Molecular mechanisms of psychiatric diseases

Blokhin, Ilya O.; Khorkova, Olga; Saveanu, Radu V.; Wahlestedt, Claes

doi:10.1016/j.nbd.2020.105136

Cited by 31 publications

(20 citation statements)

References 187 publications

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“…Dysregulation of monoamine transmitter function is the best established pathogenetic factor of major depressive disorder (MDD) (Blokhin et al, 2020). However, the long temporal delay between the restoration of monoamine levels at the synapse level and the clinical effect of antidepressive drugs, and the wide range of polygenetic risk factors (Hyman, 2014), point to alternative or complementary pathways upstream of neurotransmitter disturbances.…”

Section: Introductionmentioning

confidence: 99%

Association of CSF sTREM2, a marker of microglia activation, with cholinergic basal forebrain volume in major depressive disorder

Teipel

Bruno

Plaska

et al. 2021

Journal of Affective Disorders

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Section: Introductionmentioning

confidence: 99%

Association of CSF sTREM2, a marker of microglia activation, with cholinergic basal forebrain volume in major depressive disorder

Teipel

Bruno

Plaska

et al. 2021

Journal of Affective Disorders

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“…Schizophrenia is closely linked to genetic factors, including small nucleotide polymorphisms (SNPs), copy number variations and changes in gene expression. Combinations of different pathogenic mechanisms, including aberrant DNA methylation, altered histone code, dysregulated long noncoding RNA (lncRNA)-dependent tethering of epigenetic complexes to DNA, aberrant polyadenylation of pre-mRNAs, and mis-splicing, have been reported to play a role in schizophrenia development[ 9 ]. The hereditary burden of schizophrenia is estimated to be approximately 80%.…”

Section: Genetics and Schizophreniamentioning

confidence: 99%

“…Schizophrenia is linked to pathophysiological DNA methylation of several genes, including those encoding reelin, catechol-O-methyltransferase (COMT), monoamine oxidase A, serotonin receptor 2A, the transcription factor SOX-10, and others. Unfortunately, no schizophrenia-specific “methylation panel” has been proposed, and it has not yet been clarified whether these changes represent causes or consequences of schizophrenia development[ 9 ].…”

Section: Genetics and Schizophreniamentioning

confidence: 99%

“…MicroRNAs (miRNAs) are small noncoding RNAs that regulate more than 50% of protein-coding genes by acting as promoter or enhancer elements; miRNAs might participate in histone, DNA, or chromatin methylation and modification. Both lncRNAs and miRNAs can be affected by different genetic variants, especially SNPs, which could increase the risk of schizophrenia onset[ 9 , 10 ].…”

Section: Genetics and Schizophreniamentioning

confidence: 99%

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Novel approaches in schizophrenia-from risk factors and hypotheses to novel drug targets

Ľupták¹,

Michaličková²,

Fišar³

et al. 2021

WJP

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Schizophrenia is a severe psychiatric disorder characterized by emotional, behavioral and cognitive disturbances, and the treatment of schizophrenia is often complicated by noncompliance and pharmacoresistance. The search for the pathophysiological mechanisms underlying schizophrenia has resulted in the proposal of several hypotheses to explain the impacts of environmental, genetic, neurodevelopmental, immune and inflammatory factors on disease onset and progression. This review discusses the newest insights into the pathophysiology of and risk factors for schizophrenia and notes novel approaches in antipsychotic treatment and potential diagnostic and theranostic biomarkers. The current hypotheses focusing on neuromediators (dopamine, glutamate, and serotonin), neuroinflammation, the cannabinoid hypothesis, the gut-brain axis model, and oxidative stress are summarized. Key genetic features, including small nucleotide polymorphisms, copy number variations, microdeletions, mutations and epigenetic changes, are highlighted. Current pharmacotherapy of schizophrenia relies mostly on dopaminergic and serotonergic antagonists/partial agonists, but new findings in the pathophysiology of schizophrenia have allowed the expansion of novel approaches in pharmacotherapy and the establishment of more reliable biomarkers. Substances with promising results in preclinical and clinical studies include lumateperone, pimavanserin, xanomeline, roluperidone, agonists of trace amine-associated receptor 1, inhibitors of glycine transporters, AMPA allosteric modulators, mGLUR 2-3 agonists, D-amino acid oxidase inhibitors and cannabidiol. The use of anti-inflammatory agents as an add-on therapy is mentioned.

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“…2 It can be driven by neuroendocrine, 3 neuroimmune, 4 metabolic 5 or neurotransmitter (particularly serotonin) dysregulation. 6 The main treatment for major depressive episodes is antidepressant drugs, but these show limited efficacy: half of patients experiencing a major depressive episode do not achieve a response, and two-thirds do not achieve remission after 3 months of treatment. 7 Moreover, the mechanisms of action of these drugs are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Blood microbiota and metabolomic signature of major depression before and after antidepressant treatment: a prospective case–control study

Ciocan

Cassard-Doulcier

Becquemont

et al. 2021

jpn

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Background: The microbiota interacts with the brain through the gut–brain axis, and a distinct dysbiosis may lead to major depressive episodes. Bacteria can pass through the gut barrier and be found in the blood. Using a multiomic approach, we investigated whether a distinct blood microbiome and metabolome was associated with major depressive episodes, and how it was modulated by treatment. Methods: In this case–control multiomic study, we analyzed the blood microbiome composition, inferred bacterial functions and metabolomic profile of 56 patients experiencing a current major depressive episode and 56 matched healthy controls, before and after treatment, using 16S rDNA sequencing and liquid chromatography coupled to tandem mass spectrometry. Results: The baseline blood microbiome in patients with a major depressive episode was distinct from that of healthy controls (patients with a major depressive episode had a higher proportion of Janthinobacterium and lower levels of Neisseria) and changed after antidepressant treatment. Predicted microbiome functions confirmed by metabolomic profiling showed that patients who were experiencing a major depressive episode had alterations in the cyanoamino acid pathway at baseline. High baseline levels of Firmicutes and low proportions of Bosea and Tetrasphaera were associated with response to antidepressant treatment. Based on inferred baseline metagenomic profiles, bacterial pathways that were significantly associated with treatment response were related to xenobiotics, amino acids, and lipid and carbohydrate metabolism, including tryptophan and drug metabolism. Metabolomic analyses showed that plasma tryptophan levels are independently associated with response to antidepressant treatment. Limitations: Our study has some limitations, including a lack of information on blood microbiome origin and the lack of a validation cohort to confirm our results. Conclusion: Patients with depression have a distinct blood microbiome and metabolomic signature that changes after treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients who are experiencing a major depressive episode.

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Molecular mechanisms of psychiatric diseases

Cited by 31 publications

References 187 publications

Association of CSF sTREM2, a marker of microglia activation, with cholinergic basal forebrain volume in major depressive disorder

Association of CSF sTREM2, a marker of microglia activation, with cholinergic basal forebrain volume in major depressive disorder

Novel approaches in schizophrenia-from risk factors and hypotheses to novel drug targets

Blood microbiota and metabolomic signature of major depression before and after antidepressant treatment: a prospective case–control study

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