Neurobiological findings in early phase schizophrenia

Brain Research Reviews 31 Ž2000. 157–165 www.elsevier.comrlocaterbres

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Neurobiological findings in early phase schizophrenia 1 David Copolov a,b,c,) , Dennis Velakoulis a,c , Pat McGorry a,c,d,g , Carina Mallard e, Alison Yung c,g , Sandra Rees e, Graeme Jackson f , Alison Rehn e, Warrick Brewer a , Chris Pantelis a,b,c a

f

The Mental Health Research Institute of Victoria, 155 Oak St., ParkÕille, Victoria 3052, Australia b NHMRC Network for Brain Research into Mental Disorders, Australia c The UniÕersity of Melbourne, Department of Psychiatry, Melbourne, Australia d Early Psychosis PreÕention and InterÕention Centre, Melbourne, Australia e The UniÕersity of Melbourne, Department of Anatomy and Cell Biology, Melbourne, Australia Brain Imaging Research Institute, Austin and Repatriation Medical Centre, The UniÕersity of Melbourne, Melbourne, Australia g Personal Assistance and Crisis EÕaluation Clinic, Melbourne, Australia Accepted 29 September 1999

Abstract This paper summarises the available information on MRI-determined hippocampal morphometry in first-episode patients as an illustration of the value and interpretation of findings in the neurobiology of early phase schizophrenia. We report a thin slice Ž1.5 mm. study of 32 first episode and 39 high risk patients which demonstrated significantly smaller hippocampi Žright y9%, left y11%. in first episode patients that were of a similar magnitude to those found in chronic patients Žright y10%, left y11%. but non-significant volume reductions in high risk individuals, including the 15 subjects who subsequently developed psychoses. Consideration is given to the implications of these findings, including the possible role of early and later neurodevelopmental influences. We present animal data showing that chronic placental insufficiency, as elicited by uterine artery ligation can give rise to substantial reduction Ž31%. in hippocampal volumes and reflect on other potentially relevant pathophysiological mechanisms, including those that may occur during the early phases of psychotic illnesses, including their prodromes. Greater attention needs to be paid to the study of early phase psychosis in order to obtain a clearer understanding of the nature and time course of neurobiological changes associated with it. Although there is a growing literature on first episode psychosis, there is a striking dearth of information on the neurobiology of the prodrome. q 2000 Elsevier Science, B.V. All rights reserved. Keywords: Schizophrenia; Hippocampus; First episode; High risk; Placental insufficiency; Uterine ligation

Contents 1. Introduction .

..................................... 2. Hippocampal volumes in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . 3. The timing of factors contributing to hippocampal volume reduction in psychosis . 3.1. Investigating high risk and prodromal patients . . . . . . . . . . . . . . . . . 4. Investigating early influences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Corresponding author. Tel.: q61-3-9389-2905; Fax: q61-3-9389-2998; E-mail:[email protected] Published on the World Wide Web on 12 November 1999.

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1. Introduction Most of the necessarily limited conclusions that have been reached on the neurobiology of schizophrenia and related psychoses derive from studies that have investigated patients with established disorders, many of whom have received long-term treatment with medications which may substantially modify germane neurochemical systems w1–3x and brain ultrastructure w4–6x. For example, in our postmortem neurochemical studies w7–9x we use tissue from 81 individuals with schizophrenia who, with a mean age of 43.3, are considerably younger than many comparable schizophrenia Brain Bank donors, yet whose average onset of illness was 17.4 years prior to death. Results from studies such as these therefore need to be interpreted cautiously in the light not only of the chronic effects of medication, but also the possible influence of hospitalisation, psychosocial alienation and the interaction between aging and disease processes. The investigation of individuals in pre-psychotic and early phases of schizophrenia minimises or eliminates the likelihood of such factors confounding results which are more reflective of primary disease processes. It also provides a valuable springboard for the longitudinal study of schizophrenia and related disorders w10x including the investigation of the potential usefulness of clinical and neurobiological variables as predictors of subsequent clinical course and treatment response w11,12x. There is now a growing but still quite limited body of neurobiological data on patients with first episode psychoses. The diversity of reported findings lends support to the proposition that the neuropathological processes associated with schizophrenia and related disorders are varied and are, as yet, unable to be characterised in a conceptually satisfactory manner. Thus, for example, magnetic resonance imaging-based studies on first episode patients have described gray matter volume deficits w13,14x, increased w12,15x or normal w16x ventricular volumes, decreased caudate volume in the antipsychotic naive state w17x, increased caudate volume in patients who had already commenced pharmacological treatment w18x, an absence of the normal asymmetries in prefrontal, premotor and occipito-temporal regions w19x reduced w20x or normal w21x asymmetries of the planum temporale, smaller corpus callosum size in female patients w22x, an increase in the number of abnormalities of the septum pellucidum w23x, and changes in the volume of the hippocampus Žsee Section 2.. A common response to such diverse findings is to describe them as diffuse and subtle. An alternative view, if one temporarily discounts the quite reasonable proposition that the evidence for these findings may not end up being generally accepted, is that changes distributed in different brain regions may reflect altered structural and functional connectivities between those regions w24–28x. Particular interest has been focussed on the functional relationship

between the medial temporal lobe and the prefrontal cortex w29–32x. Dysfunction of the medial temporal lobe has been implicated as contributing to the symptomatology of schizophrenia, not only because of the various pathologies which have been described in its component structures Žsee for example w33x., but also because it is possible to conceptualise delusions and hallucinations as arising, in part, from aberrant memory functioning. Thus, Kriekhaus and colleagues w34x have postulated that hyperactivity of a subset of hippocampal pyramidal cells might strengthen synaptic efficiencies between arbitrary coactive neuronal networks in association cortices, thereby ultimately reinforcing the consolidation and fixation of false beliefs. In a similar vein, Nayani and David w35x postulate that auditory hallucinations represent ‘misremembered voices’ – a suggestion which gains some support from the PET demonstration of activation of hippocampus and other limbic and paralimbic regions during auditory hallucinations w36x and our demonstration, in a factor analysis of data obtained from 200 auditory hallucinations, of a factor loading heavily on ‘memory replays’ w37x. Memory dysfunction in schizophrenia – as revealed by neuropsychological testing – has also been considered evidence in favour of hippocampal involvement in the disorder. A recent review of more than 200 studies of neurocognitive deficits in schizophrenia w38x indeed showed that reductions in global verbal memory scores were associated with the largest mean effect sizes of all neuropsychological deficits Žalthough deficits were noted across all domains.. In keeping with neuropsychological findings such as these, Heckers et al. w32x in a w 15 0xCO 2 regional cerebral blood flow ŽrCBF. positron emission tomography ŽPET. study, reported reduced hippocampal recruitment in subjects with schizophrenia during the conscious recollection of studied words, together with increased baseline regional cerebral blood flow to the hippocampus at baseline, in comparison to controls. One explanation for this latter finding is that there is reduced transsynaptic efficiency within the hippocampus in the patient group w39x – a conclusion that derives from a juxtaposition of this PET study with numerous neuropathological and neuroradiological studies which have been conducted on the hippocampus in schizophrenia which have reported the presence of structural abnormalities in this condition w33x Žbut also note the critical review by Dwork w40x..

2. Hippocampal volumes in schizophrenia In addressing the broad area of the neurobiology of early phase schizophrenia, we will focus on the representative area of research on the structure of the hippocampus, as determined by magnetic resonance imaging ŽMRI.. A recent meta-analytic review of 18 MRI studies Ž522 patientsr346 controls. on hippocampal volume in

D. CopoloÕ et al.r Brain Research ReÕiews 31 (2000) 157–165

schizophrenia which was not specific for phase of illness w41x provided support for small Ž4%. bilateral volume reductions in the disorder. Only two studies w22,42xin their analysis exclusively enrolled first-episode patients. Although there have been other first-episode MRI studies which included hippocampal volume data w15,16,43–45x and some of these have reported volume reductions in schizophrenia, specifically affecting the left hippocampus w15,16,42,45x none has included all of the following features which characterise the study described in this paper, viz thin Ž( 1.5 mm. slices, volume comparisons between patients with first-episode psychoses, patients with chronic schizophrenia and controls and comparisons between patients with first-episode schizophreniarschizophreniform disorder and affective psychoses. We w46x used 1.5 mm coronal slice MRI to investigate hippocampal volumes in 32 Ž25Mr7F. patients with firstepisode psychosis, who had DSM-III-R diagnosis of either schizophrenia or schizophreniform disorder Ž n s 16., affective psychosis Ž n s 10., schizoaffective psychosis Ž n s 4. or other disorders Ž n s 2.. The mean ages of the first-episode patients, chronic patients Ž n s 46. and controls Ž n s 140. were 21.2 Ž"3.1., 34.4 Ž"8.4. and 30Ž"12.5 sd., respectively. All the first-episode subjects were patients in Melbourne’s Early Psychosis Prevention and Intervention Centre ŽEPPIC. w47x. Hippocampal volumes were calculated using a method described in Cook et al. w48x, which involved the manual tracing of carefully defined hippocampal boundaries by one of the authors ŽDV.. ANALYZE was used to process the MRI data and one-way and repeated measures ANOVAs, as well as one-way and two-way ANCOVAS were used to compare groups of data. The hippocampal volumes of first episode patients were similar to those of chronic patients, but significantly smaller Ž11% on the left, 9% on the right. than those of the control subjects Žsee Fig. 1; F w2,215x s 21.16, p - .001.. In first episode patients, as in the other two comparison groups, left hippocampal volume was smaller than right hippocampal volume Ž F w1,215x s 84.18, p - 0.001.. Analysis of covariance Žapplied to the subjects on whom National Adult Reading Test derived premorbid IQ data were available. demonstrated that potential confounding factors such as age, sex, height, premorbid IQ and whole brain volume could not account for between group differences in hippocampal volume; although there was a statistically significant covariance between whole brain and hippocampal volumes across all groups Ž t w100x s 6.41, p - 0.001.. A comparison between diagnostic subgroups of first episode groups which adjusted for this covariance showed that left hippocampal volumes of patients with first episode schizophrenia or schizophreniform disorder which were 8.1% smaller in comparison to control subjects. This was statistically significant Ž t w64x s 2.48, p s 0.016., whereas the 5.4% reduction in right hippocampal volume was not.

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Fig. 1. MRI-determined hippocampal volumes Žrightrleft. in patients with chronic schizophrenia Ž ns 46., first episode psychosis Ž ns 32. and control subjects Ž ns140.. Group mean volumes indicated by bars.

An analysis of first episode patients with affective psychosis also revealed a statistically significant 7.7% reduction in left hippocampal volume Ž t w64x s 2.01, p s 0.049. and a non-significant 3.5% reduction in right hippocampal volume in comparison to control subjects. In order to determine if the hippocampal volume reductions we noted were uniform or were region-specific w49x a shape analysis was performed w50x. Principal components analysis was applied to slice data to derive two latent variables or shape components, which were able to satisfactorily predict the volume of each slice. A comparison of these factors revealed no differences between first-episode patients and controls but significant differences were noted in both factors between chronic patients and controls Ž p 0.05.. This comparison, when considered alongside the total volume analyses, indicated that the distribution of the volume loss in first-episode patients was along the whole length of the hippocampus, whereas in the chronic patients the reduction occurred mainly in the posterior two thirds. These findings are hard to compare to many previous studies because, with the exception of Csernansky and colleagues w49x, none undertook formal shape analyses. Also, many previous studies have used a limited number of slices or included in the amygdala in anterior hippocampus slice calculations. With this caveat in mind, our data in relation to posterior volume reductions in chronic patients are in broad agreement with Bogerts et al. w51x and Becker et al. w52x, but not with Shenton et al. w53x, Rossi et al. w54x or Csernansky w49x who reported changes primarily affecting the anterior hippocampus. There have been no previous

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reports of evenly distributed volume reduction in first-episode patients.

3. The timing of factors contributing to hippocampal volume reduction in psychosis Both the hypothesis proposing that the brain changes responsible for the emergence of schizophrenia originate early in life, especially in the pre- and perinatal periods w55x and the proposal that such changes occur during the second decade w56x suggest that if the hippocampal volume reduction reported by us and many others is disorder-related, it should certainly be demonstrable just prior to the onset of psychosis. 3.1. InÕestigating high risk and prodromal patients In order to investigate this hypothesis, we studied high risk individuals who were being treated in a specialist clinic, the Personal Assistance and Crisis Evaluation Clinic ŽPACE. w57,58x to whom young Ž16–30 year old. people are referred if they are thought to be at risk of developing psychotic disorders. Individuals were included in the study sample if they met one of three sets of operationalised criteria. They had to either display frequent attenuated subthreshold psychotic symptoms Ža number which are considered under DSM-IV schizotypal disorder., transient psychotic symptoms Žlasting less than one week., or have both a first degree relative with a history of psychosis or schizotypal disorder plus a loss of 30 points or more on the Global Assessment of Functioning ŽGAF. w59x scale for at least one month. In the 42 month period from March 1995 to September 1998, 137 individuals met the intake criteria. Of the first such 49 individuals who were studied naturalistically, 19 Ž39%. developed a psychosis over a 12 month period w60x. As expected, the transition rate has been lower in the additional 88 patients enrolled in an early intervention study; 19 Ž21%. of these patients have developed psychoses ŽLisa Phillips, personal communication.. An MRI study in this population of patients is still in progress. Results so far indicate that the hippocampal volumes in 39 high risk individuals Žmean age 19.9 " 3.8., 15 of whom eventually developed psychosis, were similar to 145 controls subjects Ždata not shown.. These still preliminary data point to the possibility that the hippocampal volume reductions noted in first-episode and chronic patients have yet to develop in pre-psychotic individuals and that the prodromal phase of illness may represent a time of neuroanatomical remodelling in the same manner that the illness itself may be associated with ongoing brain volume losses in subpopulations of patients w61,62x. Alternatively, the results may merely reflect the small number of subjects in the transition to psychosis

population and the heterogeneity of their eventual diagnoses, with only six receiving a diagnosis of schizophrenia or schizophreniform disorder.

4. Investigating early influences Although the early neurodevelopment hypothesis of schizophrenia has received considerable attention since the late 1980s, it has proven notoriously difficult to confirm w55x. One of the lines of argument that supports the hypothesis relies on the undoubted genetic basis of schizophrenia w63x and postulates the existence of abnormalities in genes coding for neurodevelopmental signalling molecules such as cell adhesion molecules, synaptic proteins and neurotrophins or in their expression w64,65x. This parallels the suggestion that genetic factors may result in subtle disturbances or malformations in the structure of the hippocampus which predispose individuals to develop febrile convulsions and, in some cases, temporal lobe epilepsy w66x. In support of the possibility that such mechanisms may be germane to individuals who are predisposed to develop schizophrenia, are the results of the large Edinburgh high risk study w67x that involved 100 individuals who had at least two close relatives who suffered from schizophrenia. Neuroimaging studies of these high risk ŽHR. individuals revealed left amygdalarhippocampal volume which were significantly smaller than in 30 control subjects but significantly larger than this volume in 20 first episode ŽFE. patients ŽL amygrhipp FE - HR - C p s .0003.. There was a similar pattern with the right amygdalarhippocampal volumes, but with this region being significantly smaller in first episode patients Žonly., in comparison to control subjects Ž p - .05.. One possible candidate molecule which may underlie genetically determined hippocampal volume reductions was investigated by Barbeau and colleagues w68x. In a postmortem immunohistochemical study, they found a substantial reduction in the number of hippocampal hilar cells which express the embryonic, highly polysialated isoform of neural cell adhesion molecule ŽPSA–NCAM. in schizophrenia. Alterations in such molecules may be relevant to disturbances in the neuronal architecture and density of the hippocampus w69x. Another gene of interest is the KAL-X gene which codes for a product with N-CAM-like and axonal pathfinding domains. The majority of patients with Kallmann’s syndrome Žhypogonatrophic hypogonadism and anosmia. demonstrate deletions or mutations in this gene which was the first to be characterised in relation to a specific vertebrate neural migration disorder w70x. Although the neural migration disturbance primarily affects luteinizing hormone secreting and olfactory neurons w71x that share a common origin, it may also affect the hippocampus, resulting in dysplasia w72x.

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Cowen and Green w73x have drawn attention to some parallels between schizophrenia and Kallmann’s syndrome, including the fact that hyposmia is present in a subgroup of male patients with schizophrenia w74,75x. We studied nine unrelated males diagnosed with DSMIII-R schizophrenia who were selected to have a phenotypic similarity to patients with Kallmann’s syndrome by scoring on the first percentile rank of the University of Pennsylvania Smell Identification Test ŽUPSIT. w76x. Genomic DNA was extracted from the blood of the subjects and each of the 14 exons of the KAL-X gene was PCRamplified and sequenced. No mutations were identified in the patient population. This clearly does not exclude the presence of KAL-X mutations in larger populations of patients with schizophrenia. It merely illustrates one strategy of investigating neurodevelopment from a genetic perspective. In contrast to this approach, most of the investigations into the early neurodevelopment hypothesis have used epidemiological methods. These investigations have provided reasonable but far from introcontrovertible evidence which suggests that pre- and perinatal factors such as maternal influenza, famine and obstetric complications can increase the risk of schizophrenia in offspring w55,77x. Nearly 30 years ago Mednick w78x proposed that pregnancy complications might predispose individuals to schizophrenia as a result of hypoxic damage to the developing foetus w78x. Fetal and perinatal hypoxia has also recently been invoked as a possible common mediating factor in predisposing to schizophrenia individuals who experienced the two obstetric complications which were associated with early onset of illness, viz complicated Caesarian section and abnormal presentation w79x. We investigated the effect of prolonged intrauterine hypoxia on hippocampal morphology in the guinea pig in order to determine whether this insult might result in volume reductions and might therefore represent one potential mechanism underlying the hippocampal volume reduction seen in our first episode and chronic patients. Chronic placental insufficiency was induced in 17 pregnant guinea pigs by unilateral uterine artery ligation at mid-gestation Ždays 28–30; term s 68 days. w80x. Morphological and immunohistochemical analyses were then performed on near term fetuses Ž60–63 days. in order to determine differences between animals from the ligated and non-ligated sides. Stereological analyses were carried out on the hippocampus in 13 growth-restricted animals and 13 controls on sections made every 200 mm along the entire structure. Hippocampal volume was estimated using the methodological principles and formulae described in Gundersen et al. w81x. Growth restricted animals had hippocampal volumes that were significantly reduced in comparison to controls Ž52 " 2 mm3 vs 70 " 6, p - 0.05.. It must be noted that this difference in size Ž26%. is considerably greater than

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the 9–11% reductions in hippocampal volume we noted in our first episode patients and the 4% mean hippocampal volume reduction referred to in Nelson et al.’s meta-analytic study w41x. Total neuronal numbers were significantly reduced in CA1 and CA2rCA3 hippocampal sectors Ž1.9 " 0.01 = 10 5 vs 2.3 " 0.01 = 10 5, p - 0.01 and 0.9 " 0.01 vs 1.3 " 0.01 = 10 5, respectively.. Decreased neuronal numbers in the hippocampus have also been reported in schizophrenia by Falkai and Bogerts w82x, but these authors noted reductions in neuronal numbers in all CA sectors. In addition to affecting hippocampal volume and neuronal numbers, chronic placental insufficiency resulted in a loss of neural processes as indicated by a narrowing of the width of the stratum oriens Ž157 " 9 vs 205 " 9, p - 0.05., a layer which consists mainly of the dendrites and axons of pyramidal neurons. This study suggests that placental insufficiency may be a plausible explanation for the hippocampal volume changes noted in some neuroradiological and neuroanatomical studies in schizophrenia, especially in patients who have had confirmed histories of being born to mothers who suffered pregnancy or obstetric complications. It also points to a mechanism whereby offspring sharing both the same uterus as well as the same genetic complement may display different hippocampal morphologies. This is particularly relevant to the study by Suddath and colleagues w83x which demonstrated that in 15 monozygotic twin pairs who were discordant for schizophrenia, there were significant bilateral hippocampal volume reductions in the twins with schizophrenia when compared to their unaffected twin.

5. Discussion The consideration of hippocampal morphometry in first-episode and prodromal patients illustrates several points about the neurobiology of schizophrenia and about the value of investigating patients in the earliest phases of their illness. The modest but significant hippocampal volume reduction in our first episode patients is of uncertain significance, specificity and origin. In these respects, it mirrors most, if not all, the neurobiological findings so far reported in the schizophrenia literature. It is possible that the volume reduction in both our first episode and chronic patients partly reflect changes in the neuronal architecture similar to those reported by authors such as Kovelman and Scheibel w84x, Falkai and Bogerts w82x and Conrad and colleagues w85x, although it must be noted that many of these frequently cited findings have yet to be consistently replicated by others w40x. The reduced hippocampal volume may not represent a change specific to that structure, but may reflect general gray matter volume reduction found in other first episode studies w13,14x.

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Although we are able to argue against the volume reduction being due to an antipsychotic medication effect because our first episode patients had been treated on average for only a brief period Žsix weeks. and there was no relationship between medication dose either in that group or in the chronic schizophrenia group, the role of other disease-related confounding variables cannot be excluded. Thus, for example, marijuana is commonly used by both our patients and those in other early psychosis samples w86,87x. Marijuana’s main psychoactive component, D9-tetrahydrocannabinol has been shown to be neurotoxic to hippocampal neurones in concentrations as low as 0.5 – 10 mM w88x. Another factor which may contribute to hippocampal volume reduction is stress. Convincing animal data demonstrate that hippocampal morphology can substantially alter as a result of chronic psychosocial stress w89,90x. There is good experimental evidence that stress-induced atrophy of pyramidal CA3 neurons is due to a synergism between the actions of glucocorticoids and excitatory amino acids w91x. Such neurochemical mediators may be relevant to the right sided reduction in hippocampal volume reported in combat related post traumatic stress disorder ŽPTSD. w92x. Psychotic disorders such as schizophrenia are often also intensely stressful, with many patients with these disorders fulfilling criteria for post-traumatic stress disorder w93–95x and also demonstrating disinhibition of the hypothalamopituitary-adrenal axis w96,97x. The extensive literature on stress and glucocorticoid-induced damage to the hippocampus, as well as studies which point to the role of seizures in causing hippocampal damage w98,99x suggest that the role of state factors, including those intrinsic to psychotic disorders such as phase of illness related disturbances in neurotransmission w100x, may affect hippocampal morphology. Such factors should be considered alongside possible earlier neurodevelopmental abnormalities in explaining the various structural and neurochemical pathologies which have been described in established schizophrenia w101x. In a similar vein, although there are clear genetic and environmental factors w102,103x which predispose individuals to temporal lobe epilepsy, there is also evidence that seizures themselves may cause hippocampal damage throughout the life of the patient w104x. Our preliminary data on high risk subjects, together with Lawrie et al.’s w105x data which demonstrate a difference in left amygdalarhippocampal volumes between high risk and first episode patients points to the possibility that hippocampal changes may be occurring closer to the onset of the illness than can be accounted for by either the early or late neurodevelopmental hypotheses. Such suggestions require a much larger data base which includes longitudinal MRI data. Our data show that the hippocampal volume reduction in first episode psychosis is not limited to the anterior hippocampus but occurs throughout the structure. Further-

more, in our sample of subjects with chronic schizophrenia the volume reduction occured primarily in the posterior hippocampus with relative preservation of the anterior volume. This observation has an interesting parallel in that a recent report by Briellman et al. w106x also demonstrated that patients who developed post-ictal psychoses in relation to temporal lobe epilepsy ŽTLE. had a relative sparing of their anterior hippocampal volumes in comparison to TLE patients who did not experience psychotic symptoms. It is, at present, too early to reach any definitive conclusions about the site of hippocampal volume changes in schizophrenia or the significance of such changes. Additional shape analysis studies will be required before a consensus can be reached on the precise hippocampal morphology in schizophrenia, whether it changes during the course of the illness and whether it may be useful in distinguishing patients with schizophrenia from other individuals, as suggested by Csernansky et al. w49x. In addition to raising questions about the pattern of mechanisms underlying neurobiological changes in schizophrenia, the data presented in this paper highlight the sparse knowledge base that is currently available in relation to early phase psychosis, especially the pre-psychotic phases of illnesses such as schizophrenia. In the absence of studying individuals in these phases – especially from mid-adolescence until the mid-20s – it will not be possible to adequately confirm or repudiate the various neurodevelopmental models of schizophrenia. The logistic difficulties of recruiting satisfactory numbers of patients for studies such as these are significant, in part, because mental health services have understandably focussed on trying to address the major, and still often unmet, requirements of individuals with established psychiatric disorder – these individuals are therefore the most likely candidates for psychiatric and neurobiological research programs. There are compelling reasons to continue research into patients with established psychotic disorders because if a neuropathology of schizophrenia is to be characterised, there is a logic to the proposition that individuals who have the most severe illnesses are likely to demonstrate the most significant neurochemical and neuroanatomical pathologies, despite the problem of confounding variables and false positive results. If common pathologies truly exist, they should, in principle, be recognisable even if they co-exist with changes brought about by non-disease factors, such as psychotropic medication. Hand-in-hand with this approach, however, is the need to study patients prior to the development of their psychoses and in the early phase of their illness in order to determine the stage at which any yet to be recognised, putatively characteristic pathologies develop. The identification of such pathologies may help to understand the neurobiological bases for certain clinical observations, including the increasingly recognised beneficial effect of the detection of early psychotic symptoms on clinical outcomes w107,108x.

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Acknowledgements w17x

To Geoff Stuart for conducting the hippocampal shape analyses and to Megan Davie and Jeremy Crook for help in the preparation of this manuscript.

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