Premorbid adjustment in schizophrenia--an important aspect of phenotype definition

Schizophrenia is a heterogeneous disorder, and early signs of disorder such as poor premorbid adjustment (PMA) are often present before the onset of diagnosable illness. Differences in PMA between patients may be suggestive of differing aetiological pathways. Poor PMA in schizophrenia has repeatedly been reported to be associated with male sex, earlier age at onset, illness severity, negative symptoms, and poor outcome. Studies of schizophrenia patients systematically assessed for PMA have used small patient samples and have rarely used controls. OBJECTIVE: To investigate possible correlations of PMA, as measured with the Cannon-Spoor Premorbid Adjustment Scale (PAS), with such meaningful clinical characteristics as sex, age at onset, negative symptoms etc. using one of the largest samples of schizophrenia inpatients as well as controls characterised for PMA to date. METHOD: PMA, diagnosis and lifetime symptoms were assessed in 316 inpatients with schizophrenia and 137 population based controls using the PAS and the Structured Clinical Interview for DSM. RESULTS: Controls demonstrated better PAS scores than inpatients with schizophrenia. Earlier age at onset and negative symptoms were found to be associated with poorer PAS scores. There was no difference in PAS ratings between males and females in patients with schizophrenia. Among the control probands, females showed significantly better PAS scores than males. CONCLUSION: PAS scores are worse in individuals who eventually develop schizophrenia, and the distribution of these scores among schizophrenia inpatients is correlated with specific clinical features. Earlier findings, which had reported an association with age at onset and negative symptoms in small patient samples, were substantiated. The widely reported association of poor PMA with male sex, if genuinely present, does not appear to be disease specific. Our findings suggest that PMA is in itself a valuable phenotype characteristic and that it may represent a specific biological phenotype which may be of value in sub-sample selection.     

Paternal age and risk of schizophrenia in adult offspring

OBJECTIVE: The study examined the relation between paternal age at the time of birth and risk of schizophrenia in the adult offspring. METHOD: Data from the birth cohort of the Prenatal Determinants of Schizophrenia study were used in this study. Virtually all members of this birth cohort had prospective information about paternal age at the time of the offspring's birth. Subjects with schizophrenia and other schizophrenia spectrum disorders (N=71) among members of this birth cohort were previously ascertained. In separate analyses, paternal age was modeled as a continuous variable and as a categorical variable, and its relation with the risk of adult schizophrenia and other schizophrenia spectrum disorders and with the risk of schizophrenia separately were examined. RESULTS: There was a marginally significant, monotonic association between advancing paternal age and risk of adult schizophrenia and schizophrenia spectrum disorders. The association held after the analysis controlled for the effects of maternal age and other potential confounders. Similar results were observed when only subjects with schizophrenia were included in the analysis. CONCLUSIONS: Advanced paternal age at the time of birth of the offspring may be a risk factor for adult schizophrenia.     

Age at onset of schizophrenia and neuroleptic dosage

Background: Lower age at onset of schizophrenia has been traditionally associated with poorer response to treatment and less favourable prognosis. The aim of the study was to find out whether age at onset of schizophrenia is related to the dosage of typical neuroleptics in outpatients. Method: Age at onset was defined as age at first seeking of psychiatric help. Demographic, social and disease-related characteristics were studied in a group of 200 stable outpatients with schizophrenia (100 males and 100 females). Psychopathological symptoms were assessed with the Krawiecka Scale. Neuroleptic dosage was converted to milligrams of chlorpromazine equivalents and logarithmically transformed to obtain normal distribution. Results: Onset of schizophrenia occurred earlier in males than in females. The average dosage was 251.7 (SD 303.9) mg chlorpromazine equivalents. In a multivariate linear regression model, lower age at onset and higher sum of symptoms were related to the drug dosage. Conclusion: The results confirm the findings of other authors that patients with lower age at onset are less responsive to typical neuroleptics. Some of the patients with early onset would be more appropriately treated with atypical neuroleptics, which may have better therapeutic efficacy. Accepted: 3 September 1999     

Young onset hemifacial spasm

INTRODUCTION: Hemifacial spasm (HFS) frequently affects middle aged individuals and the clinical features and etiology have been well reported. However, there is limited data on the exact pathogenesis in young-onset HFS. If age is a major determinant of the etiology or influences the presentation of HFS, there may be clinical differences between the young and elderly HFS patients. OBJECTIVES: We determined the prevalence, clinical and imaging features of young-onset HFS (age of onsetor=65 years) HFS patients. METHODS: We examined consecutive patients clinically diagnosed with HFS in a tertiary referral center. The clinical (demographics, clinical presentation, severity of HFS, associated medical conditions and other variables) and imaging findings of young onset patients and old onset patients were tabulated and compared. RESULTS: Amongst 230 consecutive HFS patients, 15 (6.5%) were young-onset HFS and 50 (21.7%) were old-onset HFS. In the young-onset HFS, the mean age of onset of symptoms was 26.5+/-6.5 (6-30) years, with 80% women and 75.0% of young onset HFS having neurovascular compression (NVC) of the root exit zone (REZ) of the facial nerve on the ipsilateral side; 86.7% had initial onset of twitching in the upper eyelids that later progressed to the lower facial muscles. While the prevalence of hypertension, diabetes mellitus and other associated vascular disorders in late onset HFS was higher than in young onset groups, the clinical features and frequency of NVC of the facial REZ between the two groups were similar. CONCLUSIONS: We demonstrated a 6.5% frequency of young-onset HFS in our cohort of HFS and their clinical presentation was similar to the old onset patients. Genetic, anatomic or other unidentified factors may contribute to NVC in young-onset HFS.     

男女儿童青少年精神分裂症患者临床特征的比较

目的:比较儿童青少年精神分裂症男性与女性患者临床特征的差异。方法:对125例男性(男性组)和133例女性(女性组)儿童青少年精神分裂症患者的年龄、发病年龄、病前诱因、阳性家族史、病程特点、住院天数、简明精神病量表(BPRS)、大体评定量表(GAS)及临床疗效总评量表(CGI)评分等临床特征进行比较。结果:男性与女性患者在年龄、发病年龄、病前诱因、阳性家族史、病程特点、住院天数方面比较差异无统计学意义(P均0.05)。BPRS评分中敌对性、动作迟缓、情感淡漠、缺乏活力因子分男性组高于女性组(t=2.164,t=3.317,t=2.096,t=2.230;P0.05或P0.01);幻觉、思维障碍因子分女性组高于男性组(t=3.682,t=2.987;P0.01或P0.001)。入院时GAS、CGI-SI评分及出院时CGI-GI评分两组间差异无统计学意义(P均0.05),出院时CGI-EI评分女性组高于男性组(t=2.466)、自知力评分男性组高于女性组(t=2.403),差异有统计学意义(P均0.05)。结论:男性儿童青少年精神分裂症患者的临床特征以情感淡漠、缺乏活力等阴性症状为主,女性则以幻觉、思维障碍等阳性症状更突出;女性临床疗效优于男性。     

Evidence of a cohort effect for age at onset of schizophrenia

OBJECTIVE: The authors address whether a possible age-at-onset cohort effect may have introduced a bias into anticipation studies of schizophrenia. METHOD: A retrospective review of the medical records of all admissions for psychotic disorders (N=877) was conducted. All subjects with a confirmed DSM-IV diagnosis of schizophrenia and age-at-onset data were included (N=419). For analyses, subjects were placed into one of three successive birth cohorts: 1905-1944 (N=96), 1945-1964 (N=200), and 1965-1984 (N=123). RESULTS: The mean age at first appearance of psychotic symptoms and, similarly, the mean age at first hospitalization significantly decreased over time in successive birth cohorts (25.3, 23.3, and 20.4 years, respectively, for age at first appearance of psychotic symptoms). CONCLUSIONS: This potential birth cohort effect for age at onset of schizophrenia needs to be incorporated into genetic models.     

Obstetrical complications and childhood-onset schizophrenia.

OBJECTIVE: Increased obstetrical complications have been reported in individuals with adult-onset schizophrenia, with several studies finding an association between such complications and an earlier age at onset. Consequently, obstetrical records were examined for individuals with childhood-onset schizophrenia to determine if birth complications were more prevalent. METHOD: The birth records of 36 patients with childhood-onset schizophrenia and 35 sibling comparison subjects were rated for birth complications by two psychiatrists who were unaware of group membership. RESULTS: There were no significant differences between the groups in rates of obstetrical complications. Patients with such complications did not have a relatively earlier age at onset of schizophrenia. CONCLUSIONS: A very early age at onset of schizophrenia is probably not due to birth complications.     

Decline in the incidence of schizophrenia in Finnish cohorts born from 1954 to 1965.

BACKGROUND: The declining incidence of schizophrenia observed in several countries is believed by many to merely reflect methodological problems in the studies performed. We report the first nationwide historical cohort study of changes in the incidence of schizophrenia, in which many of the previous methodological problems were overcome. METHODS: We used the Finnish Population Register to identify everyone born in Finland from 1954 to 1965. These persons were followed up from their 16th to their 26th birthdays, and all cases of schizophrenia (International Classification of Diseases, Eighth Revision and International Classification of Diseases, Ninth Revision code 295) that emerged were identified from the National Hospital Discharge Register, the Pension Register, and the Free Medicine Register. Persons for whom an age of onset could be defined were included in the analyses (n = 5645). We used the Poisson regression model to estimate the effects of age, sex, birth cohort, period of diagnosis, and season of birth on the incidence of schizophrenia. The relative importance of cohort and period were assessed using an age-period-cohort model. RESULTS: The incidence declined significantly in each successive cohort, from 0.79 to 0.53 per 1000 among males and from 0.58 to 0.41 per 1000 among females. The effects of cohort and period on the change were both significant. CONCLUSIONS: The incidence of schizophrenia has declined in Finland. This was partly caused by confounding factors, as reflected in the significant period effect. The significant birth cohort effect suggests that the intensity or frequency of one or more risk factors for schizophrenia has decreased.     

Gender and the familial risk for schizophrenia. Disentangling confounding factors.

Recent studies of the effect of gender on the familial risk for schizophrenia have shown that relatives of females have a higher risk for schizophrenia than relatives of males. This study attempts to explain the effect by examining factors found to differentiate schizophrenic men and women and found to be related to the familial risk for schizophrenia. Cox proportional hazard regression model was used to examine the simultaneous effects of age at onset, season of birth, and premorbid history, controlled for symptoms that have been found to differ by gender (dysphoria, paranoia, and flat affect). Results showed that the effect of gender on the transmission of schizophrenia could not be explained by gender differences in age at onset, symptom expression, premorbid history, and winter birth. However, premorbid history had an effect on familial risk independent of gender, indicating that probands with a poor premorbid history had a lower familial risk for schizophrenia than those with a good premorbid history. Implications of the findings are discussed.     

The ESSEN study of childhood-onset schizophrenia: Selected results

Introduction: We present the results of a 42 year long-term follow-up of 44 patients (19 males, 25 females) with childhood-onset schizophrenia (COS, age at onset: 7-14 years) who could be traced for a second follow-up examination 27 years after the first follow-up. Methods: Data from interviews, clinical records, premorbid and social disability assessments were evaluated for statistical analyses. The symptomatology observed during the whole course of illness was rediagnosed by DSM-IV criteria. Results: The paranoid, catatonic, and schizoaffectives subtypes appeared most frequently. There have been no gender differences in age of first psychiatric symptoms (AFS), AFPS, and age of first hospitalization. Kaplan-Meier's survival-analysis carried out for AFPS with sex as the grouping factor revealed that the cumulative prevalence appears to be earlier in females (between 7 and 15 years) than in males (between 10 and 18 years). Of the 44 patients 50 % had a continuing severe course. Patients with onset before 12 years of age were characterized by a chronic/insidious onset, marked premorbid abnormalities, and by a poorer remission. Premorbid features of social withdrawal and reluctance indicated a risk for social disability within the later course. Conclusion: COS, as a rare but severe variant of schizophrenia, frequently develops from premorbid social maladaptation to an insidious onset but is subsequently followed by a transition to a course and outcome not distinguishable from that of adult-onset schizophrenia.     

Gender and schizophrenia: age at onset and sociodemographic attributes.

A consecutive series of 214 patients (125 males, 89 females) who met the Research Diagnostic Criteria for schizophrenia were studied to determine gender differences in age at onset of the illness and sociodemographic attributes. The immediate family's first awareness of psychotic symptoms or signs and age at first presentation in hospital were used as indices of onset; male patients had a significantly earlier age of onset than females. By the time they were 30 years of age, 83% of male patients had already become ill and only 66% of females had done so. Significantly more females than males were married at the time of first contact with hospital. Married males did not differ from married females in age at onset of illness, suggesting that patients who marry may have late onset.     

Gender-related clinical differences in obsessive-compulsive disorder

The purpose of the present study was to investigate the gender-related differences of clinical features in a sample of obsessive-compulsive (OCD) patients. One hundred and sixty outpatients with a principal diagnosis of obsessive-compulsive disorder (DSM-IV, Y-BOCS = 16) were admitted. Patients were evaluated with a semi-structured interview covering the following areas: socio-demographic data, Axis I diagnoses (DSM-IV), OCD clinical features (age at onset of OC symptoms and disorder, type of onset, life events and type of course). For statistical analysis the sample was subdivided in two groups according to gender. We found an earlier age at onset of OC symptoms and disorder in males; an insidious onset and a chronic course of illness were also observed in that group of patients. Females more frequently showed an acute onset of OCD and an episodic course of illness; they also reported more frequently a stressful event in the year preceding OCD onset. A history of anxiety disorders with onset preceding OCD and hypomanic episodes occurring after OCD onset was significantly more common among males, while females showed more frequently a history of eating disorders. We found three gender-related features of OCD: males show an earlier age at onset with a lower impact of precipitant events in triggering the disorder; OCD seems to occur in a relative high proportion of males who already have phobias and/or tic disorders; and a surfeit of chronic course of the illness in males in comparison with females.     

Age at onset of schizophrenia: gender differences and influence of temporal socioeconomic change

This study was undertaken to examine whether males develop schizophrenia at a younger age than females, and whether temporal socioeconomic change affects the age at onset of schizophrenia. The subjects were 848 ICD-9 schizophrenics who were admitted to Nihon University Hospital, Tokyo, Japan, during the period of 1955-64 (n = 468 (214 males and 254 females), group A) or during the period of 1982-91 (n = 380 (220 males and 160 females). group B). Schizophrenic males showed an earlier age at onset than schizophrenic females. However, the mean age at onset of schizophrenia did not differ significantly between group A and group B. These results indicate that the gender difference in age at onset of schizophrenia has not been influenced by temporal socioeconomic change.     

Late-onset hallucino-delusional psychosis. Effect of sex and age on its symptoms and course

Despite well-know semiological characteristics, the nosological position of the late onset hallucinatory-delusional psychosis with respect to schizophrenia is much debated. As regard prognosis factors, the study of 135 cases (36 men, 99 women) has shown that a sudden onset often happens in men, that, however, women often present a mental automatism syndrome, which becomes exceptional with age; finally, that influence phenomena are seldom found in men, especially after the age of 60. Rich and diversified symptoms of mental automatism are often observed in younger patients but they generally do not last. On the contrary, the clinical picture of the very late onset is comparatively simple and restricted; its main symptoms are either hallucinations or delusions and these symptoms tend to remain. Such semiological and evolutive modifications according to the age of the patient may appear in case of recurrence. The analysis of the pathoplastic role of age in the clinical picture leads to an hypothesis: a relation between the two possible evolutions (favourable and unfavourable) of the late onset hallucinatory-delusional psychosis and the two groups (atypical and nuclear) of schizophrenia.     

Relationships of age at onset with clinical features and cognitive functions in a sample of schizophrenia patients

BACKGROUND: A number of studies investigated the relationships of age at onset with clinical presentation and cognitive performance of schizophrenic patients. The aim of the present study was to assess demographic and clinical characteristics; psychopathologic, social functioning, and quality-of-life ratings; and neuropsychological measures in a sample of patients with stabilized schizophrenia and to identify which factors independently contributed to a multiple regression model with age at onset as the dependent variable. METHOD: Ninety-six consecutive outpatients with schizophrenia (DSM-IV-TR criteria) were included in the study. Assessment instruments were as follows: a semistructured interview, the Clinical Global Impressions scale, the Comprehensive Psychopathological Rating Scale, and the Positive and Negative Syndrome Scale (PANSS) for psycho-pathology of schizophrenia; the Calgary Depression Scale for Schizophrenia (CDSS) for depression; the Social and Occupational Functioning Assessment Scale and the Sheehan Disability Scale for social functioning; the Quality of Life Scale; and a neuro-psychological battery including the Wisconsin Card Sorting Test (WCST) and the Continuous Performance Test. Two models of multiple regression were tested: the first included clinical features and psychopathologic, social functioning, and quality-of-life scales; the second also considered neuro-psychological variables. Data were collected from October 2001 to November 2002. RESULTS: The first multiple regression showed that age at onset was significantly related to scores on the PANSS subscale for negative symptoms (p =.042) and the CDSS (p =.041); the second regression found a relation of age at onset with PANSS score for negative symptoms (p =.002) and 2 neuropsychological measures, number of preservative errors on the WCST and Continuous Performance Test reaction time (p =.0005 for both). CONCLUSION: Our data indicate that, when results of neuropsychological tests are considered, early age at onset of schizophrenia is associated with severity of negative symptoms and compromised cognitive measures of executive functioning and sustained attention.     

Onset and clinical course of schizophrenia in Butajira-Ethiopia

Abstract. Background: There are reports on favourable course and outcome of schizophrenia in lowincome countries. The aim of the present study was to examine onset and clinical course of the illness in a community-based sample in rural Ethiopia based on crosssectional information. Method: A two-stage survey was carried out in Butajira-Ethiopia, a predominantly rural district. Altogether 68,378 individuals aged 15–49 years were CIDI-interviewed, of whom 2,159 were identified as cases according to the CIDI interview with regard to psychotic or affective disorders. Key informants identified another group of 719 individuals as being probable cases and a total of 2,285 individuals were SCAN-interviewed. The present paper reports on cases with schizophrenia. Results: There were 321 cases of schizophrenia giving an estimated lifetime prevalence of 4.7/1,000). Of the cases,83.2% (N = 267) were males. Mean age of first onset of psychotic symptoms for males was 23.8 (sd 8.6) compared to 21.0 (sd 7.8) for females (P = 0.037; 95 %CI 0.16–5.47). Over 80% had negative symptoms and over 67% reported continuous course of the illness. Less than 10% had a history of previous treatment with neuroleptic medication. About 7% were vagrants, 9 % had a history of assaultive behaviour,and 3.8% had attempted suicide. The male to female ratio was nearly 5:1. Conclusion: This large community-based study differs from most previous studies in terms of higher male to female ratio, earlier age of onset in females and the predominance of negative symptoms.     

晚发性和早发性精神分裂症临床特征比较

目的：了解早发性和晚发性精神分裂症的临床特征。方法：用阳性症状量表（SAPS）、阴性症状量表（SANS）评定临床症状;临床疗效总评量表（CGI）、治疗中出现的症状量表（TESS）评定临床疗效及不良反应;用躯体异常量表（Waldrop scale）N量软体征。对早发性精神分裂症和晚发性精神分裂症患者各50例进行对照研究。结果：早发性精神分裂症遗传倾向明显,软体征异常率高,有更明显的阴性症状,治疗效果较差,不良反应更明显。晚发性精神分裂症女性明显多于男性,以幻觉、妄想、偏执观念为主要临床特征．结论：早发性和晚发性精神分裂症各有其临床特征。早发性比晚发性精神分裂症的遗传负荷和胚胎发育异常程度高,治疗效果和预后较差。     

Gender differences in 542 Chinese inpatients with schizophrenia

OBJECTIVE: To investigate gender differences in the onset and other clinical features of Han Chinese inpatients with schizophrenia. METHODS: Five-hundred-and-forty-two Han Chinese inpatients with DSM-IV schizophrenia were assessed with the Positive and Negative Symptoms Scale (PANSS), the Brief Psychiatric Rating Scale (BPRS), the Global Assessment of Function scale (GAF) and locally-developed standardized data collection forms. Comparisons were made between male and female patients. RESULTS: This is the largest study of gender differences in schizophrenia to be conducted in a Chinese population. In our sample, we found that schizophrenia onset occurred at a significantly earlier age in male patients compared to female patients and that late-onset schizophrenia (as defined by onset> or =45 years) was significantly more common in female patients. The paranoid subtype of schizophrenia was less common in male patients, males received higher daily doses of antipsychotics and demonstrated a different pattern of antipsychotic usage, being less likely to be treated with SGAs. Further, cigarette smoking was more common in male patients and male patients were more likely to be single or never married. By contrast, female patients showed a different pattern of ongoing symptoms and severity, being more likely to have persistent positive symptoms, more severe positive and affective symptoms, and a greater number of suicide attempts whereas male patients were more likely to show severe deterioration over time. CONCLUSIONS: There are notable gender differences in the age at onset, treatment and a range of other clinical features in Han Chinese patients with schizophrenia. Such differences were largely consistent with those reported in Western studies. These gender differences need to be considered in the assessment and management of Chinese patients with schizophrenia.     

Early-onset schizophrenia as a progressive-deteriorating developmental disorder: evidence from child psychiatry

Summary. The developmental perspective as reflected by investigations of childhood and early-onset schizophrenia has become a major research area during recent years and contributed much to the understanding of schizophrenia at all ages. This paper reviews clinical features, neurobiological and neuropsychological findings in childhood and adolescent onset schizophrenia including some results of studies of the author on age at onset, premorbid symptoms, treatment and course. Childhood-onset schizophrenia is a rare disorder with a prevalence of one child in 10,000 before the age of 12 and a remarkable increase around puberty and early adolescence. Developmental events and precursors of schizophrenia cover a wide range of dysfunctions and disturbances including elevated rates of soft neurological signs and birth complications, slow habituation and high baseline autonomic activity, high rate of developmental disorders of speech and/or language and overall and specific cognitive deficits. Brain morphological studies and intelligence testing as well as investigations of the course provide evidence of deterioration. Therefore, early-onset schizophrenia can be understood as a progressive-deteriorating developmental disorder. Received April 9, 2001; accepted September 7, 2001     

A rare and not very studied disorder: childhood-onset schizophrenia. A case report

SUMMARY: Childhood-onset schizophrenia is rare: its prevalence is about 50 times lower than the one observed in adulthood. It is also frequently unrecognized, notably because its clinical aspect varies with age. The authors report the case of a prepubertal girl who developed a typical clinical picture of schizophrenia (paranoid subtype) by age 9. CASE REPORT: The patient was 10 years old when she was hospitalized for a relapse of a suspected childhood-onset schizophrenia. Several significant mental disorders were found in her family history: her mother was treated for mood disorders (including dysthymia and major depression with postpartum onset), while her father and a aunt exhibited schizophrenic disorders. In addition, prenatal and perinatal events (including probable prenatal maternal infection and obstetric complications) were reported by her mother. Demonstrable impairments were already present in her premorbid development: from the age of 3.5, she showed significant manifestations of behavioural inhibition and separation anxiety, severe difficulties in social adaptation, and language abnormalities (qualified by her general practitioner as selective mutism). At the age of 9, when her mother was hospitalized for a diabetes mellitus, she suddenly showed auditory and visual hallucinations associated with delusions. Their content included filiation, somatic, and persecutory themes. Grossly disorganized behaviour (and more particularly catatonic motor behaviours including catatonic rigidity and negativism and bizarre postures) was also observed. Negative symptoms (eg anhedonia, affective flattening, and alogia) were noted. Her IQ scores were 74 in the verbal subtests and 53 in the performance subtests. Because the diagnostic of childhood-onset schizophrenia was suspected, a neuroleptic treatment, haloperidol 3 mg/day, was tried. After a partial remission during a few months period (characterized by a decrease in delusions, anxiety and sleep difficulties), she showed a relapse leading to her hospitalization. At the time of her admission, she showed severe manifestations of separation anxiety including agitation, anger, crying, and insomnia, for which she received a short-lived treatment by lorazepam. When sedation was obtained, the clinical picture proved similar to the one previously observed: hallucinations, delusions, grossly disorganized behaviour, and thought disorder were noted. As soon as the diagnostic of childhood-onset schizophrenia was confirmed, she was administered a new antipsychotic agent, amisulpride, at dose of 600 mg/day. This treatment was going on during several weeks with no significant clinical effect. Because the early onset of the disorder, the family history of schizophrenia, and the lack of effectiveness of the two previously administered antipsychotic agents, a treatment with clozapine was started at the dose of 12,5 mg/day. From the outset of this treatment, clinically significant reductions in hallucinations and disorganized behaviours were noted. Dose was then progressively increased until 200 mg/day, resulting in significant improvement in cognitive and motor functioning. The patient is now in an educational institute. Her adaptation is considered satisfactory, in spite of regular exacerbations of delusions in response to stressful life events. Treatment with clozapine is going on, without any significant undesirable clinical effects. DISCUSSION: If an abrupt onset is rarely observed in prepubertal children, all the authors report that patients with very early onset schizophrenia show to have demonstrable impairments in their premorbid language as well as in their motor and social development. In addition, several studies suggest that more pronounced early developmental abnormalities are usually associated with a poor outcome in schizophrenia. The clinical picture also agrees with recent studies showing that in children paranoid subtype is as frequent as seen in adult disorders. If genetic factors play a significant role in the pathogenesis of schizophrenia, the notion that such factors may be more salient in very early onset and more severe cases is now usually accepted. However, a number of environmental factors, including prenatal maternal infections and perinatal complications, may also be implicated in the pathogenesis of schizophrenia, in addition to genetic factors. Because a significant relationship between stressful life events and exacerbations in positive symptoms was found in the case reported, the authors examine the role of such stress factors in the pathogenesis of schizophrenia and in the course of illness. A brief review of studies that have examined the effects of antipsychotic agents in children with schizophrenia underscores the paucity of data available to guide clinicians in this area. However, these data suggest that children who receive conventional neuroleptics experience significant adverse effects, primarily sedation and extrapyramidal symptoms. In addition, they suggest that new antipsychotic agents, such as clozapine, may be more effective than conventional neuroleptics, particularly in negative symptoms. Lastly, the authors emphasize the poor outcome usually reported in childhood-onset schizophrenia, highlighting the need of a long-term pharmacological and behavioural treatment. CONCLUSION: This case report, such as others, supports the hypo-thesis that there is a clinical continuity between early and later onset schizophrenia. It also suggests that very early onset schizophrenia is a more severe form of the disorder and may be secondary to greater familial vulnerability. Consequently, systematic studies of these patients may be particularly informative and may provide important informations for understanding the etiologic processes involved in the pathogenesis of schizophrenia.