Neuropsychological profiles in individuals at clinical high risk for psychosis: Relationship to psychosis and intelligence
Introduction
The literature on cognitive functioning during the putative prodrome to psychosis suggests cognitive impairments are generally intermediate between those of healthy comparison (HC) subjects and first episode psychosis (Eastvold et al., 2007, Francey et al., 2005, Keefe et al., 2006, Pukrop et al., 2006, Simon et al., 2007, Jahshan et al., 2010, Seidman et al., 2010). Of particular interest are findings specific to clinical high risk (CHR) individuals who develop psychosis over the course of follow-up, suggesting possible neuropsychological (NP) predictors of psychosis onset (Brewer et al., 2005, Brewer et al., 2003, Keefe et al., 2006, Lencz et al., 2006, Seidman et al., 2010). In the largest published study to date, NP function was more impaired at baseline in those who later developed psychosis than in those who did not (Seidman et al., 2010). When placed in the context of clinical factors predicting psychosis (e.g., severity of attenuated positive symptoms, family history, social functioning, and substance abuse), however, NP functioning did not add to the prediction algorithm (Cannon et al., 2008). Just the same, verbal memory may have added value in predicting faster transition to psychosis (Seidman et al., 2010). The relative value of both specific NP measures and general cognitive ability in predicting and understanding psychosis onset warrants additional study.
A number of “specific” deficits (presumably above and beyond any general deficit) have been documented in CHR samples, most reliably spatial working memory (Bartok et al., 2005, Myles-Worsley et al., 2007, Smith et al., 2006, Wood et al., 2003), verbal learning and memory (Brewer et al., 2005, Eastvold et al., 2007, Hawkins et al., 2004, Lencz et al., 2006, Seidman et al., 2010), attention (Francey et al., 2005, Gschwandtner et al., 2006, Hambrecht et al., 2002, Hawkins et al., 2004, Niendam et al., 2006) and processing speed (Seidman et al., 2010). Executive functions such as working memory, verbal fluency, and set-shifting have also been implicated, but less consistently (Eastvold et al., 2007, Gschwandtner et al., 2003, Gschwandtner et al., 2006, Hambrecht et al., 2002, Hawkins et al., 2004, Lencz et al., 2006, Myles-Worsley et al., 2007, Pukrop et al., 2006, Simon et al., 2007). In the few studies with clinical follow-up, poorer baseline verbal memory and olfactory identification have been identified as potential proximate predictors of later psychosis (Brewer et al., 2005, Brewer et al., 2003, Eastvold et al., 2007, Lencz et al., 2006, Seidman et al., 2010).
The possible predictive value of olfactory identification deficits, although measured in only one prior CHR study (Brewer et al., 2005), is intriguing. The ability to name odors is reliably impaired in adults with schizophrenia (SCZ) and in some studies, in individuals at familial high risk (FHR; Mesholam-Gately and Seidman, 2006, Moberg and Turetsky, 2006). In one study of SCZ, this impairment (as measured by the University of Pennsylvania Smell Identification Test, UPSIT) was not significantly associated with performance on measures of attention, executive function, or IQ, suggesting some specific utility (Seidman et al., 1992). Moreover, neurobiological studies have identified abnormalities in the olfactory bulb (Turetsky et al., 2000) and olfactory event related potentials of those with SCZ (Turetsky et al., 2003), suggesting abnormalities in specific neural substrates.
In the literature, “specific” deficits are often defined by statistically significant group differences in a single cognitive domain rather than the specificity of the deficit relative to overall functioning. However, it is well established that performance on different NP tests tends to be positively correlated (Spearman, 1927). Furthermore, both degree of inter-test variability and pattern of strengths and weaknesses on a NP battery may vary according to overall cognitive ability or attention, and vary differently for SCZ relative to HC matched on IQ (Diaz-Asper et al., 2004, Dodrill, 1999, Kremen et al., 2008). Because attentional functions have long been hypothesized to be central to schizophrenia and its risk (Seidman, 1983, Nuechterlein and Dawson, 1984, Cornblatt and Keilp, 1994), we also evaluated the role of attentional impairment in the profiles of CHR versus HC.
The role of current global ability in SCZ has also been studied relative to premorbid IQ estimated with measures of single word reading, a function relatively resilient to illness (Dalby and Williams, 1986, Kremen et al., 1996, Weickert et al., 2000). Given its weaker correlation with measures of nonverbal reasoning and processing speed, single word reading may be associated with different patterns of NP performance than Full Scale measures of IQ (FSIQ). Current full scale and premorbid IQ estimates may thus have different relationships to patterns of NP functioning associated with risk and onset of psychosis. These have not yet been adequately investigated in CHR samples.
Finally, potentially important variables such as age, sex, and sociodemographic status have not been controlled routinely and some HC groups are likely to be “supernormal” as reflected by high group mean IQ scores (e.g., 119, Gschwandtner et al., 2006) or have significantly different estimated premorbid IQ relative to CHR groups (Brewer et al., 2005, Pukrop et al., 2006). Thus, there remains a need to characterize NP functioning and profiles within CHR samples relative to well-matched HC, with particular attention to the influential role of premorbid IQ. Matching on premorbid IQ has been strongly recommended in a review of the CHR literature (Brewer et al., 2006).
This study's primary goal was to characterize the overall NP profile of CHR relative to demographically well-matched HC. We predicted that CHR would differ from HC in overall mean NP profile magnitude and shape, with those subsequently developing psychotic-level symptoms showing the greatest level of NP impairment. More specifically, we predicted relatively greater impairment in verbal memory and olfactory functioning after accounting for global abilities estimated by either single word reading or estimated IQ.
Section snippets
Participants
The CHR sample consisted of participants in a randomized controlled trial (RCT) of family-aided assertive community treatment (FACT, McFarlane, 1997) through the Portland Identification and Early Referral (PIER) program in Portland, ME (McFarlane, et al., 2010). Entry into the study required residence in Greater Portland, estimated IQ ≥ 70, and meeting criteria for one of three putatively prodromal syndromes (Criteria of Prodromal Syndromes, COPS) according to the Structured Interview for
CHR sample characterization
HC were well matched to CHR participants on demographic variables (Table 2). The two groups did not differ significantly on age, gender or racial distribution, handedness, highest grade completed, parent education, or family income. Moreover, CHR subgroups were highly similar to HC on demographic variables, with one exception: the BIPS subgroup had higher family income.
Neuropsychological performance and profile analysis of CHR relative to HC
CHR and HC were highly similar on WRAT-3 Reading (Table 3). However, 38.4% (16% is expected) of CHR current WASI IQ estimates
Discussion
This study examined the NP profile magnitude and shape of a CHR sample in comparison with a very closely matched HC group in order to identify severity and specificity of NP impairments. CHR and HC groups were highly similar, not only on key demographic features such as age, gender, handedness, parental education, and family income, but on an estimate of premorbid cognition (WRAT-3 Reading). In comparison to HC, CHR participants demonstrated a moderate to large overall NP impairment (roughly
Role of funding source
This research was supported by the Sackler Scholar Programme in Psychobiology, a Harvard Graduate Society Dissertation Completion Fellowship, the Commonwealth Research Center of the Massachusetts Department of Mental Health and University Research Grant, a NARSAD Young Investigator Award to Anthony Giuliano, NIMH funding to Larry Seidman, PI: (NIMH P50 MH080272-02, NIMH 1 U01 MH081928-01A1) and by funding to William McFarlane, PI: (NIMH RO1MH065367, the Robert Wood Johnson Foundation, and the
Contributors
All authors have made significant scientific contributions to this manuscript. Kristen A. Woodberry contributed to the conceptualization of this neuropsychological study, secured part of its funding, conducted statistical analyses, and wrote the first and final draft of the manuscript. Larry J. Seidman and Anthony J. Giuliano both contributed to the conceptualization and implementation of the study, secured funding to support their advisory roles, and provided major editing of the manuscript.
Conflict of interest
None of the authors have any actual or potential conflicts of interest to disclose.
Acknowledgements
This study is based in part on the doctoral dissertation of the first author. Dissertation committee members, in addition to the second and third authors, included Matthew K. Nock, Jill M. Hooley, and William P. Milberg. The authors would like to acknowledge the assistance of the staff of the PIER program, in particular Donna Downing and Susan Winslow, for their major contributions to the recruitment and assessment of CHR participants and implementing the larger randomized controlled trial that
References (63)
- et al.
Cognitive functions in prepsychotic patients
Prog. Neuropsychopharmacol. Biol. Psychol.
(2005) - et al.
Development of the UPSIT: a microencapsulated test of olfactory function
Physiol. Behav.
(1984) - et al.
Neurocognitive deficits in the (putative) prodrome and first episode of psychosis
Schizophr. Res.
(2007) - et al.
Sustained attention in young people at high risk of psychosis does not predict transition to psychosis
Schizophr. Res.
(2005) - et al.
Neuropsychological status of subjects at high risk for a first episode of psychosis
Schizophr. Res.
(2004) - et al.
A longitudinal study of neurocognitive function in individuals at-risk for psychosis
Schizophr. Res.
(2006) - et al.
Heterogeneity of schizophrenia: a study of individual neuropsychological profiles
Schizophr. Res.
(2004) - et al.
IQ decline in cross-sectional studies of schizophrenia: methodology and interpretation
Psychiatry Res.
(2008) - et al.
Generalized and specific neurocognitive deficits in prodromal schizophrenia
Biol. Psychiatry
(2006) - et al.
The Palau Early Psychosis Study: neurocognitive functioning in high-risk adolescents
Schizophr. Res.
(2007)
Neurocognitive performance and functional disability in the psychosis prodrome
Schizophr. Res.
Identification of separable cognitive factors in schizophrenia
Schizophr. Res.
Spatial working memory deficits in adolescents at clinical high risk for schizophrenia
Schizophr. Res.
Physiological impairment of olfactory stimulus processing in schizophrenia
Biol. Psychiatry
Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenia prodrome
Biol. Psychiatry
Impairment of olfactory identification ability in individuals at ultra-high risk for psychosis who later develop schizophrenia
Am. J. Psychiatry
Memory impairments identified in people at ultra-high risk for psychosis who later develop first-episode psychosis
Am. J. Psychiatry
Generalized and specific cognitive performance in clinical high-risk cohorts: a review highlighting potential vulnerability markers for psychosis
Schizophr. Bull.
Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America
Arch. Gen. Psychiatry
Children's Memory Scale
Impaired attention, genetics, and pathophysiology of schizophrenia
Schizophr. Bull.
The schizophrenia prodrome revisited: a neurodevelopmental perspective
Schizophr. Bull.
Neuropsychological change in young people at high risk for schizophrenia: results from the first two neuropsychological assessments of the Edinburgh High Risk Study
Psychol. Med.
Preserved reading and spelling ability in psychotic disorders
Psychol. Med.
California Verbal Learning Test — Children's Version
California Verbal Learning Test
Delis–Kaplan Executive Function System Examiner's System
How well does IQ predict neuropsychological test performance in normal adults?
J. Int. Neuropsychol. Soc.
Myths of neuropsychology: further considerations
Clin. Neuropsychol.
Development of the 12-item cross-cultural smell identification test (CC-SIT)
Laryngoscope
Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version: Administration Booklet
Cited by (100)
Premorbid intelligence quotient and school failure as risk markers for bipolar disorder and major depressive disorder
2024, Journal of Psychiatric ResearchHuman stem cell-based models to study synaptic dysfunction and cognition in schizophrenia: A narrative review
2023, Schizophrenia ResearchOlfactory dysfunction and face processing of social cognition in first-episode psychosis
2022, Neuroscience ResearchEnhancing attention and memory of individuals at clinical high risk for psychosis with mHealth technology
2021, Asian Journal of PsychiatryOlfactory and cognitive functions in Chinese individuals at clinical high risk for psychosis
2019, Psychiatry ResearchFMRI correlates of olfactory processing in typically-developing school-aged children
2019, Psychiatry Research - NeuroimagingCitation Excerpt :Relationships observed between olfactory dysfunction and both neurological and psychiatric disorders support the importance of understanding the neural correlates of olfactory function. Olfactory dysfunction has been linked to brain-based disorders that emerge across the life span, including depression (Croy et al., 2014; Pause et al., 2001), autism spectrum disorder (Hilton et al., 2010), schizophrenia (Moberg et al., 1999; Woodberry et al., 2010), Parkinson's Disease (Doty, 2007; Iannilli et al., 2017), and dementia (Atanasova et al., 2008; Murphy et al., 1990). Despite these links to neurological and psychiatric disorders both in children and adults, imaging research to elucidate the developmental patterns of olfactory processing has been limited relative to other sensory systems (Wang et al., 2014).