Antipsychotic resistance tied to poorer cognitive function in schizophrenia

Resistance to antipsychotic treatment may result in worse cognitive function among patients with schizophrenia, with disorganization, doses, and negative symptoms playing a major role in this association, according to a Singapore study.

“Developing effective interventions to target specific symptom clusters, such as disorganization and negative symptoms, or overall antipsychotic load holds promise for optimizing cognitive and treatment outcomes in schizophrenia,” the researchers said. 

This study, conducted at the Institute of Mental Health, Singapore, included healthy control participants and people with schizophrenia, who were categorized into three groups: antipsychotic-responsive schizophrenia (ARS), clozapine-responsive treatment-resistant schizophrenia (TRS-CR), and clozapine-resistant/ultra TRS (UTRS).

Researchers used the Brief Assessment of Cognition-Short Form to examine cognitive function and the Positive and Negative Syndrome Scale (PANSS) to measure symptoms. They also performed statistical analyses with adjustments for age, sex, PANSS scores, and antipsychotic dose, which might affect cognitive function.

Significant differences were observed in overall cognitive performance, as measured by the PANSS score, between groups (p<0.001). Specifically, ARS showed the least impairment, followed by TRS-CR, while UTRS showed poorer cognitive function. [Singapore Med J 2024;65:552-557]

Overall cognitive function in all patient groups were significantly predicted by the following: antipsychotic dose and PANSS negative and disorganization/cognitive factors.

“Our study found differences in cognitive function that aligned with levels of treatment resistance: the greater the degree of treatment resistance, the poorer the cognitive function,” the researchers said.

“Interventions to improve negative and disorganization symptoms might be effective to enhance the cognitive function and treatment outcomes in schizophrenia,” they added.

Inverse relationship

The significant inverse relationship between PANSS cognitive/disorganization factor scores and cognitive tasks in the current study supported that found in published literature, which noted the association of higher levels of disorganization symptom with poorer performance on neuropsychological tests. [Psychiatry Res 1995;58:227-235; J Neuropsychiatry Clin Neurosci 2000;12:4-15]

These findings are also consistent with neuroimaging studies that reported the involvement of dorsal lateral prefrontal cortex (DLPFC) dysfunction in both cognitive impairment and behavioural disorganization. [Am J Psychiatry 2008;165:1006-1014]

Thus, targeting DLPFC dysfunction could be a therapeutic strategy for easing disorganization symptoms and improving cognitive outcomes, according to the researchers.

Furthermore, the significant inverse association between PANSS negative factor scores and cognitive performance is consistent with previous research findings. [Psychiatry Res 2013;210:387-395]

In longitudinal studies, patients with more pronounced negative symptoms appeared to show poorer global functioning, with cognitive composite score having an independent effect. This highlights the importance of effectively treating negative symptoms in schizophrenia. [Front Psychiatry 2022;13:841057]

"Thus, our study highlights the intricate interplay between negative symptoms and cognitive deficits in schizophrenia; both domains remain key unmet clinical needs, and effective treatment strategies are sorely lacking,” the researchers said. 

Nearly 30 percent of individuals with schizophrenia are resistant to antipsychotic treatment, and about half of the patients with TRS on clozapine do not show a meaningful clinical response, according to the researchers.