Understanding persistent negative symptoms in first episode psychosis: Implementing neurocognitive and neuroanatomical approaches

Background. Negative symptoms (alogia, blunted affect, amotivation, reduced social drive) are a core feature of psychotic disorders. In comparison to positive symptoms, negative symptoms do not respond well to treatment, thus becoming persistent in a large percentage of psychosis patients. Persistent negative symptoms (PNS) remain an unmet therapeutic need, in part, due to our lack of understanding of the cognitive and neural correlates of these symptoms. Furthermore, most studies ill investigate PNS in patients with enduring schizophrenia, which introduces confounding factors. Hence, there is a need for a better understanding of these symptoms in patients with a first episode of psychosis (FEP).Purpose. Our overall aim was to define and characterize the cognitive and neural correlates of persistent negative symptoms identified in patients with first episode psychosis. Methods. All FEP patients were treated at the Prevention and Early Intervention Program for Psychosis (PEPP) at the Douglas Mental Health University Institute in Montreal. First, the heuristic value of various PNS definitions applied in the literature was explored. The relationship between PNS definitions and functional outcome was also explored. The most clinically relevant PNS definition was then applied to subsequent studies. Secondly, memory ability was examined in three memory domains including verbal, visual and working memory. Memory was compared at baseline in FEP patients with PNS and without PNS. In addition, the trajectory of memory ability was assessed at a 12-month follow-up. Lastly, white matter microstructure was investigated in FEP patients identified as having PNS. A region of interest analysis was applied to assess fronto-temporo-limbic white matter tracts. Fractional anisotropy was measured in each tract and compared between PNS patients, non-PNS and healthy controls. Results. Persistent negative symptoms were defined as having a score of 3 or greater in at least 1 global subscales of the Scale for the Assessment of Negative Symptoms. In addition, FEP patients were required to have minimal positive, depressive, and extrapyramidal symptoms. Patients whose negative symptoms at the above-mentioned level of severity persisted beyond month 3 of their first year of treatment in the PEPP program met the criteria for PNS. Applying this definition allowed us to determine the prevalence of PNS in FEP, which was found to be 27%. Further, patients with PNS had poorer functioning at month 12 than those without PNS. All FEP patients were administered neuropsychological tests with focus being placed on memory ability in those affected with PNS. Results suggested that in comparison to patients without PNS and healthy controls, patients affected by PNS had poorer verbal memory ability. In addition, follow up memory scores indicated that memory impairments in PNS were stable through the first year. Lastly, fractional anisotropy was shown to be lower in both patient groups compared to healthy controls. While the non-PNS demonstrated significantly lower FA values in the uncinate fasciculus compared to healthy controls, lower fornix FA was found in the PNS group compared to healthy controls. Conclusions and significance.Our studies highlight a 27% prevalence of PNS in first episode psychosis, supporting previous assumptions of a greater prevalence of PNS in comparison to deficit syndrome (with a prevalence estimated at 15%). Patients with PNS present with: poorer functional outcome, greater verbal memory deficits and impaired white matter integrity in the limbic system. Thus, applying the PNS definition in future studies may help further elucidate the impact of negative symptoms in FEP, by providing a more homogenous subgroup of patients who are more severely impaired than patients without PNS.

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