Schizophrenia typically develops during late adolescence and early adulthood and is characterised by the presence of positive symptoms, such as hallucinations and delusions.
Current antipsychotic medications are reasonably effective at treating these symptoms, yet many patients continue to exhibit marked and persistent impairments in social and occupational functioning and poor quality of life (Velthorst et al., 2017).
This functional disability is associated with substantial costs, both to patients and their carers as well as the wider community (Rössler et al., 2005).
In England alone, the societal cost of schizophrenia is estimated to be around £11.8 billion a year, with more than half of this accounted for by loss of productivity, such as unemployment (Schizophrenia Commission, 2012).
Cognitive impairment is a key issue in schizophrenia
Cognitive impairment is common in patients with schizophrenia, with deficits frequently observed on both neurocognitive measures (such as processing speed, memory and executive function), as well social cognitive tasks (such as being able to accurately interpret others emotions or mental states).
Meta-analyses suggest patients with schizophrenia typically perform roughly one standard deviation below healthy control group means, though performance within a ‘normal’ range, or deficits exceeding 1.5 standard deviations, are also not uncommon (Fioravanti et al., 2012; Savla et al., 2013).
Over the past decade, studies have consistently demonstrated that cognitive impairment is among the strongest determinants of social and occupational functioning in people with schizophrenia (Fett et al., 2011; Green et al., 2015), indicating that these deficits represent an important unmet target for therapeutic intervention.
Advances in this area are likely to hold direct, real-world benefits for patients and their families, while also reducing the financial burden of the disorder on society.
Barriers in pro-cognitive drug trials
However, despite considerable efforts by pharmaceutical companies, there are currently no drugs that have been approved for the amelioration of these cognitive deficits in schizophrenia.
A series of drugs have demonstrated early promise, only to have failed at the later stages of development. It remains unclear whether this is truly due to these compounds being ineffective, or whether trial methodology itself has been a limiting factor in successfully demonstrating the efficacy of these agents.
Participant screening and recruitment, trial design and the sensitivity of outcome measures are all important considerations and potential areas for improvement in this research area.
Tackling the issues
In this blog series, we will discuss some of the key limitations of existing pro-cognitive drug trials in schizophrenia, as well as some potential solutions. The key questions for the blog series are as follows:
Are we recruiting the right patients?
Are we using the most appropriate trial designs?
Are we using the most sensitive outcome measures?
This blog post was originally published by Cambridge Cognition.
Fett AK, Viechtbauer W, Dominguez MD, Penn DL, van Os J, Krabbendam L. The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis. Neuroscience and Biobehavioral Reviews 2011;35(3):573-88.
Fioravanti M, Bianchi V, Cinti ME. Cognitive deficits in schizophrenia: an updated meta-analysis of the scientific evidence. BMC Psychiatry 2012; 12:64.
Green MF, Llerena K, Kern RS. The “right stuff” revisited: what have we learned about the determinants of daily functioning in schizophrenia? Schizophrenia Bulletin 2015;41(4):781-5.
Rössler W, Salize HJ, van Os J, Riecher-Rössler A. Size of burden of schizophrenia and psychotic disorders. European Neuropsychopharmacology 2005;15(4):399-409.
Savla GN, Vella L, Armstrong CC, Penn DL, Twamley EW. Deficits in domains of social cognition in schizophrenia: a meta-analysis of the empirical evidence. Schizophrenia Bulletin 2013;39(5):979-92.
Schizophrenia Commission. The abandoned illness: a report from the Schizophrenia Commission. London: Rethink Mental Illness; 2012.
Velthorst E, Fett AJ, Reichenberg A, Perlman G, van Os J, Bromet EJ, Kotov R. The 20-year longitudinal trajectories of social functioning in individuals with psychotic disorders. American Journal of Psychiatry 2017;174(11):1075-85.