Can Animal Research Really Tell Us How to Treat Human Mental Illness?

There is a robust ongoing public debate centered around the question of whether animal research is needed for understanding and treating human diseases. A subset of these discussions is motivated by the idea that animal research, in addition to simply being cruel, is unnecessary because it is readily replaceable by work on human organoids, computer simulations of a variety of disease processes and AI-based mining of public health data. As a consequence, policy appears to be changing across many parts of the western hemisphere. In Europe, the European Parliament has called for an action plan to accelerate the transition away from animal use in research, testing and education, while EU policy already states the long-term goal of phasing out animal use as soon as scientifically possible. In the US, similar pressure is building, with federal agencies and lawmakers urging greater public investment in non-animal methods such as organoids, organ-on-chip systems, computational modeling and AI-based approaches.

I could write multiple posts, and others have written books, to explain why animal research has been foundational to most scientific breakthroughs behind modern medicine. Yes, when cherrypicked, one can find examples of failures such as the lack of translatability of mouse models of sepsis, but on the flip side, the revolution in cancer, autoimmune and sleep disorders would not be possible without both the foundational discoveries conducted in animals and the significant translational pipeline for drug development that relies on their use.

But this post is not about these issues. Instead, it’s about the specific role of animal experiments in psychiatry.

It is no secret that the history of psychiatric drug development contains a long list of compounds that showed remarkable promise in animals but failed to address human clinical problems. Potential treatments for depression, anxiety and even cognitive dysfunction in psychotic disorders had pre-clinical signals based on animal research but never made it to clinical care. This graveyard is large enough that many stakeholders have drawn a seemingly-reasonable conclusion: the brain is not the kidney and modeling complex human behavioral abnormalities is not feasible in animals. In some instances, animal experiments are misleading. They generate hypotheses that consume years of development resources before showing utter failure in various stages of clinical development.

There is no doubt that one should be skeptical of animal models of psychiatric disorders. Afterall, many are the consequence of both the human mind and the human experience. How are we expecting a mouse (or a monkey) to model the trauma or grief associated with one’s loss of a career in the face of a global market crash? Animals cannot do that, at least not directly. But we should also be clear that neither can organoids, computer simulations or AI-mining of large datasets. So how can we make progress?

I like to approach the answer from a first principle: animal research for psychiatric disorders is a circuit reverse-engineering process. Meaning, we will not be able to model the human condition in animals (well, because it’s the human condition), but if we are able to localize a psychiatrically-relevant operation to a specific circuit, then we can study that circuit in animals under different perturbations. I have written about this in recent posts. The upshot is that when you start with a circuit suspected to be perturbed in a disorder and couple it with tasks capable of engaging that circuit in an interpretable manner, then you have a cross-species platform more likely to yield insights relevant to psychiatry.

In line with this thinking, I’d like to spend the rest of this post on a recently published paper that captures the spirit of this argument. It starts from a human finding in schizophrenia and reverse-translates it into mice. It then uses those mice to dissect a schizophrenia-relevant prefrontal circuit, tests whether a clinical drug can restore its function, and builds a predictive framework for understanding the drug’s mechanism of action.

That is the kind of experiment psychiatry needs more of. It does not ask mice to model the full human condition, but instead, to help us understand how to restore disrupted circuits we share with them. The paper also points in clinically-actionable directions: prospective patient stratification and biomarker development.

Let’s dig in…