Integrative bioinformatics and artificial intelligence analyses of transcriptomics data identified genes associated with major depressive disorders including NRG1.

Major depressive disorder (MDD) is a common mental disorder and is amongst the most prevalent psychiatric disorders. MDD remains challenging to diagnose and predict its onset due to its heterogeneous phenotype and complex etiology. Hence, early detection using diagnostic biomarkers is critical for rapid intervention. In this study, a mixture of AI and bioinformatics were used to mine transcriptomic data from publicly available datasets including 170 MDD patients and 121 healthy controls. Bioinformatics analysis using gene set enrichment analysis (GSEA) and machine learning (ML) algorithms were applied. The GSEA revealed that differentially expressed genes in MDD patients are mainly enriched in pathways related to immune response, inflammatory response, neurodegeneration pathways and cerebellar atrophy pathways. Feature selection methods and ML provided predicted models based on MDD-altered genes with ≥75% of accuracy. The integrative analysis between the bioinformatics and ML approaches identified ten key MDD-related biomarkers including NRG1, CEACAM8, CLEC12B, DEFA4, HP, LCN2, OLFM4, SERPING1, TCN1 and THBS1. Among them, NRG1, active in synaptic plasticity and neurotransmission, was the most robust and reliable to distinguish between MDD patients and healthy controls amongst independent external datasets consisting of a mixture of populations. Further evaluation using saliva samples from an independent cohort of MDD and healthy individuals confirmed the upregulation of NRG1 in patients with MDD compared to healthy controls. Functional mapping to the human brain regions showed NRG1 to have high expression in the main subcortical limbic brain regions implicated in depression. In conclusion, integrative bioinformatics and ML approaches identified putative non-invasive diagnostic MDD-related biomarkers panel for the onset of depression.

A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia.

We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for the affected haplotype in 12 further apparently unaffected members of the family. Psychiatric reports suggested an endophenotype of milder psychiatric illness in 4 of these individuals. Exome and genome sequencing revealed no potentially pathogenic coding or structural variants within the risk haplotype. Filtering for noncoding variants with a minor allele frequency of <0.05 identified 17 variants predicted to have significant effects, the 2 most significant being within or adjacent to the SCEL gene. RNA sequencing of blood from an affected homozygote showed the upregulation of transcription from NDFIP2 and SCEL. NDFIP2 is highly expressed in brain, unlike SCEL, and is involved in determining T helper (Th) cell type 1 and Th2 phenotypes, which have previously been implicated with schizophrenia.

Effect of low-dose acute tryptophan depletion on the specificity of autobiographical memory in healthy subjects with a family history of depression.

RATIONALE: Low-dose acute tryptophan depletion (LD-ATD), while having no effect on mood, has been shown to reduce specificity of autobiographical memory in patients who have recovered from a depressive episode. OBJECTIVES: This study aimed to explore if reduced specificity of autobiographical memory with LD-ATD is common to other groups of individuals at risk of depression, specifically a healthy population with a family history of depression. METHODS: Nineteen healthy young adults with at least one first-degree relative with a history of major depression were recruited. LD-ATD drinks containing 1.15 g of tryptophan (T+) or no tryptophan (T−) were administered on two separate occasions, in a double blind random order crossover design. The Autobiographical Memory Test (AMT) was administered 5 h after drink administration. RESULTS: Analysis of variance revealed a significant difference in the effects of LD-ATD drinks on plasma free tryptophan with no mood change with either drink. There was no within-subject main effect of LD-ATD on the memory task. However, there was a main effect of order of drink. Exploratory analysis of visit 1 data indicated a large between-subject effect (d=1.4) of LD-ATD on AMT with T− associated with less specificity in response to negative cue words (F(1, 17)08.71, p=0.009). CONCLUSIONS: Similar to findings following recovery from depression, LD-ATD can reduce specificity of AMT in the absence of lowered mood in healthy individuals with a strong family history of depression. These findings may reflect a 5-HT-dependent cognitive vulnerability to depression in different populations and warrant further research.

Central glucocorticoid receptor-mediated effects of the antidepressant, citalopram, in humans: a study using EEG and cognitive testing.

Our previous work in cellular and animal models has shown that antidepressants activate glucocorticoid receptor (GR) translocation, induce GR down-regulation, and decrease GR-mediated effects in the presence of GR agonists. However, whether these effects can be extrapolated to the human brain is still unclear. In this study, the effects of four days of treatment with the antidepressant, citalopram (20 mg/day), or placebo, were assessed in a double-blind, placebo-controlled, cross-over study. Central GR-mediated effects were examined by the effects of a single dose of cortisol (30 mg, orally) on two measures known to be sensitive to glucocorticoid administration: EEG alpha power and working memory function. Twenty healthy male subjects aged between 18 and 33 years participated to the study. The results suggest that GR activation by antidepressants, and the subsequent decrease in GR-mediated effects in the presence of GR agonists, indeed occurs in the human brain. Specifically, pre-treatment with citalopram decreased the well-known ability of cortisol to increase EEG alpha power and to impair working memory: cortisol-induced increase in EEG alpha power was (anteriorly) +15 to +20% (p=0.01) after placebo and +5 to +8% (p>0.5) after citalopram; and cortisol-induced increase in working memory errors was (at level 12, on average) 2.50 vs. 4.55 (p<0.05) after placebo and 4.10 vs. 3.35 (p>0.05) after citalopram. No effects were detected on alerting. These results are consistent with the notion that citalopram treatment activates GR translocation and inhibits the functional consequences of the subsequent cortisol administration. Our study further emphasizes the importance of the GR as a target for antidepressant action in humans.

Effects of cortisol on the laterality of the neural correlates of episodic memory.

Alterations in the laterality of cortical activity have been shown in depressive illnesses. One possible pathophysiological mechanism for this is an effect of corticosteroids. We have previously demonstrated that endogenous cortisol concentrations correlate with the asymmetry of cortical activity related to episodic memory in healthy subjects and depressed patients. To further-examine whether this is due to a causal effect of cortisol on the laterality of episodic memory, we studied the effect of exogenous administration of cortisol in healthy subjects. Twenty-three right-handed healthy male volunteers were tested in a double-blind cross-over study. Event-related potentials (ERPs) were recorded during an episodic memory task following a four-day course of 160mg/day cortisol or placebo. Low-resolution brain electromagnetic tomography (LORETA) was used to identify brain regions involved in the neurocognitive task. Cortisol levels were measured in saliva samples. ERP and LORETA analysis following placebo demonstrated significant left parahippocampal activation associated with successful retrieval. Cortisol led to a decrease in the mean early frontal ERP voltage and an increase in the late right ERP voltage. LORETA suggested this to be due to a significant increased late activation of the right superior frontal gyrus. There was no significant effect of cortisol on episodic memory performance. This study suggests that exogenous cortisol leads to more positive-going waveforms over the right than the left hemisphere, possibly due to increased monitoring of the products of retrieval. The results support the hypothesis of causal effects of cortisol on the laterality of cortical activity occurring during an episodic memory task.

A study of the neural correlates of episodic memory and HPA axis status in drug-free depressed patients and healthy controls.

Altered laterality of cortical activity, neuropsychological impairment and hypercortisolaemia have been shown in depression. The neural correlates of episodic memory in healthy subjects demonstrate hemispheric laterality but it is not known whether this is affected by depression and/or hypercortisolaemia. Twenty-seven drug-free depressed patients and 29 matched healthy controls were studied. Event-related potentials (ERPs) were recorded during an episodic memory test. During the study phase, subjects heard words spoken in either a male or female voice. Old and new words were presented visually during a test phase, when subjects were requested to identify words as old or new and recollect the gender of the voice for old words. Cortisol levels were measured in saliva and plasma samples. The results showed a trend for elevated salivary cortisol concentration in depressed patients. Reaction times were significantly longer in patients; however, there was no difference in memory accuracy performance between the two groups. Recollection performance was found to be negatively correlated with age, with a similar trend for cortisol concentrations. ERP activity not specifically related to episodic memory retrieval recorded 200-500ms post-stimulus from controls showed a marked laterality, with higher voltages over the right hemisphere; however, was not seen in patients. There was significant correlation between cortisol and the laterality of the neural activity specifically related to episodic memory retrieval recorded 500-1400ms post-stimulus in both depressed and healthy groups. These unique findings demonstrate that while the laterality of the neural correlates of episodic memory is sensitive to cortisol, it is not altered by the non-specific laterality effects seen in depression.

Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study.

RATIONALE: Dehydroepiandrosterone (DHEA) has been reported to enhance cognition in rodents, although there are inconsistent findings in humans. OBJECTIVES: The aim of this study was to investigate the effects of DHEA administration in healthy young men on episodic memory and its neural correlates utilising an event-related potential (ERP) technique. METHODS: Twenty-four healthy young men were treated with a 7-day course of oral DHEA (150 mg b.d.) or placebo in a double blind, random, crossover and balanced order design. Subjective mood and memory were measured using visual analogue scales (VASs). Cortisol concentrations were measured in saliva samples. ERPs were recorded during retrieval in an episodic memory test. Low-resolution brain electromagnetic tomography (LORETA) was used to identify brain regions involved in the cognitive task. RESULTS: DHEA administration led to a reduction in evening cortisol concentrations and improved VAS mood and memory. Recollection accuracy in the episodic memory test was significantly improved following DHEA administration. LORETA revealed significant hippocampal activation associated with successful episodic memory retrieval following placebo. DHEA modified ERPs associated with retrieval and led to a trend towards an early differential activation of the anterior cingulate cortex (ACC). CONCLUSIONS: DHEA treatment improved memory recollection and mood and decreased trough cortisol levels. The effect of DHEA appears to be via neuronal recruitment of the steroid sensitive ACC that may be involved in pre-hippocampal memory processing. These findings are distinctive, being the first to show such beneficial effects of DHEA on memory in healthy young men.