Pituitary in psychosis

We welcome Dr Kumar's comments, drawing attention to some of the limitations of our study (Pariante et al, 2004). Even though some of these points had already been discussed in the paper, we think it is helpful to reply to all comments.

We agree that there is a large degree of variation in the morphology of the pituitary. For example, in our sample approximately half the subjects had a ‘concave’ pituitary, and a third had a ‘flat’ pituitary. However, we have minimised the influence of morphology on the volume measurement by tracing all coronal slices where the pituitary was visualised. Dr Kumar also refers to the paper by Brooks et al (1989) showing intra-individual changes in the brightness of the posterior bright signal, representing vasopressin released in the posterior lobe for fluids control. We did not analyse the brightness of the posterior bright signal, as we were not interested in the regulation of fluids control in our sample.

In our study there were significant differences in age and gender between the groups. By definition, it was impossible to have one single control that was comparable to the young first-episode participants as well as to the older individuals with established schizophrenia, for both age and gender distribution. However, we used two strategies to control for these confounders: first, gender and age (and whole-brain volume) were included as covariates in the analysis; second, the results obtained from this analysis were further corroborated by conducting separate tests comparing the clinical groups (first-episode and established) with selected control groups that had similar age and gender distribution. Both strategies led to the same results, thus demonstrating that the smaller pituitary volume in patients with established schizophrenia is not due to differences in age and gender distribution.

We agree that the association between increased pituitary volume and HPA axis hyperactivity is speculative, and we clearly stated this in our paper (see Limitations, p. 10). Nevertheless, over 30 years ago Sachar et al (1970) found that patients experiencing a first-episode psychosis were more likely to present with HPA abnormalities, because of the distress associated with the ‘dramatic and ego-dystonic’ nature of this experience. Several studies have confirmed that patients who are in the acute phase of a psychotic disorder, with florid symptoms, newly hospitalised or unmedicated, have elevated HPA axis activity as shown by raised cortisol levels (Sachar et al, 1970), non-suppression of cortisol secretion by dexamethasone in dexamethasone suppression test and in the dexamethasone/corticotropin-releasing factor (CRF) test (Herz et al, 1985; Lammers et al, 1995), and elevated levels of CRF in the cerebrospinal fluid (Banki et al, 1987). Only patients who are clinically stable and receiving treatment tend to have a normal HPA axis (Ismail et al, 1998). Indeed, the study by Katona & Roth (1985), cited by Dr Kumar, also reports, in the authors’ own words, ‘an increased frequency of HPA axis abnormality’ in schizoaffective depression.

We agree that our study would have been more complete if we had measured the adrenal gland size. Indeed, measuring hormonal levels would have been an important addition to the study. We will take this advice into consideration in our future studies.

Finally, we support Dr Kumar's view that hyperactivity of the HPA axis occurs in a large number of conditions associated with stress. Indeed, we suggested in our paper that glucocorticoid resistance could be the molecular mechanism by which stress induces HPA axis hyperactivity in patients with different mental disorders (see Discussion, p. 8). We never suggested that this biological abnormality could have any diagnostic value. However, we believe that measuring specific biological markers can give us further insight into the pathological mechanisms affecting the brains (and the bodies) of our patients.