Browsing by Subject "Bipolar disorder"
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Item Alcohol Use and Prefrontal Cortex Volume Trajectories in Young Adults with Mood Disorders and Associated Clinical Outcomes(MDPI, 2022-02-22) Kirsch, Dylan E.; Tretyak, Valeria; Le, Vanessa; Huffman, Ansley; Fromme, Kim; Strakowski, Stephen M.; Lippard, Elizabeth T. C.; Psychiatry, School of MedicineBackground: Alcohol use in the course of mood disorders is associated with worse clinical outcomes. The mechanisms by which alcohol use alters the course of illness are unclear but may relate to prefrontal cortical (PFC) sensitivity to alcohol. We investigated associations between alcohol use and PFC structural trajectories in young adults with a mood disorder compared to typically developing peers. Methods: 41 young adults (24 with a mood disorder, agemean = 21 ± 2 years) completed clinical evaluations, assessment of alcohol use, and two structural MRI scans approximately one year apart. Freesurfer was used to segment PFC regions of interest (ROIs) (anterior cingulate, orbitofrontal cortex, and frontal pole). Effects of group, alcohol use, time, and interactions among these variables on PFC ROIs at baseline and follow-up were modeled. Associations were examined between alcohol use and longitudinal changes in PFC ROIs with prospective mood. Results: Greater alcohol use was prospectively associated with decreased frontal pole volume in participants with a mood disorder, but not typically developing comparison participants (time-by-group-by-alcohol interaction; p = 0.007); however, this interaction became a statistical trend in a sensitivity analysis excluding one outlier in terms of alcohol use. Greater alcohol use and a decrease in frontal pole volume related to longer duration of major depression during follow-up (p’s < 0.05). Conclusion: Preliminary findings support more research on alcohol use, PFC trajectories, and depression recurrence in young adults with a mood disorder including individuals with heavier drinking patterns.Item Association between poor tolerability of antidepressant treatment and brain functional activation in youth at risk for bipolar disorder(Brazilian Psychiatric Association, 2021-02-01) Nery, Fabiano G.; Masifi, Sheela L.; Strawn, Jeffrey R.; Duran, Luis R.; Weber, Wade A.; Welge, Jeffrey A.; Adler, Caleb M.; Strakowski, Stephen M.; DelBello, Melissa P.; Psychiatry, School of MedicineObjective: To investigate whether poor antidepressant tolerability is associated with functional brain changes in children and adolescents of parents with bipolar I disorder (at-risk youth). Methods: Seventy-three at-risk youth (ages 9-20 years old) who participated in a prospective study and had an available baseline functional magnetic resonance imaging (fMRI) scan were included. Research records were reviewed for the incidence of adverse reactions related to antidepressant exposure during follow-up. The sample was divided among at-risk youth without antidepressant exposure (n=21), at-risk youth with antidepressant exposure and no adverse reaction (n=12), at-risk youth with antidepressant-related adverse reaction (n=21), and healthy controls (n=20). The fMRI task was a continuous performance test with emotional distracters. Region-of-interest mean activation in brain areas of the fronto-limbic emotional circuit was compared among groups. Results: Right amygdala activation in response to emotional distracters significantly differed among groups (F3,66 = 3.1, p = 0.03). At-risk youth with an antidepressant-related adverse reaction had the lowest amygdala activation, while at-risk youth without antidepressant exposure had the highest activation (p = 0.004). Conclusions: Decreased right amygdala activation in response to emotional distracters is associated with experiencing an antidepressant-related adverse reaction in at-risk youth. Further studies to determine whether amygdala activation is a useful biomarker for antidepressant-related adverse events are needed.Item Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders(Springer Nature, 2021) Andlauer, Till F. M.; Guzman-Parra, Jose; Streit, Fabian; Strohmaier, Jana; González, Maria José; Flores, Susana Gil; Cabaleiro Fabeiro, Francisco J.; del Río Noriega, Francisco; Perez, Fermin Perez; González, Jesus Haro; Diaz, Guillermo Orozco; de Diego-Otero, Yolanda; Moreno-Küstner, Berta; Auburger, Georg; Degenhardt, Franziska; Heilmann-Heimbach, Stefanie; Herms, Stefan; Hoffmann, Per; Frank, Josef; Foo, Jerome C.; Treutlein, Jens; Witt, Stephanie H.; Cichon, Sven; Kogevinas, Manolis; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Rivas, Fabio; Mayoral, Fermín; Müller-Myhsok, Bertram; Forstner, Andreas J.; Nöthen, Markus M.; Rietschel, Marcella; Medical and Molecular Genetics, School of MedicineMultiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.Item Characterisation of age and polarity at onset in bipolar disorder(Cambridge University Press, 2021-12) Kalman, Janos L.; Olde Loohuis, Loes M.; Vreeker, Annabel; McQuillin, Andrew; Stahl, Eli A.; Ruderfer, Douglas; Grigoroiu-Serbanescu, Maria; Panagiotaropoulou, Georgia; Ripke, Stephan; Bigdeli, Tim B.; Stein, Frederike; Meller, Tina; Meinert, Susanne; Pelin, Helena; Streit, Fabian; Papiol, Sergi; Adams, Mark J.; Adolfsson, Rolf; Adorjan, Kristina; Agartz, Ingrid; Aminoff, Sofie R.; Anderson-Schmidt, Heike; Andreassen, Ole A.; Ardau, Raffaella; Aubry, Jean-Michel; Balaban, Ceylan; Bass, Nicholas; Baune, Bernhard T.; Bellivier, Frank; Benabarre, Antoni; Bengesser, Susanne; Berrettini, Wade H.; Boks, Marco P.; Bromet, Evelyn J.; Brosch, Katharina; Budde, Monika; Byerley, William; Cervantes, Pablo; Chillotti, Catina; Cichon, Sven; Clark, Scott R.; Comes, Ashley L.; Corvin, Aiden; Coryell, William; Craddock, Nick; Craig, David W.; Croarkin, Paul E.; Cruceanu, Cristiana; Czerski, Piotr M.; Dalkner, Nina; Dannlowski, Udo; Degenhardt, Franziska; Del Zompo, Maria; DePaulo, J. Raymond; Djurovic, Srdjan; Edenberg, Howard J.; Al Eissa, Mariam; Elvsåshagen, Torbjørn; Etain, Bruno; Fanous, Ayman H.; Fellendorf, Frederike; Fiorentino, Alessia; Forstner, Andreas J.; Frye, Mark A.; Fullerton, Janice M.; Gade, Katrin; Garnham, Julie; Gershon, Elliot; Gill, Michael; Goes, Fernando S.; Gordon-Smith, Katherine; Grof, Paul; Guzman-Parra, Jose; Hahn, Tim; Hasler, Roland; Heilbronner, Maria; Heilbronner, Urs; Jamain, Stephane; Jimenez, Esther; Jones, Ian; Jones, Lisa; Jonsson, Lina; Kahn, Rene S.; Kelsoe, John R.; Kennedy, James L.; Kircher, Tilo; Kirov, George; Kittel-Schneider, Sarah; Klöhn-Saghatolislam, Farah; Knowles, James A.; Kranz, Thorsten M.; Lagerberg, Trine Vik; Landen, Mikael; Lawson, William B.; Leboyer, Marion; Li, Qingqin S.; Maj, Mario; Malaspina, Dolores; Manchia, Mirko; Mayoral, Fermin; McElroy, Susan L.; McInnis, Melvin G.; McIntosh, Andrew M.; Medeiros, Helena; Melle, Ingrid; Milanova, Vihra; Mitchell, Philip B.; Monteleone, Palmiero; Monteleone, Alessio Maria; Nöthen, Markus M.; Novak, Tomas; Nurnberger, John I.; O'Brien, Niamh; O'Connell, Kevin S.; O'Donovan, Claire; O'Donovan, Michael C.; Opel, Nils; Ortiz, Abigail; Owen, Michael J.; Pålsson, Erik; Pato, Carlos; Pato, Michele T.; Pawlak, Joanna; Pfarr, Julia-Katharina; Pisanu, Claudia; Potash, James B.; Rapaport, Mark H.; Reich-Erkelenz, Daniela; Reif, Andreas; Reininghaus, Eva; Repple, Jonathan; Richard-Lepouriel, Hélène; Rietschel, Marcella; Ringwald, Kai; Roberts, Gloria; Rouleau, Guy; Schaupp, Sabrina; Scheftner, William A.; Schmitt, Simon; Schofield, Peter R.; Schubert, K. Oliver; Schulte, Eva C.; Schweizer, Barbara; Senner, Fanny; Severino, Giovanni; Sharp, Sally; Slaney, Claire; Smeland, Olav B.; Sobell, Janet L.; Squassina, Alessio; Stopkova, Pavla; Strauss, John; Tortorella, Alfonso; Turecki, Gustavo; Twarowska-Hauser, Joanna; Veldic, Marin; Vieta, Eduard; Vincent, John B.; Xu, Wei; Zai, Clement C.; Zandi, Peter P.; Psychiatric Genomics Consortium (PGC) Bipolar Disorder Working Group; International Consortium on Lithium Genetics (ConLiGen); Colombia-US Cross Disorder Collaboration in Psychiatric Genetics; Di Florio, Arianna; Smoller, Jordan W.; Biernacka, Joanna M.; McMahon, Francis J.; Alda, Martin; Müller-Myhsok, Bertram; Koutsouleris, Nikolaos; Falkai, Peter; Freimer, Nelson B.; Andlauer, Till F.M.; Schulze, Thomas G.; Ophoff, Roel A.; Biochemistry and Molecular Biology, School of MedicineBackground: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.Item Childhood maltreatment, prefrontal-paralimbic gray matter volume, and substance use in young adults and interactions with risk for bipolar disorder(Springer Nature, 2021-01-08) Kirsch, Dylan E.; Tretyak, Valeria; Radpour, Sepeadeh; Weber, Wade A.; Nemeroff, Charles B.; Fromme, Kim; Strakowski, Stephen M.; Lippard, Elizabeth T. C.; Psychiatry, School of MedicineChildhood maltreatment is associated with adverse effects on the brain, and an increased risk for psychopathology, including mood and substance use disorders. Individuals vary on the degree to which they exhibit neurobiological and clinical differences following maltreatment. Individuals with bipolar disorder exhibit greater magnitude of maltreatment-related prefrontal-paralimbic gray matter volume (GMV) deficits compared to typically developing individuals. It is unclear if greater structural differences stem from greater neural vulnerability to maltreatment in bipolar disorder, or if they relate to presence of other clinical features associated with childhood maltreatment, e.g., elevated prevalence of comorbid substance use disorders. To investigate this, we compared young adults with a family history of bipolar disorder (n = 21), but who did not fulfill diagnostic criteria for bipolar disorder, with typically developing young adults without a family history of bipolar disorder (n = 26). Participants completed structural neuroimaging, clinical and family history interviews, and assessment of childhood maltreatment and recent alcohol and cannabis use patterns. We examined relations between childhood maltreatment and prefrontal-paralimbic GMV by modeling main effects of maltreatment and family history group by maltreatment interactions on prefrontal-paralimbic GMV. We also examined relations between maltreatment and associated GMV changes with recent alcohol and cannabis use. Childhood maltreatment correlated with lower ventral, rostral and dorsolateral prefrontal and insular cortical GMV across all participants regardless of the presence or absence of familial history of bipolar disorder. However, exploratory analyses did reveal greater maltreatment-related GMV differences in individuals with prodromal symptoms of depression. Lower insula GMV was associated with greater frequency of cannabis use across all participants and greater quantity of alcohol use only in those with familial risk for bipolar disorder. Results suggest familial risk for bipolar disorder, and presumably genetic risk, may relate to outcomes following childhood maltreatment and should be considered in prevention/early intervention strategies.Item 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 MedicineBipolar 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.Item Detecting significant genotype-phenotype association rules in bipolar disorder: market research meets complex genetics(SpringerOpen, 2018-11-11) Breuer, René; Mattheisen, Manuel; Frank, Josef; Krumm, Bertram; Treutlein, Jens; Kassem, Layla; Strohmaier, Jana; Herms, Stefan; Mühleisen, Thomas W.; Degenhardt, Franziska; Cichon, Sven; Nöthen, Markus M.; Karypis, George; Kelsoe, John; Greenwood, Tiffany; Nievergelt, Caroline; Shilling, Paul; Shekhtman, Tatyana; Edenberg, Howard; Craig, David; Szelinger, Szabolcs; Nurnberger, John; Gershon, Elliot; Alliey‑Rodriguez, Ney; Zandi, Peter; Goes, Fernando; Schork, Nicholas; Smith, Erin; Koller, Daniel; Zhang, Peng; Badner, Judith; Berrettini, Wade; Bloss, Cinnamon; Byerley, William; Coryell, William; Foroud, Tatiana; Guo, Yirin; Hipolito, Maria; Keating, Brendan; Lawson, William; Liu, Chunyu; Mahon, Pamela; McInnis, Melvin; Murray, Sarah; Nwulia, Evaristus; Potash, James; Rice, John; Scheftner, William; Zöllner, Sebastian; McMahon, Francis J.; Rietschel, Marcella; Schulze, Thomas G.; Biochemistry and Molecular Biology, School of MedicineBACKGROUND: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. RESULTS: Two of these rules-one associated with eating disorder and the other with anxiety-remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. CONCLUSION: Our approach detected novel specific genotype-phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.Item Discovery and validation of blood biomarkers for suicidality(Springer Nature, 2013) Le-Niculescu, H.; Levey, D. F.; Ayalew, M.; Palmer, L.; Gavrin, L. M.; Jain, N.; Winiger, E.; Bhosrekar, S.; Shankar, G.; Radel, M.; Bellanger, E.; Duckworth, H.; Olesek, K.; Vergo, J.; Schweitzer, R.; Yard, M.; Ballew, A.; Shekhar, A.; Sandusky, G. E.; Schork, N. J.; Kurian, S. M.; Salomon, D. R.; Niculescu, A. B., III; Psychiatry, School of MedicineSuicides are a leading cause of death in psychiatric patients, and in society at large. Developing more quantitative and objective ways (biomarkers) for predicting and tracking suicidal states would have immediate practical applications and positive societal implications. We undertook such an endeavor. First, building on our previous blood biomarker work in mood disorders and psychosis, we decided to identify blood gene expression biomarkers for suicidality, looking at differential expression of genes in the blood of subjects with a major mood disorder (bipolar disorder), a high-risk population prone to suicidality. We compared no suicidal ideation (SI) states and high SI states using a powerful intrasubject design, as well as an intersubject case-case design, to generate a list of differentially expressed genes. Second, we used a comprehensive Convergent Functional Genomics (CFG) approach to identify and prioritize from the list of differentially expressed gene biomarkers of relevance to suicidality. CFG integrates multiple independent lines of evidence-genetic and functional genomic data-as a Bayesian strategy for identifying and prioritizing findings, reducing the false-positives and false-negatives inherent in each individual approach. Third, we examined whether expression levels of the blood biomarkers identified by us in the live bipolar subject cohort are actually altered in the blood in an age-matched cohort of suicide completers collected from the coroner's office, and report that 13 out of the 41 top CFG scoring biomarkers (32%) show step-wise significant change from no SI to high SI states, and then to the suicide completers group. Six out of them (15%) remained significant after strict Bonferroni correction for multiple comparisons. Fourth, we show that the blood levels of SAT1 (spermidine/spermine N1-acetyltransferase 1), the top biomarker identified by us, at the time of testing for this study, differentiated future as well as past hospitalizations with suicidality, in a live cohort of bipolar disorder subjects, and exhibited a similar but weaker pattern in a live cohort of psychosis (schizophrenia/schizoaffective disorder) subjects. Three other (phosphatase and tensin homolog (PTEN), myristoylated alanine-rich protein kinase C substrate (MARCKS), and mitogen-activated protein kinase kinase kinase 3 (MAP3K3)) of the six biomarkers that survived Bonferroni correction showed similar but weaker effects. Taken together, the prospective and retrospective hospitalization data suggests SAT1, PTEN, MARCKS and MAP3K3 might be not only state biomarkers but trait biomarkers as well. Fifth, we show how a multi-dimensional approach using SAT1 blood expression levels and two simple visual-analog scales for anxiety and mood enhances predictions of future hospitalizations for suicidality in the bipolar cohort (receiver-operating characteristic curve with area under the curve of 0.813). Of note, this simple approach does not directly ask about SI, which some individuals may deny or choose not to share with clinicians. Lastly, we conducted bioinformatic analyses to identify biological pathways, mechanisms and medication targets. Overall, suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptosis.Item Disturbed resting state EEG synchronization in bipolar disorder: A graph-theoretic analysis(Elsevier, 2013-03-22) Kim, Dae-Jin; Bolbecker, Amanda R.; Howell, Josselyn; Rass, Olga; Sporns, Olaf; Hetrick, William P.; Breier, Alan; O'Donnell, Brian F.; Psychiatry, School of MedicineDisruption of functional connectivity may be a key feature of bipolar disorder (BD) which reflects disturbances of synchronization and oscillations within brain networks. We investigated whether the resting electroencephalogram (EEG) in patients with BD showed altered synchronization or network properties. Resting-state EEG was recorded in 57 BD type-I patients and 87 healthy control subjects. Functional connectivity between pairs of EEG channels was measured using synchronization likelihood (SL) for 5 frequency bands (δ, θ, α, β, and γ). Graph-theoretic analysis was applied to SL over the electrode array to assess network properties. BD patients showed a decrease of mean synchronization in the alpha band, and the decreases were greatest in fronto-central and centro-parietal connections. In addition, the clustering coefficient and global efficiency were decreased in BD patients, whereas the characteristic path length increased. We also found that the normalized characteristic path length and small-worldness were significantly correlated with depression scores in BD patients. These results suggest that BD patients show impaired neural synchronization at rest and a disruption of resting-state functional connectivity.Item 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 MedicineBackground 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.