Numerous imaging studies have reported morphological brain abnormalities in schizophrenia, including studies in first-episode schizophrenia (for reviews see Reference McCarley, Wible and FruminMcCarley et al, 1999; Reference Wright, Rabe-Hesketh and BullmoreWright et al, 2000). However, it is difficult to establish whether these structural brain abnormalities are caused by the disease or are from the effects of treatment. Imaging studies in patients with schizophrenia who have never been exposed to antipsychotic medication may help to clarify whether brain changes are already present in an early stage of the disease and are independent of medication use. This current study examined multiple brain structures in a single sample of antipsychotic-naïve patients with schizophrenia compared with a sample of carefully matched healthy comparison subjects. Intracranial volume, total brain, grey and white matter of the cerebrum, frontal lobe, cerebellar, hippocampal, parahippocampal, thalamic, caudate nucleus and lateral and third ventricular volumes were assessed.
As evidence is accumulating that medication may alter brain structures (increases in basal ganglia volumes have been related to antipsychotic intake (Reference Chakos, Lieberman and BilderChakos et al, 1994; Reference Keshavan, Bagwell and HaasKeshavan et al, 1994; Reference Scheepers, de Wied and PolScheepers et al, 2001) and decreases in frontal lobe volume have been related to the amount of antipsychotic medication used (Reference Gur, Cowell and TuretskyGur et al, 1998a ; Reference Madsen, Keidling and KarleMadsen et al, 1998)), the study of brain morphology in antipsychotic-naïve patients with schizophrenia is crucial for an understanding of the disease. Studies comparing antipsychotic-naïve patients with first-episode schizophrenia with healthy comparison subjects have examined only one or a few brain structures (Table 1). These studies have inconsistently reported brain volume changes in antipsychotic-naïve patients with schizophrenia compared with healthy volunteers, which could be caused by factors such as a large variation in scanning acquisition and volumetric measures, inclusion of small numbers of subjects, inclusion of patients with a diagnosis other than schizophrenia and failure to match for age, gender, socio-economic class or handedness. In addition, some studies were not designed to exclusively compare antipsychotic-naïve patients with healthy comparison subjects.
Table 1 Review of magnetic resonance imaging (MRI) literature in antipsychotic-naïve patients with schizophrenia
| Author | Subjects | Brain regions examined | Matching | MRI | Results | Comment |
|---|---|---|---|---|---|---|
| Reference Buchsbaum, Someya and TengBuchsbaum et al, 1996 | 20 m-sz | Thalamus | Not clearly matched | 7.5-mm slices | No volume differences | Primarily PET study |
| 15 nc | ||||||
| Reference Keshavan, Rosenberg and SweeneyKeshavan et al, 1998a | 16 m-sz | Cranium, caudate, putamen | Age, gender, parental education and own education | 1.5 T | Left caudate reduced in both patient groups | |
| 9 non sz | 2.8-mm slices | |||||
| 17 nc | ||||||
| Reference Keshavan, Haas and KahnKeshavan et al, 1998b | 17 m-sz | Cranium, STG, cerebellum | Not clearly matched | 1.5 T | Smaller left STG | After 1 year follow-up repeat MRI showed reduced total STG |
| 8 non sz | 5-mm slices | |||||
| 17 nc | 1-mm gap | |||||
| Reference Gur, Cowell and TuretskyGur et al, 1998a 1 | 20 m-sz | Total brain, CSF, frontal lobe, temporal lobe | Not clearly matched | 1.5 T | Reduced total brain, frontal and temporal lobes. CSF no difference | Designed as a follow-up study |
| 20 prev. treat. sz | 5-mm slices | |||||
| 17 nc | ||||||
| Reference Gur, Maany and MozleyGur et al, 1998b | 21 m-sz | Cranium, caudate, putamen, globus pallidus, thalamus, total brain, CSF, ventricles | Age, parental education, handedness | 1.5 T | Thalamic volume reduction trend. Total brain, CSF, ventricles, globus pallidus, putamen no difference | Increased subcortical volumes related to amount of antipsychotics |
| 75 prev. treat. sz | 1-mm slices | |||||
| 128 nc | ||||||
| Reference Shihabuddin, Buchsbaum and HazlettShihabuddin et al, 1998 | 7 m-sz | Caudate, putamen | Age, gender | 1.2-mm slices | Smaller caudate and putamen | Primarily PET study |
| 11 drug-free sz | ||||||
| 24 nc | ||||||
| Westmoreland et al, 1999 | 36 m-sz | Cranium, grey and white matter, caudate, CSF | Age, gender, socio-economic status | 1.5 T | Smaller caudate. Differences of cranium, grey and white matter and CSF not reported | Corrected for intracranial volume (calculated by adding grey, white matter and CSF) |
| 43 nc | 1.5-mm slices | |||||
| Reference Gur, Turetsky and CowellGur et al, 2000a 1 | 39 m-sz | Hippocampus, amygdala, STG, temporal pole | Parental education | 1.5 T | Smaller hippocampus, STG and temporal pole. Amygdala no difference | |
| 61 prev. treat. sz | 1-mm slices | |||||
| 110 nc | ||||||
| Reference Gur, Cowell and LatshawGur et al, 2000b 1 | 29 m-sz | Prefrontal white and grey matter (orbital and dorsal regions) | Parental education | 1.5 T | Reduced prefrontal grey matter | |
| 41 prev. treat. sz | 1-mm slices | |||||
| 81 nc | ||||||
| Reference Laakso, Tiihonen and SyvalahtiLaakso et al, 2001 | 18 m-sz | Hippocampus | Age, gender, handedness, parental socio-economic status | 1.5 T | No difference in hippocampal volume | |
| 22 nc | 1.5-mm slices | |||||
| Reference Ichimiya, Okubo and SuharaIchimiya et al, 2001 | 20 m-sz | Cranium, cerebrum, cerebellar grey and white, vermis | Age?, handedness | 1.5 T | Reduced cerebellar vermis. Total cerebellum, cranium and cerebrum no difference | |
| 20 nc | 2-mm slices |
METHOD
Subjects
Twenty patients in their first psychotic episode of schizophrenia were recruited from the First-Episode Schizophrenia Research programme at the University Medical Centre Utrecht. Patients had not received antipsychotic treatment prior to scanning. All patients met DSM—IV (American Psychiatric Association, 1994) criteria for schizophrenia (11 paranoid, 8 undifferentiated, 1 disorganised type), on the basis of the Comprehensive Assessment of Symptoms and History (CASH; Reference Andreasen and ArndtAndreasen & Arndt, 1992) rated by two independent raters. Nineteen patients (one patient was lost to follow-up) had the diagnosis confirmed after 1 year. The start of prodromal symptoms and psychotic illness was measured by a shortened version of the Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS; Reference Häfner, Riecher-Rossler and HambrechtHäfner et al, 1992). Severity of illness was measured with the Positive and Negative Symptom Scale (PANSS; Reference Kay, Fiszbein and OplerKay et al, 1987). Twenty healthy comparison subjects were recruited and carefully matched for gender, age, parental education and handedness. They were all screened with the Schedule for Affective Disorders and Schizophrenia — Lifetime Version (SADS—L; Reference Endicott and SpitzerEndicott & Spitzer, 1978) and fulfilled criteria for ‘never mentally ill’. All subjects were physically healthy (except one patient who had congenital hypothyroidism, but was stable on supplementation medication), had neither a history of head injury nor a diagnosis of drug or alcohol misuse or dependence. All patients and healthy comparison subjects provided written informed consent to participate in the study. For demographic and clinical data see Table 2.
Table 2 Demographic and clinical data for antipsychotic-naïve patients with schizophrenia and healthy comparison subjects
| Patients (n=20) | Controls (n=20) | t or χ2 | P | |
|---|---|---|---|---|
| Gender, n | ||||
| Male | 16 | 16 | χ2=0.00 | 1.00 |
| Female | 4 | 4 | ||
| Handedness, n | ||||
| Right | 18 | 18 | χ2=0.00 | 1.00 |
| Left | 2 | 2 | ||
| Age, years (mean (s.d.)) | 27.63 (6.43) | 27.24 (6.30) | t=0.20 | 0.85 |
| Weight, kg (mean (s.d.)) | 75.50 (14.64) | 77.05 (11.68) | t=0.37 | 0.72 |
| Height, cm (mean (s.d.)) | 175.45 (9.43) | 184.68 (7.94) | t=3.30 | 0.002* |
| Parental education level, years (mean (s.d.)) | 12.3 (3.8) | 14.1 (2.7) | t=1.18 | 0.11 |
| Education, years (mean (s.d.)) | 11.6 (3.0) | 12.7 (3.0) | t=1.67 | 0.25 |
| Subtype of schizophrenia according to DSM-IV, n | ||||
| Paranoid | 11 | |||
| Disorganised | 1 | |||
| Undifferentiated | 8 | |||
| Prodromal phase, months (mean (s.d.)) | 48.1 (61.1) | |||
| Psychosis, months (mean (s.d.)) | 17.5 (27.2) | |||
| PANSS positive symptoms (mean (s.d.)) | 21.1 (5.1) | |||
| PANSS negative symptoms (mean (s.d.)) | 21.3 (6.3) | |||
| PANSS psychopathology (mean (s.d.)) | 38.0 (11.1) |
Brain imaging
MRI acquisition
Magnetic resonance images (MRIs) were acquired on a Philips NT scanner operating at 1.5 T. A T1-weighted three-dimensional fast field echo (3D-FFE: echo time (TE)=4.6 ms, repetition time (TR)=30 ms, flip angle=30°, field of view (FOV)=256/80% mm) with 160-180 contiguous coronal 1.2-mm slices, and a T2-weighted dual echo turbo spin-echo (DTSE: TE1=14 ms, TE2=80 ms, TR=6350 ms, flip angle=90°, FOV=256/80% mm) with 120 contiguous coronal 1.6-mm slices of the whole head were used for the quantitative measurements. In addition, a T2-weighted DTSE (TE1=9 ms, TE2=100 ms, TR=2200 ms, flip angle=90°, FOV=250/100% mm) with 17 axial 5-mm slices and 1.2-mm gap of the whole head was acquired for clinical neurodiagnostic evaluation. Processing was carried out on the neuroimaging computer network of the Department of Psychiatry. Before quantitative assessments, 10 images were randomly chosen and cloned for interrater reliability purposes determined by the intraclass correlation coefficient (ICC). All images were coded to ensure blindness for subject identification and diagnosis, scans were entered into Talairach frame (no scaling) (Reference Talairach and TournouxTalairach & Tournoux, 1988) and corrected for inhomogeneities in the magnetic field (Reference Sled, Zijdenbos and EvansSled et al, 1998).
Volume measurements
Intracranial, total brain, cerebral grey and white matter, lateral ventricles and third ventricle and cerebellar volumes were measured automatically by using histogram analysis algorithms and series of mathematical morphological operators to connect all voxels of interest (Schnack et al, Reference Schnack, Hulshoff Pol and Baaré2001a ,Reference Schnack, Hulshoff Pol and Baaré b ). Intracranial volume was segmented on the DTSE scans, with the foramen magnum being used as inferior boundary. Total brain volumes were segmented on the 3D-FEE (T1-weighted) scans and contained grey and white matter tissue only. In lateral ventricle segmentation automatic decision rules bridged connections not detectable and prevented ‘leaking’ into cisterns. The third ventricle was limited by coronal slices, clearly showing the anterior and posterior commissures; the upper boundary was a plane through the plexus choroideus ventriculi tertii in the midsagittal slice perpendicular to this slice. The cerebellum was limited by the tentorium cerebelli and the brain-stem. All images were checked after the measurements and corrected manually if necessary. The inter-rater reliability of the measurements determined by the ICC based on 10 brains was 0.95 and higher. Segmentation of the frontal lobe was performed automatically using the ANIMAL anatomical segmentation algorithm (Reference Collins, Neelin and PetersCollins et al, 1994), which was validated previously for frontal lobe volume measurements (Reference Mandl, Hulshoff Pol and CollinsMandl et al, 1999).
Quantitative measurements of the caudate nucleus, thalamus, hippocampus and parahippocampus were obtained manually, from the 3D-FFE image using Analyze™ (Reference RobbRobb, 1995). The caudate nucleus was anteriorly defined in the first slice in which it was clearly visible. Its medial border was the lateral ventricle. Laterally, it was limited by the internal capsule, excluding the interconnecting grey matter striae between caudate and putamen visible in the internal capsule; posteriorly, by the last slice before the one in which the posterior commissure was clearly visible. Its inferior border was defined: anteriorly by the white matter connecting the rostrus corporis callosi and the capsula externa. Then, from the first slice where the putamen is clearly visible until the slice anterior to the slice in which the anterior commissure crosses the midline, the nucleus accumbens was separated by a line from the most inferior point of the lateral ventricle to the most inferior point of the internal capsule (adapted from Reference Chakos, Lieberman and BilderChakos et al, 1994). The thalamus was anteriorly defined in the first slice in which it was clearly visible, and precisely demarcated in the subsequent slices until the first slice after the coronal slice that included the posterior commissure. Its lateral border was defined by the internal capsule; its medial border by the third ventricle and its inferior boundary was defined by the anterior commissure—posterior commissure plane. Segmentation of the hippocampus was started in the coronal slice in which the mammaillary bodies were visible and stopped when the fornix was visible as a continuous tract (adapted from Reference Watson, Andermann and GloorWatson et al, 1992). Parahippocampal gyrus segmentation began in the coronal slice in which the optic tract is situated above the amygdala. The posterior commissure was its posterior border. Single operators performed the volume measurements of the above-named structures. The ICC for the left and right caudate nucleus was 0.98 and 0.99, for the thalamus, 0.77 and 0.86, for the hippocampus, 0.81 and 0.80 and for the parahippocampal gyrus, 0.77 and 0.75.
Statistical analyses
Repeated-measures analysis of covariance was conducted for total brain, grey and white matter of the cerebrum (total brain, excluding cerebellum and brainstem), frontal lobe, cerebellum, hippocampus, parahippocampus, thalamus, caudate volumes and ventricles, with group (patients, healthy comparison subjects) as the between-subjects variable and, if applicable, side (left, right) and matter (grey, white) as the within-subjects variable. Intracranial brain volume served as covariate for total brain, grey and white matter of the cerebrum, cerebellar, lateral and third ventricle volume measures. Total brain volume served as covariant for frontal lobe, hippocampal, parahippocampal, thalamic and caudate volumes.
To examine associations between significant brain volume differences and clinical variables (prodromal phase, duration of untreated psychosis, PANSS scores) Pearson's correlations were calculated with intracranial volume as a covariate. To assess the power of the study a power analysis, uncorrected for intracranial volume, was carried out with a probability of 0.7 at an α level of 0.05.
RESULTS
As seen in Table 2, patients and healthy comparison subjects did not significantly differ for gender, handedness, age, weight and parental education. Although not matched for education, patients did not differ from healthy comparison subjects on years of education. Patients and healthy comparison subjects did significantly differ in height, but as intracranial volume was used as covariate, the results presented below are uncontrolled for height. However, results did not change when height was used as a covariate.
Mean (s.d.) volumes of total brain, frontal brain, grey matter, white matter, cerebellum, hippocampus, parahippocampus, thalamus, caudate nucleus, lateral ventricles and third ventricle are presented in Table 3 for patients and healthy comparison subjects.
Table 3 Volumes (cm3) of brain regions in antipsychotic-naïve patients with schizophrenia and comparison subjects
| Region | Patients with schizophrenia (n=20) | Comparison subjects (n=20) | Effect size | Observed power |
|---|---|---|---|---|
| Cranium | 1463.25 (130.71) | 1538.87 (164.37) | 0.06 | 0.35 |
| Total brain | 1281.57 (118.70) | 1353.94 (138.96) | 0.08 | 0.41 |
| Grey matter | 669.87 (58.66) | 691.93 (54.92) | 0.04 | 0.22 |
| White matter | 455.19 (66.27) | 499.47 (90.85) | 0.08 | 0.40 |
| Frontal lobe | 280.99 (30.69) | 299.64 (32.39) | 0.08 | 0.45 |
| Cerebellum | 142.78 (14.71) | 148.52 (13.03) | 0.04 | 0.25 |
| Caudate | 9.22 (1.08) | 9.19 (1.24) | 0.00 | 0.05 |
| Thalamus | 14.37 (1.31) | 14.97 (2.09) | 0.03 | 0.18 |
| Hippocampus | 8.01 (0.77) | 8.36 (0.80) | 0.05 | 0.28 |
| Parahippocampus | 4.93 (0.94) | 5.63 (1.14) | 0.11 | 0.55 |
| Lateral ventricles | 13.18 (6.90) | 14.82 (12.21) | 0.01 | 0.08 |
| Third ventricle* | 0.85 (0.32) | 0.62 (0.36) | 0.11 | 0.54 |
Intracranial volume and total brain measures
Intracranial volume (F=2.59, d.f.=1,38, P=0.12), total brain volume (F=0.55, d.f.=1,37, P=0.47) and cerebral volume (F=0.36, d.f.=1,37, P=0.56) did not differ significantly between the two groups, nor was there a significant interaction effect of group with matter (grey, white) of the cerebrum (F=0.21, d.f.=1,38, P=0.65).
Frontal lobe and cerebellum
Frontal lobe volume (F=0.34, d.f.=1,37, P=0.56) and cerebellar volume (F=0.34, d.f.=1,37, P=0.57) did not differ significantly between the two groups.
Hippocampus, parahippocampus, thalamus and caudate nucleus
Hippocampus (F=0.11, d.f.=1,37, P=0.74), parahippocampus (F=2.05, d.f.=1,37, P=0.16), thalamus (F=0.28, d.f.=1,37, P=0.60), and caudate nucleus (F=1.23, d.f.=1,37, P=0.27) did not differ significantly between the two groups.
Ventricles
Lateral ventricle volume (F=0.15, d.f.=1,37, P=0.70) did not significantly differ between the two groups. However, third ventricle volume was significantly larger in patients compared with the comparison subjects (F=8.92, d.f.=1,37, P=0.005) (Fig. 1).
Fig. 1 Third ventricle volume in antipsychotic-naïve patients with first-episode schizophrenia and healthy comparison subjects.—indicates mean third ventricle volume for the patients and controls.
No significant interaction effects of group with matter or with side for any of these measures were found. No correlations were found between third ventricle volume and the clinical data. Excluding the patient with congenital hypothyroidism and her matched comparison subject did not alter the results.
DISCUSSION
This study compared multiple brain structures in a sample of antipsychotic-naïve patients with schizophrenia with those of matched healthy comparison subjects. Volumes of the cranium, total brain, grey and white matter of the cerebrum, frontal lobe, cerebellum, hippocampus, parahippocampus, thalamus, caudate nucleus and lateral and third ventricles were measured. We found third ventricle enlargement in the patients. The other structures were similar in both patients with schizophrenia and healthy comparison subjects.
Third ventricle enlargement in antipsychotic-naïve patients with schizophrenia
To our knowledge, third ventricle volume has not been examined with MRI in patients with schizophrenia who were antipsychotic-naïve. Third ventricle enlargement has been reported in studies of first-episode schizophrenia examining mixed (antipsychotic-naïve and -treated subjects) samples of patients (for review see Reference Fannon, Chitnis and DokuFannon et al, 2000). A possible volume reduction in surrounding diencephalic brain regions could explain the third ventricle enlargement, although in our study this was not expressed in a reduction of thalamic volume. The absence of a reduction in thalamic volume in our study is consistent with the studies performed in anti-psychotic-naïve patients with schizophrenia (Reference Buchsbaum, Someya and TengBuchsbaum et al, 1996; Reference Gur, Maany and MozleyGur et al, 1998b ). Interestingly, third ventricle enlargement but also thalamic volume decrease were found in the healthy siblings of patients with schizophrenia (Staal et al, Reference Staal, Hulshoff Pol and Schnack1998), Reference Staal, Hulshoff Pol and Schnack1999a ; Reference Lawrie, Whalley and KestelmanLawrie et al, 1999; Reference Seidman, Faraone and GoldsteinSeidman et al, 1999), suggesting that these findings could be related to a genetic vulnerability for schizophrenia. The discrepancy of an increase of third ventricle without a corresponding decrease in thalamic volume in this study might be related to the relatively limited number of patients included, or could imply that other regions in the proximity of the third ventricle, such as the hypothalamus, are involved. Abnormalities in the hypothalamic—pituitary—adrenal axis have been suggested to be present in schizophrenia (Reference Tandon, Mazzara, De Quardo and CraigTandon et al, 1991; Reference Jansen, Gispen-de Wied and KahnJansen et al, 2000; Reference Walder, Walker and LewineWalder et al, 2000); however, to date no study has been published measuring the hypothalamus in schizophrenia.
No volume changes in brain tissue
This study found normal total brain and frontal lobe volume in antipsychotic-naïve patients. This finding is inconsistent with the findings by Gur et al Reference Gur, Cowell and Turetsky1998a , Reference Gur, Cowell and Latshaw2000b ), demonstrating total brain and frontal lobe reduction, specifically in prefrontal grey matter, in antipsychotic-naïve patients with schizophrenia. In these studies, however, a mixed sample of antipsychotic-naïve patients and previously treated patients with schizophrenia was examined. Our finding of a normal hippocampus in antipsychotic-naïve patients is congruent with the only other MRI study (Reference Laakso, Tiihonen and SyvalahtiLaakso et al, 2001) designed to examine hippocampal volumes in antipsychotic-naïve patients compared with healthy comparison subjects. Similar caudate nucleus volumes in both antipsychotic-naïve patients and healthy comparison subjects have also been reported in one study (Reference Gur, Maany and MozleyGur et al, 1998b ), but not in others (Reference Keshavan, Rosenberg and SweeneyKeshavan et al, 1998a ; Reference Shihabuddin, Buchsbaum and HazlettShihabuddin et al, 1998; Reference Corson, Nopoulos and AndreasenCorson et al, 1999). The latter studies found reduced volumes in patients. Differences in the various samples, such as diagnosis and handedness, as well as variations in quantitative assessment techniques might explain these inconsistencies.
Relative paucity of brain abnormalities
The relative paucity of brain abnormalities found in this study may actually be the most striking finding. It stands in marked contrast with findings in patients with more chronic schizophrenia, where volume reductions in total brain and medial temporal lobe structures as well as volume enlargement of lateral ventricles have been reported consistently (for review see Reference Wright, Rabe-Hesketh and BullmoreWright et al, 2000). However, the most likely reason for this relative paucity of brain abnormalities is a lack of power, as only 20 patients and 20 healthy comparison subjects were included in this study. Several other explanations, besides the lack of power, can be suggested to explain this discrepancy. First, progression of the illness could lead to an increase of brain abnormalities. A limited number of longitudinal studies in patients with first-episode schizophrenia have been conducted suggesting that brain abnormalities may indeed become more prominent over time (Reference DeLisi, Sakuma and TewDeLisi et al, 1997; Reference Gur, Cowell and TuretskyGur et al, 1998a ) at least in a subgroup of patients with poor outcome (Reference Lieberman, Chakos and WuLieberman et al, 2001). Second, medication might increase brain abnormalities and could contribute to these brain volume changes as suggested by Gur et al (Reference Gur, Cowell and Turetsky1998a ) and Madsen et al (Reference Madsen, Keidling and Karle1998). Third, finding few brain abnormalities in antipsychoticnaïve patients could be the result of a selection bias favouring the inclusion of patients who have a less severe form of schizophrenia. Two characteristics of our sample, high education and a later age of onset, suggest it might indeed not be representative of all patients with first-episode schizophrenia. In our study no difference between patients and healthy comparison subjects on years of education existed. A total of 9 patients of 20 had even completed part or all of university training. In addition, their mean age at onset was at about 27 years. Interestingly, high education and a later age of onset are both related to good outcome (Reference Johnstone, Owens and BydderJohnstone et al, 1989; Weiselgren & Lindstrom, 1996), which in turn appears to be associated with a relative lack of brain abnormalities at presentation of illness (Reference Staal, Abel and Hulshoff PolStaal et al, 1999b ). It has also been suggested that grey matter volume is related to IQ (Reference Andreasen, Flaum and SwayzeAndreasen et al, 1993). Therefore, in this study a level of education (and presumably premorbid IQ) similar in patients to that of the healthy comparison subjects could have resulted in finding no decrements in (regional) grey matter volume. Thus, although the relative paucity of brain volume abnormalities in our sample could be indicative of progressive brain changes in schizophrenia because of illness and/or medication, alternatively it could have been the result of a selection bias that may be hard to avoid when studying antipsychotic-naïve patients with schizophrenia.
Future studies
Although it may be practically impossible to determine whether brain abnormalities in schizophrenia result from the progression of the illness and/or medication, the suggestion of medication having an effect on brain volume changes should be an incentive for future longitudinal studies to carefully monitor medication intake.
CLINICAL IMPLICATIONS
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▪ Third ventricle enlargement in antipsychotic-naive first-episode patients with schizophrenia suggests abnormalities in schizophrenia in the diencephalic region of the brain at the onset of the disease.
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▪ Antipsychotic medication might be partly implicated for brain abnormalities found in schizophrenia.
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▪ The relative paucity of brain abnormalities in patients with first-episode schizophrenia suggests that an underlying neurodegenerative process cannot be excluded.
LIMITATIONS
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▪ The study group was relatively small as a result of the inclusion requirements such as no prior antipsychotic use and no illict drug or alcohol misuse/dependence, which is highly prevalent in first-episode schizophrenia.
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▪ Although previous education in patients suggested a high (premorbid) IQ, no formal IQ testing was performed.
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▪ Patients were carefully matched to the healthy comparison subjects but they did significantly differ in height. However, when height was used as a covariate results did not change.
eLetters
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