Modeling psychiatric disorders for developing effective treatments

Abstract

Recent advances in identifying risk-associated genes have provided unprecedented opportunities for developing animal models for psychiatric disease research with the goal of attaining translational utility to ultimately develop novel treatments. However, at this early stage, successful translation has yet to be achieved. Here we review recent advances in modeling psychiatric disease, discuss the utility and limitations of animal models, and emphasize the importance of shifting from behavioral analysis to identifying neurophysiological abnormalities, which are likely to be more conserved across species and thus may increase translatability. Looking forward, we envision that preclinical research will align with clinical research to build a common framework of comparable neurobiological abnormalities and to help form subgroups of patients on the basis of similar pathophysiology. Experimental neuroscience can then use animal models to discover mechanisms underlying distinct abnormalities and develop strategies for effective treatments.

Figure 1. Clinical approval of CNS-drugs

A) The clinical approval success rates for CNS drugs fall far below drugs for non-CNS disorders between 1995 and 2006. Except for a period of increased approvals of so-called me-too-drugs, the approval rates were consistently low with about 5 in a 100 compounds receiving approval. B) In contrast to compounds for CNS disorders, the share of FDA approval rate for antineoplastic drugs increased substantially between 1995 and 2006, since therapy evolved from unspecific cytotoxic compounds to highly cancer-specific compounds. Source: Tufts Center for the Study of Drug Development.

Figure 2. The change in cortical fields and medial frontal cortex architecture since the last common ancestor of rodents and humans

Bottom: The common ancestor of mice, monkeys, and humans is likely to have displayed extended somatosensory areas, but small parietal fields. On a gross scale, similar organization can be found in the rodent brain, whereas humans and monkeys, most probably driven by their visual specialization, have profoundly expanded parietal fields and reduced somatosensory areas. Considering brain architecture revealed by histological staining, the absence of a well-developed granular homotypical cortex in rodents is striking. Although rodents may possess functionally analogous regions, distinct cell-type composition and computations in these regions, which are implicated in psychiatric disease in patients, may be unique to primates. Illustrations are schematic and not drawn to scale. A1: primary auditory cortex, AC1 and AC2: anterior cingulate cortex area 1 and 2, Fr2: frontal area 2, IL: infralimbic cortex, MO: medial orbital cortex, OB: olfactory bulb, PL: prelimbic cortex, PPC: posterior parietal cortex, S1 and 2: primary and secondary somatosensory cortex, V1 and V2: primary and secondary visual cortex, VO: ventro orbital cortex. Numbers correspond to Brodmann areas. Adapted and modified from^–.

Figure 3. The path forward: convergence of clinical and preclinical research

In this hypothetic example of the way forward in treatment development, a heterogeneous group of ASD patients is sub-grouped on the basis of genetics and comprehensive Research Domain Criteria (RDoC). The genetic information obtained in this process also informs preclinical neuroscience and enables the generation of animal models that are similar to the patient in their biological basis. Mirroring the patient RDoC, the same neurophysiological abnormalities are identified, understood and tested in terms of their relevance to disease. Shown schematically here, testing causation through invasive perturbation in animal models mirrors the importance where correlative genetic observation stands in human patients. Next, these valid models are used for invasive and iterative treatment development. Finally, homogeneous treatment domains are formed based on comparable abnormalities in conserved domains and patients within these clusters receive the appropriate treatment for their specific defect, e.g. patient with neurophysiological abnormality A receives the treatment that has been developed for the corresponding defect in animal models. It is also conceivable that another group of patients displays neurobiological abnormalities A and B and thus receives a combinatorial treatment of A and B.