This study confirms the presence of baseline neuropsychological deficits in individuals at UHR for psychosis and provides the first evidence of longitudinal associations between neuropsychological functioning, clinical symptomatology, and social/role functioning in this population. At baseline, UHR individuals demonstrated a pattern of deficit in measures of speeded information processing, with a trend toward impaired verbal learning and memory. This profile is similar to that observed in other UHR samples8–18
as well as individuals with established psychotic illness,38–42
lending support to the notion that individuals showing emerging clinical signs of illness are on a continuum with fully psychotic individuals.
Additionally, this investigation is one of the first to demonstrate that a subset of UHR individuals show a pattern of improvement in multiple cognitive domains, specifically processing speed, verbal and visual learning and memory, and motor speed at follow-up approximately 8 months later. Although there is some evidence for short-term improvement in some cognitive domains in first-episode schizophrenia as a result of pharmacological interventions,43,44
the overall degree of cognitive impairment appears relatively stable across the lifetime course of the illness.45–48
The current findings suggest that the pattern of cognitive deficits observed at baseline in a subset of putatively prodromal individuals may reflect difficulties associated with generalized psychiatric distress, as opposed to a stable, underlying trait specifically associated with risk for psychosis. Therefore, some UHR individuals share certain phenotypic features with those who progress to psychosis, but possibly for different underlying reasons.
Additionally, results of the current study revealed that UHR individuals’ functional improvement at follow-up was not predicted by their cognitive performance at baseline, but functional improvement was associated with improvement in both cognition and clinical symptoms over the follow-up period. In other words, those individuals who showed improvement in social or role functioning over the follow-up period also had improved cognitive performance and decreased symptoms over time. Specifically, improvement in social functioning was associated with significant improvement in both processing speed and visual learning and memory at follow-up. Given that UHR participants in this sample show significant cognitive improvement in many domains, these findings reveal that it may be this pattern of change in cognition over the follow-up period, rather than severity of cognitive deficits at baseline, that is related to improvement in functioning over time.
Furthermore, results showed that improvement in social functioning was associated with a larger decrease in positive symptoms over the follow-up period, suggesting that acute symptomatology may play a stronger role in social functioning in UHR patients than is observed for patients with full-blown psychosis. Likewise, improvement in role functioning was associated with a larger decrease in negative symptoms over time, lending support to the notion that negative symptoms have a notable impact on role functioning in UHR individuals.
Several possible alternative explanations for the pattern of cognitive improvement observed in this study bear consideration. In particular, practice effects49
and the effects of interventions may arguably play a role. Research shows improved functional outcome with earlier intervention in the treatment of psychotic disorders,50–52
and many of the study participants received some form of psychiatric or psychological treatment during the course of the study. Such treatment is ethically necessary due to the participants’ level of distress and functional impairment, but these interventions likely affect the natural course of the disorder and contribute to clinical and functional improvement. In the current study, participants who received 2 or more types of psychotherapy over the follow-up period were significantly more likely to show a 20% decrease in positive symptoms, suggesting that psychosocial interventions may have a strong impact on clinical distress in this at-risk population. However, such treatment was not associated with changes in cognitive or psychosocial functioning. Unfortunately, sample size and the high percentage of study participants receiving treatment prohibited comparison of individuals receiving vs those who declined treatment and between individuals receiving different forms of treatment. Nevertheless, longitudinal analyses of patients with schizophrenia typically show a pattern of stable cognitive functioning across the lifespan course of illness, despite improvement in psychotic symptom severity in response to psychosocial treatment,53,54
which is in contrast to the pattern of cognitive, clinical, and functional improvement observed here. In order to address these issues definitively, future studies will need to use matched non-UHR samples to control for practice effects, as well as UHR individuals receiving alternative types of treatment to examine the effects of psychotherapy and medication on cognition and social/role functioning.
Although one also could hypothesize that these findings of improvement were driven by the subset of “false positives” within this sample, additional analyses revealed that individuals who subsequently converted to psychotic disorder diagnoses (“true positives,” n
9, 25% of the sample) showed the same patterns of baseline cognitive deficits and subsequent improvement in cognition, clinical symptoms, and functioning when compared with those who did not convert. Consistent with some recent findings in first-episode treatment studies using novel atypical antipsychotic compounds,43,44
these results suggest that early intervention may attenuate the effects of psychosis on cognition and contribute to better outcome, even for those who subsequently develop a psychotic disorder.
Many researchers have highlighted the potential of cognitive dysfunction as a possible latent marker, or endophenotype, of genetic risk for schizophrenia.4,8,38,39,42,55–60
While the current findings provide evidence supporting the growing body of research on the presence of cognitive deficits in individuals at high risk for developing psychosis, the pattern of cognitive improvement observed in this study encourages critical examination of the potential utility of baseline cognitive deficits as definitive markers for heightened risk for psychotic illness in a clinical high-risk sample. The observation of improvement in multiple cognitive domains in association with clinical and functional improvement suggests that baseline cognitive deficits in a subgroup of UHR individuals may represent a state-specific factor, associated with diffuse psychological distress and poor functioning, which may affect cognitive performance independent of final diagnostic outcome. Alternatively, the pattern of deficits observed here could represent an interaction between psychological state at ascertainment and underlying trait factors that are associated with risk for psychosis or other psychiatric disorders. These competing explanations warrant further investigation in future studies.
A previous analysis30
diagnoses in this sample revealed that many of the UHR participants met criteria for a mood or anxiety disorder diagnosis at ascertainment, diagnoses which other studies61–63
have found to be associated with cognitive impairment in the domains observed here. Given that UHR populations are a mixture of true and false positives, the cognitive deficits observed in UHR samples at ascertainment may represent the manifestation of impairment associated with generalized risk for a variety of psychological disorders rather than a vulnerability that is specific to psychosis. Therefore, the results of this study suggest that the pattern of change in cognition and functioning over time may provide a more accurate means of separating the false positives, who show improvement in state-related deficits over time, from the true positives, who show more stable trait-like deficits representing endophenotypic markers of underlying risk.
Therefore, these findings provide novel evidence suggesting that individuals identified as UHR are not predestined to a path of psychological, cognitive, and functional decline. To the contrary, the demonstration of improvement in multiple cognitive domains highlights the power of early identification and intervention in this at-risk population. Overall, the results of this study suggest that UHR individuals should be examined over time because it may be the pattern of cognitive and symptom change or stability that may differentiate those individuals who are at highest risk for further psychological deterioration.
While this study offers support for early identification as a means of improving functional outcome, results should be interpreted with caution due to the small sample size. These findings provide the first glimpse into relationships between cognition, symptoms, and functioning over time and are presented to generate hypotheses and encourage future research in this area. However, it should be noted that the lack of statistical power may have reduced the ability to detect differences between the groups. Additionally, small sample size precluded the investigation of the different patterns of association between cognitive, clinical, and social/role functioning measures presented in the current study. Further analyses should be pursued in larger samples to validate these findings, examine specificity of deficits observed here, and uncover additional relationships that may have been obscured in the current analysis.
As noted previously, this current study is limited by its lack of a normal comparison group and resulting use of published normative data for comparison to this clinical sample. However, such published normal samples were developed and published in order to provide adequate comparisons for clinical data. Given the difficulty in obtaining well-matched adolescent control samples, researchers commonly utilize such published norms.15
Nonetheless, comparison to a demographically matched control sample, assessed at similar time points, would strengthen the current findings and should be a priority for future studies. As a related issue, this investigation relied exclusively on standard clinical neuropsychological tests of the domains of cognition sampled, and it is possible that deficits in other domains, such as working memory, would have been observed had we employed experimental paradigms designed to isolate particular aspects of these functions.
Finally, it is important to note that some proportion of individuals within this sample will not progress to develop a diagnosable psychotic disorder, and these individuals would consequently be labeled false positives. As noted previously, the inclusion of such false positives in the group analyses may obscure the presence of significant cognitive deficits in some of the hypothesized domains, and the relationship between such deficits and functional outcome, that may be present if only true positives were examined. Although additional analyses suggested that the pattern of improvement was also characteristic of a small sample of true positives, longitudinal follow-up in larger samples is needed to determine the pattern of neurocognitive, symptomatic, and functional change most predictive of conversion to a full-blown psychotic disorder and to elucidate the complex relationship between such cognitive change, clinical severity, and functional outcome over time.