Effects of antipsychotics: linking brain structural imaging changes to cellular alterations and evaluating mitigation st

Antipsychotics are a common treatment for schizophrenia and many other psychiatric conditions. Since the 1990?s there has been nearly a five-fold increase in antipsychotic prescriptions, especially for non-psychotic behavioural disorders. While these medications are generally safe over the short-term, their long-term effects on the brain are unclear. While patients show some brain abnormalities before the start of treatment ? these abnormalities seem to increase as the illness goes on and as treatment continues. It is not clear if these abnormalities are due to the natural course of the disease or due to the antipsychotic medication. In order to evaluate the long-term effects of antipsychotics on brain structures and their subsequent effects, we have developed an animal model in rats that mimics the clinical administration of the drug. These studies would not be ethically possible to conduct in humans as one would not wish to give these drugs to normal volunteers for long periods and nor can one deprive patients of needed treatments for long periods. Given this, the animal models provide a much better way to examine this issue in detail.

In a small initial study, we administered antipsychotic medications to normal rodents in a way that mimicked clinical dosing patterns, and we found that both haloperidol (an older generation drug) and olanzapine (a newer generation drug) caused a decrease in brain volumes of rats treated for two months (equivalent to 3yrs human life-span). The effect was mainly in the grey matter of the brain. We now wish to test the drug in animals that bear hallmarks of schizophrenia to further distinguish the effects of the drugs from that of disease.

Furthermore, we have shown that a commonly available medication, Lithium, has the opposite effect on the brain, it increases the grey matter. We would like to test if this medication can be used to counter the effects of the antipsychotics. The results of the study will be helpful in determining the safety of the current drugs, develop treatment strategies and the animal model itself will serve as a tool to screen safer antipsychotic medications.

Since the 1990?s there has been nearly a doubling in the use of antipsychotics leading to over 50 million prescriptions per year globally and an almost five-fold increase in non-psychotic conditions and younger patients. This proliferating use assumes that antipsychotics have few long-term adverse effects. However, emerging clinical, primate, and rodent data (from our lab) show that antipsychotics lead to a loss of grey matter - a matter of substantial relevance and clinical concern.

Since antipsychotics are administered to patients with pre-existing brain abnormalities it has been difficult to differentiate the effects of illness from effect of the drugs in standard clinical studies. We have developed an animal model that provides a way to separate the effects of illness from that of drug and provides an opportunity to link MRI-observed changes to the mechanisms at the cellular level. Using this model we have demonstrated that antipsychotics cause a decrease in grey matter on MRI which is confirmed with ex-vivo MRI and histopathology, and there is early indication that Lithium administration may help overcome the deficit. In this proposal we would like to confirm these initial findings and then address the following questions: (i) Are the structural effects of antipsychotics seen in normal rats also seen in a model thought to reflect the pathology of schizophrenia (MAM model)?; ii) Are these effects of antipsychotics dose and duration dependent, and if so are they reversible on stopping the medication?; (iii) What are the underlying cellular bases and how do these relate to the MRI findings?; and (iv) What can be done to mitigate these adverse effects?

If we can confirm the adverse effects of antipsychotics on the brain ? this would have significant clinical relevance. It should provide an impetus and an imperative for more rigorous and large-scale clinical studies to confirm/reject the preclinical findings. Our pilot positive data on lithium, if confirmed further in this project, could provide a testable clinical strategy. Finally, the cellular and mechanistic findings from our studies would point to potential solutions and the model can be used to identify and develop new antipsychotics that do not show this deficit in the first place.