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Generally, immigrant status and male sex are separately documented to increase the risk of schizophrenia; although population-based risk trends by sex and immigration over time have not been examined. This study aims to examine the extent to which immigration acts as a risk factor for schizophrenia, delineated by origin, sex and year, using national population-based data over 15 years. Data on all first psychiatric admissions from 1978 to 1992 (n = 10,892) from the National Psychiatric Hospitalization Case Registry of the State of Israel were merged with aggregate national data from the Israeli Central Bureau of Statistics. Compared to native-born Israelis, people who migrated prior to the age of 15 (n = 2,335) were at a greater risk of schizophrenia (n = 8,557; RR = 1.6, 95% CI = 1.53; 1.68), particularly those from Far Eastern (RR = 2.43, 95% CI = 1.91; 3.1) and Caribbean and South American (RR = 1.94, 95% CI = 1.51; 2.51) countries. Aggregate risk was higher among female than male immigrants and over the 15-year study immigration-related risk declined across the sexes. The current findings replicate past research showing that immigrants, particularly from a social minority, as suggested by the social defeat-hypothesis, are at an increased risk of schizophrenia, and extend past findings to show that risk at least in Israel has decreased with time irrespective of sex.

Objective The hypothesized role of CNS infection during childhood in increasing later risk of brain malfunction manifested as schizophrenia has been supported by some but not other studies. We sought to contribute to this debate by linking data on persons who had been hospitalized for meningitis as children, with a National Psychiatric Hospitalization Registry. Method Data were gathered on 3599 persons who had been hospitalized for a CNS infection before the age of 16, and 6371 controls who had been hospitalized as children for gastroenteritis. Both groups were followed for later hospitalization for schizophrenia between 1970 and 2007 using the Israeli National Psychiatric Hospitalization Case Registry. Data were analyzed using Cox regression analyses. Results The mean age of the subjects at hospitalization for a CNS infection was 3.4 ± 3.6 years, mean age of the subjects at follow up was 29.3 ± 6.0 years. Compared to controls, hospitalization for any CNS infection during childhood was not associated with an increased risk of later hospitalization for schizophrenia, adjusted HR = 0.81, 95% CI: 0.5–1.32. Conclusions Overall there was no significant association between childhood CNS infection and schizophrenia. These data do not support the presence of an infectious etiology of schizophrenia.

The use of firearms is a common means of suicide. We examined the effect of a policy change in the Israeli Defense Forces reducing adolescents' access to firearms on rates of suicide. Following the policy change, suicide rates decreased significantly by 40%. Most of this decrease was due to decrease in suicide using firearms over the weekend. There were no significant changes in rates of suicide during weekdays. Decreasing access to firearms significantly decreases rates of suicide among adolescents. The results of this study illustrate the ability of a relatively simple change in policy to have a major impact on suicide rates.

Background Previous studies have found that patients with schizophrenia and bipolar disorder are more likely to be violent than the general population. The aim of this study was to investigate the association between schizophrenia and bipolar disorder and violent crime in the Israeli population. Methods Using the Israeli Psychiatric Hospitalization Case Registry we identified 3187 patients with a discharge diagnosis of schizophrenia and 506 patients with a discharge diagnosis of bipolar disorder. For each proband we identified parents and siblings, and gender- and age-matched controls for patients, parents and siblings. Information on violent crimes was obtained from police records. Results Patients with schizophrenia were at increased risk for violent crimes compared with controls [odds ratio (OR) 4.3, 95% confidence interval (CI) 3.8–4.9], especially women (OR 9.9, 95% CI 6.2–15.7). Risk for violent crimes was higher among patients with co-morbid substance misuse than in patients without such co-morbidity (OR 5.1, 95% CI 4.2–6.3). Patients with diagnosis of bipolar disorder were 2.5 times more likely to be convicted or released for mental reasons of violent crimes compared with controls and unaffected full siblings (OR=2.5, 95%CI 1.7–3.7, OR=2.5, 95%CI 1.6–4.0 respectively). Although men were more violent than women, diagnosis of bipolar disorder was a more significant risk factor for female patients than for male patients (OR=16.1 95%CI 1.8–144.6 vs. OR=2.4, 95%CI 1.5–3.7). Discussion The results of this study suggest that increased risk of violence is part of the clinical picture of schizophrenia and bipolar disorder and needs to be recognized as a legitimate, essential, aspect of clinical management.

Objective: As patients with psychotic illness have fewer offspring than controls, the persistence of psychotic illness is puzzling. We hypothesized that unaffected first-degree relatives of patients have more offspring than controls. Method: Probands were 4904, individuals with non-affective psychotic disorders identified from a hospitalization registry. Unaffected first degree relatives and matched controls were identified from the Israeli Population Registry. The number of offspring of unaffected parents, biological siblings and controls was ascertained. Results: Unaffected parents of psychotic patients had more offspring/person than controls; 4.5 ± 2.7 vs. 3.4 ± 2.2, P = 0.000. Unaffected parents from familial psychosis families (more than one affected family member) had 1.83 more offspring than controls; unaffected parents from non-familial psychosis families had 0.97 more offspring than controls (both P

Aim: Retrospective studies indicate that patients with psychotic disorders and schizophrenia often suffer from depressive symptoms before the onset of psychosis. In a historical-prospective design, we studied the association between dysthymia in adolescence and later hospitalization for psychotic disorders and schizophrenia. Methods: The Israeli Draft Board screens the entire, unselected population of 16–17 years old male adolescents for psychiatric disorders. These adolescents were followed for hospitalization for psychotic disorders and schizophrenia using the Israeli National Psychiatric Hospitalization Case Registry. Of 275 705 male adolescents screened, 1267 (0.5%) were hospitalized for psychotic disorders (International Classification of Diseases [ICD]-10 20.0–29.9), and 757 (0.3%) were hospitalized for schizophrenia (ICD-10 20.0–20.9) over the next 1–10 years. Results: Of 275 705 male adolescents screened, 513 (0.2%) were diagnosed as suffering from dysthymia by the Draft Board. Of these adolescents, 10/513 (2.0%) were later hospitalized for psychotic disorders (including schizophrenia, HR = 3.967, 95%CI (confidence intervals): 2.129–7.390), and 4/513 (0.8%) were later hospitalized for schizophrenia (HR = 2.664, 95%CI: 0.997–7.116). Conclusions: In this population-based cohort of male adolescents, dysthymia was associated with increased risk for future psychotic disorders. Dysthymia in some adolescents might be a prodromal symptom, while in others it might be a risk factor for later psychosis. Clinicians assessing dysthymic adolescents should be aware that these symptoms might be part of the prodrome.

BackgroundBeing a small and culturally different minority, or having a different appearance, has been invoked to account for the increased prevalence of psychotic disorders among immigrants. The majority of the Jewish Israeli population are first- or second-generation immigrants from Europe, North Africa or Asia, and during the late 1980s and 1990s, 885 000 persons immigrated to Israel from the former Soviet Union and 43 000 immigrated from Ethiopia. These Ethiopian immigrants came from a very different culture compared to the rest of the population, and have a distinct appearance. To further understand the association between immigration and schizophrenia, we compared risk for later schizophrenia between adolescents who immigrated from Ethiopia with risk among the other immigrant groups, and with native-born Israelis.MethodOf 661 792 adolescents consecutively screened by the Israeli Draft Board, 557 154 were native-born Israelis and 104 638 were immigrants. Hospitalization for schizophrenia was ascertained using a National Psychiatric Hospitalization Case Registry. All analyses controlled for socio-economic status (SES).ResultsRisk for schizophrenia was increased among both first- [hazard ratio (HR) 1.62, 95% confidence interval (CI) 1.18–2.22] and second-generation immigrants [HR 1.41, 95% CI 1.01–1.95 (one immigrant parent) and HR 1.49, 95% CI 1.11–2.0 (two immigrant parents)]. When risk for schizophrenia was calculated for each immigrant group separately, immigrants from Ethiopia were at highest risk of later schizophrenia (HR 2.95, 95% CI 1.88–4.65).ConclusionThis comparison between diverse groups of immigrants supports the notion that immigrants who differ in culture and appearance from the host population are at increased risk for schizophrenia.

In an individual who seeks help or is referred to a mental health professional it is common sense and clinical practice to assume that suicidal thoughts and previous attempts constitute risk factors for imminent suicide. However, this assumption has not been supported by large, population-based longitudinal studies. The current study investigated whether reports of current suicidal ideation and a history of suicide attempts indeed increase risk for later completed suicide in a historical prospective study design. Sequential records on 89,049 young males assessed by mental health professionals were screened for suicidal ideation and a history of suicide attempts. The data were linked with death records from the Israeli Central Bureau of Statistics. Over a follow-up period ranging from 2 months to 9.8 years, 54 individuals died by suicide, constituting an average suicide rate of 6.48 per 100,000 person-years. Overall, neither reporting current suicidal ideation (without a history of suicide attempts; HR=1.29, 95% CI=0.57-2.90) nor reporting a history of suicide attempts (with or without current suicidal ideation; HR=1.67, 95% CI=0.71-3.97) were significantly associated with increased risk for later completed suicide. However, young males with a previously diagnosed psychiatric disorder who reported current suicidal ideation (HR=4.52, 95% CI=1.08-18.91) or a history of suicide attempts (HR=6.43, 95% CI=1.54-26.90) were at increased risk of death by suicide. These findings indicate that in this particular population reports of current suicidal ideation or of a history of suicide attempts are helpful in predicting future suicide only among those with a previous diagnosis of a psychiatric disorder.

Suicide is a major cause of death in schizophrenia. Identifying factors which increase the risk of suicide among schizophrenia patients might help focus prevention efforts. This study examined risk of suicide in male schizophrenia patients using population-based data, examining the timing of suicide in relation to the last hospital discharge, and the effect of premorbid IQ on risk of suicide. Data on 930,000 male adolescents from the Israeli military draft board were linked with data from the Israeli Psychiatric Hospitalization Case Registry and vital statistics from the Israeli Ministry of Health. The relationship between premorbid IQ and risk for suicide was examined among 2881 males hospitalized with schizophrenia and compared to a control group of 566,726 males from the same cohort, who were not hospitalized for a psychiatric disorder, using survival analysis methods. Over a mean follow-up period of 9.9 years (SD=5.8, range: 0-22 years), 77/3806 males with schizophrenia died by suicide (a suicide rate of 204.4 per 100,000 person-years). Approximately 48% of the suicides occurred within a year of discharge from the last hospital admission for schizophrenia. Risk of suicide was higher in male schizophrenia patients with high premorbid IQ (HR=4.45, 95% CI=1.37-14.43) compared to those with normal premorbid IQ. These data indicate that male schizophrenia patients with high premorbid IQ are at particularly high risk of suicide, and the time of peak risk is during the first year after the last hospitalization discharge.

SummarySeveral often-cited meta-analyses have reported that the efficacy of antidepressant medications depends on the severity of depression. They found that drug–placebo differences increased as a function of initial severity, which was attributed to decreased responsiveness to placebo among patients with severe depression rather than to increased responsiveness to medication. We retested this using patient-level data and also undertaking a meta-analysis of trial-level data from 34 randomised placebo controlled trials (n = 10 737) from the NEWMEDS registry. Although our trial-level data support prevous findings, patient-level data did not show any significant effect of initial depression severity on drug v. placebo difference.

It is unknown whether interim analyses portend final study results. Fatigue, pressure to complete trials and recruitment differences may mitigate against this. We examined the similarity of efficacy results of the first and second half of recruited patients to complete trials and explore possible intervening variables. Using data from the NewMeds repository of patient level data from placebo-controlled randomized trials of antipsychotics (AP) (22 studies, n=7056) and antidepressants (AD) (39 studies, n=12,217) we compared treatment effect size (placebo vs. active treatment) of the first and second half of patients recruited in completed trials. We found that in AP studies median difference in treatment effect between cohorts was -0.03, indicating that overall first and second cohorts yielded similar results. In AD studies, median difference between cohorts was 0.04, indicating that overall the second cohort had slightly larger active-placebo-difference. Overall, on average there were minimal differences in effect size between the first and the second cohorts, and in 30 of 39 trials interim results were a good estimate of the results on the 2nd cohort. In AD trials first and second cohort results were more similar when the proportion of patients per study centre and recruitment time of the two cohorts was similar. Results suggest that interim analyses in AD and AP studies may reliably serve to estimate ultimate effects and, at least in AD trials, are more accurate when the same sites are used to a similar extent and recruitment time of the two consequent cohorts is similar.

Background Response to antipsychotics in schizophrenia is highly variable, and determinants are not well understood or used to design clinical trials. Objective We aimed to understand determinants of response to antipsychotic treatment. Method Supported by the Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of second-generation antipsychotics conducted in adult schizophrenia patients by 5 large pharmaceutical companies. The dataset included all placebo-controlled trials of risperidone, paliperidone, ziprasidone, sertindole, olanzapine, and quetiapine. We examined patient and trial-design-related determinants of outcome as measured by change on the Positive and Negative Syndrome Scale in 29 placebo-controlled trials (drug, n =6,971; placebo, n = 2,200) and initial findings confirmed in additional data from 5 separate trials (drug, n =1,699; placebo, n = 580). Results While it is conventional for trials to be 6 weeks long, drug-placebo differences were observable at week 4 with nearly the same sensitivity, and dropout rates were lower. Having any of these attributes was associated with significantly greater drug versus placebo differences in symptom improvement and rates of study completion: being female (P ≤ .04), being a young adult patient who is a few years beyond the first episode (P ≤ .03), having prominent positive and negative symptoms (P ≤ .03), and living in Eastern Europe versus North America (P ≤ .04). Contrary to prevalent clinical opinion, age at onset and use of benzodiazepines did not show a differential treatment response, and patients just above PANSS inclusion threshold were not overrepresented. Conclusions Proof-of-concept trials can be shorter and efficiency improved by including an even distribution of sexes and of patients with prominent symptomatology, thus reducing patient exposure to placebo and experimental treatments.

The prevalence and manifestation of posttraumatic stress symptoms in young children may differ from that observed in adults. This study examined sociodemographic, familial, and psychosomatic correlates of posttraumatic stress disorder (PTSD) among preschool children and their mothers who had been exposed to ongoing missile attacks in the Gaza war.One hundred and sixty-seven mothers of preschoolers (aged 4.0-6.5 years) were interviewed regarding PTSD and psychosomatic symptomatology of their children, as well as their own reactions to trauma.Fourteen mothers (8.4%) and 35 children (21.0%) screened positive for PTSD. Sociodemographic characteristics were not associated with PTSD among mothers or children. Among children, the only significant risk factor was having a mother with PTSD (OR = 12.22, 95% CI 2.75-54.28). Compared to children who did not screen positive for PTSD, those who did screen positive displayed significantly higher rates of psychosomatic reactions to trauma, most notably constipation or diarrhea (OR = 4.36, 95% CI 1.64-11.60) and headaches (OR = 2.91, 95% CI 1.07-7.94).Results of this study add to the burgeoning literature on child PTSD, emphasizing the important role of maternal anxiety and the psychosomatic reactions associated with exposure to ongoing traumatic experiences in young children.

BACKGROUND Observations that antagonists of the N-methyl-d-aspartate (NMDA) receptor of glutamatergic neurons can mimic symptoms of schizophrenia have raised the hope that NMDA agonists can improve symptoms. On the basis of encouraging results of trials in which NMDA agonists were added to antipsychotics, we conducted an adequately powered randomized controlled trial adding d-serine, an NMDA modulator, to antipsychotics. METHOD This study was a 195-patient, multicenter, double-blind, randomized, placebo-controlled, 16-week trial of d-serine 2 g/d as an add-on treatment to antipsychotics. Subjects had DSM-IV schizophrenia or schizoaffective disorder and were inpatients or outpatients stabilized on antipsychotics, with persistent negative symptoms. The primary outcome measures were changes in negative symptoms and cognition as measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery, respectively. The study was performed between 2003 and 2007. RESULTS Mean total Positive and Negative Syndrome Scale scores at baseline were 75.5. Subjects receiving d-serine and placebo improved in scores on the SANS and MATRICS, but no significant differences were observed between groups: improvement on SANS was 11.4% for d-serine vs 14.8% for placebo, F1,147=1.18, P=.32; and improvement on MATRICS was 6.8% for d-serine vs 6.1% for placebo, F1,125=0.96, P=.39, respectively. d-Serine was well tolerated. DISCUSSION This study did not find a significant difference between drug and placebo. However, the results are limited by a relatively large placebo response and somewhat lower-achieved doses than in prior studies. Future studies will administer higher doses and will attempt to affect the NMDA receptor using other mechanisms, such as agonists of the presynaptic metabotropic glutamate 2/3 receptor or glycine reuptake inhibitors. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00138775.

Since the implementation of the legislation of the Rehabilitation of the Mentally Disabled in the Community Law a decade ago, an increasing number of people have been receiving the psychiatric rehabilitation 'basket of service', yet the impact of these services has barely been studied. The purpose of the present study is to examine whether people with severe mental illness in Israel who consume psychiatric rehabilitation services report better outcomes than people with severe mental illness who are eligible and have applied for psychiatric rehabilitation services but have not yet utilized them.1,191 persons with severe mental illness (595 psychiatric rehabilitation service users and 596 nonusers) completed face-to-face interviews. Differences in quality of life, general satisfaction and psychiatric symptoms between psychiatric rehabilitation service users and non-users were examined using Analysis of Covariance controlling for the potential confounding effects of age and marital status.Adjusted comparisons of quality of life, general satisfaction and psychiatric symptoms revealed that psychiatric rehabilitation service users had better outcomes than non-users: they reported better quality of life and greater satisfaction alongside fewer psychiatric symptoms. The most striking difference between the groups was found in the domain of employment and income, with non-psychiatric rehabilitation service users scoring 0.9 effect sizes below psychiatric rehabilitation service users.The current study, based on a relatively large sample, provides support for the effectiveness of the psychiatric rehabilitation 'basket of services'. Future studies including clinicians ratings of more objective aspects of functioning may provide a broader picture of the association between psychiatric rehabilitation service utilization and outcome.

Background Although previous studies indicate that people with lower intelligence quotient (IQ) scores are more likely to become cigarette smokers, IQ scores of siblings discordant for smoking and of adolescents who began smoking between ages 18–21 years have not been studied systematically. Methods Each year a random sample of Israeli military recruits complete a smoking questionnaire. Cognitive functioning is assessed by the military using standardized tests equivalent to IQ. Results Of 20 221 18-year-old males, 28.5% reported smoking at least one cigarette a day (smokers). An unadjusted comparison found that smokers scored 0.41 effect sizes (ES, P

Objective: Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. Methods: Subjects were 498 patients with schizophreniform disorder or firstepisode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month followup evaluation. Results: Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. Conclusion: Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their firstepisode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.

Background Evidence indicates an association between older parents at birth and increased risk for schizophrenia and autism. Patients with schizophrenia and autism and their first-degree relatives have impaired social functioning; hence, impaired social functioning is probably an intermediate phenotype of the illness. This study tested the hypothesis that advanced father's age at birth would be associated with poorer social functioning in the general population. To test this hypothesis, we examined the association between parental age at birth and the social functioning of their adolescent male offspring in a population-based study. Methods Subjects were 403486, 16- to 17-year-old Israeli-born male adolescents assessed by the Israeli Draft Board. The effect of parental age on social functioning was assessed in analyses controlling for cognitive functioning, the other parent's age, parental socioeconomic status, birth order, and year of draft board assessment. Results Compared with offspring of parents aged 25-29 years, the prevalence of poor social functioning was increased both in offspring of fathers younger than 20 years (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.08-1.49) and in offspring of fathers 45 years old (OR = 1.52, 95% CI = 1.43-1.61). Male adolescent children of mothers aged 40 years and above were 1.15 (95% CI = 1.07-1.24) times more likely to have poor social functioning. Conclusions These modest associations between parental age and poor social functioning in the general population parallel the associations between parental age and risk for schizophrenia and autism and suggest that the risk pathways between advanced parental age and schizophrenia and autism might, at least partially, include mildly deleterious effects on social functioning.

Objective: Previous studies indicate that a poor family environment might affect vulnerability for the later manifestation of psychotic illness. The current study aims to examine family functioning prior to the onset of psychosis. Method: Subjects were 42 948, 17-year old males with behavioural disturbances who were asked about the functioning of their family by the Israeli Draft Board. Data on later psychiatric hospitalizations were obtained from a National Psychiatric Hospitalization Registry. Results: Poorer self-reported family functioning was associated with greater risk for later hospitalization for psychosis [adjusted hazard ratio (HR) = 1.16, 95% CI = 1.05–1.27], with a trend in the same direction for schizophrenia (adjusted HR = 1.1, 95% CI = 0.98–1.24). Conclusion: In male adolescents with behavioural disturbances, perceived poorer family functioning is associated with increased risk for non-affective psychotic disorders and schizophrenia. These data do not enable us to determine if perceived familial dysfunction increases vulnerability for psychosis, if premorbid behavioural abnormalities disrupt family life, or neither.

Objectives- Previous studies have shown that poor cognitive and social functioning are associated with increased risk of suicide. This study aimed to examine the association between social and cognitive functioning in adolescence and later completed suicide. Design- Historical prospective cohort study Setting and Participants- Data from the Israeli Draft Board Register for 756,223 Israeli male adolescents aged 16-17 was linked to a causes-of-death data registry, enabling up to 20 year follow-up (mean 10.4 year) for completed suicide (N=993). Results- Poorer cognitive and social functioning were both associated with increased risk of later suicide (adjusted HR=1.44, 95% CI: 1.18-1.76 and adjusted HR=2.3, 95% CI: 1.53-3.4, respectively). Regardless of their level of social functioning, adolescents who scored one point or more below their siblings on the social functioning scale had increased risk of later suicide (adjusted HR=1.41, 95% CI: 1.09-1.82).Conclusions- In adolescent males, poor cognitive and social abilities are associated with a slightly increased risk of later suicide. Male adolescents who function poorly compared to their brothers are also at increased risk for later suicide. These data underscore the importance of cognition and social abilities in understanding the phenomenon of suicide, and particularly indicate the significance of sibling rivalry in the etiology of suicide. However, because suicide is a rare event and poorer cognitive and social function in the general population is very prevalent, these characteristics are not useful as clinical predictors of suicide.