Pituitary volume and early treatment response in drug-naïve first-episode psychosis patients
Introduction
The early identification and treatment of psychotic disorders is considered crucial in order to minimise disability and improve outcome (McGorry et al., 2006). Response to treatment can vary. Only about half of FEP patients respond within three to four months of treatment (Emsley et al., 2006, Berger et al., 2007, Berger et al., 2008, Perkins et al., 2008). An early response to treatment is thought to be an important predictor for medium term outcome (May et al., 1980, Correll et al., 2003). Even symptom improvement at six weeks has been associated with later remission (Emsley et al., 2006, Emsley et al., 2007). Factors frequently associated with a poorer outcome in schizophrenia include male gender (Robinson et al., 1999), longer duration of untreated psychosis (DUP) (Perkins et al., 2005) and poor insight (Drake et al., 2007). A better understanding of factors that contribute to the variability in treatment response in FEP might lead to improved treatment strategies during this critical early stage of illness, and may also provide insight into underlying pathophysiology.
The stress-vulnerability model of psychosis (Zubin and Spring, 1977, Nuechterlein and Dawson, 1984) continues to be one of the most widely used models for research into the aetiology of psychotic disorders. Stress has been linked with both the onset and relapse of psychosis (Corcoran et al., 2003, Phillips et al., 2006). The biological effects of stress are primarily mediated by the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, the hypothalamus secretes corticotrophin-releasing factor (CRF), which stimulates the secretion of adrenocorticotropin hormone (ACTH) from the pituitary gland. ACTH, in turn, stimulates the release of glucocorticoids (e.g., cortisol) from the adrenal glands. Over-activation of the HPA axis has been found in drug-naïve first-episode schizophrenia patients (Ryan et al., 2004, Pariante et al., 2005) and elevated cortisol secretion has been linked with greater positive and overall symptom severity (Tandon et al., 1991, Walder et al., 2000, Strous et al., 2004). Even in patients at ultra-high risk for psychosis, there is a significant positive association between circulating cortisol and depressive and anxiety symptoms (Thompson et al., 2007b). Both symptom dimensions are common in prodromal patients (Yung et al., 2004) and are risk factors for the emergence of psychosis (Krabbendam et al., 2005). The mechanisms by which stress might precipitate and/or exacerbate psychosis are not fully understood. One aspect is thought to involve cortisol-induced augmentation of sub-cortical dopamine activity (Walker, Diforio 1997), whereas another potential mechanism might be the modulation of synaptic plasticity in brain areas known to be important in schizophrenia (Karssen et al., 2007).
Pituitary volume is often used as an indirect measure of HPA-axis activity and can be measured in vivo using magnetic resonance imaging (MRI). A larger pituitary size is thought to reflect greater HPA activation. In support of this, animal studies have demonstrated that increased levels of CRF cause an increase in both the size and number of corticotrophs (ACTH-producing cells) in the pituitary (Westlund et al., 1985, Gertz et al., 1987). Human studies have revealed an enlarged pituitary gland in conditions associated with HPA-axis hyperactivity, such as major depression (Krishnan et al., 1991, MacMaster et al., 2006) and pituitary volume correlates with circulating cortisol in depressed patients (Axelson et al., 1992). In a previous study (Garner et al., 2005), average pituitary volumes in a sample of healthy young adult male and female volunteers (mean age 20.2 years) were 507 mm3 and 578 mm3, respectively. The objective of this study was to explore the relationship between baseline pituitary volume and symptom change over 12 weeks in drug-naïve first-episode psychosis (FEP) patients. We hypothesised that patients with larger pituitary volumes would show less improvement in psychotic symptoms.
Section snippets
Participants
The study sample consisted of 42 FEP patients (28 male, 14 female; mean age 19.1 ± 2.8 years). Participants were previously selected for a controlled dose-finding study of quetiapine fumarate in 141 drug-naïve FEP patients (Berger et al., 2008). Briefly, the dose-finding the study consisted of two parts. Part I was a randomised, double-blind, fixed dose 4-week comparison of 200 mg vs. 400 mg quetiapine. This was followed by a single-blind, naturalistic, flexible dose 8-week period (part II) where
Baseline characteristics
Pituitary volume was slightly larger in females compared to males (mean ± SD: 574 mm3 ± 123 vs. 538 mm3 ± 138), but this did not approach significance (P = 0.4). Pituitary volume was not correlated with baseline symptom severity measured on the BPRS, BPRS PSS, CDSS or SANS (P > 0.2). Two-way ANOVA revealed no difference in pituitary volume between patients with a schizophrenia spectrum disorder (n = 26) and other psychoses (n = 16) (estimated mean ± SE: 534 mm3 ± 41 vs. 586 mm3 ± 36; P = 0.4) and no group by gender
Discussion
This study examined pituitary volume in drug-naïve or minimally-treated FEP patients and its relationship to early treatment response. We analyzed a sample of FEP patients that participated in a randomised controlled trial of 200 mg/day vs. 400 mg/day quetiapine (Berger et al., 2008). There was a significant interaction between pituitary volume and subsequent improvement in psychotic symptoms, particularly positive symptoms. FEP patients with a larger pituitary at baseline showed less
Role of funding source
Funding for the randomised controlled trial of quetiapine fumarate was provided by Astra-Zeneca Australia and ORYGEN Research Centre. Astra-Zeneca has no further role in the study design, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
BG provided the concept for the study, JPN measured the pituitary gland volumes, AM undertook the statistical analysis and BG wrote the first draft of the manuscript. GB (chief investigator) and TP (co-investigator) provided the concept for and managed the trial; MM co-ordinated the trial and MM, CM and MK recruited the participants and conducted the clinical assessments. All authors contributed to and have approved the final manuscript.
Conflict of interest
All authors declare that they have no conflict of interest.
Acknowledgements
Neuroimaging analysis was facilitated by the Neuropsychiatry Imaging Laboratory managed by Ms. Bridget Soulsby at the Melbourne Neuropsychiatry Centre and supported by Neurosciences Victoria. Dr Garner is supported by a NHMRC Postdoctoral Training Fellowship. Assoc. Prof. Wood is supported by a NHMRC Career Development Award.
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