Discussion
blurred vision, psychotic disorder, cognitive impairment, decline in verbal learning and memory, psychosis, amotivation, memory impairment, verbal learning and memory, schizophrenia
SECONDARY, DUP, MOVEMENT DISORDERS
This pre-planned secondary analysis of a triple-blind, placebo-controlled, randomised clinical trial, with a demographically matched healthy control group, enabled us to determine the effects of psychotic disorder, antipsychotic medication, and typical changes on cognitive performance over 6 months. The prospective randomised design ensured the medication and placebo groups did not significantly differ at baseline on any cognitive measure, length of DUP, or other illness variables. Two key findings emerged. First, change in cognitive functioning was similar across the placebo, medication, and healthy control groups in most cognitive domains. This suggests that the cognitive improvement or stability observed was not specifically associated with the effects of medication or illness, as the same pattern of change was also seen in healthy controls with no history of psychosis or antipsychotic exposure. The second key finding was that allocation to the risperidone/paliperidone over 6 months was associated with a decline in verbal learning and memory. In contrast, patients who received placebo improved in verbal learning and memory at a similar rate to healthy controls. The effect sizes were medium to large. These findings were broadly similar when only trial completers were included in the analysis.A significant implication of the findings is that partially or completely withholding antipsychotics is not harmful to cognitive functioning and may be specifically beneficial for verbal learning and memory in the early course of treatment. Experimentally lengthening the DUP (in the placebo group) was not associated with worsening of cognition or a slower rate of improvement in any domain measured. This finding is consistent with previous meta-analyses showing negligible associations between DUP and cognition [A second key implication of the findings is that risperidone/paliperidone may worsen verbal learning and memory at least for some young FEP patients not highly suicidal or hostile and with short DUP. This finding contrasts with earlier randomised head-to-head trials showing mildly improved cognitive functioning, including verbal learning and memory, following 3–6 months of treatment with second-generation antipsychotics, including risperidone [These effects of risperidone/paliperidone on learning and memory may arise because of their strong antagonism at dopamine (DSide-effects such as sedation, movement disorders, blurred vision and amotivation may also arise in response to taking risperidone/paliperidone [An anticholinergic mechanism could also plausibly explain the observed decline in verbal learning and memory [The specificity of the negative effect of risperidone/paliperidone to learning and memory is notable given impairment in this domain is associated with poorer community/vocational and social functioning in early psychosis [These cognition findings must be considered within the context of the full risk: benefit profile of withholding or prescribing antipsychotics in the early stages of psychosis treatment, including symptomatology, functioning, physical and metabolic health, brain health outcomes, in addition to patient-driven personal recovery goals [It is important to acknowledge that, in addition to the small sample, this was a distinctive and highly selective FEP sample due to the inclusion/exclusion criteria, so findings may not generalise to all FEP individuals and certainly require replication in confirmatory trials. Nevertheless, the degree of baseline cognitive impairment in the sample was comparable to other FEP samples diagnosed with schizophrenia [In conclusion, the findings highlight the importance of accounting for the potential longitudinal cognitive effects of antipsychotic medication following FEP. Careful consideration of the risks and benefits of antipsychotic initiation and maintenance is critical and should occur within a shared decision-making framework. Indeed, a recent study showed that of various antipsychotic side effects, memory impairment had the strongest influence on the medication preferences of people with schizophrenia [