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ICOSR 2013—Is Schizophrenia a Progressive Disease?

10 Jun 2013

As part of our ongoing coverage of the 2013 International Congress on Schizophrenia Research (ICOSR), held 21-25 April in Orlando, Florida, we bring you session summaries from some of the Young Investigator Travel Award winners. For this report, we thank Anvi K. Vora of the University of Iowa.

11 June 2013. It is a common notion that schizophrenia is progressive, but the Tuesday morning ICOSR symposium "Schizophrenia Is Not a Progressive Disease" made an emphatic assertion to the contrary. A number of studies suggest this, some of the speakers said, and perhaps clinicians should have better hope for its outcome.

Leading off the session with a talk entitled, "Schizophrenia Does Not Show Progressive Clinical Deterioration," Robin Murray of the Institute of Psychiatry, London, U.K., quoted Eugen Bleuler as saying that schizophrenia shows “no changes over five years, but has a tendency to improve.” Murray reviewed a number of studies suggesting that schizophrenia does not have a negative trajectory, starting with a cross-sectional longitudinal study called AESOP, with 10-year follow-up in three English cities, which revealed that although 23 percent of patients were not adherent to treatment and decompensated, 12 percent had no symptoms after their first episode, and 65 percent of patients had improvement.

He also showed neuroimaging data, including from a fluorodopa PET study, to analyze why some patients do not respond to treatment, which found non-responders had initially normal dopamine distribution and did not show increased dopamine concentration in striatum after treatment. Spectroscopy showed abnormality in glutamate in this group, indicating that perhaps the antipsychotic treatment was not targeting the correct pathology.

In regard to cognition, he discussed a number of studies indicating that it does not deteriorate, and cited the Cohen and Cohen, that clinicians and researchers spend more time with patients who are doing worse and have the perspective that there is a worsening in cognition (Cohen and Cohen, 1984).

About brain structure in schizophrenia, Murray referenced an imaging study from Lieberman and colleagues which found that longitudinal brain deterioration was prevented by olanzapine but not by haloperidol (Lieberman et al., 2005), offering that perhaps the haloperidol had actually contributed to the decrease in brain volume. Finally, he discussed findings that salivary cortisol is increased during the first episode of schizophrenia and that there is a known relationship between increased cortisol levels and decrease in hippocampal volume. He then showed a study by Leppin et al,, which showed that on six-year follow-up, hippocampal volume recovers as stress and cortisol levels decrease. In summary, he offered that decrease in brain matter may be attributable to other factors over time.

Eileen Joyce of University College London followed with the presentation, "Cognition Is Static After a First-Episode Psychosis," describing her group’s longitudinal West London First-Episode Schizophrenia Study in which patients and controls had three assessments of IQ, working memory, episodic memory, executive functioning, and Birchwood Social Function score at baseline, 18 months, and three-year follow-up showing no change in cognitive functioning over time but that social functioning remained impaired (Leeson et al., 2011). Additionally, she discussed a task of experience-dependent learning and a study with three years' follow-up, which revealed that patients had intact discrimination learning and rule abstraction but that their ability for reversal learning and set shifting was impaired, and that the latter was related to IQ (Leeson et al., 2009).

Joyce discussed other studies, cross-sectional and longitudinal, which revealed that IQ seems to deteriorate in some people around the time of the first episode but that this change may be amenable to cognitive remediation treatment. Finally, Joyce discussed neuroimaging work indicating that there was a baseline decrease in frontotemporal cortical area, and the degree of area reduction had a relationship with baseline IQ. Upon three-year follow-up, there were no significant changes in cortical area over time, but there was thinning of the cortex. This indicates that, as cognitive function was already present at first episode and thereafter remained static, cortical thinning after illness onset does not lead to further cognitive decline (Gutiérrez-Galve et al., 2010) .

The next speaker, Rene Kahn of the University Medical Utrecht Center, the Netherlands, took the opposite position in his talk, "Why Kraepelin Was Right: Brain Loss in Schizophrenia Is Related to Decline in IQ." He mentioned that while Bleuler believed schizophrenia could have a good outcome, Kraepelin believed it was a degenerative disease. Kahn noted that while we see patients at the onset of psychosis, the actual process starts sooner, and that lower premorbid IQ increases the risk. In a retrospective study with twins discordant for schizophrenia, both twins showed decreases in school performance, but after age 12 the twin with schizophrenia did worse, evidencing changes 10 years prior to onset of psychosis. Notably, this was not the case in a retrospective study of twins discordant for bipolar disorder, in which each twin's performance was similar. Additionally, a meta-analysis of 280 patients and controls showed that IQ scores for people with schizophrenia did not improve on retesting, but those for controls did. A longitudinal study found that, on three-year follow-up, the IQ of patients was lower than controls, yet remained stable and did not decline over time. This study also showed that worse IQ was associated with worse outcome in terms of illness. Finally, he presented a longitudinal neuroimaging study showing a decrease in brain matter volume in patients that was related to IQ change. In summary, he expressed the notion that perhaps a subgroup of people with schizophrenia who have poor cognition at baseline show decreasing brain volume and do worse symptomatically.

Robert Zipursky of McMaster University, Hamilton, Canada, summarized the presentations in his talk, "Integrating the Clinical, Imaging, and Cognitive Evidence: Expecting Recovery, Not Progression in Schizophrenia," and posed the question, While functional deterioration is a common feature of schizophrenia, should it be expected to worsen over time? He discussed a number of studies of first-episode psychosis in which smaller cerebral gray matter volumes have been reported and comparable studies in more chronically ill patients in which the gray matter deficits were even greater. Zipursky suggested that the more striking findings in chronically ill patients are not likely explained by a progressive process related to schizophrenia but rather differences in sampling, together with effects related to antipsychotic medication and other concurrent problems such as alcohol and drug use. He cited a large study by Nancy Andreasen’s research team at the University of Iowa which, in fact, revealed that reductions in gray matter volumes over time were greater in patients treated with higher doses of antipsychotic medication (Ho et al., 2011). Regarding the long-term course of cognition, he noted that while cognitive deficits are apparent at the time of the first episode of psychosis, these deficits appear to remain stable over time (Lewandowski et al., 2011). He referenced a systematic review of longitudinal studies of first-episode patients which showed that both the percentage with poor outcomes and with functional recovery remained stable over time, a pattern that would not be expected for a progressive disease (Zipursky et al., 2012).

He then discussed a systematic review designed to reveal whether remitted first-episode patients would relapse if they remained adherent to medications. It estimated that only 3 percent of adherent patients would relapse in the first year compared to an estimated 77 percent of patients who stop their medication, indicating that the risk of relapse is very low when these patients remain fully adherent to their antipsychotic medication (Menezes et al., 2006). He discussed the relevance of Berkson’s Fallacy to understanding the poor outcome and clinical deterioration often observed with schizophrenia; comorbid disorders that are themselves associated with poor outcome such as substance abuse and low IQ may better explain the poor outcomes observed than the natural course of schizophrenia per se. He concluded by stating that clinicians should convey an expectation of recovery to patients and families, as longitudinal studies of clinical outcomes, brain structure, and cognitive functioning do not support the view that schizophrenia is associated with progressive deterioration.—Anvi K. Vora.