REVIEW ARTICLE
Acute Polymorphic Psychotic Disorder
Concepts, Empirical Findings, and Challenges for ICD-11
Augusto Castagnini, MD, PhD (Cantab),* Leslie Foldager, PhD,†
and German E. Berrios, MD, FRCPsych‡
Abstract: The ICD-11 International Classification of Diseases and Related
Health Problems will move toward a narrower concept of “acute and transient
psychotic disorders” (ATPD) characterized by the remnant “polymorphic psy-
chotic disorder” (APPD) of the current ICD-10 category, also including schizo-
phrenic and predominantly delusional subtypes. To assess the validity of
APPD, relevant articles published between January 1993 and September 2017
Downloaded from http://journals.lww.com/jonmd by BhDMf5ePHKbH4TTImqenVFrctQzt46R2mDZr2CPMUkXEMcRrsONNUwfNl3QqsT0X on 11/07/2018
were found through searches in PubMed and Web of Science. APPD is a rare
mental disorder and affects significantly more women than men in early-middle
adulthood. Its diagnostic reliability is relatively low, and its consistency reaches
just 53.8% on average over 8.8 years, but is significantly greater than either of
ATPD subtypes, which are more likely to progress to schizophrenia and related
disorders. Although APPD has distinctive features and higher predictive power,
its rarity and the fleeting and polymorphic nature of its symptoms could reduce
its usefulness in clinical practice and discourage research.
Key Words: Acute transient psychosis, brief psychotic disorder, classification,
ICD, nosology
(J Nerv Ment Dis 2018;206: 887–895)
I nfluenced by findings of the World Health Organization (WHO) Col-
laborative Study on acute psychoses (Cooper et al., 1990), the F23
category “acute and transient psychotic disorders” (ATPDs) appeared
in the ICD-10 Classification of Mental and Behavioural Disorders
(WHO, 1992) within the F2 group “schizophrenia, schizotypal and de-
lusional disorder.” To avoid assumptions about etiology and symptom
patterns, ATPDs were characterized by three key features: a) acute onset
within 2 weeks; b) polymorphic, schizophrenic, or predominantly delu-
sional symptoms; and c) association (or not) with “acute stress,” de-
fined as events that would be stressful to most people—such as
bereavement, unexpected loss of partner, job, etc.—occurring within
2 weeks before the onset of psychotic symptoms. Temporal criteria
shorter than 1 or 3 months set the ATPD subtypes with schizophrenic
symptoms apart from schizophrenia, as the ICD-10 diagnosis of schizo-
phrenia requires at least 1-month duration, and the subtypes with poly-
morphic or delusional features from persistent delusional disorder,
which lasts longer than 3 months (Table 1).
*School of Child Neuropsychiatry, University of Modena and Reggio Emilia, Modena,
Italy; †Unit for Behaviour and Stress Biology, Department of Animal Science, and
Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark; and
‡Department of Psychiatry and Robinson College, University of Cambridge,
Cambridge, UK.
Send reprint requests to Augusto C. Castagnini, MD, PhD, School of Child
Neuropsychiatry, University of Modena and Reggio Emilia, Via del Pozzo 71,
41124 Modena, Italy. E‐mail: augusto.castagnini@unimore.it.
Supplemental digital content is available for this article. Direct URL citations appear in
the printed text and are provided in the HTML and PDF versions of this article on
the journal’s Web site (www.jonmd.com).
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0022-3018/18/20611–0887
DOI: 10.1097/NMD.0000000000000882
The Journal of Nervous and Mental Disease • Volume 206, Number 11, November 2018
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
The Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5; American Psychiatric Association, 2013), listed “brief
psychotic disorder” (BPD), which features delusions, hallucinations,
disorganized speech, and grossly disorganized or catatonic behavior
lasting at least 1 day but less than 1 month. In addition, the DSM cate-
gory of “schizophreniform disorder” is used for cases with schizo-
phrenic symptoms and duration intermediate between BPD and
schizophrenia. Little evidence, however, supports the validity of BPD
and schizophreniform disorder as distinct categories, and there is only
partial concordance with ICD-10 ATPDs because of differences in on-
set, symptom patterns, and temporal criteria (Castagnini and Fusar-
Poli, 2017).
The forthcoming ICD-11 revision, will replace the broader
ICD-10 category of ATPDs with “acute polymorphic psychotic disor-
der (without schizophrenic symptoms)” designated “acute and transient
psychotic disorder,” as “it best reflects the polymorphic and varying
clinical presentation typical of ATPD” (Zielasek and Gaebel, 2015,
p. 32). The remaining subtypes with schizophrenic and predominantly
delusional symptoms listed under ATPDs will be redistributed into
other classes of the newly renamed F2 section “schizophrenia spectrum
and other primary psychotic disorders” (Gaebel et al., 2015). The
characteristic clinical features of the new ATPD category are likely
to remain almost unchanged and include delusions, hallucinations,
disorganized thought, perplexity or confusion, catatonia-like symp-
toms, and disturbances of affect and mood shifting from day to day
or even faster for a period of less than 3 months (ICD-11 Beta Draft:
https://icd.who.int/dev11/). Minor proposed changes will involve
additional codes to indicate positive, negative, depressive, manic,
psychomotor, and/or cognitive symptoms associated with primary
psychotic disorders. It is also stated that symptoms are not due to
medical comorbidity, substance misuse, or medication, yet no men-
tion is made either of association with “stress” or earlier diagnostic
concepts, which are reminiscent of acute polymorphic psychotic dis-
order such as the French bouffée délirante (BD) (Magnan, 1887) and
Kleist (1928) and Leonhard's (1957) cycloid psychosis (CP).
Although ATPDs constitute a composite category, no study
comparing empirical data among the different subtypes that it en-
compasses has yet been conducted. The aim of this article is to re-
view the literature and assess the validity of “acute polymorphic
psychotic disorder without schizophrenic symptoms” (APPD),
pointing out differences from the subtypes with schizophrenic and
predominantly delusional symptoms, then to discuss implications
for ICD-11.
METHODS
The guidelines for systematic reviews and meta-analysis pro-
vided by the PRISMA statement (Liberati et al., 2009) were followed.
PubMed and Web of Science were searched for “acute polymor-
phic psychotic disorder” OR “acute polymorphic psychosis” OR
“nonaffective acute remitting psychosis” OR “acute transient psycho-
tic disorder” OR “acute transient psychosis” OR “brief psychotic
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TABLE 1. Nomenclature of ICD-10 F23 Acute and Transient Psychotic Disorders (ATPDs)

F23 ATPDs Symptoms Duration Exclusion

F23.0 Acute polymorphic disorder Delusions, hallucinations, perceptual changes, emotional <3 mo Organic disease, alcohol and drug intoxication,
without schizophrenic symptoms turmoil (i.e., feelings of happiness and ecstasy or manic disorder, depressive disorder,
anxiety and irritability) shifting daily or even faster schizophrenia
F23.1 Acute polymorphic disorder Polymorphic and rapidly changing clinical picture plus <1 mo Organic disease, alcohol and drug intoxication,
with schizophrenic symptoms schizophrenic symptoms schizophrenia, acute polymorphic disorder
F32.2 Acute schizophrenia-like Relatively stable psychotic symptoms <1 mo Organic disease, alcohol and drug intoxication,
psychotic disorder schizophrenia, acute polymorphic disorder
F23.3 Other acute predominantly Relatively stable delusions or hallucinations <3 mo Organic disease, alcohol and drug intoxication
delusional disorders schizophrenia, acute polymorphic disorder
F23.8 Other acute and transient Acute psychotic disorders not classifiable under any <3 mo –
psychotic disorders other F23 category
F23.9 Acute and transient psychotic Any acute psychotic disorders unspecified <3 mo _
disorder unspecified
Acute onset is defined as a change from a state without psychotic symptoms to a clearly psychotic state within 2 weeks or less; it is also possible to specify “abrupt
onset within 48 hours.”
A fifth character may be used to indicate whether ATPDs are associated with “acute stress” (F23. X1/0).

disorder/s”OR “acute brief psychosis/es.” The search was restricted to
articles of potentially relevant studies in English, French, and German
published in peer-reviewed journals between 1 January 1993 and
September 30, 2017. Manual checking of reference lists of included
studies provided a further source. In selecting articles for this review,
we relied on studies with at least 10 cases and diagnosis made using
ICD-10 criteria for F23.0 “acute and transient psychotic disorders
without schizophrenic symptoms.” Where publications reported
overlapping data, the most informative or recent were selected.
The validity of APPD was assessed according to Kendler's (1980)
method by mean of three classes of validators: a) antecedent validators
(i.e., family aggregation, demographic, premorbid, and precipitating
factors); b) concurrent validators (biological markers, psychological
tests, genetics, symptom measures); and c) prognostic validators
(diagnostic stability, course, outcome, and response to treatment).
When indicated, meta-analyses of pooled data of potential validators
were conducted using Mantel-Haenszel odds ratios (ORs) with
95% confidence intervals (95% CIs). Study quality was assessed
using the Newcastle-Ottawa Quality Assessment Scale (NOS) for
nonrandomized studies (http://www.ohri.ca/programs/clinical_
epidemiology/oxford.asp). NOS evaluates a) patients selection,
b) comparability, and c) outcome and provides a score ranging from 0
to 9 (see supplementary figure 1, http://links.lww.com/JNMD/A40).
Data analysis and graphics were performed by means of R statistical
software version 3.3.1 (R Foundation, 2016).
RESULTS
A total of 457 articles were found, and 82 were included in the
review (Fig. 1).
Antecedent Validators
Demographic Factors
Three studies reported on incidence of ATPDs, with overall rates
ranging from 3.9 in the UK to 10.9 cases in Denmark per 100,000
persons (Castagnini and Foldager, 2013; Queirazza et al., 2014; Singh
et al., 2004); owing to subsequent diagnosis changes, the 2- and
3-year incidence rates for ATPDs were 6.7 and 1.4 per 100,000, res-
pectively. Variance in incidence of ATPDs might reflect not only
methodological differences among the studies but also diagnostic habit
owing to the inclusion of the traditional concept of reactive psychosis in
Denmark under ATPDs, and to caution to make diagnosis of severe
enduring mental disorders associated with perceived stigma in the first
episode of psychosis.
ATPDs are also more likely to affect women or both sexes almost
equally. Male incidence tends to peak in the mid-20s, yet the highest
rates for women occur about 10 years later and are markedly greater
than those for men over 40 years (Castagnini and Foldager, 2013;
Queirazza et al., 2014).
Among the ATPD subtypes, APPD is significantly more com-
mon in women, with an age at onset intermediate between that of
the diagnostic subtypes with acute schizophrenic features, which are
preponderant in males and arise on average 4 to 5 years earlier, and
acute predominantly delusional disorder (Aadamsoo et al., 2011;
Castagnini and Foldager, 2014; Rusaka and Rancans 2014a; Salvatore
et al., 2011).
Moreover, the reported prevalence of ATPDs varies from 6% to
20% of cases admitted to hospital and/or treated in outpatient services,
and there seems to be relatively higher proportions of APPD than either
of ATPD subtypes (Castagnini and Foldager, 2014; Jäger et al., 2003a;
Jørgensen et al., 1997; Marneros et al., 2005; Reay et al., 2010;
Salvatore et al., 2011; Singh et al., 2004), mainly in developing coun-
tries where patients have an earlier age (Esan and Fawole, 2014;
Karfo et al., 2011; Mehta et al., 2014; Sajith et al., 2002).
Further evidence indicates that the risk of mortality in ATPDs is
nearly twice as high in men than in women and significantly increased
both from natural and unnatural causes (Castagnini et al., 2013a). Late-
onset ATPDs (over 60 years) appear to be associated with a higher
risk not only of mortality but also of dementia than the general popu-
lation (Kørner et al., 2009).
Vulnerability Factors
Pillmann et al. (2003b) compared personality features of patients
with ATPD with those of control groups with schizophrenia, schi-
zoaffective disorder, and surgical patients using the 5-NEO Factor
Inventory, a self-rating scale measuring neuroticism, extraversion,
openness to experience, agreeableness, and conscientiousness. It was
found that patients with ATPDs do not differ from normal controls,
but they are likely to have a better premorbid social adjustment and ex-
hibit lower neuroticism, higher extroversion, and conscientiousness
than patients with schizophrenia and/or schizoaffective disorder. These

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The Journal of Nervous and Mental Disease • Volume 206, Number 11, November 2018
FIGURE 1. The PRISMA flow diagram illustrating the number of articles identified, those selected and excluded, and the reasons for exclusion.
findings add weight to the view that ATPDs are associated neither
with premorbid impairments nor specific personality changes,
since the number of cases diagnosed with personality disorder
dropped 1 year after the onset of acute psychosis, an effect proba-
bly due to the fact that many patients had recovered or discon-
tinued treatment as described by Jørgensen et al. (1996). Such reports
included a majority of cases featuring polymorphic psychotic disorders,
but no comparison among different ATPD subtypes was made.
Moreover, two studies examined the impact of family psychiatric
morbidity on ATPDs, pointing out differences from schizophrenia and
affective disorders. In the first, Das et al. (1999) found a three-time
higher risk of ATPDs in first-degree relatives (FDRs) of cases with
ATPDs than in family members of patients with schizophrenia, whereas
the risk of schizophrenia was significantly increased in the family of
patients with schizophrenia. In addition, patients presenting acute
schizophrenia-like symptoms were more likely to have a family history
of schizophrenia. More recently, a genetic epidemiological survey
(Castagnini et al., 2013c) estimated that family psychiatric morbi-
dity effects a weaker increase of risk for ATPDs than for schizophrenia
and bipolar disorder and extends across the three categories. With re-
gard to APPD, the risk was roughly similar in patients having FDRs af-
fected with either ATPDs (1.6; 95% CI, 1.0–2.5) or schizophrenia (1.8;
95% CI, 1.1–3.1); bipolar disorder did not increase significantly the risk
for any ATPD subtype; and schizophrenia in family members had the
greatest impact on the diagnostic subtypes with schizophrenic symp-
toms (2.5; 95% CI, 1.6–3.9).
Further evidence suggests that ATPDs are more likely to be as-
sociated with stressful events than schizophrenia and/or affective dis-
orders (Castagnini et al., 2016; Chakraborty et al., 2007; Das et al.,
1999; Esan and Fawole, 2013; Jäger et al., 2003a). Psychosocial and
cultural factors have been more commonly involved as risk factors for
ATPDs in developing countries (Das et al., 2001; Karfo et al., 2011;
Okasha et al., 1993; Sajith et al., 2002) than in developed ones, where
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Acute Polymorphic Psychotic Disorder
just a small number of cases are triggered by life events (Aadamsoo
et al., 2011; Castagnini et al., 2013b; Jäger et al., 2003a; Jørgensen
et al., 1997; Marneros et al., 2005). It would also appear that patients
with ATPDs and a family history of mental disorder tend to experience
fewer life events before illness onset than those without family psychi-
atric antecedents; in keeping with the stress-vulnerability model of
psychosis, these findings would be indicative of an increased emotional
reactivity, which renders subjects less likely to cope with adverse events
(Das et al., 2001).
Moreover, migrants seem to have a higher risk of ATPDs than
native populations, but the mechanism linking environmental adver-
sities to psychosis remains unclear (Abumadini and Rahim, 2002;
Alexandre et al., 2010; Krahl and Hashim, 1998; Lau et al., 2009;
Shaltout et al., 2007). It has been argued that acute psychosis in black
immigrants would arise from interaction between social adversities
and a transient vitamin D deficit (Dealberto, 2013).
Lastly, although retrospective analysis of life events is often
problematic, examination of Welsh historical religious revival revealed
a significant increase in admission rates and a favorable outcome for
what would now be diagnosed as APPD (Linden et al., 2010).
Concurrent Validators
The Relationship of APPD, BD, and CP
Because APPD refers to clinical concepts in European psychia-
try such as BD and CP, their continuity can be regarded as an indicator
of validity.
In Anglophone psychiatry, Perris and Brockington (1981)
provided operational criteria for CP, such as sudden onset and polymor-
phic symptoms, which were later incorporated into the checklist of
ICD-10 ATPDs. Comparative studies reported that only 30% to 55%
of patients with ATPDs share Perris and Brockington's (1981) diagnosis
of CP owing to differences in onset, clinical features, and duration
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Castagnini et al. The Journal of Nervous and Mental Disease • Volume 206, Number 11, November 2018

(Peralta and Cuesta, 2003; Pillmann et al., 2001; van der Heijden et al.,
2004). Pillmann et al. (2001) also found that patients with ATPD diag-
nosed as CP experienced a better clinical and social outcome. A closer
overlap has been observed between the polymorphic psychotic sub-
types and CP (k value = 0.33–0.36) (Peralta and Cuesta, 2003;
Pillmann et al., 2001).
A further study by Pillmann et al. (2003c) revealed that less
than 30% of cases with ATPDs, most featuring polymorphic symptoms,
had a diagnosis of BD according to the criteria formulated by Pull et al.
(1987). As in the case of CP, patients with ATPDs identified as having
BD were more likely to have a favorable outcome.
While there has been little research in BD of late (Weibel and
Metzger, 2005), studies to date suggest that CP is prevalent in women
and has an episodic-remitting course and better outcome than schizo-
phrenia; hereditary factors also play only a minor role, yet there is
greater evidence of early pathological events during pregnancy and
at birth in keeping with the developmental model of psychosis
(Beckmann and Franzek, 2001).
Symptom Measures
The field trials of the ICD-10 Diagnostic Criteria for Research
(Sartorius et al., 1995) reported that the diagnostic reliability for
the three-digit category F23 ATPDs was “good” (k = 0.74), but—at
the level to which diagnosis is usually made in clinical practice—the
polymorphic psychotic subtypes “without” and “with” schizophrenic
symptoms failed to achieve established standards of reliability
(k = 0.54 and 0.42). This is probably because their distinctive features
are either fleeting and variable or separated from schizophrenia only
by temporal criteria. In addition, acute predominantly delusional dis-
order is a diagnosis of exclusion not only from persistent delusional
disorder but also from polymorphic psychotic disorder and schizophre-
nia, and showed a similarly low reliability (k = 0.51).
Despite variations in the frequency of ATPD subtypes, the clini-
cal profile is likely to converge on polymorphic psychotic featu-
res characterized by shifting and varied delusions, hallucinations,
mood changes, anxiety, agitation, and fewer negative symptoms than
schizophrenia (Esan and Fawole, 2013; Jäger et al., 2003a; Karfo
et al., 2011; Marneros et al., 2005; Salvatore et al. 2011). It seems that
only negative symptoms (e.g., poverty of thought and speech, blunted
affect, impaired volition, and social withdrawal) discriminate schizo-
phrenia from ATPDs; yet Schneider's first-rank symptoms are common
to other F2 diagnostic categories, albeit more frequently described in pa-
tients with schizophrenia (Jäger et al., 2003a; Marneros et al. 2005;
Salvatore et al. 2011).
Neurobiological Factors
Pepplinkhuizen et al. (2003) reported a series of changes in
amino acid pathways by analogy with psychedelic drug–induced psy-
chosis in cases with APPD; yet neither significant alterations in electro-
encephalogram recordings (Endres et al. 2016; Rottig et al. 2005) nor
prefrontal brain changes (Schär et al., 1995) have been found.
Preliminary findings also suggest that patients with ATPDs dif-
fer in bilirubin serum levels (Bach et al., 2010), concentrations of
pro- and anti-inflammatory cytokines (i.e., tumor necrosis factor–α,
interleukin-6, and transforming growth factor–β) (Mahadevan et al.,
2017), and auditory P300 event-related potentials from patients with
schizophrenia and healthy controls (Sahoo et al., 2016). It is known that
patients with CP feature typically higher P300 event-related potentials
indicative of cerebral hyperarousal (Strik et al., 1997).
A further genome-wide association study of 47 cases with “atyp-
ical psychosis,” a close variant of APPD as described in Japan, found
that the putative genes are more likely to overlap toward those involved
in schizophrenia than in bipolar disorder (Kanazawa et al., 2013).
Prognostic Validators
Diagnostic Stability, Course, and Outcome
To determine the predictive validity, we conducted a meta-
analysis of follow-up studies including at least 10 cases first admitted
to hospital or treated in outpatient services with APPD, minimal dura-
tion of 12 months, and clearly defined measures of stability and/or out-
come. Of 12 studies charting course and outcome of different ATPD
subtypes, 7 fulfilled the inclusion criteria and comprised a total of

TABLE 2. Clinicodemographic Features and Outcome of Follow-Up Studies of F23.0 Acute Polymorphic Psychotic Disorder Without
schizophrenic Symptoms (APPD)

Study Length, yr F23.0 APPD% (95% CI)a F23.1–9c% (95% CI)b Total Female, % Mean (SD) Age
Aadamsoo et al. (2011) 2 12/24 40/83 107 60% 27.8 (8.2)
50.0 (29.1–70.9) 48.2 (37.1–59.4)
Abe et al. (2006)c 20d 10/16 – 16 50% 34.8 (9.9)
62.5 (35.4–84.8) –
Castagnini and Foldager (2014) 9.3d 572/1108 1991/4318 5426 47% 35.0 (12.3)
51.6 (48.6–54.6) 46.1 (44.6–47.6)
Castagnini et al. (2016) 1 6/10 21/37 47 64% 36.3 (12.5)
60.0 (26.2–87.8) 56.8 (39.5–72.9)
Rusaka and Rancans (2014a) 5.6 40/54 132/240 294 54% 33.1 (12.0)
74.1 (60.3–85.0) 55.0 (48.5–61.4)
Sajith et al. (2002)c 3 33/45 – 45 71% 26.9 (10.9)
73.3 (58.1–85.4) –
Salvatore et al. (2011)e 2 14/21 20/34 55 NR NR
66.7 (43.0–85.4) 58.8 (40.7–75.4)
a
Number and proportion of cases with unchanged diagnosis and number of those followed-up.
b
F23.1–9 acute and transient psychotic disorders (except APPD).
c
Only APPD.
d
Mean follow-up period.
e
First-episode psychosis study including ATPDs.

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The Journal of Nervous and Mental Disease • Volume 206, Number 11, November 2018 Acute Polymorphic Psychotic Disorder

1278 patients with APPD (Aadamsoo et al., 2011; Abe et al., 2006;
Castagnini and Foldager, 2014; Castagnini et al., 2016; Rusaka and
Rancans, 2014a; Sajith et al., 2002; Salvatore et al., 2011) (Table 2).
Analysis of pooled data revealed that about 53.8% (95% CI,
51.0–56.5) of patients with APPD did not develop another diagnosis
over a mean period of 8.8 years (see supplementary figure 1, http://
links.lww.com/JNMD/A40). The diagnostic stability of APPD was sig-
nificantly greater than that of the remaining ATPD subtypes (46.8%;
95% CI, 45.3–48.2), and the subtypes with schizophrenic symptoms
(OR, 1.7; 95% CI, 1.4–2.0) and acute predominantly delusional dis-
order (OR, 1.3; 95% CI, 1.1–1.5) had significantly increased odds of
changing diagnosis compared with APPD. Female sex, abrupt onset,
and early remission within 4 weeks have been reported to predict tem-
poral stability of APPD (Castagnini and Foldager, 2014; Rusaka and
Rancans, 2014a; Sajith et al., 2002).
Moreover, these studies have found that the greatest variability
in APPD occurs in the 24 months following the initial episode, and
those who changed diagnosis were more likely to develop affective
disorders, mainly bipolar disorder (Castagnini and Foldager, 2014;
Rusaka and Rancans, 2014b; Sajith et al., 2002); yet, the subtypes with
schizophrenic and predominantly delusional symptoms tended more
often to herald schizophrenia and longer lasting psychotic disorders
(Aadamsoo et al., 2011; Castagnini and Foldager, 2014; Rusaka and
Rancans, 2014a; Salvatore et al., 2011). The risk of conversion into
schizophrenia and schizoaffective disorder appears to be associated
with those factors known to predict poor outcome in schizophrenia such
as family history of schizophrenia, male sex, younger age, longer hospital
admission, negative symptoms, and first-rank symptoms (Aadamsoo
et al., 2011; Castagnini and Foldager, 2014; Chang et al., 2009; Poon
and Leung, 2017; Queirazza et al., 2014; Rusaka and Rancans, 2014b;
Salvatore et al., 2011). Further evidence suggests that patients with
ATPDs have a better clinical and functional outcome than patients with
schizophrenia, schizoaffective disorders, and/or persistent delusional
disorder over the short and longer terms (Marneros et al., 2002;
Pillmann and Marneros, 2005; Pillmann et al., 2012; Möller et al., 2011).
Although follow-up studies reported that a majority of patients
with APPD do not develop longer-term illness and fare significantly
better than those later diagnosed with schizophrenia and/or bipolar
disorder (Abe et al., 2006; Sajith et al., 2002), the heterogeneity of
the clinical subtypes encompassed by ATPDs and varying rates of sub-
sequent diagnosis changes make meaningful comparison difficult.
APPD may also account for high temporal stability and low rates of
recurrence of short-lived psychotic disorders observed in developing
countries; as reported by a prospective study from India, nearly three
quarters of cases with APPD did not develop another diagnosis and
more than half experienced no relapse over 3 years (Sajith et al., 2002).
In addition, there is an increased risk of suicide in ATPDs, sim-
ilarly high to that in schizophrenia and bipolar disorder (Castagnini
et al., 2013a), and suicidal behavior seems to be associated with shifting
polymorphic symptomatology (Pillmann et al., 2003a).
Response to Treatment
Patients with ATPDs are usually treated with antipsychotics and
other psychotropic drugs, and the reported proportion of those who
achieved symptomatic remission and/or discontinued medication varies
from 30% to 60% over 1 to 7 years (Aadamsoo et al., 2011; Abe et al.,
2006; Jäger et al., 2003b; Jørgensen et al., 1997; Pillmann and
Marneros, 2005). Very few clinical trials have been conducted (Jäger
et al., 2007), and the available evidence suggests that a) low- and
higher-dose haloperidol have similar efficacy over 4 weeks (Khanna
et al., 1997); b) risperidone produces fewer extrapyramidal symptoms
and proves more rapid and effective than haloperidol against both
positive and negative symptoms (Chaudhuri et al., 2000); c) a 6-week
trial of olanzapine in pediatric patients reported symptom remission
and relatively few adverse effects (Agarwal and Sitholey, 2006). More

TABLE 3. Summary of Antecedent, Concurrent, and Prognostic Validators for ICD-10 F23.0 “Acute Polymorphic Psychotic Disorder without
Schizophrenic Symptoms” (APPD) (see text for details)

Antecedent validators
Frequency Higher proportions of APPD than either of ATPD subtypes, mainly in developing countries
Age and sex More common in women, with a mean age of onset in early-middle adulthood, intermediate between the ATPD subtypes
with schizophrenic symptoms and acute predominantly delusional disorder
Family history APPD risk similarly high in patients having FDR with either ATPDs (RR, 1.6; 95% CI, 1.0–2.5) or schizophrenia (RR, 1.8;
95% CI, 1.1–3.1); bipolar disorder does not increase significantly the risk for APPD; and schizophrenia has the greatest
impact on the subtypes with schizophrenic symptoms (RR, 2.5; 95% CI, 1.6–3.9)
Environmental risk factors Psychosocial and cultural adversities more frequently in developing countries and migrant populations
Concurrent validators
Reliability ATPDs overall reliability k = 0.74; APPD k = 0.54; acute polymorphic psychotic disorder with schizophrenic symptoms
k = 0.42
Symptom type Only negative symptoms distinguish schizophrenia from ATPDs
Neurobiological factors Altered metabolic and neurophysiological functions of uncertain clinical meaning; putative genetic loci overlap with those
for schizophrenia
Predictive validators
Stability 53.8% over a mean period of 8.8 yr, significantly greater than that of the ATPD subtypes with schizophrenic (OR, 1.7; 95%
CI, 1.4–2.0) and predominantly delusional symptoms (OR, 1.3; 95% CI, 1.1–1.5); female sex, abrupt onset, and remission
within 4 wk predicted diagnostic stability
Course and outcome Lower rates of recurrence and better outcome than ATPD cases later diagnosed with longer-lasting psychotic disorders or
bipolar disorder
Treatment No controlled trials
Suicidality Linked to shifting polymorphic symptoms
RR indicates relative risk.

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Castagnini et al. The Journal of Nervous and Mental Disease • Volume 206, Number 11, November 2018
to the point, a follow-up study from China reported that the higher the
dosage of antipsychotic prescribed to patients with ATPDs on hospital
discharge, the greater the risk of subsequent transition to schizophrenia
on average over about 3 years (Wang et al., 2018).
Given the similarity with APPD, it can be useful to extrapolate
information about efficacy and safety of treatment from studies of CP.
Patients affected with CP have greater sensitivity to rare but severe
adverse events such as malignant neuroleptic syndrome or lethal catato-
nia (Franzek and Beckmann, 2001), and the newer atypical antipsy-
chotics would be preferable because of their higher affinity for 5HT
receptors and significantly fewer extrapyramidal adverse effects than tra-
ditional antipsychotics, though they can produce other adverse effects
usually dose related. In addition, Ehlis et al. (2005) noted that atypical an-
tipsychotics bring about a positive effect on prefrontal brain functions in
cases with CP.
It also seems that electroconvulsive therapy proves effective, as
Holm et al. (2017) found response and remission rates of 90% and
45% in 42 patients with APPD admitted to Swedish hospitals in
2011–2015, using the Clinical Global Impression Severity and
Improvement scales.
Furthermore, psychotherapeutic support and psychoeducation
may be helpful not only to reduce the impact of symptoms, but also
to prevent relapse (Jäger et al., 2007).
DISCUSSION
This is the first systematic review of APPD and is part of a wider
critical scrutiny about the validity of the diagnostic categories used
to classify short-lived psychotic disorders in ICD-10 and DSM-5, and
their differentiation from longer-lasting psychotic and affective disor-
ders (Castagnini and Berrios, 2011; Castagnini and Fusar-Poli, 2017).
These findings shed light on the relationship between APPD and the
subtypes with schizophrenic and predominantly delusional symptoms
and are essential for refining the ATPD category (Table 3).
The available evidence suggests that ATPDs are rare and affect
more often women in early to middle adult life or both sexes almost
equally (Castagnini and Foldager, 2014; Queirazza et al., 2014; Singh
et al., 2004). This pattern is likely to reflect not only the putative effect
of female sex hormones on the brain but also variations in age and
sex distribution across the diagnostic subtypes, as APPD is signifi-
cantly more common in women and its onset is intermediate between
the subtypes with schizophrenic symptoms and acute predominantly
delusional disorder (Aadamsoo et al., 2011; Castagnini and Foldager,
2014; Rusaka and Rancans, 2014a; Salvatore et al., 2011). The ATPD
subtypes with schizophrenic symptoms are reported to be prepon-
derant in young males and associated with a markedly high risk of
schizophrenia in family members and a tendency to evolve into schizo-
phrenia and related disorders over time (Aadamsoo et al., 2011;
Castagnini and Foldager, 2014; Chang et al., 2009; Das et al., 1999;
Rusaka and Rancans, 2014a; Salvatore et al., 2011). Reanalysis of
WHO international studies, including Determinants of Outcome of
Severe Mental Disorder, Collaborative Study on the Assessment and
Reduction of Social Disability, and International Pilot Study of
Schizophrenia samples, showed that only 20% of patients identified
with acute schizophrenia using ICD-10 criteria for F23.1–2 did not
change diagnosis, and about half were diagnosed with schizophrenia
over a 12- to 26-year follow-up (Craig et al., 2007).
Family and genetic studies revealed that psychiatric predisposi-
tion has a weak impact on ATPDs, at least partly attributable to the
effect of schizophrenia and bipolar disorder; particularly, hereditary fac-
tors for APPD are more likely to overlap toward those for schizophrenia
(Castagnini et al., 2013c; Kanazawa et al., 2013). Moreover, ATPDs
seem to be associated neither with premorbid impairment nor specific
personality changes (Jørgensen et al., 1996; Pillmann et al., 2003b).
This suggests that there may be a greater contribution in causation from
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environmental exposures as observed in developing countries and
migrants (Alexandre et al., 2010; Das et al., 2001; Karfo et al., 2011;
Krahl and Hashim, 1998; Lau et al., 2009; Okasha et al., 1993; Sajith
et al., 2002; Shaltout et al., 2007), but “acute stress” constitutes only
an additional diagnostic feature for ATPDs and the temporal rela-
tionship with symptom onset is limited to 2 weeks and probably so
restrictive as to have underestimated the number of cases triggered by
life events. The practical implication is that it would be difficult to iden-
tify potential environmental risk factors and deliver targeted treatments
to prevent relapse.
Symptom measures indicate that identification of characteristic
clinical features proves often difficult in APPD, as they can change in
type and intensity daily or even more frequently (Sartorius et al.,
1995). It seems that only negative symptoms distinguish schizo-
phrenia from ATPDs (Jäger et al., 2003a), while the Schneiderian
first-rank symptoms have raised doubts about their diagnostic spec-
ificity (Soares-Weiser et al., 2015). In addition, neurobiological stud-
ies reported metabolic and neurophysiological differences between
APPD, schizophrenia, and healthy controls, but their clinical meaning
remains unclear.
Moreover, relatively little evidence supports the continuity be-
tween APPD and the operational diagnosis of BD and CP (Peralta
and Cuesta, 2003; Pillmann et al., 2001, 2003c; van der Heijden
et al., 2004), although these disorders bear clinical and epidemiological
similarities to APPD (Beckmann and Franzek, 2001; Weibel and
Metzger, 2005).
The results of meta-analyses of first-episode psychosis studies
suggest that the overall stability of ATPDs is about 65% on average af-
ter 4.5 years (Fusar-Poli et al., 2016). ATPDs are also reported to have
a high risk of recurrence with subsequent transitions either to schizo-
phrenia and related disorders or to, a lesser extent, affective disorders
(Castagnini and Fusar-Poli 2017). Although we identified slightly more
than 50% of APPD cases with unchanged diagnosis over a mean period
of 8.8 years, it is likely that patients who did not develop longer-term
illness fared better than those with schizophrenia, persistent delu-
sional disorder, and bipolar disorder (Abe et al., 2006; Pillmann and
Marneros, 2005; Pillmann et al., 2012; Sajith et al., 2002). The predic-
tive power of APPD is also significantly greater than that of the
subtypes featuring schizophrenic and predominantly delusional
symptoms, and female sex, abrupt onset, and remission within
4 weeks are factors associated with temporal stability (Castagnini
and Foldager, 2014; Rusaka and Rancans, 2014a; Sajith et al.,
2002). In addition, patients with APPD are more likely to develop af-
fective disorders than schizphrenia and related disorders (Castagnini
and Foldager, 2014; Chang et al., 2009; Sajith et al., 2002; Salvatore
et al., 2011). This raises the question of the relationship between APPD
and mood disorders, but studies to date have failed to support any close
kinship to bipolar disorder (Castagnini et al., 2013c; Kanazawa
et al., 2013).
Finally, conditions such as the “nonaffective acute remitting psy-
choses” (NARP) have an uneven geographical distribution with higher
rates in developing countries, particularly in women (Susser and
Wanderling, 1994). These disorders have been reported in the wake
of stressful events, fever, or systemic infections, and do not fit to either
remitting schizophrenia or affective disorders in clinical profile, course,
and outcome (Alaghband-Rad et al., 2006; Arranz et al., 2009; Collins
et al., 1999; Malhotra et al., 1998; Susser et al., 1995a, 1995b, 1998),
but seldom meet the diagnostic criteria for ATPDs lasting longer than
1 or 3 months (Mojtabai et al., 2000). Interestingly, Hopper and
Wanderling (2000) examined the effect of NARP on outcome of schizo-
phrenia using data from incident cohorts of the WHO International
Study of Schizophrenia and proved that NARP were more common
among cases earlier diagnosed as schizophrenia in developing coun-
tries, but the advantage in outcome was greater in developed countries
and nearly the same for both sexes.
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The Journal of Nervous and Mental Disease • Volume 206, Number 11, November 2018
Implications for ICD-11
ICD-11 will move toward a narrower ATPD category cha-
racterized by acute onset within 2 weeks, polymorphic psychotic symp-
toms, and complete remission within 3 months, so as to bring it closer
to NARP's duration (Gaebel et al., 2015). In this context, the subtypes
featuring schizophrenic and predominantly delusional symptoms will
be reclassified as variants of either “schizophrenia” or “delusional dis-
order,” respectively, within the new section “schizophrenia spectrum
and other primary psychotic disorders.” Although clinical and epidemi-
ological studies suggest that APPD differs not only from the subtypes
with acute schizophrenic and predominantly delusional symptoms but
also from longer lasting psychotic and affective disorders, it seems
questionable whether APPD may constitute a reliable diagnosis owing
to the fleeting and polymorphic nature of its defining features
(Castagnini and Galeazzi, 2016). In addition, it will be not easy to iden-
tify cases in practice, as patients with APPD are numerically fewer than
those diagnosed with ATPDs, with adverse implications mainly in
developing countries, where this diagnosis is more commonly used
(Faiad et al., 2017).
These issues have been recently highlighted by findings of the
ICD-11 Ecological Implementation Field Studies conducted to test
the reliability and clinical utility of the proposed ICD-11 Clinical De-
scriptions and Diagnostic Guidelines (Reed et al., 2018), which in-
cluded only 40 cases of “acute and transient psychotic disorder with
polymorphic presentation” compared with 146 cases earlier diagnosed
as ICD-10 ATPDs, and diagnostic reliability (k = 0.45) resulted lower
than that of the F23.0 subtype (Sartorius et al., 1995). Consequently,
the description of this category will be revised for the final version of
the ICD-11 guidelines.
The new ATPD category might benefit from incorporating the
clinical features that lend themselves to easier assessment and offer,
at least, greater diagnostic reliability such as acute onset, florid
psychotic symptoms, and brief duration. This approach is consistent
with the principles of symptom-based modern classification and would
enable it to embrace a larger number of cases than those that fit with-
in APPD; while “polymorphic symptoms” might be added as a sup-
plementary clinical description. Moreover, close overlap with DSM-5
BPD will have positive implications for psychiatric practice, research,
and the wider understanding of short-lived psychotic disorders.
Limitations
Although little is known about vulnerability factors and neurobi-
ological correlates of APPD, there are enough data to make a prelimi-
nary assessment of its validity in view of the proposed ICD-11
revision of ATPD category. To extend this review, we conducted a
meta-analysis of pooled data comparing temporal stability of different
ATPD subtypes featuring polymorphic, schizophrenic, and predomi-
nantly delusional symptoms. Most samples, however, were small (one
accounted for about 90% of the total), and there were differences
in age cutoff, design (i.e., case register, prospective and retrospective
studies), and cultural setting. In addition, we identified 12 follow-up
studies satisfying the inclusion criteria, but 5 were excluded owing to
incomplete information (Chang et al., 2009; Jäger et al., 2003b;
Pillmann and Marneros, 2005; Rusaka and Rancans, 2014b; Singh
et al., 2004).
A further possible issue hinges on the fact that in some studies
APPD seems to be used as a synonym for CP (Ehlis et al., 2005;
Holm et al., 2017; Pepplinkhuizen et al., 2003); hence, their clinical
and nosological implications need to be considered cautiously.
CONCLUSIONS
These findings suggest that APPD is associated neither with
premorbid impairment nor high family risk and exhibits distinctive
clinical and epidemiological features and greater predictive validity
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Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Acute Polymorphic Psychotic Disorder
than the ATPD subtypes either with schizophrenic or predominantly
delusional symptoms, but its rarity and fleeting polymorphic symptoms
could reduce its usefulness in clinical practice and discourage research.
DISCLOSURE
The authors declare no conflict of interest.
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