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ICOSR 2011—At Risk of Schizophrenia: Converters and Non-converters

As part of our ongoing coverage of the 2011 International Congress on Schizophrenia Research (ICOSR), 2-6 April, in Colorado Springs, Colorado, we bring you session summaries from some of the Young Investigator travel award winners. For this report, we thank Vidyulata Kamath of the University of Pennsylvania School of Medicine.


22 April 2011. On the morning of Monday, 4 April 2011, Mark Weiser of Sheba Medical Center, Ramt Gan, Israel, chaired the session, "Course of Risk: Conversion and Beyond." The typical age of onset in the clinical course of schizophrenia is late adolescence and early adulthood, but there is an increasing focus on the period before the onset of psychosis where functional decline often begins. This symposium covered the spectrum from the characteristics of at-risk patients to outcomes that these characteristics predict.

In the first talk of the session, Jean Addington of the University of Calgary, Canada, began by noting the dropping conversion rates in at-risk samples, which she hypothesized were due to earlier detection, a dilution effect (false-positive effects, though level of functional decline or severity of symptoms has not changed), or more helpful early interventions. She then focused on the rate of conversion in at-risk youth over a 2.5-year period in the multisite North American Prodrome Longitudinal Study (NAPLS), with particular attention to those who do not convert. One notable observation was that conversion rates were only 5 percent in the genetic risk cohort (family history plus significant deterioration in functioning), but 26 percent in the clinical high-risk cohort (presence of postive symptoms without genetic risk) over a one-year period. Addington noted that almost 70 percent of individuals did not develop a psychotic illness at the 2.5-year follow-up.

The researchers found that non-converters showed a significant improvement on the Global Assessment of Functioning and in symptomatology, but still showed significantly lower social and role functioning at the one- and two-year follow-up. Overall, only 5.4 percent of non-converters still met the initial study admission criteria by the two-year follow-up. Addington noted that there was no difference in social and role functioning between the remitted group and individuals with persistent prodromal symptoms. Interestingly, several of these individuals had emerging Axis II diagnoses, including avoidant personality disorder and borderline personality disorder. In summary, Addington reported that non-converters showed significant improvement in symptoms and functioning, and 50 percent had no attenuated symptoms at follow-up. Nevertheless, these individuals were still functioning more poorly than healthy controls.

In the second presentation, Stephan Ruhrmann, University of Cologne, Germany, discussed "Negative Symptoms and Transition to a First Episode of Psychosis—Findings from EPOS." He opened his discussion noting that negative symptoms are a persistent problem in schizophrenia and occur years before the onset of positive symptoms. In his study, Ruhrmann and his colleagues in the multi-country European Prediction of Psychosis (EPOS) examined the relationship between negative symptoms and transition to psychosis in approximately 200 at-risk individuals. In their sample, 19 percent converted to psychosis after 18 months and 29 percent at 30 months. He further observed a strong relationship between negative symptom severity and transition to psychosis. Converters had significantly higher social anhedonia than non-converters, and negative symptoms were a significant predictor of transition to psychosis, and a significant predictor of shorter time to transition. Collectively, he suggested that negative symptoms may significantly increase the risk for developing a first-episode psychosis and noted that negative symptoms (particularly social anhedonia and withdrawal) may be an important target for preventative strategies.

In the next presentation, Alison Yung of the University of Melbourne, Australia, began with the observation that, although short-term outcomes (one- to two-year follow-up) of ultra high-risk cohorts show about 36 percent conversion rate, long-term transition rates remain understudied. The focus of Yung's talk was 15-year follow-up data from the Personal Assessment and Crisis Evaluation (PACE) clinic. She noted that 27.4 percent of the cohort had transitioned, with higher conversion rates noted in the earliest years after admission to the study, and no transition noted in any individual after 10 years. She further compared four cohorts of UHR and noted that earlier cohorts had higher transition rates than later cohorts. She attributed this finding to lead time bias or a possible change in sampling.

Yung further noted that the main predictors of conversion were baseline scores, low functioning, and negative symptoms. With regard to functional outcome, transition at follow-up did not predict poor outcome at follow-up. Notably, 45 percent of converters did not have poor functioning at follow-up, and 25 percent of non-converters had poor functioning at follow-up. While transition rate was predictive of poor outcome, Yung added that not all converters have poor outcome. Thus, poor outcome can occur in the absence of transition. She suggested a need to assess the association of neurocognitive, neurostructural, and genetic variables and non-psychotic outcomes in future studies.

"Is It Possible to Identify Impending Psychosis in the Months Preceding the First Hospitalization?" symposium chair Mark Weiser asked in the title of the final talk. He presented an investigation on impending psychosis using population data from the Israeli military. As military service is mandatory in Israel, this study allowed a unique examination of mental health in individuals with a clear, illness-free baseline and examination of mental health records in over 100,000 individuals. Using this population-based longitudinal dataset combined with a psychiatric hospitalization registry, Weiser and colleagues focused on predictors of hospitalization.

They found that the presence of a thought disorder in individuals who came for primary psychiatric care predicted hospitalization, while anxiety and somatic complaints were protective factors. Furthermore, psychotic experiences predicted later hospitalization for psychotic disorder. There was a significant interaction with social functioning such that psychotic experiences and poor social functioning increased the number of hospitalizations. Limitations of this study included the use of data from non-specialized clinics, the possibility of malingering, and the use of an “unfiltered” sample. Weiser and colleagues found that a majority of individuals do not convert to psychosis but still suffer from persistent impairment. He closed his talk by emphasizing the importance of studying this cohort, noting that, "from a public health perspective, these individuals need help as well."—Vidyulata Kamath.

Comments on Related News


Related News: ICOSR 2011—Some Hope for Alleviating Negative Symptoms

Comment by:  Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011

Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.

I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.

I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.

References:

Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.

Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.

View all comments by Kimberly E. Vanover