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ICOSR 2013—Is Schizophrenia a Progressive Disease?

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.

Comments on Related News

Related News: Cortical Folding May Predict Antipsychotic Drug Response

Comment by:  Robert B. Zipursky
Submitted 6 September 2013
Posted 6 September 2013

Palaniyappan et al. demonstrated that subjects with a first episode of psychosis (FEP) had a reduction in the extent of cortical gyrification in multiple brain areas compared to healthy comparison subjects. Notably, non-responders showed more prominent hypogyria than responders did in a number of frontal and temporal areas irrespective of whether the underlying diagnosis was of an affective or non-affective psychosis.

Previous studies using structural MRI have established that subjects with FEP have smaller cerebral gray matter volumes (Zipursky et al., 1992) but have left open the question of whether these differences reflect the result of early neurodevelopmental processes that are aberrant versus progressive degenerative losses taking place more proximal to the onset of psychosis. Palaniyappan et al. suggest that measures of cortical gyrification, which is believed to be particularly active during intrauterine growth and early infancy, are more indicative of a developmental than a degenerative process. Their finding that subjects with FEP have reductions in cortical gyrification is interpreted as supporting the neurodevelopmental origin of these differences.

The debate over whether the differences in brain structure found in FEP are developmental or degenerative in nature (Zipursky et al., 2012) is of particular relevance to the question of treatment response. If the neuropathology of schizophrenia involves a progressive degenerative process, then intervening as early as possible to halt this process and bring about a remission of symptoms becomes of critical importance. There has, therefore, been intense interest in the possibility that the duration of untreated psychosis (DUP) is an important determinant of treatment response in FEP (Perkins et al., 2004). However, it has remained unclear whether the association reported between DUP and treatment response is a causal one; it is possible that individuals with longer DUPs might have more longstanding developmental problems that result in a more insidious onset and less robust response to treatment. This report by Palaniyappan et al. reinforces the view that poor treatment response is more likely to be understood as reflecting more severe longstanding developmental differences in brain structure. These possibilities need not be mutually exclusive; early developmental changes in the brain and later progressive changes occurring closer to illness onset might both contribute to poor treatment response. Poor clinical outcomes could also relate to DUP through a range of different mechanisms that do not require that a progressive process is taking place in the brains of those with an FEP (Zipursky et al., 1992).

Most patients with FEP will have a robust response to antipsychotic medication. We were able to demonstrate a number of years ago that FEP patients who did not respond to low doses of haloperidol had smaller cortical gray matter volumes than responders did (Zipursky et al., 1998) and that even with higher doses of haloperidol, these individuals had less improvement than the low-dose responders (Zhang-Wong et al., 1999).

The results of Palaniyappan et al. are in keeping with these findings. The focus of much research on treatment response has been to understand the determinants of antipsychotic response. As most FEP patients will have a robust response, it may be of greater interest to ask what factors underlie poor response. The 20-30 percent of individuals with FEP who do not have a remission of symptoms are likely to have a poor outcome in the longer run as well. Understanding that poor response may reflect the result of longstanding neurodevelopmental differences, as suggested by this study by Palaniyappan et al., may lead to more specialized approaches to identifying and treating poor responders earlier in their illness course (Agid et al., 2007). The development of more sophisticated, stratified approaches to the management of schizophrenia would be enhanced if neuroimaging markers could be proven to be valuable in predicting treatment response. The study by Palaniyappan is an important step in this direction. Further research will be required to ensure that medication effects are not confounding the measurement of cortical gyrification and that measures of gyrification are clinically meaningful determinants of treatment response.


Agid O, Remington G, Kapur S, Arenovich T, Zipursky RB. Early use of clozapine for poorly responding first-episode psychosis. J Clin Psychopharmacol. 2007;27(4):369-73. Abstract

Perkins D, Lieberman J, Gu H, Tohen M, McEvoy J, Green A, et al. Predictors of antipsychotic treatment response in patients with first-episode schizophrenia, schizoaffective and schizophreniform disorders. Br J Psychiatry. 2004;185:18-24. Abstract

Zhang-Wong J, Zipursky RB, Beiser M, Bean G. Optimal haloperidol dosage in first-episode psychosis. Can J Psychiatry. 1999;44(2):164-7. Abstract

Zipursky RB, Lim KO, Sullivan EV, Brown BW, Pfefferbaum A. Widespread cerebral gray matter volume deficits in schizophrenia. Arch Gen Psychiatry. 1992;49(3):195-205. Abstract

Zipursky RB, Zhang-Wong J, Lambe EK, Bean G, Beiser M. MRI correlates of treatment response in first episode psychosis. Schizophr Res. 1998;30(1):81-90. Abstract

Zipursky RB, Reilly TJ, Murray RM. The myth of schizophrenia as a progressive brain disease. Schizophr Bull. 2012. Abstract

View all comments by Robert B. Zipursky

Related News: Cortical Folding May Predict Antipsychotic Drug Response

Comment by:  S. Charles Schulz (Disclosure)
Submitted 6 September 2013
Posted 6 September 2013

This study by Palaniyappan et al. is an excellent step in using neuroscience measures—in this case MRI imaging—to address the important issue of treatment outcomes. As noted by the authors, this is a new way to address outcome in the early phase of psychotic disorders and may be related to the issue of poorer outcome with increased duration of untreated psychosis (DUP). In other words, the literature does show that approximately 25 percent of young people with schizophrenia are not responsive to first-line antipsychotic medication (Agid et al., 2011). Therefore, ways to provide the best treatments sooner can be very helpful in improving outcome.

The authors use an excellent test and examine more than just a single brain area. This newer strategy can lead to much better assessments than earlier work with a single measure. Further, by using MRI measures in the first episode of psychotic illness, they are adding to the initial evaluation of psychotic illness—making sure that there is not some other cause of psychosis.

In addition, it is very useful that they examined a range of psychotic disorders and note that the assessment is useful across these illnesses; therefore, the findings are not limited to schizophrenia alone. Some clinicians will be aware that this may lead to a broader assessment of treatment initiation and moving along on algorithms for a broader range of patients.

In summary, this is a very good contribution and can lead to new care pathways in the early stages of psychosis.


Agid O, Arenovich T, Sajeev G, Zipursky RB, Kapur S, Foussias G, Remington G. An algorithm-based approach to first-episode schizophrenia: response rates over 3 prospective antipsychotic trials with a retrospective data analysis. J Clin Psychiatry. 2011 Nov;72(11):1439-44. Abstract

View all comments by S. Charles Schulz