suggested a nominally stronger association between PGScog and cogntion in healthy controls than in participants with a psychotic disorder.
Conclusions: This was the largest study to date investigating the association between a broad and well-defined set of cognitive domains and PGSSCZ and PGSCOG in both healthy controls and participants with psychotic disorders. The findings overall suggest that cognitive symptoms to a lesser degree than previously thought are conferred by risk variants for the disorder. The stronger association between PGSCOG and working memory in healthy controls compared to participants with a psychotic disorder supports the notion that variation in cognitive symptoms may be influenced by clinical and environmental factors.
Study II: Cognitive functioning in patients with first-episode psychosis stratified by level of negative symptoms: A 1-year follow-up study
Background: Cognitive and negative symptoms are core features of schizophrenia spectrum disorders. Both symptom dimensions are associated with functional outcome, and they have frequently been found to correlate, at least in cross-sectional designs. Studies investigating patients with persistent negative symptoms in schizophrenia have yielded mixed findings with regard to cognitive function. Because cognitive symptoms are dimensional and vary among patients with a diagnosis within the schizophrenia spectrum, we developed an approach to stratify participants based on four levels of symptom severity. Participants who presented with absent levels of negative symptoms over time (NNS) were compared to those with mild (MNS), transitory (TNS), and sustained symptom levels (SNS), with a focus on cognitive functioning and cognitive course. Our first aim was to compare groups on baseline cognitive functioning. Our second aim was to compare cognitive course from baseline to 1-year follow-up. Our third and final aim was to explore the continuous relationship between negative symptoms (i.e. no group stratification) and cognitive function.
Methods: Eighty-seven participants with FEP and matched healthy controls underwent cognitive assessment at baseline and 1-year follow-up. Cognitive scores were used to form four separate cognitive domains and a cognitive composite score. An approach to subgroup FEP participants based on negative symptom level was applied using PANSS scores from baseline and 1-year follow-up. Analyses of variance were used to compare groups on cognitive domain scores at baseline and to investigate group differences in cognitive course. Correlation analyses were performed to investigate continuous relationship between negative symptoms and cognition.
Results: The multivariate analysis of variance where group differences were investigated for all cognitive domains was significant. This group difference could not be explained by age, sex, IQ, positive symptoms, or antipsychotic medication use. The SNS group displayed the largest cognitive impairments, whereas the NNS group did not differ from healthy controls on any cognitive domain or the cognitive composite. All other negative symptom groups were outperformed by the healthy controls on all domains, except the group with mild negative symptoms on the domain of verbal learning and memory. The group with sustained negative symptoms was outperformed on processing speed and executive functions by the group with no negative symptoms, and on verbal learning and memory by the groups with mild and transitory negative symptoms. We did not detect a difference in cognitive course between the symptom groups. We found that negative symptoms were correlated with the cognitive composite at both baseline and 1-year follow-up, but changes in negative symptoms did not significantly associate with changes in cognitive performance over the same period.
Conclusions: There was a clear dose-response relationship between level of negative symptom severity and cognitive functioning over the 1-year follow-up evident from baseline. Moreover, the large and stable cognitive differences, particularly between the groups with no and sustained negative symptoms, suggests a possible trait-like quality of this symptom combination. Early course of negative symptoms should guide clinicians when evaluating the need for thorough cognitive assessment in participants with FEP.
Study III: Cognitive and global functioning in patients with first-episode psychosis stratified by level of negative symptoms: A 10-year follow-up study
Background: Few studies have investigated how the level of negative symptoms over long follow-up periods are related to cognitive functioning. Based on findings from the previous study (II), we wanted to explore how long-term course of negative symptoms were related to cognitive functioning in a sample of FEP participants. We applied the same method for subgrouping FEP participants as in the previous study, this time based on negative symptom measures from baseline and 10-year follow-up. Our first aim was to investigate if our subgrouping method would replicate our previous findings, i.e. reproduce similar size, comparable clinical characteristics and baseline cognitive functioning. Our second aim was to investigate ten-year course of cognitive functioning, both in the entire sample and between groups. Our third and final aim was to investigate if groups differed in course of global functioning and evaluate to what degree the putative differences in the global functioning resulted from cognitive functioning or other clinical symptoms.
Methods: One hundred two FEP participants and 116 healthy controls completed baseline and 10-year follow-up clinical and cognitive assessment. The FEP participants were divided into four subgroups based on level of negative symptoms over the 10-year course. Analyses of variance were used to answer the main research questions in the study. After inspecting the data and checking assumption requirements for analyses of variance, the 116 healthy controls initially included were randomly reduced to the FEP sample average size of 26, after which the homogeneity of variance assumption was met. A follow-up analysis for the second research question was performed using linear mixed models where all 116 healthy controls were included. A multiple linear regression analysis was performed to investigate the contribution of cognitive functioning in explaining differences in global functioning at follow-up.
Results: Aside from some discrepancies in group sizes, our results largely replicate the findings from Study II. The NNS group was not outperformed by healthy controls on any cognitive domain or the cognitive composite score at baseline, whereas healthy controls significantly outperformed the remaining clinical groups on most measures, except the SNS group on attention and the MNS group on verbal learning and memory. The largest difference between the negative symptom groups was between the NNS and the SNS groups. The better scores for the NNS group on the overall cognitive composite as well as on the verbal learning and memory domain was statistically significant. Results regarding our second research question showed a significant improvement over time for verbal learning and memory, executive functioning, and the cognitive composite. No statistically significant between-group differences were detected.
For our third and final research question we found a significant improvement in global functioning over the 10-year follow-up. There was no group x time interaction. The SNS group showed the poorest level of functioning at 10-year follow-up with statistically significant differences from the NNS (mean difference 13.34, p = .018) and the MNS (mean difference 13.35, p = .007) groups. A multiple regression analysis correcting for the cognitive composite score, depression and positive symptoms (which all showed a statistically significant impact on level of global functioning) was performed. The effect on GAF from belonging to the SNS versus the remaining clinical groups remained statistically significant.
Conclusions: The stratification based on the level of negative symptoms at baseline and 10-year follow-up showed clear associations with cognitive and global functioning. As found in Study II, the greatest differences were found between the NNS and SNS groups. Therefore, stratifying level of negative symptom severity over time could be key to better understand cognitive heterogeneity in schizophrenia. A particular focus should then be on the contrast between the extreme ends of the dimension, the NNS and SNS groups, that formed a significant portion of the total participant sample. A clinical implication of these findings is that the SNS group consists of individuals who likely need cognitive remediation. This is an intervention that may also have beneficial effects on negative symptoms. Moreover, the
cognitive resourcefulness in the NNS group should be recognized and communicated to bring optimism and strengthen hope.