Hippocampal Volumes in First-Episode Psychosis

Thirty-nine patients with first-episode schizophrenia spectrum disorders and 29 comparison subjects participated in the study. Among the patient group, 82.1% were Chinese (n=32), 10.3% were Malays (n=4), 5.1% were Indians (n=2), and 2.6% were Eurasians (n=1). Among the comparison group, 69.0% were Chinese (n=20), 13.8% were Malay (n=4), and 17.2% were Indians (n=5). The other demographic and clinical characteristics of the participants are summarized in Table 1 . The comparison subjects had significantly more years of schooling (p<0.05). Also, the female patients were significantly shorter in height (p<0.05) than the male patients. Female patients did not significantly differ from the male patients in terms of age of onset of illness, or total PANSS and GAF scores.

Females had very significantly smaller right, anterior, and total (p<0.005) hippocampal volumes as compared with the males. The right anterior, right posterior, left anterior, right, left, and total hippocampal volumes were also observed to be significantly smaller in the females (p<0.05). The patients had significantly smaller right anterior (p=0.008), right (p=0.015), and anterior (p=0.021) hippocampal volumes relative to comparison subjects.

On analyzing differences between patients and comparison subjects by gender (i.e., splitting the file by gender and comparing volumes between patients and comparison subjects), there were no significant differences in the hippocampal volumes between male patients and comparison subjects. However, the female patients had significantly smaller right anterior (p=0.006), right (p=0.012) and anterior (p=0.006) hippocampal volumes than the female comparison subjects. General linear model controlling for age, gender, height, years of schooling, and diagnosis showed that there was a significant effect of diagnosis and gender on the right anterior (p=0.006 and 0.04, respectively), right (p=0.01, and 0.03), and anterior volumes (p=0.02 and 0.02).

Our finding of a smaller anterior hippocampus in patients with first-episode schizophrenia spectrum disorders relative to healthy comparison subjects is similar to that reported in previous studies. 15 – 16 Our patients were scanned as soon as they were stable enough to tolerate the MRI scan, and hence their exposure to antipsychotic medication was minimal. They also did not have a history of substance use. Hence it is very unlikely that the smaller anterior hippocampus was due to the effects of antipsychotics or any other psychoactive substances. Although the patients had significantly fewer years of education than the comparison subjects, there was no significant correlation between the hippocampal volumes and years of education, and statistical adjustment for educational levels did not alter the results. In fact, matching for educational level can be problematic because it would exclude patients with poorer premorbid adjustment caused possibly by prodromal symptoms of psychosis. The anterior hippocampus is predominantly connected with the limbic and striatal systems and, given the hypotheses that failures in the modulation of the limbic and striatal mechanisms are relevant to the pathophysiology of schizophrenia 28 and to the mechanisms of action of antipsychotic drugs, 29 the finding of a structurally smaller anterior hippocampus adds further credence to this theory. The presence of this abnormality at the beginning of the illness may also indicate that a smaller anterior hippocampus may be a trait marker of the illness either due to a genetic susceptibility or early environmental damage, as suggested by studies that have found smaller hippocampal volumes in nonaffected first-degree relatives of patients with schizophrenia as well as linked this finding with fetal hypoxia. 30 In fact, the neonatal ventral hippocampal lesion in the rat has been used as a model of schizophrenia. The same authors have also shown that this early insult to the ventral hippocampus causes reduction in dopamine transporter (DAT) mRNA, although it is unclear whether this reduction coincides with the emergence of behavioral changes in young adulthood or whether it is present from early in life. 31 – 32

We also found that there was a gender by diagnosis effect with the female patients showing significantly smaller anterior and right hippocampal volumes than female comparison subjects; an effect that was not seen in the male patients. Male and female patients with schizophrenia do differ in their clinical manifestations with females presenting with later age of onset, better premorbid social adjustment, and better long-term outcomes. 33 – 35 The male and female patients in our study did not differ significantly with regards to their age of onset and severity of psychopathology at the time of presentation, as measured by duration of untreated psychosis, PANSS, and GAF. The mean age of onset in our female patients was later than the male patients but it was not statistically significant. In fact, this is in line with the older age of onset in females. Interestingly the male patients in our sample seemed to have a later age of onset than what is normally seen in schizophrenia, and it is possible that this later onset of illness helped the male patients escape the early insult to the hippocampus.

Some previous studies looking at gender differences in schizophrenia have reported that male patients appear to manifest greater severity of structural impairment and had smaller hippocampal volumes than the female patients. 9, 36 There have been other studies that have not found any significant effect of gender. 3, 37 Our finding of a smaller right hippocampus in females is similar to that reported by Collinson and colleagues. 38 They assessed the volumes of right and left cerebral hemispheres in early onset schizophrenia and found that the female patients had a significantly reduced rightward asymmetry relative to the female control subjects, indicating that in females there is a volume loss that is relatively greater in the right hemisphere.

We note some possible limitations with our study. As a surrogate measure for intracranial volume, height was used. We also did not look at neurocognitive correlates of anterior versus posterior hippocampus that could provide further evidence for anterior and posterior differentiation of hippocampus in patients with schizophrenia spectrum disorders. Lastly, although we found a gender by diagnosis interaction, our study was not primarily designed to look at gender differences; hence this finding needs to be replicated in another study that is powered to look at the effects of gender in patients as well as healthy comparison subjects. Further research exploring anterior-posterior differentiation of the hippocampus using not only neurocognitive measures but also the connectivity with techniques such as diffusion tensor imaging could shed more light into some of these issues.