Suicide risk with selective serotonin reuptake inhibitors and other new-generation antidepressants in adults: a systematic review and meta-analysis of observational studies.

BACKGROUND: There is ongoing controversy whether antidepressant use alters suicide risk in adults with depression and other treatment indications. METHODS: Systematic review of observational studies, searching MEDLINE, PsycINFO, Web of Science, PsycARTICLES and SCOPUS for case-control and cohort studies. We included studies on depression and various indications unspecified (including off-label use) reporting risk of suicide and/or suicide attempt for adult patients using selective serotonin reuptake inhibitors (SSRI) and other new-generation antidepressants relative to non-users. Effects were meta-analytically aggregated with random-effects models, reporting relative risk (RR) estimates with 95% CIs. Publication bias was assessed via funnel-plot asymmetry and trim-and-fill method. Financial conflict of interest (fCOI) was defined present when lead authors' professorship was industry-sponsored, they received industry-payments, or when the study was industry-sponsored. RESULTS: We included 27 studies, 19 on depression and 8 on various indications unspecified (n=1.45 million subjects). SSRI were not definitely related to suicide risk (suicide and suicide attempt combined) in depression (RR=1.03, 0.70-1.51) and all indications (RR=1.19, 0.88-1.60). Any new-generation antidepressant was associated with higher suicide risk in depression (RR=1.29, 1.06-1.57) and all indications (RR=1.45, 1.23-1.70). Studies with fCOI reported significantly lower risk estimates than studies without fCOI. Funnel-plots were asymmetrical and imputation of missing studies with trim-and-fill method produced considerably higher risk estimates. CONCLUSIONS: Exposure to new-generation antidepressants is associated with higher suicide risk in adult routine-care patients with depression and other treatment indications. Publication bias and fCOI likely contribute to systematic underestimation of risk in the published literature. REGISTRATION: Open Science Framework, https://osf.io/eaqwn/.

Epigenetic variance in dopamine D2 receptor: a marker of IQ malleability?

Genetic and environmental factors both contribute to cognitive test performance. A substantial increase in average intelligence test results in the second half of the previous century within one generation is unlikely to be explained by genetic changes. One possible explanation for the strong malleability of cognitive performance measure is that environmental factors modify gene expression via epigenetic mechanisms. Epigenetic factors may help to understand the recent observations of an association between dopamine-dependent encoding of reward prediction errors and cognitive capacity, which was modulated by adverse life events. The possible manifestation of malleable biomarkers contributing to variance in cognitive test performance, and thus possibly contributing to the "missing heritability" between estimates from twin studies and variance explained by genetic markers, is still unclear. Here we show in 1475 healthy adolescents from the IMaging and GENetics (IMAGEN) sample that general IQ (gIQ) is associated with (1) polygenic scores for intelligence, (2) epigenetic modification of DRD2 gene, (3) gray matter density in striatum, and (4) functional striatal activation elicited by temporarily surprising reward-predicting cues. Comparing the relative importance for the prediction of gIQ in an overlapping subsample, our results demonstrate neurobiological correlates of the malleability of gIQ and point to equal importance of genetic variance, epigenetic modification of DRD2 receptor gene, as well as functional striatal activation, known to influence dopamine neurotransmission. Peripheral epigenetic markers are in need of confirmation in the central nervous system and should be tested in longitudinal settings specifically assessing individual and environmental factors that modify epigenetic structure.

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Transcranial magnetic stimulation intensities in cognitive paradigms.

BACKGROUND: Transcranial magnetic stimulation (TMS) has become an important experimental tool for exploring the brain's functional anatomy. As TMS interferes with neural activity, the hypothetical function of the stimulated area can thus be tested. One unresolved methodological issue in TMS experiments is the question of how to adequately calibrate stimulation intensities. The motor threshold (MT) is often taken as a reference for individually adapted stimulation intensities in TMS experiments, even if they do not involve the motor system. The aim of the present study was to evaluate whether it is reasonable to adjust stimulation intensities in each subject to the individual MT if prefrontal regions are stimulated prior to the performance of a cognitive paradigm. METHODS AND FINDINGS: Repetitive TMS (rTMS) was applied prior to a working memory task, either at the 'fixed' intensity of 40% maximum stimulator output (MSO), or individually adapted at 90% of the subject's MT. Stimulation was applied to a target region in the left posterior middle frontal gyrus (pMFG), as indicated by a functional magnetic resonance imaging (fMRI) localizer acquired beforehand, or to a control site (vertex). Results show that MT predicted the effect size after stimulating subjects with the fixed intensity (i.e., subjects with a low MT showed a greater behavioral effect). Nevertheless, the individual adaptation of intensities did not lead to stable effects. CONCLUSION: Therefore, we suggest assessing MT and account for it as a measure for general cortical TMS susceptibility, even if TMS is applied outside the motor domain.