Differences in schizophrenia treatments by race and ethnicity-analysis of electronic health records.

Racial disparities in prescriptions of anti-psychotics have been highlighted before. However, (i) the evidence on other medications, including anti-depressant or mood stabilizing medications is lacking, and (ii) the role of potentially confounding factors and (iii) specificity of such disparities to schizophrenia (SCZ), are still unknown. We used electronic health records (EHRs) from 224,212 adults to estimate the odds ratios of receiving a prescription for different nervous system medications among patients with SCZ of different race/ethnicity, and analogous linear models to investigate differences in prescribed medication doses. To verify specificity of the observed patterns to SCZ, we conducted analogous analyses in depression and bipolar disorder (BD) patients. We found that Black/African American (AA) and Hispanic patients with SCZ were more likely to be prescribed haloperidol (Black/AA: OR = 1.52 (1.33-1.74); Hispanic: OR = 1.32 (1.12-1.55)) or risperidone (Black/AA: OR = 1.27 (1.11-1.45); Hispanic: OR = 1.40 (1.19-1.64)), but less likely to be prescribed clozapine (Black/AA: OR = 0.40 (0.33-0.49); Hispanic: OR = 0.45 (0.35-0.58)), compared to white patients. There were no race/ethnicity-related differences in the prescribed medication doses. These patterns were not specific to SCZ: Asian, Hispanic and Black/AA patients with BD or depression were more likely to be prescribed anti-psychotics, but less likely to be prescribed antidepressants or mood-stabilizers. In conclusion, we found racial/ethnic disparities in the medications prescribed to patients with SCZ and other psychiatric conditions. We discuss the potential implications for the quality of care for patients of diverse races/ethnicities.

An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients.

RATIONALE: Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. OBJECTIVES: Based on animal models, we investigated the potential for roflumilast, a selective inhibitor of phosphodiesterase type 4 (PDE4), to improve cognition, which may act by increasing intracellular cyclic adenosine monophosphate in brain regions underlying cognitive deficits in schizophrenia. METHODS: This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 µg daily) with 14 days of washout between treatments. The primary endpoints were dorsolateral prefrontal cortex (DLPFC) activation during a visuospatial working memory task measured with fMRI on dosing day 8 and verbal memory and working memory performance change from baseline to day 8. Least square mean change scores were calculated for behavioural outcomes; fMRI data were analysed in SPM12 with bilateral DLPFC as regions of interest. RESULTS: Verbal memory was significantly improved under 250 µg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03). CONCLUSIONS: Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia. TRIAL REGISTRATION: NCT02079844 .

Emerging Temporal Lobe Dysfunction in People at Clinical High Risk for Psychosis.

Clinical high-risk (CHR) individuals have been increasingly utilized to investigate the prodromal phases of psychosis and progression to illness. Research has identified medial and lateral temporal lobe abnormalities in CHR individuals. Dysfunction in the medial temporal lobe, particularly the hippocampus, is linked to dysregulation of glutamate and dopamine via a hippocampal-striatal-midbrain network that may lead to aberrant signaling of salience underpinning the formation of delusions. Similarly, lateral temporal dysfunction may be linked to the disorganized speech and language impairments observed in the CHR stage. Here, we summarize the significance of these neurobiological findings in terms of emergent psychotic symptoms and conversion to psychosis in CHR populations. We propose key questions for future work with the aim to identify the neural mechanisms that underlie the development of psychosis.

Thinking positively: The genetics of high intelligence.

High intelligence (general cognitive ability) is fundamental to the human capital that drives societies in the information age. Understanding the origins of this intellectual capital is important for government policy, for neuroscience, and for genetics. For genetics, a key question is whether the genetic causes of high intelligence are qualitatively or quantitatively different from the normal distribution of intelligence. We report results from a sibling and twin study of high intelligence and its links with the normal distribution. We identified 360,000 sibling pairs and 9000 twin pairs from 3 million 18-year-old males with cognitive assessments administered as part of conscription to military service in Sweden between 1968 and 2010. We found that high intelligence is familial, heritable, and caused by the same genetic and environmental factors responsible for the normal distribution of intelligence. High intelligence is a good candidate for "positive genetics" - going beyond the negative effects of DNA sequence variation on disease and disorders to consider the positive end of the distribution of genetic effects.

Determination of psychosis-related clinical profiles in children with autism spectrum disorders using latent class analysis.

In children with autism spectrum disorders (ASD), high rates of idiosyncratic fears and anxiety reactions and thought disorder are thought to increase the risk of psychosis. The critical next step is to identify whether combinations of these symptoms can be used to categorise individual patients into ASD subclasses, and to test their relevance to psychosis. All patients with ASD (n = 84) admitted to a specialist national inpatient unit from 2003 to 2012 were rated for the presence or absence of impairment in affective regulation and anxiety (peculiar phobias, panic episodes, explosive reactions to anxiety), social deficits (social disinterest, avoidance or withdrawal and abnormal attachment) and thought disorder (disorganised or illogical thinking, bizarre fantasies, overvalued or delusional ideas). Latent class analysis of individual symptoms was conducted to identify ASD classes. External validation of these classes was performed using as a criterion the presence of hallucinations. Latent class analysis identified two distinct classes. Bizarre fears and anxiety reactions and thought disorder symptoms differentiated ASD patients into those with psychotic features (ASD-P: 51 %) and those without (ASD-NonP: 49 %). Hallucinations were present in 26 % of the ASD-P class but only 2.4 % of the ASD-NonP. Both the ASD-P and the ASD-NonP class benefited from inpatient treatment although inpatient stay was prolonged in the ASD-P class. This study provides the first empirically derived classification of ASD in relation to psychosis based on three underlying symptom dimensions, anxiety, social deficits and thought disorder. These results can be further developed by testing the reproducibility and prognostic value of the identified classes.

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.

Longitudinal association between epilepsy and schizophrenia: a population-based study.

A large number of studies have reported an association between epilepsy and major psychiatric conditions. This study investigated the association between epilepsy and later schizophrenia, utilizing a historical-prospective, population-based design. Of the 861,062 17-year-old male adolescents consecutively screened by the Israeli Draft Board and found free of major mental illness, 0.06% suffered from severe, treatment-refractory epilepsy, 0.25% had treated, controlled epilepsy, and 0.16% had a history of seizures which had abated 5 or more years prior to screening. Hospitalization for schizophrenia was ascertained through the Israeli National Psychiatric Hospitalization Case Registry, with an average follow-up of 9.6±1.0years (range: 1.0-10.0years). Risk of hospitalization was calculated using Cox regression analyses, compared to socioeconomic-adjusted risk of hospitalization in the general population of male adolescents. Among adolescents whose epilepsy was nonresponsive to medication, the adjusted risk of hospitalization was significantly increased for schizophrenia (HR=3.89, 95% CI=1.75-89.67). Male adolescents with successfully treated epilepsy were not at increased risk for schizophrenia. Male adolescents with severe, treatment-refractory epilepsy are at increased risk of later schizophrenia. Future studies attempting to understand the biology of this association might focus on this subset of patients, and these patients should be monitored for the appearance of psychosis.

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 600 mg (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 parent's age, parental education, social class, sex and birth order, birth weight and birth complications. Overall, parental age accounted for approximately 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.