Schizophrenia Research xxx (xxxx) xxx

Contents lists available at ScienceDirect

Schizophrenia Research
journal homepage: www.elsevier.com/locate/schres

Treatment of schizophrenia with catatonic symptoms: A narrative review☆

Stanley N. Caroff a, *, Gabor S. Ungvari b, c, Gábor Gazdag d, e
a
Behavioral Health Service, Corporal Michael J. Crescenz VA Medical Center and the Department of Psychiatry, University of Pennsylvania Perelman School of Medicine,
Philadelphia, PA, USA
b
Division of Psychiatry, School of Medicine, University of Western Australia, Crawley, Australia
c
Section of Psychiatry, University of Notre Dame, Fremantle, Australia
d
Department of Psychiatry and Psychiatric Rehabilitation, Jahn Ferenc South Pest Hospital, Budapest, Hungary
e
Department of Psychiatry and Psychotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary

A R T I C L E I N F O A B S T R A C T

Keywords: Catatonia is a neuropsychiatric syndrome consisting of psychomotor abnormalities caused by a broad range of
Catatonia disorders affecting brain function. While the nosological status of catatonia is no longer restricted to a subtype of
Schizophrenia schizophrenia in standardized diagnostic systems, the character, course, and clinical significance of catatonia in
Neuroleptic malignant syndrome
people with schizophrenia remain unclear. Evidence suggests that catatonia could be a nonspecific state-related
Antipsychotic agents
phenomenon, a fundamental core symptom dimension of schizophrenia, or a subcortical variant of schizo­
Electroconvulsive therapy
Benzodiazepines phrenia. Either way, the validity of catatonia in schizophrenia is clinically significant only insofar as it predicts
Drug-induced movement disorders prognosis and response to treatment. Most contemporary clinical trials of antipsychotics have targeted schizo­
Psychosis phrenia as an overly broad unitary psychosis neglecting any differential response defined by phenomenology or
course. However, early naturalistic studies showed that catatonia predicted poor response to first-generation
antipsychotics in chronic schizophrenia and case reports cautioned against the risk of triggering neuroleptic
malignant syndrome. More recent studies suggest that second-generation antipsychotics, particularly clozapine,
may be effective in schizophrenia with catatonic symptoms, while small randomized controlled trials have found
that the short-term response to ECT may be faster and more significant. Based on available data, conclusions are
limited as to whether antipsychotics are as effective and safe in acute and chronic schizophrenia with catatonic
symptoms compared to other treatments and compared to schizophrenia without catatonia. Further studies of the
pathophysiology, phenomenology, course and predictive value of catatonia in schizophrenia are worthwhile.

1. Introduction disorders as currently codified in the Diagnostic and Statistical Manual of

1.1. The catatonia syndrome
Catatonia is a neuropsychiatric syndrome caused by a broad range of
disorders (Gelenberg, 1976; Taylor and Fink, 2003). Characterized by
psychomotor signs that have been described for centuries, catatonia
came to be recognized as a key dimension of psychoses and a potential
organizing principle of nosology in the 19th century (Berrios and Mar­
kova, 2018; Hirjak et al., 2022). Thereafter, catatonia was neglected and
misunderstood as being only a subtype of schizophrenia until landmark
studies re-established its cross-diagnostic nature as a clinical syndrome
that could occur in the context of psychiatric, medical or neurological
Mental Disorders, Fifth Edition (DSM5) and the International Classification
of Diseases (ICD-10) (Gelenberg, 1976; Abrams and Taylor, 1976; Taylor
and Abrams, 1977; World Health Organization, 1992; Fink et al., 2010;
Francis et al., 2010; Tandon et al., 2013; American Psychiatric Associ­
ation, 2022). Whether catatonia also occurs in an idiopathic form as
Kahlbaum conjectured, without underlying diagnoses, remains an
intriguing question (Leonhard, 1957; Krishna et al., 2011; Caroff et al.,
2015).
1.2. Implications of catatonic symptoms in schizophrenia
While catatonic symptoms are not unique to schizophrenia and are

Declarations of Interest: Dr. Caroff served as consultant for Neurocrine Biosciences and Adamas Pharmaceuticals. Dr. Caroff also received separate research grants
☆

from Neurocrine Biosciences and Eagle Pharmaceuticals. Drs. Ungvari and Gazdag have no declarations of interest to report.
* Corresponding author at: Corporal Michael J. Crescenz VA Medical Center, University & Woodland Aves., Philadelphia, PA 19104, USA.
E-mail address: caroffs@pennmedicine.upenn.edu (S.N. Caroff).

https://doi.org/10.1016/j.schres.2022.11.015
Received 5 September 2022; Received in revised form 7 November 2022; Accepted 9 November 2022
0920-9964/© 2022 Elsevier B.V. All rights reserved.

Please cite this article as: Stanley N. Caroff, Schizophrenia Research, https://doi.org/10.1016/j.schres.2022.11.015
S.N. Caroff et al.
neither necessary nor sufficient to diagnose it, abnormalities of psy­
chomotor function are common in schizophrenia (Richard et al., 2005).
Although factor analytic studies have identified distinct but overlapping
symptom clusters within the catatonic syndrome (Krüger et al., 2003;
Ungvari et al., 2009; Wilson et al., 2015; Dawkins et al., 2022; Foucher
et al., 2022), catatonia in chronic schizophrenia as defined by Kraepelin
typically includes persistent, automatic, repetitive and qualitatively
bizarre parakinetic movements or symptoms (e.g., mannerisms, stereo­
typies, grimacing, perseveration, etc., roughly corresponding to items
6–10 and 16–21 on the Bush-Francis Catatonia Rating Scale (Bush et al.,
1996)) in addition to hypokinetic withdrawal symptoms (e.g., immo­
bility, stupor, mutism) and agitated excitement that often arise during
acute psychotic episodes (Bush et al., 1996; Ungvari et al., 2010; Peralta
and Cuesta, 2017; Ungvari et al., 2018). In surveys of people presenting
with catatonia, 4–67 % have been diagnosed with schizophrenia (Caroff
et al., 2004). Conversely, catatonic signs have been reported in 2–50 %
of people diagnosed with schizophrenia (Caroff et al., 2004; Ungvari
et al., 2005; Morrens et al., 2014). The wide variability in frequencies
reflect the lack of consensus and standardization in the diagnosis of both
catatonia and schizophrenia across population samples, institutions,
diagnostic systems and historical time periods, a shortcoming that
confounds research to this day. Psychomotor abnormalities in schizo­
phrenia correlate with neurodevelopmental aberrations in the structure
and function of premotor and motor cortices, basal ganglia, thalamus,
and connecting white matter tracts (Stöber, 2004; Nasrallah, 2005;
Walther and Strik, 2012; Mittal et al., 2017; Hirjak et al., 2018, 2019;
Fricchione and Beach, 2019; Walther et al., 2020; Sambataro et al.,
2021).
Catatonic symptoms may represent a nonspecific state-related reac­
tion that presents variably throughout the course of illness in response to
the stress and fear of an acute psychotic episode (Guggenheim and
Babigian, 1974; Moskowitz, 2004; Fink and Shorter, 2017). However,
evidence suggests that abnormalities in motor functioning including
catatonia, neurological soft signs, involuntary movements, parkin­
sonism and psychomotor slowing, comprise a fundamental symptom
dimension of schizophrenia that precedes the onset of psychosis in
children and adolescents at risk, and can already be observed in drug-
naïve and first-episode patients (Nasrallah, 2005; Ungvari et al., 2005;
Pappa and Dazzan, 2009; Mittal et al., 2010; Walther and Strik, 2012;
Compton et al., 2015; Hirjak et al., 2018, 2019; Walther et al., 2020;
Peralta et al., 2022). The validity and significance of catatonia as a core
symptom in schizophrenia is further supported by evidence that cata­
tonic and other psychomotor symptoms in schizophrenia are associated
to varying degrees with earlier age of onset, positive, negative and
cognitive symptoms, attempted suicides, poor response to treatment,
lower rates of remission, greater risk of relapse, longer hospital stays,
lower quality of life and functioning, a progressive chronic course and
increased mortality (Achte, 1961; Guggenheim and Babigian, 1974;
Marsden et al., 1975; Owens et al., 1982; Rogers, 1985; Beckmann et al.,
1992; Peralta and Cuesta, 1999; Fenton, 2000; Peralta and Cuesta, 2001;
Manschreck et al., 2003; Ungvari et al., 2005; Caroff et al., 2011; Peralta
et al., 2022; Pieters et al., 2022).
Alternatively, these findings could be interpreted as support for
catatonia as a marker for an endophenotype or subcortical variant of
schizophrenia (Jablensky, 2006). For example, categories of schizo­
phrenia in the Wernicke-Kleist-Leonhard system are based in part on a
differentiated assessment of the psychopathology and course of cata­
tonia (Leonhard, 1957; Beckmann et al., 1992; Ungvari and Carroll,
2004). In his two-syndrome concept of schizophrenia, Crow proposed a
progressive and relatively irreversible dimension or “Type II syndrome”
characterized by enduring negative symptoms, poor response to anti­
psychotics, and postulated cell loss and structural changes in the brain
associated with cognitive deficits, abnormal neurological signs and
involuntary movements that are not drug-induced and consistent with
Kleist's concept of parakinetic catatonia devised in the 1920s. In other
studies, negative symptoms such as affective flattening and poverty of
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speech which characterize Crow's Type II syndrome, correlated with
catatonic symptoms in schizophrenia patients (Salokangas et al., 2002;
Ungvari et al., 2005). The Type II syndrome also correlates with the
deficit state and poor long-term outcome (Crow, 1985), similar to
models of deficit, negative symptom or systematic forms of schizo­
phrenia proposed by others (Andreasen and Olsen, 1982; Carpenter
et al., 1988).
2. Material and methods
The aim of this narrative review is to evaluate evidence on the use of
antipsychotics in the treatment of schizophrenia with prominent cata­
tonic symptoms. A broad literature survey was summarized to address
the key topic of antipsychotic treatment of schizophrenia with catatonic
symptoms based on and integrated with our own clinical experience and
research studies of this topic. We also discuss six randomized controlled
trials of antipsychotics in the treatment of schizophrenia with catatonic
symptoms which we selected from an earlier search described previously
for a systematic review (Huang et al., 2022). While all but one failed to
meet rigorous inclusion criteria because of limited data or flawed de­
signs and were therefore excluded from a published systematic analysis,
these unique trials are described in this narrative review to be inclusive
given the scarcity of data on this topic.
3. Results
3.1. Treatment of schizophrenia with catatonic symptoms
3.1.1. Standard treatment of catatonia
The clinical significance of catatonic symptoms in schizophrenia
depends on whether they predict or influence treatment response. The
standard treatment of the catatonia syndrome per se consists of a trial of
lorazepam or other benzodiazepines followed by electroconvulsive
therapy (ECT) if no response is obtained or the situation is urgent
(Fricchione et al., 1983; Fink, 2001; Gibson and Walcott, 2008). How­
ever, the efficacy of benzodiazepines for catatonia in the context of
schizophrenia may be less assured especially in patients with chronic
symptoms (Beckmann et al., 1992; Ungvari et al., 1994; Ungvari et al.,
1999; Rosebush and Maurek, 2004; Hatta et al., 2007; Rosebush and
Mazurek, 2010; Narayanaswamy et al., 2012). Other pharmacological
agents have been tried in clinical reports (e.g., memantine, zolpidem,
carbamazepine, amineptine) but evidence of efficacy in schizophrenia
patients with chronic catatonic symptoms is limited (Ungvari, 2010;
Beach et al., 2017).
Although evidence similarly suggests that the efficacy of ECT for
catatonia in schizophrenia may be diminished, remission of both acute
catatonic and psychotic symptoms is often obtained but chronic symp­
toms may not fully remit. While patients with catatonic schizophrenia
may respond less well to ECT compared to patients with catatonia due to
affective disorders (Morrison, 1973; Pataki et al., 1992; Rohland et al.,
1993; Escobar et al., 2000), they respond significantly better compared
to schizophrenia patients without catatonia (Wells, 1973; Zervas et al.,
2012; Pompili et al., 2013). Most retrospective and prospective obser­
vational studies in patients with acute catatonic schizophrenia generally
have shown significant improvement in nearly all patients receiving
ECT, despite resistance or intolerance to treatment with benzodiaze­
pines or antipsychotics (Fink, 1990; Suzuki et al., 2003; Hatta et al.,
2007; Gazdag et al., 2009; Phutane et al., 2011; Sinclair et al., 2019).
Phenomenology, duration, and chronicity of catatonic symptoms may be
critical factors, as one study found no significant difference between
active and sham ECT in patients with chronic catatonic schizophrenia
(Miller et al., 1953), although a recent study described effective use of
ECT in patients with chronic catatonic symptoms (Ungvari et al., 2018).
In summary, while benzodiazepines and ECT are effective in nearly
all cases of acute catatonia, and may be effective in malignant catatonia
as well (Mann et al., 1990; Rummans and Bassingthwaighte, 1991;
S.N. Caroff et al. Schizophrenia Research xxx (xxxx) xxx

Petrides et al., 2004), results in patients with chronic schizophrenia may
be less certain, suggesting that catatonic symptoms may be heteroge­
neous in both psychopathology, neurobiology and treatment response.
3.1.2. Antipsychotic treatment of schizophrenia with catatonic symptoms
3.1.2.1. Efficacy of antipsychotics. While antipsychotics are the main­
stay of acute and maintenance treatment of schizophrenia, not all pa­
tients respond to treatment and not all symptoms of schizophrenia
respond equally well. There have been numerous attempts to identify
clinical and biological markers or phenomenological variants that could
predict treatment response (Jablensky, 2006; Leucht et al., 2022). In
early naturalistic studies, people with acute or periodic catatonic
schizophrenia responded at least moderately well to first-generation
antipsychotics (FGAs), whereas people who had chronic, severe and
systematic forms of schizophrenia with catatonic symptoms showed a
poor response (Achte, 1961; Fish, 1964; Astrup and Fish, 1964; Gug­
genheim and Babigian, 1974; Ban, 1990; Beckmann et al., 1992; Ungvari
et al., 2010). Other reports found that FGAs may be effective, perhaps in
patients with more acute, early-onset and positive psychotic symptoms
(Hatta et al., 2007; Peralta et al., 2010).
More recent studies demonstrated efficacy of second-generation
antipsychotics (SGAs) in schizophrenia with catatonic symptoms.
Several studies reported that SGAs may be effective (Cesková and
Svestka, 1996; Harada et al., 1991; Martenyi et al., 2001; Caroff et al.,
2002; Yoshimura et al., 2013; Arora et al., 2017; Ungvari et al., 2018),
especially clozapine (Panteleeva et al., 1987; Naber et al., 1992; Dursun
et al., 2005; England et al., 2011; Chattopadhyay et al., 2012; Tabbane
et al., 2016; Hasoglu et al., 2022), even in patients unresponsive to
benzodiazepines or ECT. Naber et al. (1992) demonstrated a favorable
response to clozapine in catatonic schizophrenia comparable to other
schizophrenia subtypes. Peralta et al. (2010) reported that catatonic
symptoms in first-episode psychosis responded well to haloperidol, ris­
peridone, or olanzapine, depending on improvement of positive symp­
toms. Van Den Eede et al. (2005) concluded that SGAs may be indicated
in the treatment of schizophrenia even in the presence of catatonic
symptoms. The Maudsley prescribing guidelines recommend consid­
ering antipsychotics, especially clozapine or olanzapine, in people who
develop stupor without signs of neuroleptic malignant syndrome (NMS)
in the context of psychosis and medication non-adherence (Taylor et al.,
2018). There also has been growing interest in studying antipsychotics,
particularly clozapine, combined with ECT augmentation in the treat­
ment of people during the chronic and often treatment refractory phase
of schizophrenia (Braga and Petrides, 2005; Zervas et al., 2012; Pompili
et al., 2013; Wang et al., 2018; Sinclair et al., 2019), although the impact
of catatonic symptoms on the response to combination therapy in these
cases has received attention in few studies (Chanpattana and Chakrab­
hand, 2001; Gazdag et al., 2006; Gazdag et al., 2009).
Despite these findings, most randomized controlled trials of anti­
psychotics in recent decades assumed an undifferentiated view of
schizophrenia as an overly broad unitary psychosis without regard to
phenomenology, course or phenotypes, and particularly neglected acute
or chronic catatonic symptoms (Haro et al., 2005; Lieberman et al.,
2005; Jones et al., 2006). As a result, a wealth of critical granular evi­
dence on differentiating variants and treatment outcomes may have
been lost. By contrast, there are a few unique randomized controlled
trials that specifically target patients with schizophrenia and catatonic
symptoms (Table 1) (Huang et al., 2022).
For example, Denef et al. presented the results of a clinical trial of
propericiazine in psychotic patients with catatonia (Denef et al., 1971).
Propericiazine, or pericyazine, is a phenothiazine derivative, effective
for psychosis with side effects of sedation and extrapyramidal symptoms
(Matar et al., 2014). In an exploratory phase, doses up to 2 mg/kg daily
were given to four acute and six chronic psychotic patients with a
reduction of catatonic behavior in the chronic patients. Subsequently, 22
patients with chronic psychosis and catatonic behavior (apragmatism,
aggression, negativism and impulsivity) were randomized to receive
propericiazine or their previous medication in a cross-over study lasting
six weeks in each stage. Subjects receiving propericiazine showed
greater improvement in agitation, aggression and excitation. Although

Table 1
Selected randomized controlled trials of antipsychotics in schizophrenia spectrum disorders with prominent catatonic symptoms.
Reference N Diagnosis Design Comparators ΔPsychotic symptoms ΔCatatonic symptoms

Denef et al. 22 Chronic psychosis, RCTd ?blind Propericiazine vs. – Improved

(1971) catatonia 6 weeks previous medication
Girish and 14 Nonaffective psychosis,a 2 RCT double- Risperidone vs. ECT Positive symptoms ECT > risperidone (PANSSe; p = Risperidone: 6.04 ±4.58k,l
Gill catatonic signs; failed blind 3 0.04) ECT: 0.68 +/− 4.58
(2003) lorazepam weeks (BFCRSf; p = 0.035)
Liu and 81 Schizophrenia, catatonic RCT double- Risperidone vs. ECT Risperidone: 29.80 ± 1.27 ECT: 27.47 ± 2.90 –
Wang subtypeb blind 4 (BPRSg; P < 0.05)
(2008) weeks
Peralta et al. 24 Nonaffective Psychosis, 1st RCT ?blind Risperidone vs. Risperidone:-9.25 ± 3.99m olanzapine:-7.13 ± 3.00 Risperidone: − 3.63 ± 4.75
(2010) episode,c ≥1 catatonic sign 4 weeks olanzapine (SAPSh; p = 0.162) olanzapine: − 1.88 ± 2.90
(MRSi; p = 0.277)
Wang et al. 56 Schizophrenia,b stupor or RCT ?blind Sulpiride vs. ECT Sulpiride: 22.9 ± 3.1 ECT: 19.9 ± 2.6 (BPRS; p < –
(2012) other catatonic signs 2 weeks 0.01)
Wang 80 Schizophrenia,c plus RCT double- Amisulpride vs. Amisulpride:41.29 ± 6.22 aripirazole:41.74 ± 6.45 –
(2016) stupor; declined ECT blind 2 aripirazole (BPRS, SANSj; N.S.) % improved >50 % on BPRS (N.
weeks S.): amisulpride: 70.2 % aripiprazole: 65.8 %
a
ICD-10 = International Classification of Diseases, Tenth Revision.
b
CCMD-3 = Chinese Classification of Mental Disorders Version 3.
c
DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.
d
RCT = randomized controlled trial.
e
PANSS=Positive and Negative Syndrome Scale.
f
BFCRS=Bush-Francis Catatonia ratings Scale.
g
BPRS=Brief Psychiatric Rating Scale.
h
SAPS=Scale for the Assessment of Positive Symptoms.
i
MRS = Modified Rogers Scale.
j
SANS=Scale for the Assessment of Negative Symptoms.
k
Mean ± standard deviation.
l
Positive mean values indicate endpoint scale scores.
m
Negative values indicate change in scale scores from baseline to endpoint.

3
S.N. Caroff et al.
details of blinding and randomization are unclear, the authors
concluded that high doses of propericiazine significantly improved the
excited catatonic behavior of chronic psychotic patients with minimal
side effects easily controlled by antiparkinsonian agents.
Girish and Gill (2003) reported a double-blind, randomized, placebo-
controlled trial of risperidone (4-6 mg/day) versus ECT (thrice weekly)
in 14 hospitalized patients with “non-affective catatonia” (9 had
schizophrenia and 5 had psychosis NOS; International Classification of
Diseases; ICD-10) (World Health Organization, 1992), who failed a five
day trial of lorazepam (6–8 mg/day). Patients receiving risperidone
underwent sham ECT while active ECT patients received oral placebo
tablets over three weeks. BFCRS scores decreased in both groups but
were significantly lower in the ECT group at endpoint (mean ± SD; 6.04
+/− 4.58 versus 0.68 +/− 4.58; p = 0.035) (Bush et al., 1996). Simi­
larly, Positive and Negative Syndrome Scale scores (PANSS) (Kay et al.,
1987) improved in both groups, but positive symptom scores were
significantly lower in the ECT group (p = 0.04). There were no unex­
pected adverse effects other than common extrapyramidal effects of
risperidone and headache and memory effects of ECT. Although
randomization and blinding procedures were followed, the confidence
in these results is limited because of the small sample, short duration of
study, allocation imbalances, skewed and missing data, and crossover
treatments at the end of the study (Huang et al., 2022). The risperidone
recipients had longer durations of illness and catatonic signs potentially
biasing results. In addition, patients with shorter duration of catatonia
achieved lower BFCRS scores, and patients who responded to the initial
lorazepam trial had relatively short duration of catatonia compared to
non-responders recruited for the randomized study confirming chro­
nicity as a negative predictive factor. Finally, the blind could have been
compromised because ECT was continued beyond the 3-week study
period in four participants due to incomplete responses and three par­
ticipants in the risperidone group were crossed-over to ECT after the
study period endpoint.
Liu and Wang (2008) reported results of a four-week double-blind,
randomized, controlled trial of risperidone (average dose of 4.3 ± 1.7
mg/d) versus ECT (thrice weekly) in 81 hospitalized patients with
schizophrenia, catatonic subtype according to the Chinese Standard for
Classification and Diagnosis of Mental Disorders (CCMD-3) (Chen, 2002).
While both interventions produced statistically significant responses by
four weeks, ECT brought about faster improvement by week one, and
showed significantly better response than risperidone at the four week
endpoint on both the Brief Psychiatric Rating Scale (BPRS; 27.47 ± 2.90
versus 29.80 ± 1.27; p < 0.05) and the Nurses' Observation Scale for
Inpatient Evaluation (NOSIE; 287.27 ± 3.35 versus 269.40 ± 3.25; p <
0.05) (Overall and Gorham, 1962; Honigfeld and Klett, 1965). Expected
side effects from risperidone and ECT were noted without any serious
adverse events. Biases included the fact that it was unclear whether
raters were blinded, patients were not blinded, placebos for risperidone
and ECT were not administered, randomization was based on order of
admission, and statistical analyses were based only on t-tests between
groups at the four-week endpoint.
To assess the treatment response of catatonia in 173 patients with a
drug-naïve first-episode Diagnostic and Statistical Manual of Mental Dis­
orders (DSM-IV) diagnosis of schizophrenia or other psychotic disorders
(American Psychiatric Association, 1994), Peralta et al. (2010) con­
ducted a one-month study of haloperidol, risperidone or olanzapine.
Although patients with catatonic symptoms responded well overall
regardless of the type of antipsychotic used depending on the remission
of psychotic symptoms, only a subgroup of 24 patients with schizo­
phrenia spectrum disorders who had at least one catatonic symptom at
baseline had been randomized to receive olanzapine or risperidone as
documented in a previous report (personal communication from V.
Peralta) (Cuesta et al., 2009). While two-thirds of these randomized
patients had no symptoms of catatonia after one month of treatment,
there was no significant difference in complete remission rates between
risperidone and olanzapine groups (62.5 % versus 68.8 %; p = 1.00).
4
Schizophrenia Research xxx (xxxx) xxx
Similarly, on the Modified Roger's scale (MRS) (Lund et al., 1991), all
subjects improved at one-month (p < 0.002) with no significant differ­
ence between groups (olanzapine = − 1.88 ± 2.90 versus risperidone;
− 3.63 ± 4.75; p = 0.277). Assessment of symptoms on the Scale for the
Assessment of Positive Symptoms (SAPS) (Andreasen, 1984) also
showed improvement for the sample as a whole (p < 0.001) without
differences between treatment groups (− 7.13 ± 3.00 versus − 9.25 ±
3.99; p = 0.162). Among seven patients whose symptoms met two or
more DSM-IV criteria for a positive diagnosis of catatonia (two patients
on olanzapine, five on risperidone), six no longer met criteria after one
month of treatment.
Wang et al. (2012) reported a two week randomized, controlled trial
of intravenous sulpride (starting at 100 mg/day) versus ECT (every
other day) in 56 patients with schizophrenia by CCMD-3 criteria who
also presented with stupor or other catatonic symptoms (psychomotor
retardation, bedridden, mute, does not move or eat, flat facial expres­
sion, urinary and fecal retention, lack of response to external stimuli,
increased muscle tone, waxy flexibility, or aggression). Both in­
terventions produced statistically significant response by two weeks, but
ECT brought about faster improvement (at Day 1) and showed signifi­
cantly better response than sulpride on the BPRS at endpoint (19.9 ± 2.6
vs. 22.9 ± 3.1; p < 0.01). Adverse events were reported as mild for both
groups. Biases were unclear as to whether raters were blinded, patients
were not blinded, placebos for sulpiride and ECT were not administered,
randomization was based on order of admission, and statistical analyses
were based only on t-tests between groups at the two-week endpoint.
Finally, Wang (2016) reported results of a two-week, double-blind,
randomized controlled study comparing amisulpride (100-300 mg/d) to
aripiprazole (15-30 mg/d) in 80 patients hospitalized with DSM-IV
defined schizophrenia and a stuporous state who declined to have
ECT. Both groups showed significant improvement at endpoint
compared to baseline with no group differences on the BPRS (ami­
sulpride:41.29 ± 6.22 versus aripirazole:41.74 ± 6.45) or Scale for the
Assessment of Negative Symptoms (SANS) (Andreasen, 1983). There
was also no significant difference in efficacy between the two groups
based on “significant improvement or cure” (≥50 % improvement in
BPRS score: amisulpride = 70.2 % versus aripiprazole = 65.8 %; p >
0.05). Side effects were mild (insomnia, sleepiness, dry mouth, and
constipation) and significantly less frequent with amisulpride (p < 0.05).
3.1.2.2. Safety of antipsychotics. Soon after phenothiazines were intro­
duced as antipsychotics, Baruk and others reported that they could
induce “experimental catatonia” in animal models (Baruk et al., 1955).
Not surprisingly, clinical reports followed of antipsychotic-induced
catatonia as an adverse drug reaction, characterized by withdrawal,
stupor, catalepsy and mutism along with parkinsonian or other extra­
pyramidal symptoms (Berry et al., 1958; May, 1959; Gelenberg and
Mandel, 1977). Continuation or rapid titration of antipsychotics in some
patients caused progression to NMS as a rare but serious side effect
(Delay et al., 1960; Meltzer, 1973; Weinberger and Kelly, 1977; Caroff,
1980).
Fricchione and others proposed that catatonia induced as a side ef­
fect of antipsychotics is a model for idiopathic catatonia (just as NMS
mimics malignant catatonia) that shares symptomatology and a com­
mon pathophysiology involving inhibition of dopamine in mesostriatal,
mesolimbic, and hypothalamic systems (Brenner and Rheuban, 1978;
Sanberg, 1980; Fricchione et al., 1983; Fricchione, 1985; Lopez-Canino
and Francis, 2004; Kirschbaum et al., 2009; Hirjak et al., 2021). Mann
and others described how specific catatonic symptoms associated with
decreased dopamine activity could be mapped to parallel basal ganglia
thalamocortical circuits; rigidity (the motor circuit); stupor, mutism,
and akinesia (anterior cingulate-medial orbitofrontal circuit); and
automatic, imitative, or perseverative behaviors (lateral orbitofrontal
circuit) (Taylor, 1990; Fricchione et al., 1997; Mann et al., 2000; Mann
et al., 2004).
S.N. Caroff et al.
Evidence suggests that catatonia may be a reflection of the inverse
reciprocal relationship between cortical and striatal dopamine activity,
and genetically determined dysregulation in synaptic dopamine ho­
meostasis. Increases in dopaminergic innervation of prefrontal cortex
triggered by extreme or chronic stress or fear may precipitate abnormal
feedback inhibition of striatal dopamine causing catatonia in individuals
genetically susceptible to either an exaggerated stress response in the
cortex and/or hypersensitive downregulation of striatal dopamine ac­
tivity (Friedhoff et al., 1995; Kanes, 2004; Mann et al., 2004). Evidence
supporting a defensive and reactive function of striatal hypo­
dopaminergia parallels the fear and anxiety reported by people during
catatonic episodes and the role of stress-induced tonic immobility/
behavioral arrest in animal models (Harthoorn, 1976; Gallup and Maser,
1977; Kanes, 2004; Moskowitz, 2004).
In schizophrenia, decreased cortical dopamine is inversely related to
increased striatal dopamine resulting in a vicious cycle whereby func­
tionally altered prefrontal cortex feeds forward to striatal regions that
are compromised in turn by genetic variants of the dopamine-2 pre­
synaptic auto-receptor resulting in amplification of dopamine release
and consequent positive symptoms (Weinberger, 1987; Frankle et al.,
2022; Weinberger, 2022). Regardless of whether the principal abnor­
mality initiating schizophrenia resides in the prefrontal cortex or stria­
tum, the subsequent loss of dopaminergic fine tuning in the striatum
may become primary eliciting an endogenous antipsychotic feedback
response in suppressing dopamine activity both in the striatum and
secondarily extending to downregulate frontal innervation as well as
parallel circuits (Friedhoff, 1988; Friedhoff et al., 1995). In susceptible
patients, psychosis induced by overactivity of dopamine in the striatum
may itself act as extreme stress prompting feedback inhibition of
dopamine in multiple pathways resulting in negative, cognitive, or
deficit symptoms and predisposing to catatonia. If endogenous restitu­
tive downregulation of striatal dopamine becomes hard wired over time
(a “floor effect”), that may also explain the poor therapeutic response to
antipsychotics, chronic catatonic symptoms, and the risk of
antipsychotic-induced catatonia and NMS in some patients with chronic
schizophrenia (Friedhoff, 1988; Weinberger, 2022).
In line with variants of the hypothesis of decreased dopamine un­
derlying catatonia in schizophrenia outlined above, several authors
cautioned against the use of antipsychotics in catatonia regardless of the
underlying diagnosis, based on credible reports of antipsychotics
causing or worsening catatonia (Gelenberg and Mandel, 1977; Brenner
and Rheuban, 1978; Fricchione, 1985; Hirjak et al., 2021), or precipi­
tating malignant transformation to NMS (Caroff, 1980; Mann et al.,
1986; White and Robins, 1991; Osman and Khurasani, 1994; Fricchione
et al., 2000; White and Robins, 2000; Berardi et al., 2002). Evidence is
limited on whether SGAs with reduced impairment of motor function
may be less likely to cause or worsen catatonia as a side effect than first-
generation antipsychotics. Although few cases of simple catatonic
symptoms attributed to SGAs have been reported (Stubner et al., 2004),
clozapine, risperidone, olanzapine, and quetiapine have been implicated
in triggering NMS (Caroff et al., 2002; Ananth et al., 2004). Although
cases of NMS have not been reported in most randomized controlled
trials of antipsychotics (Huang et al., 2022), these studies are often too
small to conclude that antipsychotics would be safe from risk of NMS in
larger samples of patients with catatonic schizophrenia or that the
relative risk of NMS is more or less likely than in schizophrenia without
catatonic symptoms. By comparison, estimates of the incidence of NMS
in people receiving antipsychotics range between 0.02 % and 0.11 %, or
roughly 1 in 1000 to 5000 treated patients (Caroff and Mann, 1993;
Caroff et al., 2021).
Despite the fact that antipsychotics remain the primary treatment of
schizophrenia and newer agents have reduced neurological side effects,
many authors argue against antipsychotics in the presence of catatonic
symptoms, even for schizophrenia, due to the potential risk of worsening
neurological and medical status (White and Robins, 1991; Hawkins
et al., 1995; Blumer, 1997; Fink and Taylor, 2003), especially in
5
Schizophrenia Research xxx (xxxx) xxx
malignant catatonia (Mann et al., 1986; Philbrick and Rummans, 1994;
Mann, 2003).
4. Discussion
There is growing evidence that abnormalities of psychomotor func­
tion are significant in understanding the pathophysiology, psychopa­
thology, course and outcome of schizophrenia. It remains unclear
whether catatonia and other psychomotor signs represent a state-related
phenomenon, a core dimension of schizophrenia in general, or a
subcortical variant of the disorder. Historical and contemporary evi­
dence suggest that persistent and chronic catatonic symptoms may
predict a worse prognosis. Catatonia also may have implications for the
response to treatment in schizophrenia and conversely, schizophrenia
may affect the treatment response of catatonia.
The predictive value of catatonia as a marker for antipsychotic
treatment response in schizophrenia has been relatively neglected. Early
studies reported that catatonia predicted a poor response to treatment in
chronic schizophrenia while anecdotal reports indicated that patients
with catatonia are at increased risk for NMS. Recent studies with SGAs
suggest that schizophrenia patients with catatonia could be safely and
effectively treated, but the quality of evidence remains low. While a few
small, short-term, randomized controlled trials of SGAs that specifically
targeted patients with schizophrenia and catatonic symptoms have
shown improvement in both catatonic and psychotic symptoms, ECT
was more effective when used as a comparator. No serious adverse
events occurred during these studies, but the samples were too small to
detect uncommon side effects such as NMS.
As a result, it may be premature to conclude that antipsychotics are
as effective and safe as other treatments for patients with schizophrenia
and catatonic symptoms or are as effective as they are for schizophrenia
patients without catatonia. Clinical management strategies and future
studies should be informed by phenomenology, course and duration of
symptoms (Table 2).
For example, first-episode and drug-naïve patients with schizo­
phrenia who present with acute stuporous catatonia should receive an
initial lorazepam trial, with ECT administered in patients who do not
respond to lorazepam or are in critical condition. Antipsychotics should
be withheld until stupor resolves to avoid confounding or worsening
catatonia. Once catatonia resolves while residual psychotic symptoms
emerge or persist, which is often the case, antipsychotic medication,
preferably a second-generation agent, should be started under the
continued protection or buffering of a benzodiazepine (Fricchione and
Beach, 2019). In patients with an acute episode of schizophrenia with
catatonic symptoms who fail to respond to both lorazepam and ECT,
SGAs or clozapine may be tried although there is a lack of controlled
evidence on the efficacy and safety of this approach compared to other
third-line treatments (Beach et al., 2017; Hasoglu et al., 2022; Saini
et al., 2022). Evidence is supportive but limited as to whether these
treatment steps are equally effective not only for an acute schizophrenic
episode presenting predominantly with negative or withdrawal symp­
toms of catatonia, but also for excited or other catatonic symptom
clusters (Denef et al., 1971; Morrison, 1973; Fink, 1999; Krüger et al.,
2003; Ungvari et al., 2009; Lee et al., 2012; Fricchione and Beach, 2019;
Oldham, 2022).
In schizophrenia patients who first develop catatonia only after
receiving an antipsychotic, the primary intervention must be to dis­
continue, reduce or switch the medication (Brenner and Rheuban, 1978;
Hirjak et al., 2021) with administration of lorazepam (Fricchione et al.,
1983). ECT is considered if catatonic symptoms persist. Once the cata­
tonic syndrome resolves while psychotic symptoms re-emerge, another
SGA could be reinstated with a benzodiazepine, or clozapine or, in rare
cases maintenance ECT. Immediate drug withdrawal is even more crit­
ical as the primary intervention in patients who show incipient signs of
NMS with >80 % of patients showing remission within two weeks after
cessation of oral antipsychotics (Caroff and Mann, 1988; Velamoor et al.,
S.N. Caroff et al. Schizophrenia Research xxx (xxxx) xxx

Table 2
Proposed research algorithmn for future treatment trials targeting schizophrenia with prominent catatonic symptoms.
Schizophrenia Predominant Baseline treatment First-line treatment Second-line Third-line treatment Antipsychotic treatment
stage catatonic status treatment
symptomsa

Acute psychotic Stuporous First-psychotic Lorazepam (2 mg IM or ECT (≥6 treatments) Amantadine, For emerging or
episode catatoniab episode, drug-naive IV q8 hours x 3–4 days; memantine, topiramate, residualpsychotic symptoms
up to 8-16 mg daily; carbamazapine, valproic once catatonia resolves; SGAs
transition to oral acid, SGAs/clozapinec ± benzodiazepine buffer
dosing)
Following recent Cessation of anti- Lorazepam ECT→ third-line For emerging or residual
initiation of any psychotic d treatments psychotic symptoms once
antipsychotic catatonia resolves; SGAs ±
benzodiazepine; clozapine
Excited Variable Lorazepam, SGAs ECT Carbamazapine, SGAs ± benzodiazepine for
catatoniae valproic acid, lithium agitation and after catatonia
resolves
Malignant Variable Lorazepam ECT within 5 days For emerging/residual
catatonia psychotic symptoms once
catatonia resolves; SGAs ±
benzodiazepine; clozapine;
(maintenance ECT)
Neuroleptic Following recent Cessation of anti- Lorazepam, ECT For emerging/residual
malignant initiation of any psychotic d amantadine, psychotic symptoms once
syndrome antipsychotic bromocriptine, catatonia resolves; SGAs ±
dantrolene benzodiazepine; clozapine;
(maintenance ECT)
Chronic Stuporous Recurrent catatonic Lorazepam ECT Amantadine,memantine, For emerging or residual
psychosis catatonia episode, drug-free, topiramate, psychotic symptoms once
non-adherent carbamazapine, valproic catatonia resolves; SGAs ±
acid, SGAs/clozapine benzodiazepine clozapine
Recurrent or persistent Cessation, reduction or Lorazepam ECT→ third-line SGAs ± benzodiazepine;
catatonic symptoms on switching antipsychotic treatments clozapine; (maintenance ECT)
maintenance
antipsychotics
Following cessation of Restore clozapine or Lorazepam (if ECT→ third-line Continue clozapine
clozapine or lorazepam catatonia persists treatments
benzodiazepines despite clozapine
treatmentc)
Automatic, Persistent catatonic Maintain or switching Lorazepam ECT→ third-line SGAs; clozapine;
repetitive, symptoms on antipsychotic, treatments (maintenance ECT)
parakinetic maintenance clozapine
symptoms f antipsychotics
a
Stuporous, excited and parakinetic catatonic symptom clusters are not mutually exclusive, often overlap and can occur during both acute and chronic stages of
schizophrenia. They are approached separately here for clarity based on the predominant symptom cluster and during stages when they may predominate.
b
Stupor, immobility, mutism, catalepsy, staring and withdrawal.
c
Use caution in concurrent prescribing of clozapine and benzodiazepines due to reports of serious adverse interactions.
d
Lorazepam can be given concurrently with cessation of antipsychotic.
e
Excitement, impulsivity, negativism and combativeness.
f
Automatic obedience, mitgehen, waxy flexibility, perseveration, stereotypy, verbigeration, mannerisms and grimacing; ECT = electroconvulsive therapy; SGAs =
second generation antipsychotics.

1994; Strawn et al., 2007). Antipsychotics should be reintroduced
cautiously in patients with a history of previous NMS episodes to prevent
recurrences (Caroff and Mann, 1993; Strawn et al., 2007), and are
contraindicated in patients who show acute systemic signs of malignant
catatonia (Mann et al., 1986; Philbrick and Rummans, 1994; Beach
et al., 2017).
Evidence is also needed on the best course of action in patients with
chronic schizophrenia who develop an acute episode or exacerbation of
catatonia while receiving maintenance antipsychotic treatment. Anti­
psychotics could be maintained, modified in dose, switched, or dis­
continued if deemed ineffective until catatonia resolves (which may be
complicated by long-acting injectable formulations) or responds to lor­
azepam or ECT. Patients with chronic schizophrenia who have been non-
adherent with maintenance antipsychotic treatment and present with
recurrent psychotic and catatonic symptoms could be treated as acute
with lorazepam or ECT before reinitiating antipsychotic treatment.
However, clozapine or benzodiazepines should be promptly restored in
patients who develop catatonia following withdrawal from these med­
ications (Beach et al., 2017; Lander et al., 2018; Fricchione and Beach,
2019; Belteczki et al., 2021; Saini et al., 2022).
Patients with chronic schizophrenia associated with longstanding
catatonic symptoms could be maintained on antipsychotics although
evidence suggests limited efficacy in this subgroup for antipsychotics as
well as for lorazepam and ECT. A trial of reducing, ceasing or switching
antipsychotics, especially high-potency or FGAs in older patients, can
have a dramatic effect in “awakening” patients who have drug-induced
hypokinetic syndromes with catatonic and parkinsonian features that
often are misdiagnosed as negative or deficit symptoms of schizophrenia
(Gelenberg and Mandel, 1977; Lopez-Canino and Francis, 2004; Hirjak
et al., 2021). There is a compelling need for additional randomized
controlled trials of benzodiazepines in combination with antipsychotics
for patients with chronic schizophrenia and catatonic symptoms, as the
only published trial showed no effect of lorazepam compared to placebo
in this condition (Ungvari et al., 1999). Finally, a trial of clozapine or
clozapine combined with ECT may be an ideal treatment choice in pa­
tients with chronic and refractory symptoms. Clozapine has broad effi­
cacy in treatment refractory chronic schizophrenia, is relatively sparing
of psychomotor side effects, and has shown at least partial remission in
over 80 % of patients with catatonia associated with schizophrenia in a
systematic review of clinical reports (Saini et al., 2022). Limitations of

6
S.N. Caroff et al.
clozapine include non-motor side effects, delays in response over several
weeks, potential adverse interactions with benzodiazepines, and the risk
of exacerbating catatonia after abrupt withdrawal.
4.1. Challenges and limitations
Challenges and limitations of previous clinical trials of antipsy­
chotics that could be addressed in future studies include the need to
randomize by phenomenology, course and potential variants of both
schizophrenia and catatonia (Huang et al., 2022). Treatment durations
of at least six weeks and ensuring an adequate sample to achieve 80 %
statistical power for primary outcomes are necessary. It is essential to
ensure blinding of participants, personnel, and outcome raters. This is
especially crucial if ECT is used as a comparator when sham treatments
and oral placebos must be considered. Use of standardized and consis­
tent criteria for diagnosing schizophrenia is essential and controlling for
and monitoring treatment response of positive and negative symptoms
and cognition. Use of standardized rating scales and consensus criteria
are necessary to diagnose catatonia and to track the significance and
treatment response of specific catatonic symptom clusters (Ungvari
et al., 1999; Yitayih et al., 2020). Additional studies are necessary to test
and compare the clinometric validity, sensitivity, specificity and reli­
ability of available catatonia rating scales and to further assess mea­
surement of specific symptom clusters in relation to contrasting
manifestations of catatonia, e.g., excited catatonia, chronic catatonia,
and drug-induced catatonia (Lopez-Canino and Francis, 2004; Mor­
timer, 2004; Ungvari et al., 2009). For example, the implications of
having an acute transient stuporous episode may be quite different than
an episode of excited catatonia or chronic mannerisms and stereotypies.
Education and training in the use of catatonia rating scales is also
essential (Wortzel et al., 2021). The previous course and pattern of
symptoms are also important and have been largely neglected in anti­
psychotic trials. For example, the response to treatment in patients with
a history of extended recoveries punctuated by periodic psychotic or
catatonic episodes may be quite different than patients with a chronic
and persistent course of symptoms. There are virtually no controlled
trials of the long-term maintenance treatment of schizophrenia with
catatonic symptoms using lorazepam, ECT or antipsychotics, which may
be especially relevant in studies of long-acting injectable antipsychotics.
Differences between antipsychotics may also be worth exploring, e.g.,
comparing clozapine to other second-generation antipsychotics, while
emerging drugs in the pipeline may offer novel mechanisms for treating
psychotic and catatonic symptoms (Kannarkat et al., 2022).
5. Conclusions
Antipsychotics are highly effective drugs for schizophrenia but evi­
dence on the role of antipsychotics in treating schizophrenia with
catatonic symptoms is incomplete. Data from naturalistic studies and
randomized controlled trials that specifically targeted schizophrenia
patients with catatonic symptoms have shown that SGAs may improve
acute catatonic and psychotic symptoms. However, the risk of uncom­
mon adverse effects including antipsychotic-induced catatonic states or
more seriously, precipitating NMS, remain a concern requiring careful
monitoring. ECT may be an effective alternative to antipsychotics in the
short-term treatment of acute schizophrenia with catatonic symptoms.
Additional research on the effectiveness of antipsychotics for different
types and durations of catatonic symptoms, on different phases of
schizophrenia with catatonic symptoms, on comparisons to alternative
treatments and the response of schizophrenia patients without cata­
tonia, could be useful in guiding clinical practice. More generally, basic,
psychopathological and treatment studies of schizophrenia should
control for the phenomenology, pattern and course of catatonic and
other psychomotor symptoms.
7
Schizophrenia Research xxx (xxxx) xxx
CRediT authorship contribution statement
Stanley N. Caroff; SNC contributed to the conception and design of
the study, acquisition, analysis and interpretation of reference data,
drafting and revisions of the manuscript
Gabor S. Ungvari; GSU contributed to the conception and design of
the study, acquisition, analysis and interpretation of reference data,
drafting and revisions of the manuscript
Gabor Gazdag; GG contributed to the conception and design of the
study, acquisition, analysis and interpretation of reference data, drafting
and revisions of the manuscript
The submitted version was approved by all authors.
Role of the funding source
There is no funding source for this manuscript.
Declaration of competing interest
Stanley N. Caroff reports a relationship with Neurocrine Biosciences
Inc. that includes: consulting or advisory. Stanley N. Caroff reports a
relationship with Adamas Pharmaceuticals Inc. that includes: consulting
or advisory. Stanley N. Caroff reports a relationship with Neurocrine
Biosciences Inc. that includes: funding grants. Stanley N. Caroff reports a
relationship with Eagle Pharmaceuticals Inc. that includes: funding
grants.
Acknowledgements
None.
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