Developmental course of hallucinatory experiences

Prior evidence suggests that the expression of psychotic experiences peaks in childhood and declines with advancing age.^{Reference Kelleher, Connor, Clarke, Devlin, Harley and Cannon3,Reference Thapar, Heron, Jones, Owen, Lewis and Zammit12,Reference Linscott and Van Os14,Reference Bartels-Velthuis, van de Willige, Jenner, van Os and Wiersma25} The findings of the present study strongly support this developmental trajectory by showing that the prevalence of hallucinatory experiences in childhood was approximately 2.5 times higher than in adolescence and approximately a fifth of children (20.5%) persisted in their endorsement of hallucinatory experiences from childhood into adolescence. Consequently, the majority of childhood hallucinatory experiences are transient phenomena, which may be clinically benign with spontaneous remission. Conversely, we found that 8.1% of youth who did not report hallucinatory experiences in childhood subsequently reported hallucinatory experiences in adolescence. This estimate is in accordance with the incidence rates reported in prior population-based studies.^{Reference Wigman, van Winkel, Raaijmakers, Ormel, Verhulst and Reijneveld13,Reference Bartels-Velthuis, van de Willige, Jenner, van Os and Wiersma25} Although these children did not endorse any hallucinatory experiences at baseline, they were already characterised by higher baseline levels of mental health problems, experienced more adverse life events, had lower non-verbal IQ scores and more often had parents of non-Dutch origin than their unaffected peers. Prior work suggested that adolescent-onset hallucinations may reflect a more severe underlying psychopathology and index a greater risk for serious mental health problems than hallucinations occurring in childhood only.^{Reference Wigman, van Winkel, Raaijmakers, Ormel, Verhulst and Reijneveld13,Reference Bartels-Velthuis, van de Willige, Jenner, van Os and Wiersma25} Taken together, the age at occurrence is an important factor to take into consideration when assessing hallucinations and their clinical relevance.

Persistent versus remittent hallucinatory experiences

Children were more likely to develop persistent hallucinatory experiences if they had more severe hallucinatory experiences or reported multisensory (auditory and visual) rather than unisensory (auditory or visual) hallucinatory experiences at baseline. These findings are in line with prior evidence showing that a higher frequency, more associated distress and poorer reality testing are associated with persistence of auditory hallucinations.^{Reference Bartels-Velthuis, van de Willige, Jenner, van Os and Wiersma25,Reference Escher, Romme, Buiks, Delespaul and Van Os26} This suggests that the attributes of psychotic experiences may have important value in persistence–risk evaluations. Furthermore, youth with persistent hallucinatory experiences displayed higher baseline levels of internalising, externalising, sleep and social problems, and lower levels of self-esteem than youth with remittent hallucinatory experiences. Given that previous studies have suggested that persistence is related to a greater likelihood of subsequent emotional and behavioural problems,^{Reference Wigman, van Winkel, Raaijmakers, Ormel, Verhulst and Reijneveld13,Reference Bartels-Velthuis, van de Willige, Jenner, van Os and Wiersma25} it is likely that psychotic experiences and other common mental health problems influence one another in a bi-directional manner. Accordingly, persistence of mental health problems, including but not limited to psychotic experiences, may ultimately culminate in severe mental health problems later in life.

Childhood adversity is one of the most replicated risk factors for psychotic experiences,^{Reference Varese, Smeets, Drukker, Lieverse, Lataster and Viechtbauer27} and has been associated with persistence.^{Reference van Os and Reininghaus1,Reference Cougnard, Marcelis, Myin-Germeys, De Graaf, Vollebergh and Krabbendam28} Although the prevalence of adverse life events was highest in the persistent group, prevalence rates did not significantly differ between persistent and remittent patterns. A potential explanation is that childhood adversity is a non-specific risk factor and therefore might poorly discriminate within a group of children that have (a certain level of) symptoms. This is supported by our finding that adolescents with any of the different trajectories of hallucinatory experiences (i.e., persistent, remittent and incident) had higher rates of adverse life events than those without hallucinatory experiences. In addition, adverse life events were retrospectively measured and often occurred years before the assessment of hallucinatory experiences, which makes it less likely to detect an association with trajectories of hallucinatory experiences, as opposed to the association with baseline symptoms.

Importantly, we found lower non-verbal IQ scores at age 6 years and higher baseline levels of both self- and mother-reported attention problems among youth with persistent versus remittent patterns of hallucinatory experiences. These findings extend prior evidence of decreased working memory performance in relation to persistence.^{Reference Fonville, Cohen Kadosh, Drakesmith, Dutt, Zammit and Mollon29} Interestingly, in a prior study we did not find evidence for a relationship between non-verbal IQ at age 6 years and hallucinatory experiences at age 10 years.^{Reference Steenkamp, Bolhuis, Blanken, Luijk, Hillegers and Kushner10} Together with the finding that the incident group also exhibited lower non-verbal IQ scores in early childhood, this may suggest that adolescent hallucinatory experiences index a greater neurodevelopmental vulnerability than childhood hallucinatory experiences. Future work is needed to examine whether other neurodevelopmental problems, such as impaired social cognition, may be predictive of hallucination persistence. This is based on evidence suggesting that impaired theory of mind is associated with increased risk of future delusions among children with auditory hallucinations.^{Reference Bartels-Velthuis, Blijd-Hoogewys and Van Os30} A link with social cognition would also extend the current findings of social problems in relation to persistence of hallucinations.

Proneness–persistence–impairment model of psychosis

Overall, the current findings provide support to the proneness–persistence–impairment model of psychosis.^{Reference Linscott and Van Os14} This model suggests that psychotic experiences are more likely to become persistent if neurodevelopmentally predisposed individuals are exposed to a higher degree of stressors, which, in turn, increases the probability for transition to psychosis and other clinical outcomes, such as mental health service use. It is likely that an accumulation of genetic, neurocognitive and environmental risk factors account for the incidence and particularly persistence of psychotic experiences – especially if these manifest during sensitive developmental windows in childhood/adolescence.^{Reference Linscott and Van Os14} Persistent psychotic experiences may therefore reflect an underlying neurodevelopmental vulnerability, which is phenotypically expressed through neurocognitive impairments, decreased social skills and increased psychopathological risk, as shown in the current study. Evidence from twin studies has indicated a genetic component in the stability of psychotic experiences over time,^{Reference Havers, Taylor and Ronald31} and it has been reported that cumulative exposure to environmental risk factors (such as trauma, cannabis use and urbanicity) affect the likelihood that psychotic experiences become persistent.^{Reference Cougnard, Marcelis, Myin-Germeys, De Graaf, Vollebergh and Krabbendam28}

Future waves of the Generation R Study will permit further longitudinal assessment of these youth into middle/late adolescence, enabling us to examine the impact of age-specific risk factors, such as substance use and risk-taking behaviour, which may interact with a pre-existing neurodevelopmental vulnerability. In addition, longitudinal assessments throughout child and adolescent development will allow further investigation of the relationship between persistence and age at onset of hallucinations, as well as the clinical significance and aetiology of childhood-onset versus adolescent-onset persistent hallucinations, which may have important implications for the notion of a neurodevelopmental vulnerability to hallucinations.

Individual risk prediction of symptom persistence

In addition to descriptive analyses, we evaluated a prediction model leveraging all psychosocial characteristics in the data-set to assess whether we could identify which children with hallucinatory experiences at 10 years of age would persistently endorse hallucinatory experiences four years later. The results suggest that, given the included parameters and within this sample, the model was not able to accurately predict which children are at higher risk for persistence. This does not imply that the included predictors or their assessments are of poor validity as these are supported by the excellent discriminatory power of the prediction model using absent rather than remittent hallucinatory experiences as the reference outcome.

A likely explanation for the poor discrimination despite multiple group-level differences is the large variance of the predictor variables relative to their differences between persistent and remittent groups. Congruently, small effect sizes are observed in nearly all studies comparing the clinical characteristics of these subgroups.^{Reference Kalman, Bresnahan, Schulze and Susser7,Reference Thapar, Heron, Jones, Owen, Lewis and Zammit12,Reference Wigman, van Winkel, Raaijmakers, Ormel, Verhulst and Reijneveld13} In other words, although we were able to detect differences at a group level, predicting an individual's risk of persistence proved to be more difficult because of the large overlap in likely predictor values. This suggests that persistent hallucinatory experiences are a complex and multifactorial phenotype. In addition, the dynamic expression of hallucinatory experiences over time (i.e. instability) may have contributed to the poor predictive accuracy.

Suggestions for improving future prediction models of persistence may include:

1. (a) a shorter follow-up period (for example 1–2 years) or repeated measurements over a longer period,

2. (b) more in-depth information on hallucinatory experiences at baseline (for example frequency, multimodality and associated distress),

3. (c) information on substance use, which was not possible in our study because of the young age of participants at baseline, and

4. (d) non-clinical predictors, such as genetic data, neuroimaging and biological markers.

Although we are not aware of any prediction models for persistence of childhood psychotic experiences, one previous study has evaluated a prediction model for persistence in middle adolescence.^{Reference Calkins, Moore, Satterthwaite, Wolf, Turetsky and Roalf4} This model had a slightly higher discriminatory power (AUC of 0.74) than the current prediction model, which might be explained by the different age range of study participants (15–17 years), shorter follow-up period (2 years), potential overfitting because of the high number of predictors relative to the number of participants and the absence of internal validation.^{Reference Steyerberg, Harrell, Borsboom, Eijkemans, Vergouwe and Habbema24} Given the lack of prognostic studies to date, future efforts are needed to assess the potential of prediction models for persistent psychotic experiences.

Predictive psychiatry

In comparison to other fields of medicine, predictive modelling in psychiatry is at an early stage. The multifactorial aetiology of psychiatric phenotypes, ethical considerations (such as stigmatisation) and a lack of implementation research have posed challenges for the utilisation of prediction models in psychiatry.^{Reference Salazar de Pablo, Studerus, Vaquerizo-Serrano, Irving, Catalan and Oliver32} Despite these challenges, early identification through risk prediction can guide evidence-based decision-making in clinical practice, particularly in the context of preventive interventions. This may substantially improve clinical and functional outcomes and could potentially even prevent or delay the development of mental illness. To date, the majority of studies in the field of ‘precision psychiatry’ have focused on predicting psychosis in clinical high-risk (CHR) populations.^{Reference Salazar de Pablo, Studerus, Vaquerizo-Serrano, Irving, Catalan and Oliver32} CHR criteria include subthreshold psychotic symptoms, overall functional impairment and help-seeking behaviour,^{Reference Yung, Yung, Pan Yuen, McGorry, Phillips and Kelly33} and thus is markedly different from the concept of psychotic experiences in the general population.

There are encouraging reports that targeted early interventions improve outcomes and delay the onset of psychosis in CHR individuals,^{Reference McGorry, Hartmann, Spooner and Nelson34} although some scholars question the population benefits of these strategies because of the low prevalence of individuals at CHR in the general population (the ‘prevention paradox’).^{Reference Guloksuz, Pries, Ten Have, de Graaf, van Dorsselaer and Klingenberg35} Evaluating risk assessments in population-based samples and settings is therefore an important contribution to existing research in risk-enriched samples. Ultimately, using risk assessments in population settings (such as primary care or schools) may offer new opportunities to prevent adverse psychiatric outcomes, such as enduring and distressing psychotic experiences.

Strengths and limitations

Although the present study had several strengths, including its prospective design with repeated measurements of hallucinatory experiences and multi-informant assessments of a range of relevant psychosocial characteristics, several limitations should be noted.

First, since the self-report questionnaire on psychotic experiences was restricted to hallucinations, our findings may not extend to the full range of psychotic experiences including delusions. However, self-reported auditory and visual hallucinations have the highest predictive power for clinician-confirmed psychotic experiences.^{Reference Kelleher, Harley, Murtagh and Cannon36}

Second, our self-report questionnaire of hallucinations may have led some children to misinterpret the questions, potentially resulting in an overestimation of the prevalence and remittance rates of childhood hallucinations, which may partly explain the large decline in prevalence and the low stability of hallucinations between childhood and adolescence. Such misinterpretations may be caused by the restricted questionnaire on hallucinations, which did not include examples or assessment of the children's understanding of the questions. Ideally, studies may consider using instruments that are specifically tailored for children, which also involve strategies to lower barriers for self-disclosure of hallucinations.^{Reference Maijer, Hayward, Fernyhough, Calkins, Debbané and Jardri2} Nevertheless, a recent study reported that the positive predictive value of self-reported psychotic experiences benchmarked against clinical interviews did not differ between ages 6 to 10 years and 11 to 14 years,^{Reference Moriyama, van Os, Gadelha, Pan, Salum and Manfro37} thereby providing support for the validity of a brief and general questionnaire for assessing hallucinations in younger children.

Third, it may have been preferable to use a data-driven approach to identify trajectories of hallucinatory experiences (such as growth mixture modelling), but this was not feasible given that hallucinatory experiences were assessed at only two time points in the setting of a limited questionnaire regarding hallucinatory experiences.

Implications

In conclusion, this study provides evidence for the dynamic and mostly transitory developmental expression of childhood hallucinatory experiences. Children and their parents who are concerned should be informed about the high prevalence rates and frequent spontaneous remission of psychotic experiences occurring in childhood. This knowledge may contribute to reduce the stigma of hallucinations. However, psychotic experiences that are distressing, frequent and persistent over time are likely to be indicative of an underlying neurodevelopmental vulnerability, which might, in turn, result in serious mental conditions later in life. Together, these findings highlight the relevance of assessing psychotic experiences prospectively across development.