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. 2022 May 26;17(1):183–190. doi: 10.1007/s11571-022-09814-1

The age of onset and cognitive impairment at the early stage of schizophrenia

Yi Yin 1, Shuangshuang Li 1, Jinghui Tong 1, Junchao Huang 1, Baopeng Tian 1, Song Chen 1, Yimin Cui 2, Shuping Tan 1, Zhiren Wang 1, Fude Yang 1, Yongsheng Tong 1,3, L Elliot Hong 4, Yunlong Tan 1,✉
PMCID: PMC9871127  PMID: 36704632

Abstract

In schizophrenia, the age of first episode onset can reflect genetic loading and predict prognosis. Little is known about the association between the age of onset and cognition among individuals with early-stage schizophrenia. We aimed to compare the pre-treatment neurocognition profile between individuals with early-onset schizophrenia (EOS, the age of onset < 18 years), typical-onset schizophrenia (TOS, the age of onset between 18 and 39 years), and late-onset schizophrenia (LOS, the age of onset between 40 and 59 years). We included individuals with a current diagnosis of schizophrenia within 3 years and medication naive or less than 2 weeks of cumulative antipsychotic exposure and current daily antipsychotic dosage equivalent to ≤ 15 mg of olanzapine. Assessments included the MATRICS Consensus Cognitive Battery (MCCB) and the Positive and Negative Syndrome Scale (PANSS). We used linear regression to compare the difference between age-of-onset groups. We included 356 participants (67 EOS, 195 TOS, and 94 LOS). Compared with LOS, TOS was associated with lower scores in the verbal learning scores of the MCCB after adjusting for education years and the subscale scores of the PANSS (45.5 ± 12.9 vs. 40.5 ± 14.1, adjusted B = − 5.79, p = 0.001). The three groups had no difference in other cognitive domain scores. The association between the age of onset and MCCB verbal memory was U-shape (square of the age of onset, adjusted B = 0.02, p = 0.003). Patients with LOS had a better verbal learning function compared with individuals with TOS. These findings suggest that involvement of cognition assessment and rehabilitation training is necessary for patients with TOS.

Keywords: Schizophrenia, Cognition, Age of onset, Psychosis symptoms, Antipsychotics

Introduction

Schizophrenia is a serious mental disorder and the peak age of onset is at 20.5 years (Solmi et al. 2021). The younger age of onset can predict some long-term clinical outcomes, such as more negative symptoms, higher risk for relapses, and poor social/occupational function (Immonen et al. 2017). Although cognition impairment is one of the core symptoms suffering by individuals with schizophrenia (Zhang et al. 2019), little is known about the association between the age of onset and neurocognition among schizophrenia at the early phase.

A few studies have compared early-onset schizophrenia (EOS, the age of onset < 18 years), typical-onset schizophrenia (TOS, the age of onset between 18 and 39), and late-onset schizophrenia (LOS, the age of onset between 40 and 59) on cognitive function, but they had small samples, inconsistent criteria for the age of onset, and long duration of illness (Suen et al. 2019). A meta-analysis has reported that those with EOS demonstrated larger deficits in visual and auditory attention than those with LOS and performed better in digit symbol coding and vocabulary (Rajji et al. 2009). However, its major limitation was that the age of onset was missing for approximately 1/4 participants. Patients with LOS were reported to perform better in the speed of processing, spatial working memory, and verbal fluency than those whose onset of schizophrenia was before 45 years old (n = 69; Brichant-Petitjean et al. 2013). A study on > 40-year-old patients, who varied greatly on the course of illness, found that the LOS subgroup had better processing speed, abstraction, and verbal memory than the chronic EOS or TOS subgroup; however, their performance in auditory working memory was similar (Vahia et al. 2010). More studies focus on the comparison between the onset at puberty and adulthood. One study found that the age of onset (before/after 18 years old) was not associated with any between-group difference in inhibition, switching, and cognitive flexibility (Holmén et al. 2012). Among individuals with chronic schizophrenia, the age of onset after 18 years old was associated with worse processing speed and cognitive flexibility, but better verbal fluency, than EOS (Grover et al. 2019). Another study found that first-episode EOS patients performed worse on tasks of working memory, language, and motor function than first-episode TOS patients (White et al. 2006). Latest research among individuals with a psychotic disorder of fewer than 12 months’ duration reported that the age of onset < 18 years old had a lower score in sustained attention and executive functions compared with those with the age of onset between 18 and 35 years old (De la Serna et al. 2021). Differences in familiality between EOS and TOS may lead to a different performance in attention, working memory, and verbal learning (Bigdeli et al. 2020). In a group of 12–43 years old, first-episode antipsychotic-naïve schizophrenia patients, age had an inverted U-curve effect on the performance in the verbal memory task and the digit sequencing task (Fagerlund et al. 2021). This contrasts with a previous study (Tuulio-Henriksson et al. 2004), which found the earlier onset of age among adults with schizophrenia was linearly associated with lower scores in verbal learning and memory.

The comparison of LOS with EOS and TOS at the early stage of illness is few, although several studies have compared the cognition between first-episode EOS and TOS (Bigdeli et al. 2020; De la Serna et al. 2021; Fagerlund et al. 2021; White et al. 2006). The cognition function of individuals with schizophrenia may be stable over the first two years of illness (Sánchez-Torres et al. 2018) but declines in the long term. Speed processing, learning, and executive function decline among individuals with schizophrenia compared with no change in healthy controls, reported in a reprehensive birth-cohort study (from age 7 to age 38) (Meier et al. 2014). Latest longitudinal studies with matched controls reported that cognitive aging in memory, verbal knowledge (Fett et al. 2019; Zanelli et al. 2019), attention, and processing speed (Fett et al. 2019) were more rapid than general populations in the decade followings the first episode (Fett et al. 2022). Thus, it is needed to restudy the association between the age of onset and cognition in those with a short duration of illness.

Another limitation of previous research is that, to date, no study has investigated the association between the age of onset and cognitive performance measured using the MATRICS Consensus Cognitive Battery (MCCB; Nuechterlein et al. 2008). The United States National Institute of Mental Health developed this battery. With its advantages on test selection, reliability, and validity, it has become a standard tool for assessing cognitive ability in schizophrenia and related disorders (Green et al. 2014). In addition, normative data for this battery allow for multiple demographic corrections (Kern et al. 2008), especially limiting the confounding effect of age.

Cognition is important for occupational functioning and independent living among individuals with schizophrenia (Fu et al. 2017; Kharawala et al. 2022; Nuechterlein et al. 2014; Santesteban-Echarri et al. 2017). Finding associates of cognitive impairment would help deliver personalized interventions and improve their quality of life. Our study aimed to compare the pre-treatment baseline cognition performance by different onset-age groups. Also, we would explore the linear or nonlinear association between cognition with the age of onset.

Method

This cross-sectional study was conducted at five mental health hospitals, located in five cities in China: Beijing Huilongguan Hospital, Chongqing Sanmenxia Mental Health Center, Changchun Sixth Hospital, Harbin First Specialist Hospital, and Zhumadian Second People’s Hospital. The Institutional Review Board (IRB) of Beijing Huilongguan Hospital, the central IRB, approved this research and other research sites accepted this approval. Written informed consent was provided by adult participants or legal guardians of juveniles.

Participants

The inclusion criteria were: (1) age between 15 and 59 years old; (2) met a current diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV-TR); (3) duration of illness < 36 months; and (4) medication naive or less than 2 weeks of cumulative antipsychotic exposure and current daily antipsychotic dosage equivalent to ≤ 15 mg of olanzapine. Exclusion criteria included: (1) ≤ 6 years of education; (2) mental retardation, serious somatic or neurological illness, or history of brain injury; (3) substance dependence or abuse (except nicotine); (4) having received electroconvulsive therapy or repetitive transcranial magnetic stimulation within 6 months. Duration of illness was the months between the date of the first onset of psychotic symptoms and the interview date.

Procedures

Trained psychiatrists administered the diagnoses, interviews, and clinical assessments.

Measurement

Age of schizophrenia onset

Its definition is the age when the participant first appears psychotic symptoms (Howard et al. 2000). We collected this information through interviewing patients and their family members and reviewing their medical records. EOS was the age of onset < 18, TOS was the age of onset between 18 and 39, and LOS was the age of onset between 40 and 59 according to the international consensus (Howard et al. 2000).

Psychopathological symptoms

The Positive and Negative Syndrome Scale for Schizophrenia—30 items (PANSS; Kay et al. 1987) was used to assess symptom severity where symptoms were rated from 1 absent to 7 extreme. Subscale scores (positive symptoms, negative symptoms, and general psychopathology) were the sum of corresponding items (Xiao et al. 2015). The inter-observer reliability was greater than 0.8.

Neurocognitive function

Cognitive assessments were obtained using the MCCB. The MCCB (Nuechterlein et al. 2008; Zou et al. 2009) uses ten tests to cover seven neurocognitive domains: speed of processing, verbal learning, working memory, reasoning and problem-solving, visual learning, social cognition, and attention/vigilance. As most Chinese are not familiar with alphabetical order, the Letter-Number Span Test in the verbal working memory domain is replaced with the Digit Sequencing Test of the Wechsler Adult Intelligence Scale in the adapted Chinese MCCB (Zou et al. 2009). Raw scores were standardized to T scores, which were corrected for age and sex based on the Chinese norm.

Statistical analysis

Between-group differences in continuous variables were determined using ANOVA. Tukey–Kramer HSD correction was performed for correcting multiple comparisons problems. Pearson’s χ2 tests were used to compare sex proportions across different groups.

Multivariate analysis of variance (MANOVA) was used to test the overall between-group difference in the MCCB domains between age-of-onset groups. Multivariable linear regression was used to explore the onset-age-group difference in the corrected T score for each MCCB domain after adjusting for education years, duration of illness (months), and the subscale scores of the PANSS. The age was not included as a covariate because the high collinearity of age and the age of onset would introduce bias (van der Werf et al. 2012). Then, the inclusion of the age of schizophrenia onset and the squared age-of-onset-term in a multi-variable linear model was to explore possible nonlinear associations between the age of onset and each MCCB domain score. Multiple comparisons for scores of each MCCB domain were adjusted for Bonferroni corrections.

The software was Stata 15.0. Statistical significance was defined as a two-sided p < 0.05.

Results

Demographics and clinical characteristics

The study recruited 356 patients with first-episode schizophrenia, including EOS (n = 65), TOS (n = 195), and LOS (n = 94). Three groups had no difference in gender, education, and the positive symptoms and negative symptoms subscales scores of the PANSS (Table 1). Three group differed in the general psychopathology subscale scores of the PANSS (F = 8.90, p < 0.001) and the average scores of the LOS group were lower than that of the EOS group (Turkey HSD test, p < 0.001) and that of the TOS group (Turkey HSD test, p < 0.001).

Table 1.

Demographics and clinical characteristics

Variables Early-onset
n = 67		 Typical-onset
n = 195		 Late-onset
n = 94		 Statistic P
Mean(SD) Mean( SD) Mean (SD)
Age, year 17.4 (1.2) 25.8 (5.8) 43.1 (2.9) F = 703.63  < 0.001
Female, n (%) 31 (46.3%) 91 (46.7%) 52 (55.3%) χ2 = 2.12 0.346
Education, year 10.0 (2.3) 10.0 (3.1) 10.4 (3.2) F = 0.57 0.568
Age of onset, year 16.3 (1.0) 24.9 (5.7) 42.7 (2.9) F = 788.34  < 0.001
Duration of illness, month 15.3 (9.0) 14.3 (10.8) 8.3 (3.1) F = 16.94  < 0.001
PANSS
Positive 23.6 (5.7) 24.6 (4.9) 23.6 (4.1) F = 1.75 0.176
Negative 20.8 (7.5) 19.9 (6.3) 19.1 (6.2) F = 1.39 0.250
General psychopathology 40.9 (8.2) 39.9 (7.7) 36.5 (6.2) F = 8.90  < 0.001
MCCB
Speed of processing 42.3 (9.4) 41.1 (10.2) 43.7 (8.8) F = 2.27 0.105
Verbal learning 44.7 (10.9) 40.5 (14.1) 45.5 (12.9) F = 5.58 0.004
Working memory 41.7 (11.1) 40.3 (11.8) 44.8 (10.6) F = 4.99 0.007
Reasoning and problem solving 43.4 (11.3) 41.6 (12.5) 44.5 (11.6) F = 2.02 0.134
Visual learning 43.0 (11.1) 39.6 (11.1) 43.2 (10.4) F = 4.54 0.011
Social cognition 46.6 (8.9) 45.3 (10.6) 47.6 (10.4) F = 1.66 0.193
Attention/vigilance 39.2 (8.8) 38.3 (9.7) 40.4 (8.8) F = 1.66 0.192
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PANSS Positive and Negative Syndrome Scale for Schizophrenia—30 items; MCCB the MATRICS Consensus Cognitive Battery

The age of onset and cognition

The scores of the MCCB by three groups (EOS, TOS, and LOS) were shown in Table 1. Individuals with TOS had lower scores than those with LOS in verbal learning (40.5 ± 14.1 vs. 45.5 ± 12.9; Cohen’s d = − 0.36; Turkey HSD test, p = 0.008, Fig. 1), working memory (40.3 ± 11.8 vs. 44.8 ± 10.6, Cohen’s d = − 0.39; Turkey HSD test, p = 0.005), and visual learning (39.6 ± 11.1 vs. 43.2 ± 10.4; Cohen’s d = − 0.33; Turkey HSD test, p = 0.026). Other bi-variate tests did not find any difference in domain scores of the MCCB between the three onset-age groups (p > 0.05).

Fig. 1.

Fig. 1

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Scores for the verbal learning domain in the MATRICS Consensus Cognitive Battery by different onset-age groups

MANOVA showed that the three groups did not significantly differ overall in the seven MCCB domain scores (seven scores were dependent variables simultaneously), F(14, 692) = 1.27, exact p = 0.219. The association was still nonsignificant after adjusting for education years and duration of illness, F(14, 676) = 1.33, exact p = 0.183.

Multivariable linear regression showed that compared with LOS, the TOS only performed worse in verbal learning (B = − 5.79, p = 0.001) after adjusting for education years, duration of illness, and subscale scores of the PANSS (Table 2). The difference between bi-variate associations of EOS, TOS, and LOS in each MCCB domain was nonsignificant.

Table 2.

Multi-variable linear regression of each domain score in the MATRICS Consensus Cognitive Battery (MCCB) on different age-of-onset groups

Variables (1)
SP		 (2)
VEL		 (3)
WM		 (4)
RP		 (5)
VIL		 (6)
SC		 (7)
AV
B (p) B(p) B(p) B(p) B(p) B(p) B(p)

Age of onset ref: Late-onset

Early-onset

 − 1.60 − 1.78 − 2.37 − 1.75 − 0.36 − 0.29 − 1.48
(0.335) (0.431) (0.220) (0.392) (0.845) (0.868) (0.351)
Typical-onset − 2.88 − 5.79 − 4.09 − 3.32 − 3.59 − 1.72 − 2.31
(0.029) (0.001) (0.008) (0.041) (0.015) (0.214) (0.067)
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a. The sample size for the model (1) was 351, model (7) 354, and others 356. b. Adjusted for years of education, duration of illness (months), and subscale scores of the Positive and Negative Syndrome Scale. c. P values < 0.007 (≈ 0.05/7) are in boldface

SP Speed of processing; VEL Verbal learning; WM Working memory; RP Reasoning and problem solving; VIL Visual learning; SC Social cognition; AV Attention/vigilance

Then, the multi-variable linear regression showed that the association between the age of onset and MCCB’s verbal learning scores was a U curve after adjusting for education years, duration of illness, and subscale scores of the PANSS (Table 3; the age of onset, adjusted B = − 1.34, p = 0.009; the age of onset ^2, adjusted B = 0.02, p = 0.003). The significance of the associations between the age of onset and other MCCB scores did not reach a significant level after Bonferroni’s corrections.

Table 3.

Multi-variable linear regression of each domain score in the MATRICS Consensus Cognitive Battery (MCCB) on different age-of-onset groups

Variables (1)
SP		 (2)
VEL		 (3)
WM		 (4)
RP		 (5)
VIL		 (6)
SC		 (7)
AV
B (p) B(p) B(p) B(p) B(p) B(p) B(p)
Age of Onset 0.10 − 1.34 0.15 0.13 − 0.81 0.01 0.12
(0.070) (0.009) (0.014) (0.042) (0.056) (0.830) (0.020)
Age of Onset ^2 0.02 0.01
(0.003) (0.035)
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a. The sample size for the model (1) was 351, model (7) 354, and others 356. b. Adjusted for years of education, duration of illness (months), and subscale scores of the Positive and Negative Syndrome Scale. c. P values < 0.007 (≈ 0.05/7) are in boldface

SP Speed of processing; VEL Verbal learning; WM Working memory; RP Reasoning and problem solving; VIL Visual learning; SC Social cognition; AV Attention/vigilance

Power analysis

We computed the power for a two-sided two-sample means test using the verbal learning scores of the MCCB in the TOS group and the LOS group: mean1 [sd1] = 40.5 (14.1), mean2 [sd2] = 45.5 [12.9], α = 5%, n = 289, n2: n1 = 0.482. The power was 0.843.

Discussion

This study demonstrated that LOS was associated with small but significantly better performance in verbal learning than TOS among patients with minimal-treated, first-episode schizophrenia. Our study also showed a U-curve association between the age of onset and verbal learning.

Previous research found individuals with first-episode schizophrenia had deficiencies in all cognitive domains compared to healthy controls (Zhang et al. 2019). The cognitive profile has been regarded as a distinct dimension of clinical symptoms to picture the heterogeneity of individuals with schizophrenia. However, our study revealed that the effect of the age of onset on cognitive impairment was domain-specific rather than global. We did not find evidence for differential effects of the onset of age on majority cognition domains. The LOS was associated with better performance in verbal learning than TOS, although the effect size was relatively small. This immediate recall ability was evaluated through the Hopkins Verbal Learning Test, which used twelve words from three semantic groups. This finding was consistent with a study that detected the individuals with LOS were less impaired in verbal learning, assessed using the corrected long-delay free recall score of the California Verbal Learning Test, than those whose age of onset schizophrenia was before 40 years old (Vahia et al. 2010). However, their sample included individuals with chronic TOS and the difference in verbal learning became nonsignificant after adjusting for the duration of illness. Moreover, another study also found that the LOS group performed better in verbal fluency tests than those whose age of onset schizophrenia before 45 years old (Brichant-Petitjean et al. 2013). Compared to their study design, our study used standardized MCCB scores, making it possible for controlling the effect of age and sex when we compared the cognitive difference in different age-of-onset groups.

In addition, our study was the first to show that the association between the age of onset and performance in verbal learning was U-shape (the lowest point at 34 years old) independent of psychopathology. A study among antipsychotic-naive schizophrenia patients aged between 12 and 43 years old has detected an inverted U-curve relationship between age and verbal memory (Fagerlund et al. 2021). This difference may be because their study did not include individuals with LOS and the performance may be task-specific. Another study demonstrated that earlier onset of psychosis was associated with worse age-corrected performance on immediate recall of verbal learning, measured using the Groningen Word Learning Task, before adjusting for demographics and clinical variables (van der Werf et al. 2012). However, the majority (93.3%) of their participants had the onset of psychosis before 40 years old and they had fewer psychotic symptoms than our samples. Thus, our study can better demonstrate the cognitive profile of individuals with LOS. Less genetic loading for LOS may explain their better verbal learning abilities (Woolston et al. 2017). Also, genetic alternations during special development windows can also result in progressive brain changes (Gogtay et al. 2011; Zalesky et al. 2015). However, the poor performance in verbal learning of the TOS group than the LOS group could not be explained by aging-induced central nervous system differences (Howard et al. 2000).

Additionally, we did not detect any significant cognitive differences between the EOS and LOS groups, although EOS is likely to reflect neurodevelopmental vulnerability. The reason may be that strategic verbal memory recall ability reflects the maturation of the prefrontal cortex, which is late neurodevelopment (Yu et al. 2018). It means that the verbal learning function does not fully develop for both adolescents with or without EOS, resulting in the nonsignificant difference in cognitive impairment between individuals with EOS and those with TOS. Moreover, in our study, the speed of processing did not differ between onset-age groups. In contrast, a previous study showed that patients with LOS had better scores on the digit symbol test compared with those whose onset of schizophrenia was before 40 years old, but they did not control for the confounding effects of illness duration and psychopathology symptoms (Vahia et al. 2010).

A major strength of our study was that all participants were in the early stage of illness, thus minimalizing confounding effects of treatment history and illness phases. Additionally, we measured cognition function using a standard cognitive battery and the resultant standardized domain scores allowed us to control for the confounding effects of age and sex. Then, our samples were across the entire age-of-onset range and the study had enough sample with EOS or TOS. Our sample had a higher proportion of individuals with LOS than other studies because we over-selected individuals with LOS to enlarge the sample’s power. Then, LOS, especially for paranoia schizophrenia among middle-aged women, was not rare in China’s clinical settings. The reason may be associated with adversity in the early years, such as famine (Wang and Zhang 2017).

There were several limitations. First, recall bias was inevitable in collecting information, such as the age of schizophrenia onset. Second, the representative problem existed because completing cognitive assessment required relatively high education levels, skills of using the computer, and stable condition of illness. Finally, this was a cross-sectional study and it was hard to clarify the mechanisms underlying cognitive differences between the TOS and LOS groups. In addition, future researchers can use other techniques, such as electroencephalogram (EEG) (Sharma and Acharya 2021), to detect the effect of the onset of age on cognition.

In conclusion, the age of schizophrenia onset was associated with specific cognitive impairment among individuals with first-episode, minimally treated schizophrenia. Individuals with LOS were less impaired in verbal learning than those with TOS.

Funding

This work was supported by the National Natural Science Foundation of China [YLT, 81761128021, 81771452, 82171507]; Beijing Natural Science Foundation [YLT, 7151005]; the National Institutes of Health [LEH, R01MH112180].

Data availability

Please contact YL Tan for reasonable request.

Code availability

Not applicable.

Declarations

Conflict of interest

Dr. Hong has received or is planning to receive research funding or consulting fees from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho, Heptares, Pfizer, Sound Pharma, Luye Pharma, Takeda, and Regeneron. None was involved in the design, analysis, or outcomes of the study. Other authors declare that the research was conducted without any relationships that could be interpreted as a potential conflict of interest or financial conflict.

Consent to participate

Written informed consent was provided by adult participants or legal guardians of juveniles.

Consent for publication

All participants provided consent for publication.

Ethics approval

The Institutional Review Board (IRB) of Beijing Huilongguan Hospital, central IRB, approved this research and other research sites accept this approval.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yi Yin and Shuangshuang Li have equal contributions as first authors.

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Please contact YL Tan for reasonable request.

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