Earlier puberty as a predictor of later onset of schizophrenia in women.

OBJECTIVE: The aim of this study was to determine whether puberty plays a mediating role in onset of schizophrenia. The hypothesis was that there is an inverse relation between age at puberty (menarche) and age at onset in women. METHOD: Competent and consenting individuals with DSM-IV-defined schizophrenia or schizoaffective disorder and their mothers underwent a 45-minute interview to ascertain age at first odd behavior, age at first psychotic symptoms, age at first hospitalization, and ages at various indices of puberty. Information about substance use, head injury, perinatal trauma, and first-degree family history of schizophrenia was also obtained. RESULTS: In the women (N = 35), the earlier the age at menarche, the later the ages at both the first psychotic symptoms and the first hospitalization. There was no significant association between puberty and onset in the men (N = 45). Other than gender, none of the examined variables played a role in the interaction of puberty and onset of illness. CONCLUSIONS: In women, early puberty (whether through hormonal or social influence) was associated with later onset of schizophrenia. This effect was not found in men; in fact, the trend was in the opposite direction.     

MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals

The thalamus is a key structure in brain anatomic circuits potentially involved in the pathophysiology of mood disorders. Available findings from studies that examined this brain region in mood disorder patients have been conflicting. To examine the hypothesis of anatomical abnormalities in the thalamus in patients with mood disorders, we conducted a magnetic resonance imaging (MRI) study in 25 bipolar patients (mean age±S.D.=34.4±9.8 years), 17 unipolar patients (mean age±S.D.=42.8±9.2 years), and 39 healthy control subjects (mean age±S.D.=36.6±9.7 years). Thalamic volumes Gray Matter were measured blindly with a semi-automated technique. Multivariate analysis of variance, with age and gender as covariates, revealed no significant differences in left or right thalamic volumes among bipolar patients, unipolar patients and healthy individuals. There were no significant effects of gender, age at illness onset, episode type, number of episodes, length of illness, or family history of mood disorders on thalamic measurements. Although functional abnormalities in the thalamus are likely to be implicated in the pathophysiology of mood disorders, no abnormalities in thalamic size appear present in bipolar or unipolar individuals.     

Oxidative mechanisms in schizophrenia and their relationship with illness subtype and symptom profile

Aim:  The aim of the present study was to investigate the differences in the antioxidant–oxidant balance (AO-OB) between schizophrenic patients and healthy individuals and to explore the relationship of AO-OB with illness subtypes and symptom profiles.
Methods:  After a 15-day drug-free period, schizophrenia patients ( n  = 50) in a clinical sample, and age- and sex-matched healthy subjects ( n  = 49) were enrolled. Total antioxidant potentials (TAOP) and total peroxide levels (TPEROX) of all participants were measured and the oxidative stress index (OSI) was calculated. The assessment included structured measurements, including the Positive and Negative Syndrome Scale (PANSS), and the Brief Psychiatric Rating Scale (BPRS).
Results:  TAOP had a significant positive correlation with age at onset of schizophrenia ( P  = 0.013), a negative correlation with the PANSS negative subscale scores ( P  = 0.008), a negative correlation with the PANSS total scores ( P  < 0.001), and a significant negative correlation with BPRS scores ( P  = 0.001). OSI had a significant negative correlation with age at onset ( P  = 0.046) and a significant positive correlation with PANSS negative subscale ( P  = 0.015). A multiple regression model indicated a significant linear combination of age, gender, duration of illness, subtype of schizophrenia, and PANSS scores, in which only the subtype of schizophrenia made a statistically significant contribution to predicting mean OSI ( F [5,35] = 2.44, P  = 0.04).
Conclusion:  Several parameters in the pathogenesis of schizophrenia, such as age of onset, level of negative symptoms, and subtype of illness, but not the presence of the illness itself, are associated with the level of oxidative stress.     

Age of menarche and schizophrenia onset in women

OBJECTIVE: The "estrogen hypothesis" posits that this hormone serves as a protective factor in the development of schizophrenia. If true, then it is expected that the earlier the age of menarche, the later the onset of schizophrenia (as has been reported by some investigators). This study attempts to replicate this relationship in a sample of women with schizophrenia and schizoaffective disorder. METHOD: Self-report menarche age, clinical status, and onset of disorder were collected in a sample of 68 women (55 diagnosed with schizophrenia and 13 with schizoaffective disorder). RESULTS: Menarche age and schizophrenia onset were not negatively correlated as would be predicted by the estrogen hypothesis. Two clinical measures, however, did correlate with age of menarche as predicted. Higher negative symptom scores (total SANS) and greater functional impairment (lower GAF) were reported in subjects who reported a later age at menarche. CONCLUSION: This study suggests that an earlier age at menarche might predict improved clinical outcome after schizophrenia onset (in support of the estrogen hypothesis). Our data, however, do not support Cohen et al.'s findings regarding the relationship between age at menarche, and the timing of the onset of the disorder. Further investigations regarding the relationship between estrogen and schizophrenia development in women are needed. It is suggested that other developmental factors, both biological and psychosocial, might play a crucial role in both the age at onset and the outcome of the disorder in women.     

Minor physical anomalies in patients with schizophrenia and their parents: prevalence and pattern of craniofacial abnormalities

The frequency of minor physical anomalies (MPAs) in patients with schizophrenia suggests an early disturbance in the development of the neuroectoderm. To improve the phenotypic delimitation of this disorder, we used a comprehensive scale of MPAs (41 items) in patients with schizophrenia and their first-degree relatives. This scale, adapted from a revised version of the Waldrop Scale (Ismail et al. Minor physical anomalies in schizophrenic patients and their siblings, American Journal of Psychiatry 155, 1998a, 1695-1702), introduced new items assessing facial and limbs asymmetry. The interrater reliability between two examiners was good: intraclass correlation coefficient: 0.68 (0.42-0.92). Patients with schizophrenia (n=40; mean=5.8, S.D.=4) and their non-psychotic parents (n=45; mean=4.7, S.D.=2.8) had significantly more MPAs than healthy comparison subjects (n=42; mean=2.2, S.D.=1.2). A logistical regression model showed the ability of several items to predict group status, including facial asymmetry, cleft palate, hair whorls and abnormal palmar crease. The high prevalence of facial asymmetry in patients with schizophrenia and their first-degree relatives provides new insights into the underlying dysembryogenic processes. This revised scale thus appears to be a useful complementary tool in pathophysiological studies aiming at the identification of developmental factors in schizophrenia.     

MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals.

The thalamus is a key structure in brain anatomic circuits potentially involved in the pathophysiology of mood disorders. Available findings from studies that examined this brain region in mood disorder patients have been conflicting. To examine the hypothesis of anatomical abnormalities in the thalamus in patients with mood disorders, we conducted a magnetic resonance imaging (MRI) study in 25 bipolar patients (mean age+/-S.D.=34.4+/-9.8 years), 17 unipolar patients (mean age+/-S.D.=42.8+/-9.2 years), and 39 healthy control subjects (mean age+/-S.D.=36.6+/-9.7 years). Thalamic volumes Gray Matter were measured blindly with a semi-automated technique. Multivariate analysis of variance, with age and gender as covariates, revealed no significant differences in left or right thalamic volumes among bipolar patients, unipolar patients and healthy individuals. There were no significant effects of gender, age at illness onset, episode type, number of episodes, length of illness, or family history of mood disorders on thalamic measurements. Although functional abnormalities in the thalamus are likely to be implicated in the pathophysiology of mood disorders, no abnormalities in thalamic size appear present in bipolar or unipolar individuals.     

Menopause and menarche in patients with primary blepharospasm: an exploratory case-control study

We studied the relationships between blepharospasm (BSP) and menopause/menarche in female patients with primary BSP (n = 83) and age-matched healthy (n = 83) and disease controls (n = 83). BSP patients and matched controls had comparable age at menopause, and there was no correlation between age at menopause and age at BSP onset. Thus, menopause probably exerts no significant influence on the age-dependent development of BSP. BSP cases tended to have a later menarche than either group of controls. The association was independent of age, disease duration and education level. Because the higher the age at menarche, the higher the age at BSP onset, later menarche was unlikely to be a risk factor for BSP. Rather, the two conditions may share pathophysiologic mechanisms, for example minor abnormality of neurotransmitter systems controlling both the motor system and the maturation of the hypothalamic-pituitary-gonadal axis responsible for the onset of puberty.     

Evaluation of growth in anorexia nervosa from serial measurements

Measured longitudinal growth data in a sample of 66 patients with anorexia nervosa (AN) (58 females and 8 males) is compared to expected growth from normative standards. The data was subject to cross-sectional as well as longitudinal analysis. Females had a normal growth rate and pattern, in particular a normal sequence and timing of pubertal events. Distribution of weight for age indicated a slight (non-significant) overweight before onset of anorexia nervosa. Weight by height was significantly above the expected before onset of AN. Mean age at Peak Height Velocity (PHV) was 11.5 yr. Mean size of PHV 8.03 cm/yr. A subsample of females (those with onset of AN after menarche) had a mean age of menarche of 12.88 yr. Mean distance in time from age at PHV to age at menarche was 1.34 yr. These results are normal for Scandinavian girls. Male anorexics were tall for age, heavy for age and, where a PHV could be seen (5 out of 8 cases), had signs of early puberty. Mean age at PHV was 11.8 yr, a highly significant difference from the normal mean age at PHV which is 14.06 yr for Scandinavian boys. Weight by height was distributed as in the reference population, that is, with no indication of pre-morbid obesity for male probands.     

S100B and schizophrenia

The research for peripheral biological markers of schizophrenia, although abundant, has been unfruitful. In the last 2 decades, the S100B protein has made its own room in this area of research. S100B is a calcium‐binding protein that has been proposed as a marker of astrocyte activation and brain dysfunction. Research results on S100B concentrations and schizophrenia clinical diagnosis are very consistent; patients with schizophrenia have higher S100B concentrations than healthy controls. The results regarding schizophrenia subtypes and clinical characteristics are not as conclusive. Age of patients, body mass index, illness duration and age at onset have been found to show no correlation, a positive correlation or a negative correlation with S100B levels. With respect to psychopathology, S100B data are inconclusive. Positive, negative and absence of correlation between S100B concentrations and positive and negative psychopathology have been reported. Methodological biases, such as day/night and seasonal variations, the use of anticoagulants to treat biological samples, the type of analytical technique to measure S100B and the different psychopathological scales to measure schizophrenia symptoms, are some of the factors that should be taken into account when researching into this area in order to reduce the variability of the reported results. The clinical implications of S100B changes in schizophrenia remain to be elucidated.     

Normal pituitary volumes in chronic schizophrenia

Pituitary volumes were shown to be abnormally large in pre- or first-psychotic episode patients and abnormally reduced in established schizophrenia by magnetic resonance imaging (MRI) studies. We present here the results of the second ever published MRI study exploring pituitary size in a large population of patients with chronic schizophrenia recruited from the geographically defined catchment area of South Verona, Italy. No significant differences for pituitary volumes were reported between 65 subjects with chronic schizophrenia and 65 normal individuals (mean age+/-S.D.=42.31+/-11.44 and 40.54+/-11.12 years). In contrast to Pariante et al. (2004), normal pituitary size was found in our population of chronic schizophrenia. Discrepancies between these two studies may partially be accounted by sample age and gender. Considering increased pituitary volumes in pre- or first-psychotic episode patients, we put forward the hypothesis that pituitary size may normalize or reduce with the progression of the illness as a result of reduced numbers of acute episodes and consequent diminished hypothalamus-pituitary-adrenal axis activity. To better test this hypothesis, future large MRI studies should investigate pituitary volumes in chronic schizophrenia longitudinally, also collecting pituitary hormones and cortisol, and comparing the effects of typical and atypical antipsychotics on pituitary size in a randomized trial.     

The measurement of puberty: a review

This paper has two main objectives. Firstly, to review the feasibility and validity of the various methods that have been used to measure puberty. With an appreciation of these measurement issues, the second objective is to summarize the evidence-base as to whether the age at menarche and the age at onset of puberty has decreased in recent years. In consideration of these methodologies, all of which report different levels of reliability and validity, it is only possible at present to draw inferences about possible changes in pubertal age and onset. Moreover, the wide variations in sample size, selection of participants (usually non-random), and study design reported in the reviewed studies have compounded this situation further. The paper closes by providing a summary of the findings which will be of relevance to those intending to critically review the current evidence surrounding age of puberty, as well as those set on carrying out future research into this area.     

MRI study of posterior fossa structures and brain ventricles in bipolar patients

Previous brain imaging studies have suggested anatomical abnormalities in posterior fossa structures and brain ventricles in bipolar patients. Such abnormalities could possibly be implicated in the pathophysiology of bipolar disorder. Twenty-two DSM-IV bipolar outpatients (mean age±S.D.=36±10 years) and 22 healthy controls (mean age±S.D.=38±10 years) underwent an 1.5T MRI (3D-gradient echo-imaging SPGR), performed in the coronal plane (TR=25 ms, TE=5 ms, slice THICKNESS=1.5 mm). The brain structures of interest were traced blindly with a semi-automated software. No significant differences were found between bipolar patients and healthy controls for any posterior fossa measures, or for measures of third or lateral ventricles (MANOVA, age covariate, P>0.05). Age was directly correlated with 3rd ventricle volumes in bipolar patients (Pearson correlation COEFFICIENT=0.458, P=0.032), but not in healthy controls (Pearson correlation COEFFICIENT=0.313, P=0.155). There was a significant direct correlation between the number of prior illness episodes and right lateral ventricle volumes (Partial correlation COEFFICIENT=0.658, P=0.011). Familial patients had smaller left and right cerebellar hemispheres and total vermis volumes, and larger left lateral ventricle volumes compared with non-familial ones (MANOVA, age covariate, P<0.05). In this preliminary study, we were not able to replicate previous findings of abnormalities in cerebellum or brain ventricles in bipolar individuals. However, there were suggestions that abnormalities in cerebellum, vermis, and lateral ventricle sizes may be present in familial cases of the disorder, which should be further examined in future studies with larger patient samples.     

The epidemiology of onset and course of schizophrenia

Traditionally the heterogeneity of schizophrenia was dealt with by subdividing the syndrome into different subtypes. However, due to lacking standards, the result was an immense variety of subtypes partly based on cross-sectional assessments, partly taken the whole course between onset, resp. first admission and outcome after many years into account. Some solutions were based on symptomatology only, other also relied on social characteristics as the ability to fulfil different roles in family and the world of employment. So it is not surprising that the number of subtypes ranges from two up to more than 70. As one possible solution Carpenter and Kirkpatrick (1988) suggest that attempts to subdivide the schizophrenic syndrome should concentrate on few significant parts of the course thought of to represent specific disease processes. Based on two epidemiological studies finding about the onset, middle course and late course of schizophrenia are presented. In three quarter of the cases the onset of the first psychotic episode in schizophrenia is preceded by a prodromal phase with a mean length of about five years. The earliest signs of the disorder are depressive and negative symptoms. Early depressive symptoms predict higher overall symptom scores in the first illness episode and lower scores for affective flattening in the medium-term course. There is no decrease in the number of patients with acute symptomatology over fifteen years after first hospital admission, rather there is a tendency of an increase. With respect to social abilities we found a significant increase of disability over time. But the change already takes place during the first five years. Approx. 60% of those falling ill with schizophrenia become chronic and approx. 25% will recover during the first five to six years. Received: 10 April 2000 / Accepted: 25 April 2000     

Subgenual prefrontal cortex of child and adolescent bipolar patients: a morphometric magnetic resonance imaging study

The subgenual prefrontal cortex (SGPFC) plays an important role in emotional processing. We carried out a magnetic resonance imaging (MRI) study comparing the volume of the SGPFC in child and adolescent bipolar patients and healthy controls. The sample consisted of 15 children and adolescents who met DSM-IV criteria for bipolar disorder (mean age +/- S.D.=15.5 +/- 3.5 years) and 21 healthy adolescents (mean age +/- S.D.=16.9 +/- 3.8 years). MR images were obtained with a 1.5 T GE Signa Imaging System with Signa 5.4.3 software. SGPFC volumes were measured with the semi-automated software MedX (Sensor Systems, Sterling, VA, USA). ANCOVA was performed to compare SGPFC volumes between groups, using age, gender and intra-cranial volume (ICV) as covariates. The volumes (mean +/- S.D.) of the right and left SGPFC for bipolar patients were 291.27 +/- 88.70 mm(3) and 284.86 +/- 83.98 mm(3), respectively. For healthy controls, the right and left SGPFC volumes were 284.95 +/- 73.33 mm(3) and 307.55 +/- 73.67 mm(3), respectively. There were no statistically significant differences between groups regarding right or left SGPFC volumes. We found no evidence of volumetric abnormalities in the SGPFC of bipolar children and adolescents.     

Does family history of schizophrenia influence age at onset of schizophrenia?

The relation between age at onset of schizophrenia diagnosed using DSM-III criteria and the presence or absence of this illness among first-degree relatives was investigated in 2417 patients. The mean age at onset among those with a family history of schizophrenia was slightly and nonsignificantly earlier than that of schizophrenic patients without a positive family history. The former developed their illness before the age of 25 years more frequently than did the latter.     

Precipitation and determination of the onset and course of schizophrenia by substance abuse--a retrospective and prospective study of 232 population-based first illness episodes

Onset and lifetime prevalence of substance abuse were assessed retrospectively using the IRAOS interview in a population-based, controlled sample of 232 first episodes of schizophrenia (ABC sample). Subjects with schizophrenia were twice as likely as controls to have a lifetime history of substance abuse at the age of first admission (alcohol abuse: 23.7 versus 12.3%; drug abuse: 14.2 versus 7.0%). 88% of the patients with drug abuse took cannabis. The sequence of substance abuse and schizophrenia was studied on the timing of abuse onset and illness onset, the latter as based on various definitions: first sign of the disorder, first psychotic symptom and first admission. 62% of the patients with drug abuse and 51% of those with alcohol abuse began the habit before illness onset (=first sign of the disorder). Abuse onset and illness onset occurred highly significantly within the same month (drug abuse in 34.6%, alcohol abuse in 18.2%). Unexpectedly, no temporal correlation was found between abuse onset and the onset of the first psychotic episode. We concluded that a small proportion of schizophrenias might have been precipitated by substance--mainly cannabis--abuse. Long-term effects of early substance abuse were studied prospectively at six cross-sections over five years from first admission on in a subsample of 115 first episodes of schizophrenia. Abusers showed significantly more positive symptoms and a decrease in affective flattening compared with controls. Five-year outcome as based on treatment compliance, utilization of rehabilitative measures and rate of employment was also poorer for patients with than without early substance abuse.     

Pubertal timing,sexual behaviour and self-reported depression in middle adolescence

The associations between pubertal timing, sexual activity and self-reported depression were analysed in a population sample of 17,082 girls and 15,922 boys aged 14-16 as a par of a classroom survey. Pubertal timing was assessed by age at onset of menstruation (menarche) or ejaculations (oigarche). Sexual experiences elicited included kissing, light petting, heavy petting and intercourse. Self-reported depression was measured by the 13-item Beck Depression Inventory. Among girls, self-reported depression was associated with early puberty and intimate sexual relationship. Among boys depression was associated with very early and late puberty and experience of intercourse. Early puberty is a risk factor for self-reported depression. Intimate sexual relationships in middle adolescent are likely to indicate problems in adolescent development rather than successful adolescent passage.     

The roots of depression in adolescent girls: is menarche the key?

Before adolescence, the rates of depression are similar in girls and boys (or are slightly higher in boys). Yet with the onset of puberty, the gender proportion of depression dramatically shifts to a two girls to one boy ratio. What, then, is the relationship between menarche and the onset of major depression in early adolescence? Recent literature intimates that vulnerability to depression may be rooted in an intricate meld of genetic traits, normal female hormonal maturational processes, and gender socialization. Information regarding gender differences in the presentation of depressive symptoms is provided along with biologic, psychologic, and sociologic factors contributing to depression in adolescent girls. The burden of illness associated with onset of depression after menarche reinforces the importance of prevention or else expeditious recognition and intervention.     

Routine outcome monitoring in clinical practice: service and non-service costs of psychiatric patients attending a Community Mental Health Centre in Italy

OBJECTIVE: This study estimated service and non-service costs in a random sample of patients attending a community psychiatric mental health centre in Italy. METHODS: A randomly selected sample of patients identified during 1 week of routine clinical activity was enrolled. Information was collected using the Italian-language checklist Questionario Economico per l'attivita clinica dei Servizi Psichiatrici (QESP). Costs were classified in two categories: service costs (from the provision of services) and non-service costs (loss of productivity and informal care). RESULTS: One hundred and twenty patients were included. Patients suffering from schizophrenia and related disorders (n = 50) had a mean age of 44.5 years (S.D. 12.9), and patients with other diagnoses (n = 70) had a mean age of 44.9 years (S.D. 14.8). More patients in the schizophrenia group were single, living alone, had a low educational level and a higher unemployment rate. In patients suffering from schizophrenia, the monthly service cost per patient was nearly double that for patients with other diagnoses. Non-service costs associated with patients' lack of job opportunities were more than three times higher for patients with schizophrenia. Non-service costs associated with patients' and care-givers' time off work were similar in the two groups. In the multivariate analysis, being unemployed was associated with higher service costs. Younger age, length of illness and diagnosis of schizophrenia were determinants of higher non-service costs. The latter three independent variables were also associated with overall (service and non-service) costs. CONCLUSION: The present study estimated service and non-service costs under routine circumstances to provide information on costs that community psychiatric services, patients and care-givers sustain when dealing with psychiatric problems.     

Longitudinal assessment of premorbid cognitive functioning in patients with schizophrenia through examination of standardized scholastic test performance

OBJECTIVE: Studies suggest the presence of premorbid cognitive impairment in patients with schizophrenia, yet the onset and course of these deficits remain unclear. The purpose of this study was to investigate the longitudinal course of premorbid cognitive functioning in individuals with schizophrenia by using prospective data obtained from scholastic test results. METHOD: Scores from grades 4, 8, and 11 on the Iowa Tests of Basic Skills and the Iowa Tests of Educational Development were obtained for 70 subjects who later developed schizophrenia. The mean percentile rank of the subjects' scores in the areas of vocabulary, reading comprehension, language, mathematics, sources of information, and an overall composite category were compared with state norms. RESULTS: The subjects scored below the 50th percentile for each category in all three grades, but only language, reading, sources of information, and composite scores from grade 11 were significantly below state norms. With regard to longitudinal course, there was a significant linear decrease in language scores over time. Scores from grade 11 were positively correlated with WAIS-R IQ, verbal fluency, and Rey Auditory Verbal Learning scores at first illness episode. Scores from grade 11 were not significantly correlated with age at illness onset or ratings of disorganized, psychotic, or negative symptoms. CONCLUSIONS: Scholastic test scores at grades 4 and 8 were nonsignificantly below average in this group of children who later developed schizophrenia. However, test scores dropped significantly between grades 8 and 11. This corresponds to ages 13-16 years, or the onset of puberty. Poor or declining scholastic performance may be a precursor to the cognitive impairment seen during the first episode of illness.