Neurocognitive deficits in the (putative) prodrome and first episode of psychosis,☆☆

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Abstract

Objective

International research programs have contributed to the creation of operationally defined criteria to identify individuals at risk for schizophrenia. Although there has been substantial progress in the prospective study of the schizophrenia prodrome, the utility of current diagnostic criteria remains questionable because of the relatively low base rates of incident psychoses, the high false-positive rate and ethical concerns regarding the treatment of individuals at risk. The identification of brain based neurocognitive vulnerability markers for schizophrenia may contribute to the development of an at risk algorithm with greater predictive accuracy.

Methods

Forty subjects at risk (AR) for schizophrenia, 15 in their first episode (FE) of schizophrenia, and 36 healthy comparison (HC) subjects were administered a neurocognitive battery that assessed the domains of processing speed, working memory, verbal episodic memory, executive functioning and general intelligence.

Results

At baseline, AR subjects showed neurocognitive deficits across all domains compared to HC subjects that were less severe than those observed in the FE sample. In preliminary analyses, AR subjects who later converted to psychosis (N = 5) had greater neurocognitive impairment at baseline evaluation compared to those individuals who remained “at risk” at follow-up.

Conclusions

Neurocognitive deficits may be important in the pathogenesis of early psychosis and could help to define individuals at greatest risk for schizophrenia. Continued research in larger cohorts is needed to test the validity of this neurocognitive profile and its utility as a vulnerability marker.

Introduction

Over the last decade, there have been considerable efforts to prospectively identify young people at risk for developing schizophrenia. There is evidence suggesting that longer durations of untreated psychosis is integrally related to poorer outcomes. Therefore, if the early prodromal phase of schizophrenia can be reliably predicted and/or recognized there is hope that early intervention efforts may delay or prevent the onset of psychosis or at least reduce the morbidity of the illness.

Improved understanding of the schizophrenia prodrome is slowly emerging as the result of international prodromal research programs, including the Cognitive Assessment and Risk Evaluation (CARE) Program at the University of California, San Diego. These programs have contributed to the development of operationally defined “prodromal criteria” that include attenuated or transient psychotic symptoms and/or familial risk plus a decline in overall global functioning that aim to identify a group of individuals at high risk for developing psychosis. Although there has been substantial progress made in the ability to prospectively identify individuals at risk for psychosis, the clinical utility of assessment measures alone remains suboptimal since the false-positive rate is over 50% in most studies and the incidence of “conversion” to psychosis over even moderately long study durations is relatively low (Haroun et al., 2006).

The high false-positive rate raises ethical concerns regarding pharmacologic treatment of individuals who are identified as “at risk” but may not be in the prodromal phase of the illness (Corcoran et al., 2005, Haroun et al., 2006, McGlashan, 2001, McGorry et al., 2001). Therefore, improved predictive accuracy for distinguishing individuals at imminent risk for developing psychosis is needed. The identification of brain based neurobiological or neurocognitive vulnerability markers for schizophrenia may contribute to the development of an “at risk algorithm” with greater predictive accuracy.

Neurocognitive dysfunction has been well established in schizophrenia and is an uncontested core component of the illness. A broad array of neurocognitive deficits across multiple domains, including motor abilities, learning/memory, executive functions, attention, language, spatial abilities, and general intelligence has been well documented (Heinrichs and Zakanis, 1998). Similar neurocognitive impairments, particularly deficits in verbal memory, executive functioning, working memory and attention, have been detected at the first episode of psychosis (Bilder et al., 2000). Neurocognitive dysfunction has also been demonstrated in nonpsychotic first-degree relatives of patients with schizophrenia (Cornblatt and Obuchowski, 1997) and individuals with schizotypal personality disorder (Cadenhead et al., 1999, Siever and Davis, 2004), both of which have been shown to be at greater risk of developing psychosis. Detection of impairment prior to onset of psychosis suggests that some neurocognitive abnormalities precede and are not solely a consequence of psychosis, and thus may represent a trait marker for schizophrenia.

Evidence of neurocognitive impairment in individuals putatively in the prodromal phase of schizophrenia is rapidly emerging (Brewer et al., 2006a, Francey et al., 2005, Hawkins et al., 2004, Keefe et al., 2006, Lencz et al., 2006a). Preliminary results indicate that at risk individuals generally perform intermediate to healthy controls and first episode psychosis patients, particularly on measures of verbal learning/memory, attention, executive abilities and general intellectual functioning (Bartok et al., 2005, Brewer et al., 2005, Brewer et al., 2006a, Cosway et al., 2000, Francey et al., 2005, Gschwandtner et al., 2003, Hambrecht et al., 2002, Hawkins et al., 2004, Keefe et al., 2006, Lencz et al., 2006b, Wood et al., 2003). Measures of verbal memory and spatial working memory in particular, as well as olfactory identification have demonstrated utility in predicting the transition to psychosis (Brewer et al., 2003, Brewer et al., 2005, Lencz et al., 2006b, Wood et al., 2003). Thus, consistent with a neurodevelopmental model of schizophrenia, neurocognitive dysfunction may precede the onset of psychosis and prove to be an effective vulnerability marker, especially when combined with other known neurobiological markers: P50 event related potential suppression (Myles-Worsley et al., 2004), prepulse inhibition of the startle response (Abel et al., 2004, Cadenhead et al., 2000, Tenn et al., 2005), anti-saccade (O'Driscoll et al., 1998, Thaker et al., 2000, Thaker et al., 1998), mismatch negativity (Brockhaus-Dumke et al., 2005) and sub-threshold psychotic symptoms, enhancing our ability to identify individuals truly in the prodromal phase of schizophrenia (Haroun et al., 2006).

Although considerable progress has been made, replication of the few published reports is needed in order to accurately characterize the neurocognitive profile of those in the prodromal phase of psychosis. Additional studies are needed in order to establish specific neurocognitive impairments that are sensitive enough to serve as effective predictors of psychosis. Studies utilizing a broad neuropsychological battery among a sample that includes at risk individuals in addition to those who have recently progressed to psychosis (e.g., Keefe et al., 2006) would allow for the examination into the trajectory of psychotic illnesses.

Here we compare the baseline neurocognitive profiles of individuals at risk (AR) for developing psychosis, to those who have experienced their first episode (FE) of psychosis, and healthy comparison (HC) subjects in the CARE (Cognitive Assessment and Risk Evaluation) program at the University of California, San Diego. Our a priori hypothesis was that the AR sample would have neurocognitive deficits when compared to the HC group across multiple domains that are intermediate to those observed in FE patients. Additionally, we aimed to identify neurocognitive vulnerability markers for psychosis that would help predict psychotic outcome in the AR sample. Preliminary data are presented that compare baseline neurocognitive performance of AR subjects who later converted to psychosis (true prodromals) to that of subjects who remained at risk at one year follow-up.

Section snippets

The CARE Program

The CARE Program provides assessment, evaluation, and referral for individual treatment as needed, for individuals between the ages of 12 and 30, who are putatively at risk for, or experiencing early symptoms of schizophrenia (Seeber and Cadenhead, 2005). After extensive community outreach and education, individuals are referred from various professionals in the community (i.e., physicians, mental health practitioners, school personnel). After telephone screening, individuals deemed appropriate

Results

This paper reports the baseline neurocognitive results of a sample of 91 adult participants, ages 16 to 30 (AR = 40, FE = 15, HC = 36). The younger adolescent participants (< age 16) were not included in the current analyses due to the small sample size and the administration of different tests (e.g., WISC-III subtests).

Discussion

Subjects at risk for developing psychosis have neurocognitive deficits across multiple domains consistent with the pattern seen in patients experiencing their first episode of schizophrenia. These baseline findings support previous reports in putatively prodromal samples (Brewer et al., 2006b, Hawkins et al., 2004, Keefe et al., 2006, Lencz et al., 2006a) and generally implicate dysfunction in the frontotemporal regions of the brain, consistent with imaging studies in first episode samples (

Acknowledgements

The authors would like to acknowledge Nasra Haroun, MD, Karin Kristensen, PsyD, Kathy Shafer, BS, Iliana Marks, BS, and Shah Golshan, PhD for their clinical expertise, technical assistance and statistical review.

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  • Cited by (0)

    Role of Funding Source. This work was supported by the National Institute of Mental Health (NIMH) Cognitive Assessment and Risk Evaluation (CARE, MH60720). NIMH had no further role in study design, data collection, data analysis, data interpretation, writing of the manuscript, nor the decision to submit the manuscript for publication.

    ☆☆

    Contributors: Angela Eastvold was the primary writer of this manuscript; she also worked as the project coordinator of the CARE program which entailed working directly with the patients, assisting with subject recruitment, and managing the data. Robert Heaton provided ongoing consultation on the design of the study, data analysis and the preparation of this manuscript. Kristin Cadenhead is the primary investigator of this project and the Director of the CARE Program; she designed this study, provides ongoing patient care and assisted with data analysis and the preparation of this manuscript.

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