Whether one focuses on the glass as half full or half empty, there can be little doubt that we need a different approach for medication development for mental disorders. For the past five decades, the biological study of mental illness has been dominated by the study of the action of the available drugs. In retrospect, this might have been productive if the drugs targeted the core pathophysiology of the disorders. Certainly, the study of insulin action has been useful for developing new approaches to diabetes and research on adrenergic pharmacology has been helpful for cardiovascular medicine. However, as we have just reviewed, the available medications in psychiatry are insufficient for treating the disorders. Indeed, after five decades, we need to recognize that we may never get from neuropharmacology to the pathophysiology of mental disorders.
The canonical approach to treatment development in psychiatry is essentially a recipe for developing ‘me-too’ compounds, as the entire process is based on developing drugs modeled on an existing, insufficient drug (). In other areas of medicine, from heart disease to cancer, treatment development begins by defining pathophysiology (). Through cell biology (identifying the tyrosine kinase for myeloid cell division) or epidemiology (recognizing the role of cholesterol in heart disease), the process begins with target identification.
How will we identify new targets for mental disorders? This will happen just as it is happening in the rest of medicine, through research on the core mechanism of these diseases. There are three key steps in this process. First, comprehensive studies of people with these disorders, using genomics, transcriptomics, and proteomics, should identify cellular pathways that are affected. This will undoubtedly be more difficult than in other areas of medicine, but genetics is already providing some hints. The study of the serotonin transporter promoter demonstrates that the short allele is associated with an increase in the vulnerability to depression.25, 26
This allele also is associated with a reduction in the volume of Area 25 in the ventromedial prefrontal cortex, a region with one of the most intense serotonergic innervations in the forebrain.27
Along with reduced volume of this brain region, the short allele is associated with a functional dissociation of this region from the amygdala during the processing of negative affect.27
Understanding how this allele alters development of Area 25 and affects functional connectivity in the forebrain could serve as a starting point for defining targets for major depressive disorder.
However, the search for genomic variations associated with mental illness is really just beginning. With the recent completion of the human haplotype map and the advent of rapid genotyping capacity, we should finally make rapid progress identifying some of the vulnerability genes and thus critical pathways for the pathophysiology of the major mental illnesses.28
In other complex genetic diseases, such as age-related macular degeneration, this strategy is already revealing new targets that would not have been suspected based on decades of descriptive research.29
A second step, the use of in vitro screening, will be critical for identifying new compounds. What we have learned elsewhere in medicine is that target identification is a long and high-risk process with many false leads. It is also the easy part, in that cellular pathways frequently have specific pressure points for modifying function and these may be implicated in many diseases. The second step, developing small molecules that affect these pressure points, may prove more difficult. Indeed, this step has historically been ceded to the pharmaceutical industry. The recent creation of a molecular library screening centers network (MLSCN) in universities and the NIH has, for the first time, encouraged academic investigators to engage in the early phase of identifying small molecules for influencing specific cellular pathways.30
The MLSCN uses a library of small molecules, an array of assays recommended by the field, and high throughput screening centers to identify ‘hits’ for any given target. Of course, there will be a vast amount of medicinal chemistry necessary to translate a ‘hit’ in a small molecule screen into a drug, but this network promises to increase the number and the range of targets that can be interrogated. One might expect that early years of this project will largely be focused on cancer and metabolic targets, but the advent of targets for mental disorders should allow rapid development of new compounds for cell biology, some of which may graduate to medications with novel mechanisms of action.
Once new compounds are available from in vitro screening, they can be tested in whole animals. Whereas ‘animal models’ in psychiatry have largely been developed to simulate psychopathology and validated by their response to existing medications, drug discovery models are created based on a pathologic mechanism and used to search for new targets and ultimately new compounds. For instance, the identification of the role of specific genes in Alzheimer’s disease has led to the creation of flies, fish, and mice with homologous alleles, a similar phenotype, and a model system for testing new interventions.31
While similar progress has been reported in a number of neurodevelopmental disorders recently, including Fragile X and Rett syndrome, we have not yet seen the first ‘animal model’ of a psychiatric disorder in which various genetic lesions are used to develop the phenotype.32, 33
Finally, new compounds can be tested in clinical trials. Trials may increasingly be public rather than private. The NIH Roadmap as part of its effort to re-engineer clinical research has proposed the development of a national network of clinical trialists who can move quickly to test the efficacy and the effectiveness of new treatments. Networks have already been developed in pediatric cancer and cystic fibrosis, such that nearly every patient becomes a participant. The NIMH effectiveness trials, such as CATIE, STAR-D, and STEP-BD may represent the beginning of such a network for mental illness.