Stephen Z. Levine

Advancing Paternal Age and Risk of Autism New Evidence from a Population-Based Study and a Meta-Analysis of Epidemiological Studies.

Advanced paternal age has been suggested as a risk factor for autism, but empirical evidence is mixed. This study examines whether the association between paternal age and autism in the offspring (1) persists controlling for documented autism risk factors, including family psychiatric history, perinatal conditions, infant characteristics and demographic variables; (2) may be explained by familial traits associated with the autism phenotype, or confounding by parity; and (3) is consistent across epidemiological studies. Multiple study methods were adopted. First, a Swedish 10-year birth cohort (N=1 075 588) was established. Linkage to the National Patient Register ascertained all autism cases (N=883). Second, 660 families identified within the birth cohort had siblings discordant for autism. Finally, meta-analysis included population-based epidemiological studies. In the birth cohort, autism risk increased monotonically with increasing paternal age. Offspring of men aged ⩾50 years were 2.2 times (95% confidence interval: 1.26–3.88: P=0.006) more likely to have autism than offspring of men aged ⩽29 years, after controlling for maternal age and documented risk factors for autism. Within-family analysis of discordant siblings showed that affected siblings had older paternal age, adjusting for maternal age and parity (P<0.0001). Meta-analysis demonstrated advancing paternal age association with increased risk of autism across studies. These findings provide the strongest evidence to date that advanced paternal age is a risk factor for autism in the offspring. Possible biological mechanisms include de novo aberration and mutations or epigenetic alterations associated with aging.

Negative symptoms have greater impact on functioning than positive symptoms in schizophrenia: analysis of CATIE data.

Increased attention has been given to treatment of negative symptoms and its potential impact on functional outcomes, however previous inferences have been confounded by the fact that measures of functional outcomes often use items similar to those of negative symptoms. We attempted to discern the relative effects of negative symptoms on functioning, as compared to other symptoms, using data from the National Institute of Mental Health CATIE trial of chronic schizophrenia (n=1447) by examining correlations of Positive and Negative Syndrome Scale factors, Calgary Depression Rating Scale and select items from Heinrichs and Lehmans Quality of Life Scales measuring aspects of functioning that did not overlap with negative symptoms. Baseline functioning and change in functioning were more strongly related to PANSS negative factor than any of the other symptoms - though the amount of variance explained by symptom changes in general was small. The data suggests that improvement in negative symptoms may have a distinctive and independent effect on functional outcome relative to other symptoms. This should be further tested in studies where negative symptoms improve without concomitant improvement of other symptoms.

Examining the Relationship Between Resilience and Posttraumatic Growth

To extend the literature the present study aims to examine the interrelationships between resilience (defined by a lack of posttraumatic stress disorder following trauma) and posttraumatic growth. Two studies were conducted of Israeli: (a) adolescents exposed to terror (N = 2908), and (b) citizens and army personnel following the second Lebanon War (N = 588). Across studies the results showed that high levels of resilience were associated with the lowest posttraumatic growth scores. The results imply that although growth and resilience are both salutogenic constructs they are inversely related. The theoretical and clinical implications of these findings are discussed.

A population based elaboration of the role of age of onset on the course of schizophrenia

BACKGROUND Despite suggestions that an earlier age of onset and being male confer to a poorer course of schizophrenia, evidence regarding when these effects are most salient appears to be ambiguous. AIMS To examine the relationship of age of first hospitalization and sex with the course of hospitalization in a population based cohort. METHOD All first admissions for schizophrenia in a national population based cohort in Israel from 1978 to 1992 were followed through 1996 (n=12,071) using data from the National Psychiatric Hospitalization Case Registry of the State of Israel, a complete national registry of psychiatric admissions. Recursive partitioning was conducted to empirically determine cut-off points for age groups showing the greatest difference on the variables of interest. RESULTS A younger age of first hospital admission was associated with a greater likelihood of having more than one hospital admission, longer first admissions, more hospital admissions and more inpatient days per year. Of patients with age of first admission below 17, 82.5% had more than one admission which decreased for subsequent age groups to 73.54% (18-28), 69.36% (29-31), 62.88% (32-45), and 50.77% (over 45). Men had an earlier first admission than women, and had slightly more cut-off values. Irrespective of sex, the relationship between age at first admission and later hospitalization conformed to a linear trend. CONCLUSIONS An earlier onset corresponds linearly with the severity of the course of illness and appears to have prognostic value.

Posttraumatic growth in adolescence: Examining its components and relationship with PTSD

To address gaps in the literature, this study examined the components of posttraumatic growth, and the relationship between growth and posttraumatic stress disorder (PTSD). Participants were from a pooled sample of 4,054 Israeli adolescents exposed to terror of whom 210 (5.5%) met criteria for PTSD. Measures included the Child Post-Traumatic Stress Reaction Index and Posttraumatic Growth Inventory. Principal components analysis showed two correlated components of outward and intrapersonal growth. Regression modeling showed that the relationship between the growth and PTSD measures was linear and curvilinear (inverted-U). These results replicated accounting for heterogeneity in PTSD, exposure and subsamples. Collectively, the results imply that posttraumatic growth in adolescence is characterized by two robust components, and is greatest at moderate posttraumatic stress levels.

Trajectories of the course of schizophrenia: from progressive deterioration to amelioration over three decades.

BACKGROUND The extent of heterogeneity in the long-term course of schizophrenia is unclear. AIMS To examine the course of schizophrenia in a population-based cohort. METHODS This study included all Israeli individuals born in 1970-1988, of North African or European origin (N=2290), entered in the National Psychiatric Hospitalization Case Registry with a last discharge diagnosis of schizophrenia (1978-2004) and followed to 2009. Linked socio-demographic information was extracted from the Population Registry. Based on the number of hospitalized days at each age, trajectory groups were empirically derived, plotted and compared on psychiatric hospitalization measures of the course of illness, social factors and family stressors. RESULTS Trajectory analysis identified four course groups. Group I (57%) assumed a prototypical course, had an average first hospitalization age of 20, deteriorated until 23 and then ameliorated. Group II (15.5%) assumed an early-onset protracted course, had an average first hospitalization age of 17.1, and deteriorated until 21. Group III (15%) assumed a late-onset with longest deterioration period course, had an average first hospitalization age of 22.7, and deteriorated until 29. Group IV (12%) assumed an early-onset refractory illness course, had an average first hospitalization age of 18, and had the longest hospitalization period. Groups significantly differed on hospitalization (i.e., onset), social (i.e., socioeconomic and ethnic status) and familial factors (i.e., parental death). Despite group differences all deteriorated and then ameliorated on average by the age of 23. CONCLUSIONS The course of schizophrenia was heterogeneous, yet evolved from deterioration to assume a course consistent with amelioration.

Initial Severity of Schizophrenia and Efficacy of Antipsychotics: Participant-Level Meta-analysis of 6 Placebo-Controlled Studies

IMPORTANCE Antipsychotic drugs constitute the mainstay in the treatment of schizophrenia, and their efficacy is well established in hundreds of randomized clinical trials. However, it is not known whether they are effective or how effective they are across the wide range of baseline symptom severity. OBJECTIVE To examine the influence of baseline severity of schizophrenia on the efficacy of antipsychotic drugs. DESIGN, SETTING, AND PARTICIPANTS Meta-analysis of participant-level data from 3 pivotal randomized trials of acute schizophrenia (n = 611) and 3 pivotal trials in patients with predominantly negative symptoms of schizophrenia (n = 475). INTERVENTIONS Olanzapine or risperidone vs placebo, and amisulpride vs placebo. MAIN OUTCOMES AND MEASURES Change scores on the Positive and Negative Syndrome Scale (PANSS; score range, 30-210) and the Scale for the Assessment of Negative Symptoms (SANS; score range, 0-125) up to 6 weeks after baseline. The relationship between baseline and change scores for the drug and placebo groups was examined with 8 competing mixed-effects models for repeated measures. RESULTS The best-fitting models showed that, for both types of patients, the interactions between baseline symptom severity and treatment were statistically significant (P < .01). The greater the baseline severity was, the greater the magnitude of the differences was between active treatment and placebo. In acute treatment, the mean differences in PANSS change scores were 9.5 points for patients who were mildly ill at baseline (baseline PANSS score of 58), 13.7 for moderately ill patients (baseline PANSS score of 75), 18.8 for markedly ill patients (baseline PANSS score of 95), and 24.0 for severely ill patients (baseline PANSS score of 116). In treatment of predominantly negative symptoms, the mean differences in SANS change scores were 1.7 for those who were moderately ill (baseline SANS score of 55), 5.7 for markedly ill patients (baseline SANS score of 70), and 9.7 for severely ill patients (baseline SANS score of 85). CONCLUSIONS AND RELEVANCE We can expect benefits of antipsychotic drugs for the full spectrum of patients likely to be treated for acute schizophrenia and for highly symptomatic patients with predominantly negative symptoms. Toward the mildest end of the spectrum, clinicians need to be aware that patients benefit less in terms of symptom improvement but may experience full adverse effects of antipsychotics. Clinicians also need to be aware that in addition to the treatment of active symptoms, which was the focus of this study, antipsychotics have another important action, namely to prevent relapses among patients in remission.

Trajectories and Antecedents of Treatment Response Over Time in Early-Episode Psychosis

BACKGROUND Little is known about the extent of heterogeneity of symptomatology in treated early-onset psychosis. The current study aims to quantify the extent of heterogeneity in trajectories of treated symptom severity in early-episode psychosis and their antecedents. METHODS Data were from 491 persons with early-episode psychosis from a clinical trial of haloperidol and risperidone. Positive and Negative Syndrome Scale (PANSS) administrations were used to measure symptom severity trajectories for (a) rapid treatment response scores over 4 weeks and (b) medium-term course over 24 weeks. Baseline antecedents included sex, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis, age of onset, the Premorbid Adjustment Scale, and a cognitive test battery. Symptom severity trajectories were calculated with mixed mode latent class regression modeling from which groups were derived. RESULTS Five groups based on PANSS scores over time were identified. Over 4 weeks, 3 groups with varied baseline PANSS scores (54-105) did not surpass 30% PANSS improvement. Another group improved and then was stable (n = 76,15.3%), and another showed marked improvement (n = 94,18.9%). Logistic regression showed that membership in the best response trajectory was associated with not having a diagnosis of schizophrenia, good premorbid functioning, and higher cognitive functioning, whereas membership in the poor response trajectory was associated with earlier age of onset and poorer cognitive functioning. CONCLUSION Amelioration generally characterizes treated symptom severity. Age of onset, diagnosis, cognitive functioning, and premorbid functioning have prognostic value in predicting treatment response trajectories.

Elaboration on the Early-Onset Hypothesis of Antipsychotic Drug Action: Treatment Response Trajectories

BACKGROUND To extend the early treatment response literature, this article aims to quantify the extent of heterogeneity and describe the characteristics of treatment response trajectories in schizophrenia. METHODS Data were extracted from two double-blind, randomized clinical trials that compared amisulpride with risperidone in schizophrenia (n = 538). Available Brief Psychiatric Rating Scale (BPRS) administrations from baseline to Week 8 were used to assess treatment response. Trajectories were calculated with mixed-mode latent class regression modeling from which groups were derived. These groups were compared on clinical and background characteristics. RESULTS At Week 8, five treatment response trajectories were identified, undifferentiated by medication received, and characterized by varied amelioration levels. Three trajectory groups (n = 414, 76.9%) showed a treatment response trend of amelioration. Of these, two trajectory groups had similar dropout rates (22%, 25%), and two did not significantly differ on BPRS % reduction (approximately 55%, approximately 58%). Trajectory Group 2 (n = 44, 8.2%) was characterized by being oldest, a 21.3 BPRS % reduction, the highest BPRS severity scores, the highest dropout rate (61.4%), and 11.8% meeting Andreasens remission criterion. Among Trajectory Group 4 (n = 80, 14.9%) symptom reduction was considerable during the first 2 weeks and then gradual. This trajectory group was characterized by being youngest, male, suffering from paranoid schizophrenia, the lowest dropout rate (6.3%), average BPRS baseline scores, an 88.9% BPRS reduction, and 96% meeting Andreasens remission criterion. CONCLUSIONS Generally, amelioration characterizes early treatment response, such that approximately 77% are moderate responders, approximately 15% are rapid treatment responders, and approximately 8% are poor responders.

A Population-Based Psychometric Validation Study of the Strengths and Difficulties Questionnaire – Hebrew Version

This study presents the psychometric properties of the Strengths and Difficulties Questionnaire – Hebrew version (SDQ-H), used in the Israel Survey on Mental Health among Adolescents (ISMEHA). The SDQ-H was administered to a representative sample of 611 adolescents and their mothers. Structural validity was evaluated by exploratory and confirmatory factor analysis and the Development and Well-Being Assessment (DAWBA) inventory was used as “gold standard” to test convergent and discriminant validity. Internal consistency and normative scores were established. Agreement was found with the original factor structure, except for the Peer problem scale. Concurrent and discriminant validity varied from fair to very good for most scales. Total Difficulties scores showed better discriminant validity for the adolescents’ than the mothers’ report for internalizing disorders, and the opposite for externalizing disorders. Internal consistency for the Total Difficulties was 0.77 and for the Hyperactivity scale it was 0.73. It was lower for the other scales, particularly for the Peer problems scale. The findings suggest reasonable psychometric properties of the SDQ-H. Comparisons with other translated SDQ versions are presented.