Objectives: The aim of the present study was to assess differences and correlations between the hippocampal volumes (HCVs), serum nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) levels in adolescents with bipolar disorder (BP) compared to healthy controls. Methods: Using structural magnetic resonance imaging, we compared HCVs of 30 patients with euthymic BP who were already enrolled in a naturalistic clinical follow-up. For comparison, we enrolled 23 healthy controls between the ages of 13 and 19. The boundaries of the hippocampus were outlined manually. The BDNF and NGF serum levels were measured with the sandwich ELISA. Results: The groups did not differ in the right or left HCVs or in the NGF or BDNF serum levels. However, negative correlations were found between the right HCVs and the duration of the disorder and medication and positive correlations were found between the duration of the medications and the NGF and BDNF levels in the patient group. Additionally, positive correlations were found between the follow-up period and left normalized HCVs in both the BP and lithium-treated groups. Conclusions: The right HCVs may vary with illness duration and the medication used to treat BP; NGF and BDNF levels may be affected by long-term usage. Further research is needed to determine whether these variables and their structural correlates are associated with clinical or functional differences between adolescents with BP and healthy controls.

1.
Axelson D, Birmaher B, Strober M, Gill MK, Valeri S, Chiappetta L, Ryan N, Leonard H, Hunt J, Iyengar S, Bridge J, Keller M: Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006;63:1139-1148.
2.
Birmaher B, Axelson D, Goldstein B, Strober M, Gill MK, Hunt J, Houck P, Ha W, Iyengar S, Kim E, Yen S, Hower H, Esposito-Smythers C, Goldstein T, Ryan N, Keller M: Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry 2009;166:795-804.
3.
Schneider MR, DelBello MP, McNamara RK, Strakowski SM, Adler CM: Neuroprogression in bipolar disorder. Bipolar Disord 2012;14:356-374.
4.
Kronmüller KT, Schröder J, Köhler S, Götz B, Victor D, Unger J, Giesel F, Magnotta V, Mundt C, Essig M, Pantel J: Hippocampal volume in first episode and recurrent depression. Psychiatry Res 2009;174:62-66.
5.
Soares JC, Mann JJ: The anatomy of mood disorders - review of structural neuroimaging studies. Biol Psychiatry 1997;41:86-106.
6.
Goldstein BI, Birmaher B: Prevalence, clinical presentation and differential diagnosis of pediatric bipolar disorder. Isr J Psychiatry Relat Sci 2012;49:3-14.
7.
Brambilla P, Glahn DC, Balestrieri M, Soares JC: Magnetic resonance findings in bipolar disorder. Psychiatr Clin North Am 2005;28:443-467.
8.
McDonald C, Zanelli J, Rabe-Hesketh S, Ellison-Wright I, Sham P, Kalidindi S, Murray RM, Kennedy N: Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder. Biol Psychiatry 2004;56:411-417.
9.
Blumberg HP, Kaufman J, Martin A, Whiteman R, Zhang JH, Gore JC, Charney DS, Krystal JH, Peterson BS: Amygdala and HCVs in adolescents and adults with bipolar disorder. Arch Gen Psychiatry 2003;60:1201-1208.
10.
Brambilla P, Hatch JP, Soares JC: Limbic changes identified by imaging in bipolar patients. Curr Psychiatry Rep 2008;10:505-509.
11.
Frazier JA, Chiu S, Breeze JL, Makris N, Lange N, Kennedy DN, Herbert MR, Bent EK, Koneru K, Dieterich ME, Hodge SM, Rauch SL, Grant PE, Cohen BM, Seidman LJ, Caviness VS, Biederman J: Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. Am J Psychiatry 2005;162:1256-1265.
12.
Chang K, Karchemskiy A, Barnea-Goraly N, Garrett A, Simeonova DI, Reiss A: Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44:565-573.
13.
Chen BK, Sassi R, Axelson D, Hatch JP, Sanches M, Nicoletti M, Brambilla P, Keshavan MS, Ryan ND, Birmaher B, Soares JC: Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder. Biol Psychiatry 2004;56:399-405.
14.
Dickstein DP, Milham MP, Nugent AC, Drevets WC, Charney DS, Pine DS, Leibenluft E: Frontotemporal alterations in pediatric bipolar disorder: results of a voxel-based morphometry study. Arch Gen Psychiatry 2005;62:734-741.
15.
Bearden CE, Soares JC, Klunder AD, Nicoletti M, Dierschke N, Hayashi KM, Narr KL, Brambilla P, Sass RB, Axelson D, Ryan N, Birmaher B, Thompson PM: Three-dimensional mapping of hippocampal anatomy in adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2008;47:515-525.
16.
Shaltiel G, Chen G, Manji HK: Neurotrophic signaling cascades in the pathophysiology and treatment of bipolar disorder. Curr Opin Pharmacol 2007;7:22-26.
17.
Suzuki F, Junier MP, Guilhem D, Sorensen JC, Onteniente B: Morphogenetic effect of kainite on adult hippocampal neurons associated with a prolonged expression of brain-derived neurotrophic factor. Neurosciences 1995;64:665-674.
18.
Altar CA, Dugich-Djordjevic M, Armanini M, Bakhit C: Medial-to-lateral gradient of neostriatal NGF receptors: relationship to cholinergic neurons and NGF like immunoreactivity. J Neurosci 1991;11:828-836.
19.
Duman RS, Monteggia LM: A neurotrophic model for stress-related mood disorders Biol Psychiatry 2006;59:1116-1127.
20.
Groves JO: Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry 2007;12:1079-1088.
21.
Jornada LK, Moretti M, Valvassori SS, Ferreira CL, Padilha PT, Arent CO, Fries GR, Kapczinski F, Quevedo J: Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain. J Psychiatr Res 2010;44:506-510.
22.
Katoh-Semba R, Wakako R, Komori T, Shigemi H, Miyazaki N, Ito H, Kumagai T, Tsuzuki M, Shigemi K, Yoshida F, Nakayama A: Age-related changes in BDNF protein levels in human serum: differences between autism cases and normal controls. Int J Dev Neurosci 2007;25:367-372.
23.
Perovic M, Tesic V, Djordjevic AM, Smiljanic K, Loncarevic-Vasiljkovic N, Ruzdijic S, Kanazir S: BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat. Age 2013;35:2057-2070.
24.
Baykara B, Inal-Emiroglu N, Karabay N, Çakmakçı H, Cevher N, Şentürk Pilan B, Alşen S: Increased HCVs in lithium treated adolescents with bipolar disorders: a structural MRI study. J Affect Disord 2012;138:433-439.
25.
Gökler B, Ünal F, Pehlivantürk B, Çengel-Kültür E, Akdemir D, Taner Y: Reliability and validity of schedule for affective disorders and schizophrenia for school age children present and lifetime version - Turkish version (K-SADS-PL-T). Çocuk ve Gençlik Ruh Saglıgı Dergisi 2004;11:109-116.
26.
Inal-Emiroglu FN, Baykara B, Miral S: A case series of Turkish children and adolescents with bipolar spectrum disorder: a naturalistic clinical phenomenological follow-up. Minerva Pediatr 2008;60:51-57.
27.
Robbins DR, Alessi NE, Colfer MV, Yanchyshyn GW: Use of the Hamilton Rating Scale for Depression and the Carroll Self-Rating Scale in adolescents. Psychiatry Res 1985;14:123-129.
28.
Yee AM, Algorta GP, Youngstrom EA, Findling RL, Birmaher B, Fristad MA; The Lams Group: Unfiltered administration of the YMRS and CDRS-R in a clinical sample of children. J Clin Child Adolesc Psychol 2014;2:1-16.
29.
Lukasiewicz M, Gerard S, Besnard A, Falissard B, Perrin E, Sapin H, Tohen M, Reed C, Azorin JM; Emblem Study Group: Young Mania Rating Scale: how to interpret the numbers? Determination of a severity threshold and of the minimal clinically significant difference in the EMBLEM cohort. Int J Methods Psychiatr Res 2013;22:46-58.
30.
Konrad C, Ukas T, Nebel C, Arolt V, Toga AW, Narr KL: Defining the human hippocampus in cerebral magnetic resonance images - an overview of current segmentation protocols. Neuroimage 2009;47:1185-1195.
31.
Lang UE, Hellweg R, Seifert F, Schubert F, Gallinat J: Correlation between serum brain-derived neurotrophic factor level and an in vivo marker of cortical integrity. Biol Psychiatry 2007;62:530-535.
32.
Frazier JA, Ahn MS, DeJong S, Bent EK, Breeze JL, Giuliano AJ: Magnetic resonance imaging studies in early-onset bipolar disorder: a critical review. Harv Rev Psychiatry 2005;13:125-140.
33.
MacMaster FP, Carrey N, Langevin LM, Jaworska N, Crawford S: Disorder-specific volumetric brain difference in adolescent major depressive disorder and bipolar depression. Brain Imaging Behav 2014;8:119-127.
34.
Sapolsky RM: The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry 2000;48:755-765.
35.
Pandey GN, Hooriyah SR, Yogesh D, Pavuluri MN: Brain-derived neurotrophic factor gene expression in pediatric bipolar disorder: effects of treatment and clinical response. J Am Acad Child Adolesc Psychiatry 2008;9:1077-1085.
36.
Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G: The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 2003;23:7311-7316.
37.
Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S: Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berl) 2001;158:100-106.
38.
Gould TD, Picchini AM, Einat H, Manji HK: Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders. Curr Drug Targets 2006;7:1399-1409.
39.
Zarate CA Jr, Singh J, Manji HK: Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 2006;59:1006-1020.
40.
Hallahan B, Newell J, Soares JC, Brambilla P, Strakowski SM, Fleck DE, Kieseppä T, Altshuler LL, Fornito A, Malhi GS, McIntosh AM, Yurgelun-Todd D, Labar KS, Sharma V, MacQueen GM, Murray RM, McDonald C: Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biol Psychiatry 2011;69:326-335.
41.
Moore GJ, Bebchuk JM, Wilds IB, Chen G, Manji HK: Lithium-induced increase in human brain gray matter. Lancet 2000;356:1241-1242.
42.
Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Glitz DA, Jolkovsky L, Manji HK: Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects? Biol Psychiatry 2000;48:1-8.
43.
Sassi RB, Nicoletti M, Brambilla P, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC: Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett 2002;329:243-245.
44.
Yucel K, McKinnon MC, Taylor VH, Macdonald K, Alda M, Young LT, MacQueen GM: Bilateral hippocampal increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berl) 2007;195:357-367.
45.
Hajek T, Kopecek M, Höschl C, Alda M: Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. J Psychiatry Neurosci 2012;37:333-343.
46.
Germana C, Kempton MJ, Sarnicola A, Christodoulou T, Haldane M, Hadjulis M, Girardi P, Tatarelli R, Frangou S: The effects of lithium and anticonvulsants on brain structure in bipolar disorder. Acta Psychiatr Scand 2010;122:481-487.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.