Therapy Response Prediction in Major Depressive Disorder: Current and Novel Genomic Markers Influencing Pharmacokinetics and Pharmacodynamics

Shalimova, Alena A.; Babasieva, Viktoria; Chubarev, Vladimir N.; Tarasov, Vadim V.; Schiöth, Helgi B.; Mwinyi, Jessica

doi:10.2217/pgs-2020-0157

Cited by 12 publications

(8 citation statements)

References 196 publications

(190 reference statements)

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“…Our observations are in line with published data demonstrating an association between the PAM pathway and psychiatric illness [ 39 ]. PAM pathway disruption of protein synthesis and actin dynamics can lead to abnormal neuronal morphology, learning/memory deficits, and psychiatric disease [ 19 , 22 , 40 – 45 ].…”

Section: Discussionsupporting

confidence: 93%

AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology

et al. 2022

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Background Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms. Methods (1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in the AKT3 gene. (3) We analyzed the psychiatric adverse events (AEs) of patients treated with M2698 (p70S6K/AKT1/AKT3 inhibitor) and with other PI3K/AKT/mTOR pathway inhibitors. Results (1) Proteins encoded by AKT3 (AKT3Q60H) and AKT1 (AKT1Q61H) mutants had lower kinase activity than those encoded by wild-type AKT3 and AKT1, respectively. Molecular modeling of the AKT1-Q61H mutant suggested conformational changes that may reduce the binding of D3-phosphorylated phosphoinositides to the PH domain. (2) We identified multiple SNPs in the AKT3 gene that were strongly associated with schizophrenia (p < 0.5 × 10–8). (3) Psychiatric AEs, mostly insomnia, anxiety, and depression, were noted in 29% of patients treated with M2698. In randomized studies, their incidence was higher in PI3K/AKT/mTOR inhibitor arms compared with placebo arms. All psychiatric AEs were reversible. Conclusions Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring.

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Section: Discussionsupporting

confidence: 93%

AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology

et al. 2022

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“…In this group, genes related to the cytochrome p450 (CYP) family are abundant and shared between different pathways. Previous studies have focused on variants in CYP genes and their association with SSRI metabolism and the effectiveness of the treatment (Hodgson et al, 2013; Shalimova et al, 2021; Thakur et al, 2007; Veldic et al, 2019). On the other hand, our approach puts forward the idea that they can be used for diagnosis.…”

Section: Resultsmentioning

confidence: 99%

Downregulated NPAS4 in multiple brain regions is associated with Major Depressive Disorder

Selçuk

Aksu

Dereli

et al. 2022

Preprint

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Major Depressive Disorder (MDD) is a commonly observed psychiatric disorder that affects more than 2% of the world population with a rising trend. However, disease-associated pathways and biomarkers are yet to be fully comprehended. In this study, we analyzed previously generated RNA-seq data across seven different brain regions from three distinct studies to identify differentially and co-expressed genes for patients with MDD. Differential gene expression (DGE) analysis revealed that NPAS4 is the only gene downregulated in three different brain regions. Furthermore, co-expressing gene modules responsible for glutamatergic signaling are negatively enriched in these regions. We used the results of both DGE and co-expression analyses to construct a novel MDD-associated pathway. In our model, we propose that disruption in glutamatergic signaling-related pathways might be associated with the downregulation of NPAS4 and many other immediate-early genes (IEGs) that control synaptic plasticity. In addition to DGE analysis, we identified the relative importance of KEGG pathways in discriminating MDD phenotype using a machine learning-based approach. We anticipate that our study will open doors to developing better therapeutic approaches targeting glutamatergic receptors in the treatment of MDD.

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“…Importantly, no reduction in the global prevalence or burden has been detected for depression or anxiety since 1990, despite compelling evidence of interventions that reduce their impact ( 4 ). The high costs to individuals and society demand efficacious treatments, yet 30% of patients fail to respond to current serotoninergic-based pharmacotherapeutics, while 70% do not achieve complete remission ( 5 ). Outcomes for Major Depressive Disorder (MDD) are associated with a reduced life expectancy of 10–20 years, despite active treatment.…”

Section: Introductionmentioning

confidence: 99%

The effects of physical activity on glutamate neurotransmission in neuropsychiatric disorders

Baskerville

McGrath²,

Castell³

2023

Front. Sports Act. Living

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Physical activity (PA) is an effective way of increasing cognitive and emotional health and counteracting many psychiatric conditions. Numerous neurobiological models for depression have emerged in the past 30 years but many struggle to incorporate the effects of exercise. The hippocampus and pre-frontal cortex (PFC) containing predominantly glutamate neurotransmission, are the centres of changes seen in depression. There is therefore increasing interest in glutamatergic systems which offers new paradigms of understanding mechanisms connecting physical activity, stress, inflammation and depression, not explained by the serotonin theories of depression. Similar hippocampal glutamate dysfunction is observed in many other neuropsychiatric conditions. Excitatory glutamate neurones have high functionality, but also high ATP requirements and are therefore vulnerable to glucocorticoid or pro-inflammatory stress that causes mitochondrial dysfunction, with synaptic loss, culminating in depressed mood and cognition. Exercise improves mitochondrial function, angiogenesis and synaptogenesis. Within the glutamate hypothesis of depression, the mechanisms of stress and inflammation have been extensively researched, but PA as a mitigator is less understood. This review examines the glutamatergic mechanisms underlying depression and the evidence of physical activity interventions within this framework. A dynamic glutamate-based homeostatic model is suggested whereby stress, neuroinflammation and PA form counterbalancing influences on hippocampal cell functionality, which manifests as depression and other neuropsychiatric conditions when homeostasis is disrupted.

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Therapy Response Prediction in Major Depressive Disorder: Current and Novel Genomic Markers Influencing Pharmacokinetics and Pharmacodynamics

Cited by 12 publications

References 196 publications

AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology

AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology

Downregulated NPAS4 in multiple brain regions is associated with Major Depressive Disorder

The effects of physical activity on glutamate neurotransmission in neuropsychiatric disorders

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