Avi Reichenberg

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.

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment

Community-based studies suggest that cannabis products that are high in Δ9-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ2=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6±18.9%) compared with the CBD group (-0.4%±9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

Paternal age and intelligence: implications for age-related genomic changes in male germ cells.

Background A robust association between advancing paternal age and schizophrenia risk is reported, and genetic changes in the germ cells of older men are presumed to underlie the effect. If that is so, then the pathway may include effects on cognition, as those with premorbid schizophrenia are reported to have lower intelligence. There are also substantial genetic influences on intelligence, so de novo genetic events in male germ cells, which accompany advancing paternal age, may plausibly influence offspring intelligence. Objective An association of paternal age with IQ in healthy adolescents may illuminate the mechanisms that link it to schizophrenia. Method We examined the association of paternal age and IQ scores using the Israeli Army Board data on 44 175 individuals from a richly described birth cohort, along with maternal age and other potential modifiers. Results A significant inverted U-shaped relationship was observed between paternal age and IQ scores, which was independent from a similar association of IQ scores with maternal age. These relationships were not significantly attenuated by controlling for multiple possible confounding factors, including the other parents age, parental education, social class, sex and birth order, birth weight and birth complications. Overall, parental age accounted for ∼2% of the total variance in IQ scores, with later paternal age lowering non-verbal IQ scores more than verbal IQ scores. Conclusion We found independent effects of maternal and paternal age on offspring IQ scores. The paternal age effect may be explained by de novo mutations or abnormal methylation of paternally imprinted genes, whereas maternal age may affect fetal neurodevelopment through age-related alterations in the in-utero environment. The influence of late paternal age to modify non-verbal IQ may be related to the pathways that increase the risk for schizophrenia in the offspring of older fathers.

Deficits in visual sustained attention differentiate genetic liability and disease expression for Schizophrenia from Bipolar Disorder

BACKGROUND There is mounting evidence for shared genetic liability to psychoses, particularly with respect to Schizophrenia (SZ) and Bipolar Disorder (BD), which may also involve aspects of cognitive dysfunction. Impaired sustained attention is considered a cardinal feature of psychoses but its association with genetic liability and disease expression in BD remains to be clarified. METHODS Visual sustained attention was assessed using the Degraded Symbol Continuous Performance Test (DS-CPT) in a sample of 397 individuals consisting of 50 remitted SZ patients, 119 of their first degree relatives, 47 euthymic BD patients, 88 of their first degree relatives and 93 healthy controls. Relatives with a personal history of schizophrenia or bipolar spectrum disorders were excluded. Performance on the DS-CPT was evaluated based on the response criterion (the amount of perceptual evidence required to designate a stimulus as a target) and sensitivity (a signal-detection theory measure of signal/noise discrimination). RESULTS We found no effect of genetic risk or diagnosis for either disorder on response criterion. In contrast, impaired sensitivity was seen in SZ patients and to a lesser degree in their relatives but not in BD patients and their relatives. These findings were not attributable to IQ, medication, age of onset or duration of illness. CONCLUSIONS Our results argue for the specificity of visual sustained attention impairment in differentiating SZ from BD. They also suggest that compromised visual information processing is a significant contributor to these deficits in SZ.

Do autism-related personality traits explain higher paternal age in autism?

LD block within the ACE gene, identified as described in Baghai and co-workers, which spans the promoter region as well as all coding regions for ACE isoforms 1 and 2. Only for rs4311, the P-value was still significant after Bonferroni correction for multiple testing (Table 1). All five SNPs entered the replication and significant P-values after Bonferroni correction were found for rs4311 and rs4333 (Table 1); rs4329 (P = 0.04), rs4344 (P = 0.01), rs4353 (P = 0.04) were nominally associated in sample 2. Although the association replicated in both samples, the direction of this association was different. The T allele of rs4311 and 4333 was the risk allele in sample 1, while we observed a heterozygous disadvantage for both SNPs in sample 2. The reason for true but diverse, in extreme reversed associations, known as the flip-flop phenomenon, are discussed in a recent publication by Lin et al. Flip-flop associations may indicate heterogeneous effects of the same true variant due to differences in the LD structure between the genotyped SNPs and the disease susceptibility locus in two investigated samples. Following this idea, the reported SNPs could be non-causal but in LD with a genuine causal variant and/or multilocus effects that we are not able to account for, and this may lead to different associations. Interestingly, these SNPs are located in the same LD block as the promoter variant associated with unipolar depression, but are clustered at the 30 end of this block. While the variant rs4291 associated with unipolar depression was not significantly associated with panic disorders, all of the five SNPs associated with panic disorder were also nominally associated with unipolar depression. The ACE gene may thus be an example for a genetic or locus overlap between anxiety and depression. Taken together, we have identified an association of two SNPs (rs4311 and rs4333) in the ACE gene with syndromal panic attacks, which could be replicated in an independent case/control sample, although in a different direction. Further studies have to be performed to elucidate the functional correlates of this association, especially regarding ACE activity in vivo in patients with panic attacks.

Advanced paternal age is associated with altered DNA methylation at brain-expressed imprinted loci in inbred mice: Implications for neuropsychiatric disease

Advanced paternal age is associated with altered DNA methylation at brain-expressed imprinted loci in inbred mice: implications for neuropsychiatric disease

Genetic modulation of the response bias towards facial displays of anger and happiness

BACKGROUND Investigating genetic modulation of emotion processing may contribute to the understanding of heritable mechanisms of emotional disorders. The aim of the present study was to test the effects of catechol-O-methyltransferase (COMT) val158met and serotonin-transporter-linked promoter region (5-HTTLPR) polymorphisms on facial emotion processing in healthy individuals. METHODS Two hundred and seventy five (167 female) participants were asked to complete a computerized facial affect recognition task, which involved four experimental conditions, each containing one type of emotional face (fearful, angry, sad or happy) intermixed with neutral faces. Participants were asked to indicate whether the face displayed an emotion or was neutral. The COMT-val158met and 5-HTTLPR polymorphisms were genotyped. RESULTS Met homozygotes (COMT) showed a stronger bias to perceive neutral faces as expressions of anger, compared with val homozygotes. However, the S-homozygotes (5-HTTLPR) showed a reduced bias to perceive neutral faces as expressions of happiness, compared to L-homozygotes. No interaction between 5-HTTLPR and COMT was found. CONCLUSIONS These results add to the knowledge of individual differences in social cognition that are modulated via serotonergic and dopaminergic systems. This potentially could contribute to the understanding of the mechanisms of susceptibility to emotional disorders.

Early-life metal exposure and schizophrenia: A proof-of-concept study using novel tooth-matrix biomarkers.

BACKGROUND Despite evidence for the effects of metals on neurodevelopment, the long-term effects on mental health remain unclear due to methodological limitations. Our objective was to determine the feasibility of studying metal exposure during critical neurodevelopmental periods and to explore the association between early-life metal exposure and adult schizophrenia. METHODS We analyzed childhood-shed teeth from nine individuals with schizophrenia and five healthy controls. We investigated the association between exposure to lead (Pb(2+)), manganese (Mn(2+)), cadmium (Cd(2+)), copper (Cu(2+)), magnesium (Mg(2+)), and zinc (Zn(2+)), and schizophrenia, psychotic experiences, and intelligence quotient (IQ). We reconstructed the dose and timing of early-life metal exposures using laser ablation inductively coupled plasma mass spectrometry. RESULTS We found higher early-life Pb(2+) exposure among patients with schizophrenia than controls. The differences in log Mn(2+) and log Cu(2+) changed relatively linearly over time to postnatal negative values. There was a positive correlation between early-life Pb(2+) levels and psychotic experiences in adulthood. Moreover, we found a negative correlation between Pb(2+) levels and adult IQ. CONCLUSIONS In our proof-of-concept study, using tooth-matrix biomarker that provides direct measurement of exposure in the fetus and newborn, we provide support for the role of metal exposure during critical neurodevelopmental periods in psychosis.

Effects of advanced paternal age on trajectories of social behavior in offspring

Our study is the first investigation of the effects of advanced paternal age (APA) on the developmental trajectory of social behavior in rodent offspring. Given the strong epidemiological association between APA and sexually dimorphic neurodevelopmental disorders that are characterized by abnormalities in social behavior (autism, schizophrenia), we assessed sociability in male and female inbred mice (C57BL/6J) across postnatal development (N = 104) in relation to paternal age. We found differences in early social behavior in both male and female offspring of older breeders, with differences in this social domain persisting into adulthood in males only. We showed that these social deficits were not present in the fathers of these offspring, confirming a de novo origin of an altered social trajectory in the offspring generation. Our results, highly novel in rodent research, support the epidemiological observations in humans and provide evidence for a causal link between APA, age‐related changes in the paternal sperm DNA and neurodevelopmental disorders in their offspring.

How antipsychotics impact the different dimensions of Schizophrenia: A test of competing hypotheses

The clinical expression of schizophrenia is generally reported to be expressed by three to five different factors (i.e. positive, negative, disorganization, excitability, anxiety-depression symptoms). It is often claimed that antipsychotic medications are particularly helpful for positive symptoms, but not for the others, suggesting a differential efficacy for different aspects of the disorder. We formally tested this claim. Using Structural Equation Modeling in two large [1884 patients] clinical trials in schizophrenia, we compared the model of a common general effect of antipsychotics to models whereby the antipsychotics have multiple and differential effects on the different factors of the illness. We validated the generalizability of the model in further trials involving antipsychotics in chronic [1460 patients] and first-episode patients [1053 patients]. Across different populations, different trials and different antipsychotics - the best-fitting model suggests that symptom response in schizophrenia is underpinned by a single general effect with secondary and minor lower-order effects on specific symptom domains. This single-factor model explained nearly 80% of the variance, was superior to the assumption of unique efficacy for specific domains; and replicated across antipsychotics and illness stages. Despite theoretical and pharmacological claims the differential efficacy of antipsychotics on the various dimensions of schizophrenia is not supported in the prevailing data. The implication of this finding for the measurement of treatment response and our understanding of the neurobiology of antipsychotic action, for clinical practice and for future drug development are discussed.