Schizophrenia Research 263 (2024) 214–222

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Schizophrenia Research
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Seasonality of presentation and birth in catatonia

Tomas Mastellari a, b, *, Jonathan P. Rogers b, c, Mario Cortina-Borja d, Anthony S. David e,
Michael S. Zandi f, g, Ali Amad h, a, Glyn Lewis b
a
University of Lille, Inserm U1172, CHU de Lille, Lille Neuroscience & Cognition (LilNCog), Lille, France
b
Division of Psychiatry, University College London, London, UK
c
South London and Maudsley NHS Foundation Trust, London, UK
d
Population, Policy and Practice Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
e
Institute of Mental Health, University College London, London, UK
f
Queen Square Institute of Neurology, University College London, London, UK
g
National Hospital for Neurology and Neurosurgery, London, UK
h
Department of Neuroimaging, King's College London, London, UK

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

Keywords: Background: Catatonia is a neuropsychiatric syndrome associated with both psychiatric disorders and medical
Catatonia conditions. Understanding of the pathophysiology of catatonia remains limited, and the role of the environment
Seasonality is unclear. Although seasonal variations have been shown for many of the disorders underlying catatonia, the
Seasonality of presentation
seasonality of this syndrome has not yet been adequately explored.
Season of birth
Cosinor model
Methods: Clinical records were screened to identify a cohort of patients suffering from catatonia and a control
group of psychiatric inpatients, from 2007 to 2016 in South London. In a cohort study, the seasonality of pre­
sentation was explored fitting regression models with harmonic terms, while the effect of season of birth on
subsequent development of catatonia was analyzed using regression models for count data. In a case-control
study, the association between month of birth and catatonia was studied fitting logistic regression models.
Results: In total, 955 patients suffering from catatonia and 23,409 controls were included. The number of
catatonic episodes increased during winter, with a peak in February. Similarly, an increasing number of cases
was observed during summer, with a second peak in August. However, no evidence for an association between
month of birth and catatonia was found.
Conclusions: The presentation of catatonia showed seasonal variation in accordance with patterns described for
many of the disorders underlying catatonia, such as mood disorders and infections. We found no evidence for an
association between season of birth and risk of developing catatonia. This may imply that recent triggers may
underpin catatonia, rather than distal events.

1. Introduction depression, bipolar depression and mania), schizophrenia, postpartum

psychosis, and autism (Solmi et al., 2018). In 20 % of cases, a catatonic
Catatonia is a severe neuropsychiatric syndrome that includes motor, syndrome has been observed in patients suffering from non-psychiatric
behavioral and neurovegetative symptoms and signs. Described by conditions (Oldham, 2018; Solmi et al., 2018), such as metabolic al­
Kraepelin as a subtype of schizophrenia (Fink et al., 2010), it is today terations, infections, inflammatory conditions, structural abnormalities
considered as a specifier of mental disorders, or associated with non- or trauma to the central nervous system (CNS), and intoxication with
psychiatric conditions (American Psychiatric Association, 2013). Cata­ various drugs or substances of abuse (Oldham, 2018). However,
tonia has been reported in 10 % of patients admitted to psychiatric inflammation of the CNS seems to be one of the main causes of catatonia
wards (Fink et al., 2010), and in 80 % of cases is thought to be caused by in patients without a history of psychiatric disorders, either of an
a primary psychiatric disorder (Oldham, 2018). The main psychiatric infective or auto-immune etiology (Rogers et al., 2019). As for autoim­
illnesses associated with catatonia are mood disorders (unipolar mune causes, a large spectrum of autoimmune disorders has been

* Corresponding author at: University of Lille, Inserm U1172, CHU de Lille, Lille Neuroscience & Cognition (LilNCog), 59800 Lille, France.
E-mail address: [email protected] (T. Mastellari).

https://doi.org/10.1016/j.schres.2023.03.015
Received 27 November 2022; Received in revised form 6 March 2023; Accepted 7 March 2023
Available online 16 March 2023
0920-9964/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
T. Mastellari et al. Schizophrenia Research 263 (2024) 214–222

described, including anti-N-methyl-D-aspartate receptor (NMDAR) en­ Tramer, 1929). Subsequently, several studies have been conducted and
cephalitis (Rogers et al., 2019). Similarly, catatonia has been recently have replicated these results in different countries and across different
defined as a “red flag” for the suspicion of autoimmune encephalitis in years (Boyd et al., 1986; Castrogiovanni et al., 1998; Wang and Zhang,
patients presenting with (almost) isolated psychotic symptoms (Pollak 2017). The effect of season of birth on mental illness has also been
et al., 2020). Therefore, catatonia can be considered as a transdiagnostic evaluated for other psychiatric disorders, such as eating disorders, bi­
syndrome across various neuropsychiatric etiologies, and seems to polar disorders and suicidal behaviors (Boyd et al., 1986; Döme et al.,
represent an intersection between psychiatry, neurology, immunology 2010; Liang et al., 2018; Salib and Cortina-Borja, 2006). Neuro­
and infectious diseases medicine. biologically, the association between season of birth and the subsequent
Regarding the epidemiology of catatonia, findings are still contro­ development of psychiatric conditions should be interpreted in the light
versial. According to some authors (Mahendra, 1981; Tanskanen et al., of the neurodevelopmental hypothesis of mental illness, as seasons may
2021), a decline in the prevalence of catatonia over several decades has reflect differential exposure to environmental factors during the pre­
been evident, this being attributed to various hypotheses, including natal and perinatal stages of CNS development. Some of the exposures
earlier and better treatment of underlying disorders, better hospital that are thought to be involved include infections, low levels of vitamin
conditions, and less exposure to “catatoniogenic infections”, such as D, temperature, weather conditions, maternal diet and exposure to
poliomyelitis. However, according to a recent meta-analysis (Solmi toxins (Puthota et al., 2021; Salib and Cortina-Borja, 2006; Watson et al.,
et al., 2018), catatonia is not a rare syndrome, and its prevalence has 1984).
been estimated around 9.2 % among inpatient populations, this being As described above, previous literature provided numerous findings
stable across several years (1935–2017). Finally, a recent large study by on the relationship between seasons and psychiatric disorders. However,
Rogers et al., 2021 (Rogers et al., 2021) found an incidence of 10.6 to our knowledge there are no major studies evaluating the effect of
catatonic episodes per 100,000 person-years, with cases increasing be­ seasons on catatonia. A previous study on 31 children in India evaluated
tween 2007 and 2016, possibly as a result of improved diagnosis and use the seasonal pattern of the presentation of catatonia, describing fewer
of novel psychoactive drugs. Overall, catatonia is still underdiagnosed cases from November to January and in April (Gupta et al., 2017).
by clinicians and often confused with other conditions (Walther et al., Another study on 59 patients with catatonia suffering from schizo­
2019). phrenia in Croatia explored the effect of season of birth, but did not find
The relationship between catatonia and potential environmental any significant seasonal patterns (Mimica et al., 1996). However, as
external triggers e.g., infectious diseases or antipsychotic-induced previous studies on the relationship between season of birth and
catatonia, is gaining research interest (Hirjak et al., 2021; Rogers schizophrenia found associations with a modest effect size, studies
et al., 2019), but still little is known about the environmental factors including a large population are likely to be necessary to identify a
playing a role in its pathophysiology and clinical course. Interestingly, significant association between season of birth and catatonia
regardless of the underlying disorder, catatonia usually responds well to (McCutcheon et al., 2020).
specific treatments, including benzodiazepines (lorazepam in particular) Therefore, the objective of this study is to explore for the first time
and electro-convulsive therapy (ECT). In 80 % of cases, lorazepam is an the seasonality of catatonia in a large sample. In particular, we hy­
effective treatment (Solmi et al., 2018). When catatonia persists in spite pothesize that 1) seasonal variations might exist for the presentation of
of high doses of benzodiazepines, electro-convulsive therapy (ECT) catatonia during the year and 2) season of birth might represent a risk
should be considered (Pelzer et al., 2018). Catatonia treatment does not factor for subsequent development of catatonia. We hypothesised that
depend on the underlying disorder, which clearly suggests some com­ seasonality in the presentation of catatonia might exist, considering its
mon pathophysiological mechanisms for the syndrome. association not only with psychiatric disorders that have shown seasonal
Environmental factors have a major role in psychiatry, as they are patterns, but also with infections. Similarly, we speculated that season of
potentially modifiable events, thus a target for prevention. One of the birth may predict the risk of catatonia, as the neurodevelopmental
first environmental features to be studied in medicine and thus psychi­ approach has already shown interesting results for psychiatric disorders
atry is the effect of seasons on diseases. Physicians identified that the that can cause catatonia. Finally, a seasonal pattern in the presentation
incidence of some disorders was not equally distributed over the year of catatonia and/or an effect of season of birth would provide important
(Fisman, 2007). For example, seasonal variations have been studied for insights into the mechanisms and risk factors of this still poorly under­
infectious, cardiovascular and rheumatologic diseases (Fisman, 2007; stood psychomotor syndrome.
Iikuni et al., 2007; Stewart et al., 2017). Two main categories of studies
published in the literature exist on the relationship between seasons and 2. Methods
psychiatric disorders.
The first includes studies focusing on the presentation of psychiatric 2.1. Setting, participants and study design
symptoms. Here, we can cite the striking examples of studies on seasonal
affective disorder, where depressive phases are more likely to occur in Data from the Clinical Records Interactive Search (CRIS) system,
winter (Partonen and Lönnqvist, 1998), and bipolar disorder, where from the South London and Maudsley NHS Foundation Trust, UK, were
manic symptoms are more likely to be experienced during summer and used for this retrospective cohort and case-control study. CRIS allows
depressive phases during winter (Geoffroy et al., 2014). More generally, researchers to access anonymized health-care records (Fernandes et al.,
the number of psychiatric admissions in hospitals has also been studied 2013; Stewart et al., 2009), registered or imported since 1999, for pa­
across seasons, showing consistent results in different countries. In tients being referred to specialist mental health services in four South
particular, rates of admissions for psychiatric reasons seem to be London boroughs (Lambeth, Southwark, Lewisham and Croydon) and in
significantly higher during summer, when temperatures are higher national and specialist services also run by the Trust. The South London
(Chan et al., 2018; Geoffroy and Amad, 2016; Hinterbuchinger et al., and Maudsley NHS Foundation Trust provides mental health services for
2020; Nori-Sarma et al., 2022; Yoo et al., 2021). a total local population of 1.3 million people, offering inpatient as well
The second category of studies around seasonality concerns the as­ as community care (Fernandes et al., 2013; Rogers et al., 2021). CRIS
sociation between season of birth and the subsequent development of currently contains data on electronic records for over 500,000 subjects
psychiatric disorders. One of the most replicated associations is the (Rogers et al., 2021).
increased risk of developing schizophrenia among people born in (late) A cohort of patients suffering from catatonia was identified retro­
winter and (early) spring (Castrogiovanni et al., 1998; McCutcheon spectively through CRIS as described previously (Dawkins et al., 2022;
et al., 2020; Puthota et al., 2021; Radua et al., 2018). The earliest Jeyaventhan et al., 2022; Rogers et al., 2021; Yeoh et al., 2022). In brief,
description of this effect seems to date back to 1929 (Hare et al., 1974; a natural language processing service was used to identify catatonic

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episodes. Then, records obtained with the natural language algorithm using a likelihood-ratio test for equidispersion, testing the null hy­
were analyzed manually, to ensure that identified episodes satisfied the pothesis that mean equals variance (p > 0.05). Frequencies were stan­
inclusion criteria. The following inclusion criteria were established for dardized to 31-day months. For any episodes that occurred on 29th
this study: 1) a diagnosis of catatonia made by a clinician; 2) evidence of February, these were amended to 28th February, to standardize the
at least two features of catatonia according to the Bush-Francis Cata­ length of February. When patients had more than one episode, only the
tonia Screening Instrument (BFCSI) (Bush et al., 1996a, 1996b); 3) first catatonic episode was included. The total population between 2007
available date for the diagnosis of the catatonic episode; and 4) a time and 2016, for the four London boroughs included in CRIS was used to
interval not longer than 30 days between date of onset of catatonia and calculate the rate of catatonic episodes by month. The logged total
the date of inclusion in the health-care records. population was also included in the model as an offset term. Days of the
While the initial data extractions were performed between 2018 and months were transformed into angles from 0 to 2π, then trigonometric
2021 (Rogers et al., 2021), two complementary data extractions were terms were created using sine and cosine functions. Seasonal patterns
performed on 06/06/2022 and 09/06/2022, not modifying the number were modelled using yearly, semesterly and quarterly harmonics, to
of patients included, but adding additional variables for seasonality obtain sufficiently complex variations. A stepwise-type model selection
analyses, such as number of total admissions by month, for all psychi­ procedure was used to build the final model, minimizing Akaike's in­
atric disorders in the South London and Maudsley NHS Foundation formation criterion (AIC). Both AIC and, for nested models, likelihood-
Trust, from 2007 to 2016, and country of origin for patients included in ratio tests were used to choose the final model. Post-estimation ana­
the study. lyses were performed for the models' diagnostics where appropriate,
A control group obtained from CRIS was used in this study including including analysis of residuals and exploration of influence. After the
all patients admitted as psychiatric inpatients to the hospitals of the main model was fitted, sensitivity analyses were performed, including in
South London and Maudsley NHS Foundation Trust between 01/01/ the model the total number of admissions by month in psychiatric
2007 and 31/12/2016. The control group included a large variety of hospitals from the South London and Maudsley NHS Foundation Trust
psychiatric disorders, with patients' ages ranging from childhood to old from 2007 and 2016, and the average monthly temperature in London. A
age. To compare patients with catatonia and patients from the control likelihood-ratio test was then performed to compare this larger model,
group, and to minimize the percentage of missing data, the years' range with a nested model not including the trigonometric terms.
from 2007 to 2016 was applied to all subjects included in this study
(Rogers et al., 2021). The aim of the inclusion of this control group was 2.2.2. Season of birth — cohort and case-control study
to compare season of birth between patients with catatonia and patients To explore the role of month of birth on the risk of developing
suffering from a wide range of psychiatric disorders, without any cata­ catatonia, a Poisson or negative binomial regression was fitted, ac­
tonic symptoms. cording to whether data exhibited overdispersion. The dispersion of
Psychiatric diagnoses were classified according to the International count data was assessed using a likelihood-ratio test for equidispersion.
Classification of Diseases, Tenth Revision (ICD-10) (World Health Or­ The model was adjusted for year of birth, and an offset term was used to
ganization, 2004). The total population living in the four boroughs of account for the different length of months. Post-estimation analyses
London included in CRIS, by month, from 2007 to 2016 was obtained were performed for the models' diagnostics where appropriate. After
from the Office for National Statistics (ONS). Data on mean tempera­ fitting this main model, the analyses were repeated in a subgroup of
tures by month in London, from 2007 to 2016, were obtained from patients born in countries above and not crossing the Tropic of the
London City Airport weather station. Cancer.
The presentation of catatonia across seasons was explored using a Regarding the case-control study, a logistic regression was fitted to
cohort study design. The effect of month of birth on the subsequent assess the effect of month of birth on subsequent development of cata­
development of catatonia was explored using both a cohort and a case- tonia. The model was adjusted for year of birth, gender, and ethnicity.
control study design. After fitting the main regression, the analyses were repeated in the
All procedures used in this project comply with the ethical standards subgroup of patients born in countries above and not crossing the Tropic
of National and Institutional Committees on Human Experimentation of the Cancer.
and follow the Declaration of Helsinki — Ethical principles for medical Statistical analyses were conducted on Stata MP 15.1. Statistical
research involving humans. The use of CRIS system has been approved significance was set to p < 0.05. STROBE guidelines (von Elm et al.,
by the Oxfordshire C Research Ethics Committee (ref: 18/SC/0372) and 2014) were applied to write this manuscript, and the checklist is showed
this project was approved by the CRIS Oversight Committee (ref: 17- in Supplementary Material (Table A1). Some of the graphical repre­
102) (Rogers et al., 2021). sentations were finalized on Microsoft Excel LTSC MSO Version 2204.

2.2. Statistical analysis 3. Results

First, descriptive analyses were conducted, summarizing socio- A sample of 955 patients with catatonia was obtained for this study,
demographic factors and clinical characteristics such as age, gender, from 1st January 2007 to 31st December 2016. Overall, 58.74 % of
ethnicity, country of origin and psychiatric diagnoses. Patients with patients were diagnosed as having catatonia in hospital, 35.18 % were
catatonia were compared to the control group by fitting logistic initially diagnosed in an outpatient setting and 6.07 % were missing this
regression models, without adjustments. The odds ratio for age was information. A sample of 23,409 inpatients suffering from psychiatric
calculated using age in decades. Missing data were handled using pair­ disorders, without any diagnosis of catatonia, was included as a control
wise deletion and conducting available-case analyses. group. Table 1 describes and compares the demographic and clinical
characteristics of patients with and without catatonia. Patients with
2.2.1. Catatonia presentation — cohort study catatonia were significantly younger (OR 0.89, p < 0.001, 95 % CI
Seasonal variation for the presentation of catatonia was analyzed 0.86–0.93) and more likely to belong to an ethnic minority group (OR
using a Cosinor model, which expresses seasonal patterns as harmonic from 2.58 [95 % CI 1.95–3.40] to 3.60 [95 % CI 3.11–4.17]). Patients
functions (Cox, 2006; Stolwijk et al., 1999). Regression models for count with catatonia were more likely to be born in Africa, Asia and North
data (Poisson or negative binomial regression according to whether data America, compared to psychiatric patients not suffering from catatonia
exhibited overdispersion) were fitted to assess the potential effect of (OR from 2.16 [95 % CI 1.59–2.95] to 3.03 [2.46–3.73]). In terms of the
months on the frequency of catatonic episodes. Adjustment for year of underlying disorder, patients with catatonia were less likely to suffer
presentation was included. The dispersion of count data was assessed from mood disorders (ICD-10 codes F30–F39) (OR 0.43, p < 0.001, 95 %

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Table 1 CI 0.36–0.51), non-psychiatric mental disorders (ICD-10 codes F00–F09

Socio-demographic and clinical characteristics of patients with and without & non-F codes) (OR 0.38, p < 0.001, 95 % CI 0.28–0.52), neurotic dis­
catatonia. orders (F40–F49) (OR 0.23, p < 0.001, 95 % CI 0.17–0.31), personality
Patients Patients Odds ratio p-Value and behavioral disorders (F50–F69 & F91–F94, F98) (OR 0.17, p <
with without (95 % CI) 0.001, 95 % CI 0.11–0.26) and substance use disorders (F10–F19) (OR
catatonia catatonia unadjusted 0.07, p < 0.001, 95 % CI 0.05–0.11).
n = 955 n = 23,409 analysis

Age, mean (SD) 36.6 39.8 (17.1) 0.89 <0.001 3.1. Catatonia presentation — cohort study
(16.5) (0.86–0.93)*
Median (range, IQR) 33 (7–90, 38 (5–100,
23–47) 27–49) Fig. 1 shows the incidence of catatonic episodes per million person-
Not stated n=0 n=3 years, in South London, from 2007 to 2016. The monthly rate of first
Sex, n (%) catatonic episodes is showed as a line with several peaks across years,
Female 445 (46.6) 10,709 1 (reference) – while the straight line running in the middle of the graph represents the
(45.8)
Male 510 (53.4) 12,697 0.97 0.61
fitted values for the monthly rate, and shows an increase of the incidence
(54.2) (0.85–1.10) from 2007 to 2016.
Not stated 0 (0.0) 3 (0.0) Regarding the Cosinor model, we obtained a final Poisson model,
Ethnicity, n (%) including a yearly harmonic component (sin1, incidence rate ratio
White 315 (33) 14,488 1 (reference) –
[IRR] = 1.097, p = 0.042, 95 % CI 1.003–1.199) and a semesterly
(61.9)
Black/African/ 451 (47.2) 5762 3.60 <0.001 harmonic component (sin2, IRR = 1.15, p = 0.002, 95 % CI
Caribbean/Black (24.6) (3.11–4.17) 1.050–1.254). The model was adjusted for year of presentation, showing
British a significant increase of 3.9 % in the annual risk of catatonia, from 2007
Asian/Asian British 74 (7.7) 1206 (5.2) 2.82 <0.001 to 2016 (IRR = 1.039, p = 0.001, 95 % CI 1.016–1.062). The likelihood-
(2.18–3.66)
Mixed/Multiple ethnic 35 (3.7) 567 (2.4) 2.84 <0.001
ratio test for equidispersion found Poisson to be the best model to fit
groups (1.98–4.07) (Chi-squared value = 0.56, p = 0.227, d.f. = 1). Similarly, residuals were
Other ethnic groups 63 (6.6) 1125 (4.8) 2.58 <0.001 found to be normally distributed with a constant variance (Fig. A1, in
(1.95–3.40) Supplementary Material), confirming the appropriateness of the sys­
Not stated 17 (1.8) 261 (1.1) – –
tematic part of the Poisson model. To look for potentially influential
Continent of origin, n
(%) observations, Cook's distances were calculated. No influential observa­
Europe 334 (35) 11,825 1 (reference) – tions were found (all distances <0.5). However, when the most influ­
(50.5) ential observations were excluded, the model did not show any
– United Kingdom – 268 – 10,103 significant changes.
(80.2) (85.4)
Africa 133 (13.9) 1553 (6.6) 3.03 <0.001
Fig. 2 shows the final Cosinor model, with its predictions, compared
(2.46–3.73) to the observed frequencies of catatonic episodes, by month and by year,
Asia 48 (5.1) 785 (3.4) 2.16 <0.001 standardized to 31-day months. Observed frequencies are represented
(1.59–2.95) using a stacked area chart. The model predicted a first peak of episodes
North America 43 (4.5) 607 (2.6) 2.51 <0.001
around February, and a secondary peak of cases around August. A
(1.81–3.48)
South America 9 (0.9) 189 (0.8) 1.69 0.131 trough of catatonic episodes appeared around November. According to
(0.86–3.32) the predictions made by this model, the month of February showed a 50
Oceania 2 (0.2) 59 (0.2) 1.20 0.8 % increased risk of catatonic cases, compared to November, while the
(0.29–4.93) month of August showed a 32 % increased risk of catatonic cases,
Not stated 386 (40.4) 8391
compared November. The month of February showed a 14 % increased
– –
(35.9)
BFCSI score, mean (SD) 3.6 (1.7) Not – – risk of catatonic cases, compared to August.
Median (range, IQR) 3 (2–14, applicable Sensitivity analyses were conducted adding to the main model the
2–5) global number of admissions by month, in the psychiatric hospitals from
Diagnostic subgroup, n
the South London and Maudsley NHS Foundation Trust, from 2007 to
(%)
Schizophrenia and 481 (50.4) 5464 1 (reference) – 2016, and the average monthly temperature in London, for the same ten-
related disorders (23.3) year period. The likelihood-ratio test compared this larger model, with a
(F20–F29) nested model not including the trigonometric terms. The model
Mood disorders 188 (19.7) 5017 0.43 <0.001 including the trigonometric terms provided statistical evidence for an
(F30–F39) (21.4) (0.36–0.51)
improvement in the fit (Chi-squared value = 11.12, p = 0.004, d.f. = 2).
Non-psychiatric 42 (4.4) 1255 (5.4) 0.38 <0.001
mental disorder (0.28–0.52)
(F00–F09 & non-F 3.2. Season of birth — cohort study
codes)
Neurodevelopmental 34 (3.6) 496 (2.1) 0.78 0.173
The same cohort of patients with catatonia (n = 955) was used to
disorders (F70–F90 & (0.54–1.12)
F95) explore the effect of season of birth on subsequent development of
Neurotic disorders 45 (4.7) 2242 (9.6) 0.23 <0.001 catatonia. Fig. 3 shows the frequency of births aggregated by month and
(F40–F49) (0.17–0.31) year (1921–2007), for patients developing catatonia later in life. All
Personality and 22 (2.3) 1494 (6.4) 0.17 <0.001 frequencies were standardized to 31-day months.
behavioral disorders (0.11–0.26)
(F50–F69 & F91–F94,
To explore the effect of season of birth on subsequent development of
F98) catatonia, a negative binomial regression model was fitted. The model
Substance use 27 (2.8) 4254 0.07 <0.001 was standardized for year of birth and an offset term was used to account
disorders (F10–F19) (18.2) (0.05–0.11) for the different length of every month. No evidence was found for an
Not stated (missing or 116 (12.1) 3.187 – –
effect of month of birth on subsequent development of catatonia (IRR
F99) (13.6)
0.98, p = 0.147, 95 % CI 0.961–1.006). The likelihood-ratio test for
*
Odds ratio calculated using age in decades. Text in bold indicates statistical equidispersion found the negative binomial regression to be the best
significance. model to be fitted (Chi-squared value = 73.14, p < 0.001, d.f. = 1).

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Fig. 1. Monthly rate of first catatonic episodes per million people, from 2007 to 2016.

Fig. 2. Graphical representation of the predictions obtained with the Cosinor model, compared to the observed frequencies of catatonic episodes, by month and year,
standardized to 31-day months. Observed frequencies are represented using a stacked area chart.

Residuals were found to be distributed following a clear pattern (Fig. A2, Tropic of the Cancer, to obtain a more homogeneous sample in terms of
in Supplementary material), as the outcome count contained a small characteristics of the seasons. This subgroup sample of patients with
number of unique variables. However, the negative binomial regression catatonia consisted of 359 patients (37.6 % of the initial sample).
model had smaller residuals compared to the Poisson model, indicating Similarly to the main analyses, a negative binomial regression was fitted
a better fit. To look for potentially influential observations, Cook's dis­ and showed no evidence for an effect of month of birth on later devel­
tances were calculated. No influential observations were found (all opment of catatonia (IRR 0.97, p = 0.10, 95 % CI 0.94–1.01).
distances were lying under 0.5). However, when the most influential
observations were excluded, the model did not show any significant
3.3. Season of birth — case-control study
changes.
After fitting this main model, the analyses were repeated in a sub­
For the case-control section of this study, a logistic regression model
group of patients being born in countries above and not crossing the
was fitted to evaluate the association between month of birth and later

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stressor with a cytotoxic effect, derived by DNA damage, apoptosis,

protein oxidation and lipid peroxidation (Belhadj Slimen et al., 2014).
Moreover, psychiatric disorders have been associated with the activity
of Transient Receptor Potentials (TRP) channels, which can be activated
by different stimuli, including temperature (Nazıroğlu and Demirdaş,
2015). Cold can also trigger cellular stress responses, modifying the gene
expression of some specific HSP, and activating cold-induced apoptosis
(Sonna et al., 2002). However, the effect of cold temperatures on mental
health is less studied, and findings are still controversial, including both
protective and harmful outcomes (He et al., 2022; Li et al., 2022; Mullins
and White, 2019). Interestingly, autonomic and thermoregulatory al­
terations can occur in severe forms of catatonia, suggesting that these
patients may be particularly susceptible to extreme temperatures, that
usually happen in winter and summer. Another reason that could link
altered thermoregulation and catatonia may be related to patients
treated with antipsychotics to target the underlying condition. Anti­
psychotic drugs can alter thermoregulatory processes and metabolism,
and represent a risk factor for the neuroleptic malignant syndrome,
which can be considered as a cause of malignant catatonia. In our study,
mean monthly temperature was included in the analyses, which sug­
gested it was not explaining our findings. However, mean temperature
did not capture the impact of extremely high and low temperatures.
Infections are another environmental factor that could explain the
seasonal pattern of catatonia. In fact, various pathogens have been
described as a cause of catatonia (Rogers et al., 2019). A recent study
Fig. 3. Polar plot showing the frequency of births aggregated by month and analyzing seasonal patterns of infections in England and Wales, found a
year (1921–2007) seasonality for most of the pathogens included, with higher rates in
winter and end of summer (Cherrie et al., 2018).
development of catatonia, adjusting for gender, ethnicity, and year of Furthermore, catatonia has been associated with autoimmune dis­
birth. No evidence for an effect of month of birth was found in devel­ orders and immune dysregulation (Rogers et al., 2019). Interestingly,
oping catatonia (OR 0.99, p = 0.463, 95 % CI 0.974–1.011). When human immunity showed seasonal patterns in terms of gene regulation
focusing the analyses on patients with catatonia (n = 359) and controls and inflammatory response. Recent studies have suggested that the
(n = 12,243, 52.3 % of the initial control group) born in countries above immune activity may be more pro-inflammatory during winter in
and not crossing the Tropic of the Cancer, a similar logistic regression Europe, with levels of C-Reactive Protein, Interleukin-6, and different
found no evidence for an effect of month of birth on later development of peripheral blood mononuclear cells, such as neutrophils and lympho­
catatonia (OR 0.99, p = 0.396, 95 % CI 0.957–1.018). cytes, being significantly higher during the winter months (Dopico et al.,
2015; Wyse et al., 2021). Finally, one of the most common autoimmune
4. Discussion etiologies of catatonia is anti-NMDAR encephalitis. A few studies have
evaluated a potential seasonal pattern in this condition and have shown
To our knowledge, this study was the first one to explore the sea­ evidence for peaks in the warm season (Adang et al., 2014; Lai et al.,
sonality of catatonia in a large sample of patients. Both season of onset of 2021).
the catatonic syndrome and the effect of season of birth for patients with A previous study conducted in India on 31 children has also
catatonia were studied. described a seasonal pattern in the presentation of catatonia, with fewer
Regarding the seasonality of presentation in catatonia, a first peak of cases in November–January and in April (Gupta et al., 2017). However,
cases was described around February. Based on frequencies of catatonia a direct comparison with our findings might be difficult, considering the
by month from 2007 to 2016, our model predicted increasing cases from different climatic seasons as well as the different cultural and socio-
early winter to late winter. Then, a smaller peak was observed around demographic characteristics of the populations included.
August, with cases increasing throughout the summer. Regarding the effect of month of birth on subsequent development of
The interpretation of seasonal disease patterns is complex and catatonia, we did not find any evidence for an association. Month of
multifactorial. Approximately 20 % of our catatonic sample had a birth did not predict the development of catatonia, both in the whole
diagnosis of mood disorders, thus the increased number of catatonic population included and in patients being born exclusively in countries
episodes at the end of winter and during summer could be related to above and not crossing the Tropic of the Cancer. Similarly, patients with
exacerbations of depression or mania — with catatonia as a common catatonia and controls did not show significant differences in terms of
end-point. Similarly, the summer peak of catatonia could be related to month of births. The effect of season of birth on the development of
more psychiatric consultations, as described in the literature during illnesses later in life is to be interpreted using a neurodevelopmental
periods of high temperatures (Nori-Sarma et al., 2022). However, our perspective, where prenatal, perinatal and early postnatal factors might
analyses included the total number of admissions for psychiatric reasons play a role in generating disease vulnerability. If an effect of month of
in South London, and suggested this was not explaining our findings. birth has been shown for schizophrenia, such an effect could not be
Low and high temperatures can affect brain functioning through replicated for movement disorders that share with catatonia some
various mechanisms. High temperature can act as an exogenous stressor, common pathophysiological pathways, such as Parkinson's disease
altering the permeability of the blood-brain barrier and modify neuronal (Gardener et al., 2010; Palladino et al., 2015; Postuma et al., 2007).
activity (Wang et al., 2014). Through the activation of heat shock pro­ Similarly to our findings, a previous study conducted in Croatia on
teins (HSP), hyperthermia also has a pronounced pro-inflammatory ef­ 59 patients suffering from catatonic schizophrenia did not provide any
fect, which might play a role in psychiatric disorders (Miller and Fort, evidence for an effect of season of birth (Mimica et al., 1996). However,
2018; Sonna et al., 2002). Heat can then be considered as an external it is important to note that catatonia is not a frequent condition and that
even our sample was probably not powerful enough to identify an effect

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of month of birth on the development of the condition. Further studies might also focus on diagnostic subgroups for the un­
derlying disorders, and on patients that show repeated episodes of
4.1. Strengths, limitations, perspectives catatonia. Stratifying for gender and age could also apport interesting
insights. A study from Owens and McGorry (2003), found for example
To our knowledge, this study was the first to explore, in a large and that first-episode schizophrenia was showing a peak in winter, in male
ecological sample, the seasonality of catatonia, focusing on both season patients only. Unfortunately, subgroup analyses and stratification were
of presentation and effect of month of birth. In terms of sampling vari­ not possible in our study, as we were limited by statistical power and
ation and chance, the large number of patients included in this study was sample size. To repeat the study of seasonality in these subgroups of
likely to reduce the sampling error. Furthermore, we did not perform patients, a multicentered design might be necessary to increase the
repeated tests, reducing the risk that our results were due to chance. In number of patients included, but would then require a higher
terms of selection bias, patients with catatonia were included using a complexity of adjustment. In terms of external validity, it is important to
standardized, rigorous and validated screening tool. The use of this tool note that seasonal factors highly differ between countries, and that the
depends on the physicians' clinical practice, potentially leading to un­ prevalence of schizophrenia and related disorders was particularly high
derestimation of catatonic episodes in our study, but this is unlikely to in our sample, which could be related to the high prevalence of cannabis
differ across seasons. The inclusion of a large control group of inpatients consumption that has been described in South London.
allowed us to compare month of birth between patients with catatonia
and patients suffering from psychiatric disorders without catatonia. 5. Conclusions
Nevertheless, the inclusion of both inpatients and outpatients in the
catatonic group is to be considered as a limitation, as it may represent a Catatonia is still a poorly understood syndrome in terms of etiology
bias in terms of severity of catatonia, when compared to inpatient and pathophysiology. Studies exploring seasonality are useful epide­
controls. However, it is likely that patients diagnosed with catatonia as miological tools that can help understand the mechanisms and risk
outpatients are rapidly transferred to hospital to receive optimal treat­ factors of diseases. In our study, we found a seasonal pattern in the onset
ment, which would mean still being classified as outpatients in CRIS. A of catatonia, showing more cases in late winter and late summer. This is
measurement bias could result from a different latency between onset of in accordance with the seasonality described for many of the disorders –
catatonia and recognition of catatonia, but this is unlikely to be more both psychiatric and non-psychiatric – that are often associated with
than a few days, considering the severity of this syndrome. As for con­ catatonia, and may suggest that proximal causes are of greater impor­
founders, adjustments for gender, ethnicity and year of birth were tance in the manifestation of catatonia. Moreover, psychiatric clinical
conducted where appropriate. Data on prescribed medication were not services might anticipate seasonal peaks of catatonic episodes, that often
available in our sample, which represents a limitation. require specific treatment, e.g., electroconvulsive therapy. No evidence
In terms of the methods, one of the main strengths of this study was was found for an effect of season of birth on the development of cata­
the use of a Cosinor model, a specific statistical tool that allows the tonia, but more robust studies are needed to better explore this neuro­
analysis of seasonal patterns using sinusoidal waves, as previously per­ developmental factor.
formed by other authors (Barnett and Dobson, 2010; Cox, 2006; Fisman,
2007; Stolwijk et al., 1999). In fact, although a large number of pub­ CRediT authorship contribution statement
lished studies have used Chi-squared tests to explore the seasonality of
various phenomena, aggregating data by month or seasons (Hinterbu­ This study was designed and conceived by TM, JPR and GL. TM
chinger et al., 2020; Liang et al., 2018; Suhail and Cochrane, 1998), conducted the analyses, with support from JPR, MCB, AA and GL. TM
these tests often do not detect efficiently the complexity of seasonal drafted the manuscript with support from JPR, MCB, AA, GL, AD and
patterns (Salib and Cortina-Borja, 2006; Stolwijk et al., 1999). However, MSZ.
in our study, the use of a Cosinor model was not possible to explore the
effect of month of birth on later development of catatonia, where a Role of the funding source
regression for count data without trigonometric terms was used instead.
This was due to the unavailability of data on the total number of births The funders of the study had no role in study design, data collection,
by month, for the general population, between 1921 and 2007. As a data analysis, data interpretation, or writing of the report. TM and JPR
matter of consistency with the previous section of the study, a first had access to the raw data. The corresponding author had full access to
general exploratory analysis was performed to assess the effect of month all the data in the study and had final responsibility for the decision to
of birth on the development of catatonia. Then, a subgroup was iden­ submit for publication.
tified according to the country of birth. Although country of origin might
perfectly reflect only the perinatal stages of CNS development, we Declaration of competing interest
consider it as a legitimate approximation for both prenatal, perinatal
and postnatal life in most of the patients, and the Tropic of Cancer was MSZ declares honoraria for a lecture from Eisai Co., Ltd. All other
chosen to identify more homogenous seasons in terms of weather con­ authors declare no competing interests.
ditions. However, the season of birth section of this study should be
interpreted with caution in the light of these methodological limitations. Data availability
Future studies should try to replicate our findings focusing on births
from a single country, where seasons might be more homogeneous in Data are owned by a third party, Maudsley Biomedical Research
terms of weather conditions and social behaviors. This would also allow Centre (BRC) Clinical Records Interactive Search (CRIS) tool, which
the use of a Cosinor model, where the total number of births by month provides access to anonymised data derived from South London and
could be included, to control for variations in the pattern of births for the Maudsley electronic medical records. These data can only be accessed by
general population (Borja and Haigh, 2007). For the presentation of permitted individuals from within a secure firewall (i.e., the data cannot
catatonia, future studies might include in the analyses a more complete be sent elsewhere), in the same manner as the authors. For more in­
panel of variables, including maximum and minimal temperatures, formation please contact: [email protected].
percentages of humidity, hours of sunshine, and atmospheric pressure.
The hypothesis of a peak of cases caused by infections might be tested Acknowledgments
analyzing the concentrations of inflammatory markers, acute viral se­
rologies and alterations in the white cell count for patients included. This paper represents independent research part-funded by the

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National Institute for Health Research (NIHR) Biomedical Research Gardener, H., Gao, X., Chen, H., Schwarzschild, M.A., Spiegelman, D., Ascherio, A., 2010.
Prenatal and early life factors and risk of Parkinson’s disease. Mov. Disord. 25,
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necessarily those of the NHS, the NIHR or the Department of Health and Health 106, e15. https://doi.org/10.2105/AJPH.2016.303065.
Social Care. This research was funded in whole, or in part, by the Geoffroy, P.A., Bellivier, F., Scott, J., Etain, B., 2014. Seasonality and bipolar disorder: a
systematic review, from admission rates to seasonality of symptoms. J. Affect.
Wellcome Trust. This research was supported by the National Institute Disord. 168, 210–223. https://doi.org/10.1016/j.jad.2014.07.002.
for Health Research (NIHR) Great Ormond Street Hospital Biomedical Gupta, S.K., Chaudhary, A., Bairwa, K., 2017. Seasonal decomposition of incidence of
Research Centre. For the purpose of Open Access, the author has applied admission of children and adolescents with catatonia in a tertiary care neuro-
psychiatric hospital in delhi: seasonal allergy as a putative etiological factor. J. Int.
a CC BY public copyright license to any Author Accepted Manuscript Research in Medical and Pharmaceutical Sciences 28–32.
version arising from this submission. TM received a grant from Uni­ Hare, E., Price, J.S., Slater, E., 1974. Mental disorder and season of birth: a National
versity of Lille, Faculty of Medicine and Lille University Hospital, and Sample Compared with the general population. Br. J. Psychiatry 124, 81–86.
https://doi.org/10.1192/bjp.124.1.081.
from the Erasmus+ programme. JPR is supported by a Wellcome Trust He, Y., Zhang, X., Gao, J., Gao, H., Cheng, J., Xu, Z., Pan, R., Yi, W., Song, J., Liu, X.,
Clinical Training Fellowship (102186/B/13/Z). MSZ, GL, and ASD are Tang, C., Song, S., Su, H., 2022. The impact of cold spells on schizophrenia
supported by the UK NIHR University College London Hospitals admissions and the synergistic effect with the air quality index. Environ. Res. 212,
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