Schizophrenia is a heterogeneous disorder, associated with varied clinical and cognitive profiles among patients.
Cognitive performance is relatively independent of the severity of psychosis, emphasising the need to assess and treat these as distinct domains. Nevertheless, patients are predominantly recruited into clinical trials on the basis of an established diagnosis (DSM-5) and psychosis severity (Positive and Negative Syndrome Scale; PANSS), neither of which is indicative of cognitive ability. This presents a potential problem for pro-cognitive drug trials in this population.
Screen for cognitive dysfunction
Though the majority of patients with schizophrenia exhibit some general cognitive dysfunction compared to antecedent expectations, such as premorbid intelligence, up to a quarter display cognitive performance in the ‘normal’ range (Fanning et al., 2012; Heinrichs et al., 2017).
Inclusion of those patients without a clinically significant deficit in cognitive performance inflates baseline scores, and reduces the scope to see improvement between drug and placebo groups.
This suggests a possible need to screen prospective participants in order to identify those with a deficit within a relevant domain, based on the hypothesised mechanism of action of the study drug.
To put this theory into context, in a trial of a compound intended to improve memory it is unlikely that you will see considerable gains in memory performance among patients whose task performance at baseline is in the normal range.
The use of cognitive screening measures to identify patients with relevant deficits for inclusion into pro-cognitive drug trials has the potential to increase the likelihood of identifying a positive signal from the compound.
An alternative approach could be to include all patients in a trial, but to stratify the sample to ensure an equal representation of cognitively impaired and cognitively ‘normal’ individuals among the trial arms.
Targeted patient recruitment
Even more targeted patient recruitment may also be possible. There is a growing international recognition of the importance of stratified medicine and precision psychiatry, the idea that certain individuals within a broad diagnostic grouping may benefit more from different forms of treatment.
To date, trials of pro-cognitive drugs in people with schizophrenia have largely adopted a ‘one size fits all’ approach, with little consideration for exactly which individuals are most likely to be responsive to particular treatments.
Future pro-cognitive drug trials in schizophrenia may consider primarily selecting patients for treatment on the basis of their specific profile of cognitive dysfunction.
This area remains in its relative infancy; though secondary analyses of existing trials may help to provide a data-driven approach to the identification of individuals who are most likely to benefit from particular compounds, which could then be further explored in future trials.
This blog post was originally published by Cambridge Cognition.
Fanning JR, Bell MD, Fiszdon JM. Is it possible to have impaired neurocognition but good social cognition in schizophrenia? Schizophrenia Research 2012;135(1-3):68-71.
Heinrichs RW, Parlar M, Pinnock F. Normal-range verbal-declarative memory in schizophrenia. Neuropsychology 2017;31(7):778-86.