© 2007 The Royal College of Psychiatrists
Duration of prodromal phase and severity of volumetric abnormalities in first-episode psychosis*
King’s College London, Institute of Psychiatry, London
Brain Mapping Unit, University of Cambridge
King’s College London, Institute of Psychiatry, London
Department of Psychiatry, University of Cambridge
King’s College London, Institute of Psychiatry, London
Department of Psychiatry, University of Cambridge
King’s College London, Institute of Psychiatry, London, UK
Correspondence: Dr Paola Dazzan, PO Box 63, Division of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF. Email: Paola.Dazzan{at}iop.kcl.ac.uk
Declaration of interest None. Funding detailed in Acknowledgements.
* Preliminary analysis of these data was presented in abstract form at the
XIII Biennial Winter Workshop on Schizophrenia, Davos, Switzerland, 2006. 
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Background First-episode psychosis is typically preceded by a prodrome in which there is deterioration in global and social functioning.
Aims To examine whether the duration ofthe prodromal phase influences grey and white matter volumes at the onset of psychosis.
Methods Eighty-two people were scanned using magnetic resonance imaging when they developed a first episode of psychosis. The duration of the prodromal phase was estimated from detailed interviews and medical records. Voxel-based morphometry was used to assess neuroanatomical abnormalities.
Results A long prodromal phase was associated with smaller grey matter volumes in the cingulate, frontal and left insular cortex, and with less white matter volume bilaterally in the superior longitudinal and uncinate fasciculi and the cingulum.
Conclusions The severity of volumetric abnormalities in first-episode psychosis was greater in those with a long prodrome.
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The first episode of psychosis is typically preceded by a prodromal phase during which there is a gradual deterioration in global and social functioning and the emergence of attenuated positive and negative psychotic symptoms (Hafner & Nowotny, 1995; Yung et al, 2003). We set out to establish whether the duration of such sub-threshold symptoms, or prodrome, prior to illness onset is related to severity of neuroanatomical changes at the onset of frank psychosis. A large group of people was scanned using magnetic resonance imaging (MRI) at the time of the first episode. We expected that the longer the duration of the prodrome, the smaller the volumes in grey matter regions and white matter tracts implicated in psychotic disorders. Thus, we predicted that a longer prodrome would be associated with relatively smaller grey matter volumes in the prefrontal, cingulate and medial temporal cortex, and smaller white matter volumes in the tracts that interconnect these regions.
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Participants
Participants were recruited as part of a large epidemiological study of first-episode psychosis (Dazzan et al, 2004). A total of 281 people met inclusion criteria for a functional psychotic illness (DSM–IV 295–298, psychotic codings; American Psychiatric Association, 1994); 90 declined to participate; of the remaining 191, 115 consented to an MRI scan. These 115 patients were a mean of 6 years younger (mean age 27.9 years, s.d.=8.4 v. 33.7, s.d.=12.3, t=3.5, P=0.001) and had a higher proportion of White British members (36% v. 18%,
2=6.95, P=0.008) but were otherwise
comparable to the total sample in terms of gender, years of education,
diagnosis and duration of illness. There were no significant group differences
in demographic or clinical features between those who did and did not consent
to scanning. Of those who consented to MRI, 10 terminated scanning before image acquisition could be completed and 15 were excluded owing to participant motion (n=13) or radiological abnormalities (1 congenital hydrocephalus, 1 subarachnoid cyst). Data from 90 participants were thus available for image analysis.
Clinical measures
Participants were assessed using the Schedule for Clinical Assessment in
Neuropsychiatry (SCAN; World Health
Organization, 1994) interview. Diagnostic codes were assigned
according to DSM–IV criteria in consensus meetings with senior
clinicians. A total symptom score was obtained by summing the individual
symptom item scores according to Wing & Sturt’s (1978) procedure for
the Present State Examination (PSE). Premorbid IQ was assessed using the
National Adult Reading Test (NART; Nelson
& Willison, 1991) and handedness using the Annett Hand
Preference Questionnaire (Annett,
1970).
Prodrome
The prodrome was defined as the period in weeks from the time of first
definite change in behavioural, psychological or emotional functioning to the
onset of the first psychotic episode. The key feature of this criterion was
the presence of a fundamental change in function that persisted from its onset
until the time of first episode of psychosis (e.g. non-attendance at
work/college with no clear explanation for change in behaviour). In line with
previous studies (Craig et al,
2000), onset of psychosis was defined as the presence for 1 week
or more of one of the following psychotic symptoms (as defined in the SCAN):
delusions; hallucinations; marked thought disorder; marked psychomotor
disorder (other than simple retardation or acceleration); and bizarre, grossly
inappropriate and/or disorganised behaviour with a marked deterioration in
function. Data relating to date of first behavioural change and date of onset
of psychosis were collated from interviews with the participant and a close
relative, and clinical notes using the Personal and Psychiatric History
Schedule (PPHS; Jablensky et al,
1992; World Health
Organization, 1994). Interrater reliability was assessed for those
involved in rating (C.M. and J.M.L.) by each independently rating these
measures on a random subset of 50 participants from the original sample.
Reliability was judged as satisfactory (inter-class correlation
r=0.903). Duration of untreated psychosis was measured and defined as
the period in weeks from the onset of frank psychotic phenomena to first
contact with statutory mental health services. Duration of untreated illness
was defined as the sum of duration of prodrome plus the duration of untreated
psychosis.
MRI protocol
Magnetic resonance images were acquired with a GE Signa 1.5 T system (GE
Medical Systems, Milwaukee, USA) at the Maudsley Hospital (London, UK).
Contiguous, high-resolution 3-mm thick, interleaved dual-echo images were
acquired in the coronal plane, providing coverage of the entire brain. Proton
density- and T2-weighted image acquisition was almost simultaneous: time to
echo (TE1) 20 ms, (TE2) 85 ms; time to resolution (TR) 4000 ms; 8-echo train
length; matrix size 256 x 192; field of view 22 cmx16.5 cm).
Images were processed using SBAMM voxel-based semi-automated methods (Bullmore et al, 1999; Suckling et al, 1999). In brief, extracerebral tissues were removed using an automated algorithm and manual editing. Intracerebral tissue voxels were categorised into grey matter, white matter, cerebrospinal fluid (CSF), or dura/vasculature using a modified fuzzy clustering algorithm (Suckling et al, 1999). A template image was constructed in standard space from proton-density images of six healthy controls using the AFNI program (Dazzan et al, 2004). Each participant’s proton-density weighted image was then registered onto the template with a nine-parameter affine registration, minimising between-level difference between images. The derived mapping was applied to the corresponding tissue maps.
Length of prodrome was regressed onto estimated grey matter and white matter volumes at each voxel in standard space. The test statistic calculated was the regression coefficient divided by its standard deviation to generate an effect map. Permutation testing was used to assess statistical significance, and regional relationships were tested at the level of voxel clusters (Bullmore et al, 1999; Sigmundsson et al, 2001). The statistical threshold for cluster significance was set such that the expected number of false-positive clusters (P value times number of tests) was less than one.
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Sample
Socio-demographic and clinical characteristics of the sample are shown in Table 1.
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View this table: [in a new window] | Table 1 Socio-demographic and clinical characteristics of 82 participants |
Prodrome
The distribution of prodrome length expressed in weeks was non-Gaussian. A
small number of participants (n=8) had an extremely long prodrome
(>169 weeks), which was grossly outwith the distribution for the sample as
a whole. Logarithmic transformation was not sufficient to convert the data to
normal distribution, and therefore these participants were excluded as
statistical outliers.
Eighty-two participants remained for subsequent analyses; these were a mean
of 5 years younger (mean age 27.1, s.d.=8.0 v. 32.7, s.d.=11.1 years,
t=3.8, P=0.002) and had a higher proportion of White British
members (38% v. 21%, 2= 6.24, P=0.01), but
were otherwise comparable to the total sample in terms of gender, years of
education, diagnosis and duration of illness.
The mean length of prodrome was 21 weeks (s.d.=36, range 1–157, IQR 1=27). The mean duration of untreated psychosis was 26 weeks (s.d.=52, range 1–313, IQR=2–22). The mean duration of untreated illness was 46 weeks (s.d.=64, range 1–344, IQR=7–52). Seventy participants (85%) had received antipsychotic treatment at the time of the MRI scan. The mean duration of antipsychotic treatment was 9 weeks.
Length of prodrome did not vary significantly with gender, age, type of psychotic disorder (schizophrenia, affective psychosis, other), total duration of antipsychotic exposure, illness severity (as indexed by total symptom score on the SCAN) or premorbid IQ (NART; Table 2).
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View this table: [in a new window] | Table 2 Relationship of socio-demographic and clinical variables to prodrome length |
Global brain volumes
Length of prodrome was not significantly correlated with the total volume
of any of the grey matter, the white matter or the CSF
(Table 2).
Regional brain volumes
Grey matter
There were two regions where there was an inverse relationship between
length of prodrome and grey matter volume (P=0.002, < 1
false-positive; Table 3; Fig.
DS1 in the data supplement to the online version of this paper). The first
cluster included the anterior and posterior cingulate gyri bilaterally, and
extended locally into the medial frontal gyri bilaterally (Fig. DS1). A second
cluster was focused on the left insula, extending into the left inferior
frontal gyrus.
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View this table: [in a new window] | Table 3 Regional differences in grey and white matter associated with length of prodrome |
White matter
Length of prodrome was inversely correlated with white matter volume in two
similar regions in each hemisphere (P=0.003, <1 false-positive;
Table 3; Fig. DS2 in the data
supplement to the online version). Both clusters had their focus in the
superior longitudinal fasciculus at the level of the genu of the corpus
callosum, and also included white matter in the cingulum, corpus callosum and
internal capsule.
There were also three much less extensive clusters where prodrome duration was positively correlated with white matter volume (P=0.003, <1 false positive; Table 3; Fig. DS2). One was centred in the right inferior longitudinal fasciculus (ILF), with involvement of the right uncinate fasciculus. The second involved the white matter subjacent to the right orbital gyrus, with extension into the right fusiform gyrus; and the final cluster was centred in the left acoustic radiation with involvement of the left ILF at the level of the mid-thalamus, and extended anteriorly in the uncinate fasciculus.
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Grey and white matter abnormalities
This study provides the first data to indicate that the length of time spent in prodromal illness directly correlates with the degree of brain structural abnormalities present at the onset of psychosis. Moreover, this relationship was evident in grey and white matter areas that are typically affected in psychotic disorders, and the polarity of the relationship in these areas (smaller volume with longer prodrome) corresponds to the reduction that is evident in psychotic disorders. Reduced prefrontal, insular and cingulate volume have consistently been reported in neuroimaging studies of schizophrenia (Wright et al, 2000; Sigmundsson et al, 2001; Job et al, 2002) and, to a lesser extent, bipolar illness (Drevets et al, 1997; McDonald et al, 2004). Similarly, reduced white matter volume in the superior longitudinal and uncinate fasciculi, and in the cingulum has been described in volumetric MRI studies of schizophrenia (Sigmundsson et al, 2001) and bipolar disorder (Haznedar et al, 2005). Diffusion tensor imaging studies indicate that these tracts are also sites of reduced fractional anisotropy in schizophrenia (interpreted as reflecting reduced white matter integrity), but this technique has been less frequently employed in bipolar disorder (Lim et al, 1999; Kubicki et al, 2002). Our white matter findings are of particular interest because the superior longitudinal fasciculi and the cingulum carry connections to and from the prefrontal, cingulate and temporal regions (Catani et al, 2002; Wakana et al, 2004), where we found grey matter reductions correlated with longer prodrome.
Comparison with high-risk studies
A correlation between the duration of the prodromal phase and the severity
of MRI abnormalities at the first episode is consistent with data from
prospective MRI studies of individuals at high risk of psychosis during the
prodromal period. To date, only two previous studies have examined changes in
brain structure at several time points in small numbers of people at high risk
for psychosis. Pantelis et al
(2003) scanned people in the
prodromal phase and again after they developed psychosis and found that there
was a progressive reduction in grey matter volume in the cingulate, prefrontal
and medial temporal cortex. Job et al
(2005) also reported a
longitudinal reduction in medial temporal and cerebellar volume during the
prodrome, and that these changes occurred within the prodromal phase well in
advance of the first episode. Our study provides complementary findings: we
have established that there is a correlation between length of prodromal
symptoms and severity of neuroanatomical abnormalities. This is important
because if these occur secondary to progressive changes caused by subthreshold
prodromal symptoms, it is clear that the length of prodromal illness is
important in pathogenesis, rather than there being some ‘toxic’
threshold being reached with the onset of frank psychotic symptoms.
However, although our findings are consistent with this hypothesis, we cannot conclude from our cross-sectional study that the brain abnormalities identified represent progressive changes. Indeed, the differences in regional volumes within our participants with first-episode psychosis may already have been present before the prodromal phase, perhaps reflecting factors that vary between patients and differentially affect both brain structure and the form of onset of the disorder. For example, this explanation might apply if those who developed schizophrenia had both a longer prodrome and more extensive MRI abnormalities than those with an affective psychosis, or if people who were highly symptomatic at the first episode had a longer prodrome than those who presented with less florid symptoms. In the present study the length of prodrome was similar for people with schizophrenia, affective or other psychoses, and it was also unrelated to the overall severity of symptoms. Similarly, prodrome duration was unrelated to age, gender, IQ, nature of antipsychotic treatment and duration of treatment prior to scanning. Thus, although an effect of factors other than a progressive process cannot be excluded, we found no evidence to support this. None the less, it is important to acknowledge the possibility that any changes occurring in brain structure need not follow a purely linear course throughout the entire prodrome. Indeed it seems likely that, after a given time, rate of change must diminish or brain volume would decrease to zero. Our interpretation of the findings as representing a linear change over time is both scientifically plausible and parsimonious.
Definition of prodrome
Estimates of prodrome duration in the present study were made
retrospectively, which might have limited their accuracy. We sought to
minimise inaccuracy by using information from the participants’
relatives and friends, as well as from the participants themselves, and by
systematically examining all available clinical records. Moreover, in practice
a truly prospective measure of prodrome duration is difficult to obtain. Even
people who are ascertained before the first episode will have been
experiencing prodromal symptoms for some time
(Yung et al, 2003),
such that their date of illness onset still has to be estimated
retrospectively. In any event, in the present study it is the relative length
of the prodrome in different participants rather than its absolute duration
that is relevant, making the precision of the absolute estimate less critical.
The average length of prodrome in our sample was shorter than reported in
previous studies (Pantelis et al,
2003), and this might reflect differences in the respective
samples examined. Our participants were people with first-episode psychosis
ascertained in an epidemiological study, whereas previous estimates have been
derived from people with prodromal symptoms referred to specialist clinics
(Pantelis et al,
2003).
Voxel-based methodology
We used voxel-based morphometry for the evaluation of brain structure,
measuring relative intensities of grey or white matter values at a given
voxel. Thus, observed differences between groups might represent differences
in factors affecting tissue intensity such as hydration status, or vascular or
metabolic changes. Also, it is always possible that some of the grey and white
matter abnormalities that we have demonstrated could be a result of an
artefact of the warping of the images into standard (Talairach) space.
We also considered the possibility that brain changes might occur secondary to antipsychotic treatment in our subjects. There was no difference in length of prodrome between participants considered according to their treatment status (typical antipsychotics, atypicals, mixed, or drug-free; Table 2), so medication status is unlikely to explain our findings.
Relationship with duration of untreated psychosis
The duration of untreated psychosis has been regarded as another period
when a neurotoxic process may be active
(Wyatt, 1995). Some studies
have reported that the severity of volumetric abnormalities in schizophrenia
varies with its duration (Keshavan et
al, 1998), but others have not
(Hoff et al, 2000;
Ho et al, 2003). We
have previously examined the volumetric correlates of duration of untreated
psychosis in this same sample, and found that a long duration was associated
with more extensive reductions in grey matter volume that were limited to a
single region (temporal cortex) distinct from those identified in the present
study (Lappin et al,
2006). Taken together, these data invoke the question of whether
there are dynamic changes occurring across integrated brain networks in a
temporal sequence. Thus, changes occurring in the prodromal phase predominate
in the frontal regions and white matter, whereas later changes related to the
transition from prodrome to psychosis (when the duration of untreated
psychosis begins) involve other areas such as the temporal cortex. Studies of
longitudinal design with scans at several time points are necessary to
investigate this possibility.
Clinical implications
Conventionally, clinical intervention in psychotic disorders begins after
the first episode. However, there is increasing interest in the potential
benefits of introducing treatment in the prodromal phase
(McGorry et al,
2002). Although our findings are consistent with the operation of
a progressive process during this period, this requires confirmation through
further longitudinal MRI studies of people within the prodrome.
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We wish to thank the ÆSOP researchers who helped with data collection, and Dr Marco Catani for his help and advice. The ÆSOP study was funded by the Medical Research Council (UK) and the Stanley Medical Research Institute. P.D. is funded by a NARSAD Young Investigator Award.
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