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

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.

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.

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.