Papers by Rashmitha Nayak
ABSTRACTBackgroundLithiumis the first-line mood stabilizer for the treatment of bipolar disorder ... more ABSTRACTBackgroundLithiumis the first-line mood stabilizer for the treatment of bipolar disorder (BD). In order to interrogate cellular phenotypes related to disease and lithium treatment response, this study used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs) from BD patients who are well characterized for clinical lithium response.MethodsBDpatientsdiagnosed according to the DSM-IV criteria; were recruited from the outpatient services of the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Clinical lithium response was assessed using the “Alda scale” and “NIMH Retrospective Life chart method”. The controls were ethnically matched healthy subjects with no family history of neuropsychiatric illness. NPCs from two BD patients from the same family who clearly differed in their clinical response to lithium were chosen, and compared with healthy population controls. Whole transcriptome sequencing (RNA-Seq) and analysis were performed,...
European Neuropsychopharmacology, 2019
Background: Lithium and valproate are being used as the first line mood stabilizers for the treat... more Background: Lithium and valproate are being used as the first line mood stabilizers for the treatment of bipolar disorder (BP). We used patient derived lymphoblastoid cell line (LCL) to examine specific cellular phenotypes related to BP and lithium treatment response. Methods: BP subjects attending the outpatient services of National Institute of Mental Health and Neurosciences, Bangalore, India were evaluated by team of psychiatrists and recruited after informed consent. The initial diagnosis was made using DSM-IV criteria. Further assessments were done using Clinical Interview and MINI 5.0.0. Lithium treatment response was assessed for the BP subjects by using the Alda scale and "NIMH Retrospective Life chart method". Alda score ≥ 7 were considered as responders and score < 7 as non-responders. The controls were consenting, ethnically matched healthy subjects having no lifetime personal or family history of neuro-psychiatric illness. LCL were generated from BP subjects and controls. For the in vitro experiment, 5 million cells were treated with medium containing lithium (1mM) or valproate (0.7mM) for 7 days. The mitochondrial membrane potential, cell death and cell cycle experiments were carried out using standard flow cytometry techniques. Genome wide gene expression (GWGE) analysis was also studied to decipher the molecular changes responsible for the cellular phenotypes. In addition, quantitative PCR analysis was done to examine specific candidate gene expression. Results: Our study sample consists of 24 BP subjects (including 14 responders and 10 non-responders) (age: 40.19 ±12.5; age at onset 20.2 ± 6 years) and 11 controls (age: 39 ± 17.8 years). Mean Alda scores for responders and non-responders was 2.8 and 7.8 respectively. Overall, nonresponders had more episodes and hospital admissions, suggestive of a more severe illness. The in vitro studies showed lower mitochondrial potential, greater cell death and cell cycle abnormalities (greater proportion in G2/M phase) in BP (both responders and non-responders). Lithium and valproate reversed these abnormalities in BP; however, cell death reversal was specific to clinical lithium responders only. The latter finding correlated with enhanced BCL2, NR1D1 and GSK3B expression in the lithium responder group. Discussion: We have been able to find specific cellular phenotypes in relation to BP and clinical lithium response.
European Neuropsychopharmacology, 2019
(5%) of their 60 cases was unlike in our population where CC genotype was found in 24.6% of the s... more (5%) of their 60 cases was unlike in our population where CC genotype was found in 24.6% of the subjects. In a study by Serretti et al. in 2007, a trend was noted with CC genotype carriers having higher delusion scores while no significant association was noted with presence of CC genotype and the presence of psychotic symptoms in our studied population. No association was found between GSK-3B 50 T/C and total number of episodes in our studied population which is consistent with study by Szczepankiewiczi et al., 2006. We are also in the process of doing gene expression analysis from cell lines derived from patients with this SNP along with assessment of response to Lithium to obtain further insights into the functions of this SNP in bipolar disorder.
European Neuropsychopharmacology, 2019
variants, 3'-UTR/5'-UTR variants); and with no known effect on function (synonymous and intron va... more variants, 3'-UTR/5'-UTR variants); and with no known effect on function (synonymous and intron variants). Genes were prioritized by mutation burden analysis based on the average number of functional occurrences per 1000 bp of the gene CDS. The RVIS scoring system for assessing the intolerance of individual genes to protein-altering variants (Petrovski et al., 2013) was used in conjunction with the burden score for the final ordering. Results: 5373 variants were detected, of which 2826 were found in affecteds (1831 singletons and 995 recurrent). No significant associations between cases and controls could be detected, that survived the correction for multiple testing. In total we found in patients 14 rare LOF variants; 889 nonsynonymous variants (243 of which were potentially damaging); 109 splice site variants and 32 in regulatory regions. Discussion: We could find no significant association of common or rare variants in the analyzed samples, most likely due to small sample size. However, we could identify both recurrent and singleton rare variants with potential functional relevance in genes associated with ion channels, postsynaptic plasticity, neurogenesis and signalling cascade pathways.
Scientific Reports, 2020
Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mecha... more Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mechanisms of its action, and reasons for variations in clinical response, are unclear. We used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs), from BD patients characterized for clinical response to lithium (using the “Alda scale” and “NIMH Retrospective Life chart method”), to interrogate cellular phenotypes related to both disease and clinical lithium response. NPCs from two biologically related BD patients who differed in their clinical response to lithium were compared with healthy controls. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were also examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. MMP was lower in both NPCs and LCLs from BD; but it was reversed with in vitro lithium only in...
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Papers by Rashmitha Nayak