Patients with schizophrenia, compared with healthy controls, show a significantly higher progressive reduction in cortical gray matter volume over time. A substantial progressive loss of total gray matter volume, with a moderate ES (g
=–0.50), was demonstrated. However, the pattern of gray tissue loss does not affect the brain uniformly but is specific to discrete cortical areas, which appear to be affected by such progression at different stages of the disease. For the first time with a meta-analytic approach, and at variance with other quantitative reviews on the time course of brain abnormalities in schizophrenia,17, 63
we demonstrated a selective, rather than generalized, involvement of cortical gray matter in the trajectory of brain tissue loss.
In particular, we detected a significantly more pronounced decrease of gray matter volume in the STG and STG subregions (HG and PT) in patients with schizophrenia: the magnitudes of the ES for the left STG (g
=−0.80), left HG (g
=−1.05) and left PT (g
=−1.18) were large; on the other hand, several other cortical subregions did not exhibit such a large reduction in volume over time. The role of superior temporal lobe structures in the pathophysiology of schizophrenia was intensely debated in the 1990s, but has not been systematically addressed by later studies. This is a case where traditional ROI methodology may be more informative than more sophisticated techniques that rely on automated computation of surface or whole gray matter volumes, with which the opportunity to detect subtle, localized or deep brain alterations is lost. Changes in STG volume have been related to positive symptom severity, especially of thought disorder (posterior STG)6, 64, 65
and hallucinations (anterior and middle STG);66, 67, 68, 69
HG volume abnormalities have been correlated to severity of formal thought disorder70, 71
and PT alterations to language and thought disorder of schizophrenia.64, 71
The higher involvement of these areas in the trajectory of progression of brain abnormalities strengthens the hypothesis of a specific relevance of these brain regions in the pathophysiology of the disorder or, in turn, of the centrality of thought and language disorders in schizophrenia, according to a relevant, still actual, phenomenological literature,72
only partly incorporated in the current diagnostic criteria of the disease (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV TR) and International Classification of Disease, 10th revision (ICD-10)).
A significant effect of hemisphere has also been clearly demonstrated in this meta-analysis for volume loss of temporal gray matter. The anterior STG, HG and PT appeared to show excessive tissue loss over time in the left, but not the right hemisphere. This may explain the finding of abnormalities in cerebral asymmetries frequently, but inconsistently reported in previous literature on the brain pathology of schizophrenia.73, 74, 75, 76
The progression of cortical volume changes seems to affect especially the left hemisphere: this could justify the finding of abnormal asymmetries reported particularly in chronic, rather than first-episode cases, when this phenomenon may be less detectable. A reduced lateralization of cortical structures has been recently reported also at the onset of schizophrenia, before medical treatment is initiated, most prominent in the inferior frontal gyrus (part of Broca's area) and the STG (part of Wernicke's area).77
Moreover, a reduction in normal cerebral asymmetries, particularly in superior temporal structures, has been proposed as a trait marker of schizophrenia by some authors.78, 79, 80
According to the existing literature81, 82
and our own findings, however, this reduction may be even more relevant over time, after progressive tissue loss affected the two hemispheres differently. Our findings therefore confirm that the left (dominant) hemisphere may be involved in the pathophysiology of schizophrenia, and may also be particularly sensitive to the trajectory of pathological progressive brain changes characterizing this disease. Consistently with this hypothesis, a polymorphism of NRG1
gene has been found to be involved in determining STG size in schizophrenia, and suggested to have a role in the neurogenetic basis of the language disturbances seen in this disorder.83
Analyses of the subsample of studies that selectively investigated first-episode patients gave us the opportunity to make some more specific inferences about the time of occurrence of such progressive loss of cortical gray matter.
In the case of first-episode patients, larger ESs than those detected in the whole sample for the difference in brain tissue loss between patients and controls were detected for all brain regions considered in the analyses. This strongly supports the hypothesis that progressive tissue loss is especially active in the first phases of the illness. Such an early tissue loss affects diffuse cerebral regions and indicates a process that may lead at a later stage (that is, in chronic samples) to a decrease in whole brain volume.17
The latter may be consistent also with the notion of progressive ventricular enlargement acknowledged by most, although not all, studies,30, 37, 84, 85, 86, 87, 88, 89, 90
and quantitatively reviewed by Kempton et al.
who demonstrated a larger than normal increase in the volume of lateral ventricles over time in chronic schizophrenia. Although not directly investigated by our meta-analysis, this could be compatible with the evidence of progressive loss of white matter volume over the disease course,91
which may determine, or parallel, cerebral ventricular enlargement. On the other hand, the most divergent trajectory of cortical structural changes between patients with schizophrenia and normal subjects arises during the very first phases of the disease, when there is evidence of accelerated gray matter loss; at a later stage, the decrease in gray matter volume is likely to be similar to what appears to be a physiological correlate of aging.
The notion of a different trajectory of brain changes over time between patients and controls is also supported by the results of the few original longitudinal studies with three or more MRI measurements for the same cohorts. The largest such study from Andreasen et al.53
showed that reductions in brain tissue volume in patients with first-episode schizophrenia were greatest during the first interscan interval (2 years) when patients had significantly greater reductions than healthy volunteers in nearly all gray matter measures. Conversely, changes in brain volume in patients during the second (3–4 years after the second scan) and third (3–4 years after the third MRI measurement) interscan intervals did not differ significantly from those found in healthy volunteers. The results of our meta-regression analysis between the ES of the differences in gray matter loss between patients and controls and the duration of illness at first MRI scan confirms this hypothesis; the longer the duration of illness, the lower the difference in volume change over time detected between patients and controls. This may be again somewhat specific to defined brain areas, involving the frontal and occipital lobes, and, only in the left hemisphere, STG, the anterior and posterior portions of STG, HG and PT.
Since the definition we used for first episode, including patients who had the first scan within 24 months from onset, may be somehow misleading because many of such patients could have been exposed to long-term psychotropic drugs, we conducted a supplemental meta-analysis of first-episode cases limited to those patients with a duration of illness no longer than 12 months. In fact, adopting this more conservative approach, the magnitude of the differences between volumetric changes in schizophrenic and control groups became even larger as for the only cortical brain region that could be investigated according to our inclusion criteria (at least three study suitable for analysis), that is, whole brain gray matter (g=−0.61; confidence interval=−0.87 to −0.37; P<.001). Moreover, our findings relative to left HG in first-episode schizophrenia derived from studies that recruited only patients within their 1st year of illness.
Meta-regression analysis between the ES of the differences in gray matter loss between patients and controls and the age of patients at baseline scan showed lower ES in older patients for temporal and parietal lobes, for STG and its anterior component only in the right hemisphere and for left PT. This indicates that the trajectory of gray matter changes may be affected differently by the disease process and aging, the former being more active in the left hemisphere and the latter involving cerebral gray matter more generally.
Our findings are consistent, and complementary, to those obtained in recent meta-analyses of VBM studies in antipsychotic naïve subjects at high risk of psychosis and first-episode schizophrenia patients, which indicate that gray matter reductions in the anterior cingulated may be a marker of genetic liability to psychosis, while reductions in the STG can be interpreted as markers of first onset schizophrenia.92, 93
Taken together, the results of our study provide useful information about the time and site of occurrence of progressive gray matter changes in schizophrenia, substantially refining and shaping the hypothesis of schizophrenia as a general progressive brain disease.17, 53
A number of hypotheses, not mutually exclusive, may be advocated to explain the different time course of brain structural changes over the lifespan between patients with schizophrenia and healthy individuals. The existence of a cortical neurodegenerative process acting differently at different stages of the disease, particularly detectable around the onset and the first phases of overt illness, can be proposed. It is also possible to speculate on the existence of a pathological maturational program determining both early (pre- or perinatal) neurodevelopmental anomalies and later development of abnormal brain processes during adolescence and early adulthood, leading to, or paralleling, the onset of the disease. It is also plausible that there is an interaction between the two, that is, that anomalous neurodevelopmental processes may interact with other factors occurring around the onset of psychosis leading to accelerated tissue loss, which adds to the earlier abnormalities, to determine the ultimate brain pathology possibly relevant to the clinical manifestations of schizophrenia. This accelerated tissue loss may be especially active in the first phases of the disease and progressively less evident as the disease stabilizes, and may be counteracted by continuous treatment. Consistent with this possibility, it has been claimed that some of the brain abnormalities found at the onset of psychoses may be at least in part reversible.94
Even if the cause of the observed pattern of progressive brain changes during the course of schizophrenia remains largely unclear, it is possible to state that certain brain areas are involved in substantial alteration just around the time of onset and during the early course of the disease.
Another finding of the present meta-analysis is that the type of antipsychotic treatment may be a significant moderator of the time course of brain abnormalities in schizophrenia. In particular, treatment with atypical antipsychotics seems to reduce or at least, in part, counteract the progressive loss of cortical gray matter tissue in the whole brain, especially in the temporal lobe. Treatment with antipsychotic medications has been considered to be an important potential confounder of the progressive changes in brain volume detected in schizophrenia by other authors.15, 27
Our finding is consistent with that of a controlled longitudinal MRI study comparing the effects of an SGA (olanzapine) and an FGA (haloperidol) on gray and white matter volumes in first-episode schizophrenia, reporting substantial progressive (global) gray matter loss over a 1-year period in the patients on haloperidol, but not in those treated with olanzapine.34
It has been hypothesized that SGAs may have a neuroprotective effect in schizophrenia, either increasing the expression of neurotrophic factors95
or stimulating neurogenesis,96
or interacting with and increasing the activity of N
-aspartate glutamate receptors.97
Conversely, the excess reduction in cortical gray matter observed in patients treated with FGAs may be attributable to a direct neurotoxic effect secondary to oxidative stress and/or excitotoxic phenomena, which have been well documented in animals treated with haloperidol98, 99, 100
or may indicate a hypothetical lower capacity of FGAs to interfere with the natural pathophysiological trajectory of the disease, which may also be reflected in the different impact on cerebral blood flow and metabolism of FGAs versus SGAs.101, 102, 103
A recently published MRI longitudinal study33
reported progressive brain tissue loss in patients with schizophrenia followed for up to 14 years and related such loss to antipsychotic drug use. However, it seems likely that the results of this uncontrolled study could not distinguish between the highly intercorrelated variables of illness severity and antipsychotic dose taken. In fact, it is now well known that brain abnormalities are present even before the onset of schizophrenia, in the prodromal stage of the disease or in first-episode drug-naive patients4, 18
independently of drug treatment, and that these anomalies show progression over time even during the phase of transition to psychosis,104
again without or with little potential effect of pharmacotherapy. Alternatively, morphological abnormalities in the brain, and their progression over time, may represent a significant correlate of poor outcome of schizophrenia, for which a larger prescription and use of antipsychotic drugs may be considered an epiphenomenon. Early105, 106, 107
and more recent108
literature confirm that the most consistent clinical correlate of structural brain abnormalities and their progressive change is poor clinical outcome of the disease.
Age at onset of schizophrenia was a significant moderator of change of whole brain gray matter, of right STG (and its anterior component) and left PT gray matter loss ES. This suggests that the trajectory of cortical gray matter loss is more pronounced in early-onset schizophrenia. That is not surprising given the large literature reporting a different severity of clinical presentation and course of early- versus late-onset schizophrenia.109, 110
The ratio of male to female patients included in the studies was not a significant moderator of ES, with the only exception of a more pronounced tissue loss in left anterior STG in female patients, compatible with a higher prevalence of hallucinations and positive versus negative symptoms in female than in male patients.111
Slice thickness of MRI scans was a significant moderator of the ES for whole brain and STG gray matter, indicating more evident differences between patients and controls detected in technologically more sophisticated studies. We also calculated a composite index of overall quality of the study, and this was found to be a significant moderator of ES for STG, the higher the study quality, the higher the differences detected between patients and controls, and for PT (left) in the opposite direction. Study quality may therefore affect MRI findings from different brain structures differently, especially in those discrete areas that present difficult or controversial segmentation procedures.
This study suffers from several limitations. First, common to all meta-analyses, a complete control of the quality of the primary studies, that is, on the possibility that certain biases were present in the original studies, was not possible. For instance, most of the studies considered in the meta-analysis included both schizophrenia and schizophrenia spectrum disorders patients without presenting separate results for these subgroups; others investigated both drug-naive and previously treated first-episode subjects again without presenting separate data for the subgroups. We tried to address the issue of the quality of primary studies, assigning them a ‘value' reflecting the degree of rigorousness and reliability of methods and results, and analyzing this as a potential moderator of ESs. The presence of significant results for this moderator indicates that weaknesses of the studies might have a role in the findings of each original study. Second, the choice of performing analyses without correction for multiple comparisons could have generated type I errors in the results. However, the independence of each meta-analysis on different brain structures, each driven by a single hypothesis, and the exploratory nature of meta-regressions, which were performed not to confirm but to elicit new testable hypotheses, justified the choice and the risk to obtain results that could be not confirmed by specifically addressed new research. Third, in general, our analysis was limited to the variables reported in the original studies. This was particularly evident for the description of the pharmacological regimen of patients during the study period, with only a small minority of studies reporting the amount of antipsychotic drugs taken between scans and therefore limiting the possibility to investigate more carefully this variable. In fact, the moderator ‘percentage of patients using atypical antipsychotics' is a very rough index of actual intake of specific antipsychotic drugs. However, there was no better way to analyze this issue since the studies available did not report either the cumulative dose of different classes of antipsychotics or of specific drugs taken. The correlation of the ES of different cortical gray matter changes and the proportion of patients treated with SGAs versus FGAs may be in any case meaningful. Rather than allowing any conclusive interpretation on the relationship between type of antipsychotic taken and cortical brain changes, such findings may indicate the need for further studies specifically aimed at clarifying the issue. Fourth, the number of published papers eligible for the analysis was small, so that some brain regions potentially implicated in the pathophysiology of schizophrenia, such as the prefrontal cortex or cingulate gyrus gray matter, could not be investigated. Fifth, the largely unbalanced sex distribution in the studies did not allow to analyze in a definitive manner the role of gender on brain structural changes and progressive tissue loss in schizophrenia, even if the moderator variable analyzed (percentage of males in the sample) did not resulted significant in explaining the heterogeneity of ESs. Sixth, the course over time of cerebral lateralized structures could be inferred but not directly analyzed, as no study reported laterality indices for individual subjects or group of subjects. Finally, the results of both ES and meta-regressions were not corrected for multiple comparisons, so they may have been vulnerable to type I error. We carefully considered the relative costs of detecting versus failing to detect significant effects and decided to avoid statistical corrections. In fact, each meta-analysis on any specific brain region should be considered a separate analysis for which any statistical correction should be questionable; moreover, also applying a more stringent level of significance (that is, <0.01), all but one ES remained significant. On the other hand, meta-regressions, there were in any case limited a priori in number, were intended to be exploratory analyses with the aim to generate, rather than prove, hypotheses, so that correction for multiple comparisons would be too restrictive, particularly for revealing otherwise elusive effects.
In conclusion, with all the above-mentioned limitations in mind, the picture emerging from this series of meta-analyses could be useful to generate new hypotheses and suggests the need for further studies specifically aimed to test them. A more refined progressive brain pathology hypothesis of schizophrenia is emerging, with meaningful regional and temporal specificity of the pathological brain process. Whether preceded by substantial early brain changes, genetic or environmental in origin, the time around the onset and the first phases of the disease seem crucial for a rapid, progressive, cortical tissue loss that could partly determine the clinical and outcome severity of the disorder. This process is especially active in the left hemisphere and in the superior temporal structures, the same structures that are involved in the mediation of core psychotic symptoms of schizophrenia and/or their severity. The time and type of antipsychotic treatment seem to counteract partially such process, but are not able to arrest it. Future studies should address some specific issues raised by these results, such as the course over time not only of the volume of cortical gray matter but also of other brain components before the onset of schizophrenia compared with well-matched healthy controls, in relation to potential moderators such as specific genetic polymorphisms or the presence or absence of crucial environmental factors. Even short-term longitudinal studies may be informative, since the longer the follow-up the greater the number of potential confounders of the effects analyzed. Further studies will be required to better understand how the progressive brain changes affect the morphological lateralization of the schizophrenic brain, an issue of potentially high heuristic value. The clinical correlates of tissue loss in specific brain areas in the different phases of illness are largely unknown. The hypothesis of schizophrenia as a progressive generalized brain disease is far less established than believed by many authors, and requires further, more specific, straightforward and thoughtful search.