25 January 2018
How to select sensitive outcome measures in pro-cognitive drug trials for schizophrenia
The outcome measure selected for a pro-cognitive drug trial in schizophrenia must be sensitive enough to detect potentially subtle changes in cognition.
Schizophrenia Clinical Trials series: part 4 of 4
- Improving clinical trials for pro-cognitive drugs in schizophrenia
- Patient recruitment: are we selecting the right patients for schizophrenia clinical trials?
- Trial design: 4 ways to improve trials of pro-cognitive drugs in schizophrenia
- How to select sensitive outcome measures in pro-cognitive drug trials for schizophrenia
These factors create the necessary environment to facilitate identification of pro-cognitive drug signals. However, outcome measures must be sufficiently sensitive to these potentially subtle effects in order to convincingly support any pro-cognitive claims.
Co-primary end points in clinical trials
The United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommend that drugs that exert a pro-cognitive effect should also be accompanied by measureable improvements in real-world functioning.
This has led to the development of several instruments specifically for use in this population that seek to capture the subjective experience and impact of cognitive dysfunction on daily living for use as co-primary (cognitive, functional) endpoints in clinical trials.
Case study: outcome measure sensitivity determines whether a drug is effective
A recent study conducted by Lees et al. (2017) is a classic example of how a pro-cognitive drug can be considered both effective and ineffective, depending upon the sensitivity of the outcome measure.
The study investigated why modafinil, a successful cognitive enhancer for healthy adults (Turner et al., 2003), has an inconsistent history of pro-cognitive effects in schizophrenia (Lees et al., 2017).
A central hypothesis for this inconsistency was outcome measure sensitivity. This hypothesis was tested by comparing how 46 adults with schizophrenia performed on two different cognitive test batteries, following modafinil administration.
Sensitivity to the pro-cognitive effects of modafinil, in schizophrenia, was compared for the MATRICS Consensus Cognitive Battery (MCCB) and the Cambridge Neuropsychological Test Automated Battery (CANTAB).
This study found that modafinil offered significant pro-cognitive effects for performance on the CANTAB Paired Associated Learning (PAL) task among patients with schizophrenia, whilst performance on the MCCB tasks was unchanged (Lees et al., 2017).
The results suggested that CANTAB PAL is specifically sensitive to the pro-cognitive effects of modafinil in schizophrenia.
Improving pro-cognitive drug trials trans-diagnostically
Whilst this blog series has focused on some of the issues with pro-cognitive drug trials in the context of schizophrenia, these recommendations are equally applicable to a range of serious mental illnesses.
Major depressive disorder, bipolar disorder, and anxiety disorders are all associated with the presence of psychiatric symptoms (which can generally be improved with existing treatment) and cognitive dysfunction (which currently cannot).
Both symptom severity and the degree of cognitive impairment are also recognised as important and independent drivers of functional disability trans-diagnostically across these disorders, consistent with that observed among patients with psychosis.
As such, the successful amelioration of cognitive deficits could hold potential benefits for a number of adversely affected individuals.
The development of an effective pro-cognitive drug would therefore provide a major breakthrough in the treatment of psychiatric disorders.
What are the most sensitive outcome measures for pro-cogntive drug trials?
Lees J, Michalopoulou PG, Lewis SW, Preston S, Bamford C, Collier T, … Drake RJ. Modafinil and cognitive enhancement in schizophrenia and healthy volunteers: the effects of test battery in a randomised controlled trial. Psychological Medicine, 2017;1–11. https://doi.org/10.1017/S0033291717000885
Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian, BJ. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology, 2003;165(3), 260–269. https://doi.org/10.1007/s00213-002-1250-8