Exploratory |
N/a |
iPSCs Neurons |
Investigation of the cellular behavior and developmental pathways of iPSC derived neurons from BD patients and controls |
-Increased membrane receptors and ion-controlled genes were noted in BD patient derived neurons compared to controls |
Chen et al. (2014Chen HM, DeLong CJ, Bame M, Rajapakse I, Herron TJ, McInnis MG and O’Shea KS (2014) Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients. Transl Psychiatry 4:e375.) |
Exploratory |
N/a |
Postmortem cerebral tissue iPSCs Neurons NPCs |
Examination of the expression of hsa-miR-34a in postmortem tissue and various IPSCs derived cell types |
-Increased expression of microRNAs in BD patient derived iPSC cultures and postmortem cerebral tissue |
Bavamian et al. (2015Bavamian S, Mellios N, Lalonde J, Fass DM, Wang J, Sheridan SD, Madison JM, Zhou F, Rueckert EH, Barker D et al. (2015) Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder. Mol Psychiatry 20:573-584.) |
Exploratory |
N/a |
iPSCs NPCs Neurons |
Models of iPSCs, NPCs and neurons of a 1st degree family cohort analyzed using microarray technology to investigate the existence of global gene expression patterns in individuals with BD |
-Differently expressed genes were observed during iPSC to NPC differentiation in BD patients -Enrichment of genes correlated with cell cycle regulation and homeostasis |
Kim et al. (2015Kim KH, Liu J, Sells Galvin RJ, Dage JL, Egeland JA, Smith RC, Merchant KM and Paul SM (2015) Transcriptomic analysis of induced pluripotent stem cells derived from patients with bipolar disorder from an old order amish pedigree. PLoS One 10:e0142693.) |
Exploratory |
N/a |
iPSCs Neurons NPCs |
A family-based paradigm model was used to examine iPSCs lines from brothers with DB compared to non-BD parents |
-NPCs and neuronal cells derived from BD patients showed phenotypical differences in channeled subunits and Wnt pathway components related to neuroplasticity |
Madison et al. (2015Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R, van der Ven K, Hsu J, Wolf P, Fleishman M et al. (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20:703-717.) |
Exploratory and Treatment |
Lithium |
iPSC-derived neurons |
Study of phenotypical differences in neurons derived from iPSCs generated from lithium responder and non-responder patients and controls |
- Discovered that BD derived neurons were hyperexcitable compared to control neurons -Lithium reversed hyperexcitability only on neurons derived from lithium responders |
Mertens et al. (2015Mertens J, Wang Q-W, Kim Y, Yu DX, Pham S, Yang B, Zheng Y, Diffenderfer KE, Zhang J, Soltani S et al. (2015) Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nat 527:95-99., 2016) |
Treatment |
Lithium |
iPSC-derived neurons |
Study of neurons derived from BD lithium responder patients to gain insight to BD molecular mechanisms and lithium targets |
-Lithium acts on CRMP2 which alters neuronal cytoskeletal dynamics and spine formation in BD iPSC derived neurons |
Tobe et al. (2017Tobe BTD, Crain AM, Winquist AM, Calabrese B, Makihara H, Zhao W, Lalonde J, Nakamura H, Konopaske G, Sidor M et al. (2017) Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis. Proc Natl Acad Sci U S A 114:e4462-e4471.) |
Exploratory |
N/a |
iPSCs NPCs |
Examination of transcriptomes during the transition from iPSCs to NPCs in BD patients and controls using RNA sequencing |
-Increased expression of genes related to inflammation in BD-derived NPCs -The most significantly differentially expressed genes were NLRP2 and genes associated with GABA and dopamine receptor canonical pathways |
Vizlin-Hodzic et al. (2017Vizlin-Hodzic D, Zhai Q, Illes S, Södersten K, Truvé K, Parris TZ, Sobhan PK, Salmela S, Kosalai ST, Kanduri C et al. (2017) Early onset of inflammation during ontogeny of bipolar disorder: The NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages. Transl Psychiatry 7:e1010.) |
Exploratory |
N/a |
iPSC-derived neurons |
Modeled and compared activity of neurons derived iPSCs from lithium responders and non-responders BD patients |
-Created a model to predict if a patient will respond to lithium or not with a 92% accuracy rate |
Stern et al. (2018Stern S, Santos R, Marchetto MC, Mendes APD, Rouleau GA, Biesmans S, Wang Q-W, Yao J, Charnay P, Bang AG et al. (2018) Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients’ responsiveness to lithium. Mol Psychiatry 23:1453-1465.) |
Exploratory |
N/a |
iPSC-derived neurons |
Study of the behavior of neurons of hippocampus CA3 and dentate gyrus and motor neurons from lithium responders and non-responders BD patients |
- Hyperexcitability is dependent on the type of neurons and unstable in neurons derived from lithium non-responders |
Stern et al. (2020aStern S, Sarkar A, Galor D, Stern T, Mei A, Stern Y, Mendes APD, Randolph-Moore L, Rouleau G, Bang AG et al. (2020a) A physiological instability displayed in hippocampal neurons derived from lithium-nonresponsive bipolar disorder patients. Biol Psychiatry 88:150-158.,bStern S, Sarkar A, Stern T, Mei A, Mendes APD, Stern Y, Goldberg G, Galor D, Nguyen T, Randolph-Moore L et al. (2020b) Mechanisms underlying the hyperexcitability of CA3 and dentate gyrus hippocampal neurons derived from patients with bipolar disorder. Biol Psychiatry 88:139-149.) |
Exploratory |
N/a |
Organoids |
Exploration of functional mechanisms in BD by comparing BD-derived and control organoids |
-BD derived patient neurons expressed upregulation of genes involved in neurogenesis, cell adhesion, synaptic morphology, and function and a downregulation of genes involved in immune signaling along with a reduction in mitochondria-associated endoplasmic reticulum membranes (MAMs) -BD derived organoids responded differently to electrical stimuli but similarly to non-BD derived models in the absence of electrical stimuli |
Kathuria et al. (2020Kathuria A, Lopez-Lengowski K, Vater M, McPhie D, Cohen BM and Karmacharya R (2020) Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder. Genome Med 12:e34.) |
Treatment |
Lithium |
iPSC-derived NPCs and lymphoblastoid cell lines |
Examination of cellular phenotypes of lithium responder and non-responder BD patients compared to healthy controls |
-In vitro lithium treatment of BD derived iPSC lines encouraged cell proliferation, enhanced the expression of BCL2 and GSK3B and lowered mitochondrial membrane potential (MMP) - Low MMP was reversed using in vitro lithium exposure but remained unaffected in clinical lithium therapy treatment |
Paul et al. (2020Paul P, Iyer S, Nadella RK, Nayak R, Chellappa AS, Ambardar S, Sud R, Sukumaran SK, Purushottam M, Jain S et al. (2020) Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines. Sci Rep 10:e7428.) |
Treatment |
Valproate |
iPSCs |
Examination of how valproate interacts with iPSCs from lithium responders and non-responders |
-Valproate rescued dysregulation of cell proliferation and cell death in lithium responders and non-responders |
Paul et al. (2020Paul P, Iyer S, Nadella RK, Nayak R, Chellappa AS, Ambardar S, Sud R, Sukumaran SK, Purushottam M, Jain S et al. (2020) Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines. Sci Rep 10:e7428.) |
Exploratory |
N/a |
iPSC-derived astrocytes |
Generated astrocyte models derived from iPSC from BD patients and controls to examine inflammation related phenotypes |
-IL-6, a proinflammatory cytokine, was upregulated in iPSC-derived astrocytes from BD patients compared to controls -When BD iPSC derived astrocytes were co-cultured with neurons, there was a reduction in neuronal activity |
Vadodaria et al. (2021Vadodaria KC, Mendes APD, Mei A, Racha V, Erikson G, Shokhirev MN, Oefner R, Heard KJ, McCarthy MJ, Eyler L et al. (2021) Altered neuronal support and inflammatory response in bipolar disorder patient-derived astrocytes. Stem Cell Reports 16:825-835.) |
Exploratory and Treatment |
Lithiumand Valproic Acid |
iPSC-derived neurons |
Examined lithium resistance in iPSC-derived neurons derived from lithium non-responder patients with B |
-NR neurons displayed less activity of the Wnt/β-catenin signaling pathway and a significant decrease in LEF1 expression |
Santos et al. (2021Santos R, Linker SB, Stern S, Mendes APD, Shokhirev MN, Erikson G, Randolph-Moore L, Racha V, Kim Y, Kelsoe JR et al. (2021) Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients. Mol Psychiatry 26:2440-2456.) |
Exploratory |
N/a |
Stem Cells Neurons NPCs |
Mapped the presence and arrangement of lithium ions in cells |
-Unveiled the mechanisms of lithium ion distribution in multiple cell types including patient derived cells from individuals with BD to further explore and understand lithium- response pathways |
McGhee et al. (2021McGhee CE, Yang Z, Guo W, Wu Y, Lyu M, DeLong CJ, Hong S, Ma Y, McInnis MG, O’Shea KS et al. (2021) DNAzyme-based lithium-selective imaging reveals higher lithium accumulation in bipolar disorder patient-derived neurons. ACS Cent Sci 7:1809-1820.) |
Exploratory |
N/a |
iPSC-derived neurons |
Examined the circadian-rhythm regulation in neurons derived from iPSCs of BD lithium responder and non-responder patients |
- BD neurons showed differences in circadian-rhythm regulation with the most significant difference seen in lithium non-responders |
Mishra et al. (2021Mishra HK, Ying NM, Luis A, Wei H, Nguyen M, Nakhla T, Vandenburgh S, Alda M, Berrettini WH, Brennand KJ et al. (2021) Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: Preliminary studies. Mol Psychiatry 26:3383-3394.) |
Treatment |
Trimetazidine |
iPSC-derived neurons and astrocytes |
Study aimed to repurpose trimetazidine to treat bipolar depression |
- Trimetazidine increased the production of ATP, which can be deficient in BD patients, by altering cellular metabolic processes |
Bortolasci et al. (2023Bortolasci CC, Kidnapillai S, Spolding B, Truong TTT, Connor T, Swinton C, Panizzutti B, Liu ZSJ, Sanigorski A, Dean OM et al. (2023) Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression. Bipolar Disord 25:661-670.) |
Treatment |
Lithium |
iPSC-derived cortical spheroids |
Examination of phenotypic effects of prolonged lithium exposure on corticoid spheroids derived from BD patients |
-BD patient-derived corticoid spheroids exhibited transcriptional profiles with enriched differentially expressed genes associated with kidney function and ion homeostasis when exposed to chronic lithium treatment |
Osete et al. (2023Osete JR, Akkouh IA, Ievglevskyi O, Vandenberghe M, de Assis DR, Ueland T, Kondratskaya E, Holen B, Szabo A, Hughes T et al. (2023) Transcriptional and functional effects of lithium in bipolar disorder iPSC-derived cortical spheroids. Mol Psychiatry 28:3033-3043.) |
Treatment |
Apigenin |
iPSC-derived astrocytes |
Tested the effects of apigenin, a neuroprotective and anti-inflammatory compound, on stimulated iPSC-derived astrocytes from BD and control individuals to examine alternative treatment methods for bipolar disorder |
-BD and control astrocytes experienced an increase in the percentage of IL-6 expressing astrocytes irrespective of the proinflammatory stimuli used (IL-1b or TNF-a) - Both BD and control astrocytes showed higher sensitivity to proinflammatory cytokine IL-6 compared to TNF-a -Apigenin treatment successfully counteracted the inflammatory response in BD and control astrocytes |
This study |