Alexander B. Niculescu

Oxidative Mechanisms and Tardive Dyskinesia

Tardive dyskinesia has been and continues to be a significant problem associated with long-term antipsychotic use, but its pathophysiology remains unclear. In the last 10 years, preclinical studies of the administration of antipsychotics to animals, as well as clinical studies of oxidative processes in patients given anti-psychotic medications, with and without tardive dyskinesia, have continued to support the possibility that neurotoxic free radical production may be an important consequence of antipsychotic treatment, and that such production may relate to the development of dyskinetic phenomena.In line with this hypothesis, evidence has accumulated for the efficacy of antioxidants, primarily vitamin E (α-tocopherol), in the treatment and prevention of tardive dyskinesia. Early studies suggested a modest effect of vitamin E treatment on existing tardive dyskinesia, but later studies did not demonstrate a significant effect. Because evidence has continued to accumulate for increased oxidative damage from antipsychotic medications, but less so for the effectiveness of vitamin E, especially in cases of long-standing tardive dyskinesia, alternative antioxidant approaches to the condition may be warranted. These approaches may include the use of antioxidants as a preventive measure for tardive dyskinesia or the use of other antioxidants or neuroprotective drugs, such as melatonin, for established tardive dyskinesia.

Convergent functional genomics: application to bipolar disorder.

The recent development of microarray technologies has made possible the simultaneous measurement of mRNA levels for thousands of genes and a new genomic method termed gene expression profiling. The application of this approach to animal models or post-mortem tissue provides a powerful tool for the discovery of novel genes involved in psychiatric disorders. This approach has strengths that are complementary to those of another genomic method for gene discovery, positional cloning. Microarray technologies and their application to post-mortem tissue and animal models of bipolar disorder are reviewed. A novel approach termed convergent functional genomics, which integrates gene profiling and positional cloning in order to rapidly identify candidate disease genes, is also described.

Finding genes for bipolar disorder in the functional genomics era: From convergent functional genomics to phenomics and back

Psychiatric genetics, while promising to unravel the mechanisms of psychiatric disorders, has proven to be a challenging field. Psychiatric disorders, like other common genetic traits, are complex and heterogeneous. Psychiatric genetics has also suffered from a lack of quantifiable, biology-based phenotypes. However, the field is currently at an opportune moment. The work of various investigators is on the verge of paying rich dividends. Efforts at positional cloning are being greatly accelerated by the fruits of the Human Genome Project. New tools of functional genomics, such as expression profiling and proteomics, are being applied to animal models. These two methods can complement each other in an approach we have termed convergent functional genomics. Lastly, improvements in the measurement of biologically distinct endophenotypes--or phenomic--will lead to a better understanding of the mapping of genes to phenotypes in both animal and human systems.