The present study provides new evidence that baseline frontal lobe volume deficits in male EOP show progressive differentiation from control subjects during the early stages of the illness. Patients showed a loss of GM and an increase of CSF volumes at a greater rate than matched control subjects. Considering the short illness duration and follow-up time in our sample, these changes must have occurred within a relatively short period after onset of symptoms and were only observed in the frontal lobe.
The age-related whole-brain changes observed in our study consisted of WM and CSF volume increase and GM loss, in agreement with the expected pattern described for adolescents.43,48,49
The main difference in volume change rates between patients and controls during the follow-up period was a higher rate of GM loss and higher rate of CSF increase in the frontal lobe of patients. These differences in volume change rates were observed in both male and female patients, although only males showed significant time × diagnosis interactions. It has been hypothesized that shorter duration or lesser severity of illness may account for more subtle brain volume changes in women.50,51
The small number of female patients in our sample does not allow for reliable testing of those gender differences. Our results should not be seen as an indication of distinct longitudinal patterns in male and female patients. Because of our choice to make a separate analysis for each sex, we can only be certain that at least male patients show some progressive changes relative to control subjects. However, the question of whether this finding is restricted to males or common to both sexes can only be resolved by performing a separate analysis using an equally representative sample of both sexes. The GM deficit and CSF excess in the frontal lobe present at baseline in psychotic males is consistent with previous cross-sectional studies.8,20,52–55
Progressive reduction in frontal GM volume and increase in frontal CSF volume have been reported to occur during the initial years after onset of schizophrenia in young adults13,38
and later in the course of the illness.45
Frontal abnormalities are also in agreement with the findings of Vidal et al25
documenting baseline bilateral deficits in medial frontal cortices in chronically ill patients with childhood-onset schizophrenia and faster progression of those deficits during adolescence as compared with healthy controls. The same baseline and progressive deficits were also present, although with less degree of severity, in a matched group of psychosis patients who did not meet schizophrenia criteria.25
These results suggest a continuum between early onset and adult-onset/chronic disorders. Other studies of childhood-onset schizophrenia have found results different from those reported here. The National Institute of Mental Health (NIMH) longitudinal 5-year follow-up study of 12 childhood-onset schizophrenia patients and 12 matched controls did not find GM deficits in temporal or frontal cortices in the baseline scan (more than 3 years after onset of illness), although frontal and temporal deficits progressed during follow-up.24
In our sample of adolescent-onset psychosis patients, we documented frontal GM volume deficits already 3 months after onset of illness and, unlike in the Thompson et al24
study, the pattern of change after 2 years included only frontal lobe decrease.
Clinical differences in the patients studied may account for some of those differences in findings. Whereas the NIMH childhood-onset schizophrenia studies24
included treatment-resistant patients who had been ill for some years, our sample was more clinically representative, including consecutive admissions to a hospital covering a catchment area, with significant clinical improvement of patients at follow-up. The greater severity of the NIMH cases may partly be responsible for their findings with greater and more widespread GM loss, even after longer duration of illness. The fact that frontal deficits appear earlier than those in other brain areas may be related to the timing of maturation of the frontal lobe relative to other brain regions.43
Childhood-onset schizophrenia patients showed widespread changes relative to controls at an early age, but at follow-up differences persisted only in the frontal and temporal areas.56
Previous studies of adolescent-onset schizophrenia showed smaller prefrontal cortex27
and larger CSF volumes26
in patients than in controls, but failed to show further changes over 2–3 years of follow-up.26,27
Clinical differences in the patient sample may partly explain their results, compared with those observed in this study. In the James et al studies,26,27
patients had been ill for a mean of 1.5 years (2 years for males) before the first scan. Longer follow-up could help determine if our patients, with very similar age of onset and referred also within the community, follow a course similar to those reported by James et al.26,27
Our findings seem to support the neurodevelopmental hypothesis of schizophrenia. Even though, with our data, we cannot determine when frontal lobe changes started, the appearance of volume changes already at the baseline scan, shortly after onset of the first positive symptoms, may reflect earlier disruption of developmental processes (eg, neuronal migration,57
). Frontal lobe deficits seem to be more genetically mediated than deficits in other areas60
and are even present during the prodromal phases of psychosis.61
Although the progressive decrease in frontal GM and the subsequent increase in frontal CSF sulci in our sample could be understood as a consequence of the toxic effect of psychosis on brain structures, some researchers have argued against explanations based solely on volume differences in the absence of concurrent and consistent data on evidence of neuronal death and acceleration of clinical progression.11,62
Alternatively, neurodevelopmental mechanisms active during adolescence may be disrupted in psychotic patients (eg, impaired synaptic plasticity62
), therefore acting after onset and during the early years of illness. Brain development continues until early adulthood and any prior event could be conceptualized as neurodevelopmental in nature. Concerning the duration of the progressive loss of GM observed in our patients, we can only speculate that the rate of progressive changes would reach a plateau after the age of 18, according to the study of Sporn.20
This stop of GM loss observed by Sporn suggests that young adult or late adolescent studies would need longer time periods and larger samples to assess this attenuated effect.
Our results suggest a lack of association between symptomatology and volume changes, in agreement with previous studies.12,63,64
These results further jeopardize the hypothesis of neurodegeneration. In fact, in our sample, negative and positive psychotic symptoms, although present at follow-up, significantly improved over time, which would be difficult to reconcile with a scenario of brain degeneration. Our analysis could imply that excess GM loss, as an expression of abnormal brain maturation, may not be so critical at the functional level in the short term. Among the potential explanations for this finding is the existence of compensatory synaptic and cellular pruning of malfunctioning neurons. Excessive pruning in those adolescents could represent an appropriate response to a dysfunctional mechanism for establishing cortical representations.12,24
Differences in brain volume changes between different subtypes of adolescent-onset psychosis were not observed in the present study. The group of “nonschizophrenia psychotic disorders” showed no pattern distinct from the schizophrenia group. If differences appear after a longer follow-up, therefore implying that early phases of psychosis are less differentiated, this will need to be tested in longer term studies.
The present report has several limitations. Firstly, the follow-up period was short and included only one follow-up point, which may not be fully representative of the complex overall pattern of brain changes in adolescents, considering the large individual variability observed in longitudinal studies.20
Secondly, the small sample size, especially with respect to females, limits the generalization of our results. For this reason, negative findings in females should be interpreted with caution as the study was underpowered to detect change in women due to limited sample size. Thirdly, absent a medication-free comparison group, an impact of antipsychotic medication on our longitudinal findings cannot be ruled out. Finally, our measurement protocol restricted to brain lobes constrains findings to large-scale changes in the brain. Use of voxel-based methods would complement our study, allowing the analysis of small-scale regional gray and WM volume abnormalities not necessarily related to major subdivision in brain lobes. Strengths of the study include the short duration of disease, and short antipsychotic treatment prior to scanning, and homogeneity of the patient and control samples, which limits the impact of sociodemographic factors and maturational processes on findings. The length of the follow-up period was also carefully set the same for all participants, thus reducing the confounding factors affecting the analysis of longitudinal changes.
In conclusion, this study lends further support to the extant literature on frontal GM deficits after the first episode of psychosis. Patients featured in this study were adolescents with less than 6 months since onset of illness, followed for 2 years after their first psychotic episode. Progression of brain change was statistically significant only in male patients, although female patients showed similar rates of change over time. Improvement in clinical status was not associated with brain changes. Differences between patients and controls in the brain regions showing significant changes seemed to be the same in patients with schizophrenia and patients with other psychotic diagnoses. Longer follow-up studies will help to determine whether such changes are limited to adolescence or progress into adulthood.