Cognitive impairments are widespread in schizophrenia and related psychotic disorders. A considerable body of research has established that mild cognitive impairment in schizophrenia is evident long before illness onset (as far back as early childhood). Impairments become more marked around the first psychotic episode, whereafter they persist even in periods of symptomatic remission. However, it is increasingly recognized that the degree of cognitive impairment within the schizophrenia spectrum varies. Because the impairments constitute a stable feature throughout the illness course and are robustly associated with occupational and social functioning, it is of great importance to gain increased understanding of this cognitive heterogeneity within the schizophrenia spectrum.
Both cognitive functioning and schizophrenia are heritable complex traits. Some studies find that genetic susceptibility variants for schizophrenia associate with cognitive function in both in healthy controls and in participants with schizophrenia. Moreover, negative symptoms, such as apathy and emotional blunting, have been found to correlate with measures of cognitive function.
The current thesis set out to better understand how genetic variants and negative symptoms over time are associated with function in separate cognitive domains and overall cognitive function. It is comprised of three studies . EVT: The current thesis, consisting of three studies, set out to better understand how genetic variants and negative symptoms over time are related to functioning in specific cognitive domains and overall cognitive function.
In Study I we sought to gain new knowledge about the genetic underpinnings of cognitive functioning in psychotic disorders. Based on previous research, we investigated how a set of well-defined cognitive domains were associated with common genetic variants conferring risk for schizophrenia (PGSSCZ) as well as common genetic variants shown to explain differences in cognitive ability in the general population (PGSCOG). We also wanted to compare the effects of
these genetic influences in participants with a psychotic and healthy controls separately. In Study II we developed a method for stratifying participants with first-episode psychosis (FEP) (defined as non-affective i.e. schizophrenia spectrum disorder included within the first year of adequate treatment) according to level of negative symptoms from baseline to 1-year follow-up. Participants were here grouped together based on whether they had no (NNS), mild (MNS), transitory (TNS), or sustained negative symptoms (SNS). The primary aim was to investigate baseline differences in cognitive functioning, and the course of cognitive functioning over one year between the negative symptom groups. In Study III we employed the same method for subtyping as in Study II using 10-year follow-up data. Our aim in Study III was to investigate baseline differences in cognitive functioning and 10-year cognitive course between negative symptom groups. To assess functional consequences, we also explored group differences in global functioning and 10-year course of global functioning across groups, and the relation to differences in cognitive functioning.
In Study I we found no association between the PGSSCZ and any of the cognitive domains either in the sample of healthy controls or in participants with a psychotic disorder. The PGSCOG was associated with the working memory domain, but only in healthy controls. The association of PGSCOG with working memory in healthy controls was stronger than in participants with a psychotic disorder with a statistically significant effect. Overall, our findings did not support the notion that variation in well-defined cognitive domains is associated with common genetic variants conferring risk for schizophrenia.
In studies II and III we found that level of negative symptoms over both short- (1-year) and long-term (10-year) follow-up was associated with cognition in FEP participants at baseline. The largest differences in cognitive functioning were between the NNS and SNS groups, with the SNS group showing the largest impairments. Though the healthy controls performed with mean scores nominally better than all negative symptom groups, the NNS group was not significantly outperformed by healthy controls on any domain or the cognitive composite score. We did not find that the negative symptom groups differed in cognitive course over the short- or long-term follow-up with most groups showing improvement of similar magnitude
in cognitive performance. In the 10-year follow-up we observed a cognitive course with statistically significant improvement for the entire sample in verbal learning and memory, executive functioning, and the cognitive composite. Long-term course of global functioning in the FEP sample as a whole also showed significant improvement with no difference between groups in course. At 10-year follow-up the SNS group had the poorest level of functioning. There was an independent effect of cognition on level of functioning, not accounted for by negative symptoms alone.
From studies II and III, we see that both short- and long-term course of negative symptoms is associated with cognitive functioning in FEP, particularly when contrasting the NNS and SNS subgroups. This implies very different treatment needs and should be taken into consideration in the clinical setting for improved individualization of treatment. Furthermore, individuals who do not show any signs of negative symptoms early in the course of illness may be a group with better cognitive functioning and a better prognosis.