Twenty-two ARMS subjects were recruited from the Consultation Support Service in Toyama (CAST), which was launched in 2006 as a specialized clinical setting to study and treat young people (aged 15–30 years) at risk for developing psychosis. The ARMS subjects, who had no previous episode of overt psychosis and no clear diagnosis of major depression or borderline personality disorder, were diagnosed according to the Comprehensive Assessment of At Risk Mental States (CAARMS); inclusion into the study required one or more of (i) attenuated psychotic symptoms defined by subthreshold intensity or frequency (n = 21); (ii) brief limited intermittent psychotic symptoms with spontaneous resolution (n = 2); and/or (iii) family history of psychosis or a personal history of schizotypal personality disorder accompanied by a decline in general functioning (n = 1). At intake, they were also assessed using the Beck Depression Inventory (BDI) and State Trait Anxiety Inventory (STAI) (Table 1).[23, 24] Eighteen ARMS subjects were antipsychotic naïve at the time of scanning, but three subjects were receiving low doses of atypical antipsychotics (risperidone, blonanserin, or aripiprazole) and one was treated with sulpiride. They were also receiving benzodiazepines (n = 3), antidepressants (n = 1), and/or tandospirone (n = 3). The mental condition of each subject was regularly assessed by experienced psychiatrists to check for the emergence of full-blown psychosis at outpatient clinics of the Department of Neuropsychiatry of Toyama University Hospital; five (22.7%) of the ARMS subjects in this group developed schizophrenia fulfilling ICD-10 research criteria and 17 (77.3%) did not develop psychosis during follow up (mean clinical follow-up period after scanning, 15.6 ± 17.4 months).
Table 1. ARMS and FESz subject data vs matched controls (mean ± SD)
|Parameters||ARMS (11 M, 11 F)||Controls (11 M, 11 F)||Group comparisons|
|Age (years)||19.1 ± 4.1||19.4 ± 4.2||F(1,42) = 0.05, P = 0.830|
|Height (cm)||162.2 ± 9.5||164.3 ± 8.5||F(1,42) = 0.62, P = 0.436|
|Education (years)||11.1 ± 1.6||13.1 ± 2.6||F(1,42) = 8.99, P = 0.005|
|Parental education (years)||13.8 ± 1.7||12.4 ± 1.6||F(1,42) = 7.68, P = 0.008|
|Medication dose (HPD equiv., mg/day)†||2.2 ± 3.1 (n = 4)||–||–|
|Duration of medication (months)||2.3 ± 4.1 (n = 4)||–||–|
|Time between intake and scan (days)||50.8 ± 74.4||–||–|
|Time between scan and onset (months)||8.2 ± 9.9 (n = 5)||–||–|
|STAI trait at intake‡||65.3 ± 10.9||–||–|
|STAI state at intake‡||58.4 ± 11.3||–||–|
|BDI at intake‡||24.1 ± 10.0||–||–|
|SAPS total at scanning||20.4 ± 10.9||–||–|
|SANS total at scanning ||48.5 ± 19.4||–||–|
| ||FESz (37 M, 27 F)||Controls (37 M, 27 F)||Group comparisons|
|Age (years)||24.0 ± 4.7||25.1 ± 5.0||F(1,126) = 1.64, P = 0.203|
|Height (cm)||164.9 ± 7.6||167.0 ± 7.5||F(1,126) = 2.60, P = 0.109|
|Education (years)||13.5 ± 1.9||16.5 ± 2.6||F(1,126) = 57.55, P < 0.001|
|Parental education (years)||13.0 ± 2.0||13.2 ± 2.5||F(1,124) = 0.50, P = 0.482|
|Onset age (years)||23.1 ± 4.7||–||–|
|Illness duration (months)||11.2 ± 12.2||–||–|
|Medication dose (HPD equiv., mg/day)||10.3 ± 8.8||–||–|
|Duration of medication (months)||8.3 ± 12.6||–||–|
|SAPS total at scanning||27.3 ± 21.9||–||–|
|SANS total at scanning||53.1 ± 25.2||–||–|
Sixty-four FESz patients who fulfilled the ICD-10 research criteria, with illness duration ≤1 year (n = 48) or under first psychiatric hospitalization (n = 16) at the time of scanning,[26-29] were recruited from inpatient and outpatient clinics of the Department of Neuropsychiatry of Toyama University Hospital (Table 1). The diagnosis of schizophrenia was confirmed for all patients at least 6 months after illness onset based on information obtained from a detailed chart review as well as their clinical symptoms rated at the time of scanning. They were also screened for other neuropsychiatric conditions (e.g. depressive/manic symptoms) by experienced psychiatrists. All but two of the patients were on antipsychotic medication; 18 were treated with typical antipsychotics, 43 were receiving atypical antipsychotics and one received both typical and atypical antipsychotics.
The control subjects consisted of 86 healthy volunteers recruited from the community, hospital staff, and university students. Given the sexual dimorphism (male < female) and age-related atrophy of the pituitary gland,[30-32] the control subjects comprised two groups that were age- and gender-matched for ARMS (n = 22) and for FESz (n = 64), respectively (Table 1). Although the controls did not receive a full diagnostic interview, they were given a questionnaire consisting of 15 items concerning their personal (13 items; e.g. a history of obstetric complications, substantial head injury, seizures, neurological or psychiatric diseases, impaired thyroid function, hypertension, diabetes, and substance use) and family (two items) histories of illness. They did not have any personal or family history of psychiatric illness among their first-degree relatives.
All subjects in this study (ARMS, FESz, and controls) were screened using the same exclusion criteria (except family history of psychiatric illness, which was applied only to controls). They were right-handed and physically healthy at the time of the study, and none had a history of serious head trauma, severe obstetric complications, neurological illness, substance abuse disorder, or serious medical disease (e.g. impaired thyroid function, hypertension, and diabetes). The FESz and ARMS participants were screened for these conditions using a detailed chart review at scanning (FESz) or direct interview at study intake (ARMS). None of the participants was pregnant or taking exogenous estrogens at the time of the study, but hormone levels as well as menstrual cycle in female subjects were not assessed in this study. All participants were also screened for gross brain abnormalities by neuroradiologists.
The clinical symptoms of the ARMS and FESz subjects were rated at the time of scanning using the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms (SANS/SAPS). Of the 172 participants in this study, 60 controls (35 male) and 37 schizophrenia patients (21 male) were also included in our previous pituitary study. This study was approved by the Committee on Medical Ethics of Toyama University. After a complete description of the study was provided, written informed consent was obtained from all subjects.
Magnetic resonance imaging procedures
The subjects were scanned on a 1.5-T Magnetom Vision (Siemens Medical System, Erlangen, Germany) with a 3-D gradient-echo sequence fast low-angle shots (FLASH) yielding 160–180 contiguous T1-weighted slices of 1.0-mm thickness in the sagittal plane. The imaging parameters were as follows: repetition time, 24 ms; echo time, 5 ms; flip angle, 40°; field of view, 256 mm; and matrix size, 256 × 256 pixels. The voxel size was 1.0 × 1.0 × 1.0 mm. The scanner was calibrated weekly with the same phantom to ensure measurement stability.
To assess the pituitary volume, the images were processed on a Linux PC (Fujitsu, Tokyo, Japan) using Dr. View software (AJS, Tokyo, Japan). Brain images were realigned in three dimensions to standardize for differences in head tilt during image acquisition and were then reconstructed into entire contiguous coronal images of 1-mm thickness perpendicular to the anterior commissure–posterior commissure line. The signal intensity histogram distributions from the T1-weighted images across the whole cerebrum were then used to semi-automatically segment the voxels into brain tissue components and cerebrospinal fluid. The intracranial volume (ICV) was measured to correct for differences in head size as described previously; there were no significant group differences for ICV (ARMS vs their controls, F(1,41) = 0.88, P = 0.353; FES vs their controls, F(1,125) < 0.01, P = 0.984; and FES vs ARMS vs all controls, F(2,168) = 0.43, P = 0.654; Table 2).
Table 2. Intracranial and pituitary volume (mean ± SD)
|Variables||ARMS (11 M, 11 F)||Controls for ARMS (11 M, 11 F)||FESz (37 M, 27 F)||Controls for FESz (37 M, 27 F)|
|Intracranial volume (cm3)||1460 ± 132||1500 ± 146||1500 ± 147||1502 ± 150|
|Pituitary volume (mm3)||763 ± 124a||697 ± 143||802 ± 153a||708 ± 140|
The pituitary gland volume was manually traced on consecutive 1-mm coronal slices based on a method used by Garner et al. Briefly, we traced around the usually well-defined borders of the anterior and posterior pituitary: the diaphragma sellae, superiorly; the sphenoid sinus, inferiorly; and the cavernous sinuses, bilaterally. As presented in Figure 1, the pituitary stalk was excluded from the tracings, but we included a posterior bright spot, corresponding to the posterior pituitary (the intensity of which is thought to reflect the vasopressin concentration). All measurements were carried out by a trained rater (TT) without knowledge of the subjects' identities or the times of their scans. To determine the reliability of the measurement, a second rater (VL) measured the pituitary volume in a subset of 10 randomly selected brains. Each pituitary volume in these 10 brains was then remeasured after at least 4 weeks by the first rater. Inter- (TT and VL) and intra-rater intraclass correlation coefficients were >0.93.
Figure 1. (a) Sagittal and (b) coronal views of the pituitary gland manually traced in this study. The pituitary stalk was excluded from the tracings, but a posterior bright spot was included.
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