{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T02:07:33Z","timestamp":1783649253870,"version":"3.55.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T00:00:00Z","timestamp":1465257600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T00:00:00Z","timestamp":1465257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Patients with subthreshold hypomania (SBP; subthreshold bipolar disorder) were indistinguishable from those with bipolar disorder (BP)-II on clinical bipolar validators, but their analyses lacked biological and pharmacological treatment data. Because inflammation and neuroprogression underlies BP, we hypothesized that cytokines and brain-derived neurotrophic factor (BDNF) are biomarkers for BP. We enrolled 41 drug-na\u00efve patients with SBP and 48 with BP-II undergoing 12 weeks of pharmacological treatment (valproic acid, fluoxetine, risperidone, lorazepam). The Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were used to evaluate clinical responses at baseline and at weeks 0, 1, 2, 4, 8, and 12. Inflammatory cytokines (tumour necrosis factor [TNF]-\u03b1, transforming growth factor [TGF]-\u03b21, interleukin [IL]-6, IL-8 and IL-1\u03b2) and BDNF levels were also measured. Mixed models repeated measurement was used to examine the therapeutic effect and changes in BDNF and cytokine levels between the groups. HDRS and YMRS scores significantly (P\u2009&lt;\u20090.001) declined in both groups, the SBP group had significantly lower levels of BDNF (P\u2009=\u20090.005) and TGF-\u03b21 (P\u2009=\u20090.02). Patients with SBP and BP-II respond similarly to treatment, but SBP patients may have different neuroinflammation marker expression.<\/jats:p>","DOI":"10.1038\/srep27431","type":"journal-article","created":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T09:37:13Z","timestamp":1465292233000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Comparing clinical responses and the biomarkers of BDNF and cytokines between subthreshold bipolar disorder and bipolar II disorder"],"prefix":"10.1038","volume":"6","author":[{"given":"Tzu-Yun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Yu","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiou-Lan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Hsuan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-Jen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po See","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Heng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Hsien","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"San-Yuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nian-Sheng","family":"Tzeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Ling","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Lun","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsai-Hsin","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I Hui","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kao Chin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen Kuang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jau-Shyong","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru-Band","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,6,7]]},"reference":[{"key":"BFsrep27431_CR1","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1176\/ajp.150.5.720","volume":"150","author":"W Coryell","year":"1993","unstructured":"Coryell, W. et al. The enduring psychosocial consequences of mania and depression. Am J Psychiatry 150, 720\u2013727 (1993).","journal-title":"Am J Psychiatry"},{"key":"BFsrep27431_CR2","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1192\/bjp.130.2.162","volume":"130","author":"MT Tsuang","year":"1977","unstructured":"Tsuang, M. T. & Woolson, R. F. Mortality in patients with schizophrenia, mania, depression and surgical conditions. A comparison with general population mortality. Br J Psychiatry 130, 162\u2013166 (1977).","journal-title":"Br J Psychiatry"},{"key":"BFsrep27431_CR3","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1001\/archpsyc.64.5.543","volume":"64","author":"KR Merikangas","year":"2007","unstructured":"Merikangas, K. R. et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 64, 543\u2013552 (2007).","journal-title":"Arch Gen Psychiatry"},{"key":"BFsrep27431_CR4","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1176\/appi.ajp.2010.09071011","volume":"167","author":"J Angst","year":"2010","unstructured":"Angst, J. et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry 167, 1194\u20131201 (2010).","journal-title":"Am J Psychiatry"},{"key":"BFsrep27431_CR5","doi-asserted-by":"publisher","first-page":"S5","DOI":"10.1016\/S0165-0327(00)00203-2","volume":"59","author":"HS Akiskal","year":"2000","unstructured":"Akiskal, H. S. et al. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 59 Suppl 1, S5\u2013S30 (2000).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR6","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/S0165-0327(02)00322-1","volume":"73","author":"J Angst","year":"2003","unstructured":"Angst, J. et al. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 73, 133\u2013146 (2003).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR7","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/S0165-0327(02)00327-0","volume":"73","author":"F Benazzi","year":"2003","unstructured":"Benazzi, F. & Akiskal, H. S. Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania. J Affect Disord 73, 33\u201338 (2003).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR8","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1001\/archgenpsychiatry.2009.158","volume":"66","author":"P Zimmermann","year":"2009","unstructured":"Zimmermann, P. et al. Heterogeneity of DSM-IV major depressive disorder as a consequence of subthreshold bipolarity. Arch Gen Psychiatry 66, 1341\u20131352 (2009).","journal-title":"Arch Gen Psychiatry"},{"key":"BFsrep27431_CR9","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1111\/j.1399-5618.2011.00957.x","volume":"13","author":"R Nusslock","year":"2011","unstructured":"Nusslock, R. & Frank, E. Subthreshold bipolarity: diagnostic issues and challenges. Bipolar Disord 13, 587\u2013603 (2011).","journal-title":"Bipolar Disord"},{"key":"BFsrep27431_CR10","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/BF02279764","volume":"240","author":"W Wicki","year":"1991","unstructured":"Wicki, W. & Angst, J. The Zurich Study. X. Hypomania in a 28- to 30-year-old cohort. Eur Arch Psychiatry Clin Neurosci 240, 339\u2013348 (1991).","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"key":"BFsrep27431_CR11","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1001\/archpsyc.1979.01780060025002","volume":"36","author":"HS Akiskal","year":"1979","unstructured":"Akiskal, H. S. et al. Differentiation of primary affective illness from situational, symptomatic, and secondary depressions. Arch Gen Psychiatry 36, 635\u2013643 (1979).","journal-title":"Arch Gen Psychiatry"},{"key":"BFsrep27431_CR12","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1007\/s004060170065","volume":"251","author":"F Benazzi","year":"2001","unstructured":"Benazzi, F. Is 4 days the minimum duration of hypomania in bipolar II disorder? Eur Arch Psychiatry Clin Neurosci 251, 32\u201334 (2001).","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"key":"BFsrep27431_CR13","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/S0165-0327(02)00330-0","volume":"73","author":"HS Akiskal","year":"2003","unstructured":"Akiskal, H. S. & Benazzi, F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord 73, 113\u2013122 (2003).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR14","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.jad.2004.04.006","volume":"96","author":"F Benazzi","year":"2006","unstructured":"Benazzi, F. & Akiskal, H. The duration of hypomania in bipolar-II disorder in private practice: methodology and validation. J Affect Disord 96, 189\u2013196 (2006).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR15","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/0165-0327(92)90044-7","volume":"26","author":"GB Cassano","year":"1992","unstructured":"Cassano, G. B., Akiskal, H. S., Savino, M., Musetti, L. & Perugi, G. Proposed subtypes of bipolar II and related disorders: with hypomanic episodes (or cyclothymia) and with hyperthymic temperament. J Affect Disord 26, 127\u2013140 (1992).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR16","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1111\/bdi.12236","volume":"17","author":"K Lin","year":"2015","unstructured":"Lin, K. et al. Neuropsychological performance of patients with soft bipolar spectrum disorders. Bipolar Disord 17, 194\u2013204 (2015).","journal-title":"Bipolar Disord"},{"key":"BFsrep27431_CR17","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1001\/archgenpsychiatry.2011.87","volume":"68","author":"J Angst","year":"2011","unstructured":"Angst, J. et al. Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study. Arch Gen Psychiatry 68, 791\u2013798 (2011).","journal-title":"Arch Gen Psychiatry"},{"key":"BFsrep27431_CR18","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1016\/j.neubiorev.2010.10.001","volume":"35","author":"M Berk","year":"2011","unstructured":"Berk, M. et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neuroscience and biobehavioral reviews 35, 804\u2013817 (2011).","journal-title":"Neuroscience and biobehavioral reviews"},{"key":"BFsrep27431_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2165\/00023210-200721010-00001","volume":"21","author":"T Kato","year":"2007","unstructured":"Kato, T. Mitochondrial dysfunction as the molecular basis of bipolar disorder: therapeutic implications. CNS drugs 21, 1\u201311 (2007).","journal-title":"CNS drugs"},{"key":"BFsrep27431_CR20","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1126\/science.1088417","volume":"302","author":"ML Monje","year":"2003","unstructured":"Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760\u20131765 (2003).","journal-title":"Science"},{"key":"BFsrep27431_CR21","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1097\/YCO.0b013e32835aa4b4","volume":"26","author":"L Stertz","year":"2013","unstructured":"Stertz, L., Magalhaes, P. V. & Kapczinski, F. Is bipolar disorder an inflammatory condition? The relevance of microglial activation. Current opinion in psychiatry 26, 19\u201326 (2013).","journal-title":"Current opinion in psychiatry"},{"key":"BFsrep27431_CR22","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.bbi.2014.03.016","volume":"40","author":"BC Haarman","year":"2014","unstructured":"Haarman, B. C. et al. Neuroinflammation in bipolar disorder - A [(11)C]-(R)-PK11195 positron emission tomography study. Brain, behavior, and immunity 40, 219\u2013225 (2014).","journal-title":"Brain, behavior, and immunity"},{"key":"BFsrep27431_CR23","doi-asserted-by":"publisher","first-page":"e350","DOI":"10.1038\/tp.2013.119","volume":"4","author":"CC Watkins","year":"2014","unstructured":"Watkins, C. C., Sawa, A. & Pomper, M. G. Glia and immune cell signaling in bipolar disorder: insights from neuropharmacology and molecular imaging to clinical application. Translational psychiatry 4, e350 (2014).","journal-title":"Translational psychiatry"},{"key":"BFsrep27431_CR24","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1503\/jpn.100080","volume":"36","author":"J Soderlund","year":"2011","unstructured":"Soderlund, J. et al. Elevation of cerebrospinal fluid interleukin-1ss in bipolar disorder. J Psychiatry Neurosci 36, 114\u2013118 (2011).","journal-title":"J Psychiatry Neurosci"},{"key":"BFsrep27431_CR25","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.biopsych.2013.01.007","volume":"74","author":"A Modabbernia","year":"2013","unstructured":"Modabbernia, A., Taslimi, S., Brietzke, E. & Ashrafi, M. Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry 74, 15\u201325 (2013).","journal-title":"Biol Psychiatry"},{"key":"BFsrep27431_CR26","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jad.2012.06.010","volume":"144","author":"K Munkholm","year":"2013","unstructured":"Munkholm, K., Vinberg, M. & Vedel Kessing, L. Cytokines in bipolar disorder: a systematic review and meta-analysis. J Affect Disord 144, 16\u201327 (2013).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR27","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.psychres.2004.08.005","volume":"129","author":"YK Kim","year":"2004","unstructured":"Kim, Y. K. et al. T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients. Psychiatry Res 129, 267\u2013272 (2004).","journal-title":"Psychiatry Res"},{"key":"BFsrep27431_CR28","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1111\/j.1399-5618.2007.00444.x","volume":"9","author":"EM Knijff","year":"2007","unstructured":"Knijff, E. M. et al. An imbalance in the production of IL-1beta and IL-6 by monocytes of bipolar patients: restoration by lithium treatment. Bipolar Disord 9, 743\u2013753 (2007).","journal-title":"Bipolar Disord"},{"key":"BFsrep27431_CR29","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.jad.2005.11.015","volume":"90","author":"SM O\u2019Brien","year":"2006","unstructured":"O\u2019Brien, S. M., Scully, P., Scott, L. V. & Dinan, T. G. Cytokine profiles in bipolar affective disorder: focus on acutely ill patients. J Affect Disord 90, 263\u2013267 (2006).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR30","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1111\/j.1399-5618.2007.00493.x","volume":"9","author":"A Ortiz-Dominguez","year":"2007","unstructured":"Ortiz-Dominguez, A. et al. Immune variations in bipolar disorder: phasic differences. Bipolar Disord 9, 596\u2013602 (2007).","journal-title":"Bipolar Disord"},{"key":"BFsrep27431_CR31","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1590\/2237-6089-2014-0002","volume":"37","author":"A Roda","year":"2015","unstructured":"Roda, A., Chendo, I. & Kunz, M. Biomarkers and staging of bipolar disorder: a systematic review. Trends in psychiatry and psychotherapy 37, 3\u201311 (2015).","journal-title":"Trends in psychiatry and psychotherapy"},{"key":"BFsrep27431_CR32","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.pnpbp.2013.09.017","volume":"48","author":"AL Lopresti","year":"2014","unstructured":"Lopresti, A. L., Maker, G. L., Hood, S. D. & Drummond, P. D. A review of peripheral biomarkers in major depression: the potential of inflammatory and oxidative stress biomarkers. Prog Neuropsychopharmacol Biol Psychiatry 48, 102\u2013111 (2014).","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"BFsrep27431_CR33","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/sj.mp.4001111","volume":"7","author":"F Bosetti","year":"2002","unstructured":"Bosetti, F. et al. Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain. Mol Psychiatry 7, 845\u2013850 (2002).","journal-title":"Mol Psychiatry"},{"key":"BFsrep27431_CR34","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.biopsych.2005.07.024","volume":"59","author":"RP Bazinet","year":"2006","unstructured":"Bazinet, R. P., Rao, J. S., Chang, L., Rapoport, S. I. & Lee, H. J. Chronic carbamazepine decreases the incorporation rate and turnover of arachidonic acid but not docosahexaenoic acid in brain phospholipids of the unanesthetized rat: relevance to bipolar disorder. Biol Psychiatry 59, 401\u2013407 (2006).","journal-title":"Biol Psychiatry"},{"key":"BFsrep27431_CR35","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.4088\/JCP.08r04505","volume":"70","author":"BI Goldstein","year":"2009","unstructured":"Goldstein, B. I., Kemp, D. E., Soczynska, J. K. & McIntyre, R. S. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry 70, 1078\u20131090 (2009).","journal-title":"J Clin Psychiatry"},{"key":"BFsrep27431_CR36","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1016\/j.pnpbp.2010.07.015","volume":"34","author":"H Horikawa","year":"2010","unstructured":"Horikawa, H. et al. Inhibitory effects of SSRIs on IFN-gamma induced microglial activation through the regulation of intracellular calcium. Prog Neuropsychopharmacol Biol Psychiatry 34, 1306\u20131316 (2010).","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"BFsrep27431_CR37","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.schres.2007.01.019","volume":"92","author":"T Kato","year":"2007","unstructured":"Kato, T., Monji, A., Hashioka, S. & Kanba, S. Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro . Schizophrenia research 92, 108\u2013115 (2007).","journal-title":"Schizophrenia research"},{"key":"BFsrep27431_CR38","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.nbd.2009.11.010","volume":"37","author":"HW Kim","year":"2010","unstructured":"Kim, H. W., Rapoport, S. I. & Rao, J. S. Altered expression of apoptotic factors and synaptic markers in postmortem brain from bipolar disorder patients. Neurobiology of disease 37, 596\u2013603 (2010).","journal-title":"Neurobiology of disease"},{"key":"BFsrep27431_CR39","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1016\/S0028-3908(98)00141-5","volume":"37","author":"W Pan","year":"1998","unstructured":"Pan, W., Banks, W. A., Fasold, M. B., Bluth, J. & Kastin, A. J. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology 37, 1553\u20131561 (1998).","journal-title":"Neuropharmacology"},{"key":"BFsrep27431_CR40","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1586\/14737175.8.7.1101","volume":"8","author":"F Kapczinski","year":"2008","unstructured":"Kapczinski, F., Frey, B. N., Kauer-Sant\u2019Anna, M. & Grassi-Oliveira, R. Brain-derived neurotrophic factor and neuroplasticity in bipolar disorder. Expert review of neurotherapeutics 8, 1101\u20131113 (2008).","journal-title":"Expert review of neurotherapeutics"},{"key":"BFsrep27431_CR41","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.neubiorev.2007.10.005","volume":"32","author":"F Kapczinski","year":"2008","unstructured":"Kapczinski, F. et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neuroscience and biobehavioral reviews 32, 675\u2013692 (2008).","journal-title":"Neuroscience and biobehavioral reviews"},{"key":"BFsrep27431_CR42","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1017\/S1461145708009310","volume":"12","author":"M Kauer-Sant\u2019Anna","year":"2009","unstructured":"Kauer-Sant\u2019Anna, M. et al. Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. The international journal of neuropsychopharmacology\/official scientific journal of the Collegium Internationale Neuropsychopharmacologicum 12, 447\u2013458 (2009).","journal-title":"The international journal of neuropsychopharmacology\/official scientific journal of the Collegium Internationale Neuropsychopharmacologicum"},{"key":"BFsrep27431_CR43","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/j.jpsychires.2011.03.002","volume":"45","author":"BS Fernandes","year":"2011","unstructured":"Fernandes, B. S. et al. Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res 45, 995\u20131004 (2011).","journal-title":"J Psychiatr Res"},{"key":"BFsrep27431_CR44","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1016\/j.jpsychires.2013.06.017","volume":"47","author":"SY Lee","year":"2013","unstructured":"Lee, S. Y. et al. Add-on memantine to valproate treatment increased HDL-C in bipolar II disorder. J Psychiatr Res 47, 1343\u20131348 (2013).","journal-title":"J Psychiatr Res"},{"key":"BFsrep27431_CR45","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1097\/JCP.0000000000000109","volume":"34","author":"SY Lee","year":"2014","unstructured":"Lee, S. Y. et al. The effects of add-on low-dose memantine on cytokine levels in bipolar II depression: a 12-week double-blind, randomized controlled trial. J Clin Psychopharmacol 34, 337\u2013343 (2014).","journal-title":"J Clin Psychopharmacol"},{"key":"BFsrep27431_CR46","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1016\/j.euroneuro.2014.09.001","volume":"24","author":"SL Chen","year":"2014","unstructured":"Chen, S. L. et al. Therapeutic effects of add-on low-dose dextromethorphan plus valproic acid in bipolar disorder. Eur Neuropsychopharmacol 24, 1753\u20131759 (2014).","journal-title":"Eur Neuropsychopharmacol"},{"key":"BFsrep27431_CR47","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1001\/archpsyc.60.3.261","volume":"60","author":"LL Judd","year":"2003","unstructured":"Judd, L. L. et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 60, 261\u2013269 (2003).","journal-title":"Arch Gen Psychiatry"},{"key":"BFsrep27431_CR48","doi-asserted-by":"publisher","first-page":"914","DOI":"10.4088\/JCP.v66n0715","volume":"66","author":"HS Akiskal","year":"2005","unstructured":"Akiskal, H. S. & Benazzi, F. Optimizing the detection of bipolar II disorder in outpatient private practice: toward a systematization of clinical diagnostic wisdom. J Clin Psychiatry 66, 914\u2013921 (2005).","journal-title":"J Clin Psychiatry"},{"key":"BFsrep27431_CR49","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1001\/archpsyc.1978.01770310043002","volume":"35","author":"J Endicott","year":"1978","unstructured":"Endicott, J. & Spitzer, R. L. A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35, 837\u2013844 (1978).","journal-title":"Arch Gen Psychiatry"},{"key":"BFsrep27431_CR50","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1097\/01.ALC.0000117832.62901.61","volume":"28","author":"SY Huang","year":"2004","unstructured":"Huang, S. Y. et al. Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. Alcohol Clin Exp Res 28, 374\u2013384 (2004).","journal-title":"Alcohol Clin Exp Res"},{"key":"BFsrep27431_CR51","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1192\/bjp.133.5.429","volume":"133","author":"RC Young","year":"1978","unstructured":"Young, R. C., Biggs, J. T., Ziegler, V. E. & Meyer, D. A. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133, 429\u2013435 (1978).","journal-title":"Br J Psychiatry"},{"key":"BFsrep27431_CR52","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1136\/jnnp.23.1.56","volume":"23","author":"M Hamilton","year":"1960","unstructured":"Hamilton, M. A rating scale for depression. Journal of neurology, neurosurgery, and psychiatry 23, 56\u201362 (1960).","journal-title":"Journal of neurology, neurosurgery, and psychiatry"},{"key":"BFsrep27431_CR53","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1111\/j.2044-8260.1967.tb00530.x","volume":"6","author":"M Hamilton","year":"1967","unstructured":"Hamilton, M. Development of a rating scale for primary depressive illness. The British journal of social and clinical psychology 6, 278\u2013296 (1967).","journal-title":"The British journal of social and clinical psychology"},{"key":"BFsrep27431_CR54","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1007\/s11920-012-0319-2","volume":"14","author":"GR Fries","year":"2012","unstructured":"Fries, G. R. et al. Staging and neuroprogression in bipolar disorder. Current psychiatry reports 14, 667\u2013675 (2012).","journal-title":"Current psychiatry reports"},{"key":"BFsrep27431_CR55","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.jad.2011.08.022","volume":"136","author":"SY Tsai","year":"2012","unstructured":"Tsai, S. Y. et al. Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder. J Affect Disord 136, 110\u2013116 (2012).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR56","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/S0167-5699(97)01000-1","volume":"18","author":"W Strober","year":"1997","unstructured":"Strober, W. et al. Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. Immunology today 18, 61\u201364 (1997).","journal-title":"Immunology today"},{"key":"BFsrep27431_CR57","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.jad.2014.12.033","volume":"174","author":"H Li","year":"2015","unstructured":"Li, H. et al. IL-23 and TGF-beta1 levels as potential predictive biomarkers in treatment of bipolar I disorder with acute manic episode. J Affect Disord 174, 361\u2013366 (2015).","journal-title":"J Affect Disord"},{"key":"BFsrep27431_CR58","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.bbi.2013.10.007","volume":"36","author":"K Patas","year":"2014","unstructured":"Patas, K. et al. Association between serum brain-derived neurotrophic factor and plasma interleukin-6 in major depressive disorder with melancholic features. Brain, behavior, and immunity 36, 71\u201379 (2014).","journal-title":"Brain, behavior, and immunity"},{"key":"BFsrep27431_CR59","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1097\/YIC.0000000000000058","volume":"30","author":"AA Nierenberg","year":"2015","unstructured":"Nierenberg, A. A. et al. Predictors of placebo response in bipolar depression. International clinical psychopharmacology 30, 59\u201366 (2015).","journal-title":"International clinical psychopharmacology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep27431.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep27431","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep27431.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T05:30:24Z","timestamp":1672896624000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep27431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,7]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,6,20]]}},"alternative-id":["BFsrep27431"],"URL":"https:\/\/doi.org\/10.1038\/srep27431","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,7]]},"assertion":[{"value":"26 January 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 May 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 June 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"27431"}}