Early and very early‐onset schizophrenia compared with adult‐onset schizophrenia: French FACE‐SZ database

Abstract Objective To compare the clinical symptomatology in patients with Early‐Onset Schizophrenia (EOS, N = 176), especially the subgroup Very Early Onset Schizophrenia (VEOS) and Adult Onset Schizophrenia (AOS, N = 551). Method In a large French multicentric sample, 727 stable schizophrenia patients, classified by age at onset of the disorder, were assessed using standardized and extensive clinical and neuropsychological batteries: AOS with onset ≥ 18 years and EOS with onset < 18 years (including 22 VEOS < 13 years). Results The importance of better diagnosing EOS group, and in particularly VEOS, appeared in a longer DUP Duration of Untreated Psychosis (respectively, 2.6 years ± 4.1 and 8.1 years ± 5.7 vs. 1.0 years ± 2.5), more severe symptomatology (PANSS Positive And Negative Syndrome Scale scores), and lower educational level than the AOS group. In addition, the VEOS subgroup had a more frequent childhood history of learning disabilities and lower prevalence of right‐handedness quotient than the AOS. Conclusion The study demonstrates the existence of an increased gradient of clinical severity from AOS to VEOS. In order to improve the prognosis of the early forms of schizophrenia and to reduce the DUP, clinicians need to pay attention to the prodromal manifestations of the disease.


| INTRODUC TI ON
Classically, schizophrenia often starts in adolescence or in young adults (Chen, Selvendra, Stewart, & Castle, 2018) and is one of the most common and severe forms of mental illness (APA, 2013). It is also very expensive (Laidi et al., 2018;Van Os & Kapur, 2009) for society and is a major public health concern, especially toward an early diagnosis.
The World Health Organization (WHO) estimated that schizophrenia was the 5th leading worldwide cause of global disease burden (Millier et al., 2014) in 2004 among males, with 2.8% of total Years Lived With Disability (YLD), and 6th among females, with 2.6% of YLD. However, it is not easy to describe and define schizophrenia from childhood to adulthood. Since the early 1990s, definitions have tended to harmonize, with Adult Onset Schizophrenia (AOS), where the age of onset is greater than or equal 18 years, Early Onset Schizophrenia (EOS), defined by an onset strictly before the age of 18 years, and the subgroup Very Early Onset Schizophrenia (VEOS), developing strictly before the age of 13 years (Werry, 1992).
Consequently, an examination of the DUP, and its reduction (an international goal in World Health Organization, 2011), may have important implications for the clinical management of patients . Finally, the study of the age at onset could also be used to identify schizophrenia subtypes Werry, 1992) thus distinguishing more homogeneous subgroups of patients, especially and 8.1 years ± 5.7 vs. 1.0 years ± 2.5), more severe symptomatology (PANSS Positive And Negative Syndrome Scale scores), and lower educational level than the AOS group.
In addition, the VEOS subgroup had a more frequent childhood history of learning disabilities and lower prevalence of right-handedness quotient than the AOS.

Conclusion:
The study demonstrates the existence of an increased gradient of clinical severity from AOS to VEOS. In order to improve the prognosis of the early forms of schizophrenia and to reduce the DUP, clinicians need to pay attention to the prodromal manifestations of the disease.

K E Y W O R D S
adult-onset schizophrenia, duration of untreated psychosis, early-onset schizophrenia, symptomatology, very early-onset schizophrenia in genetic studies (Ahn, An, Shugart, & Rapoport, 2016;Rapoport & Inoff-Germain, 2000;Schürhoff et al., 2004). Overall, identifying differences in the presentation of VEOS, EOS, and AOS may have important implications for a better description of the disease, thereby improving the possibility of precision medicine for clinically defined homogeneous patient subgroups.

| Aims of the study
The objective of the present study was to compare, for the first time with the consensual definition, the clinical presentation of EOS/VEOS with AOS, in a large multicentric sample of stabilized subjects with schizophrenia. We hypothesized that EOS patients,  (Schürhoff et al., 2015).

| Inclusion criteria
Consecutive clinically stable patients (defined by no hospitalization and no treatment changes during the 4 weeks before evaluation) with a DSM IV-TR diagnosis of schizophrenia or schizoaffective disorder were included in the study between 2010 and 2017. The sample was divided into three groups of age at onset (AOS, EOS groups, and VEOS subgroup according to classical cutoff values). Age at onset schizophrenia was defined as the age at which the patient first met DSM IV-TR criteria for schizophrenia. To limit the recall bias, this age was defined with the help of the patient, his/her family, his/ her referring psychiatrist, and with the use of medical case notes.
All study participants were referred by their general practitioner or psychiatrist, who subsequently received a detailed evaluation report with suggestions for personalized interventions.

| Clinical data
Patients were interviewed by members of the specialized multidis- hypnotic) were recorded, and the presence of an extrapyramidal syndrome was evaluated with 10 questions of the French version of Neurological Soft Signs Scale (Krebs, Gut-Fayand, Bourdel, Dischamp, & Olié, 2000). We also used the Edinburgh Handedness Inventory (Oldfield, 1971), a measurement scale in order to assess the dominance of a person's right or left handedness in everyday activities.
This provides a quotient of laterality (positive for right-handers, negative for left-handers). Finally, the Global Functional Assessment Scale (GAF; Bodlund et al., 1994;Endicott, Spitzer, Fleiss, & Cohen, 1976), which is a DSM IV numerical scale with a range from 0 to 100, was used to assess the participants psychological, social, and professional functioning.

| Neuropsychological measures
We used the Wechsler Adult Intelligence Scale (Wechsler, 2008), which provides a measure of general intellectual function in older adolescents and adults. As data from both WAIS-III and WAIS-IV were available, we applied a correction algorithm to pool the results.
Lichtenberger and Kaufman (2009)  Information (degree of general information acquired from culture).
We also used the National Adult Reading Test (Mackinnon & Mulligan, 2005;Nelson & O'Connell, 1978) which consists of a list of 40 phonetically irregular words that participants were asked to read aloud. The total raw score ranges from 0 to 40 and was included in regression equations to provide an estimate of premorbid intellectual ability.
Finally, the history of learning disabilities was explored during the neuropsychological evaluation by asking a single question: "have you had learning disabilities" with a dichotomous response (yes/no).

| Ethical concerns
The study was carried out in accordance with ethical principles for medical research involving humans (WMA, Declaration of Helsinki). All data were collected anonymously. As this study includes data coming from regular care assessments, a nonopposition form was signed by all participants, all being adults at the time of the assessment. A webbased application was developed to collate assessment data for clinical monitoring ad research purposes. Access to the system was carefully regulated, and approval was obtained from the Committee in charge of the safety of computerized databases (CNIL DR 2012-157).

| Statistical analysis
Subjects were first divided into two groups and compared: AOS, onset at or over the age of 18 and EOS, onset strictly before the age of 18.
Second, specific characteristics were sought in the VEOS subgroup (onset strictly before the age of 13), which was initially included within the EOS group. Three groups, VEOS, EOS, and AOS, were therefore compared. Analyses were conducted using SAS (release 9.4; SAS  (Leucht et al., 2005;Suzuki et al., 2015), and GAF with three steps (100-71 "no to slight functional impairment"; 70-51 "mild/moderate functional impairment"; and <51 "serious functional impairment" APA, 2000) were studied in the model.
To estimate the relationships between age at onset and DUP, and between DUP and PANSS scores, Pearson's correlation coefficient was used for normally distributed data and Spearman's correlation coefficient for non-normally distributed data.

| RE SULTS
A sample of 727 individuals with stable schizophrenia, enrolled in FACE-SZ cohort, was included in this study. The sample was composed of 539 (74%) males and 188 (26%) females. The mean age at assessment was 32.2 ± 9.7 years, with a mean age at onset of 21.6 ± 6.5 years. First, individuals with early-onset schizophrenia (EOS, N = 176) were compared to individuals with adult-onset schizophrenia (AOS, N = 551).  Table 3.

| EOS compared to AOS
On the one hand, there was no statistically significant difference be- this difference is 0.15, which correspond to small effect. Note also that even the PANSS total score was significantly higher for EOS than AOS, the GAF interval was the same (41-50) with a signification of "serious symptoms or any serious impairment in social, occupational, or school functioning" (2), regardless of onset schizophrenia.
Educational level was at last significantly lower in the EOS, versus AOS, group (11.1 ± 2.4 years vs. 12.6 ± 2.8 years; p < .0001), and even if there was no significant difference in the neuropsychological evaluation between EOS and AOS groups (see Table 2), it was interesting to note that there was no difference in the premorbid IQ scores between the two groups.

| Multivariate analysis
After taking into account potential confounders, the risk of having early onset is significantly associated with higher DUP, lower education level, and higher severity of the disease (PANSS > 70). See Figure 1.

| Correlation
A negative correlation was found between age at onset and DUP (ρ = −226, p < .001), while DUP was not correlated to any PANSS scores across all groups (AOS group, EOS group with or without VEOS subgroup, isolated VEOS subgroup, or total population).

| D ISCUSS I ON
The main objective of the present study was to compare the pres-  Table 1).
The longer DUP for the EOS, versus AOS, group: 2.6 years versus.  Table 1). An increased level of severity on the PANSS psychopathology general score has also previously been found in the EOS, versus AOS group (Biswas et al., 2007). In contrast, no significant difference on PANSS negative score was found according to age at onset in schizophrenia in some previous studies (Biswas et al., 2007;Schimmelmann et al., 2007). In the current study, the PANSS-positive score showed no significant differences between groups, as in previous studies (Ballageer et al., 2005;Holmén et al., 2012;Joa et al., 2009;White et al., 2006). These data were finally relevant in confrontation with the literature; in particular, in the meaning of the PANSS (Leucht et al., 2005;Suzuki et al., 2015): In 40 articles (N = 8,000), cross-sectional data on the GAF and PANSS (Suzuki et al., 2015) at study baseline or its equivalent were close to our study with a GAF mean score = 49. Second, from VEOS to EOS to AOS groups, there was also an increase in severity, with longer DUP (8.1 years vs. 1.8 years and 1.0 years respectively) and more pronounced symptomatology (psychopathology general PANSS score and total PANSS score). Psychosis-Early Detection). Consequently, there is a growing awareness of this area as a public health problem (Rubio & Correll, 2017 Thirdly, a lower level of education was found from VEOS to AOS groups (p < .0001) and this result could be explained simply by an active onset of the disease earlier, thus disturbing more studies.

Although DUP has been previously investigated in EOS (
Nevertheless, there was no significant difference among the three groups regarding neuropsychological functioning (IQ, premorbid IQ). On the one hand, similar inclusion criteria, apart from the age at onset schizophrenia and a relatively similar duration of the disease, could explain these similarities. However, in particular about premorbid IQ, the result might seem counterintuitive because it was more expected a lower premorbid IQ in EOS/VEOS compared with AOS, in relation to higher neurodevelopmental part. With our study, the result might appear to be in favor of a little faster decline in patients with EOS compared with AOS group; hence, the importance of early diagnosis, early management, and more study is needed. On the other hand, in our work, neurocognitive functioning was assessed using a battery of neuropsychological tests; however, we cannot exclude that more accurate tests could lead to the identification of subtle-specific deficits. In the literature for example, a broad question is if the deficit was present early or was associated with a decline, or a cessation of the development (Kremen et al., 2010). As we observed, Fujino et al. (2017) estimated the cognitive decline in patients with schizophrenia and showed the distribution of approximately 70% of patients had a deterioration. In White et al. (2006), when the developmental course was controlled, there were no significant differences between the adolescent and adult patients' groups in any domains (language, working memory), except in motor function where adolescent performance was worse.
In addition, the type II error was also to be considered in our results.
However, despite the small sample, it may be notable that the as previously reported (Biswas et al., 2006;Karp et al., 2001;Kumra et al., 2000), our results support the neurodevelopmental hypothesis in the VEOS group, as indicated by a history of learning disabilities and lower levels of handedness lateralization. About cerebral development in fact, hand preference-or dominance-has been extensively used as an easy-to-measure proxy of brain asymmetry, since it has been regarded as a manifestation of cerebral dominance (Sommer, Ramsey, Kahn, Aleman, & Bouma, 2001). The hemispheres of the human brain are anatomically and functionally asymmetric (Gazzaniga, 2005;Oertel-Knochel & Linden, 2011). The loss of hemispheric lateralization has long been proposed to be a consequence of disrupted neurodevelopment in individuals with psychotic disorder (Oertel-Knochel & Linden, 2011).

| Strengths
The strengths of the study were the use of homogeneous and exhaustive standardized diagnostic protocols and neuropsychological assessments in a large French national multicentric study, as well as the use of hospital records and interviews with patients, their families, and their medical referents, especially important in regard to DUP and illness history. Our study is one of the most important in terms of total sample size (see Table 1

| Limitations
As the patients have been recruited in different centers, we cannot rule out differences, but meetings allowed us to standardize the quotation between the centers. Particularly in the estimation could also reinforce the estimation of premorbid intellectual ability.
We have a large nonselected national sample of 727 individuals, but with three groups of different size, particularly VEOS subgroup (which also emphasizes the importance of improving the diagnosis of young patients). Therefore, in order to limit statistical errors related to the small VEOS subgroup, we first analyzed the main groups, AOS (N = 551) and EOS (N = 176) and we secondly conducted an in-depth examination of the significant results. However, we had to specify this limitation several times in the interpretation of our results (PANSS results, neuropsychological evaluation).
Our data were analyzed in a cross-sectional design, with a stabilized psychotic phenomenology and require now investigation within a longitudinal design. A stable condition is also important to note for the interpretation of the clinic and neuropsychology and could also mitigate some differences. In all cases, the present results may indicate VEOS to be underdiagnosed and undertreated in child populations, which requires investigation in future studies, as this help to reduce DUP and improve illness prognosis.
In conclusion, the EOS group, especially the VEOS subgroup, exhibited longer DUP, more severe symptomatology and a lower educational level than the AOS group. The study demonstrated the existence of an increased gradient of clinical severity from AOS to VEOS. In order to improve the prognosis of the early forms of schizophrenia and to reduce the DUP, clinicians need to pay attention to the prodromal manifestations of the disease.
Improving early diagnosis and organizing targeted programs may be crucial to the management and outcome of EOS. An innovative and multidisciplinary public health approach may prove of utility, involving care and educational professionals, as well as the patient's family. Nurses, patients and Team Fondamental. We also express all our thanks to the nurses, and to the patients who were included in the present study. We thank Hakim Laouamri, and his team (Stéphane Beaufort, Seif Ben Salem, Karmène Souyris, Victor Barteau and Mohamed Laaidi) for the development of the FACE-SZ computer interface, data management, quality control and regulatory aspects.

CO N FLI C T O F I NTE R E S T
The authors have declared that there are no conflicts of interest in relation to the subject of this study.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are the property of the hospital and the Foundation FondaMental. Any request goes through the corresponding author and the Foundation FondaMental. The data are not publicly available due to privacy or ethical restrictions.