Pituitary volume and early treatment response in drug-naïve first-episode psychosis patients

https://doi.org/10.1016/j.schres.2009.05.008Get rights and content

Abstract

Background

An early response to antipsychotic treatment in patients with psychosis has been associated with a better course and outcome. However, factors that predict treatment response are not well understood. The onset of schizophrenia and related disorders has been associated with increased levels of stress and hyper-activation of the hypothalamic-pituitary-adrenal (HPA) axis. This study examined whether pituitary volume at the onset of psychosis may be a potential predictor of early treatment response in first-episode psychosis (FEP) patients.

Methods

We investigated the relationship between baseline pituitary volume and symptomatic treatment response over 12 weeks using mixed model analysis in a sample of 42 drug-naïve or early treated FEP patients who participated in a controlled dose-finding study of quetiapine fumarate. Logistic regression was used to examine predictors of treatment response. Pituitary volume was measured from magnetic resonance imaging scans that were obtained upon entry into the trial.

Results

Larger pituitary volume was associated with less improvement in overall psychotic symptoms (Brief Psychiatric Rating Scale (BPRS) P = 0.031) and positive symptoms (BPRS positive symptom subscale P = 0.010). Regardless of gender, patients with a pituitary volume at the 25th percentile (413 mm3) were approximately three times more likely to respond to treatment by week 12 than those at the 75th percentile (635 mm3) (odds ratio = 3.07, CI: 0.90–10.48).

Conclusion

The association of baseline pituitary volumes with early treatment response highlights the importance of the HPA axis in emerging psychosis. Potential implications for treatment strategies in early psychosis are discussed.

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.

References (53)

  • StrousR.D. et al.

    Increased circulatory dehydroepiandrosterone and dehydroepiandrosterone-sulphate in first-episode schizophrenia: relationship to gender, aggression and symptomatology

    Schizophrenia Research

    (2004)
  • TandonR. et al.

    Dexamethasone suppression test in schizophrenia: relationship to symptomatology, ventricular enlargement, and outcome

    Biological Psychiatry

    (1991)
  • ThompsonK.N. et al.

    HPA axis functioning associated with transition to psychosis: combined DEX/CRH test

    Journal of Psychiatric Research

    (2007)
  • ThompsonK.N. et al.

    Stress and HPA-axis functioning in young people at ultra high risk for psychosis

    Journal of Psychiatric Research

    (2007)
  • UpadhyayaA. et al.

    Pituitary volume in neuroleptic-naïve schizophrenia: a structural MRI study

    Schizophrenia Research

    (2007)
  • WalderD.J. et al.

    Cognitive functioning, cortisol release, and symptom severity in patients with schizophrenia

    Biological Psychiatry

    (2000)
  • YungA.R. et al.

    Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features

    Schizophrenia Research

    (2004)
  • Abi-DarghamA. et al.

    Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort

    American Journal of Psychiatry

    (1998)
  • AickinM. et al.

    Adjusting for multiple testing when reporting research results: the Bonerroni vs Holm methods

    American Journal of Public Health

    (1996)
  • BergerG.E. et al.

    Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial

    Journal of Clinical Psychiatry

    (2007)
  • BergerG.E. et al.

    Dosing quetiapine in drug-naive first-episode psychosis: a controlled, double-blind, randomized, single-center study investigating efficacy, tolerability, and safety of 200 mg/day vs. 400 mg/day of quetiapine fumarate in 141 patients aged 15 to 25 years

    Journal of Clinical Psychiatry

    (2008)
  • BrownE.S. et al.

    Mood and cognitive changes during systemic corticosteroid therapy

    Primary Care Companion to the Journal of Clinical Psychiatry

    (2001)
  • BrownH. et al.

    Applied Mixed Models in Medicine

    (2006)
  • CohrsS. et al.

    Quetiapine reduces nocturnal urinary cortisol excretion in healthy subjects

    Psychopharmacology

    (2004)
  • CohrsS. et al.

    The atypical antipsychotics olanzapine and quetiapine, but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects

    Psychopharmacology

    (2006)
  • CorcoranC. et al.

    The stress cascade and schizophrenia: etiology and onset

    Schizophrenia Bulletin

    (2003)
  • Cited by (0)

    View full text