Series

Catatonia 1
Structure and neural mechanisms of catatonia
Sebastian Walther, Katharina Stegmayer, Jo Ellen Wilson, Stephan Heckers

Lancet Psychiatry 2019; Catatonia is a psychomotor syndrome associated with several psychiatric and medical conditions. Psychomotor signs
6: 610–19 range from stupor to agitation, and include pathognomonic features such as verbigeration and waxy flexibility.
Published Online Disturbances of volition led to the classification of catatonia as a subtype of schizophrenia, but changes in nosology
June 10, 2019
now recognise the high prevalence in mood disorders, overlap with delirium, and comorbidity with medical
http://dx.doi.org/10.1016/
S2215-0366(18)30474-7 conditions. Initial psychometric studies have revealed three behavioural factors, but the structure of catatonia is still
See Comment page 554 unknown. Evidence from brain imaging studies of patients with psychotic disorders indicates increased neural
This is the first in a Series of two
activity in premotor areas in patients with hypokinetic catatonia. However, whether this localised hyperactivity is due
papers on catatonia to corticocortical inhibition or excess activity of inhibitory corticobasal ganglia loops is unclear. Current treatment of
Translational Research Center, catatonia relies on benzodiazepines and electroconvulsive therapy—both effective, yet unspecific in their modes
University Hospital of of action. Longitudinal research and treatment studies, with neuroimaging and brain stimulation techniques, are
Psychiatry, University of Bern, needed to advance our understanding of catatonia.
Bern, Switzerland (S Walther MD,
K Stegmayer MD); and
Department of Psychiatry and Introduction Catatonia is a psychomotor syndrome
Behavioral Sciences, Vanderbilt Herman Melville’s Bartleby, the Scrivener: a Story of Catatonia, a well known syndrome during the early part
University Medical Center, Wall-street is a story about a New York City law clerk, who of the 20th century, almost disappeared from psychiatric
Nashville, TN, USA
(J E Wilson MD,
retreats from the world around him, becomes mute and discourse, leading some to ask: “Where have all the
Prof S Heckers MD) stuporous, wastes away and dies.¹ The tale is the skillful catatonics gone?”22 A contributing factor might be that
Correspondence to: description of a previ­ously unknown psychiatric condition: exact prevalence and incidence estimates of catatonia
Dr Sebastian Walther, “the scrivener was the victim of innate and incurable depend on the proper detection and description of the
Translational Research Center, disorder. I might give alms to his body; but his body did signs and symptoms of the syndrome.23 However,
University Hospital of Psychiatry,
University of Bern, 3008 Bern,
not pain him; it was his soul that suffered, and his soul I clinicians are often confused by catatonia, reframing the
Switzerland could not reach”.² signs and symptoms as something else, or missing them
sebastian.walther@upd.unibe. Two decades later, Karl Kahlbaum³ published the altogether. Much of the confusion stems from the poorly
ch monograph Die Katatonie oder das Span­nungsirresein, in defined term psychomotor.24–26 The ex­pression is generally
which he describes peculiar ab­normal­ities of apparently taken to refer to the volitional aspects and affective
volitional motor acts. This dis­order is now known as modulation of spontaneous or cued motor behaviour. The
catatonia, a psychomotor syn­ drome, with symp­­ toms term includes the will to act, and the planning and
ranging from inhibition to agi­ tation, with prom­inent execution of a motor act, but also includes the modulation
disturbances of volition and, in severe cases, autonomic of motor behaviour by sensorium and affect—leading to
nervous system dysregulation.4–7 the remarkable complex­ity regarding the voluntariness of
Since Kahlbaum and others speculated about the path­ motor acts. Just consider the many ways to speak a
ology of catatonia, the disease mechanisms have sentence, sing a song, or play an instrument.
remained elusive.8–11 Mortality of catatonia was high The signs of catatonia can be separated into increased,
before the introduction of medication and electro­ abnormal, and decreased psychomotor behaviour, as
convulsive ther­ apy (ECT).12,13 Nowadays, it remains categor­ised by observation, interview, and physical examin­
elevated in malignant forms of the syndrome.14–17 An ation (figure 1). Carl Wernicke proposed that psycho­motor
abundance of case reports and conceptual reviews of behaviour is abnormal if there is too little (hypo­function or
catatonia have been reported, but well powered research akinesis) or too much (hyperfunction or hyperkinesis)
studies are rare.18 This paucity of research is one reason motor activity, or if the act itself is qualitatively abnormal
that current treatment approaches remain non-specific (parakinesis).28 This framework is still helpful nowadays.
and without evidence-based criteria. Catatonia has a changeable nature which could mis­
To make progress in the diagnosis and treatment lead the examiner to interpret the signs as volitional or
of catatonia, it is essential to unravel the disease mecha­ behavioural. However, these features are better classified
nisms. Specifically, neuroimaging studies of catatonia as readouts of dysfunctional motor circuits, as seen in
could inform the development of novel brain stimulation neurological disorder patients affected by functional
techniques.19,20 In this Series paper, we summarise the move­ment disorders.29 Many signs are triggered in
current state of knowledge on catatonia, focusing on response to the examiner and might be a response to the
clinical and neuroimaging findings. Elsewhere in this examiner’s physical presence. For example, the patient’s
issue of The Lancet Psychiatry, Rogers and colleagues21 mutism or hypokinesis might be pronounced in the
report on neuroinflammation associated with catatonia. presence of the examiner, but decreased when the

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 Series

examiner leaves. The patients in Kahlbaum’s monograph Observation Interview Physical examination
(appendix) can be captured well with this checklist
Psychomotor activity
(figure 1). One classic feature of cata­tonia is autonomic
abnormality (ie, tachycardia, hyper­ tension, or fever), Agitation* or excitement
which does not occur in every patient, is not a psycho­
motor sign, and should be listed separately. Increased Impulsivity
Psychomotor abnormalities are found in various clinical
Combativeness
settings. Three psychiatric disorders include psycho­motor
abnormalities as DSM-5 diagnostic cri­teria or specifiers:
mood disorders, schizophrenia spec­trum dis­orders, and
Grimacing* Echolalia*† Waxy flexibility*
delirium. Additionally, the DSM-5 diagnostic criteria for
autism spectrum disorders de­scribe psycho­motor signs of Stereotypy* Echopraxia*† Catalepsy*†
catatonia as core diag­ nostic criteria. Not surprisingly,
catatonia can be a promin­ent feature in patients diagnosed Mannerism* Verbigeration Rigidity
with these psychiatric disorders. Abnormal
Psychomotor retardation has long been recognised Posturing*† Automatic obedience Gegenhalten

as a cardinal feature of depression, especially

Perseveration Mitgehen
melancholia.30,31 Signs include, but are not limited to,
slowed reaction time, discrete body move­ ments Grasp reflex
(especially of the face), and abnormalities of speech
(such as changes in speed and modulation). Psychomotor
retardation or agitation is recognised in DSM-5 as one of
Stupor* Negativism*
the nine diagnostic cri­teria for major depressive disorder.
Whether psycho­ motor retardation or agitation in Decreased Ambitendency Mutism*
depression resembles a minor form of catatonia remains
to be determined. Schizophrenia has been associated Staring Withdrawal
with catatonia since Kraepelin32 defined dementia
praecox as a natural disease unit of three previously Autonomic abnormality
separate clinical syn­ dromes: dementia paranoides,
hebephrenia, and cata­tonia.33 Critics have observed that
Figure 1: Catatonia checklist
most patients who present with catatonic features do not The checklist recognises all 23 items of the Bush-Francis Catatonia Rating Scale (BFCRS).27 *12 DSM-5 criteria for
have a diagnosis of schizophrenia.34 However, the DSM catatonia.4 †Items that are combined in the BFCRS (item 5: posturing or catalepsy; item 7: echolalia or echopraxia),
con­tinued Kraepelin’s tradition of linking catatonia but are separate items in the DSM-5.
with schizo­phrenia until 2013, when DSM-5 removed
all schizo­phrenia subtypes, allowed for the recognition Structure of catatonia See Online for appendix
of cata­ tonic symptoms in many psychiatric and Several rating scales and diagnostic criteria sets, such as
medical conditions via a specifier, and introduced the the Bush-Francis Catatonia Rating Scale (BFCRS)27 and
term unspecified catatonia for cases with insufficient the DSM-5 criteria,42 are available to measure catatonia
information or those in which the underlying condition (table),4 but the structure of catatonia is still unclear.
is unclear. Few psychometric studies of the syndrome have been
Delirium is defined by disturbances of attention, published, and most of them have focused on psychiatric
awareness, and cognition, frequently with perceptual cohorts, primarily patients with psychotic dis­orders,43–48
disturbances and delusional thought content, which and so are not fully representative.
develops over a short period, and tends to fluctuate in In a mixed medical and psychiatric population, Wilson
course. For some, delirium can result in a dementia-like and colleagues41 studied 339 acutely ill patients who were
illness at long-term follow-up.35,36 Delirious patients can evaluated for catatonia using the BFRCS at a single
be further characterised to have hyperactive, hypo­active, academic medical centre. Of those screened, 232 met
or mixed forms, on the basis of psychomotor behaviour their definition of so-called validated catatonia (≥2 cata­
abnormalities.34 Catatonia is now recognised to frequently tonia items present on examination and a positive
co-occur with delirium in the context of general medical response to treatment with a benzodiazepine or ECT). Of
and critical illnesses;38–41 however, the clinical relevance the validated catatonia cases, 211 (91%) met DSM-IV
of this co-occurrence remains unknown. To what extent catatonia criteria, however, only 170 (73%) met DSM-5
the clinical presentation and course of psychomotor criteria. Principal component ana­ lysis identified three
abnormalities differ between schizophrenia, affective catatonia components: increased, de­creased, and abnor­
disorders, delirium, and other conditions is unclear. mal psychomotor behaviours. Only 37% of the variance
Studying this issue will encourage appropriate diagnosis of the condition was explained, leading the authors to
and treatment of cata­tonia. conclude that the under­ lying structure of catatonia

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Definition Item number

BFCRS DSM-5

Agitation* or excitement Extreme hyperactivity with non-purposeful movements and uncontrollable, extreme emotional reactions 1 9
Ambitendency Appearance of being stuck in indecisive or hesitant movement 19 NA
Automatic obedience Mechanical and reproducible compliance with examiner’s request, even if dangerous 16 NA
Autonomic abnormality Diaphoresis, palpitations, or abnormal temperature, blood pressure, pulse, or respiratory rate 23 NA
Catalepsy* Passive induction of a posture held against gravity 5† 2
Combativeness Striking out against others, with or without potential for injury 22 NA
Echolalia* Mimicking another’s speech 7† 11
Echopraxia* Mimicking another’s movements 7† 12
Gegenhalten Resistance to positioning by examiner that increases proportionally to applied force 18 NA
Grasp reflex Strong grasp of any object in proximity of the hand or upon touch 20 NA
Grimacing* Odd and inappropriate facial expressions, irrespective of situation 6 10
Impulsivity Patient suddenly engages in inappropriate behaviour without provocation; afterwards can give no, or only a 15 NA
facile, explanation
Mannerism* Odd, circumstantial caricatures of normal actions 9 7
Mitgehen Exaggerated movements in response to light pressure 17 NA
Mutism* No, or very little, verbal response (exclude if known aphasia) 3 4
Negativism* Opposing or not responding to instructions or external stimuli 12 5
Perseveration Whole or partial repetition of actions or verbal content that is not goal directed 21 NA
Posturing* Spontaneous and active maintenance of a posture against gravity 5† 6
Rigidity Resistance by way of increased muscle tone 11 NA
Staring or blinking Fixed gaze, decreased blinking, and widely opened eyes, or increased blinking 4 NA
Stereotypy* Repetitive, abnormally frequent movements that are not goal directed 8 8
Stupor* No, or markedly reduced, psychomotor activity; no activity in relation to environment 2 1
Verbigeration Continuous, directionless repetition of words, phrases, or sentences 10 NA
Waxy flexibility* Slight, even resistance to positioning by examiner 13 3
Withdrawal No eye contact, refusal to take food or drink when offered, or both; turning away from examiner, or social 14 NA
isolation

Catatonia signs are not fully operationalised and definitions vary slightly between authors. BFCRS=Bush-Francis Catatonia Rating Scale. NA=not applicable. *DSM-5 criteria
for catatonia.4 †Items are combined in the BFCRS (item 5: posturing or catalepsy; item 7: echolalia or echopraxia), but are separate items in the DSM-5.

Table: Definitions of catatonia signs

remains unknown. The scarce psychometric evidence for neurological soft signs, or disorganisation). This co-
a model of catatonia has not kept authors from speculating occurrence is due to both conceptual overlap between
how best to conceptualise this condition. Here, we discuss rating scales and truly common pathways in patho­
catatonia as a motor syndrome, a paralysis of will, a fear biology.6,50–52 Depending on which scale is used, catatonia
syndrome, or a result of immune dysregulation, with the symptoms are readily missed or confused. This problem,
emphasis of this Series paper on the motor syndrome. which Rogers50 has termed the “conflict of paradigms”,
particularly hampers research of psychomotor symptoms
Motor syndrome in severe psychiatric illness. More research is needed to
Although volitional disturbances and fear might drive clarify whether the underlying symptom structure differs
abnormal psychomotor behaviours, most researchers have be­tween psychiatric conditions associated with catatonia.
focused on motor acts as the central feature of cata­tonia. Objective assessment and comparison between disorders
Karl Kleist8,49 developed an elaborate neural circuitry model is most likely to be achieved for pure motor symptoms,
for psychomotor abnormalities in various psychi­ atric which can be approached with instrumentation.53,54
conditions. More recently, Georg Northoff11 inte­grated
current neuroscience data into a top-down modu­ lation Paralysis of will
model of catatonia. Many studies in schizo­ phrenia Kraepelin55 identified 11 disturbances of volition and
have reported striking covariance between catatonia and action. Most are now represented in DSM-5 as criterion
other motor abnormalities or symptom dimen­ sions A4 of schizophrenia (grossly disorganised or catatonic
(eg, parkinsonism, negative symptoms, dys­ kinesia, behaviour, or both), but some are scored separately as

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criterion A5 (avolition). After separating Kraepelin’s Catatonia is a medical condition

“paralysis of will” into two distinct domains, much of the Taylor and Fink77 have advocated that catatonia should be
clinical and research focus shifted to negative symptoms given a home of its own in psychiatric nosology. From
of schizo­phrenia.56 Bleuler recognised loosening of asso­ their per­spective, various conditions might be related as
ciations as the primary feature of schizophrenia, leading catatonia-spectrum illnesses, including malignant cata­
to its recog­nition as a thought disorder.57,58 However, tonia, neuroleptic malignant syndrome, serotonin syn­
he also con­ sidered negativism and ambivalence as drome, lethal catatonia,78 and the growing number of
fundamental.59 The term ambivalence appropriately autoantibody-related encephalitis cases with catatonia.79
describes the alter­ nating increases and decreases in These life-threatening conditions are characterised by
wilful behaviour seen in catatonia. autonomic abnormalities and encephalopathy, which are
both rarely studied in catatonia. Future studies should
Fear syndrome focus on the characterisation and course of symptoms
Similarities between catatonia and tonic immobility, such as tachycardia and hyperthermia in catatonia.
an animal defence strategy in response to fear, led to
the hypothesis that catatonia is a primitive fear syn­ Disease mechanisms
drome.60,61 The affective symptoms and neuroendocrine Neuroimaging findings
abnormalities seen in patients with melancholic Catatonia is associated with alterations of cerebral motor
depression with catatonic symptoms, and the therapeutic circuits.6,80,81 Similar to Parkinson’s disease, the syndrome
effects of benzodiazepines, have been cited in support of com­prises hypokinetic and hyperkinetic motor abnormal­
catatonia as a fear syndrome.62 Imaging studies of the ities, suggesting dysfunction of more than one motor
amygdala and the ventromedial and dorsolateral pre­ circuit. The Research Domain Criteria initiative added a
frontal cortices could explore this hypothesis.63 motor domain in January, 2019. Three main circuits have
been implicated in psychosis.26 One is thought to serve
Immune dysregulation inhibition and excitation of move­ments, and comprises
The course and presentation of acute catatonia mimics a circuit from primary motor cortex (M1) to putamen,
encephalitis in some cases, which led to the hypothesis internal and external pallidum, thalamus, and back to
that catatonia results from immune dysregulation.64 This M1; another circuit focuses on motor dynamics and
evolving research field is covered by the Article by Rogers timing, and includes M1, thalamus, cerebellum, and
and colleagues in this issue of The Lancet Psychiatry.21 pontine nuclei; and the final cortico­ cortical circuit is
thought to control motor organisation and speed, and
Nosology and epidemiology of catatonia includes M1, supplementary motor area (SMA), posterior
The nosology of catatonia changed in 2013. With DSM-5, parietal cortex, and medial prefrontal cortex. Thus,
the syndrome is now recognised in many psychiatric according to this model, catatonia symp­toms affecting
and medical conditions, but will probably remain motor inhibition or excitation, as well as motor
under­diagnosed.23 Most estimates of catatonia preva­ organisation, would be associated with at least two of the
lence are derived from studies of acutely ill psychiatric three circuits. Some authors, however, argue that so-
inpatients, and range from 9% to 18%.27,62,65–67 The called horizontal abnormalities within the cortico­cortical
prevalence essentially depends on the assessment loop are most relevant to catatonia.26,80
method—rating scales such as the BFCRS provide Initial neuroimaging studies of patients with a history of
higher numbers than DSM-5 criteria.23,67 In a meta- catatonia indicated poor functional activation of SMA,
analysis of 74 studies of catatonia, the mean catatonia primary and secondary motor cortices, inferior parietal
prevalence was 9%, but was as high as 23·9% in patients cortex, and basal ganglia during self-initiated move­
referred for ECT.18 In a population-based cohort study, ments,82–84 lower cerebral blood flow in right pre­frontal and
Kleinhaus and colleagues,68 found that 7·6% of patients parietal cortex,85 and reduced γ-aminobutyric-acid (GABA)-
with schizo­phrenia had the catatonic subtype. Abrams A-receptor density in the left sensorimotor cortex.86
and Taylor69–72 reported an even higher prevalence in Furthermore, functional MRI studies reported that orbito­
patients with affective conditions, with up to 20% of frontal cortex dysfunction, which is partly reversible by
patients with bipolar disorder ex­hibiting catatonic signs. lorazepam administration, would contribute to poor
Catatonia is a frequent manifest­ation of many general connectivity in medial prefrontal cortices in catatonia.87,88
medical conditions.5,66,73,74 Studies have suggested that Various case reports also point to reduced neural activity
perhaps as many as a third of patients with delirium in frontal and parietal cortices in catatonia.6,7 A study that
secondary to a general medical condition will develop used arterial spin labelling revealed that patients with
catatonia during their acute hospital­isation.38,39 Catatonia schizo­ phrenia in a catatonic episode have increased
incidence ranged from 1·6% to 8·9% on medical cerebral blood flow in the left M1 and SMA compared with
services assessed by a psychiatry liaison service, with patients with schizophrenia without history of cata­tonia.20
prevalence varying across age groups and associated This finding is supported by another investi­ gation
medical conditions.75,76 in patients with chronic periodic catatonia, indi­ cating

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A Healthy controls
increased perfusion of the SMA and left M1 in patients
with catatonia compared with noncatatonic patients and
controls.89 Furthermore, case reports showed increased
neural activity in SMA and M1 in acute cata­ tonia.90,91
Increased resting state neural activity in the SMA could
vmPFC CMA PreSMA SMA M1 IPL
also explain the reduced activation in functional MRI tasks
in catatonia.83,84 Transcranial magnetic stimulation (TMS)
indicated a hyperimitative state in a case of acute catatonia:
a patient was found to exhibit increased motor evoked
potentials in response to TMS while this patient was
Striatum observing motor acts.92 This effect was no longer seen after
catatonia remitted, suggesting disinhibition within the
Indirect Direct motor and premotor cortices during catatonia. Likewise,
an electro­ encephalogram study reported delayed late
GPe GPi Thalamus readiness potentials and movement potentials over
frontoparietal midline structures in catatonia.93 This
finding suggests ineffective coupling of premotor and
motor cortices. Lorazepam administration further delayed
Cerebellum
Hyperdirect STN readiness poten­tials, supporting compromised inhibitory
control within the motor network in catatonia.
We found aberrant hyperconnectivity between the
B Patients with hypokinetic catatonia thalamus and bilateral M1 and SMA in schizophrenia,19
similar to previous studies.94,95 This resting state
thalamocortical hyperconnectivity (to M1) was linked to
ratings on the BFCRS (ie, increased connectivity in
vmPFC CMA PreSMA SMA M1 IPL patients with more severe catatonia symptoms).19
Together, these findings implicate the motor system in
catatonia (figure 2), and suggest hyperactivity within the
SMA and preSMA. These tightly interconnected brain
structures are critically involved in motor control, move­
Striatum
ment selec­tion, initiation, timing, and inhibition.96–98 In
particular, the concentration of the inhibitory neuro­
Indirect Direct
transmitter GABA causes individual variation in re­
sponding to motor cues.99 In addition, the SMA is
GPe GPi Thalamus
thought to initiate the inhibitory processes in down­
stream brain areas such as the basal ganglia.99 SMA
hyperactivity could result from increased feedforward
stimulation of the subthalamic nucleus, from activation
Hyperdirect
Cerebellum of other cortical areas exerting inhibitory control, or
STN
from an attempt to overcome inhibitory pro­cesses, such
as basal ganglia output on the (pre)motor cortex
Pathway type
Net facilitatory (figure 2). Connecting white matter could also be
Net inhibitory involved, even though direct evidence in patients with
Neutral or modulatory
catatonia is scarce.100
Figure 2: Motor network pathology in catatonia
Motor systems in healthy controls (A), and in patients with hypokinetic catatonia (B). Cortical (pre)motor areas are Genetics
the ventromedial prefrontal cortex (vmPFC), cingulate motor area (CMA), presupplementary motor area (preSMA),
supplementary motor area (SMA), primary motor cortex (M1), and inferior parietal lobe (IPL). In catatonia,
First-degree relatives of patients with catatonia are more
the preSMA and SMA have increased neural activity concurrently with motor behavioural inhibition, which can likely to have affective disorders.101,102 A study of multiplex
either result from corticocortical inhibition, or from dominant indirect or hyperdirect pathway activity. families reported substantial heritability estimates for
Net facilitatory pathways include the direct pathway. Net inhibitory pathways include the indirect and hyperdirect catatonia symptoms, symptom endorsement frequency,
pathways. Increased thickness of pathway lines indicates increase in patients relative to healthy controls, reduced
thickness indicates decrease in patients relative to healthy controls. Arrowheads indicate stimulation of the target,
and syndrome severity.103 The most frequent signs, such
round ends indicate inhibition of the target. Inhibition of an inhibitory pathway might have net facilitatory effects. as psychomotor retardation and excitement, showed a
Yellow boxes indicate increased neural activity relative to controls. GPe=external globus pallidus. GPi=internal moderate degree of familiality, whereas classical signs,
globus pallidus. STN=subthalamic nucleus. such as mutism or rigidity, showed a high degree of
familiality.
Karl Leonhard104 reported that periodic catatonia runs in
families, while stable (systematic) catatonias or re­active

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motility psychoses show little familial aggre­ gation.105

Lifetime morbidity risk of cata­ tonia for first-degree Panel 1: Clinical recommendations
relatives of patients with periodic catatonia is 27%, with • Ensure correct diagnosis of catatonia including use of
an autosomal domin­ant link­age to chromosome 15q15, rating scales (tables 1 and 2) or other diagnostic criteria
and hetero­ geneous link­age to chromosome 22q13.106,107 • Prophylaxis of venous thromboembolism,
In patients with intel­lectual disability who present with prevent pressure ulcers, prevent muscle contractions,
catatonia, re­ search has detected rare copy number ensure proper hydration, and avoid malnutrition
variants.108,109 • Administer benzodiazepines (lorazepam) sublingually,
Mice heterozygous for oligodendroglial myelin basic intravenously, or intramuscularly in acute catatonia
protein (ie, Mbp+/–) or cyclic nucleotide phosphodiesterase • If no response to benzodiazepines or life-threatening
(ie, Cnp+/–), both crucial for oligodendroglial function and condition, pursue electroconvulsive therapy
myelination, developed spontaneous catalepsy, apathy,
and social withdrawal during ageing.110,111 Like­wise,
patients with schizophrenia with the same genotype have showing only partial symptom reduction.65,119 Predictive
a similar phenotype in terms of behaviour and corpus factors for re­sponse to benzodiazepines include chronicity,
callosum white matter after the age of 40 years.111 The symptom­atology, age, and cause (ie, affective, psychotic,
CNP genotype is more prevalent among schizophrenia or organic),123 with evidence for poorer response with in­
patients with catatonic symptoms compared with schizo­ creasing age or duration of illness, chronicity, and in
phrenia patients without catatonic symptoms.64 Finally, in patients with psychosis.65,121,123 If effective for ameliorating
the Cnp–/– (null) mutant mice, catatonia was alleviated by catatonia, the effects of repeated benzo­ diazepine ad­
pharmacological microglia inactivation.64 White matter ministration should be observed within a few days.122
alterations in frontal motor areas have been reported The treatment of patients who present with signs of
in patients with schizophrenia and major depression, catatonia and delirium poses challenges. For example,
who showed reduced spontaneous motor behaviour— antipsychotic drugs are currently standard treatment for
poten­tially a minor form of catatonia.112,113 delirium but can worsen catatonia, and benzodiazepines
are first-line treatment for catatonia but can worsen
Treatment delirium. One author of this Series paper (JEW) is
Current state studying the overlap of delirium and catatonia,38 but
Catatonia is a potentially life-threatening condition, often further research must be done before clear treatment
requiring inpatient medical or psychiatric treatment. recommendations can be made.
Medically, catatonia can lead to deep vein thrombosis When patients do not respond to benzodiazepines,
and pulmonary embolism, decubitus ulcers, muscle they should be referred for ECT.122 ECT can also be
contracture, and rhabdomyolysis leading to renal applied as first-line treatment in life-threatening
failure.114–116 General preventive recommendations for conditions (eg, severe autonomic instability or with­
patients with catatonia include pharmacological prophy­ drawal that leads to insufficient oral intake). One meta-
laxis of venous thromboembolism, skin assess­ments and analysis on the effect of ECT for the treatment of
frequent repositioning to prevent pressure ulcers, daily catatonia docu­mented symptom improvement with ECT
stretching to prevent muscle contractions, and tube (standardised mean difference –3·1, 95% CI –3·95 to
feeding and intravenous fluids when necessary to avoid –2·34). However, according to the authors the studies
dehydration and malnutrition.117 A summary of clinical (three RCTs, five observational studies, and one
recommendations is given in panel 1. retrospective chart review) did not show efficacy and
Few prospective investigations have examined the effectiveness of ECT because of low-quality data (missing
effective­ness of available treatments for catatonia (appen­ rigorous quality RCTs) and heterogeneity (different ECT
dix). Additionally, a systematic review did not iden­ tify protocols, differ­ent scales assessed treatment response).124
trial-derived data meeting inclusion criteria.118 Benzo­ The combined ad­ minis­tration of ECT and benzo­
diazepines62,119,120 and ECT121,122 are safe and effective diazepines has been associated with reduced efficacy of
standard treatments, particularly in acute cata­ tonia. ECT; however, some synergism has been discussed.125
Loraze­pam—the preferred benzodiazepine for catatonia— Bifrontal ECT results in clinical and cognitive outcomes
is ad­ ministered sublingually, intra­ venously, or intra­ superior to bitemporal ECT in patients with schizo­
muscularly, and is effective at both low (1–3 mg/day)62 or phrenia with catatonia.126 Import­ antly, the sug­ gested
high doses (6–16 mg/day).119,121 Al­though lorazepam had no reduced risk of cognitive side-effects with uni­ lateral
effect on chronic catatonia symptoms in one randomised stimulation was not con­firmed in a small case series.127
controlled trial (RCT),123 acute catatonia responds well to Prospective investigations of treatments for catatonia
benzo­diazepines in 66–100% (mean 88%; SD 15·7%) of are rare. Some evidence indicates that patients with
cases according to prospective investigations (appendix). psychotic disorders who present with catatonic signs
Still, response to benzo­diazepines is not satisfactory in a respond better to clozapine, and to antipsychotics with
considerable number of patients,122 with 27% of patients low affinity for dopamine receptors than antipsychotics

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Panel 2: Next steps in catatonia research Search strategy and selection criteria
• Use catatonia rating scales to establish symptom We searched PubMed for relevant publications using the terms:
presentation in multiple conditions, also report “catatonia”, “prevalence”, “neuroimaging”, “MRI”, “ECT”,
dimensional assessments “treatment”, “clinical trial”, “meta-analysis”, “transcranial
• Apply neuroimaging of the resting state in catatonia in magnetic stimulation”, “benzodiazepines”, “lorazepam”,
various conditions, with specific symptoms, in acute and “antipsychotic”, “symptom structure”. Additionally, we carefully
chronic cases, and longitudinally within individual cases checked books, reference lists of articles, and the ClinicalTrials.
• Explore the dynamics of vegetative instability in catatonia gov database for further studies, reports, or reviews on
• Organise double-blind randomised controlled trials of catatonia. Literature published in either English or German was
catatonia treatment regimens selected for relevance to the topics of this Review
• Test repetitive transcranial magnetic stimulation effects (ie, prevalence, presentation, neuroimaging, or treatment).
on various catatonia conditions Finally, we also searched specifically for some topics using
• Establish a catatonia animal model Google Scholar. We applied no date restrictions to our search;
the last search was done on June 27, 2018.

with high affinity for dopamine receptors.128,129,130 A

systematic review of alternative treatment strategies for Neuroimaging is likely to advance our understanding
catatonia concluded that intra­ venous lorazepam and of catatonia. Resting-state functional, perfusion, and
ECT should remain first-line treatments.130 The authors structural MRI scans are feasible methods to study
proposed a treatment algorithm with glutamate patients with catatonia who are unable to engage in
antagonists and antiepileptic drugs (carbamazepine and functional MRI tasks. We will need well powered
valproic acid) as second-line treatments if benzo­ studies, and longitudinal studies, as well as studies in
diazepines and a full course of ECT are not sufficient. patients with distinct catatonia symptom profiles.
Motor network properties are likely to differ between
New developments patients with volitional issues such as negativism and
Novel brain stimulation techniques hold promise in patients with pure motor inhibition. Furthermore,
targeting the motor network directly with local and distant these neuroimaging approaches should be applied to
effects within the network,131 ultimately allowing for all types of catatonia. Finally, vegetative signs remain
individualised treatment of catatonia. Repetitive TMS poorly understood in catatonia. We need characterisation
(rTMS) is being studied in two RCTs, informed by of vegetative dys­ regulation in cross-sectional and
neuroimaging evidence20,84 of increased neural activity in longitudinal studies.
premotor cortices (figure 2). One trial (NCT03275766) is a Negativism, avolition, and mutism have made it
four arm parallel trial, testing add-on rTMS in patients difficult to obtain informed consent from patients with
with schizophrenia spectrum disorders and major catatonia. Consenting of surrogate decision makers and
depressive disorder. One arm will test inhibitory rTMS prospective recruitment of patients during catatonia-
and another will test facilitatory rTMS of the SMA. The free periods are ethical solutions to this obstacle. Given
second trial (NCT03116425) aims to treat catatonia by the prevalence of catatonia, larger medical centres
rTMS on the basis of individual brain perfusion should be able to do interventional studies, ideally with
abnormalities. Both trials target motor inhibition in multicentre designs. In addition to testing established
catatonia. Without conclusive evidence regarding treatments (eg, benzodiazepines and ECT), use of non-
pathophysiology, the field is struggling to develop novel invasive brain stimulation techniques, such as rTMS,
treatment approaches. Currently, non-invasive brain should be explored, and the use of deep brain
stimulation is a promising new develop­ment that allows stimulation for severe and chronic cases should be
for careful hypothesis testing of disease mechanisms and considered. Animal models of catatonia will be required
treatment efficacy. for the development of invasive brain stimulation
techniques.
Future perspectives Finally, establishing individualised treatment regi­
Adoption of Kraepelin’s nosology, which links cata­ mens is a high priority. Treatment effects will depend
tonia to schizophrenia, impeded progress in cata­tonia on the underlying condition and the specific symptom
research for many years. With the greater recognition of clusters. Current studies with broad inclusion criteria
catatonia as not just a subtype of schizo­phrenia, we are might not work because of heterogeneous responses to
now ready to explore clinical presentation, symptom treatment.
structure, and course of catatonia in various conditions. We have summarised the next steps in catatonia
Dimensional assessments of psycho­motor be­haviour in research in panel 2. Clinicians can aid this process by
psychiatric and medical conditions could prove especially applying screening instruments, such as the BFCRS, to
useful. recognise catatonia patients.

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Conclusions 17 Fink M. Rediscovering catatonia: the biography of a treatable

Catatonia remains a poorly understood syndrome of syndrome. Acta Psychiatr Scand Suppl 2013; 127: 1–47.
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in several psychiatric and medical conditions. We con­ meta-regression analysis. Schizophr Bull 2017; 44: 1133–50.
ceptualise the syndrome as a disorder of cerebral motor 19 Walther S, Stegmayer K, Federspiel A, Bohlhalter S, Wiest R,
Viher PV. Aberrant hyperconnectivity in the motor system at rest is
network dysfunction. Future research should aim to linked to motor abnormalities in schizophrenia spectrum disorders.
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Contributors immune system: a review. Lancet Psychiatry 2019; published online
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SW and SH produced the figures. SH and KS produced the
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Declaration of interests Psychopathology 2005; 38: 3–8.
SW reports personal fees from Eli Lilly, Janssen-Cilag, Otsuka, Sunovion, 24 Schrijvers D, Hulstijn W, Sabbe BG. Psychomotor symptoms in
and Lundbeck, and grants from the Swiss National Science Foundation depression: a diagnostic, pathophysiological and therapeutic tool.
(152619, 155954, and 182649), outside the submitted work. JEW reports J Affect Disord 2008; 109: 1–20.
salary support from the Vanderbilt Clinical and Translational Research 25 Morrens M, Hulstijn W, Sabbe B. Psychomotor slowing in
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Health grants (GM120484 and HL111111). SH reports grant MH70560 26 Mittal VA, Bernard JA, Northoff G. What can different motor
from the National Institute of Mental Health, personal fees from circuits tell us about psychosis? An RDoC perspective.
JAMA Psychiatry, and lectures (Stony Brook University, Harvard Schizophr Bull 2017; 43: 949–55.
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