Trajectories of symptom severity and functioning over a three-year period in a psychosis high-risk sample: A secondary analysis of the Neurapro trial

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Highlights

  • In 304 individuals at risk for psychosis, different trajectories were identified.

  • All trajectories showed symptomatic and functional improvements over time.

  • Subgroups with similar trajectories differed in severity of impairments at baseline.

  • Substance use predicted severe risk, depressive and general symptom trajectories.

  • Further predictors were being female, older age, and lower cognitive functioning.

Abstract

The Ultra-High Risk (UHR) for psychosis group is known to be heterogeneous with diverse outcomes. This study aimed to: 1. Identify subclasses of UHR individuals based on trajectories of symptomatic and functional change over time, 2. Identify predictors of these trajectories.

A sample of 304 UHR individuals participating in the Neurapro trial were followed over an average of 40 months. All participants received cognitive-behavioural case management (CBCM). Symptomatic and functional profiles were investigated using latent class growth analysis. Multinomial regression was employed to investigate predictors of classes.

Identified trajectories showed mostly parallel slopes (i.e. improving symptoms/functioning over time), which were primarily distinct regarding the severity of symptomatology/level of functioning at baseline (i.e. the intercept). Higher symptomatic/lower functioning classes were predicted by higher substance use, older age, female gender, and lower cognitive functioning.

No divergent trajectories were identified as all classes improved over time. This may reflect effective treatment through CBCM, natural illness course, or effective engagement with mental health services. Nonetheless, classes highest in symptoms/lowest in functioning still showed considerable impairment during follow-up, highlighting the need for targeted intervention in these subgroups. The study emphasizes the need for more clinical attention directed towards UHR patients being female or using substances.

Introduction

The notion that symptoms may develop along a continuum of illness course has gained traction in recent years (P. D. McGorry, Hartmann, Spooner, & Nelson, 2018; Patrick D. McGorry, Nelson, Goldstone, & Yung, 2010; van Os & Guloksuz, 2017). Despite this notion, most longitudinal studies in ultra-high risk (UHR) for psychosis samples2 are based on a categorical, dichotomized outcome measure. That is, outcome is defined as whether or not an UHR individual has progressed or ‘transitioned’ to full-threshold psychosis over the follow-up period, with the delineation between subthreshold and frank psychosis being an arbitrary decision (albeit informed by need for change in treatment approach) (Fusar-Poli & Van Os, 2012; Nelson, McGorry, Wichers, Wigman, & Hartmann, 2017; van Os & Guloksuz, 2017; Alison R. Yung, Nelson, Thompson, & Wood, 2010). Similarly, the traditional time to transition approach uses only one endpoint, ignoring the temporal pattern of change in clinical picture and functioning over time (Yuen et al., 2018). Continuous measures, such as severity of negative symptoms or severity of attenuated psychotic symptoms (APS), are routinely (and often repeatedly) obtained during the study period, however rarely adequately analysed and reported in outcome papers, which typically focus on the dichotomous final endpoint (transition vs non-transition).

Moreover, while heterogeneity of the UHR group has been recognized (Fusar-Poli, Cappucciati, Borgwardt, & et al., 2016; Nelson & Yung, 2009; van Os & Guloksuz, 2017), the existing literature treats the UHR population as a homogeneous construct with a common pathway, thereby masking individual symptom and functional trajectories for which course and thus treatment indication may differ considerably (Xie, McHugo, & Drake, 2009). Latent Class Growth Modelling (LCGM), however, can be used to investigate unobserved heterogeneity by identifying homogenous subpopulations with comparable growth trajectories over time (‘latent classes’), as well as their characteristics and correlates (Muthen, 2004; Nylund, Asparouhov, & Muthén, 2007). By identifying more homogeneous subclasses and their predictors, we may gain insight into UHR profiles, enabling the tailoring and targeting of interventions towards certain profiles. While this methodology has recently been employed in psychosis samples to map (natural or treatment-response) trajectories of symptomatology (e.g. Abdin et al., 2017; Austin et al., 2015; Levine, Rabinowitz, Case, & Ascher-Svanum, 2010; Levine, Rabinowitz, Faries, Lawson, & Ascher-Svanum, 2012; Marques et al., 2011; Schennach et al., 2012), suicidal ideation (Madsen, Karstoft, Secher, Austin, & Nordentoft, 2016), (social) functioning (Chang et al., 2018; Cole, Apud, Weinberger, & Dickinson, 2012; Hodgekins et al., 2015; Nordon et al., 2014; Velthorst et al., 2017), and cognition (J. H. Barnett et al., 2007; Thompson et al., 2013), we are not aware of any LCGM studies conducted in UHR samples to date.

While there has certainly been interest and attempts to identify course/trajectories in the UHR group (Polari et al., 2018), the sub-groups and corresponding thresholds in these studies have been defined using a consensus process among clinical and research experts (e.g., to define symptomatic remission). The advantage of LCGM is that it offers a data-driven opportunity to identify subgroups, their predictors and characteristics, without the need to define artificial cut-off points for dichotomous categories. Furthermore, factors influencing latent class membership can be explored and critical periods for interventions be identified.

The present study aims to: (1) identify classes of UHR individuals with distinct longitudinal symptom and functional trajectories (including APS, negative symptoms, depressive symptoms and level of functioning) over a 2-year follow-up period using LCGM and (2) identify sociodemographic, clinical, biological, and functional predictors of class membership. Based on the existing literature in early psychosis, we hypothesise that the analysis will identify heterogeneous trajectories with improving, stable and deteriorating temporal patterns.

Section snippets

Sample and procedures

The current study constitutes a secondary analysis of the Neurapro data set. The Neurapro trial is a multi-centre, double-blind randomised controlled trial investigating the effects of omega-3 polyunsaturated fatty acids (PUFA) versus placebo in UHR individuals (ACTRN 12608000475347) (Markulev et al., 2017). In this trial, participants meeting UHR criteria received either omega-3 PUFA or placebo over a six-month period. Both treatment arms received a cognitive-behavioural intervention

Results

The sample consisted of 304 participants (153 assigned to omega-3 PUFA treatment, 151 to placebo). Baseline demographic and symptomatic information is presented in Table 1. Other characteristics are presented in McGorry et al. (P. D. McGorry et al., 2017). According to the traditional ‘transition to psychosis’ categorical approach, 40 individuals (13%) were considered as ‘transitioned’ within the study period.

Discussion

In psychiatric prediction research, an important aim is to better understand symptomatic and functional change over time. Young people at UHR are recognised as being a very heterogeneous population with diverse outcomes and therefore, subgroups may differ with regard to the course of functional and symptomatic outcomes over time. The present study aimed to identify homogenous subclasses of UHR individuals based on trajectories of level of functioning and symptoms using LCGA.

Conclusion

Identified UHR trajectories demonstrated largely parallel, significant slopes, indicating significant symptomatic and functional improvement over the course of the study for all subclasses. Trajectories differed mainly in their intercept, i.e., severity of impairment at baseline. The pattern of improvement across trajectories may reflect the effects of CBCM, the natural course, or active engagement in a mental health service. While improving, higher symptom classes remained considerably

Funding sources

This work was supported by Grant 07TGF-1102 from the Stanley Medical Research Institute, a National Health and Medical Research Council (NHMRC) Australia Program Grant (ID: 566529; PDM, IBH, ARY,GPA) and a grant from the Colonial Foundation. JAH is supported by a University of Melbourne Postdoctoral McKenzie Fellowship. PDM was supported by a Senior Principal Research Fellowship from the NHMRC (ID: 1060996); GPA and ARY were supported by NHMRC Senior Research Fellowships (ID: 1080963 and 566593

Disclosure statement

PDM reported receiving grant funding from National Alliance for Research on Schizophrenia and Depression and unrestricted research funding from AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, and Novartis, as well as honoraria for educational activities with AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, Bristol-Myers Squibb, Roche, and the Lundbeck Institute. BN, IBH, ARY, and GPA have received National Health and Medical Research Council (NHMRC) funding. No other conflicts were reported.

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