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DSM-5 Attenuated Psychosis Syndrome in Adolescents Hospitalized With Non-psychotic Psychiatric Disorders

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Introduction: Although attenuated psychotic symptoms often occur for the first time during adolescence, studies focusing on adolescents are scarce. Attenuated psychotic symptoms form the criteria to identify individuals at increased clinical risk of developing psychosis. The study of individuals with these symptoms has led to the release of the DSM-5 diagnosis of Attenuated Psychosis Syndrome (APS) as a condition for further research. We aimed to characterize and compare hospitalized adolescents with DSM-5-APS diagnosis vs. hospitalized adolescents without a DSM-5-APS diagnosis. Methods: Interviewing help-seeking, hospitalized adolescents (aged 12-18 years) and their caregivers independently with established research instruments, we (1) evaluated the presence of APS among non-psychotic adolescents, (2) characterized and compared APS and non-APS individuals regarding sociodemographic, illness and intervention characteristics, (3) correlated psychopathology with levels of functioning and severity of illness and (4) investigated the influence of individual clinical, functional and comorbidity variables on the likelihood of participants to be diagnosed with APS. Results: Among 248 consecutively recruited adolescents (age=15.4 ± 1.5 years, females = 69.6%) with non-psychotic psychiatric disorders, 65 (26.2%) fulfilled APS criteria and 183 (73.8%) did not fulfill them. Adolescents with APS had higher number of psychiatric disorders than non-APS adolescents (3.5 vs. 2.4, p < 0.001; Cohen's d = 0.77), particularly, disruptive behavior disorders (Cramer's V = 0.16), personality disorder traits (Cramer's V = 0.26), anxiety disorders (Cramer's V = 0.15), and eating disorders (Cramer's V = 0.16). Adolescents with APS scored higher on positive (Cohen's d = 1.5), negative (Cohen's d = 0.55), disorganized (Cohen's d = 0.51), and general symptoms (Cohen's d = 0.84), and were more severely ill (Cohen's d = 1.0) and functionally impaired (Cohen's d = 0.31). Negative symptoms were associated with lower functional levels (Pearson ρ = -0.17 to -0.20; p = 0.014 to 0.031). Global illness severity was associated with higher positive, negative, and general symptoms (Pearson ρ = 0.22 to 0.46; p = 0.04 to p < 0.001). APS status was independently associated with perceptual abnormalities (OR = 2.0; 95% CI = 1.6-2.5, p < 0.001), number of psychiatric diagnoses (OR = 1.5; 95% CI = 1.2-2.0, p = 0.002), and impaired stress tolerance (OR = 1.4; 95% CI = 1.1-1.7, p = 0.002) (r 2 = 0.315, p < 0.001). Conclusions: A considerable number of adolescents hospitalized with non-psychotic psychiatric disorders meet DSM-5-APS criteria. These help-seeking adolescents have more comorbid disorders and more severe symptoms, functional impairment, and severity of illness than non-APS adolescents. Thus, they warrant high intensity clinical care. Keywords: Attenuated Psychosis Syndrome (APS); adolescence; epidemiology; prevention; psychosis; risk.
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Year: 2020
DSM-5 Attenuated Psychosis Syndrome in Adolescents Hospitalized With
Non-psychotic Psychiatric Disorders
Salazar de Pablo, Gonzalo ; Guinart, Daniel ; Cornblatt, Barbara A ; Auther, Andrea M ; Carrión,
Ricardo E ; Carbon, Maren ; Jiménez-Fernández, Sara ; Vernal, Ditte L ; Walitza, Susanne ;
Gerstenberg, Miriam ; Saba, Riccardo ; Lo Cascio, Nella ; Brandizzi, Martina ; Arango, Celso ; Moreno,
Carmen ; Van Meter, Anna ; Fusar-Poli, Paolo ; Correll, Christoph U
Abstract: Introduction: Although attenuated psychotic symptoms often occur for the rst time during
adolescence, studies focusing on adolescents are scarce. Attenuated psychotic symptoms form the criteria
to identify individuals at increased clinical risk of developing psychosis. The study of individuals with
these symptoms has led to the release of the DSM-5 diagnosis of Attenuated Psychosis Syndrome (APS)
as a condition for further research. We aimed to characterize and compare hospitalized adolescents with
DSM-5-APS diagnosis vs. hospitalized adolescents without a DSM-5-APS diagnosis. Methods: Inter-
viewing help-seeking, hospitalized adolescents (aged 12-18 years) and their caregivers independently with
established research instruments, we (1) evaluated the presence of APS among non-psychotic adolescents,
(2) characterized and compared APS and non-APS individuals regarding sociodemographic, illness and
intervention characteristics, (3) correlated psychopathology with levels of functioning and severity of ill-
ness and (4) investigated the inuence of individual clinical, functional and comorbidity variables on the
likelihood of participants to be diagnosed with APS. Results: Among 248 consecutively recruited ado-
lescents (age=15.4 ± 1.5 years, females = 69.6%) with non-psychotic psychiatric disorders, 65 (26.2%)
fullled APS criteria and 183 (73.8%) did not fulll them. Adolescents with APS had higher number of
psychiatric disorders than non-APS adolescents (3.5 vs. 2.4, p < 0.001; Cohen’s d = 0.77), particularly,
disruptive behavior disorders (Cramer’s V = 0.16), personality disorder traits (Cramer’s V = 0.26), anx-
iety disorders (Cramer’s V = 0.15), and eating disorders (Cramer’s V = 0.16). Adolescents with APS
scored higher on positive (Cohen’s d = 1.5), negative (Cohen’s d = 0.55), disorganized (Cohen’s d = 0.51),
and general symptoms (Cohen’s d = 0.84), and were more severely ill (Cohen’s d = 1.0) and functionally
impaired (Cohen’s d = 0.31). Negative symptoms were associated with lower functional levels (Pearson ฀
= -0.17 to -0.20; p = 0.014 to 0.031). Global illness severity was associated with higher positive, negative,
and general symptoms (Pearson ฀ = 0.22 to 0.46; p = 0.04 to p < 0.001). APS status was independently
associated with perceptual abnormalities (OR = 2.0; 95% CI = 1.6-2.5, p < 0.001), number of psychiatric
diagnoses (OR = 1.5; 95% CI = 1.2-2.0, p = 0.002), and impaired stress tolerance (OR = 1.4; 95% CI
= 1.1-1.7, p = 0.002) (r 2 = 0.315, p < 0.001). Conclusions: A considerable number of adolescents
hospitalized with non-psychotic psychiatric disorders meet DSM-5-APS criteria. These help-seeking ado-
lescents have more comorbid disorders and more severe symptoms, functional impairment, and severity of
illness than non-APS adolescents. Thus, they warrant high intensity clinical care. Keywords: Attenuated
Psychosis Syndrome (APS); adolescence; epidemiology; prevention; psychosis; risk.
DOI: https://doi.org/10.3389/fpsyt.2020.568982
Posted at the Zurich Open Repository and Archive, University of Zurich
ZORA URL: https://doi.org/10.5167/uzh-192092
Journal Article
Published Version
The following work is licensed under a Creative Commons: Attribution 4.0 International (CC BY 4.0)
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Originally published at:
Salazar de Pablo, Gonzalo; Guinart, Daniel; Cornblatt, Barbara A; Auther, Andrea M; Carrión, Ricardo
E; Carbon, Maren; Jiménez-Fernández, Sara; Vernal, Ditte L; Walitza, Susanne; Gerstenberg, Miriam;
Saba, Riccardo; Lo Cascio, Nella; Brandizzi, Martina; Arango, Celso; Moreno, Carmen; Van Meter, Anna;
Fusar-Poli, Paolo; Correll, Christoph U (2020). DSM-5 Attenuated Psychosis Syndrome in Adolescents
Hospitalized With Non-psychotic Psychiatric Disorders. Frontiers in Psychiatry, 11:568982.
DOI: https://doi.org/10.3389/fpsyt.2020.568982
2
ORIGINAL RESEARCH
published: 21 October 2020
doi: 10.3389/fpsyt.2020.568982
Frontiers in Psychiatry | www.frontiersin.org 1October 2020 | Volume 11 | Article 568982
Edited by:
Alessio Squassina,
University of Cagliari, Italy
Reviewed by:
George Foussias,
Center for Addiction and Mental
Health (CAMH), Canada
Arthur D. P. Mak,
The Chinese University of
Hong Kong, China
*Correspondence:
Christoph U. Correll
ccorrell@northwell.edu
Specialty section:
This article was submitted to
Neuroimaging and Stimulation,
a section of the journal
Frontiers in Psychiatry
Received: 02 June 2020
Accepted: 14 September 2020
Published: 21 October 2020
Citation:
Salazar de Pablo G, Guinart D,
Cornblatt BA, Auther AM, Carrión RE,
Carbon M, Jiménez-Fernández S,
Vernal DL, Walitza S, Gerstenberg M,
Saba R, Lo Cascio N, Brandizzi M,
Arango C, Moreno C, Van Meter A,
Fusar-Poli P and Correll CU (2020)
DSM-5 Attenuated Psychosis
Syndrome in Adolescents Hospitalized
With Non-psychotic Psychiatric
Disorders.
Front. Psychiatry 11:568982.
doi: 10.3389/fpsyt.2020.568982
DSM-5 Attenuated Psychosis
Syndrome in Adolescents
Hospitalized With Non-psychotic
Psychiatric Disorders
Gonzalo Salazar de Pablo 1,2 , Daniel Guinart 3,4 , Barbara A. Cornblatt 3,4, 5,
Andrea M. Auther 3,4, Ricardo E. Carrión 3,4,5, Maren Carbon 3, Sara Jiménez-Fernández 6,7 ,
Ditte L. Vernal 8, Susanne Walitza 9, Miriam Gerstenberg 9, Riccardo Saba 10 ,
Nella Lo Cascio 11, Martina Brandizzi 12 , Celso Arango 2, Carmen Moreno 2,
Anna Van Meter 3, 4,5 , Paolo Fusar-Poli1, 13,14 and Christoph U. Correll 3,4,5,15
*
1Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry,
Psychology & Neuroscience, King’s College London, London, United Kingdom, 2Department of Child and Adolescent
Psychiatry, Centro de Investigación Biomédica en Red de Salud Mental, General Universitario Gregorio Marañón School of
Medicine, Institute of Psychiatry and Mental Health, Hospital Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM),
Universidad Complutense, Madrid, Spain, 3Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen
Oaks, NY, United States, 4Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of
Medicine at Hofstra/Northwell, Hempstead, NY, United States, 5Institute for Behavioral Science, The Feinstein Institutes for
Medical Research, Manhasset, NY, United States, 6Child and Adolescent Mental Health Unit, Jaén Medical Center, Jaén,
Spain, 7Department of Psychiatry, University of Granada, Granada, Spain, 8Research Unit for Child- and Adolescent
Psychiatry, Aalborg University Hospital, Aalborg, Denmark, 9Psychiatric University Hospital Zurich, Department of Child and
Adolescent Psychiatry and Psychotherapy, Zurich, Switzerland, 10 Department of Mental Health, Rome, Italy, 11 Prevention
and Early Intervention Service, Department of Mental Health, Rome, Italy, 12 Local Health Agency Rome 1, Santo Spirito in
Sassia Hospital, Department of Mental Health, Inpatient Psychiatric Unit, Rome, Italy, 13Department of Brain and Behavioral
Sciences, University of Pavia, Pavia, Italy, 14Outreach and Support in South London Ser vice, South London and Maudsley
National Health Service Foundation Trust, London, United Kingdom, 15 Department of Child and Adolescent Psychiatry,
Charité Universitätsmedizin, Berlin, Germany
Introduction: Although attenuated psychotic symptoms often occur for the first time
during adolescence, studies focusing on adolescents are scarce. Attenuated psychotic
symptoms form the criteria to identify individuals at increased clinical risk of developing
psychosis. The study of individuals with these symptoms has led to the release of
the DSM-5 diagnosis of Attenuated Psychosis Syndrome (APS) as a condition for
further research. We aimed to characterize and compare hospitalized adolescents with
DSM-5-APS diagnosis vs. hospitalized adolescents without a DSM-5-APS diagnosis.
Methods: Interviewing help-seeking, hospitalized adolescents (aged 12–18 years) and
their caregivers independently with established research instruments, we (1) evaluated
the presence of APS among non-psychotic adolescents, (2) characterized and compared
APS and non-APS individuals regarding sociodemographic, illness and intervention
characteristics, (3) correlated psychopathology with levels of functioning and severity of
illness and (4) investigated the influence of individual clinical, functional and comorbidity
variables on the likelihood of participants to be diagnosed with APS.
Results: Among 248 consecutively recruited adolescents (age=15.4 ±1.5 years,
females =69.6%) with non-psychotic psychiatric disorders, 65 (26.2%) fulfilled APS
criteria and 183 (73.8%) did not fulfill them. Adolescents with APS had higher number
Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
of psychiatric disorders than non-APS adolescents (3.5 vs. 2.4, p<0.001; Cohen’s
d=0.77), particularly, disruptive behavior disorders (Cramer’s V =0.16), personality
disorder traits (Cramer’s V =0.26), anxiety disorders (Cramer’s V =0.15), and eating
disorders (Cramer’s V =0.16). Adolescents with APS scored higher on positive (Cohen’s
d=1.5), negative (Cohen’s d =0.55), disorganized (Cohen’s d =0.51), and general
symptoms (Cohen’s d =0.84), and were more severely ill (Cohen’s d =1.0) and
functionally impaired (Cohen’s d =0.31). Negative symptoms were associated with lower
functional levels (Pearson ρ= −0.17 to 0.20; p=0.014 to 0.031). Global illness
severity was associated with higher positive, negative, and general symptoms (Pearson
ρ=0.22 to 0.46; p=0.04 to p<0.001). APS status was independently associated
with perceptual abnormalities (OR =2.0; 95% CI =1.6–2.5, p<0.001), number of
psychiatric diagnoses (OR =1.5; 95% CI =1.2–2.0, p=0.002), and impaired stress
tolerance (OR =1.4; 95% CI =1.1–1.7, p=0.002) (r2=0.315, p<0.001).
Conclusions: A considerable number of adolescents hospitalized with non-psychotic
psychiatric disorders meet DSM-5-APS criteria. These help-seeking adolescents have
more comorbid disorders and more severe symptoms, functional impairment, and
severity of illness than non-APS adolescents. Thus, they warrant high intensity
clinical care.
Keywords: Attenuated Psychosis Syndrome (APS), adolescence, epidemiology, risk, psychosis, prevention
INTRODUCTION
Psychotic disorders, such as schizophrenia, are usually preceded
by a clinical high-risk for psychosis (CHR-P) state (1), which
is characterized by subtle symptoms, functional impairment
and help-seeking behavior (24), as well as non-psychotic
comorbidity (5,6). The CHR-P state, which includes individuals
at ultra-high risk for psychosis and/or those with basic
symptoms, has allowed preventive efforts to be implemented
(7,8). This area of clinical research has grown until it has
become one of the most established preventive approaches in
psychiatry (7,8).
The achievements and challenges of the CHR-P paradigm
have been recently appraised by an umbrella review (9). In
brief, three CHR-P subgroups have been established: attenuated
psychotic symptoms; brief limited and intermittent psychotic
symptoms (BLIPS) and genetic risk and deterioration (GRD)
syndrome (9,10). There are substantial diagnostic (11),
prognostic (10,12), clinical (13), and therapeutic (14) differences
across these three subgroups. For example, psychosis risk is
higher in the BLIPS group (38%) than in the attenuated psychotic
symptoms group (24%) and higher in both groups than in the
GRD group (8%) at >48 months follow-up (10).
Although most research and clinical studies have evaluated the
three groups together (1517), the most common group by far is
the attenuated psychotic symptoms group, which includes 85%
of CHR-P individuals (10). Psychosis-risk syndromes, including
attenuated psychotic symptoms, are usually characterized using
semi-structured interviews as the Structured Interview for
Psychosis-Risk Syndromes (SIPS) (18,19) or the Comprehensive
Assessment of At-Risk Mental States (CAARMS) (1), which
have comparable prognostic accuracy (20). In the SIPS,
the characterization used is Attenuated Positive Symptoms
Syndrome (APSS). Seven years ago, the DSM-5 introduced
the Attenuated Psychosis Syndrome (APS) diagnosis in the
research appendix, listed in both section II and section III
(21) (Figure 1). This diagnosis is defined by the presence of
delusions, hallucinations, or disorganized speech in attenuated
form, but with sufficient severity and frequency to warrant
clinical attention (23,24) (Figure 1). The diagnostic, prognostic,
and therapeutic characteristics of this diagnosis have been
recently appraised by a systematic review and meta-analysis (21).
This review concluded that DSM-5-APS criteria have received
substantial concurrent and prognostic validation, mostly driven
by research in adult populations (21). A previous study looking
at the agreement between CAARMS and DSM-5-APS criteria
found that the agreement was only moderate (kappa 0.59) (25).
Meanwhile, as findings from other studies point out (26,27), SIPS
and DSM criteria for APS are more similar (Figure 1).
While most reports to date on APS are based on cohorts that
also include adults (25,2830), APS features often occur for
the first time in adolescence (31,32). Broadly speaking, studies
that focus on DSM-5-APS in adolescents are scarce (21,22), and
there are few studies on APS in adolescents in clinical care and
hospital settings.
To our knowledge, only a few efforts have been made (22,33,
34) to characterize APS, excluding other ultra-high risk criteria,
and advance knowledge specifically in children and adolescents,
comparing them to other help-seeking individuals. Among them,
22 APS individuals were compared to other treatment-seeking
individuals and healthy controls regarding clinical and cognitive
features (34), finding that APS was associated with impaired
Frontiers in Psychiatry | www.frontiersin.org 2October 2020 | Volume 11 | Article 568982
Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
FIGURE 1 | DSM-5-APS Attenuated Psychosis Syndrome diagnostic criteria compared with SIPS operationalization [adapted from (Gerstenberg et al. (22); Salazar De
Pablo et al. (21)]. APS, Attenuated Psychosis Syndrome; APSS, Attenuated Positive Symptoms Syndrome; SIPS, Structured Interview for Psychosis-Risk Syndromes.
neurocognition. Also, APS was associated with self-reported
internalizing problems and thought problems in a study with 7
APS adolescents (33). One further study without a comparison
group found that an older age of APS presentation in adolescents
(comparing 9–14 years vs. 15–18 years) was associated with better
social and role functioning and fewer depressive symptoms (35).
There is little evidence on how many help-seeking adolescents
accessing inpatient care meet APS criteria. Our preliminary
data from the Adolescent Mood Disorder and Psychosis Study
(AMDPS) clinical study compared the first 21 APS and 68
non-APS adolescents who were recruited and found that APS
was present in 23.6% of psychiatrically hospitalized adolescents,
who suffered from a broad range of psychiatric symptoms and
disorders (22).
Although specific knowledge for APS is limited, CHR-P
individuals show impairments in work, educational and social
functioning as well as poor quality of life (9,36). Furthermore,
psychopathology can adversely influence functioning (37).
Negative symptoms have been associated with functioning, both
daily (38), work related (39) and real-world functioning (40).
Among CHR-P individuals, the severity of attenuated positive
and negative symptoms has been associated with some outcomes
[e.g., transition to psychosis (9,21)] but not with others [e.g.,
cannabis use (9)]. Our preliminary results showed that poorer
functioning in adolescents with APS was associated with more
severe attenuated positive, negative, and general symptoms (22).
In the CHR-P field, the influence of sociodemographic and
clinical variables on diagnostic and treatment outcomes has
been widely studied, particularly regarding the transition to
psychosis (4145). Unusual thought content and suspiciousness
have been found to predict conversion to psychosis along
with decline in social functioning, lower verbal learning and
memory performance (46). However, there is no convincing
evidence of the association between any variable and the onset
of psychotic disorders according to a meta-analysis, and only
attenuated positive psychotic symptoms and global functioning
show suggestive evidence (47). The influence of demographic
and clinical variables on the presence of APS, particularly in
adolescents, is even less known. In the first 89 individuals
recruited into AMDPS, lowest GAF score in the past year, and
social isolation were independently associated with APS (22).
The current study analyzes the final sample of this cohort
of hospitalized adolescents to (1) assess how many non-
psychotic, help-seeking adolescents accessing inpatient care meet
APS criteria, (2) describe and compare both groups regarding
sociodemographic, illness and intervention characteristics, (3)
correlate attenuated positive, negative, general and disorganized
symptoms with the level of functioning and severity of illness,
and (4) investigate the influence of individual clinical, functional
and comorbidity variables, selected empirically, on the likelihood
of participants to be diagnosed with APS.
Based on prior literature, we hypothesized that (1) a
significant number of adolescents with non-psychotic psychiatric
disorders would fulfill APS criteria, (2) APS individuals would
report significant comorbidity, clinical burden and functional
impairment that would exceed those of non-APS individuals, (3)
severity of negative symptoms would be significantly associated
with the level of functioning and severity of illness, and (4)
Frontiers in Psychiatry | www.frontiersin.org 3October 2020 | Volume 11 | Article 568982
Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
APS status would be associated with specific attenuated positive
symptoms and other clinical variables.
MATERIALS AND METHODS
Design and Setting
AMDPS was registered at ClinicalTrials.gov (NCT01383915).
Participants were recruited consecutively into AMDPS
between September 2009 and July 2017 from the Adolescent
Child and Adolescent Inpatient Unit of The Zucker Hillside
Hospital, New York, USA (48,49). AMDPS is an ongoing,
prospective study that aims to assess predictors of the
development of bipolar disorder and psychotic disorders in
hospitalized adolescents. Analyses for this study are restricted
to baseline data. The protocol was approved by the Institutional
Review Board of the North Shore-Long Island Jewish Health
System in accordance with the Helsinki Declaration of 1975
and the UNESCO Universal Declaration on human rights.
Written informed consent was obtained from subjects aged 18 or
the guardians/legal representatives of minors, obtaining written
assent from the minors.
Participants
Inclusion criteria for AMDPS study were: (1) age 12–18 years;
(2) hospitalized at the adolescent inpatient unit of The Zucker
Hillside Hospital, a self-standing psychiatric hospital; (3)
admission chart diagnosis of any bipolar-spectrum disorder,
cyclothymia, major depressive disorder, depressive disorder
not otherwise specified (NOS), dysthymia or mood disorder
NOS, schizophrenia, schizoaffective disorder, schizophreniform
disorder or psychotic disorder NOS, re-evaluated by research
interview, using the Structured Clinical Interview for DSM
Disorders (SCID) (50), supplemented for missing pediatric
diagnoses by the Schedule for Affective Disorders and
Schizophrenia for School-Age Children-Present and Lifetime
version (K-SADS-PL) (51); (4) subject and guardian/caregiver
(if subject<18) willing and able to provide written, informed
consent/assent. Exclusion criteria were: (1) an estimated
premorbid IQ<70; (2) DSM-5 clinical criteria for autism
spectrum disorders or pervasive developmental disorder and (3)
history of any neurological or medical condition known to affect
the brain.
For the purpose of this study, we also excluded patients: (1)
with a psychotic disorder according to DSM-5 criteria; (2) in
whom the Structured Interview for Psychosis-Risk Syndromes,
version 4.0 (52) was not completed (Figure 2).
Psychiatric diagnoses were established in diagnostic research
consensus conferences based on in-person independent
interview assessments of the adolescents and caregivers
whenever possible. The interviews were typically conducted a
few days after hospital admission. In consensus conferences,
both assessments were integrated assuming that symptoms are
more likely forgotten or hidden than invented or exaggerated.
Also, SIPS items were discussed one by one for both interviews
to reach to the correct value, and every psychiatric primary or
comorbid diagnosis, including APS, was discussed among all
the attendees and confirmed by the study lead (CUC). In order
to conduct AMDPS assessments, experienced clinicians had to
be certified by the study PI (CUC) after having gone through a
structured training program, which involved observing several
assessments, followed by conducting several assessments in front
of one of the certified trainers, and presenting their ratings as
part of a diagnostic consensus conference led by the study PI.
All raters continually took part in the diagnostic consensus
conference, during which all interview ratings were discussed
and finalized as part of a group consensus, which served to
assure validity of the ratings, facilitate interrater reliability via
consensual rating, and avoid rater drift after completion of the
initial training and certification.
Diagnostic Assessments
The Structured Interview for Psychosis-Risk Syndromes (SIPS)
(18,19) is a semi-structured interview used to diagnose
psychosis-risk syndromes in the last month. We used SIPS
Version 4.0 (53). It includes four primary sections according to
the symptoms evaluated: attenuated positive symptoms, negative
symptoms, disorganized symptoms, and general symptoms. As
part of the SIPS, the Scale of Prodromal Symptoms (SOPS) is
used to determine whether participants meet research criteria for
APSS. SIPS/SOPS psychometric instruments and DSM-5 criteria
were both used to diagnose DSM-5-APS in a precise way.
Clinical and Functional Assessments
Additional rating scales were administered to both adolescents
and their caregivers, including the Clinical Global Impression–
Severity scale (CGI-S; range =1–7) to assess the overall severity
of illness (54) and Global Assessment of Functioning (GAF) scale
(55) to assess global functioning. Social and role functioning were
assessed as well, using the Global Functioning: Social (GF: Social)
and the Global Functioning: Role (GF: Role) (56,57) scales.
Insight was assessed using the Scale to Assess Unawareness of
Mental Disorder (SUMD) (58), using three general awareness
items: mental disorder, social consequences of mental disorder,
and achieved effect of medication. Suicidality was assessed as the
% of individuals who reported suicidal ideation lifetime and those
with a history of at least one suicide attempt prior to admission.
Data Analysis
We used descriptive statistics to characterize the study
population, including diagnosis according to DSM-5 criteria,
demographic variables, clinical characteristics and treatment
characteristics. Between-group comparisons of categorical
variables were performed using χ2-test or Fisher’s exact
test, whenever at least one cell contained 5 patients. For
comparisons of continuous variables, we used t-test. The
following effect sizes were calculated: (a) Cramer’s V for χ2(59),
which was interpreted as follows: 0.1=small; 0.3=moderate;
0.5=large effect size; and (b) Cohen’s d (60) for t-test, which
was interpreted as follows: 0.2=small; 0.5=moderate; 0.8=large
effect size, using effect size calculator for t-test (61). We
correlated attenuated positive, negative, general and disorganized
symptoms with the level of functioning and severity of illness
using Pearson’s correlation. We finally conducted a multivariable,
backward logistic regression analysis, entering into the model
Frontiers in Psychiatry | www.frontiersin.org 4October 2020 | Volume 11 | Article 568982
Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
FIGURE 2 | Flowchart outlining selection of study population. SIPS, Structured Interview for Psychosis-Risk Syndromes.
variables that were significantly different (p<0.05) between
APS vs. non-APS groups in univariate analyses with data in
>67% of subjects. For DSM-5 diagnoses, we entered into the
multivariable model broad diagnostic categories (e.g., anxiety
disorders), instead of single diagnoses (e.g., panic disorder),
that were significantly different between the APS and non-APS
group, in order to maximize power for the analyses. For the SIPS
psychopathology symptoms, we included only individual items
and not subscale sum scores to identify potentially clinically
relevant symptoms that can guide clinical identification of APS
status. The percent variance explained by the significant variables
retained in the final multivariable logistic regression model was
expressed as r2. Significance level was set at alpha=0.05, and all
tests were two-tailed. Statistical analyses were performed with
SPSS 21 for Windows software (IBM) (62).
RESULTS
Demographic, Comorbidity and Treatment
Characteristics
Altogether, 403 help-seeking adolescents and their
guardians/legal representatives were consented into AMDPS.
Of those, 79 (16.9%) were excluded from this study due to
incomplete information on the SIPS, and of the remaining
324 patients, 76 (23.5%) had a psychotic disorder and were
therefore also excluded. Finally, 248 hospitalized adolescents
with non-psychotic psychiatric disorders were included in this
study. Of those, 65 (26.2%) fulfilled DSM-5-APS criteria and 183
(83.8%) did not fulfill APS criteria (Figure 2). Agreement was
100% between DSM-5 clinical criteria and the SIPS.
Table 1 shows the demographic, illness and baseline
treatment characteristics of the sample at the time of the
interview. The average age of participants was 15.4 years
(SD=1.5). Most participants were female (69.4%) and white
(54.6%). There were no significant differences between
the two groups in any of the demographic characteristics
(Table 1).
APS individuals had a higher number of comorbid disorders
(3.5 vs. 2.4, p<0.001; Cohen’s d =0.77) compared
to non-APS individuals. The most frequent in the total
sample (APS plus non-APS) were depressive disorders (77.0%),
particularly major depressive disorder (55.2%), followed by
anxiety disorders (42.7%), and disruptive behavior disorders
(39.1%). The following disorders were significantly more
common in individuals with APS vs. non-APS: disruptive
behavior disorders (p=0.011; Cramer’s V =0.16), including
oppositional defiant disorder (p=0.03; Cramer’s V =0.14),
and conduct disorder (p=0.049; Cramer’s V =0.12); bipolar
disorders (p=0.002, Cramer’s V =0.20), including other
specified bipolar and related disorders (p=0.005; Cramer’s
V=0.18)—also known as bipolar disorder NOS as defined
by the COBY study criteria (63)–; personality disorder traits
(p<0.001; Cramer’s V =0.26), including borderline personality
disorder traits (p=0.002; Cramer’s V =0.20) and other
personality disorder traits (p<0.001; Cramer’s V =0.27);
anxiety disorders (p=0.016; Cramer’s V =0.15), including
panic disorder (p=0.031; Cramer’s V =0.14), generalized
anxiety disorder (p=0.011; Cramer’s V =0.16) and specific
phobia (p=0.005; Cramer’s V =0.18); and eating disorders
(p=0.012; Cramer’s V =0.16). The two groups did
not differ in comorbid depressive disorders, substance use
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Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
TABLE 1 | Demographic, comorbidity and treatment characteristics.
Total
(n=248)
APS
(n=65)
Non-APS
(n=183)
P-value Effect size
Demographic characteristics
Sex, male, n(%) 76 (30.6) 16 (24.6) 60 (32.8) 0.22 0.078
Age (years) mean ±SD 15.4 ±1.5 15.5 ±1.3 15.4 ±1.5 0.63 0.070
Race/ethnicity, n, (%)a0.60 0.11
White 124 (54.6) 32 (55.2) 92 (54.4)
Black or African American 41 (18.1) 13 (22.4) 28 (16.6)
Other 31 (13.7) 8 (13.8) 23 (13.6)
Asian or Pacific Islander 28 (12.3) 5 (8.6) 23 (13.6)
Indian American 3 (1.3) 0 (0.0) 3 (1.8)
Estimated IQ, mean ±SD 108.4 ±18.9 107.2 ±17.8 108.8 ±19.3 0.56 0.088
Lifetime consensus diagnoses, n(%)
Number of psychiatric diagnoses 2.6 ±1.5 3.5 ±1.5 2.4 ±1.4 <0.001 0.77
Depressive disorders 191 (77.0) 52 (80.0) 139 (76.0) 0.51 0.042
Major depressive disorder 137 (55.2) 42 (64.6) 95 (51.9) 0.077 0.11
Other specified depressive disorder 53 (21.4) 10 (15.4) 43 (23.5) 0.170 0.087
Persistent depressive disorder 18 (7.3) 5 (7.7) 13 (7.1) 0.87 0.010
Disruptive, impulse-control and conduct disorders 97 (39.1) 34 (52.3) 63 (34.4) 0.011 0.16
Attention-deficit/hyperactivity disorder 58 (23.4) 13 (20.0) 45 (24.6) 0.45 0.048
Oppositional defiant disorder 40 (16.1) 16 (24.6) 24 (13.1) 0.03 0.14
Conduct disorder 26 (10.5) 11 (16.9) 15 (8.2) 0.049 0.12
Disruptive behavior disorder not otherwise specified 11 (4.4) 4 (6.2) 7 (3.8) 0.43 0.050
Bipolar disorders 57 (23.0) 24 (36.9) 33 (18.0) 0.002 0.20
Other specified bipolar and related disorder 41 (16.5) 18 (27.7) 23 (12.6) 0.005 0.18
Bipolar I disorder 12 (4.8) 6 (9.2) 6 (3.3) 0.055 0.12
Bipolar II disorder 8 (3.2) 3 (4.6) 5 (2.7) 0.46 0.047
Personality disorder traits 48 (19.4) 24 (36.9) 24 (13.1) <0.001 0.26
Borderline personality disorder traits 42 (16.9) 19 (29.2) 23 (12.6) 0.002 0.20
Other personality disorder traits 13 (5.2) 10 (15.4) 3 (1.6) <0.001 0.27
Substance use disorders 39 (15.7) 13 (20.0) 26 (14.2) 0.27 0.070
Cannabis use disorder 31 (12.5) 9 (13.8) 22 (12.0) 0.70 0.024
Alcohol use disorder 14 (5.6) 6 (9.2) 8 (4.4) 0.14 0.093
Others 6 (2.4) 2 (3.1) 4 (2.2) 0.67 0.026
Trauma- and stressor-related disorders 38 (15.3) 8 (12.3) 30 (16.4) 0.43 0.050
Posttraumatic stress disorder 20 (8.1) 7 (10.8) 13 (7.1) 0.35 0.059
Adjustment disorder 19 (7.7) 2 (3.1) 17 (9.3) 0.11 0.10
Anxiety disorders 106 (42.7) 36 (55.4) 70 (38.3) 0.016 0.15
Panic disorder 63 (25.4) 23 (35.4) 40 (21.9) 0.031 0.14
Generalized anxiety disorder 37 (14.9) 16 (24.6) 21 (11.5) 0.011 0.16
Social phobia 24 (9.7) 10 (15.4) 14 (7.7) 0.07 0.11
Others 20 (8.1) 5 (7.7) 15 (8.2) 0.90 0.008
Obsessive-compulsive disorder 13 (5.2) 6 (9.2) 7 (3.8) 0.093 0.11
Specific phobia 9 (3.6) 6 (9.2) 3 (1.6) 0.005 0.18
Other diagnostic categories
Eating disorders 20 (8.1) 10 (15.4) 10 (5.5) 0.012 0.16
Enuresis (not due to a general medical condition) 9 (3.6) 3 (4.6) 6 (3.3) 0.62 0.031
Treatment characteristics at time of the interview n(%)b
Antipsychoticsc118 (53.6) 37 (66.1) 81 (49.4) 0.031 0.15
Antidepressantsd112 (50.9) 24 (42.9) 88 (53.7) 0.16 0.094
Mood stabilizerse55 (25.0) 14 (25.0) 41 (25.0) 1.0 0.000
(Continued)
Frontiers in Psychiatry | www.frontiersin.org 6October 2020 | Volume 11 | Article 568982
Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
TABLE 1 | Continued
Total
(n=248)
APS
(n=65)
Non-APS
(n=183)
P-value Effect size
Lithium 41 (18.6) 9 (16.1) 32 (19.5) 0.57 0.038
Anxiolyticsf23 (10.5) 7 (12.5) 16 (9.8) 0.56 0.039
Othersh21 (9.5) 7 (12.5) 14 (8.5) 0.38 0.059
Antiepileptic drugs 18 (8.2) 6 (10.7) 12 (7.3) 0.42 0.054
ADHD medicationg4 (1.8) 0 (0.0) 4 (2.4) 0.24 0.080
Two or more drugs 91 (41.4) 22 (39.3) 69 (42.1) 0.71 0.025
Three or more drugs 25 (11.4) 7 (12.5) 18 (11.0) 0.76 0.021
ADHD, Attention Deficit Hyperactivity Disorder; APS, Attenuated Psychosis Syndrome.
aInformation available for 227 individuals.
bInformation available for 220 individuals.
cAntipsychotics: aripiprazole, molindone, quetiapine, risperidone, lurasidone, ziprasidone, olanzapine, haloperidol, chlorpromazine, clozapine.
dAntidepressants: amitriptyline, nortriptyline, bupropion, citalopram, escitalopram, duloxetine, fluoxetine, paroxetine, sertraline, venlafaxine, mirtazapine.
eMood stabilizers: lamotrigine, lithium, valproic acid.
fAnxiolytics/tranquilizers: clonazepam, lorazepam, hydroxyzine, buspirone.
gAnti-ADHD medications: atomoxetine, lisdexamphetamine, methylphenidate, modafinil, clonidine, guanfacine.
hOthers: zolpidem, melatonin, propranolol, diphenhydramine, amlodipine.
Bold values indicate p <0.05 for between-groups analysis.
disorders, trauma and stressor-related disorders or enuresis
(all p>0.05).
Overall, the most used psychotropic medications at the time
of the interview were antipsychotics (53.6%; p=0.031), followed
by antidepressants (50.9%; p=0.16), and mood stabilizers
(25.0%; p=1.0). Antipsychotics, which were more common
in the APS group (p=0.031; Cramer’s V =0.15), were the
only medication class that was significantly different between the
groups. The use of multiple medications (use of two or more
drugs or use of three or more drugs) was equally frequent in both
groups (p=0.71 to 0.76).
Severity of Symptoms and Symptom
Domains
Total attenuated positive (p<0.001; Cohen’s d =1.5), negative
(p<0.001; Cohen’s d =0.55), disorganized (p<0.001;
Cohen’s d =0.51), and general (p<0.001; Cohen’s d =0.84)
symptom scores were significantly higher in APS individuals
vs. non-APS hospitalized adolescents. All group-defining
SIPS attenuated positive symptoms (unusual thought content,
suspiciousness, grandiosity, perceptual abnormalities and
disorganized communication) were significantly more severe in
the APS group (Cohen’s d =0.39 to 1.3), with the largest effect
size for perceptual abnormalities (Cohen’s d =1.3) (Table 2).
Additionally, the following symptoms were more severe in the
APS vs. non-APS group: social anhedonia (p<0.001; Cohen’s
d=0.57), avolition (p=0.002; Cohen’s d =0.51), experiences
of emotions and self (p<0.001; Cohen’s d =0.54), bizarre
thinking (p<0.001; Cohen’s d =0.60), trouble with focus and
attention (p=0.001; Cohen’s d =0.53), sleep disturbances
(p=0.002; Cohen’s d =0.38), dysphoric mood (p=0.004;
Cohen’s d =0.34) and impaired stress tolerance (p<0.001;
Cohen’s d =0.63).
Illness Severity, Functional Level, Illness
Insight and Suicidality
Overall illness severity (CGI-S) was higher in the APS group
(p<0.001) and the effect size was large (Cohen’s d =1.0). The
mean current GAF score was 23.0 ±11.9 in the APS group
and 28.1 ±17.9 in the non-APS group (p=0.012; Cohen’s
d=0.31). Scores for the highest functioning in the past year
(p=0.002; Cohen’s d =0.52) and lowest functioning in the past
year (p=0.002; Cohen’s d =0.38) were lower in the APS group
as well (i.e., poorer functioning in the APS group). Unlike current
role functioning, which did not differ significantly between the
groups (p=0.35), current social functioning was better in the
non-APS group (p=0.003; d =0.66). Both groups did not differ
regarding awareness of mental disorder or social consequences,
suicidal ideation or suicidal attempts (all p>0.05) (Table 3).
Correlation Between Symptom Domains
and Functioning (GAF)–Severity of Illness
(CGI-S)
Total negative symptoms were significantly correlated with lower
current functioning (Pearson ρ= −0.17; p=0.031), lower lowest
functioning in the past year (Pearson ρ= −0.20; p=0.014)
and lower highest functioning reached in the past year (Pearson
ρ= −0.19; p=0.022). Functioning was not significantly
correlated with attenuated positive symptoms, disorganized
symptoms or general symptoms. The severity of illness was
associated with more severe SIPS positive, negative, disorganized
and general symptoms (Pearson ρ=0.22 to 0.46; p=0.04 to
p<0.001) (Table 4).
Multivariable Logistic Regression Analysis
Independent correlates of APS in the final model were perceptual
abnormalities (OR =2.0; 95% CI =1.6–2.5, p<0.001), number
of psychiatric diagnoses (OR =1.5; 95% CI =1.2–2.0, p=0.002),
Frontiers in Psychiatry | www.frontiersin.org 7October 2020 | Volume 11 | Article 568982
Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
TABLE 2 | Severity of structured interview of prodromal syndromes (SIPS) assessed symptoms and symptom domains.
Total
(n=248)
APS
(n=65)
Non-APS
(n=183)
P-value Effect size
Structured interview of prodromal syndromes mean±SD
Positive symptoms
Total positive symptom score 3.2 ±4.1 7.4 ±4.6 1.9 ±3.3 <0.001 1.5
Highest positive symptom score 1.8 ±1.8 3.5 ±1.3 1.2 ±1.6 <0.001 1.5
P1 unusual thought content 0.73 ±1.4 1.6 ±1.6 0.41 ±1.1 <0.001 0.95
P2 suspiciousness 0.84 ±1.3 1.8 ±1.6 0.48 ±0.93 <0.001 1.2
P3 grandiosity 0.54 ±1.2 0.89 ±1.5 0.41 ±1.1 0.024 0.39
P4 perceptual abnormalities/hallucinations 0.99 ±1.7 2.3 ±1.9 0.47 ±1.2 <0.001 1.3
P5 disorganized communication 0.29 ±0.86 0.63 ±1.1 0.16 ±0.68 <0.001 0.58
Negative symptoms
Total negative symptom score 8.0 ±6.22 10.4 ±6.7 7.1 ±5.8 <0.001 0.55
Highest negative symptom score 3.4 ±1.83 3.8 ±1.6 3.2 ±1.9 0.012 0.33
N1 social anhedonia 1.5±1.79 2.2 ±1.9 1.2 ±1.7 <0.001 0.57
N2 avolition 2.1 ±2.0 2.9 ±1.7 1.9 ±2.0 0.002 0.51
N3 expression of emotions 0.88 ±1.5 1.2 ±1.6 0.75 ±1.4 0.061 0.31
N4 experience of emotions and self 0.87 ±1.7 1.6 ±2.3 0.65 ±1.4 <0.001 0.54
N5 ideational richness 0.20 ±0.65 0.18 ±0.18 0.21 ±0.75 0.88 0.050
N6 occupational functioning 2.4 ±2.1 2.5 ±2.4 2.3 ±2.0 0.31 0.11
Disorganized symptoms
Total disorganized symptom score 3.1 ±3.2 4.3 ±3.7 2.7 ±2.9 <0.001 0.51
Highest disorganized symptom score 2.2 ±1.9 2.9 ±1.7 2.03 ±1.9 0.003 0.47
D1 odd behavior or appearance 0.16 ±0.94 0.14 ±1.4 0.17 ±0.71 0.297 0.03
D2 bizarre thinking 0.18 ±0.7 0.48 ±1.1 0.08 ±0.4 <0.001 0.60
D3 trouble with focus and attention 1.9 ±1.8 2.6 ±1.7 1.66 ±1.81 0.001 0.53
D4 impairment in personal hygiene 0.76 ±1.7 0.86 ±2.1 0.73 ±1.54 0.45 0.08
General symptoms
Total general symptom score 8.4 ±4.5 11.0 ±3.5 7.5 ±4.4 <0.001 0.84
Highest general symptom score 4.3 ±1.7 5.0 ±1.1 4.1 ±1.8 <0.001 0.55
G1 sleep disturbance 2.3 ±1.9 2.8 ±2.0 2.1 ±1.8 0.002 0.38
G2 dysphoric mood 4.0 ±2.1 4.5 ±2.3 3.8 ±2.0 0.004 0.34
G3 motor disturbance 0.14 ±0.80 0.17 ±1.4 0.13 ±0.52 0.73 0.05
G4 impaired stress tolerance 1.9 ±2.1 2.9 ±2.3 1.6 ±1.9 <0.001 0.63
Bold values indicate p <0.05 for between-groups analysis.
and impaired stress tolerance (OR =1.4; 95%CI =1.1–1.7,
p=0.002). The model including these three variables explained
31.5% of the variance (r2=0.315, p<0.001) (Table 5).
DISCUSSION
To our knowledge, this study is one of the very few and the
largest to date to characterize and describe sociodemographic,
illness and intervention characteristics in adolescents with APS
vs. non-APS. Additionally, this study focused on help-seeking
adolescents who had been admitted into an inpatient unit.
According to our results, 26.2% of the adolescents without a
psychotic disorder diagnosis fulfilled APS criteria, a somewhat
lower prevalence compared to a previous study including mostly
adolescent outpatients (33%) (64,65), but still a clinically
significant and higher prevalence than the one found in non-
help-seeking adolescents with disruptive behaviors (13%) (33).
In the general population, a 7.2% meta-analytical prevalence of
psychotic experiences was estimated in children and adults (66).
In the Philadelphia Neurodevelopmental Cohort study, 15.5%
of the 8–21 year old individuals reported significant psychotic
symptoms and another 9.8% reported milder symptoms (67).
APS individuals had a higher number and distribution
of comorbid conditions than non-APS individuals (Cohen’s
d=0.77), particularly consisting of depressive disorders (5),
anxiety disorders (5), and disruptive behavior disorders (68).
This finding is clinically relevant because APS status has been
associated with hospital treatment for mood and conduct
disorders (33). Personality disorder traits, bipolar disorders,
disruptive behavior disorders, eating disorders and anxiety
disorders, were more frequent in the APS group than the
non-APS group, although effect sizes were small. This result
supports evidence of the association between APS (21,22) as
well as CHR-P (9,69) with other comorbid mental disorders.
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Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
TABLE 3 | Illness severity, functional level, illness insight and suicidality.
Total
(n=248)
APS
(n=65)
Non-APS
(n=183)
P-value Effect size
Characteristics
Illness severity: clinical global impressions-severity scale (CGI-S) mean ±SDa
Overall severity of illness 4.2 ±1.03 4.8 ±0.94 3.9 ±0.9 <0.001 1.0
Functional level: global assessment of functioning-scale (GAF) mean ±SDb
Current GAF 26.8 ±16.7 23.0 ±11.9 28.1 ±17.9 0.012 0.31
Highest GAF of past year 57.7 ±14.7 52.2 ±16.6 59.7 ±13.5 0.002 0.52
Lowest GAF of past year 23.1 ±15.0 18.9 ±10.2 24.5 ±16.0 0.002 0.38
Global functioning: role scale mean ±SDc
Current role functioning 5.9 ±1.8 5.7 ±1.7 6.1 ±1.9 0.35 0.20
Global functioning: social scale mean ±SDc
Current social functioning 6.5 ±1.7 5.8 ±1.5 6.9 ±1.7 0.003 0.66
Scale to assess unawareness of mental disorder mean ±SDd
Awareness of mental disorder 2.2 ±1.7 2.2 ±1.6 2.2 ±1.7 0.98 0.006
Awareness of the effect of medication 2.1 ±1.5 2.2 ±1.5 2.0 ±1.5 0.45 0.14
Awareness of the social consequences 1.9 ±1.5 1.9 ±1.4 1.9 ±1.5 0.99 0.0
Suicidality, n(%)e
Suicidal ideation 131 (61.8) 38 (73.1) 93 (58.1) 0.29 0.067
Suicide attempts 21 (10.0) 8 (15.3) 13 (8.2) 0.19 0.082
aData available for 86 patients.
bData available for 225 patients.
cData available for 88 patients.
dData available for 168 patients.
eData available for 212 patients.
Bold values indicate p <0.05 for between-groups analysis.
TABLE 4 | Correlation between Structured Interview of Prodromal Syndromes (SIPS) symptom domains and functioning as well as severity of illness.
Current GAF Lowest GAF past year Highest GAF past year Severity of illness CGI-S
Pearson’s Rho p-value Pearson’s Rho p-value Pearson’s Rho p-value Pearson’s Rho p-value
Total SIPS positive symptom score 0.034 0.66 0.045 0.57 0.0005 0.95 0.46 <0.001
Total SIPS negative symptom score 0.17 0.031 0.20 0.014 0.19 0.022 0.39 <0.001
Total SIPS disorganized symptom score 0.04 0.58 0.06 0.46 0.043 0.61 0.22 0.04
Total SIPS general symptom score 0.095 0.21 0.082 0.3 0.017 0.36 0.45 <0.001
CGI-S, Clinical Global Impression–Severity scale; GAF, Global Assessment of Functioning; SIPS, Structured Interview for Psychosis-Risk Syndromes.
Bold values indicate p <0.05 for between-groups analysis.
TABLE 5 | Results of the multivariable, backward elimination logistic regression analysis of variables distinguishing APS vs. non-APS at p<0.05 in univariate analyses.
B SE Wald Sig OR 95.0% C.I.
Lower Upper
SIPS P4 perceptual abnormalities/hallucinations 0.69 0.11 38.9 <0.001 2.0 1.6 2.5
SIPS G4 impaired stress tolerance 0.31 0.10 9.8 0.002 1.4 1.1 1.7
Number of psychiatric diagnoses 0.42 0.14 9.5 0.002 1.5 1.2 2.0
(r2=0.315, p <0.001).
Bold values indicate p <0.05 for between-groups analysis.
Thus, comorbidity should not rule out APS, but, if anything,
increase the diagnostic suspicion. On the other hand, it is
also possible for APS status to be a byproduct of overlapping
disease processes and expressions of non-psychotic disorders,
lowering the true risk for developing a psychotic disorder in the
future (22,28,70).
Regarding psychopharmacological treatment, as previously
reported (22), a high percentage of our non-psychotic APS
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Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
sample received atypical antipsychotics (66.1%), which was
also high in the non-psychotic non-APS individuals (49.4%).
This finding is worrying because no consistent meta-analytical
evidence supports the use of atypical antipsychotic drugs
in delaying or preventing transition to psychosis over other
interventions (71,72). However, it is also true that rates
of antipsychotics were high in other diagnostic groups in
this sample, including bipolar-spectrum disorders (49), which
supports that atypical antipsychotic use is likely related to
the reason for admission to the psychiatric unit and not
only to efforts to treat attenuated psychotic symptoms or to
prevent full-blown psychosis. Nevertheless, the widespread use of
antipsychotics in adolescents for non-psychotic, predominantly
depressive disorders is concerning due to the established adverse
effects risks that atypical antipsychotics have in youth (7377).
APS status was associated with a significantly higher severity
of attenuated psychotic symptoms according to the SIPS. Effect
sizes for these differences were moderate to large (Cohen’s
d=0.51 to 1.5). Regarding individual items, differences were
found in 13/19 items. Effect sizes were large for unusual thought
content, suspiciousness and perceptual abnormalities (Cohen’s
d=1.0 to 1.3), medium for disorganized communication, social
anhedonia, avolition, experience of emotions and self, bizarre
thinking, trouble with focus and attention and impaired stress
tolerance (Cohen’s d =0.50 to 0.63), and small for grandiosity,
sleep disturbances and dysphoric mood (Cohen’s d =0.34
to 0.39).
This greater severity in psychopathology also translated into
greater illness severity (Cohen’s d =1.0) and poorer functioning
(Cohen’s d =0.31 to 0.52), as found before (9,22,78,
79), including social functioning (Cohen’s d =0.66), but not
role functioning. However, a previous study using the same
instruments found that both social and role functioning were
significantly more impaired in CHR-P individuals compared to
controls from as early as age 12, which was our lower age limit
(80). However, controls in that study were healthy, while in our
sample, we compared hospitalized adolescents with vs. without
APS who were likely admitted for symptoms related to other
psychiatric disorders, which can explain the difficulties in role
functioning as well as social and general functioning. The fact
that all adolescents (APS and non-APS) reached stringent US
criteria for inpatient care resulted in the low functioning scores
found in both groups. Nevertheless, our results support previous
evidence that APS status is associated with marked functional
impairment (21,81,82). This finding is particularly relevant
because functional impairment can be helpful to differentiate
youth meeting CHR-P from other help-seeking individuals (83).
Interestingly, while illness severity was associated with
overall psychopathology, including more severe SIPS total
positive, negative, disorganized and general symptoms (Pearson
ρ= −0.22 to 0.46), functioning (current, lowest and
highest) was only and weakly (Pearson ρ= −0.17 to
0.20) correlated with total negative symptoms, but not
with attenuated positive, disorganized and general symptoms.
Negative symptoms have been associated with functioning (38
40), not only in schizophrenia, but also in other psychotic
individuals, and non-psychotic depressed patients (84). This
association was found to be greater with negative than attenuated
positive symptoms (85), in line with our results. In contrast,
trauma has been found to be correlated with the severity of
attenuated positive symptoms but not with negative symptoms
in CHR-P individuals (86); yet, CHR-P individuals’ negative
symptoms may impact the transition to psychosis even more than
attenuated positive symptoms (87), although this has not been
found consistently (53).
According to our results, perceptual abnormalities (OR=2.0),
number of psychiatric diagnoses (OR=1.5), and impaired stress
tolerance (OR=1.4) were independently associated with APS
status. Among perceptual abnormalities, auditory perceptual
abnormalities have been associated with a higher risk of
psychosis, while visual perceptual abnormalities have been
associated with a lower risk (88). While the number of psychiatric
diagnoses was independently associated with APS status in
our study, and while APS has previously been associated with
comorbid mental disorders, the impact of the different comorbid
conditions may vary (21,22). The most common comorbid
conditions in our sample, anxiety and depressive diagnoses, have
been associated with impaired global functioning, as well as
higher suicidality or self-harm behaviors, but not with transition
to psychosis (5). Implications of the presence of other comorbid
conditions in APS and their relevance for true risk for conversion
to psychosis need further study, particularly in adolescents. Our
results further support previous evidence that impaired stress
tolerance is a core CHR-P feature, which is associated with
more severe psychopathology (89). The presence of impaired
stress tolerance has been also suggested to have therapeutic
implications in CHR-P (90).
We also found that APS was associated with functioning in
univariate analyses, but not in multivariable analyses, supporting
that lower functioning is related to other features, including
the presence and duration of attenuated positive symptoms
(21,91) and impaired stress tolerance (89). A model including
disorganized communication, suspiciousness, verbal memory
deficits, and decline in social functioning was found to predict
conversion to psychosis (53). Due to having introduced the
Global Functioning scales later into the study, they were
only available in a subset of patients and could not be
entered into the backward elimination logistic regression model.
However, APS was associated with significantly lower levels of
social functioning. Clinicians should thus monitor functioning,
especially social functioning in adolescents with APS.
Finally, our results stress that in adolescent inpatients, DSM-
5 APS is associated with higher severity of overall illness, lower
functioning and impaired stress tolerance, requiring a higher
intensity of clinical care compared to non-APS adolescents
admitted into an inpatient unit. This result is supported by prior
findings showing that youth with APS have complex medical
histories and frequent comorbidities that require therapeutic
attention (22,28,70). Research about effective treatments for
DSM-5-APS has been limited (21), and evidence from studies
analyzing CHR-P individuals—from which knowledge could
arguably be applied to APS individuals—does not support one
treatment over another (72). At the moment, at least needs-based
interventions should be offered (9). Perceptual abnormalities
and impaired stress tolerance may be targets of needs-based
interventions in adolescents aiming to improve quality of life
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Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
and aiming to reduce burden for them and their families. Still,
prospective studies are needed to inform and develop guidelines
regarding youth fulfilling APS criteria.
Strengths and Limitations
The current study has several strengths and limitations that
must be taken into consideration when interpreting its results.
First, some symptom assessments were based on retrospective
recall, which may be prone to recall bias. However, all SIPS
symptoms were rated for presence in the last month. Second,
the comparison group, including non-psychotic adolescents who
fulfilled criteria for inpatient care in the US health care system,
was otherwise heterogeneous and functionally impaired. The
results should thus be interpreted in the context of help-seeking
APS and non-APS samples in need of inpatient care. Third,
data were not available to determine to what degree adolescents
with APS sought help specifically for APS-related symptomology.
Fourth, we did not collect some potentially relevant information,
including the reason for the use of psychotropic medications or
dosage, which could have relevant implications. Similarly, verbal
memory deficits and other cognitive measures, which are relevant
according to previous research, were not included in the current
analysis. Fifth, we could not retrieve the data for the total number
of patients fulfilling our inclusion criteria within our study
timeframe outside of this study. Thus, we could not report the
participation rate. Sixth, we did not test for interrater reliability
of interviewers for all scales used in this study. However, using
the same training, certification and ongoing recalibration system
via mandatory presence and presentation of all rating scale scores
for all interviewers as part of the regular diagnostic consensus
conference (led by the study PI CUC) the interrater reliability
of the BPSS-FP indices ranged from intraclass-correlations of
0.93–0.98 (92). Seventh, since the Clinical Global Impressions of
Severity Scale and social and role function scales were introduced
later into the study, data were not available in a sufficiently large
number of patients to enter this variable into the multivariable
regression analysis; Eighth, the final model obtained from the
multivariable regression analysis was not validated, which may
have led to overfitting, thus requiring replication and limiting its
generalizability and consequently its implementation in clinical
practice. Finally, the cross-sectional design precludes any analysis
of the predictive value of APS.
Nevertheless, despite these limitations, the study has
several strengths. First, this is the largest study to date to
comprehensively describe and characterize DSM-5-APS
in adolescents. Second, we used structured and validated
assessments that were carried out independently and face-to-face
for both adolescents and their parents or caregivers to obtain as
precise information as possible. These assessments were led by
experienced and internally certified Master or MD level clinicians
and psychologists. Third, we focused on individuals with a wide
variety of psychopathology and treatment characteristics, both in
the DSM-5-APS group and in the non-APS comparison group,
increasing clinical value vs. comparisons with healthy control
subjects. Finally, focusing on APS individuals allowed us to
obtain results from a more homogeneous high-risk sample.
CONCLUSIONS
Approximately one in four adolescents hospitalized with non-
psychotic disorders meet DSM-5-APS criteria. These help-
seeking adolescents have more comorbid psychiatric disorders as
well as more severe symptoms, functional impairment and global
severity of illness. Thus, they warrant high intensity clinical care.
To what degree APS in adolescents with existing and emerging
non-psychotic mental disorders is predictive of future transition
to a psychotic disorder and what the predictors are for such
transition requires further prospective study.
DATA AVAILABILITY STATEMENT
Datasets generated for this study are included in the article.
Additional data might be shared upon request from the first or
corresponding author.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by Institutional Review Board of the North Shore-
Long Island Jewish Health System; Ethical Committee of Human
Experimentation in the USA. Written informed consent to
participate in this study was provided by the participants’ legal
guardian/next of kin.
AUTHOR CONTRIBUTIONS
GS had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy
of the data analysis. CC: study concept and design. GS, DG,
BC, AA, RC, MC, SJ-F, DV, SW, MG, RS, NL, MB, and CC:
acquisition of data. GS and CC: statistical analysis, drafting of
the manuscript, administrative, technical, and material support.
All authors critical revision of the manuscript for important
intellectual content and interpretation of data.
FUNDING
This study was partially funded by a grant from the John
and Maxine Bendheim Foundation (PI: CC). GS is supported
by the Alicia Koplowitz Foundation. CM and CA have
received support by the Spanish Ministry of Science and
Innovation. Instituto de Salud Carlos III (PI17/02227), co-
financed by ERDF Funds from the European Commission,
A way of making Europe, CIBERSAM. Madrid Regional
Government (B2017/BMD-3740 AGES-CM-2), European Union
Structural Funds. European Union Seventh Framework Program
under grant agreements FP7-4-HEALTH-2009-2.2.1-2-241909
(Project EU-GEI), FP7- HEALTH-2013-2.2.1-2-603196 (Project
PSYSCAN) and FP7- HEALTH-2013-2.2.1-2-602478 (Project
METSY); and European Union H2020 Program under the
Innovative Medicines Initiative 2 Joint Undertaking (grant
agreement No. 115916, Project PRISM, and grant agreement No.
777394, Project AIMS-2-TRIALS), Fundación Familia Alonso,
Fundación Alicia Koplowitz and Fundación Mutua Madrileña.
Frontiers in Psychiatry | www.frontiersin.org 11 October 2020 | Volume 11 | Article 568982
Salazar de Pablo et al. DSM-5 Attenuated Psychosis Syndrome in Adolescents
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Conflict of Interest: DG has been a consultant for and/or has received speaker
honoraria from Otsuka America and Janssen Pharmaceuticals. DV has received
speaking fees from Lundbeck. SW has received in the last 5 years royalties from
Thieme Hogrefe, Kohlhammer, Springer, Beltz. Outside professional activities
and interests are declared under the link of the University of Zurich https://
www.uzh.ch/prof/apps/interessenbindungen/client/. CA has been a consultant to
or has received honoraria or grants from Acadia, Ambrosseti, Gedeon Richter,
Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering Plow,
Sumitomo Dainippon Pharma, Sunovion and Takeda. CM has acted as consultant
or participated in DMC for Janssen, Servier, Lundbeck, Nuvelution, Angelini and
Otsuka. PF-P has received grants and personal fees from Lundbeck and personal
fees from Menarini. CC has been a consultant and/or advisor to or has received
honoraria from: Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter,
Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, LB Pharma,
Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer,
Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva.
He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka.
He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and
Teva. He received royalties from UpToDate and grant support from Janssen and
Takeda. He is also a shareholder of LB Pharm.
The remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest.
Copyright © 2020 Salazar de Pablo, Guinart, Cornblatt, Auther, Carrión, Carbon,
Jiménez-Fernández, Vernal, Walitza, Gerstenberg, Saba, Lo Cascio, Brandizzi,
Arango, Moreno, Van Meter, Fusar-Poli and Correll. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these
terms.
Frontiers in Psychiatry | www.frontiersin.org 14 October 2020 | Volume 11 | Article 568982
... Detection of CHR-P individuals is largely based on idiosyncratic recruitment strategies, which combine helpseeking behaviors and referrals made on suspicion of a psychosis risk [11]. Therefore, to estimate the prevalence of CHR-P, it is necessary to focus on studies systematically assessing CHR-P cases across clinical samples [13,14]. These studies report conflicting findings [13,[15][16][17], and the actual prevalence of CHR-P individuals within clinical samples is not determined. ...
... Therefore, to estimate the prevalence of CHR-P, it is necessary to focus on studies systematically assessing CHR-P cases across clinical samples [13,14]. These studies report conflicting findings [13,[15][16][17], and the actual prevalence of CHR-P individuals within clinical samples is not determined. Some studies have also systematically investigated the prevalence of CHR-P in the general population [18][19][20], despite the CHR-P paradigm [2] not being primarily conceived to prevent psychosis in healthy individuals (universal prevention). ...
... The high prevalence of CHR-P "hiding in plain sight" among adolescents and young adults in clinical services suggests that even though individuals are receiving care, their CHR-P symptoms may frequently be going unrecognised in clinics that are not specifically evaluating for them and the opportunity to monitor these individuals and identify transitions to frank psychosis as soon as possible may be being missed. Interestingly, this finding of unrecognised CHR-P cases in clinical services may also explain the putative prognostic value of non-psychotic mental disorders for later schizophrenia [11][12][13]. This raises the possibility that psychosis onset from non-psychotic disorders may be associated with undetected comorbid CHR-P. ...
Article
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(1) The consistency and magnitude of the prevalence of Clinical High-Risk for Psychosis (CHR-P) individuals are undetermined, limiting efficient detection of cases. We aimed to evaluate the prevalence of CHR-P individuals systematically assessed in the general population or clinical samples. (2) PRISMA/MOOSE-compliant (PROSPERO: CRD42020168672) meta-analysis of multiple databases until 21/01/21: a random-effects model meta-analysis, heterogeneity analysis, publication bias and quality assessment, sensitivity analysis—according to the gold-standard CHR-P and pre-screening instruments—leave-one-study-out analyses, and meta-regressions were conducted. (3) 35 studies were included, with 37,135 individuals tested and 1554 CHR-P individuals identified (median age = 19.3 years, Interquartile range (IQR) = 15.8–22.1; 52.2% females, IQR = 38.7–64.4). In the general population (k = 13, n = 26,835 individuals evaluated), the prevalence of the CHR-P state was 1.7% (95% Confidence Interval (CI) = 1.0–2.9%). In clinical samples (k = 22, n = 10,300 individuals evaluated), the prevalence of the CHR-P state was 19.2% (95% CI = 12.9–27.7%). Using a pre-screening instrument was associated with false negatives (5.6%, 95% CI = 2.2–13.3%) and a lower CHR-P prevalence (11.5%, 95% CI = 6.2–20.5%) compared to using CHR-P instruments only (28.5%, 95% CI = 23.0–34.7%, p = 0.003). (4) The prevalence of the CHR-P state is low in the general population and ten times higher in clinical samples. The prevalence of CHR-P may increase with a higher proportion of females in the general population and with a younger population in clinical samples. The CHR-P state may be unrecognized in routine clinical practice. These findings can refine detection and preventive strategies.
... An area of research known as the 'ultra-high-risk state for psychosis paradigm' [18] predicts the risk of conversion from basic and attenuated symptomatology (which are common subclinical psychosis-like signs), to clinical psychosis [19,20]. Exposure to racism is positively associated with the distribution of subclinical psychosis symptomatology in non-clinical populations [21]. ...
Article
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Black people and People of Color are disproportionately affected by racism and show increased rates of psychosis. To examine whether racialized migrant groups are particularly exposed to racism and therefore have higher risks for psychosis, this paper (1) systematically assesses rates of psychosis among racialized migrant groups concerning the country of origin, and (2) analyzes interviews regarding the association of racism experiences with psychosis-related symptoms in racialized Black people and People of Color populations in Germany. We present an umbrella review of meta-analyses that report the incidence of positive symptoms (e.g., hallucinations and delusions) and negative symptoms (e.g., apathy and incoherent speech) of diagnosed schizophrenia, other non-affective psychotic disorders (e.g., schizoaffective disorder) or first-episode psychosis among migrants by country of origin. We also report 20 interviews with first- and second-generation migrants racialized as Black and of Color in Germany to capture and classify their experiences of racism as well as racism-associated mental health challenges. In the umbrella review, psychosis risk was greatest when migration occurred from developing countries. Effect size estimates were even larger among Caribbean and African migrants. In the qualitative study, the application of the constant comparative method yielded four subordinate themes that form a subclinical psychosis symptomatology profile related to experiences of racism: (1) a sense of differentness, (2) negative self-awareness, (3) paranoid ideation regarding general persecution, and (4) self-questioning and self-esteem instability. We here provide converging evidence from a quantitative and qualitative analysis that the risk of poor mental health and psychotic experiences is related to racism associated with minority status and migration.
... We found that functioning (Hedges' g = 0.623) and attenuated psychotic symptoms (Hedges' g = 0.706) improved in CHR-P individuals who did not transition to psychosis compared to those who did. Functioning is closely related to both the duration and severity of attenuated psychotic symptoms (Salazar de Pablo et al., 2020a). These findings indicate that the level of functioning of CHR-P individuals is strictly closed to transition to psychosis (Fusar-Poli et al., 2015c), confirming that transition to psychosis from a CHR-P state is associated with severe real-world clinical outcomes. ...
Article
Full-text available
Aims The clinical outcomes of individuals at clinical high risk of psychosis (CHR-P) who do not transition to psychosis are heterogeneous and inconsistently reported. We aimed to comprehensively evaluate longitudinally a wide range of outcomes in CHR-P individuals not developing psychosis. Methods “Preferred Reporting Items for Systematic reviews and Meta-Analyses” and “Meta-analysis Of Observational Studies in Epidemiology”-compliant meta-analysis (PROSPERO: CRD42021229212) searching original CHR-P longitudinal studies in PubMed and Web of Science databases up to 01/11/2021. As primary analysis, we evaluated the following outcomes within CHR-P non-transitioning individuals: (a) change in the severity of attenuated psychotic symptoms (Hedge's g ); (b) change in the severity of negative psychotic symptoms (Hedge's g ); (c) change in the severity of depressive symptoms (Hedge's g ); (d) change in the level of functioning (Hedge's g ); (e) frequency of remission (at follow-up). As a secondary analysis, we compared these outcomes in those CHR-P individuals who did not transition vs. those who did transition to psychosis at follow-up. We conducted random-effects model meta-analyses, sensitivity analyses, heterogeneity analyses, meta-regressions and publication bias assessment. The risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale (NOS). Results Twenty-eight studies were included (2756 CHR-P individuals, mean age = 20.4, 45.5% females). The mean duration of follow-up of the included studies was of 30.7 months. Primary analysis: attenuated psychotic symptoms [Hedges’ g = 1.410, 95% confidence interval (CI) 1.002–1.818]; negative psychotic symptoms (Hedges’ g = 0.683, 95% CI 0.371–0.995); depressive symptoms (Hedges’ g = 0.844, 95% CI 0.371–1.317); and functioning (Hedges’ g = 0.776, 95% CI 0.463–1.089) improved in CHR-P non-transitioning individuals; 48.7% remitted at follow-up (95% CI 39.3–58.2%). Secondary analysis: attenuated psychotic symptoms (Hedges’ g = 0.706, 95% CI 0.091–1.322) and functioning (Hedges’ g = 0.623, 95% CI 0.375–0.871) improved in CHR-P individuals not-transitioning compared to those transitioning to psychosis, but there were no differences in negative or depressive symptoms or frequency of remission ( p > 0.05). Older age was associated with higher improvements of attenuated psychotic symptoms ( β = 0.225, p = 0.012); publication years were associated with a higher improvement of functioning ( β = −0.124, p = 0.0026); a lower proportion of Brief Limited Intermittent Psychotic Symptoms was associated with higher frequencies of remission ( β = −0.054, p = 0.0085). There was no metaregression impact for study continent, the psychometric instrument used, the quality of the study or proportion of females. The NOS scores were 4.4 ± 0.9, ranging from 3 to 6, revealing the moderate quality of the included studies. Conclusions Clinical outcomes improve in CHR-P individuals not transitioning to psychosis but only less than half remit over time. Sustained clinical attention should be provided in the longer term to monitor these outcomes.
... However, two recent meta-analyses of randomised controlled trials conducted in CHR-P individuals found that antipsychotics were not superior to other interventions for improving APS [24,60]. It is also likely that antipsychotics are initially prescribed to those CHR-P individuals who have higher levels of APS [11,61] and are perceived as being at higher risk of developing psychosis, and therefore have more chances to display relative improvements over follow-up time. Although in the past antipsychotics have been compared to placebo in CHR-P individuals [47], they are currently not recommended by clinical guidelines for CHR-P individuals due to the lack of preventive evidence and low benefit to risk ratio [4]. ...
Article
Full-text available
Background Little is known about clinical outcomes other than transition to psychosis in people at Clinical High-Risk for psychosis (CHR-P). Our aim was to comprehensively meta-analytically evaluate for the first time a wide range of clinical and functional outcomes beyond transition to psychosis in CHR-P individuals. Methods PubMed and Web of Science were searched until November 2020 in this PRISMA compliant meta-analysis (PROSPERO:CRD42020206271). Individual longitudinal studies conducted in individuals at CHR-P providing data on at least one of our outcomes of interest were included. We carried out random-effects pairwise meta-analyses, meta-regressions, and assessed publication bias and study quality. Analyses were two-tailed with α=0.05. Findings 75 prospective studies were included (n=5,288, age=20.0 years, females=44.5%). Attenuated positive symptoms improved at 12 (Hedges’ g=0.753, 95%CI=0.495-1.012) and 24 (Hedges’ g=0.836, 95%CI=0.463-1.209), but not ≥36 months (Hedges’ g=0.315. 95%CI=-0.176–0.806). Negative symptoms improved at 12 (Hedges’ g=0.496, 95%CI=0.315–0.678), but not 24 (Hedges’ g=0.499, 95%CI=-0.137–1.134) or ≥36 months (Hedges’ g=0.033, 95%CI=-0.439–0.505). Depressive symptoms improved at 12 (Hedges’ g=0.611, 95%CI=0.441–0.782) and 24 (Hedges’ g=0.583, 95%CI=0.364–0.803), but not ≥36 months (Hedges’ g=0.512 95%CI=-0.337–1.361). Functioning improved at 12 (Hedges’ g=0.711, 95%CI=0.488–0.934), 24 (Hedges’ g=0.930, 95%CI=0.553–1.306) and ≥36 months (Hedges’ g=0.392, 95%CI=0.117–0.667). Remission from CHR-P status occurred in 33.4% (95%CI=22.6–44.1%) at 12 months, 41.4% (95%CI=32.3–50.5%) at 24 months and 42.4% (95%CI=23.4–61.3%) at ≥36 months. Heterogeneity across the included studies was significant and ranged from I²=53.6% to I²=96.9%. The quality of the included studies (mean±SD) was 4.6±1.1 (range=2-8). Interpretation CHR-P individuals improve on symptomatic and functional outcomes over time, but these improvements are not maintained in the longer term, and less than half fully remit. Prolonged duration of care may be needed for this patient population to optimize outcomes. Funding None.
Article
Background and hypothesis: Youth at clinical high-risk (CHR) for psychosis present with neuropsychological impairments relative to healthy controls (HC), but whether these impairments are distinguishable from those seen among putatively lower risk peers with other psychopathology remains unknown. We hypothesized that any excess impairment among CHR cohorts beyond that seen in other clinical groups is minimal and accounted for by the proportion who transition to psychosis (CHR-T). Study design: We performed a systematic review and meta-analysis of studies comparing cognitive performance among CHR youth to clinical comparators (CC) who either sought mental health services but did not meet CHR criteria or presented with verified nonpsychotic psychopathology. Study results: Twenty-one studies were included representing nearly 4000 participants. Individuals at CHR showed substantial cognitive impairments relative to HC (eg, global cognition: g = -0.48 [-0.60, -0.34]), but minimal impairments relative to CC (eg, global cognition: g = -0.13 [-0.20, -0.06]). Any excess impairment among CHR was almost entirely attributable to CHR-T; impairment among youth at CHR without transition (CHR-NT) was typically indistinguishable from CC (eg, global cognition, CHR-T: g = -0.42 [-0.64, -0.19], CHR-NT: g = -0.09 [-0.18, 0.00]; processing speed, CHR-T: g = -0.59 [-0.82, -0.37], CHR-NT: g = -0.12 [-0.25, 0.07]; working memory, CHR-T: g = -0.42 [-0.62, -0.22], CHR-NT: g = -0.03 [-0.14, 0.08]). Conclusions: Neurocognitive impairment in CHR cohorts should be interpreted cautiously when psychosis or even CHR status is the specific clinical syndrome of interest as these impairments most likely represent a transdiagnostic vs psychosis-specific vulnerability.
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Mental disorders frequently begin in childhood or adolescence. Psychotropic medications have various indications for the treatment of mental dis­orders in this age group and are used not infrequently off‐label. However, the adverse effects of these medications require special attention during developmentally sensitive periods of life. For this meta‐review, we systematically searched network meta‐analyses and meta‐analyses of randomized controlled trials (RCTs), individual RCTs, and cohort studies reporting on 78 a priori selected adverse events across 19 categories of 80 psychotropic medications – including antidepressants, antipsychotics, anti‐attention‐deficit/hyperactivity disorder (ADHD) medications and mood stabilizers – in children and adolescents with mental disorders. We included data from nine network meta‐analyses, 39 meta‐analyses, 90 individual RCTs, and eight cohort studies, including 337,686 children and adolescents. Data on ≥20% of the 78 adverse events were available for six antidepressants (sertraline, escitalopram, paroxetine, fluoxetine, venlafaxine and vilazodone), eight antipsychotics (risperidone, quetiapine, aripiprazole, lurasidone, paliperidone, ziprasidone, olanzapine and asenapine), three anti‐ADHD medications (methylphenidate, atomoxetine and guanfacine), and two mood stabilizers (valproate and lithium). Among these medications with data on ≥20% of the 78 adverse events, a safer profile emerged for escitalopram and fluoxetine among antidepressants, lurasidone for antipsychotics, methylphenidate among anti‐ADHD medications, and lithium among mood stabilizers. The available literature raised most concerns about the safety of venlafaxine, olanzapine, atomoxetine, guanfacine and valproate. Nausea/vomiting and discontinuation due to adverse event were most frequently associated with antidepressants; sedation, extrapyramidal side effects, and weight gain with antipsychotics; anorexia and insomnia with anti‐ADHD medications; sedation and weight gain with mood stabilizers. The results of this comprehensive and updated quantitative systematic meta‐review of top‐tier evidence regarding the safety of antidepressants, antipsychotics, anti‐ADHD medications and mood stabilizers in children and adolescents can inform clinical practice, research and treatment guidelines.
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Aims To investigate clinical outcomes and unmet needs in individuals at Clinical High Risk for Psychosis presenting with Brief and Limited Intermittent Psychotic Symptoms (BLIPS). Methods Prospective naturalistic long-term (up to 9 years) cohort study in individuals meeting BLIPS criteria at the Outreach And Support In South-London (OASIS) up to April 2016. Baseline sociodemographic and clinical characteristics, specific BLIPS features, preventive treatments received and clinical outcomes (psychotic and non-psychotic) were measured. Analyses included Kaplan Meier survival estimates and Cox regression methods. Results One hundred and two BLIPS individuals were followed up to 9 years. Across BLIPS cases, 35% had an abrupt onset; 32% were associated with acute stress, 45% with lifetime trauma and 20% with concurrent illicit substance use. The vast majority (80%) of BLIPS individuals, despite being systematically offered cognitive behavioural therapy for psychosis, did not fully engage with it and did not receive the minimum effective dose. Only 3% of BLIPS individuals received the appropriate dose of cognitive behavioural therapy. At 4-year follow-up, 52% of the BLIPS individuals developed a psychotic disorder, 34% were admitted to hospital and 16% received a compulsory admission. At 3-year follow-up, 52% of them received an antipsychotic treatment; at 4-year follow-up, 26% of them received an antidepressant treatment. The presence of seriously disorganising and dangerous features was a strong poor prognostic factor. Conclusions BLIPS individuals display severe clinical outcomes beyond their very high risk of developing psychosis and show poor compliance with preventive cognitive behavioural therapy. BLIPS individuals have severe needs for treatment that are not met by current preventive strategies.
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Increasing evidence shows that personality pathology is common among patients at clinical high risk (CHR) for psychosis. Despite the important impact that this comorbidity might have on presenting high-risk psychopathology, psychological functioning, and transition to full psychotic disorders, the relationship between personality syndromes and CHR state has received relatively little empirical attention. The present meta-analytic review aimed at 1) estimating the prevalence rates of personality disorders (PDs) in CHR individuals and 2) examining the potential role of PDs in predicting transition from CHR state to a full-blown psychotic disorder. The systematic search of the empirical literature identified 17 relevant studies, including a total of 1,868 CHR individuals. Three distinct meta-analyses were performed to provide prevalence estimates of PDs in the CHR population. The first and more comprehensive meta-analysis focused on any comorbid PD (at least one diagnosis), the second one focused on schizotypal personality disorder (SPD), and the last one focused on borderline personality disorder (BPD). Moreover, a narrative review was presented to define the predictive role of personality disorders in promoting more severe outcomes in CHR patients. The findings showed that the prevalence rate of personality disorders in CHR patients was 39.4% (95% CI [26.5%–52.3%]). More specifically, 13.4% (95% CI [8.2%–18.5%]) and 11.9% (95% CI [0.73%–16.6%]) of this clinical population presented with SPD and BPD, respectively. Finally, the studies examining the effects of baseline personality diagnoses on conversion to psychotic disorders showed contradictory and insufficient results concerning the potential significant impact of SPD. Conversely, no effect of BPD was found. This metaanalytic review indicated that the CHR population includes a large subgroup with serious personality pathology, that may present with attenuated psychotic symptoms conjointly with distinct and very heterogeneous personality features. These findings support the need for improved understanding of both core psychological characteristics of CHR patients and differentiating aspects of personality that could have relevant clinical implications in promoting individualized preventive interventions and enhancing treatment effectiveness.
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Twenty percent of individuals at clinical high risk for psychosis (CHR-P) develop the disorder within 2 years. Extensive research has explored the factors that differentiate those who develop psychosis and those who do not, but the results are conflicting. The current systematic review and meta-analysis comprehensively addresses the consistency and magnitude of evidence for non-purely genetic risk and protective factors associated with the risk of developing psychosis in CHR-P individuals. Random effects meta-analyses, standardized mean difference (SMD) and odds ratio (OR) were used, in combination with an established stratification of evidence that assesses the association of each factor and the onset of psychotic disorders (from class I, convincing evidence to class IV weak evidence), while controlling for several types of biases. A total of 128 original controlled studies relating to 26 factors were retrieved. No factors showed class I-convincing evidence. Two further factors were associated with class II-highly suggestive evidence: attenuated positive psychotic symptoms (SMD = 0.348, 95% CI: 0.280, 0.415) and global functioning (SMD = −0.291, 95% CI: −0.370, −0.211). There was class III-suggestive evidence for negative psychotic symptoms (SMD = 0.393, 95% CI: 0.317, 0.469). There was either class IV-weak or no evidence for all other factors. Our findings suggest that despite the large number of putative risk factors investigated in the literature, only attenuated positive psychotic symptoms, global functioning, and negative psychotic symptoms show suggestive evidence or greater for association with transition to psychosis. The current findings may inform the refinement of clinical prediction models and precision medicine in this field.
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Background: The Clinical High Risk state for Psychosis (CHR-P) has become the cornerstone of modern preventive psychiatry. The next stage of clinical advancements rests on the ability to formulate a more accurate prognostic estimate at the individual subject level. Individual Participant Data Meta-Analyses (IPD-MA) are robust evidence synthesis methods that can also offer powerful approaches to the development and validation of personalized prognostic models. The aim of the study was to develop and validate an individualized, clinically based prognostic model for forecasting transition to psychosis from a CHR-P stage.Methods: A literature search was performed between January 30, 2016, and February 6, 2016, consulting PubMed, Psychinfo, Picarta, Embase, and ISI Web of Science, using search terms (“ultra high risk” OR “clinical high risk” OR “at risk mental state”) AND [(conver* OR transition* OR onset OR emerg* OR develop*) AND psychosis] for both longitudinal and intervention CHR-P studies. Clinical knowledge was used to a priori select predictors: age, gender, CHR-P subgroup, the severity of attenuated positive psychotic symptoms, the severity of attenuated negative psychotic symptoms, and level of functioning at baseline. The model, thus, developed was validated with an extended form of internal validation.Results: Fifteen of the 43 studies identified agreed to share IPD, for a total sample size of 1,676. There was a high level of heterogeneity between the CHR-P studies with regard to inclusion criteria, type of assessment instruments, transition criteria, preventive treatment offered. The internally validated prognostic performance of the model was higher than chance but only moderate [Harrell’s C-statistic 0.655, 95% confidence interval (CIs), 0.627–0.682].Conclusion: This is the first IPD-MA conducted in the largest samples of CHR-P ever collected to date. An individualized prognostic model based on clinical predictors available in clinical routine was developed and internally validated, reaching only moderate prognostic performance. Although personalized risk prediction is of great value in the clinical practice, future developments are essential, including the refinement of the prognostic model and its external validation. However, because of the current high diagnostic, prognostic, and therapeutic heterogeneity of CHR-P studies, IPD-MAs in this population may have an limited intrinsic power to deliver robust prognostic models.
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Background: The first rate-limiting step for primary indicated prevention of psychosis is the detection of young people who may be at risk. The ability of specialized clinics to detect individuals at risk for psychosis is limited. A clinically based, individualized, transdiagnostic risk calculator has been developed and externally validated to improve the detection of individuals at risk in secondary mental health care. This calculator employs core sociodemographic and clinical predictors, including age, which is defined in linear terms. Recent evidence has suggested a nonlinear impact of age on the probability of psychosis onset. Aim: To define at a meta-analytical level the function linking age and probability of psychosis onset. To incorporate this function in a refined version of the transdiagnostic risk calculator and to test its prognostic performance, compared to the original specification. Design: Secondary analyses on a previously published meta-analysis and clinical register-based cohort study based on 2008-2015 routine secondary mental health care in South London and Maudsley (SLaM) National Health Service (NHS) Foundation Trust. Participants: All patients receiving a first index diagnosis of non-organic/non-psychotic mental disorder within SLaM NHS Trust in the period 2008-2015. Main outcome measure: Prognostic accuracy (Harrell's C). Results: A total of 91,199 patients receiving a first index diagnosis of non-organic and non-psychotic mental disorder within SLaM NHS Trust were included in the derivation (33,820) or external validation (54,716) datasets. The mean follow-up was 1,588 days. The meta-analytical estimates showed that a second-degree fractional polynomial model with power (-2, -1: age1 = age-2 and age2 = age-1) was the best-fitting model (P < 0.001). The refined model that included this function showed an excellent prognostic accuracy in the external validation (Harrell's C = 0.805, 95% CI from 0.790 to 0.819), which was statistically higher than the original model, although of modest magnitude (Harrell's C change = 0.0136, 95% CIs from 0.006 to 0.021, P < 0.001). Conclusions: The use of a refined version of the clinically based, individualized, transdiagnostic risk calculator, which allows for nonlinearity in the association between age and risk of psychosis onset, may offer a modestly improved prognostic performance. This calculator may be particularly useful in young individuals at risk of developing psychosis who access secondary mental health care.
Article
Importance Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry. Objective To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations. Evidence Review Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes. Findings In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered. Conclusions and Relevance This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions.
Article
Objectives: Bipolar disorder (BD) is a debilitating illness that often starts at an early age. Prevention of first and subsequent mood episodes, which are usually preceded by a period characterized by subthreshold symptoms is important. We compared demographic and clinical characteristics including severity and duration of subsyndromal symptoms across adolescents with three different bipolar-spectrum disorders. Methods: Syndromal and subsyndromal psychopathology were assessed in adolescent inpatients (age = 12-18 years) with a clinical mood disorder diagnosis. Assessments included the validated Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P). We compared phenomenology across patients with a research consensus conference-confirmed DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnoses of BD-I, BD-not otherwise specified (NOS), or mood disorder (MD) NOS. Results: Seventy-six adolescents (age = 15.6 ± 1.4 years, females = 59.2%) were included (BD-I = 24; BD-NOS = 29; MD-NOS = 23) in this study. Median baseline global assessment of functioning scale score was 21 (interquartile range = 17-40; between-group p = 0.31). Comorbidity was frequent, and similar across groups, including disruptive behavior disorders (55.5%, p = 0.27), anxiety disorders (40.8%, p = 0.98), and personality disorder traits (25.0%, p = 0.21). Mania symptoms (most frequent: irritability = 93.4%, p = 0.82) and depressive symptoms (most frequent: depressed mood = 81.6%, p = 0.14) were common in all three BD-spectrum groups. Manic and depressive symptoms were more severe in both BD-I and BD-NOS versus MD-NOS (p < 0.0001). Median duration of subthreshold manic symptoms was shorter in MD-NOS versus BD-NOS (11.7 vs. 20.4 weeks, p = 0.002) and substantial in both groups. The most used psychotropics upon discharge were antipsychotics (65.8%; BD-I = 79.2%; BD-NOS = 62.1%; MD-NOS = 56.5%, p = 0.227), followed by mood stabilizers (43.4%; BD-I = 66.7%; BD-NOS = 31.0%; MD-NOS = 34.8%, p = 0.02) and antidepressants (19.7%; BD-I = 20.8%; BD-NOS = 10.3%; MD-NOS = 30.4%). Conclusions: Youth with BD-I, BD-NOS, and MD-NOS experience considerable symptomatology and are functionally impaired, with few differences observed in psychiatric comorbidity and clinical severity. Moreover, youth with BD-NOS and MD-NOS undergo a period with subthreshold manic symptoms, enabling identification and, possibly, preventive intervention of those at risk for developing BD or other affective episodes requiring hospitalization.
Article
Importance Since the release of the DSM-5 diagnosis of attenuated psychosis syndrome (DSM-5–APS) in 2013, several research studies have investigated its clinical validity. Although critical and narrative reviews have reviewed these progresses, no systematic review has comprehensively summarized the available evidence regarding the clinical validity of DSM-5–APS. Objective To provide current evidence on the clinical validity of DSM-5–APS, focusing on recent advances in diagnosis, prognosis, and treatment. Evidence Review A multistep literature search using the Web of Science database, Cochrane Central Register of Reviews, Ovid/PsychINFO, conference proceedings, and trial registries from database inception to June 16, 2019, was conducted following PRISMA and MOOSE guidelines and PROSPERO protocol. Studies with original data investigating individuals diagnosed using DSM-5–APS or meeting comparable criteria were included. The results of the systematic review were summarized in tables and narratively synthesized against established evidence-based antecedent, concurrent, and prognostic validators. A quantitative meta-analysis was conducted to explore the cumulative risk of psychosis onset at 6, 12, 24, and 36 months in individuals diagnosed using DSM-5–APS criteria. Findings The systematic review included 56 articles, which reported on 124 validators, including 15 antecedent, 55 concurrent, and 54 prognostic validators. The epidemiological prevalence of the general non–help-seeking young population meeting DSM-5–APS criteria was 0.3%; the prevalence of individuals meeting DSM-5–APS criteria was variable in clinical samples. The interrater reliability for DSM-5–APS criteria was comparable with that of other DSM-5 mental disorders and can be optimized by the use of specific psychometric instruments. DSM-5–APS criteria were associated with frequent depressive comorbid disorders, distress, suicidality, and functional impairment. The meta-analysis included 23 prospective cohort studies, including 2376 individuals. The meta-analytical risk of psychosis onset was 11% at 6 months, 15% at 12 months, 20% at 24 months, and 23% at 36 months. Research into predisposing and precipitating epidemiological factors, neurobiological correlates, and effective treatments for DSM-5–APS criteria has been limited. Conclusions and Relevance Over recent years, DSM-5–APS criteria have received substantial concurrent and prognostic validation, mostly driven by research into the clinical high-risk state for psychosis. Precipitating and predisposing factors, neurobiological correlates, and effective treatments are undetermined to date.
Article
The Attenuated Psychosis Syndrome (APS), proposed as a condition warranting further study in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), is a controversial diagnostic construct originally developed to identify individuals at clinical high-risk for psychosis. The relationship of APS and Schizotypal Personality Disorder (SPD) remains unclear with respect to their potential co-occurrence and the effect of SPD on risk for conversion to threshold psychosis. We examined the prevalence and effect on conversion of SPD in a cohort of 218 individuals whose symptoms met APS criteria. Results indicated that SPD was highly prevalent (68%), and that SPD did not influence risk for conversion. Rather, total positive symptom burden measured by the Structured Interview for Psychosis-Risk Syndromes (SIPS; OR 1.12, p = 0.02) emerged as the strongest predictor of conversion. These data suggest that when encountering a patient whose presentation meets SPD criteria, the clinician should assess whether APS criteria are also met and, for 1–2 years, carefully monitor positive symptoms for possible conversion to threshold psychosis.