Psychiatry Research 270 (2018) 357–364

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Psychomotor agitation in subjects hospitalized for an acute exacerbation of T

Schizophrenia
Emilio Sacchettia, Paolo Valsecchib,c, Elena Tamussic, Laura Paullib,c, Raffaele Morigib,c,
Antonio Vitab,c
a
Brescia University, Medical School, Brescia, Italy
b
Department of Clinical and Experimental Sciences - University of Brescia, Brescia, Italy
c
Department of Mental Health, Spedali Civili Hospital, Brescia, Italy

ABSTRACT

The aims of this study were to establish the prevalence of moderate and severe psychomotor agitation in patients hospitalized for an active phase of schizophrenia,
the associations between psychomotor agitation and patients’ demographic and clinical variables, the intra-individual stability of the agitated/non-agitated di-
chotomy in independent psychotic breakdowns. The study was performed on a database relative to 630 inpatients hospitalized with a diagnosis of schizophrenia.
Psychomotor agitation was measured with the Positive and Negative Syndrome Scale – Excited Component (PANSS-EC). Prevalence of moderate and severe psy-
chomotor agitation was 40.5% and 23.7%, respectively. Non-agitated patients were older, with longer illness history and duration of untreated psychosis, were more
frequently on antipsychotic medication, had lower incidence of recent use of substances, and functioned better before the index hospitalization than moderately and/
or severely agitated patients. Non-agitated patients had lower scores for total PANSS and Emsley's positive and anxiety dimensions. Compared with the severely
agitated group, non-agitated and moderately agitated patients scored more in Emsley's depression dimension. Poor functioning before index hospital admission,
higher scores for negative subscale and Emsley's positive dimension and use of substances exerted an effect on risk of psychomotor agitation.

1. Introduction generation antipsychotics and inhaled loxapine (Citrome and Volavka,

Psychomotor agitation is a widespread, complex syndrome char-
acterized by an appreciable increase in ideational, emotional, motor,
and/or behavioural activity that may occur transdiagnostically in
many psychiatric and non-psychiatric medical conditions (American
Psychiatric Association, 2013; Garriga et al., 2016; Sacchetti et al.,
2017). Its presence is common cause of persistent clinical concern,
frequently imposes a significant burden on patients, families, caregivers
and medical staff, detracts resources in health care systems and can be
life-threatening to the patient and others when it escalates into ag-
gressive variants (Abderhalden et al., 2007; Cardoso et al., 2005; Cots
et al., 2016; Garriga et al., 2016; Peiró et al., 2004; Sacchetti et al.,
2017; Stephens et al., 1999; Sugibayashi et al., 2014).
Given this unfavourable scenario, it is not surprising that the
management of psychomotor agitation continues to be a topic of con-
siderable interest as testified by the proliferation of systematic reviews,
guidelines, and expert consensus papers (Allen et al., 2011, 2003;
Garriga et al., 2016; Marder et al., 2007; National Collaborating Centre
for Mental Health (UK), 2015; National Collaborating Centre for
Nursing and Supportive Care (UK), 2005; Richmond et al., 2012;
Sacchetti et al., 2017; Wilson et al., 2012; Zeller and Rhoades, 2010)
and the recent ad hoc development of rapid-acting injectable second-
2014; Garriga et al., 2016; Nordstrom and Allen, 2013).
Therapeutic progress, however, has not been accompanied by im-
provement in knowledge of the pathophysiology of psychomotor agi-
tation and profiling of patients affected by the syndrome. A number of
obstacles have contributed to generate and maintain the gap. As high-
lighted previously, a major barrier lies in the fact that, because it is not
a definite disorder but a complication of numerous clinical conditions,
psychomotor agitation may be mediated by different, disease-specific
mechanisms and pathways (Garriga et al., 2016; Sacchetti et al., 2017).
Clearly, the possibility that the same individual may develop episodes
of psychomotor agitation through distinct processes adds to the diffi-
culty. In addition, the lack of a unitary definition of psychomotor agi-
tation and the high number of measures to assess the syndrome are
relevant confounders because they make comparison between studies
difficult (Citrome and Volavka, 2014; Day, 1999; Garriga et al., 2016;
Sacchetti et al., al.,2017; Sachs, 2006). The frequent use in the clinical
debate of aggression and psychomotor agitation as synonyms, despite
the fact that the former is only a partial component of the latter, is
representative of this limitation. Furthermore, the list of obstacles is
maximized by a common lack of control for a number of causal and
moderating factors, in particular medication adherence, adequacy of
the therapeutic plan and contingent clinical setting.

E-mail address: emilio.sacchetti@unibs.it (E. Sacchetti).

https://doi.org/10.1016/j.psychres.2018.09.058
Received 7 February 2018; Received in revised form 25 September 2018; Accepted 25 September 2018
Available online 26 September 2018
0165-1781/ © 2018 Elsevier B.V. All rights reserved.
E. Sacchetti et al.
This study was planned to improve our knowledge of some of these
critical issues. In particular, the objective of the study was to analyse
the prevalence of psychomotor agitation in patients with schizophrenia
during an exacerbation of their disease and to identify the socio-de-
mographic and clinical correlates of psychomotor agitation of different
degrees of severity.
To this aim, a retrospective analysis of clinical charts was restricted
at the start of an index hospital admission for an active phase of schi-
zophrenia, the diagnosis was based on operational criteria, and a large
number of socio-demographic and clinical variables were tested for
putative associations with psychomotor agitation.
Access to data on a subsample of patients followed in two sub-
sequent hospitalizations caused by a psychotic exacerbation has also
given us the opportunity to assess whether, in the presence of similar
clinical conditions, psychomotor agitation may constitute a recurrent
complication.
2. Materials and methods
2.1. Study design
This is an exploratory, hypothesis-free, naturalistic, observational,
retrospective study.
Data were obtained from a database of information derived from
clinical charts of patients hospitalized for an active phase of schizo-
phrenia at the Brescia University & Spedali Civili Psychiatric Clinic
between 2006 and 2016. The Clinic, a 24 bed unit of a General Hospital,
operates within the Lombardy Health Care System, serves a catchment
area of about 350.000 inhabitants, and is functionally jointed with a
number of in- and - out-patient facilities of the Psychiatric Unit n° 22
and 20 of the Department of Mental Health of the Spedali Civili
Hospital, Brescia. In the Psychiatric Unit, the inpatient facilities include
20 beds for chronic patients, 35 beds dedicated to intensive re-
habilitation, 32 beds located in Communities with a medium or low
level of protection, and 19 social housing beds. The outpatient facilities
consist of 3 Community Mental Health Services and 3 Day Centers for
rehabilitation. During the 2006–2016 period, the Clinic has hospita-
lized a mean of 419 patients per year, with a bed occupation higher
than 90%, while the Community psychiatric services have delivered a
mean of about 30.000 visits per year. In agreement with Italian Health
Care System, the Clinic is primarily responsible for all the acute psy-
chiatric admissions for people living in its catchment area. The decision
to hospitalize the patients has always been taken by psychiatrists per-
forming their service at the hospital .
Individual patient data were entered in the database using routine
procedures adopted at the Clinic and coded with a unique file number
to ensure anonymity during the processing and data analyses and
linking of information relative to independent hospital admissions.
2.2. Patients
In accordance with the naturalistic design of the study, the inclusion
criteria were minimal: age between 16 and 70 years, a definite DSM-5
diagnosis of schizophrenia (American Psychiatric Association, 2013),
absence of a diagnosis of a substance-related disorder at hospital ad-
mission, hospitalization due to an active psychotic phase (i.e. a condi-
tion that satisfied the DSM-5 criterion A for schizophrenia), a Clinical
Global Impression-Severity Scale (CGI-S) (Guy, 1976) score ≥ 3, and
administration of the Positive and Negative Syndrome Scale (PANSS)
(Kay et al., 1987) within 2 days of admission in the Psychiatric Clinic.
Records stored before 2014 were re-analysed a posteriori to check
the compatibility of the original DSM-IV-TR diagnosis of schizophrenia
(American Psychiatric Association, 2000) with the DSM-5 criteria.
Patients initially entered in the database with a diagnosis of schizo-
phreniform disorder were considered eligible only when the transition to
schizophrenia was unequivocally proven in the following months.
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Psychiatry Research 270 (2018) 357–364
Subjects entered in the subsample followed in two successive hos-
pitalizations was also requested to have a 6-month at least interval
between the two psychotic breakdown leading to hospitalization.
2.3. Assessments
Symptom severity was quantified with CGI-S and PANSS, which are
administered routinely at the Psychiatric Clinic at admission, every
week during hospitalization, and at discharge.
The storage of scores for each PANSS item allowed the use of an
extended battery of measures, including total PANSS, the positive, ne-
gative, and general psychopathology subscales, and the seven PANSS
dimensions emerged from a factor analytic study (Emsley et al., 2003).
Given the explorative nature of the study and the primary objective of
qualifying as much as possible patients with and without psychomotor
agitation, it was judged acceptable the use of all the components of the
extended PANSS-derived battery because, despite the common origin,
the PANSS subscales and the Emsley's domains are not fully equivalent.
The use of a backward stepwise selection that removes at each step the
variable with the lower significant value further justifies this inclusive
approach.
Psychomotor agitation was measured by extrapolating the PANSS
scores for the five items (excitement, tension, hostility, uncoopera-
tiveness, and poor impulse control) included in the Positive and
Negative Syndrome Scale – Excited Component (PANSS-EC) (Kay and
Sevy, 1990; Lindenmayer et al., 2004). The adoption of this scale was
justified by validations with other dedicated measures, extensive use in
research and clinical settings (Baker et al., 2003; Breier et al., 2002;
Garriga et al., 2016; Lesem et al., 2011; Marder, 2006; Montoya et al.,
2011; Sacchetti et al., 2017; Sachs et al., 2007) and origin from PANSS
that made possible the direct access to the information from the data-
base. The PANSS-EC scores generated three categories of patients
characterized by increasing levels of severity as follows (Montoya et al.,
2011): < 14, without psychomotor agitation; 14–19, moderate psy-
chomotor agitation; 20–35, severe psychomotor agitation.
Individual functioning in the year and the week before the index
hospitalization was routinely assessed with the Global Assessment of
Functioning (GAF) scale (American Psychiatric Association, 2000).
The age at onset was identified as the age of onset of active psy-
chotic symptoms (Gasparotti et al., 2009). The time spent with illness
and the duration of untreated psychosis were calculated by subtracting
the age at disease onset from the age at index hospitalization and at the
time of the first psychiatric contact with prescription of antipsychotic
medications, respectively.
The patients were also subdivided as antipsychotic-naive, anti-
psychotic-free, or antipsychotic-treated, according to their status at the
time of hospital admission. The label antipsychotic-free was applied to
patients already treated with antipsychotic medications who, at the
time of the index hospitalization, were not receiving for any reason the
oral formulation by at least 4 weeks and/or had a 6-week or more delay
in receiving the planned long-acting injectable antipsychotic.
Current psychiatric and medical comorbidities, a history of schizo-
phrenia or related disorders in first-degree relatives, and recreational
use of substances in the month before the hospitalization were in-
vestigated separately, together with the occurrence of obstetric com-
plications and paternal age at the birth of the patient. The label re-
creational use of substances identified an use in absence of a definite
DSM-5 substance-related disorder.
The data reported in the clinical records and included in the data-
base had been collected through direct examination, detailed inter-
views with the patients, and critical review of all medical records
available in the Clinic and associated Community Psychiatric Services.
In some cases, the information had been supplemented by interviews
with close relatives (Sacchetti et al., 2007) and the administration of a
modified version of the Structured Clinical Interview for DSM-IV Axis I
Disorders (SCID-I) (First et al., 1996).
E. Sacchetti et al.
Fig. 1. Frequency distribution of PANSS-EC Scores in newly hospitalized patients with an active phase of Schizophrenia.
Given the duration of the data collection, it was necessary to certify
raters subsequently included. These were experienced psychiatrists who
had to obtain at least 90% inter-rater reliability in recorded training
demos relative to CGI-S and PANSS. For example, in one of the most
recent evaluations, to assess inter-rater reliability for PANSS, three
video recorded clinical interviews were independently evaluated by
five clinicians. Subsequently, they individually (autonomously) rated
each clinical case. Intraclass correlation coefficient was calculated using
SPSS Statistic version 21 and was found to be equal to 0.982
(p < 0.001) in the average measures.
The evaluations for eligibility for the study, the conversion of a
DSM-IV-TR diagnosis to DSM-5, the transition from schizophreniform
disorder to schizophrenia, and critical revision of the information were
made jointly in 2016 by two academic psychiatrists (A.V. and P.V.) with
the support, in the presence of discordances, of an independent eva-
luator (E.S.) who made the final decision after discussion and re-ana-
lysis of the available material.
All the assessments were completed before planning and designing
the study.
2.4. Statistical analysis
The point prevalence of non-agitated, moderately agitated, and se-
verely agitated patients was estimated with descriptive statistics.
The three PANSS-EC groups were tested for differences in several
socio-demographic characteristics, psychiatric history, and symptom
profile using chi-squared tests or univariate analyses of variance, ac-
cording to the categorical or parametric nature of the variable under
study. In comparisons involving the symptom profile, the individual
components of the PANSS-derived battery were analysed after removal
of the items shared with the PANSS-EC because the corresponding
scores affected categorization to the non-agitated, moderately agitated,
and severely agitated groups.
All the variables associated with a definite PANSS-EC group in the
first-order analyses (i.e. the variables that reached a p value < 0.05 at
least) were entered as predictive variables in an ordinal logistic re-
gression analysis that used the presence of a non-agitated, moderately,
or severely agitated status as the outcome variable. In order to avoid the
chance of collinearity between Kay's and Emsley's categorization of
PANSS symptoms and to see more detailed components of symptom
profiles, we included in the logistic regression analysis Emsley's do-
mains, while Kay's were not entered, except for the negative subscale,
that has no items in common with Emsley domains. A backward
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Psychiatry Research 270 (2018) 357–364
stepwise selection was applied so that the variable with the least sig-
nificant value was removed at each step.
The stability of the categorization into the three PANNS-EC groups
was tested in two independent hospitalizations of the same patient
using Cohen's kappa to take into account the effect of chance con-
cordance.
All the statistical analyses were carried out using SPSS 20 (IBM Inc.,
Armonk, New York, USA). Data extraction and analysis were performed
in 2017.
3. Results
3.1. Sample population
The study included 630 patients with a definite diagnosis of schi-
zophrenia. Of these, 6,5% fulfilled the criteria for schizophreniform
disorder at the time of the index hospitalization but later transitioned to
schizophrenia. Two-hundred-ninety-one patients (46.2%) were anti-
psychotic-free or -naive at the time of admission. In the group on
medication at the moment of hospitalization, 242 (73.3%) was re-
ceiving a second-generation antipsychotic. Among the 51 patients who
reported an use of substances in the month preceding the hospitaliza-
tion, 93% indicated cannabis.
3.2. Prevalence of psychomotor agitation
At the index admission, 64.2% of the sample population presented a
PANSS-EC score equal to or higher than 14 and thus satisfied the op-
erational criterion for psychomotor agitation (Fig. 1). The prevalence of
cases of moderate and severe agitation was 40.5% and 23.7%, respec-
tively.
3.3. Associations of psychomotor agitation with individual characteristics
Non-agitated, moderately agitated, and severely agitated patients
did not differ in relation to gender, age at schizophrenia onset, paternal
age at patient's birth, presence of obstetric complications, history of a
schizophrenia spectrum disorder in first-degree relatives, and current
rate of psychiatric and medical comorbidities (Table 1).
However, differences emerged relative to other characteristics
(Table 1). In particular, when compared with their non-agitated coun-
terparts, severely agitated patients were younger, had a shorter illness
duration, presented a lower rate of subjects with less than 5 years of
E. Sacchetti et al. Psychiatry Research 270 (2018) 357–364

Table 1
Relationship between psychomotor agitation and key individual variables of newly hospitalized patients witH Schizophrenia.
Variable Sample n° Non-agitated Moderately agitated Severely agitated Chi2 (p) F (p)
NA vs MA NA vs SA MA vs SA

Female sex - % (n°) 630 41.2 (93) 40.8 (104) 32.2 (48) 3.67 (n.s.)
Age at onset – mean (s.d.) 624 28.05 (9.29) 27.70 (8.90) 27.41 (8.62) n.s. n.s. n.s.
Paternal age at birth – mean (s.d.) 415 32.28 (6.59) 32.32 (7.05) 31.27 (6.67) n.s. n.s. n.s.
Obstetric complications %(n°) 568 6.5 (13) 8.5 (20) 6.8 (9) 0.74 (n.s.)
Family history of psychosis -% (n°) 605 20.1 (44) 15.2 (37) 17.5 (25) 1.89 (n.s.)
Psychiatric codiagnoses - % (n°) 629 10.6 (24) 10.6 (27) 15.5 (23) 2.66 (n.s.)
Medical codiagnoses - % (n°) 630 34.1 (77) 36.1 (92) 34.2 (51) 0.25 (n.s.)
Age at admission – mean (s.d.) 630 42.14 (13.52) 40.61 (14.01) 38.27 (11.39) n.s. <0.01 n.s.
Duration of illness – months (s.d) 622 169.98 (156.01) 156.73 (157.90) 133.88 (129.35) n.s. <0.05 n.s.
Duration of illness > 10 yrs %(n°) 622 51.8 (116) 44.2 (111) 42.9 (63) 3.82 (n.s.)
DUP* > 5 years - % (n°) 543 17.1 (34) 23.5 (52) 9.8 (12) 10.33 (<0.01)
No AP** at admission - % (n°) 623 38.8 (87) 51.6 (128) 51.0 (76) 9.07 (<0.05)
Substance use - % (n°) 628 7.1 (16) 5.9 (15) 13.5 (20) 7.77 (<0.05)
GAF*** last year- mean (s.d.) 366 54.88 (15.50) 51.93 (13.89) 49.73 (15.90) n.s. <0.05 n.s.
GAF*** last week – mean (s.d.) 519 30.31 (10.20) 26.97 (7.80) 26.19 (7.88) <0.001 <0.001 n.s.

(°) NA = non-agitated, MA = moderately agitated, SA = severely agitated

DUP*Duration of Untreated Psychosis; AP **Antipsychotic Medications; GAF***Global Assessment od Functioning

untreated psychosis and an excess of cases in an antipsychotic-naive or Table 3

-free status, and referred more frequently a recent use of substances. Ordinal logistic regression analysis of variables associated with psychomotor
The comparison with non-agitated patients has also shown that severely agitation in newly hospitalized patients with Schizophrenia.
and moderately agitated patients had lower GAF scores relative to the VARIABLE B Exp(B) 95% c.i. p
year and the week preceding the index hospitalization (Table 1).
Furthermore, non-agitated, moderately agitated, and severely agi- VGF last week −0.032 0.97 0.95–0.99 <0.001
Emsley positive 0.115 1.12 1.09–1.16 <0.001
tated patients differed with regard to symptom severity. In particular,
Emsley depression −0.334 0.72 0.64–0.80 <0.001
when compared with moderately or severely agitated individuals, those PANSS negative 0.183 1.20 1.15–1.25 <0.001
in the non-agitated group had lower scores for total PANSS, positive, Substance use 0.701 2.02 1.08–3.94 <0.05
negative, and general psychopathology subscales, and Emsley's positive
and anxiety factors. In addition, severely agitated patients had lower Pseudo R-Squared (Cox and Snell): 0.27
scores for the Emsley's depression factor than non-agitated and mod- Hosmer and Lemeshow test: (a) no agitation vs. moderate agitation Chi-
squared = 14.77, p = 0.06, 68% correct classification; (b) moderate vs severe
erately agitated patients (Table 2).
agitation Chi-squared = 3.47, p = n.s., 72.9% correct classification

3.4. Factors associated with psychomotor agitation
The variables associated with different levels of agitation in the
first-order analyses were entered in an ordinal logistic regression ana-
lysis. Of the variables selected, only one (the treatment) was catego-
rical, with robust values in crosstabs.
The final model showed that global functioning in the week pre-
ceding the hospitalization, Emsley's positive and depression factors,
PANSS negative, and recent substance use had an independent effect in
predicting inclusion in the non-agitated, moderately agitated, and se-
verely agitated groups.
Table 3 reports the change in the odds ratios for each one point
variation of GAF and PANSS scores and for being a substance user. All
variables predicted a higher risk of being in a class with a more severe
psychomotor agitation, except for the Emsley's depression factor that
was protective.
3.5. Psychomotor agitation in independent active phases of schizophrenia
In the subsample of 190 individuals evaluated in two independent
hospitalizations, categorization into the non-agitated, moderately agi-
tated, and severely agitated groups showed concordance between the
episodes (Cohen's kappa 0.26, p < 0.001); the non-agitated, moderately
agitated, and severely agitated status at the index hospital admission
was maintained in the following hospitalization in 60.0%, 45.3%, and
48.9% of cases, respectively (Fig. 2).
In more detail, patients originally classified as moderately agitated
had shifted at the second hospitalization to the group with severe

Table 2
Relationship between psychomotor agitation and symptom profile of newly hospitalized patients with Schizophrenia°.
PANSS Score Non-agitated Moderately agitated Severely agitated F (p)
mean (s.d.) (226) (255) (149) NA vs MA NA vs SA MA vs SA (*)

Total 82.72 (13.44) 86.56 (12.43) 87.54 14.65) <0.01 <0.01 n.s.
Positive subscale 19.55 (5.34) 21.41 (3.95) 23.02 (4.35) <0.001 <0.001 <0.001
Negative subscale 17.80 (5.51) 19.38 (4.75) 21.22 (3.73) <0.001 <0.001 <0.001
General psychopathology subscale 37.94 (6.57) 39.93 (6.77) 40.21 (7.19) <0.01 <0.01 n.s.
EMSLEY positive factor 29.59 (6.69) 32.30 (4.92) 34.92 (5.49) <0.001 <0.001 <0.001
EMSLEY negative factor 24.74 (7.23) 24.98 (6.79) 24.14 (6.93) n.s. n.s. n.s.
EMSLEY disorganized factor 14.92 (4.13) 15.58 (4.03) 15.76 (4.24) n.s. n.s. n.s.
EMSLEY motor factor 4.85 (1.90) 4.83 (1.77) 4.64 (1.69) n.s. n.s. n.s.
EMSLEY depression factor 3.36 (1.96) 3.15 (1.88) 2.64 (1.37) n.s. <0.001 <0.01
EMSLEY anxiety factor 5.26 (2.13) 5.72 (2.34) 6.01 (2.36) <0.05 <0.01 n.s.

° 630 patients
(*) NA = non-agitated, MA = moderately agitated, SA = severely agitated

360
E. Sacchetti et al.
Fig. 2. Intra-individual stability of psychomotor agitation in patients followed
during two independent active phases of Schizophrenia.
agitation in 20% of cases or to the group without agitation in 34.7% of
cases. In the group with severe agitation at the index hospitalization,
40.0% changed to moderate psychomotor agitation, and only 11.1%
moved to the non-agitated group. Among the non-agitated patients at
the index episode, 22.9% presented a moderate episode of psychomotor
agitation at the new hospitalization and 17.1% moved to the group with
a PANSS-EC score in the 20–35 range. The mean interval of two hos-
pitalization was 31.1 ( ± 35.8 SD) months.
4. Discussion
The study supports first of all the indication that moderate to severe
episodes of psychomotor agitation should be definitively considered a
widespread complication that affects subjects hospitalized because of
florid symptoms of schizophrenia. The observed prevalence of 64.2% is
in agreement with the 60.4% found in a group of Spanish patients with
schizophrenia recently admitted to acute psychiatric units (Orta et al.,
2007) and is close to the 87.5% of cases with signs of aggression and
agitation observed in a group of patients hospitalized because of an
acute psychotic episode (Peiró et al., 2004).
The non-agitated, moderately agitated, and severely agitated sub-
groups showed concordance in successive episodes of schizophrenia.
This original finding was not completely unexpected. Indeed, an expert
panel (Becerra et al., 2013) concluded that patients with schizophrenia
have a median of two episodes per year characterized by psychomotor
agitation; a study of 503 patients with schizophrenia registered a high
frequency of repeated episodes of aggression during the post-acute
period of hospitalization (Orta et al., 2007); and schizophrenia has been
classified as the most frequent diagnosis in a review of repetitively
assaultive psychiatric patients (Flannery, 2002). In turn, the wide
temporal window between the two hospitalizations suggests that
grouping concordance refers to independent psychotic exacerbations
rather than to mere symptom fluctuations during the same illness epi-
sode.
In agreement with previous literature (Abderhalden et al., 2007;
Cornaggia et al., 2011; Cots et al., 2016; Steinert, 2002; Woods and
Ashley, 2007), the study did not demonstrate an appreciable involve-
ment of gender on the risk for psychomotor agitation and suggests a
possible, marginal effect of age.
The overrepresentation of patients with less than 5 years of un-
treated psychosis in the group with severe agitation conflicts with
previous reports indicating that first-episode violent patients had a
longer duration of untreated psychosis than their non-violent counter-
parts (Milton et al., 2001; Verma et al., 2005). However, violence is a
common feature in episodes of severe psychomotor agitation but the
overlap between the two conditions is far from complete. In any case,
the effect played by duration of untreated psychosis on psychomotor
agitation seems weak, since in our study the association with psycho-
motor agitation did not survive in the ordinal logistic regression
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Psychiatry Research 270 (2018) 357–364
analysis and, as underlined in a recent review (Látalová, 2014), no
relationship with violence has been reported in other studies.
The finding that moderately and severely agitated subgroups had a
lower rate of individuals currently treated with antipsychotics was
largely predictable given the relevant calming effects of these medica-
tions. However, the influence of antipsychotic treatment on psycho-
motor agitation was no more confirmed in the final model of the logistic
regression analysis. This result may be attributable to the lack of
stringent control of medication adherence, which may have weakened
the role of treatment for the possible inclusion of false adherent pa-
tients.
The excess of cases with psychomotor agitation in the group with
less than 10 years of illness is not surprising: indeed, 5–10 years after
the development of the first, frank symptoms of psychosis, many schi-
zophrenia patients move to a residual stage characterized by less per-
vasive symptoms (American Psychiatric Association, 2013; Lieberman
et al., 2001; Committee of Psychopathology, Group for the
Advancement of Psychiatry, 1992; Stroup et al., 2014) . The association
between psychomotor agitation and recent use of substances in a
sample population that excluded a priori patients with definite sub-
stance-use disorders may be regarded as an extension of the well-known
relationship between substance-related disorders and psychomotor
agitation (Burk et al., 2014; Garriga et al., 2016; Leventhal and
Zimmerman, 2010; Sacchetti et al., 2017). A further, indirect support to
this association comes from literature on violence, i.e. a rough proxy of
severe psychomotor agitation. Indeed, violent behaviour has been
found in about 30% of the patients with comorbid substance abuse
(Räsänen et al., 1998; Swanson et al., 1990); patients with schizo-
phrenia have shown, compared with the general population, to have
odds ratios for violent crime of 4.4 and 1.2 according to the presence or
absence of comorbid substance abuse (Fazel et al., 2009); comorbid
substance misuse in patients with first-episode psychosis has been re-
ported to triple the risk of aggression (Milton et al., 2001). Further-
more, patients with schizophrenia and alcohol abuse are resulted 25.2
times more likely to commit violent crimes in comparison with men-
tally healthy males and 3.6 times more than patients with schizo-
phrenia without comorbid alcohol abuse (Räsänen et al., 1998). These
data may explain why, in an interview with Italian health professionals,
75.7% of the responders judged the recent intake of new psychoactive
substances a relevant to very relevant triggering factor for psychomotor
agitation (Simonato et al., 2013). The widespread and increasing dif-
fusion of substances among people with schizophrenia (Buckley, 2006;
Regier et al., 1990; Swartz et al., 2006) makes the clinical impact of the
observed association between substance use and psychomotor agitation
really dramatic.
Any hypothesis about the nature of the determinants and mod-
erators responsible of the stability of the agitated/non agitated
grouping in independent active phases of schizophrenia is prevented by
the study design. Nevertheless, it seems possible to exclude since now
any appreciable influence of two accredited risk factors for the disorder
such as obstetric complications and family history of schizophrenia
spectrum disorders in first-degree relatives (Ek et al., 2015; Foutz and
Mezuk, 2015; Grattan et al., 2015; Hameed and Lewis, 2016; Hamlyn
et al., 2013; Helenius et al., 2012; Hui et al., 2015; McGrath et al., 2014;
Merikangas et al., 2014; Nicodemus et al., 2008; Tandon et al., 2008;
Walder et al., 2014; Wang et al., 2015) . The observed lack of any as-
sociation between advanced paternal age at conception and psycho-
motor agitation diverges instead from demonstration in a large-scale
study on the general population, that advancing paternal age predicted
violent-offending offspring (Kuja-Halkola et al., 2012).
Looking at the various components of the PANSS-derived battery, it
emerges that psychomotor agitation develops preferentially in patients
who are severely affected in most psychopathologic domains of schi-
zophrenia. This finding is supported by a discrete body of evidence. For
example, a relationship between psychomotor agitation and positive
symptoms has been observed in aggressive patients with schizophrenia
E. Sacchetti et al.
(Krakowski and Czobor, 2004; Soyka and Ufer, 2002). Similarly, the
negative domain is resulted significantly represented in a group of
hospitalized patients with schizophrenia presenting high rates of psy-
chomotor agitation (Orta et al., 2007) and verbal assaults have been
linked to negative symptoms (Krakowski and Czobor, 2004). The des-
cendent gradient of severity of the Emsley's depression factor moving
from non-agitated to moderately and severely agitated patients appears
instead to conflict with the repeated demonstration of a high prevalence
of psychomotor agitation during episodes of major depression, espe-
cially in bipolar patients (Angst et al., 2009, 2007; Garriga et al., 2016;
Gaudiano et al., 2008; Iwanami et al., 2015; Judd et al., 2012;
Leventhal and Zimmerman, 2010; Maj et al., 2003; Olgiati et al., 2006;
Ryan et al., 1987; Sacchetti et al., 2017; Serretti and Olgiati, 2005;
Tollefson and Sayler, 1996). However, psychomotor agitation and re-
tardation are equally listed among the diagnostic criteria for major
depression and the symptom profile for the Emsley's depression factor is
closer to retardation than agitation.
Demonstrations that, when compared with the non-agitated coun-
terparts, patients with psychomotor agitation function worse in the year
preceding the hospitalization and show an increase of the impairment
as they go nearer to the hospital admission suggest that psychomotor
agitation may be related to a long-lasting poor prognosis of schizo-
phrenia and that a quick deterioration of functioning may represent an
early indicator of a psychotic recrudescence characterized by psycho-
motor agitation.
The study suffers from some limitations. First, the requirement for
hospitalization due to an active phase of schizophrenia prevents gen-
eralization of the results not only to people affected by other mental
disorders but also to schizophrenia patients with less florid symptoms
or treated as outpatients. Second, since all the information derived from
procedures routinely adopted at the Psychiatric Clinic, some measures
may result relatively rough and oversimplified when compared with
those used in pure experimental settings. For example, the benchmark
(Gasparotti et al., 2009) for identifying the age at schizophrenia onset is
certainly rough since it refers to age at the onset of active psychotic
symptoms and this obviously prevents consideration of prodromal
symptoms heralding the disorder and this influenced the estimates re-
lative to the duration of untreated psychosis and the total time spent in
illness. However, the impact of this methodological flaw on the results
is reasonably marginal because there is no reason to assume a non-
randomized distribution among non-agitated, moderately agitated and
severely agitated patients. Furthermore, the use of a database originally
organized for different research purposes prevents possibilities to in-
vestigate the associations between psychomotor agitation and several
potentially relevant socio-demographic and clinical variables such as
educational level, income, therapeutic alliance, intensity of outpatient
assistance, and number of previous hospitalizations. Third, the 13/14
PANSS-EC cut-off for separating agitated and non-agitated patients
could represent another potential limitation although this value is
commonly used in the international literature (Baker et al., 2003; Breier
et al., 2002; Lesem et al., 2011; Marder, 2006; Montoya et al., 2011;
Sachs et al., 2007): in fact, our results raise doubts on whether it re-
presents the best threshold because, in the comparisons between agi-
tated and non-agitated patients, the differences were more frequently
found in individuals with PANSS-EC scores of 20 or more. Finally, no
specific analysis of collinearity of PANSS factor scores was performed;
however such factors are not equivalent and all of clinical interest and
therefore were maintained in the analyses.
On the other hand, the naturalistic setting of the study, the inclusion
of consecutively hospitalized patients, the lack of assessments and in-
terventions outside the normal psychiatric practice, and the minimal
inclusion and exclusion criteria strongly justify the real-world qualifi-
cation of the study and this will facilitate the transfer of the results
obtained into the usual clinical routine.
362
Psychiatry Research 270 (2018) 357–364
5. Conclusions
The study proposes a preliminary identikit of schizophrenia patients
presenting psychomotor agitation during the early phase of a hospita-
lization. In particular, when compared with the counterpart without
psychomotor agitation, patients with psychomotor agitation resulted,
especially when the syndrome was severe, to be younger, to have spent
less time in illness, to present a shorter duration of untreated psychosis,
to be more frequently antipsychotic-free or –naïve and with recent use
of substances, and to function worse before the admission.
Furthermore, even after subtraction of PANSS-EC items, patients with
psychomotor agitation scored more at total PANSS, negative and gen-
eral psychopathology PANSS subscales, and Emsley's PANSS positive
and anxiety factors. Instead, severely agitated patients scored less at
Emsley's depression factor than those without psychomotor agitation.
A deep understanding of this profile goes beyond the possibilities of
a retrospective cross-sectional study. Nevertheless, it appears since now
evident that a unitary interpretative approach is unjustified. Indeed, the
results have involved indifferently first- and second-order associations,
some variables unequivocally predate psychomotor agitation while
others are contemporaneous or quasi-contemporaneous and, more im-
portant, several putative causal relationships are bidirectional and thus
able to influence each other. The association of psychomotor agitation
with antipsychotic-free status, recent use of substances, poor func-
tioning in the week preceding the hospitalization and specific symp-
toms profile are evident examples of a probable bidirectional inter-
relationship.
Despite these relevant unresolved issues, current demonstration that
psychomotor agitation is likely to recur in the same patient during
successive psychotic exacerbations and is associated with numerous
socio-demographic and clinical characteristics qualifies since now these
variables as accessible candidate markers of the psychomotor agitation
status. This is an appreciable opportunity that merits to be validated in
prospective replication studies since psychomotor agitation frequently
imposes heavy burdens and can be prevented and/or controlled by
valid pharmacologic and non-pharmacologic interventions. However,
successful results depend largely from possibilities to individuate as
soon as possible people at risk or with soft symptoms. Predictors of
psychomotor agitation represent a viable option that contributes to
bypass this last requirement.
Author contribution
Professors Sacchetti and Vita planned the study. All the authors
participated in the extraction and analysis of the data, critically dis-
cussed the results, and cooperated for the selection of literature.
Professor Sacchetti drafted the initial version of the manuscript.
Conflict of interest
In the past 5 years Professor Sacchetti has received funding for re-
search, advisory board membership and sponsored lectures from
Angelini, Chiesi, Content Rd Net srl, Edra-LSWR, Dainippon Sumitomo
Pharma, Eli Lilly, Glaxo SmithKline, Health & Publishing Services Srl,
Janssen-Cilag, Lundbeck, McCann, Otsuka, Pfizer, Recordati, Roche,
Rottapharm, Servier, Stroder, Sunovion, Takeda, and Valeas. Prof
Sacchetti is editorial consultant for Edra - LSWR and is editor in Chief of
Evidence –based Psychiatric Care, the official Journal of Italian Society
of Psychiatry.
In the last 5 years, Professor Vita has received funding for research
and advisory board membership, and sponsored lectures from
Boheringer, Eli Lilly, FBHealth, Fidia, Forum Ph., Janssen-Cilag,
Lundbeck, Otsuka, Roche.
The other Authors do not declare any conflict of interest.
E. Sacchetti et al. Psychiatry Research 270 (2018) 357–364

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