Advancing understanding of the mechanisms of antipsychotic-associated cognitive impairment to minimise harm: a call to action

Abstract

The discovery in the 1950s that antipsychotic medication could dramatically improve the positive (and in some cases negative) symptoms of severe psychotic disorders led to antipsychotics becoming the first-line treatment for acute recovery, with maintenance for at least one to two years recommended for relapse prevention. Yet, antipsychotic medications do not usually improve the symptoms that underpin poor functional outcome, such as cognitive impairment. Clinically significant cognitive impairment is a hallmark of psychotic illness and is already present prior to the introduction of antipsychotics [ 1 ]. Whilst variable, the bulk of evidence shows that antipsychotic effects on general cognitive functioning are at best mildly positive and that these positive effects can mostly be explained by cognitive test practice effects, or atypical antipsychotics being less cognitively impairing than typical antipsychotics [ 2 , 3 ]. A growing body of more recent literature suggests that antipsychotic medication may in fact worsen cognitive functioning, including specific domains such as verbal learning and memory as well as composite functioning [ 4 , 5 ]. Subjective cognitive impairment, particularly cognitive slowing, is commonly reported by people taking antipsychotics. Naturalistic studies have shown higher cumulative antipsychotic exposure to be associated with poorer cognitive functioning [ 4 ], although these findings may reflect confounding by indication. Our recent triple-blind randomised controlled trial compared the effects of risperidone/paliperidone versus placebo on cognitive functioning over the first six months of treatment for first-episode psychosis [ 5 ]. A healthy control group not taking placebo or medication was also recruited. We found that in several cognitive domains the stability or improvement observed was similar across the three groups, suggesting improvements were in fact typical and not related to illness or medication [ 5 ]. However, a significant interaction was observed for verbal learning and memory, where the healthy control and placebo groups improved, but the risperidone/paliperidone group declined in performance. The effect sizes were moderate to large [ 5 ]. At the same time, there has been a rise in the number of randomised controlled trials comparing antipsychotic dose reduction with antipsychotic maintenance to evaluate their risk: benefit profile across a range of outcomes not limited to relapse. Cognition is a common outcome of these studies, where preliminary evidence suggests that medically guided dose reduction may be associated with superior cognitive outcomes, including in processing speed and global cognitive function (see Table 1 ). Table 1 Randomised controlled trials comparing antipsychotic dose reduction with maintenance with cognition as an outcome. Full size table

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