Table 4.
Studies evaluating the association between RNA markers and response to mood stabilizers in cellular models.
| Ref. | Sample | RNA Source | RNA Type | Measurement Method | Targets | Main Findings |
|---|---|---|---|---|---|---|
| [70] | 16 patients treated with lithium. Response was evaluated based on the rate of relapse | LCLs | mRNA | NGS | Genome wide | In vitro treatment with LiCl 1 mM for 1 week modulated 22 coexpression modules |
| [66] | 20 patients with BD (11 responders and 9 non-responders). Response was evaluated with the Alda scale | LCLs | mRNA, miRNA | Microarray | Genome wide | 335 genes (217 upregulated and 118 downregulated) and 77 miRNAs (46 upregulated and 31 downregulated) were nominally differentially expressed between responders and non-responders |
| [72] | 36 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | mRNA | qPCR | 20 circadian genes | Differential temporal evolution between non-responders and responders for levels of different circadian genes |
| [67] | 16 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | mRNA, miRNA | Microarray, qPCR | Genome wide | In vitro treatment with LiCl 1 mM for 1 week induced downregulation of THRAP3 and TFAM in responders |
| [77] | 8 patients with BD with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs, fibroblasts | mRNA | Microarray, qPCR | Genome wide | No significant difference in gene expression levels based on lithium response |
| [71] | 22 patients treated with lithium for 6 weeks. Response was evaluated with the MADRS and YMRS at 6 weeks | Olfactory neurons | mRNA | qPCR | GSK3B, AKT1, PRKCE and CRMP1 | Treatment-associated downregulation of CRMP1 predicted improvement of both manic and depressive symptoms |
| [75] | 6 patients treated with lithium. Response was evaluated with the CGI at 4 months | Neurons differentiated from iPSCs | mRNA | NGS | Genome wide | In vitro treatment with LiCl 1 mM for 1 week modulated 560 genes in responders and 40 genes in non-responders. Genes for which lithium rescued expression in responders were related to the PKA/PKC pathways, action potential firing and mitochondria |
| [78] | 17 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | miRNA | qPCR | let7-c | Nonsignificant trend for higher let-7c expression in non-responders compared with responders |
| [79] | 24, 41 and 17 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | mRNA | NGS, qPCR | Genome wide | 56 genes showed nominal differential expression between responders and non-responders. HDGFRP3 and ID2 were validated in the independent cohorts |
| [80] | 36 patients with BD with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | mRNA | qPCR | GADL1 | No difference in GADL1 levels between responders and non-responders. In vitro treatment with LiCl 1 mM for 4 or 8 days did not modify GADL1 levels |
| [74] | 6 patients with BD responders to lithium, 5 patients with BD non-responders to lithium and 6 HCs. Response was evaluated with the Alda scale | Neurons differentiated from iPSCs | mRNA | NGS, qPCR | Genome wide | 41 genes were differentially expressed between responders and non-responders, regardless of in vitro treatment with LiCl 1 mM for 1 week. Focal adhesion and the extracellular matrix were the most significant functions based on functional enrichment analysis of the top 500 proximal network genes |
| [81] | 20 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | mRNA | Microarray, qPCR | RBM3 | RBM3 was upregulated in responders compared with non-responders. In vitro treatment with LiCl 1 mM for 1 week did not modify RBM3 levels |
| [82] | LCL: 25 patients with long-term lithium treatment and 12 HCs. NPC: 2 patients with BD. Response was evaluated with the Alda scale | LCLs, NPCs | mRNA | NGS, qPCR | BCL2, GSK3B and NR1D1 | In vitro treatment with LiCl 1 mm for 1 week increased the expression of BCL2 and GSK3B in responders |
| [83] | 20 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | mRNA | Microarray, qPCR | Genome wide | In vitro treatment with LiCl 1 mm for 1 week modified levels of 29 genes, including ZNF493 and ZNF429, in responders |
| [73] | 20 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | mRNA | Microarray | 17 circadian genes | Higher levels of BHLHE40 in responders compared with non-responders |
| [68] | 20 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | miRNA, mRNA | Microarray, NGS, qPCR | Genome wide | miR-320a, miR-155-3p and three of their targeted genes (CAPNS1 and RGS16 for miR-320 and SP4 for miR-155-3p) were differentially expressed between responders and non-responders |
| [76] | 3 patients with BD responders to lithium, 3 non-responders and 4 HCs. Response was evaluated with the Alda scale | Neurons differentiated from iPSCs | mRNA | NGS, qPCR | Genome wide | Alterations of the Wnt/β-catenin signaling pathway and decreased levels of the LEF1 transcription factor, which were observed in neurons derived from lithium non-responders |
| [84] | 30 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | mRNA | qPCR | PDLIM5 | No association between PDLIM5 levels and response |
| [85] | 20 and 12 patients with long-term lithium treatment. Response was evaluated with the Alda scale | LCLs | mRNA | Microarray, qPCR | Genome wide | 2060 genes were differentially expressed between responders and non-responders; IGF1 was validated in the independent sample |
| [86] | 12 patients (all responders to long-term lithium treatment according to [87]) | LCLs | mRNA | Microarray, Northern blot | Genome wide | In vitro treatment with LiCl 1 mM for 1 week decreased the expression of 7 genes |
AKT1, AKT serine/threonine kinase 1; BCL2, BCL2 apoptosis regulator; BDNF, brain-derived neurotrophic factor; BHLHE40, basic helix–loop–helix family member E40; CAPNS1, calpain small subunit 1; CRMP1, collapsin response mediator protein 1; GADL1, glutamate decarboxylase-like 1; GO, gene ontology; GSK3B, glycogen synthase kinase 3 beta; HDGFRP3, hepatoma-derived growth factor, related protein 3, isoform CRA_a; ID2, inhibitor of DNA-binding 2; IGF1, insulin-like growth factor 1; LCL, lymphoblastoid cell line; LEF1, lymphoid enhancer-binding factor 1; LiCL, lithium chloride; mRNA, messenger RNA; miRNA, microRNA; NR1D1, nuclear receptor subfamily 1 group D member 1; PDLIM5, PDZ and LIM domain 5; PKA A, protein kinase A; PKC, protein kinase C; PRKCE, protein kinase C epsilon; RBM3, RNA-binding motif protein 3; RGS16, regulator of G protein signaling 16; SP4, Sp4 transcription factor; TFAM, transcription factor A mitochondrial; THRAP3, thyroid hormone receptor-associated protein 3; ZNF429, zinc finger protein 493; ZNF 429, zinc finger protein 493.