Browsing by Subject "Lithium"

Now showing 1 - 10 of 13
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    Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: Preliminary studies
    (Springer Nature, 2021) Mishra, Himanshu K.; Ying, Noelle M.; Luis, Angelica; Wei, Heather; Nguyen, Metta; Nakhla, Timothy; Vandenburgh, Sara; Alda, Martin; Berrettini, Wade H.; Brennand, Kristen J.; Calabrese, Joseph R.; Coryell, William H.; Frye, Mark A.; Gage, Fred H.; Gershon, Elliot S.; McInnis, Melvin G.; Nievergelt, Caroline M.; Nurnberger, John I.; Shilling, Paul D.; Oedegaard, Ketil J.; Zandi, Peter P.; The Pharmacogenomics of Bipolar Disorder Study; Kelsoe, John R.; Welsh, David K.; McCarthy, Michael J.; Psychiatry, School of Medicine
    Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30–40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of “clock genes” and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low-amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.
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    Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes
    (Karger Publishers, 2016-10) Anand, Amit; McClintick, Jeanette N.; Murrell, Jill; Karne, Harish; Nurnberger, John I.; Edenberg, Howard J.; Psychiatry, School of Medicine
    Background This study investigated the effect of lithium monotherapy on peripheral lymphocyte gene expression in bipolar disorder (BD). Method Twenty-two medication-free bipolar subjects (11 hypomanic, 11 depressed) were started on lithium monotherapy. Closely matched healthy subjects (n = 15) were included as controls but did not receive treatment. Blood RNA samples were collected at baseline and after 2 and 8 weeks of treatment. RNA expression was measured using the Affymetrix GeneChip® Human Gene 1.0 ST Array followed by Ingenuity pathways analysis. The results for the contrast of weeks 2 and 8 were not significantly different and were combined. Results In BD subjects, 56 genes showed significant (false discovery rate <0.1) expression changes from baseline; the effect sizes and directions for all of these were similar at weeks 2 and 8. Among these were immune-related genes (IL5RA, MOK, IFI6, and RFX2), purinergic receptors (P2RY14, P2RY2, and ADORA3) and signal transduction-related genes (CAMK1 and PIK3R6). Pathway and upstream regulator analysis also revealed that lithium altered several immune- and signal transduction-related functions. Differentially expressed genes did not correlate with week 8 clinical response, but other genes involved in protein synthesis and degradation did. Conclusion Peripheral gene expression may serve as a biomarker of lithium effect.
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    Effects of somatic treatments on suicidal ideation and completed suicides
    (Wiley, 2021-11) Hawkins, Elise M.; Coryell, William; Leung, Stephen; Parikh, Sagar V.; Weston, Cody; Nestadt, Paul; Nurnberger, John I., Jr.; Kaplin, Adam; Kumar, Anupama; Farooqui, Ali A.; El-Mallakh, Rif S.; Psychiatry, School of Medicine
    Objective: This work was undertaken to define and characterize the role of currently available somatic treatments in psychiatry in either increasing or reducing the risk for suicide. Methods: Members of the Suicide Prevention Task Group of the National Network of Depression Centers performed a literature review of somatic treatments known to increase or reduce the risk for suicide. The reviews ventured to include all relevant information about the risk for both suicide ideation and completed suicides. Results: Lithium and clozapine are the only two somatic treatments that have high-quality data documenting their antisuicide effects in mood disorders and schizophrenia, respectively. Lithium discontinuation is also associated with increased suicide risk. Ketamine and esketamine may have a small, but immediate, antisuicide effect. Despite the recent Food and Drug Administration approval of esketamine use in depressed suicidal patients, the small disproportional overrepresentation of suicide in subjects who had received esketamine versus placebo (3 vs. 0 among > 3500 subjects) requires ongoing evaluation. The purported antisuicide effect of electroconvulsive therapy is based on low-quality data. The effect of antidepressants is not at all clear. There appears to be direct evidence for antidepressants increasing suicidal ideation and the risk for suicide over the short-term in young people, but indirect (low quality) evidence that antidepressants reduce suicide risk over the long term. Conclusions: Clinicians have an expanding pharmacopeia to address suicide potential in their patients. Some of the agents with documented antisuicide effects may also increase suicidality under specific circumstances.
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    Extrinsic Characterization Sustainability in Zirconia Reinforced Lithium Silicate Ceramics
    (2021-04-08) Gadah, Thrya; May, Jaren; Levon, John; Chu, Tien-Min G; Gregory, Richard; Wei Shao, Lin; Feitosa, Sabrina
    ABSTRACT OBJECTIVE. To investigate the effect of aging on the surface roughness and the color sustainability of externally characterized zirconia reinforced lithium silicate glass-ceramics treated with different surface protocols. METHODS. Sixty blocks (12-mm X 14-mm; 1.5-mm) of pre-crystalized zirconia reinforced-lithium silicate glass-ceramic (Vita Suprinity, Vita Zahnfabrick, Germany) CAD/CAM were crystalized and treated with different surface protocols, as extrinsic characterization (EC), mechanical polishing (MP), glaze layer (GL), surface adjustment (SA) and no treatment – control group (CG). Experimental groups (n=10) were divided as follow: CG; EC-MP-GZ; EC-GZ; EC-MP; EC-GZ-SA-GZ; EC-GZ-SA-MP and submitted to thermocycling (5,000 cycles, 5-55C) and toothbrushing simulation (5,000 cycles). Surface roughness (Ra and Rq), color change (CIED2000) and biofilm growth were evaluated. Statistical analysis was performed with a two-sided 5% significance level for all tests. RESULTS. For the parameter RaX, the control differed from EC-GZ and EC-MP (p = 0.04). For the parameter RqX, EC-GZ presented higher surface roughness compared than EC-MP-GZ and the group EC-GZ-SA-MP (p=0.02). EC-MP (p<0.01) and the EC-GZ-SA-MP (p<0.01) showed higher color change E00 after aging, while CG and EC-MP-GZ the least. For the biofilm growth, no significant group effect on bacteria counts was found (p=0.089). CONCLUSION. The aging protocol affected the surface roughness, and color of externally characterized zirconia reinforced lithium silicate glass-ceramics submitted to different surface treatment protocols. In the present study, when the mechanical polishing was performed before glaze application, the slightest color change and surface roughness were observed compared to the other surface treatments. Bacteria were not able to grow in the material surface, under the conditions tested in the present study.
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    Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis
    (Springer Nature, 2024) Niemsiri, Vipavee; Rosenthal, Sara Brin; Nievergelt, Caroline M.; Maihofer, Adam X.; Marchetto, Maria C.; Santos, Renata; Shekhtman, Tatyana; Alliey-Rodriguez, Ney; Anand, Amit; Balaraman, Yokesh; Berrettini, Wade H.; Bertram, Holli; Burdick, Katherine E.; Calabrese, Joseph R.; Calkin, Cynthia V.; Conroy, Carla; Coryell, William H.; DeModena, Anna; Eyler, Lisa T.; Feeder, Scott; Fisher, Carrie; Frazier, Nicole; Frye, Mark A.; Gao, Keming; Garnham, Julie; Gershon, Elliot S.; Goes, Fernando S.; Goto, Toyomi; Harrington, Gloria J.; Jakobsen, Petter; Kamali, Masoud; Kelly, Marisa; Leckband, Susan G.; Lohoff, Falk W.; McCarthy, Michael J.; McInnis, Melvin G.; Craig, David; Millett, Caitlin E.; Mondimore, Francis; Morken, Gunnar; Nurnberger, John I.; O'Donovan, Claire; Øedegaard, Ketil J.; Ryan, Kelly; Schinagle, Martha; Shilling, Paul D.; Slaney, Claire; Stapp, Emma K.; Stautland, Andrea; Tarwater, Bruce; Zandi, Peter P.; Alda, Martin; Fisch, Kathleen M.; Gage, Fred H.; Kelsoe, John R.; Psychiatry, School of Medicine
    Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.
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    Lithium alters expression of RNAs in a type-specific manner in differentiated human neuroblastoma neuronal cultures, including specific genes involved in Alzheimer’s disease
    (Nature Research, 2019-12-04) Maloney, Bryan; Balaraman, Yokesh; Liu, Yunlong; Chopra, Nipun; Edenberg, Howard J.; Kelsoe, John; Nurnberger, John I.; Lahiri, Debomoy K.; Psychiatry, School of Medicine
    Lithium (Li) is a medication long-used to treat bipolar disorder. It is currently under investigation for multiple nervous system disorders, including Alzheimer’s disease (AD). While perturbation of RNA levels by Li has been previously reported, its effects on the whole transcriptome has been given little attention. We, therefore, sought to determine comprehensive effects of Li treatment on RNA levels. We cultured and differentiated human neuroblastoma (SK-N-SH) cells to neuronal cells with all-trans retinoic acid (ATRA). We exposed cultures for one week to lithium chloride or distilled water, extracted total RNA, depleted ribosomal RNA and performed whole-transcriptome RT-sequencing. We analyzed results by RNA length and type. We further analyzed expression and protein interaction networks between selected Li-altered protein-coding RNAs and common AD-associated gene products. Lithium changed expression of RNAs in both non-specific (inverse to sequence length) and specific (according to RNA type) fashions. The non-coding small nucleolar RNAs (snoRNAs) were subject to the greatest length-adjusted Li influence. When RNA length effects were taken into account, microRNAs as a group were significantly less likely to have had levels altered by Li treatment. Notably, several Li-influenced protein-coding RNAs were co-expressed or produced proteins that interacted with several common AD-associated genes and proteins. Lithium’s modification of RNA levels depends on both RNA length and type. Li activity on snoRNA levels may pertain to bipolar disorders while Li modification of protein coding RNAs may be relevant to AD.
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    Lithium Treatment in the Prevention of Repeat Suicide-Related Outcomes in Veterans With Major Depression or Bipolar Disorder
    (American Medical Association, 2022) Katz, Ira R.; Rogers, Malcolm P.; Lew, Robert; Thwin, Soe Soe; Doros, Gheorghe; Ahearn, Eileen; Ostacher, Michael J.; DeLisi, Lynn E.; Smith, Eric G.; Ringer, Robert J.; Ferguson, Ryan; Hoffman, Brian; Kaufman, James S.; Paik, Julie M.; Conrad, Chester H.; Holmberg, Erika F.; Boney, Tamara Y.; Huang, Grant D.; Liang, Matthew H.; Li+ plus Investigators; Psychiatry, School of Medicine
    Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression. Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event. Design, setting, and participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019. Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo. Main outcomes and measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide. Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group. Conclusions and relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities.
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    Relation of hyperparathyroidism and hypercalcemia to bipolar and psychotic disorders
    (Taylor & Francis, 2022-04-08) Enyi, Chioma O.; D’Souza, Brendan; Barloon, Linda; Ilonze, Onyedika J.; Chacko, Ranjit; Medicine, School of Medicine
    Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone. PHPT leads to hypercalcemia and presents with renal, skeletal, and neuropsychiatric symptoms. Neuropsychiatric manifestations of PHPT such as psychotic, depressive, and anxiety disorders are rare. Delirium may also be present in patients with PHPT. Parathyroidectomy is the treatment of choice for patients with physically symptomatic PHPT, but it remains unclear if parathyroidectomy is indicated for its psychiatric manifestations. It is unclear if parathyroidectomy should be performed as a treatment for medication-refractory psychiatric symptoms or deferred until psychiatric symptoms have been better controlled. We present two cases of hyperparathyroidism (HPT)-associated hypercalcemia-one with lithium-associated HPT-in which psychiatric manifestations resolved with parathyroidectomy.
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    Synthesis of lithium manganese phosphate by controlled sol-gel method and design of all solid state lithium ion batteries
    (2015) Penumaka, Rani Vijaya; Zhu, Likun
    Due to the drastic increase in the cost of fossil fuels and other environmental issues, the demand for energy and its storage has risen globally. Rather than being dependent on intermittent energy sources like wind and solar energy, focus has been on alternative energy sources. To eliminate the need for fossil fuels, advances are being made to provide energy for hybrid electric vehicles (HEV), plug-in hybrid vehicles (PHEV) and pure electric vehicles (EV) thus providing scope for much greener environment. Hence, focus has been on development in lithium ion batteries to provide with materials that have high energy density and voltage. Ortho olivine lithium transitional metals are known to be abundant and inexpensive; these compounds are less noxious than other cathode materials. Advancement in research is being done in finding iron and manganese compounds as cathode materials for advanced technologies. However, Lithium manganese phosphates are known to suffer with poor electrochemical performances due the manganese dissolution in the organic liquid electrolyte due to Jahn-Teller Lattice distortion. This problem was tried to endorse in this thesis. In the second chapter by synthesizing nano sized cathode particles with good electronic conductivity, good performance was achieved. In the third chapter additive olivine cathode was synthesized my modified sol gel process. A wt. % of TMSP was added as an additive in the organic liquid electrolyte. By comparing the properties between the two kinds of electrolytes it was observed that by the addition of the additive in the organic electrolyte good electrochemical properties could be achieved hindering the Mn dissolution in the electrolyte. In the final chapter, a composite solid electrolyte was fabricated by using NASICON-type glass ceramic of Lithium aluminum titanium phosphate (LATP) with organic binder of Polyethylene oxide. The flexible solid electrolyte exhibited good ionic conductivity. An all solid state cell was fabricated using the composite solid electrolyte using LiMn2O4 as the symmetric electrodes. At different pressures, the performance of the solid state cell was studied.