Division of Psychological Medicine, Institute of Psychiatry, Kings College London, UK
Department of Psychiatry, Eginition Hospital, University of Athens, Greece
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Australia
Personal Assessment and Crisis Evaluation (PACE) Clinic, Orygen Research Centre, Australia
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Australia
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, and Brain Research Institute, Melbourne, Australia
Orygen Research Centre, Australia
Division of Psychological Medicine, Institute of Psychiatry, Kings College London, UK
Personal Assessment and Evaluation (PACE) Clinic, Orygen Research Centre, Australia
Department of Psychiatry, Eginition Hospital, University of Athens, Greece
Division of Psychological Medicine, Institute of Psychiatry, Kings College London, UK
Early Psychosis Prevention and Intervention Centre (EPPIC), Orygen Research Centre, Australia
Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, and Centre for Neuroscience, University of Melbourne, Australia
Correspondence: Dr Carmine M. Pariante, Division of Psychological Medicine, Box PO51, Institute of Psychiatry, Kings College London, 1 Windsor Walk, Denmark Hill, London SE5 8AF, UK. Tel: +44(0)20 7848 0807; fax: +44 (0)20 7848 0051; e-mail: spjucmp{at}iop.kcl.ac.uk
Declaration of interest None. Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To examine pituitary volume variation in people at different stages of psychotic disorder.
Method Pituitary volume was measured using 1.5 mm, coronal magnetic resonance images in 24 people with first-episode psychosis, 51 with established schizophrenia and 59 healthy controls.
Results Compared with the control group, the people with first-episode psychosis had pituitary volumes that were 10% larger, whereas those with established schizophrenia had pituitary volumes that were 17% smaller. In both of the groups with psychosis, there was no difference in pituitary volume between those receiving typical antipsychotic drugs and those receiving atypical antipsychotics.
Conclusions The first episode of a psychosis is associated with a larger pituitary volume, which we suggest is due to activation of the HPA axis. The smaller pituitary volume in the group with established schizophrenia could be the consequence of repeated episodes of HPA axis hyperactivity.
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INTRODUCTION |
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The period of acute psychotic turmoil (or panic, or ego disintegration), which initiated the psychotic episodes,... was shown to be associated with very great elevations in cortico-steroid... excretion (Sachar et al, 1970).
People who are in the acute phase of a psychotic disorder, with florid symptoms, newly hospitalised or unmedicated, show hypothalamicpituitaryadrenal (HPA) axis hyperactivity, but the central mechanisms underlying this neuroendocrine abnormality are unclear (Cotter & Pariante, 2002). In major depression, HPA axis hyperactivity has been associated with an increased volume of the pituitary gland measured using magnetic resonance imaging (MRI), which correlates with the circulating cortisol levels (Krishnan et al, 1991; Axelson et al, 1992). To investigate whether HPA axis activation in psychosis is also associated with increased pituitary volume, we measured the pituitary glands of patients experiencing their first episode of psychosis, when they are most likely to show HPA axis abnormalities. We also measured pituitary volumes in a group of people with established schizophrenia, to investigate whether this putative abnormality varies at different stages of the psychotic disorder.
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METHOD |
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First-episode group
Twenty-four in-patients with first-episode psychosis were recruited from
the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne,
Australia (McGorry et al,
1996). Study inclusion criteria were age at onset 1630
years and current psychosis, reflected by the presence of at least one of
delusions, hallucinations, disorder of thinking or speech (other than simple
accelerations or retardation) or disorganised, bizarre or markedly
inappropriate behaviour. Patients DSMIV diagnoses were based on
chart review, the Structured Clinical Interview for DSMIV Disorders
(SCID; First et al,
1997) and the Royal Park Multidiagnostic Instrument for Psychosis
(RPMIP; McGorry et al,
1989), administered during the initial treatment episode. Eleven
patients had a diagnosis of schizophrenia or schizophreniform disorder, 9 of
schizoaffective disorder, 2 of bipolar disorder with psychotic symptoms, 1 of
psychosis not otherwise specified and 1 of delusional disorder. Members of
this group were antipsychotic-naïve before their admission. At the time
of the scan, 23 out of 24 patients were taking antipsychotic medication: 14
were receiving a typical antipsychotic agent (mean daily dosage 153 mg
(s.d.=81) chlorpromazine equivalents) and 9 an atypical agent, of whom 7 were
receiving risperidone (mean daily dosage 2.9 mg (s.d.=1.5)), 1 olanzapine and
1 clozapine. Thirteen patients were taking benzodiazepines, 6 were taking an
anticholinergic, 4 lithium and 2 an antidepressant. We collected
socio-demographic and clinical information including the date of first
admission, medication data and level of compliance.
Established schizophrenia group
Fifty-one people with established schizophrenia were recruited from the
rehabilitation unit of the Royal Park Hospital in Melbourne, Australia.
Diagnoses were based on clinical and chart review using DSMIIIR
criteria (American Psychiatric Association,
1987). All of these patients had been ill for at least 5 years
from the time of their first admission. Of the 42 patients for whom complete
medication data were available, 39 were receiving antipsychotic treatment at
the time of scanning: 19 were taking a typical antipsychotic agent (mean daily
dosage 682 mg (s.d.=554) chlorpromazine equivalents a significantly
higher dosage than that in the group with first-episode psychosis: analysis of
variance, F=12.5, d.f.=1,31; P=0.001) and 20 were taking an
atypical antipsychotic, of whom 16 were receiving clozapine (mean daily dosage
450 mg (s.d.=225)), 2 olanzapine, 1 quetiapine and 1 risperidone. Sixteen
patients were taking benzodiazepines, 8 were taking an anticholinergic, 6 an
antidepressant and 5 lithium. We collected socio-demographic and clinical
information including the date of first admission, medication data and level
of compliance.
Control group
Fifty-nine healthy volunteers were recruited by approaching ancillary
hospital staff and through advertisements. They were drawn from
socio-demographic backgrounds similar to those of the participants with
psychotic disorders.
Scanning and data analysis
All participants were scanned using a GE Sigma 1.5 T scanner (GE Medical
Systems, Milwaukee, USA) at the Royal Melbourne Hospital. Head movement was
minimised by the use of foam padding and restraining straps across the
forehead and chin. All patients received their normal medication on the day of
scanning. A three-dimensional volumetric spoiled gradient recalled echo in the
steady state sequence generated 124 contiguous 1.5 mm coronal slices. Imaging
parameters were time to echo (3.3 ms, time to repetition (14.3 ms, flip angle
30°, matrix size 256 x 256, field of view 24 cm x 24 cm and
voxel dimension 0.938 mmx 0.938 mm x 1.5 mm. The scanner was
calibrated fortnightly using the same proprietary phantom to ensure stability
and accuracy of measurements. Imaging data were transferred from digital
audiotape to an SGI O2 workstation (SGI, Mountain View, California, USA) and
coded to ensure patient confidentiality and masked rating of data. All volumes
were estimated using ANALYZE 7.5 (Mayo Clinic). Methods for estimating whole
brain volume and intracranial volume have been described by Velakoulis et
al (1999) and Eritaia
et al (2000). Whole
brain volume includes the hemispheres, cerebellum, brain-stem and the
ventricles, but not the cisterns or sulcal cerebrospinal fluid. Intracranial
volume represents the space within the following boundaries: dura mater, the
undersurfaces of the frontal lobe, the dorsum sellae, the clivus and, at the
craniovertebral junction, the attachment of the dura to the posterior, cutting
across to the anterior arch of C1. Interrater and intrarater reliabilities
were 0.99 for both measurements.
Pituitary measurement
Each pituitary gland was traced in all coronal slices where it could be
visualised, using a method described by Sassi et al
(2001). The mean number of
coronal slices traced per case was 13 (range 916). The pituitary stalk
was excluded from the tracings, but we included a posterior bright spot,
corresponding to the posterior pituitary, the intensity of which is thought to
reflect vasopressin concentrations (Sassi
et al, 2001). We traced around the usually well-defined
borders of the anterior and posterior pituitary: the diaphragma sellae,
superiorly; the sphenoid sinus, inferiorly; and the cavernous sinuses,
bilaterally (Fig. 1)
(Lurie et al, 1990;
Elster, 1993; Lum et al, 2002).
Volume of the pituitary (in mm3) was calculated by summing volumes
for all relevant slices. One rater (K.V.) traced all the pituitaries in the
study. Before starting the study, she trained with a senior author involved in
the development and optimisation of the technique (B.S.). The intrarater and
interrater reliabilities were calculated by measuring the pituitary volumes in
ten scans randomly selected from the original pool of MRI scans from all the
study groups. The interrater reliability was 0.85, the intrarater reliability
was 0.97 and the average variation between two measurements of the same
pituitary was 5%.
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Statistical analysis
Original data are presented as mean and standard deviation. Adjusted means
are presented as mean and standard error of the mean (s.e.m.). Clinical and
socio-demographic differences between groups were examined using one-way
analysis of variance (ANOVA) followed by post hoc
StudentNewmanKeuls test
(Table 1). To limit the number
of statistical comparisons, the differences in pituitary volumes between the
control group and the two clinical groups were examined by conducting a single
two-way analysis of covariance (ANCOVA) test, using the intracranial volume as
a covariate, followed by pairwise comparisons of estimated means. By
definition, it was impossible to have a single control group that was
comparable with the young first-episode group as well as the older group with
established schizophrenia, for both age and gender distribution. Therefore, to
control for these potential confounders, gender was used as between-subject
factor, and age (and whole brain volume) were included as covariates in a
second set of confirmatory analyses. We have previously used this approach to
demonstrate differences in hippocampal volumes between normal volunteers,
people with a first psychotic episode and people with established
schizophrenia (Velakoulis et al,
1999). Moreover, the results obtained from this analysis were
corroborated by conducting two separate ANCOVA tests comparing each of the
clinical groups with another control group that had a similar age and gender
distribution. These two control subgroups were obtained from the original
control sample by ranking males and females by age (masked to their pituitary
volume) and excluding older controls (in the comparison with the first-episode
group) or younger controls (in the comparison with the established
schizophrenia group) until comparable age and gender distributions were
achieved (see Results). The ANCOVA test was also used to compare pituitary
volumes between the following subgroups:
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Partial correlations, covarying for intracranial volume, were conducted between pituitary volume and age.
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RESULTS |
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Pituitary volume
There was a significant difference in pituitary volume between the three
groups (ANCOVA, F=18.0, d.f.=2,132; P<0.001).
Figure 2 shows the pituitary
volumes of all participants, and the estimated mean and s.e.m. values for each
group after adjustment for intracranial volume and gender. Although
examination of the individual data showed an overlap between the groups, the
presence of group differences was suggested by the fact that 17 of the 24
patients in the first-episode group (71%) had pituitary volumes that were
larger than the median of the control group, whereas 35 of the 51 patients in
the established disease group (69%) had pituitary volumes that were smaller
than the median of the control group. The ANCOVA analysis showed that
pituitary volumes in the first-episode group were, on average, 10% larger than
those of the control group (+52 mm3, s.d.=24, P=0.032),
whereas pituitary volumes in the group with established schizophrenia were, on
average, 17% smaller than controls (-91 mm3, s.d.=19,
P<0.001). These differences remained significant when age and
whole brain volume were used as covariates in the analysis. Furthermore, these
differences remained significant when each clinical group was compared with a
control group that had similar age and gender distribution (obtained as
described in the statistical analysis section, above; 32 controls in the
comparison with the first-episode group and 29 controls in the comparison with
the established illness group; ANOVA for age differences, F<0.2,
P>0.6, for both comparisons; chi-squared test for gender
differences, w2<2.1, P>0.2, for both
comparisons).
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In the whole sample, women had larger pituitaries than men: 553 mm3 (s.d.=17) v. 484 mm3 (s.d.=10); ANCOVA, F=11.7, d.f.=1,133; P=0.001. There was a trend for a gender x group interaction (ANOVA, F=2.5, d.f.=2,132; P=0.085), which was due to a smaller gender effect in the group with established schizophrenia in comparison with the other groups (Fig. 2). In the whole sample, there was a negative correlation between age and pituitary volume (r=-0.36, d.f.=131; P<0.001), present in both males (r=-0.26, d.f.=89, P=0.012) and females (r=-0.56, d.f.=39; P<0.001).
Effects of clinical characteristics and subgroups
In the first-episode group, both patients with schizophrenia or
schizophreniform psychosis (n=11) and patients with other diagnoses
(n=13) had larger pituitary volumes than the control group; this
subgroup analysis, however, did not reach statistical significance (ANCOVA,
F=1.9, d.f.=2,54; P=0.17; schizophrenia/schizophreniform
psychosis +48 mm3 (s.d.=30) v. controls, P=0.12;
other diagnoses +50 mm3 (s.d.=36) v. controls,
P=0.16).
There was no difference in pituitary volume between patients receiving typical and atypical antipsychotics, either in the first-episode group (ANCOVA, F=1.6, d.f.=1,22; P=0.2) or in the established schizophrenia group (ANCOVA, F=1.3, d.f.=1,38; P=0.3). Similarly, there was no difference in pituitary volume between the patients receiving antidepressants or lithium and the other patients, either in the first-episode group (ANCOVA, F<0.1, d.f.=1,23; P=0.97) or in the established illness group (ANCOVA, F=0.5, d.f.=1,41; P=0.5).
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DISCUSSION |
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Mechanisms leading to increased pituitary volume
We suggest that the increased pituitary volume in patients with
first-episode psychosis is due to activation of the HPA axis and, in
particular, to an increase in the size and number of corticotrophs (cells
producing adrenocorticotrophic hormone). The few studies that have examined
the HPA axis in people with a first episode of psychosis have found
hyperactivity of this hormonal system
(Sachar et al, 1970;
Ryan et al, 2003).
Interestingly, both HPA axis hyperactivity and increased pituitary volume have
been described in patients with severe major depression
(Krishnan et al,
1991; Axelson et al,
1992), and have been interpreted in these patients as showing a
lack of negative inhibitory feedback by circulating glucocorticoid hormones on
the HPA axis, especially at the level of the pituitary (glucocorticoid
resistance) (Pariante & Miller,
2001; Pariante,
2003). Indeed, increased size and number of corticotrophs and
increased pituitary volume are present also in people with a lack of negative
inhibitory feedback by circulating glucocorticoid hormones due to
Addisons disease (Mineura et
al, 1987). Therefore, our findings suggest that
glucocorticoid resistance may be present in people with first-episode
psychosis. As glucocorticoid resistance is a common correlate of
stress-induced HPA axis activation in animals and humans
(Raison & Miller, 2003),
our findings could be explained by an activation of the stress response. Such
activation could be due to the distress caused by the first psychotic
experience, to an increased biological susceptibility to daily life stress or
to an increased level of independent stressors leading to the psychotic
episode or to all these causes
(Sachar et al, 1970;
Bebbington et al,
1993; Myin-Germeys et
al, 2001). Reassuringly, there is no evidence that HPA axis
hyperactivity causes damage to the brain in people with mental disorders
(Muller et al, 2001).
We did not measure hormonal levels in our study participants, however, so our
proposed relationship between pituitary hyperplasia and hyperactivity of the
HPA axis remains speculative.
Mechanisms leading to decreased pituitary volume
The second major finding of our study was that the group of people with
established schizophrenia had smaller pituitary volumes than the control
group. This finding is remarkably consistent with other studies, which have
shown reduced pituitary volumes in patients with an eating disorder
(Doraiswamy et al,
1990) and in euthymic and depressed patients with bipolar disorder
(Sassi et al, 2001).
Therefore, it is possible that common pathological mechanisms are present in
people with mental disorders that lead to hypoplasia of the pituitary gland.
Interestingly, based on the evidence that patients with bipolar disorder can
present with HPA axis hyperactivity, Sassi et al
(2001) have suggested that
chronic activation of the HPA axis might decrease pituitary volume by reducing
(through negative feedback) the function of cells producing other pituitary
hormones. Because psychotic relapses are associated with activation of the HPA
axis (Tandon et al,
1991), it is possible that repeated episodes of HPA axis
activation associated with previous relapses in our group of patients with
established schizophrenia led to the reductions in pituitary volume. Again,
without having measured pituitary hormones, we do not know whether this volume
reduction has any functional consequences. Previous studies have found normal
HPA axis function in people with established psychosis, especially if they
were clinically stable and receiving treatment
(Tandon et al,
1991).
This is a cross-sectional study comparing different people at various stages of psychosis, not a prospective study; therefore, we can only speculate that the people in the first-episode group with large pituitary glands would progress to having small pituitary glands 5 years later. It is also possible that these two groups are biologically distinct. The patients with established schizophrenia might have had a smaller pituitary volume even at the onset of their psychosis, for example, because of a neurodevelopmental problem (Lum et al, 2002). Equally, patients with first-episode psychosis might have a normal pituitary volume if scanned in the future, as found in people with major depression in the euthymic phase (Sassi et al, 2001).
Limitations of the study
As already stated, we did not measure hormonal levels in these samples.
Moreover, the neuroimaging data were initially collected to examine brain
structure, rather than neuroendocrine abnormalities. Future studies on this
topic should include hormone measurements. A possible limitation of our study,
common to all studies examining pituitary volume by imaging methods, is the
difficulty in distinguishing between anterior and posterior pituitary volumes
(Doraiswamy et al,
1990; Lurie et al,
1990; Krishnan et al,
1991; Axelson et al,
1992; Sassi et al,
2001). However, the posterior pituitary, which releases
vasopressin and oxytocin, constitutes less than 20% of the total pituitary
volume and in contrast to the anterior pituitary there is no
known condition associated with its enlargement, except tumour
(Krishnan et al,
1991; Elster,
1993). Therefore, we believe that the changes in volume we have
described are due to changes in the volume of the anterior pituitary.
Finally, we cannot exclude that pituitary hyperplasia in first-episode psychosis is due to increased function of pituitary cells secreting hormones other than adrenocorticotrophic hormone, such as growth hormone and prolactin; levels of these hormones are also elevated by stress. Furthermore, the patients in our first-episode group were receiving neuroleptic treatment, and antipsychotic drugs can induce proliferation of prolactin-secretingsecreting cells in animals (Saiardi et al, 1997). However, in these patients pituitary volume did not seem to be univocally correlated with antipsychotic administration. In fact, patients in both the first-episode group and the established schizophrenia group were receiving antipsychotic medication, but the differences in pituitary volume, compared with controls, were in opposite directions; moreover, there was no difference in pituitary volume between patients taking typical and atypical antipsychotics, even though the effects of these two kinds of drugs on prolactin secretion are quite different (Halbreich & Kahn, 2003).
Strengths of the study
Three lines of evidence support our conclusions. First, the effects of age
and gender on pituitary volume in our sample are consistent with previously
published studies (Lurie et al,
1990; Sassi et al,
2001). Second, the most common causes of increased pituitary
volume administration of exogenous oestrogens, hypothalamic tumour,
pregnancy, primary hypothyroidism and puberty
(Elster, 1993) were
excluded in our study sample. Third, these results are not limited by the
socio-demographic differences between the three groups, because variables that
could regulate pituitary volumes (age, gender, intracranial volume and whole
brain volume) are controlled, both in the main statistical analysis and in the
two direct comparisons between each clinical group and the matched control
groups.
Although the fact that the first-episode sample was clinically heterogeneous could be interpreted as a limitation, studies on such individuals usually include all diagnoses of psychosis. In fact, because of the temporal instability of the diagnosis in these patients, restricting the analysis to a single diagnostic group in the initial stages would imply missing or misdiagnosing a large number of individuals who would have qualified at a later stage (Amin et al, 1999). Future studies on similar, larger samples would clarify whether there are differences in pituitary volume across psychiatric diagnoses. Moreover, prospective studies of HPA axis function and brain imaging in people at various stages of psychosis, including those at high risk of developing psychosis, will clarify whether these pituitary abnormalities are indeed related to HPA axis function and whether measurements of the stress response could be used to predict the development of psychosis.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication August 6, 2003. Revision received December 8, 2003. Accepted for publication January 24, 2004.
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