Pituitary volume in unaffected relatives of patients with schizophrenia and bipolar disorder

Summary

Background

Hypothalamic–pituitary–adrenal (HPA) axis hyperactivity has been demonstrated in both schizophrenia and bipolar disorder, but the mechanisms underlying this abnormality are still unclear. Enlarged pituitary volume has been recently reported in patients with first episode psychosis and been interpreted as a consequence of an increased activation of the HPA axis. The aim of this study was to assess the contribution of familial liability to pituitary volume in schizophrenia and bipolar disorder. Pituitary volume may be an indirect measure of HPA axis activity.

Methods

MRI brain scans and measurements of pituitary volumes were obtained for 183 subjects: 26 patients with established schizophrenia or schizoaffective disorder, 44 of their unaffected first-degree relatives (22 familial schizophrenia, 22 non-familial schizophrenia), 29 patients with established bipolar disorder, 38 of their unaffected first-degree relatives, and 46 healthy comparison subjects.

Results

We found a significantly larger pituitary volume (effect size = 0.7) in unaffected relatives of patients with schizophrenia compared with controls (p = 0.002); the pituitary was even larger in relatives of patients with familial schizophrenia (effect size = 0.8, p = 0.005). We did not find a significant difference in pituitary volume when comparing the relatives of bipolar patients with controls. Among patients, those with schizophrenia who were receiving prolactin-elevating antipsychotics had an increased pituitary volume compared with controls (effect size = 1.0, p = 0.006).

Conclusions

These results suggest that the larger pituitary volume previously reported in first episode schizophrenia could be partly due to a genetic susceptibility to over-activate the HPA axis.

Introduction

Our recent work has found an enlarged pituitary volume in antipsychotic-free subjects at their first episode of psychosis, but the mechanisms underlying this abnormality are still unclear (Pariante et al., 2004, Pariante et al., 2005, Garner et al., 2005). The pituitary gland has an important role in the regulation of the main hormonal stress response system, the hypothalamic–pituitary–adrenal (HPA) axis. Specifically, HPA axis activity is mediated by the release of the corticotropin releasing hormone (CRH) from the hypothalamus, which in turn activates the secretion of adrenocorticotropic hormone (ACTH) from the pituitary, which finally stimulates the secretion of cortisol from the adrenal gland. The increase of cortisol can in turn regulate the activity of the HPA axis through a negative inhibitory feedback at hypothalamic and pituitary level, reducing the secretion of CRH and ACTH. The volume of the pituitary gland can change in size as consequence of both physiological and pathological alterations in the patterns of hormone secretion. Animal studies have shown that adrenalectomy induces the proliferation of hormonally null cells, a progenitor cell population, in the anterior pituitary, that later differentiate in cells producing ACTH (Nolan et al., 1998, Nolan et al., 2004, Nolan and Levy, 2006). Indeed, increased size and number of cells producing ACTH and increased volume of the pituitary are present also in subjects with a lack of negative inhibitory feedback on HPA axis by circulating cortisol because of Addison's disease (Mineura et al., 1987). Patients experiencing a first episode of psychosis show a hyperactivity of the HPA axis, as indicated by elevated plasma cortisol and ACTH levels (Ryan et al., 2003, Ryan et al., 2004), and patients with schizophrenia have also been shown to present a lack of inhibitory feedback by cortisol on the HPA axis (Tandon et al., 1991). Therefore, the enlarged pituitary volume in first episode psychotic patients has been interpreted as a consequence of an increased activation of the HPA axis and possibly of the impaired negative feedback, reflecting an increase in size and number of corticotrope cells producing ACTH (Pariante et al., 2004, Pariante et al., 2005, Garner et al., 2005). Interestingly, in our previous study we found an enlarged pituitary volume not only in patients with a first episode of schizophrenia, but also in patients with a first episode of bipolar disorder (Pariante et al., 2005). Enlarged pituitary gland in young bipolar patients has been also reported recently by another group (MacMaster et al., 2008). Indeed, HPA axis hyperactivity has been demonstrated both in schizophrenia and in bipolar disorder (Sachar et al., 1970, Ryan et al., 2004, Watson et al., 2004). It is of note that schizophrenia and bipolar disorder share some clinical features as well as genetic and epidemiological risk factors, although additional genetic and environmental factors may then act, or interact, upon this common background to launch an individual on a trajectory towards schizophrenia rather than towards bipolar disorder (Murray et al., 2004).

Interestingly, it has been hypothesised that HPA axis hyperactivity could contribute to the pathogenesis of psychotics disorders by increasing brain dopaminergic activity (Walker and Diforio, 1997). Indeed, recent studies indicate that the HPA axis hyperactivity is not simply a consequence of these disorders, but rather a risk factor for their development (Garner et al., 2005). For example, we have recently described that, among subjects at ultra-high risk of developing psychosis, those who go on to develop psychosis (schizophrenia or bipolar) already have an enlarged pituitary volume months before the psychosis onset (Garner et al., 2005). Moreover, schizotypal adolescents, another population at risk for schizophrenia, have been recently shown to have higher cortisol levels compared to controls (Mittal et al., 2007).

One of the possible mechanisms underlying the HPA axis hyperactivity before the onset of (and possibly leading to) the psychosis could be an increased susceptibility to daily life stress, possibly mediated by the genetic background. Data supporting this notion come from studies showing that unaffected relatives of psychotic patients have an increase in emotional reactivity and in the intensity of subtle psychotic experiences in response to daily life stress (Myin-Germeys et al., 2001, Myin-Germeys et al., 2005). Another previous study has shown that the serotonergic regulation of the stress response is reduced in first-degree relatives of patients with bipolar disorder, further supporting the role of stress in familial liability to bipolar disorder (Sobczak et al., 2002).

It is also of note that patients with established schizophrenia or bipolar disorder, assessed a few years after the onset, have been described as having normal (Chen et al., 2004, Tournikioti et al., 2007) or decreased (Sassi et al., 2001, Pariante et al., 2004, Pariante et al., 2005, Upadhyaya et al., 2007) pituitary volume. This discrepancy might partly be explained by the effect of the duration of illness and by the confounding effects of prolactin-elevating antipsychotics. In fact, these drugs have been shown to increase pituitary volume in first episode patients (Pariante et al., 2005, MacMaster et al., 2007). Whether or not this effect is also present in patients with established diagnoses is currently unknown.

The first aim of the present study was to assess the contribution of familial liability (presumably genetic) to the enlarged pituitary volume in schizophrenia and in bipolar disorder. We measured the pituitary volume in unaffected relatives of patients with schizophrenia or bipolar disorder, and we hypothesised that the unaffected relatives of patients with either psychotic illness would have larger pituitary volume when compared with healthy controls. We also specifically tested whether this effect could be due to the possible stress of living with the patient with schizophrenia, by comparing the relatives living in the same house with the patients with relatives not living with the patients. Our secondary aim was to clarify the effects of prolactin-elevating antipsychotics in a sample of patients with established schizophrenia and bipolar disorder: we hypothesised that patients taking prolactin-elevating drugs would have the largest pituitary volumes.