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SIRS 2008—Can Drug Response Be Enhanced in Schizophrenia?

30 June 2008. It was hot in Venice, and it was not just the Mediterranean sun. The first ever Schizophrenia International Research Society conference, held 21-26 June 2008 on the Venetian island of Lido, featured sparks and conflagrations—mostly about the conundrum of schizophrenia genetics. More on that in one of our later reports. Your roving reporter, Hakon Heimer, attended and will report on as many sessions as the espresso could fuel, and we have promises of missives from some of the participating scientists as well. Herewith is our first report.

In a session that took place even before the opening ceremonies, on the afternoon of 21 June, Chairs Anil Malhotra, of Zucker Hillside Hospital, Glen Oaks, New York, and Carol Tamminga, University of Texas Southwestern, in Dallas, helped kick off the conference with a session entitled, "Dissecting the Heterogeneity of Antipsychotic Drug Response: New Approaches to an Old Problem." Although the speakers were hopeful about the possibility that neuroimaging, pharmacogenetics, and other new methodologies would improve the ability of psychiatrists to tailor treatments for different groups of patients, they also seemed to agree that this remains a promise, rather than a reality.

In his opening talk, "The heterogeneity of antipsychotic drug response and prediction of outcome: Are we further ahead?," George Awad of the University of Toronto, Canada, presented a rather sobering historical picture. Sixty years after the advent of antipsychotic drugs (APDs), the situation may be more promising, but the reality is that there are few agreed upon predictors of response to medications. What we have are not biomarkers but some crude clinical predictors, in particular, two, according to Awad—early symptom change and dysphoria. Early symptom change predicts better response, according to work first published by his group several decades ago, and recently supported by a paper from Stefan Leucht and colleagues (Leucht et al., 2008). Conversely, dysphoria reported by patients in the first two hours of treatment portends a cascade including motor and cognitive symptoms.

There have certainly been attempts to find better clinical predictors in schizophrenia, but Awad noted that evaluating these is difficult because investigators have employed different methods in studying sometimes non-comparable study populations. In particular, he singled out shortcomings in the available rating scales—questionable metrics; lengthy, cumbersome, and not particularly sensitive study instruments; too many, poorly validated instruments—and suggested that new assessment scales were needed. Despite this rather sparse résumé, he is optimistic that better predictive ability is in the offing, in part from pharmacogenetics and imaging, but also from better definitions of response and the time framework to achieve this. The "item bank" approach of having a repository of validated assessment has been successful in assessing drug response in depression and anxiety, he said, and should be considered in schizophrenia.

Richard Keefe, of Duke University, Durham, North Carolina, discussed what currently seems like a cul-de-sac in trying to predict the effects of drugs on patients. His talk, "Neurocognitive task performance as an outcome measure in antipsychotic treatment trials," focusing on cognitive assessments of subjects in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), found little to separate any of the typical and atypical drugs from each other. Indeed, the minor improvement seen for these drugs over placebo may signal practice (see SRF related news story) or placebo effects. Although analysis of the CATIE cognition results may be limited by the fact that the study enrolled chronic patients, the European First-Episode Schizophrenia Trial (EUFEST; see SRF related news story) has similar findings, according to unpublished data relayed by Keefe from the authors of that study.

The next major step forward in the attempt to distinguish antipsychotic drugs by their effects on cognition is the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery of tests. Although there are 10 tests across the seven MATRICS domains (Nuechterlein et al., 2008), Keefe cautioned against assuming that the best dissection of antipsychotic drug effects on cognition would come from selective application of these tests. Composite scores may be less specific but are statistically more powerful, he said. Cognitive analysis of CATIE results showed that there are (modest) correlations between cognitive domains, and that a single composite score describes data best according to modeling (Keefe et al., 2006). He also added that the MATRICS battery should be an improvement over the methods used in CATIE in the way that it takes into account missing data.

Has imaging fared any better as a way to distinguish schizophrenia patients from each other with respect to predicting treatment response? Malhotra's colleague at Zucker Hillside Hospital, Philip Szeszko, described a complex historical picture where structural imaging has served up some candidate structural markers of disease outcome, though they remain unconfirmed. He then described a new MRI study that searched for cortical surface differences between responders and non-responders to risperidone or olanzapine in first-episode schizophrenia, using newer, pattern-matching technologies that can control better for inter-individual differences in the size and shapes of anatomical areas and better assess cortical thickness. Although the researchers report no significant differences in overall gray or white matter, or total volume, they do find that non-responders had greater thinning of occipital and ventral prefrontal cortex than responders.

Moving from structural imaging to functional imaging, Carol Tamminga reported on her group's investigations into medial temporal lobe (MTL) deficits in schizophrenia. Among the questions that she and her colleagues are addressing is whether the antipsychotic effects of dopamine D2 receptor blockers derive in part from "normalization" of neuronal activity in MTL structures. Previous work from her lab has indicated that people with schizophrenia (off medication) show constitutively increased regional cerebral blood flow (rCBF) in the anterior hippocampus, but decreased neuronal activation to memory tasks in this region (as measured by fMRI BOLD). Antipsychotic drugs partially rescue these phenomena, and it may be possible to use measurements of rCBF and neuronal activation to help predict patients' likely responses to medications.

In their current studies, using a task that assesses novelty detection, an early component of encoding new memories, Tamminga and colleagues have found evidence that the same set of abnormalities found in schizophrenia patients in anterior hippocampus is present, but with an even stronger discrepancy between schizophrenia patients and controls, in perirhinal and parahippocampal cortex. Similarly, on memory tasks that measure the flexible use of learned associations, schizophrenia patients off medication show decreased fMRI activation compared with those on medication or normal controls. Tamminga believes aspects of these alterations (those in the CA3 subfield of hippocampus) are related to psychosis, and alterations in dentate gyrus are related to memory per se. As to how these differences are mediated, and how APDs might intervene, Tamminga offered several possibilities—a direct effect of DRD2 and/or D1 receptors in the hippocampus, or indirect effects of dopamine on cholinergic neurotransmission in the hippocampus.

To close out the session, Anil Malhotra addressed the question of whether there has been any movement toward the much vaunted "personalized medicine" in terms of pharmacogenetics? The first generation of studies in this realm focused on whether variation in dopamine or serotonin receptor genes helped determine the likelihood of clinical response to clozapine, but the results were mixed, Malhotra said. More recently, some researchers have moved their work into first-episode patients, in an attempt to avoid the confound of changes that previous APD treatment might introduce for important clinical characteristics such as weight gain. Malhotra's group has reported an association between polymorphisms in the promoter region of DRD2 in a small sample, but larger studies will be needed to confirm and extend this finding. In terms of adverse events, there is evidence for an effect of serotonergic receptor genotype and APD-induced weight gain, and in new work, Malhotra and colleagues have found preliminary support for a role of DRD2 variation in first-episode patients. Their newest work in this regard is a genomewide analysis of treatment response, which has identified a handful of genes with significance below 5 x 106 and which will need additional association evidence for confirmation.—Hakon Heimer.

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