23 Apr 2015
As part of our ongoing coverage of the 2015 International Congress on Schizophrenia Research (ICOSR), held March 29 through April 1 in Colorado Springs, we bring you session summaries from some of the participants in the Young Investigator program. We are, as always, grateful for the gracious assistance of conference directors Carol Tamminga and Chuck Schulz, as well as meeting staff Cristan Tamminga and Dorothy Denton. For this report, we thank Matej Markota of Harvard University.
April 24, 2015. A number of presentations at the 2015 International Congress on Schizophrenia Research in Colorado Springs addressed potential strategies for prevention in schizophrenia. These ranged from prenatal supplements to what constitutes an optimal maintenance therapy in schizophrenia.
One of the most hotly debated sessions at the conference centered on whether patients with schizophrenia need maintenance antipsychotic treatment. Wolfgang Fleischhacker from Medical School Innsbruck in Austria argued that, although it is unclear which antipsychotics are most effective for maintenance treatment after the first episode of psychosis, it has been consistently shown that in the short term, antipsychotic use is associated with significantly reduced relapse rates. Robin Emsley from Stellenbosch University in South Africa showed that discontinuation of antipsychotic maintenance results in treatment failure of the next relapse in one out of six patients. However, the overwhelming majority of studies exploring the effectiveness of antipsychotic maintenance treatment are relatively short, with limited data available beyond three years after the first episode of psychosis.
Lex Wunderink from Friesland Mental Health Services in the Netherlands presented the results of a first randomized clinical trial with a seven-year follow-up. Patients were randomly assigned to early antipsychotic dose reduction/discontinuation or to standard maintenance treatment groups. Wunderink's findings suggest that relapse rates were initially higher in the dose reduction/discontinuation group but leveled at three years. At seven years of follow-up, patients in the dose reduction/discontinuation arm of the study showed a significantly better recovery rate and functional remission compared to patients in the maintenance treatment group (Wunderink et al., 2013; see SRF related news report). This study underscores the importance of using longer follow-up periods in clinical trials of maintenance treatment and of including functional status, in addition to relapse rate, as an outcome evaluation. Although the findings of this study strongly indicate that guided dose reduction and, if possible, discontinuation may be a feasible strategy leading to better long-term functional outcome, Wunderink pointed out that additional studies are needed before such a strategy can become a general guideline in treating patients with first-episode psychosis.
Intervening before psychosis
A number of presenters had investigated the effect of dietary supplementation on the risk of developing schizophrenia. Perhaps the most anticipated was an attempted replication of a 2010 study which found that omega-3 polyunsaturated fatty acids reduce the risk of transition to psychosis in ultra-high-risk subjects (Amminger et al., 2010; see SRF related news report). Patrick McGorry from the University of Melbourne presented results from an ongoing multicenter, international randomized, controlled trial on a larger cohort, which found no significant effect of omega-3 polyunsaturated fatty acids on transition rate of ultra-high-risk subjects at a 12-month follow-up. McGorry pointed out that there was a trend for dimensional measures of symptoms and functioning to favor the omega-3-treated group at six months, and that further analyses looking at the subgroup with good adherence to the omega-3s may reveal beneficial effects. A two-year follow-up study is underway to determine whether a delayed effect of omega-3 polyunsaturated fatty acids can be identified. A potentially important difference between the original study by Amminger at al. and the replication is that the psychosocial interventions in the latter were more substantial and may have enabled the placebo-treated group to reach the same low level of transition to psychosis. In a similar study, Emsley tested the effectiveness of omega-3 polyunsaturated fatty acids plus antioxidants on relapse prevention in subjects with schizophrenia and found no significant effect (Emsley et al., 2014).
Randy Ross of the University of Colorado in Aurora found that infants of healthy mothers who received prenatal supplementation with phosphatidylcholine have improved cerebral inhibition, a mechanism postulated to be deficient in schizophrenia (Ross et al., 2013). While these early findings are intriguing, it is currently unknown if a prenatal phosphatidylcholine-rich diet and/or supplementation can decrease the risk of developing schizophrenia in offspring.
Alan Brown of Columbia University in New York City conducted a study with potentially important implications for primary prevention of schizophrenia. Based on the data from a Finnish national birth cohort, Brown's team found that pregnancy levels of maternal cotinine, a nicotine metabolite and a reliable measure of maternal smoking, are associated with higher risk of schizophrenia in offspring. The association between maternal cotinine levels and schizophrenia in offspring remained significant after adjusting for parental history of psychiatric disorders, maternal age, and birth provenance. The offspring included in the study were between 15 and 26 years old, with additional follow-up study planned in the future to test this effect in older offspring. While the observed correlation between maternal smoking and schizophrenia does not necessarily imply causation, these findings are interesting in light of strategies aimed at prevention of schizophrenia.
There is robust evidence that cognitive impairments precede the onset of psychosis by many years (Woodberry et al., 2008). Larry Seidman from Harvard University in Cambridge, Massachusetts, presented results from a pilot study showing that computer-based, targeted cognitive training significantly improves processing speed and role functioning in clinically high-risk individuals (Hooker et al., 2014). It is currently unclear, however, if cognitive training can prevent or delay the onset of schizophrenia.
A number of animal models used to test strategies for preventing the behaviors and phenotypes associated with schizophrenia were also a focus of this year's ICOSR. Patricio O'Donnell, formerly of the University of Maryland in Baltimore and now with Pfizer, used a rodent neonatal ventral hippocampal lesion model of schizophrenia to test the effect of antioxidant treatment on development of schizophrenia-associated phenotypes. Using this model, he and his collaborators found that antioxidant treatment during juvenile periods prevents the loss of perineuronal nets and parvalbumin neurons, both repeatedly shown to be decreased in schizophrenia (Zhang and Reynolds, 2002; Pantazopoulos et al., 2010; Pantazopoulos et al., 2015; Lewis et al., 2012; Mauney et al., 2013; Berretta et al., 2015). Juvenile or adolescent antioxidant treatment also prevented the development of behavioral and electrophysiological abnormalities in adult animals in this model (Cabungcal et al., 2014; see SRF related news report). O'Donnell, however, warns that manipulating redox balance in patients carries significant risks, and reliable markers of oxidative stress should be developed before such interventions can be safely used in subjects at risk for schizophrenia. Tony Grace from the University of Pittsburgh in Pennsylvania asserted that converging evidence shows that children hyper-responsive to stress have a higher chance of later conversion to schizophrenia. Offspring of mitotoxin methylazoxymethanol acetate (MAM)-treated pregnant rats show hyper-responsivity to stress in the prepubertal period and in adulthood, together with other behavioral, histological, and electrophysiological alterations reminiscent of schizophrenia. Grace found that peripubertal diazepam administration prevents electrophysiological and behavioral alterations in adult offspring of MAM-treated animals. While peripubertal anxiety and stress reduction with diazepam in humans would not be appropriate, Grace pointed out that these results do indicate a potential role for psychosocial interventions aimed at reducing stress and anxiety in individuals at high risk of schizophrenia.
Many pressing questions on prevention in schizophrenia were addressed at the 2015 ICOSR. While important steps have been made in the past several years, more needs to be learned before safe and effective strategies for prevention can be developed.—Matej Markota.