Innovative drugs to treat depression: did animal models fail to be predictive or did clinical trials fail to detect effects?

Abstract

Over recent decades, encouraging preclinical evidence using rodent models pointed to innovative pharmacological targets to treat major depressive disorder. However, subsequent clinical trials have failed to show convincing results. Two explanations for these rather disappointing results can be put forward, either animal models of psychiatric disorders have failed to predict the clinical effectiveness of treatments or clinical trials have failed to detect the effects of these new drugs. A careful analysis of the literature reveals that both statements are true. Indeed, in some cases, clinical efficacy has been predicted on the basis of inappropriate animal models, although the contrary is also true, as some clinical trials have not targeted the appropriate dose or clinical population. On the one hand, refinement of animal models requires using species that have better homological validity, designing models that rely on experimental manipulations inducing pathological features, and trying to model subtypes of depression. On the other hand, clinical research should consider carefully the results from preclinical studies, in order to study these compounds at the correct dose, in the appropriate psychiatric nosological entity or symptomatology, in relevant subpopulations of patients characterized by specific biomarkers. To achieve these goals, translational research has to strengthen the dialogue between basic and clinical science.

Figure 1

The different steps in the discovery of antidepressants. Abnormalities of some biomarkers (eg, as detected via plasma biochemical assays or molecular imaging) or polymorphism of some genes were first described in depressed patients. In some cases, preclinical research has already shown that some of the targets are expressed in crucial brain areas of rodents, eg, corticolimbic networks. Together, these findings enable pharmacological compounds targeting these dysfunctions to be designed. These drugs are then tested in animal models. It is important first to check whether the targets are expressed in a similar way in humans and the species that is going to be tested. In case no effect is detected (negative findings), clinical development is stopped (at this point, it is not possible to know whether the drug was a true negative or a false negative). In case an effect is found in different models, the drug/molecule can be tested in randomized double-blind clinical trials. When an effect is seen, it indicates that the drug was a true positive and patients can be treated with this drug. When the clinical trial does not reveal an antidepressant effect of the drug, the compound was a false positive.