2006; ter Haar et al., 2006;
Thomas et al., 1994), especially in those unable to tolerate a ben-
zodiazepine (Geretsegger and Rochowanski, 1987).
Recommendations for catatonia in kidney, liver and lung
disease
? In renal impairment, lorazepam dosing does not usually
need to be altered, but consider additional monitoring for
side effects. (C)
? In mild or moderate hepatic impairment, lorazepam dos-
ing does not usually need to be altered, but caution should
be exercised when considering lorazepam in severe
hepatic impairment. (B)
? In severe respiratory disease, consider giving ECT as a
first-line treatment rather than benzodiazepines. (D)
Research priorities
One 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
(Oldham, 2022).
As this guideline has highlighted, the most urgent research goal
for catatonia is to develop a more robust evidence base for its treat-
ment. Despite the wealth of small reports and observational data, a
Cochrane systematic review of the use of benzodiazepines for cata-
tonia found that no RCT met its inclusion criteria (Zaman et al.,
2019). Although some might consider an RCT infeasible in catato-
nia, the Cochrane review found several examples. Unfortunately,
though, these studies had methodological issues, introducing ques-
tions of validity. Conducting clinical trials in catatonia is an impor-
tant priority for psychiatric research in the next decade.
In 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.
We provide a list of priority research questions in Table 11.
Table 11. Key research questions.
What are the boundaries of the catatonic syndrome? Specifically, can validation by a lorazepam challenge test confirm how mild or severe the
phenotype is?
Given that the last two decades are continuing to reveal medical aetiologies of catatonia, what other medical conditions might account for
catatonia?
Do the associations of various neurological and medical conditions with catatonia identified in case reports and series hold in larger observational
studies?
What are the genetic or environmental factors that predispose certain individuals to the development of drug-induced catatonia or NMS?
Does the use of benzodiazepines in catatonia stand up to rigorous clinical trial methodology?
How long after recovery should patients with catatonia be treated with benzodiazepines?
What are the optimal conditions for ECT treatment, in terms of electrode placement, frequency and timing?
What is the reproductive safety of ECT?
How might the parameters of rTMS be optimised for catatonia?
What treatments are effective in individuals who do not respond to benzodiazepines or ECT?
What is the role of antipsychotic medications in the treatment of individuals with catatonia?
Are there any psychosocial treatments that might support the prevention or treatment of catatonia?
How does the pathophysiology and treatment of catatonia in children, adolescents and older adults differ from those of younger adults?
ECT: electroconvulsive therapy; NMS: neuroleptic malignant syndrome; rTMS: repetitive transcranial magnetic stimulation.
30 Journal of Psychopharmacology 00(0)
Acknowledgements
The authors would like to thank Professor Thomas Barnes for his advice
in preparing this guideline.
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with
respect to the research, authorship and/or publication of this article: NA,
SA, ASD, AF, S Grover, DH, DK, GL, SCM, GN, LEW, TS, JEW, S Gee
and AW declare no conflicts of interest.
MAO is one of the creators of the free videographic educational resources
for the Bush-Francis Catatonia Rating Scale mentioned in the guideline.
DSB is President of the BAP and KF is the Past President of the BAP.
GF is a consultant for Revival Therapeutics.
JPR is supported by the Wellcome Trust.
GL is supported by the Wellcome Trust and NIHR.
MSZ declares salary support to support research time from the NIHR
UCLH BRC. MSZ declares honoraria for one lecture each for each of the
four mentioned in the last 3 years: Norwegian Neurological Society;
Copenhagen Neuropsychological Society, Rigshospitalet; Cygnet
Healthcare; and UCB Pharma. MSZ declares travel and hotel support for
a stay in Florence from the European Association of Neurology (EAN)
for an EAN meeting on autoimmune encephalitis in April 2022. MSZ
represents neurology in the UK for the Association of British Neurologists
for matters related to Covid in meetings with NHS England and Royal
College of Physicians.
AY is the Editor of Journal of Psychopharmacology and Deputy Editor,
BJPsych Open. He has given paid lectures and has been on advisory
boards for the following companies with drugs used in affective and
related disorders: Astrazenaca, Boehringer Ingelheim, Eli Lilly,
LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan,
Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis
and Neurocentrx. He is the principal investigator on the Restore-Life
VNS registry study (funded by LivaNova); ESKETINTRD3004: ‘An
Open-label, Long-term, Safety and Efficacy Study of Intranasal
Esketamine in Treatment-resistant Depression’, ‘The Effects of
Psilocybin on Cognitive Function in Healthy Participants’ and ‘The
Safety and Efficacy of Psilocybin in Participants with Treatment-
Resistant Depression (P-TRD)’. He is the UK Chief Investigator for
Compass: COMP006 & COMP007 studies and for Novartis MDD study
MIJ821A12201. He has received grant funding (past and present) from
NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical
Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal
College of Physicians (Edin); BMA (UK); UBC-VGH Foundation
(Canada); WEDC (Canada); CCS Depression Research Fund (Canada);
MSFHR (Canada); NIHR (UK); Janssen (UK), and EU Horizon 2020. He
has no shareholdings in pharmaceutical companies.
Funding
The author(s) disclosed receipt of the following financial support for the
research, authorship and/or publication of this article: JPR is funded by
the Wellcome Trust (220659/Z/20/Z). MSZ, GL and ASD are supported
by the UK NIHR University College London Hospitals Biomedical
Research Centre. MAO is supported by the National Institute on Aging of
the National Institutes of Health (K23AG072383). The content is solely
the responsibility of the authors and does not necessarily represent the
official views of the National Institutes of Health. DH received support
from the German Research Foundation (DFG, grant number DFG HI
1928/5-1 and HI 1928/6-1). JEW received support from the Veterans
Affairs (VA) Tennessee Valley Healthcare System Geriatric Research,
Education and Clinical Center, the VA Office for Rural Health and from
the National Institutes of Health (NIH) MH070560.
AH’s independent research is funded by the National Institute for Health
and Care Research (NIHR) Maudsley Biomedical Research Centre at
South London and Maudsley NHS Foundation Trust and King''s College
London. The views expressed are those of the author(s) and not necessar-
ily those of the NIHR or the Department of Health and Social Care.
AY has received grant funding (past and present) from NIMH (USA);
CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute
(USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians
(Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada);
CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR
(UK); Janssen (UK), and EU Horizon 2020. He has no shareholdings in
pharmaceutical companies.
ORCID iDs
Jonathan P Rogers https://orcid.org/0000-0002-4671-5410
Glyn Lewis https://orcid.org/0000-0001-5205-8245
Siobhan Gee https://orcid.org/0000-0003-1020-6777
Supplemental Material
Supplemental material for this article is available online.
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