Duration of untreated psychosis and neurocognition in first-episode psychosis: A meta-analysis

doi:10.1016/j.schres.2017.06.021

Schizophrenia Research

Volume 193, March 2018, Pages 3-10

https://doi.org/10.1016/j.schres.2017.06.021 Get rights and content

Abstract

Neurocognitive impairment is a well-established feature of first-episode psychosis (FEP). Neurotoxicity hypothesis of psychosis suggests that untreated psychosis before the initiation of first effective treatment is associated with loss of acquired cognitive abilities. However, the outcome of the studies investigating the relationship between duration of untreated psychosis (DUP) and cognitive impairment in FEP remains inconclusive. No previous meta-analysis investigating the relationship between DUP and cognitive impairment in FEP has been published. Following the systematic review of FEP studies, a random-effects meta-analysis of the relationship between DUP and neurocognition in schizophrenia was conducted. Current meta-analysis included 27 studies including 3127 patients with first-episode psychosis. Overall, DUP and cognitive abilities were not significantly related, with the exception of evidence for a weak relationship with a single cognitive domain. There was a very small but significant association between longer DUP and reduced performance in planning/problem-solving ability (r = − 0.09, CI = − 0.14 to − 0.03). Current findings do not provide support for the neurotoxicity hypothesis of psychosis.

Introduction

Schizophrenia is associated with significant cognitive impairment (Heinrichs and Zakzanis, 1998, Bora et al., 2009, Mesholam-Gately et al., 2009, Schaefer et al., 2013, Bora, 2016). Cognitive impairment in schizophrenia has a significant effect on the level of functioning in individuals with schizophrenia (Fett et al., 2011, Hoe et al., 2012).

Cognitive deficits in schizophrenia are evident not only in chronic patients but also at first-episode (Mesholam-Gately et al., 2009, Bora and Pantelis, 2013, Aas et al., 2014, McCleery et al., 2014, Bora and Pantelis, 2015).

Several models have been proposed to explain the pronounced cognitive deficits which are evident from the beginning of the illness in schizophrenia. Neurodevelopmental model suggests that cognitive deficits in schizophrenia are mostly a consequence of problems in acquisition of cognitive abilities (developmental lag or arrest) during development (Weinberger, 1986, Murray and Lewis, 1987, Bora, 2015, Testa and Pantelis, 2009). It is widely accepted that neurodevelopmental factors play a significant role in cognitive impairment in schizophrenia. Also, emergence of psychotic symptoms might interfere with normal maturation of advanced cognitive abilities (i.e planning/problem-solving) which are complete until late adolescence/early adulthood. However, neurotoxicity hypothesis of psychosis suggests that cognitive deficits might also emerge as a consequence of untreated active psychosis in early years of the illness (Lieberman et al., 1993, Sheitman and Lieberman, 1998, Wyatt, 1991). There is usually a delay between the emergence of first psychotic symptoms and initiation of treatment. The time elapsing between onset of first psychotic symptoms and initiation of first effective intervention has been defined as the duration of untreated psychosis (DUP) (Marshall et al., 2005, Polari et al., 2011). The neurotoxicity hypothesis suggests that longer DUP can lead to structural brain changes and cognitive deficits in FEP.

Available evidence suggests that there is a modest but significant relationship between longer DUP and poor symptomatic and functional outcomes in FEP (Harrigan et al., 2003, Penttila et al., 2014). However, the studies investigating the relationship between DUP and cognitive deficits in FEP provided a weaker support for neurotoxicity hypothesis (Rund et al., 2004). While some studies found a positive association between longer DUP and cognitive impairment, most studies found no significant relationship between DUP and neurocognition in FEP (Rund, 2014).

The negative findings in studies investigating the relationship between DUP and neurocognition in FEP might be related to a number of factors including the low statistical power of the individual studies and heterogeneity of cognitive impairment in psychotic disorders (Reser et al., 2015, Bora et al., 2016, Bora, 2016). A meta-analysis might be beneficial in improving the statistical power by increasing sample size. To our knowledge, no previous meta-analysis investigating the relationship between DUP and neurocognition has been published. In this paper, a meta-analysis of the relationship between cognitive impairment and DUP in FEP was conducted for providing a reliable estimate of the strength of the potential relationship. We also aimed to investigate the effect of potential factors including diagnosis and demographic factors on the strength of the relationship between DUP and neurocognition. The primary hypothesis of the current meta-analysis was that there would be a significant relationship between longer DUP and cognitive impairment in FEP. We also hypothesized that the relationship between DUP and neurocognition would be particularly evident for advanced cognitive abilities which still continue to develop in late adolescence and early adulthood.

Section snippets

Study selection

PRISMA guidelines were used in conducting this meta-analysis (Moher et al., 2009). A literature search was conducted using the databases Pubmed and Scopus to identify the relevant studies (January 1980 to February 2017) using the combination of keywords as follows: (“duration of untreated psychosis” and “cogn*”). Reference lists of published reports were also searched for additional studies. Literature search was conducted independently by E.B and BY and final selection of articles were decided

Results

The selection process is summarized in Fig. 1. A total of 27 studies were included in the meta-analysis (Table 1). Twenty-five of these studies, including 3127 patients with FEP (61.7% males, mean age = 26.6) were selected as main studies and 2 overlapping studies (Leeson et al., 2010, Malla et al., 2011) included only for the outcome of cognitive variables not reported in two of the main studies. Six of these FEP studies included only schizophrenia patients and 19 studies also included some

Discussion

The current meta-analysis sought to provide a systematic overview of studies investigating the relationship between neurocognition and DUP. In general, DUP had no significant impact on the severity of cognitive impairment. However, there was an exception for the planning/problem-solving domain. Longer DUP was very modestly (r = − 0.09) but significantly associated with low performance in planning/problem-solving.

In general, these findings do not support the notion that DUP has a “toxic” effect on

Conflict of interest

The authors have no conflicts of interest regarding subject of this manuscript.

Contributors

EB and BY conducted the literature search. EB conducted the analyses and wrote the first draft. All authors contributed to the planning of the study. All authors critically reviewed the paper. All authors contributed to and have approved the final manuscript.

Funding body agreements and policies

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Acknowledgements

Dr. Bora is supported by The Scientific and Technological Research Council of Turkey (TÜBİTAK)BİDEB2232 fellowship.

We would like to thank authors of Addington et al., 2004, Chou et al., 2015, Galderisi et al., 2009, Wang et al., 2016, Zhou et al., 2012, Zhuo et al., 2013 for providing additional information about their published studies.

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Duration of untreated psychosis and neurocognition in first-episode psychosis: A meta-analysis

Abstract

Introduction

Section snippets

Study selection

Results

Discussion

Conflict of interest

Contributors

Funding body agreements and policies

Acknowledgements

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