Change in neuropsychological functioning over one year in youth at clinical high risk for psychosis

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Abstract

Schizophrenia and related psychotic disorders are associated with significant neuropsychological (NP) impairments. Yet the onset and developmental evolution of these impairments remains incompletely characterized. This study examined NP functioning over one year in a sample of youth at clinical high risk (CHR) for psychosis participating in a treatment study. We assessed functioning across six cognitive domains at two time points in a sample of 53 CHR and 32 healthy comparison (HC) subjects. Linear regression of HC one-year scores was used to predict one-year performance for CHR from baseline scores and relevant demographic variables. We used raw scores and MANOVAs of the standardized residuals to test for progressive impairment over time. NP functioning of CHR at one year fell significantly below predicted levels. Effects were largest and most consistent for a failure of normative improvement on tests of executive function. CHR who reached the highest positive symptom rating (6, severe and psychotic) on the Structured Interview of Prodromal Syndromes after the baseline assessment (n = 10/53) demonstrated a particularly large (d =  1.89), although non-significant, discrepancy between observed and predicted one-year verbal memory test performance. Findings suggest that, although much of the cognitive impairment associated with psychosis is present prior to the full expression of the psychotic syndrome, some progressive NP impairments may accompany risk for psychosis and be greatest for those who develop psychotic level symptoms.

Introduction

Clinicians have long observed a period of apparent decline in functioning prior to psychosis onset (Sullivan, 1927), a period retrospectively recognized as the prodrome to psychosis. Prospective study of this period is possible through recruitment of “clinical high risk” (CHR) samples (McGlashan and Johannessen, 1996, Yung and McGorry, 1996). Identified primarily by the presence of attenuated positive symptoms derived from structured interviews, CHR individuals are at heightened risk for transition to psychosis (mean rates of conversion: 18–36%) within six months to three years (Miller et al., 2002, Yung et al., 2003, Cannon et al., 2008, Fusar-Poli et al., 2012). An important question in prospective research of CHR samples is whether clinical decline is associated with changes in brain and neuropsychological (NP) function.

Longitudinal neuroimaging studies have identified both gray and white matter volume reductions over time in CHR subjects who transitioned to acute psychosis relative to those who did not (Walterfang et al., 2008, Sun et al., 2009, Takahashi et al., 2009). Taken together with observations that post-onset levels of cognitive functioning in schizophrenia are significantly worse than those observed in the premorbid period (Woodberry et al., 2008, Mesholam-Gately et al., 2009) these findings suggest an active process of altered brain function that underlies NP decline and/or failure of normative NP development during the transition to psychosis. The transition to psychosis typically occurs during adolescence and early adulthood, a period important for complete maturation of cortical gray matter, particularly in frontal networks. Pathology during this period might be expected to interrupt NP development, especially of functions dependent on prefrontal cortical (PFC) functioning, such as executive functions (EF, Paus et al., 2008) and episodic memory, which is dependent on spontaneous organization of features for memory encoding (Cirillo and Seidman, 2003).

Although the evidence is not definitive, both cross-sectional and longitudinal studies suggest that progressive NP impairment may accompany the onset of psychosis. Three longitudinal studies that varied in length of follow-up found a decline in intellectual functioning over time in individuals who developed psychosis relative to those who did not (Lubin et al., 1962, Caspi et al., 2003, Seidman et al., 2006). Progressive decline prior to acute psychosis, however, has been less consistently observed (Cosway et al., 2000, Rabinowitz et al., 2000, Fuller et al., 2002, Ang and Tan, 2004, Bilder et al., 2006, Woodberry et al., 2008, Reichenberg et al., 2010). When NP development is found to differ in youth who later develop a psychotic disorder relative to healthy controls, it is often due to a lower rate of growth rather than a decline per se (e.g., Reichenberg et al., 2010).

Six published studies have reported on NP functioning over time in putatively prodromal samples, five of which evaluated longitudinal change in relation to psychosis outcome (Keefe et al., 2006, Wood et al., 2007, Hawkins et al., 2008, Becker et al., 2010, Jahshan et al., 2010, Barbato et al., 2012). Studies examining composite scores found no significant group-by-time effects for CHR who converted to psychosis versus CHR who did not (Keefe et al., 2006, Hawkins et al., 2008, 13 and 11 converters, respectively). Three studies identified similar overall results but noted altered performance trajectories for some individual tests. Significantly lower scores over time were reported for CHR who transitioned to psychosis relative to those who did not on tests of visual memory and visual–spatial processing speed (Wood et al., 2007), working memory (Jahshan et al., 2010), and verbal memory (Becker et al., 2010). In the first two of these, converters demonstrated a decline in performance over time. However, sample sizes in these studies were small, particularly for converters (7, 6, and 17, respectively). Replication and larger samples are needed to determine the reliability of these findings.

For developmental reasons noted, our interest has been on cortically based NP functions, especially those associated with the PFC, such as EF. Importantly, olfactory identification, another function associated with PFC, although more with ventral (e.g., orbitofrontal cortex, Seidman et al., 1992), than dorsal sections, is reliably impaired in schizophrenia (SCZ). Deficits have been found in two CHR samples (Brewer et al., 2003, Woodberry et al., 2010), with a failure of expected olfactory development being possibly specific to CHR who developed SCZ (Brewer et al., 2003). Yet the developmental course of these deficits remains largely unknown.

The purpose of this study was to examine neuropsychological development over one year in a CHR sample relative to healthy comparisons (HC). Given some preservation of NP function in CHR relative to first episode samples, even in those who later developed psychosis (Keefe et al., 2006, Seidman et al., 2010, Giuliano et al., 2012), we predicted increased NP impairment over time, particularly in those who transitioned to a psychotic level of symptoms. Specifically, we expected a degradation of normal development to be evident in performance on tests reliant on memory, EFs, and olfactory identification.

Section snippets

Participants

The CHR sample consisted of participants, ages 12–25, in a randomized controlled trial of family-aided assertive community treatment (FACT, McFarlane, 1997, McFarlane et al., 2000) through the Portland Identification and Early Referral (PIER) program in Portland, ME. All participants were offered family education, crisis intervention, assertive follow-up, and medication according to indication and protocol. Those randomized to FACT were also offered multifamily psychoeducation, assertive

Longitudinal CHR sample characterization

HC and CHR participants did not differ significantly on age, gender distribution, handedness, highest grade completed, parent education, family income, or racial distribution (see Table 1). This remained true for the smaller subgroups as well. CHR with longitudinal data (CHR-L) had statistically similar parental education, gender, handedness, and racial distributions, and median family income as CHR with only baseline data (CHR-B, N = 15). However, CHR-B were significantly older (mean age = 17.9, SD

Discussion

The purpose of this study was to examine the trajectory of neuropsychological development over one year in a CHR sample relative to HC. We predicted progressive relative impairment, particularly on tests of executive, memory and olfactory functions, and most marked in those who developed psychosis. Results revealed an overall failure of the CHR sample as a whole to perform at predicted levels at one year. Based on this battery, progressive NP impairment appeared to be specific to tests most

Role of funding source

Kristen Woodberry was supported by the Sackler Scholar Programme in Psychobiology and a Harvard Graduate Society Dissertation Completion Fellowship. Kristen Woodberry, Anthony Giuliano, and Larry Seidman were also supported by the Commonwealth Research Center of the Massachusetts Department of Mental Health (SCDMH82101008006), NIMH funding to Larry Seidman, PI: (clinical core of NIMH P50 MH080272-02 [McCarley overall PI], NIMH 1 U01 MH081928-01A1), and the Sidney R. Baer Jr. Foundation. Mary

Contributors

Kristen A. Woodberry contributed to the conceptualization of the study, secured part of its funding, conducted statistical analyses, and wrote the first draft of the manuscript. William R. McFarlane and William L. Cook contributed to the conceptualization and implementation of the study, secured funding for the larger clinical trial from which this study was derived, and contributed to editing of the manuscript, Anthony J. Giuliano and Larry J. Seidman contributed to the conceptualization and

Conflict of interest

Dr. McFarlane provides consultation on request to non-profit organizations establishing clinical services similar to the PIER program. The authors report no other potential conflicts of interest.

The following are the supplementary data related to this article.

. Effect sizes (Cohen's d) for CHR relative to HC on memory tests.

. CHR vs. HC effect sizes (Cohen's d) on letter number sequencing tests.

. CHR vs. HC effect sizes (Cohen's d) for remaining tests and domains.

Acknowledgments

This article is based in part on the published dissertation of the first author. Portions of results have been presented at the Schizophrenia International Research Society Conference (2010, April), the Harvard Medical School Department of Psychiatry Research Day (2010, 2011, 2012 March), the International Congress on Schizophrenia Research (2011, April), and the Society for Research in Psychopathology Conference (2011, September). The authors would like to acknowledge staff of the PIER

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