Billed as a “Brainstorming” session, the room was packed for an early morning session on Day 2 of ECNP on translational research. We report some of the themes and thoughts from “Neurotransmitter interactions and cognitive function: can this optimally be studied in humans?” since these could have future relevance to the understanding of antidepressant therapies.
Is it possible, or even relevant, to try to study neurotransmitter interactions or the effects of centrally acting compounds on cognitive function in human subjects, in the same way as we do in animal models? This became the broad theme of a discussion session led by Professor Arjan Blokland of Maastricht University in The Netherlands, and prompted by brief overviews given by Drs Mitul Mehtra of King’s College, London, UK and Anke Sambeth, also of Maastricht University.
Drs Mehta and Sambeth are both involved in experimental medicine and clinical research studies that focus on understanding and measuring the effects of compounds on brain systems and functions in human subjects – both healthy volunteers and patients. While they have a number of tools to aid their endeavours – such as state-of-the-art brain imaging with machine-learning to help assess treatment-related changes in cognitive function - they both agreed that translating study design concepts from animal models to human research is fraught with challenges.
The degree of control over, and the homogeneity of animal subjects is hard to replicate in human research.
Of mice and men
Discussion in the room highlighted some of the inherent and sometimes immutable differences between preclinical and clinical research. One delegate in the room pointed to tests of cognitive function with a focus on memory: an animal model would typical involve object recognition, while the equivalent human model might focus on verbal or word recall. As he succinctly put it: “rats don’t talk” and his view was that researchers shouldn’t try to compare results from memory tests based on speech and language recall with animal tests based on non-verbal memory, many of which may be further confounded and removed from the human memory test scenario by dint of including an element of reward.
The workshop group also noted that the degree of control over, and the homogeneity of animal subjects is hard to replicate in human research. It was pointed out that even ‘healthy volunteers’ may actually have features, symptoms and behaviours that impact on observed outcomes and that often the screening of such volunteers could be more made more exhaustive.
Other topics discussed were the need to understand the differences in animal and human pharmacokinetics and pharmacodynamics when studying acute effects of different therapies under study.
The early-morning discussions ended with agreement that animal and human studies are each essential to building the picture of how therapeutic agents may impact on cognitive function, and acknowledgement that there should also be back-translation from the clinic to animal modelling for truly tandem research.