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Brain Volume Decreases Accompany Early-Onset Psychosis

20 January 2012. Teenagers struck by early-onset psychosis quickly exhibit brain volume decreases over two years, according to a longitudinal study published online on January 2 in the Archives of General Psychiatry. The study, led by Celso Arango of Hospital General Universitario Gregorio Marańón in Madrid, Spain, finds that individuals later diagnosed with schizophrenia or other psychoses—but not bipolar disorder—had significant reductions in gray matter volume and increases in cerebral spinal fluid (CSF) volume compared to control adolescents.

Previous longitudinal studies have also found brain volume decreases in early-onset cases of schizophrenia (Vidal et al., 2006), but the new study offers a glimpse of the brain soon after illness has set in, on average only three months after the first psychotic episode and 10 weeks of antipsychotic medication. Though disentangling whether these kinds of progressive brain changes are causes or effects of a disorder is complicated (see SRF related news story), the study reinforces the notion that these changes occur even at the earliest stages of illness, and do not necessarily reflect the toll of years of chronic mental illness or antipsychotic medication.

The study also tried to discern whether these kinds of changes were disorder specific by imaging teenagers with early-onset psychosis, in which symptoms arise before the age of 18. Early-onset psychosis eventually develops into schizophrenia, bipolar disorder, or other psychoses (Fraguas et al., 2008), and participants were grouped according to these later diagnoses.

Frontal losses
Arango and colleagues enrolled 61 individuals with early-onset psychosis (average age at onset about 15 years) at five centers in Spain as part of the Child and Adolescent First-Episode Psychosis Study (CAFEPS) (Castro-Fornieles et al., 2007). Their brains were scanned with magnetic resonance imaging (MRI) and clinical assessments made at baseline and two years later, and compared to scans made from 70 healthy controls matched for age, sex, socioeconomic status, and education.

Though some gray matter loss is normal in healthy controls, it was more prominent in cases of schizophrenia and other psychoses. The 25 individuals who ended up with a schizophrenia diagnosis had significant decreases of total brain gray matter in the two-year period, losing 37.1 cm3 compared to 14.5 cm3 in controls. This loss was pronounced in both frontal lobes, with the schizophrenia group exhibiting a decrease about five times that of controls, as well as an increase in frontal CSF volume, presumably reflecting enlarged ventricles. They also exhibited a significant decrease in left parietal lobe compared to controls. The 20 individuals in the other psychoses group—some of whom may or may not go on to receive a schizophrenia diagnosis—showed a similar pattern of brain changes.

The 16 individuals in the bipolar disorder group, however, did not differ from controls in any measure, suggesting a fairly normal trajectory of brain changes during this period. Though this hints that gray matter volume decreases could be diagnosis specific rather than something general to psychosis (Reig et al., 2009), direct comparisons between the patient groups did not turn up any significant differences. The researchers concluded that their results did not support the idea of diagnosis-specific trajectories of brain volume, at least not ones apparent in the first two years of illness.

Clinical correlations
To get at what these changes might be related to, the researchers looked at various clinical and functional measures, and found significant correlations within the schizophrenia group. Among these individuals, frontal lobe changes correlated with prognosis: more severe reductions in frontal lobe gray matter volume, and increases in frontal CSF volume, correlated with more weeks of hospitalization during the two-year follow-up—a sign of poor prognosis. Increasing CSF volume was also associated with more severe negative symptoms, as measured by Positive and Negative Syndrome Scale (PANSS) scores, and larger reductions in the left temporal lobe were also associated with less clinical improvement, as assessed by PANSS general change scores.

The amount of antipsychotics taken over the two years did not correlate with any of the brain changes in any diagnostic subgroup. Consistent with this, the three groups did not differ in their antipsychotic exposure. This suggests that the brain changes are not solely the result of medication. Given that previous studies have put forth a role for medication in reducing brain volume (Dorph-Petersen et al., 2005; Ho et al., 2011), medication may still contribute subtly to these early changes.

The researchers suggest that these brain changes could reflect a disrupted program of brain maturation, a process lasting into early adulthood. This outlook fits adolescent brain changes into the familiar view that neurodevelopmental abnormalities contribute to schizophrenia. Future research will have to identify the cellular components underlying progressive brain change, the extent to which it reflects an active disease process, and whether it might be reversible.—Michele Solis.

Arango C, Rapado-Castro M, Reig S, Castro-Fornieles J, González-Pinto A, Otero S, Baeza I, Moreno C, Graell M, Janssen J, Parellada M, Moreno D, Bargalló N, Desco M. Progressive brain changes in children and adolescents with first-episode psychosis. Arch Gen Psychiatry. 2012 Jan; 69: 16-26. Abstract

Comments on News and Primary Papers

Primary Papers: Progressive brain changes in children and adolescents with first-episode psychosis.

Comment by:  Nitin Gogtay
Submitted 25 January 2012
Posted 25 January 2012

This is a well-done, prospective imaging study by Arango et al. looking at brain changes in early-onset psychosis. Early-onset psychosis populations in general are less studied, but are important, as they provide a window into earlier neurodevelopmental correlates and are less likely to show environmental influences. As quoted in the paper, a majority of these studies have come from the NIMH childhood schizophrenia sample, so it is nice to see findings being replicated in independent samples.

The sample size is small when divided in subgroups, but they do find significant frontal gray matter (GM) loss in schizophrenia, not shared by psychotic bipolar patients, as was observed in the NIMH psychotic bipolar sample. This is an important observation in favor of careful diagnostic/phenotypic characterization of patients, as increasing evidence from longitudinal studies seems to suggest that underlying brain pathology and trajectories are quite distinct as well. Interestingly, the "other" psychosis group also showed GM loss, and although we do not have further information on the diagnoses in this group, these observations support the increasing discussion of the dimensionality of psychosis. A more or less similar/comparable antipsychotic exposure of all groups also suggests, like in the NIMH studies, that the brain findings may be less due to medication influence.

I am hoping that this group has also collected siblings of patients to address the endophenotype question, and will also do more subregional/cortical thickness analyses rather than just lobar volumes. Finally, many reports publish CSF findings, but there is not enough talk in the literature about what they mean. Is the CSF increase secondary to the loss of GM (or white matter)? Or is it the other way around (increase in CSF resulting in brain substance loss)? Or is it increased gyral folding and hence more space for CSF? What mechanistic/pathophysiologic implications does that have? More elucidation is needed in the field rather than just showing increases in CSF volume.

View all comments by Nitin Gogtay

Comments on Related News

Related News: Interpret With Care: Cortical Thinning in Schizophrenia

Comment by:  Cynthia Shannon Weickert, SRF Advisor
Submitted 4 January 2012
Posted 4 January 2012

Plump Enough
Thanks for your thought-provoking review of structural MRI changes in schizophrenia. I had a couple of quick comments.

You make the statement that, "Though cortical thickness itself is below the resolution of typical MRI, image analysis algorithms can now infer thickness across the entire cortical sheet as it winds its way throughout the brain." I thought sMRI gathers information for about 2 mm cubed or so. So maybe the point to make is that cortex thickness is not below the resolution, but the putative change in thickness is below the resolution. It would be interesting to know if the putative change in cortical thickness in schizophrenia could be better viewed with 3T or 7T scanners.

Also, I wonder how to interpret decreases in volume over five years that seem to be as much as 5 percent in some areas. How long could this continue to be progressive at this rate, and what would be the final cortical volume expected in the final decade of life? For example, if the DLPFC BA46 is about 3,500 microns thick, then a 5 percent loss/five years over 20 years would leave you with about 2,850 microns, and that would be about a 20 percent decrease in thickness. While postmortem studies may be limited, as Karoly points out, certainly we know that the frontal cortex is still "plump enough" to define cyto-architecturally, and to examine at the histological level. We also consider that there is about a 10 percent loss in cortical thickness in people with schizophrenia. Certainly, the cortex does not degenerate completely as would be expected with relentless progression of loss and accumulated deterioration of cortical grey matter over time.

Thus, this is an interesting issue, but many questions remain. Is there a lot of case-to-case variability that underlies these averages such that some cases lose more cortical volume and some do not lose any at all? Could it be that, while there is cortical volume loss, there are some patients in whom this loss slows or even reverses naturally over the course of the disease? What is the physical substrate of such cortical volume loss in people with schizophrenia? Can we prevent cortical volume loss over time, and would this be beneficial to patient outcomes?

View all comments by Cynthia Shannon Weickert

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