Offspring of parents with bipolar disorder (BD) have been shown to be at high risk for BD. Anxiety symptoms, even at subclinical levels, have been associated with increased risk for BD in these youth. The s-allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in the pathophysiology of both BD and anxiety disorders and has been associated with pharmacological treatment response and increased risk for antidepressant side effects. Therefore, we aimed to explore 1) whether anxiety symptoms in offspring of BD parents were associated with presence of the 5-HTTLPR s-allele and 2) whether anxiety symptoms in the offspring of BD parents according to the 5-HTTLPR genotypes are related to antianxiety medication status.
Methods:
A total of 64 offspring of BD parents (mean age: 13.7 years) and 51 healthy controls (HC) (mean age: 13.7 years) were compared genetically and on the Multidimensional Anxiety Scale for Children (MASC).
Results:
Offspring of BD parents showed higher levels of overall anxiety than did the HC group. Only antianxiety medication naïve offspring of BD parents were found to have an association between 5-HTTLPR genotypes and anxiety symptoms. The antianxiety medication naïve offspring of BD parents with the s-allele showed higher level of overall anxiety than offspring of BD parents with the l/l genotype. No significant differences in anxiety symptoms or their association with the 5-HTTLPR genotype were found in the HC group.
Conclusions:
This study indicated that there may be an association between 5-HTTLPR genotypes and anxiety symptoms in offspring of BD parents, and that antianxiety medication status may affect anxiety symptoms in the offspring of BD patients according to genotype.
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References
1.
AmbrosiniPJ, WagnerKD, BiedermanJ, GlickI, TanC, EliaJ, HebelerJR, RabinovichH, LockJ, GellerD: Multicenter open-label sertraline study in adolescent outpatients with major depression. J Am Acad Child Adolesc Psychiatry, 38:566–572, 1999.
2.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994.
3.
AndreasenNC, EndicottJ, SpitzerRL, WinokurG: The family history method using diagnostic criteria. Reliability and validity. Arch Gen Psychiatry, 34:1229–1235, 1977.
4.
BaumerFM, HoweM, GallelliK, SimeonovaDI, HallmayerJ, ChangKD: A pilot study of antidepressant-induced mania in pediatric bipolar disorder: Characteristics, risk factors, and the serotonin transporter gene. Biol Psychiatry, 60:1005–1012, 2006.
5.
BengelD, GreenbergBD, Corá–LocatelliG, AltemusM, HeilsA, LiQ, MurphyDL: Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder. Mol Psychiatry, 4:463–466, 1999.
6.
BlackfordJU, PineDS: Neural substrates of childhood anxiety disorders: A review of neuroimaging findings. Child Adolesc Psychiatr Clin N Am, 21:501–525, 2012.
7.
BlayaC, SalumGA, LimaMS, Leistner–SegalS, ManfroGG: Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and panic disorder: A systematic review and meta-analysis. Behav Brain Funct, 3:41, 2007.
8.
BraconnierA, Le CoentR, CohenD: Paroxetine versus clomipramine in adolescents with severe major depression: A double-blind, randomized, multicenter trial. J Am Acad Child Adolesc Psychiatry, 42:22–29, 2003.
9.
CalapoğluM, Sahin–CalapoğluN, KaraçöpA, SoyözM, ElyildirimUY, AvşaroğluS: Serotonin transporter bi- and triallelic genotypes and their relationship with anxiety and academic performance: A preliminary study. Neuropsychobiology, 63:103–111, 2011.
10.
CaspiA, SugdenK, MoffittTE, TaylorA, CraigIW, HarringtonH, McClayJ, MillJ, MartinJ, BraithwaiteA, PoultonR: Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science, 301:386–389, 2003.
11.
ChangK, SteinerH, DienesK, AdlemanN, KetterT: Bipolar offspring: A window into bipolar disorder evolution. Biol Psychiatry, 53:945–951, 2003a.
12.
ChangK, SteinerH, KetterT: Studies of offspring of parents with bipolar disorder. Am J Med Genet C Semin Med Genet, 123C:26–35, 2003b.
13.
ChangKD: Course and impact of bipolar disorder in young patients. J Clin Psychiatry, 71:e05, 2010.
14.
ChangKD, BlaseyC, KetterTA, SteinerH: Family environment of children and adolescents with bipolar parents. Bipolar Disord, 3:73–78, 2001.
15.
ChoHJ, Meira–LimaI, CordeiroQ, MichelonL, ShamP, ValladaH, CollierDA: Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: A systematic review and meta-analysis. Mol Psychiatry, 10:771–781, 2005.
16.
ContrerasJ, HareE, PachecoA, EscamillaM, RaventosH: Is subclinical anxiety an endophenotype for bipolar I patients? A study from a Costa Rican sample. J Affect Disord, 122:267–272, 2010.
17.
CookEH, WagnerKD, MarchJS, BiedermanJ, LandauP, WolkowR, MessigM: Long-term sertraline treatment of children and adolescents with obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry, 40:1175–1181, 2001.
18.
DavidsonRJ: Anxiety and affective style: Role of prefrontal cortex and amygdala. Biol Psychiatry, 51:68–80, 2002.
19.
DeckertJ, CatalanoM, HeilsA, Di BellaD, FriessF, PolitiE, FrankeP, NothenMM, MaierW, BellodiL, LeschKP: Functional promoter polymorphism of the human serotonin transporter: lack of association with panic disorder. Psychiatr Genet, 7:45–47, 1997.
20.
DelBelloMP, GellerB: Review of studies of child and adolescent offspring of bipolar parents. Bipolar Disord, 3:325–334, 2001.
21.
DierkerLC, MerikangasKR, SzatmariP: Influence of parental concordance for psychiatric disorders on psychopathology in offspring. J Am Acad Child Adolesc Psychiatry, 38:280–288, 1999.
22.
DuL, BakishD, LapierreYD, RavindranAV, HrdinaPD: Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder. Am J Med Genet, 96:56–60, 2000.
23.
DurhamLK, WebbSM, MilosPM, ClaryCM, SeymourAB: The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology (Berl), 174:525–529, 2004.
24.
EleyTC, SugdenK, CorsicoA, GregoryAM, ShamP, McGuffinP, PlominR, CraigIW: Gene–environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry, 9:908–915, 2004.
25.
EmslieGJ, HeiligensteinJH, WagnerKD, HoogSL, ErnestDE, BrownE, NilssonM, JacobsonJG: Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry, 41:1205–1215, 2002.
26.
FaeddaGL, BaldessariniRJ, GlovinskyIP, AustinNB: Treatment-emergent mania in pediatric bipolar disorder: a retrospective case review. J Affect Disord, 82:149–158, 2004.
27.
FirstMB, SpitzerRL, GibbonM, WilliamsJ: Structured Clinical Interview for DSM-IV Axis I Disorders – Patient Edition (SCID-I/P, Version 2.0). New York: Biometrics Research Department, New York State Psychiatric Institute; 1996.
28.
GellerB, ZimermanB, WilliamsM, BolhofnerK, CraneyJL, DelBelloMP, SoutulloC: Reliability of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections. J Am Acad Child Adolesc Psychiatry, 40:450–455, 2001.
29.
HamiltonSP, HeimanGA, HaghighiF, MickS, KleinDF, HodgeSE, WeissmanMM, FyerAJ, KnowlesJA: Lack of genetic linkage or association between a functional serotonin transporter polymorphism and panic disorder. Psychiatr Genet, 9:1–6, 1999.
30.
HaririAR, MattayVS, TessitoreA, KolachanaB, FeraF, GoldmanD, EganMF, WeinbergerDR: Serotonin transporter genetic variation and the response of the human amygdala. Science, 297:400–403, 2002.
31.
HeinzA, BrausDF, SmolkaMN, WraseJ, PulsI, HermannD, KleinS, GrüsserSM, FlorH, SchumannG, MannK, BüchelC: Amygdala–prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci, 8:20–21, 2005.
32.
HeninA, BiedermanJ, MickE, SachsGS, Hirshfeld–BeckerDR, SiegelRS, McMurrichS, GrandinL, NierenbergAA: Psychopathology in the offspring of parents with bipolar disorder: A controlled study. Biol Psychiatry, 58:554–561, 2005.
33.
HolickKA, LeeDC, HenR, DulawaSC: Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology, 33:406–417, 2008.
34.
IshiguroH, ArinamiT, YamadaK, OtsukaY, ToruM, ShibuyaH: An association study between a transcriptional polymorphism in the serotonin transporter gene and panic disorder in a Japanese population. Psychiatry Clin Neurosci, 51:333–335, 1997.
35.
JacobCP, StrobelA, HohenbergerK, RingelT, GutknechtL, ReifA, BrockeB, LeschKP: Association between allelic variation of serotonin transporter function and neuroticism in anxious cluster C personality disorders. Am J Psychiatry, 161:569–572, 2004.
36.
JiangHY, QiaoF, XuXF, YangY, BaiY, JiangLL: Meta-analysis confirms a functional polymorphism (5-HTTLPR) in the serotonin transporter gene conferring risk of bipolar disorder in European populations. Neurosci Lett, 549:191–196, 2013.
37.
JormAF, PriorM, SansonA, SmartD, ZhangY, EastealS: Association of a functional polymorphism of the serotonin transporter gene with anxiety-related temperament and behavior problems in children: A longitudinal study from infancy to the mid-teens. Mol Psychiatry, 5:542–547, 2000.
38.
KargK, BurmeisterM, SheddenK, SenS: The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Arch Gen Psychiatry, 68:444–454, 2011.
39.
KatsuragiS, KunugiH, SanoA, TsutsumiT, IsogawaK, NankoS, AkiyoshiJ: Association between serotonin transporter gene polymorphism and anxiety-related traits. Biol Psychiatry, 45:368–370, 1999.
40.
KaufmanJ, BirmaherB, BrentD, RaoU, FlynnC, MoreciP, WilliamsonD, RyanN: Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Initial reliability and validity data. J Am Acad Child Adolesc Psychiatry, 36:980–988, 1997.
41.
KaufmanJ, YangBZ, Douglas–PalumberiH, GrassoD, LipschitzD, HoushyarS, KrystalJH, GelernterJ: Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry, 59:673–680, 2006.
42.
KaufmanJ, YangBZ, Douglas–PalumberiH, HoushyarS, LipschitzD, KrystalJH, GelernterJ: Social supports and serotonin transporter gene moderate depression in maltreated children. Proc Natl Acad Sci U S A, 101:17,316–17,321, 2004.
43.
KendlerKS: “A gene for…”: the nature of gene action in psychiatric disorders. Am J Psychiatry, 162:1243–1252, 2005.
44.
KennaGA, Roder–HannaN, LeggioL, ZywiakWH, CliffordJ, EdwardsS, KennaJA, ShoaffJ, SwiftRM: Association of the 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism with psychiatric disorders: review of psychopathology and pharmacotherapy. Pharmgenomics Pers Med, 5:19–35, 2012.
45.
KimDK, SeoMY, LimSW, KimH, KimS: Serotonin transporter gene polymorphsims and its phenotypic characteristics expressed in platelet [3H]-serotonin uptake study in Korean depressed patients. J Korean Neuropsychiatr Assoc, 42:54–60, 2003.
46.
KronenbergS, ApterA, BrentD, SchirmanS, MelhemN, PickN, GothelfD, CarmelM, FrischA, WeizmanA: Serotonin transporter polymorphism (5-HTTLPR) and citalopram effectiveness and side effects in children with depression and/or anxiety disorders. J Child Adolesc Psychopharmacol, 17:741–750, 2007.
47.
LapalmeM, HodginsS, LaRocheC: Children of parents with bipolar disorder: A metaanalysis of risk for mental disorders. Can J Psychiatry, 42:623–631, 1997.
48.
Lasky-SuJA, FaraoneSV, GlattSJ, TsuangMT: Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B Neuropsychiatr Genet, 133B:110–115, 2005.
49.
LeschKP, BengelD, HeilsA, SabolSZ, GreenbergBD, PetriS, BenjaminJ, MüllerCR, HamerDH, MurphyDL: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274:1527–1531, 1996.
50.
LonsdorfTB, RückC, BergströmJ, AnderssonG, OhmanA, SchallingM, LindeforsN: The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism. Prog Neuropsychopharmacol Biol Psychiatry, 33:1479–1483, 2009.
51.
MarchJS, BiedermanJ, WolkowR, SaffermanA, MardekianJ, CookEH, CutlerNR, DominguezR, FergusonJ, MullerB, RiesenbergR, RosenthalM, SalleeFR, WagnerKD, SteinerH: Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA, 280:1752–1756, 1998.
52.
MarchJS, ParkerJD, SullivanK, StallingsP, ConnersCK: The Multidimensional Anxiety Scale for Children (MASC): Factor structure, reliability, and validity. J Am Acad Child Adolesc Psychiatry, 36:554–565, 1997.
53.
MargoobMA, MushtaqD: Serotonin transporter gene polymorphism and psychiatric disorders: is there a link?. Indian J Psychiatry, 53:289–299, 2011.
54.
MaronE, LangA, TasaG, LiivlaidL, TõruI, MustA, VasarV, ShlikJ: Associations between serotonin-related gene polymorphisms and panic disorder. Int J Neuropsychopharmacol, 8:261–266, 2005.
55.
Martinez–BarrondoS, SaizPA, MoralesB, Garcia–PortillaMP, CotoE, AlvarezV, BobesJ: Serotonin gene polymorphisms in patients with panic disorder. Actas Esp Psiquiatr, 33:210–215, 2005.
56.
MatsushitaS, MuramatsuT, KimuraM, ShirakawaO, MitaT, NakaiT, HiguchiS: Serotonin transporter gene regulatory region polymorphism and panic disorder. Mol Psychiatry, 2:390–392, 1997.
57.
MazzantiCM, LappalainenJ, LongJC, BengelD, NaukkarinenH, EggertM, VirkkunenM, LinnoilaM, GoldmanD: Role of the serotonin transporter promoter polymorphism in anxiety-related traits. Arch Gen Psychiatry, 55:936–940, 1998.
58.
McDougleCJ, EppersonCN, PriceLH, GelernterJ: Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Mol Psychiatry, 3:270–273, 1998.
59.
MelkeJ, LandénM, BagheiF, RosmondR, HolmG, BjörntorpP, WestbergL, HellstrandM, ErikssonE: Serotonin transporter gene polymorphisms are associated with anxiety-related personality traits in women. Am J Med Genet, 105:458–463, 2001.
60.
MiddeldorpCM, de GeusEJ, BeemAL, LakenbergN, HottengaJJ, SlagboomPE, BoomsmaDI: Family based association analyses between the serotonin transporter gene polymorphism (5-HTTLPR) and neuroticism, anxiety and depression. Behav Genet, 37:294–301, 2007.
61.
MorenoDH, BioDS, PetrescoS, PetrescoD, GuttEK, Soeiro-de-SouzaMG, MorenoRA: Burden of maternal bipolar disorder on at-risk offspring: A controlled study on family planning and maternal care. J Affect Disord, 143:172–178, 2012.
62.
MunafòMR, BrownSM, HaririAR: Serotonin transporter (5-HTTLPR) genotype and amygdala activation: A meta-analysis. Biol Psychiatry, 63:852–857, 2008.
63.
MunafòMR, FreimerNB, NgW, OphoffR, VeijolaJ, MiettunenJ, JärvelinMR, TaanilaA, FlintJ: 5-HTTLPR genotype and anxiety-related personality traits: a meta-analysis and new data. Am J Med Genet B Neuropsychiatr Genet, 150b:271–281, 2009.
OhJE, ZupanB, GrossS, TothM: Paradoxical anxiogenic response of juvenile mice to fluoxetine. Neuropsychopharmacology, 34:2197–2207, 2009.
66.
OharaK, NagaiM, SuzukiY, OchiaiM, OharaK: Association between anxiety disorders and a functional polymorphism in the serotonin transporter gene. Psychiatry Res, 81:277–279, 1998.
67.
OsherY, HamerD, BenjaminJ: Association and linkage of anxiety-related traits with a functional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling pairs. Mol Psychiatry, 5:216–219, 2000.
68.
PernaG, FavaronE, Di BellaD, BussiR, BellodiL: Antipanic efficacy of paroxetine and polymorphism within the promoter of the serotonin transporter gene. Neuropsychopharmacology, 30:2230–2235, 2005.
69.
PollockBG, FerrellRE, MulsantBH, MazumdarS, MillerM, SweetRA, DavisS, KirshnerMA, HouckPR, StackJA, ReynoldsCF, KupferDJ: Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology, 23:587–590, 2000.
Rey–SánchezF, Gutiérrez–CasaresJR: Paroxetine in children with major depressive disorder: An open trial. J Am Acad Child Adolesc Psychiatry, 36:1443–1447, 1997.
72.
RoerigJL: Diagnosis and management of generalized anxiety disorder. J Am Pharm Assoc (Wash), 39:811–821; quiz 877–879, 1999.
73.
SalaR, StroberMA, AxelsonDA, GillMK, Castro–FornielesJ, GoldsteinTR, GoldsteinBI, HaW, LiaoF, IyengarS, YenS, HowerH, HuntJ, DicksteinDP, RyanND, KellerMB, BirmaherB: Effects of comorbid anxiety disorders on the longitudinal course of pediatric bipolar disorders. J Am Acad Child Adolesc Psychiatry, 53:72–81, 2014.
74.
SamochowiecJ, HajdukA, SamochowiecA, HorodnickiJ, StepieńG, GrzywaczA, Kucharska–MazurJ: Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Res, 128:21–26, 2004.
75.
SchinkaJA, BuschRM, Robichaux–KeeneN: A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety. Mol Psychiatry, 9:197–202, 2004.
76.
SenS, BurmeisterM, GhoshD: Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet B Neuropsychiatr Genet, 127B:85–89, 2004.
77.
SinghMK, DelBelloMP, StanfordKE, SoutulloC, McDonough–RyanP, McElroySL, StrakowskiSM: Psychopathology in children of bipolar parents. J Affect Disord, 102:131–136, 2007.
78.
SmeraldiE, ZanardiR, BenedettiF, Di BellaD, PerezJ, CatalanoM: Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry, 3:508–511, 1998.
79.
SteinMB, ChartierMJ, KozakMV, KingN, KennedyJL: Genetic linkage to the serotonin transporter protein and 5HT2A receptor genes excluded in generalized social phobia. Psychiatry Res, 81:283–291, 1998.
80.
SteinMB, SchorkNJ, GelernterJ: Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology, 33:312–319, 2008.
81.
SteinMB, SeedatS, GelernterJ: Serotonin transporter gene promoter polymorphism predicts SSRI response in generalized social anxiety disorder. Psychopharmacology (Berl), 187:68–72, 2006.
82.
StrawnJR, AdlerCM, McNamaraRK, WelgeJA, BitterSM, MillsNP, BarzmanDH, CerulloMA, ChangKD, StrakowskiSM, DelbelloMP: Antidepressant tolerability in anxious and depressed youth at high risk for bipolar disorder: A prospective naturalistic treatment study. Bipolar Disord, 16:523–530, 2014.
83.
StrugLJ, SureshR, FyerAJ, TalatiA, AdamsPB, LiW, HodgeSE, GilliamTC, WeissmanMM: Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Mol Psychiatry, 15:166–176, 2010.
WagnerKD, AmbrosiniP, RynnM, WohlbergC, YangR, GreenbaumMS, ChildressA, DonnellyC, DeasD: Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. JAMA, 290:1033–1041, 2003.
86.
WarrenBL, IñiguezSD, AlcantaraLF, WrightKN, PariseEM, WeakleySK, Bolaños–GuzmánCA: Juvenile administration of concomitant methylphenidate and fluoxetine alters behavioral reactivity to reward- and mood-related stimuli and disrupts ventral tegmental area gene expression in adulthood. J Neurosci, 31: 10,347–10,358, 2011.
87.
Willis–OwenSA, TurriMG, MunafòMR, SurteesPG, WainwrightNW, BrixeyRD, FlintJ: The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biol Psychiatry, 58:451–456, 2005.
88.
YoshidaK, ItoK, SatoK, TakahashiH, KamataM, HiguchiH, ShimizuT, ItohK, InoueK, TezukaT, SuzukiT, OhkuboT, SugawaraK, OtaniK: Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry, 26:383–386, 2002.
89.
YoungRC, BiggsJT, ZieglerVE, MeyerDA: A rating scale for mania: Reliability, validity and sensitivity. Br J Psychiatry, 133:429–435, 1978.
90.
ZanardiR, BenedettiF, Di BellaD, CatalanoM, SmeraldiE: Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol, 20:105–107, 2000.
91.
ZanardiR, SerrettiA, RossiniD, FranchiniL, CusinC, LattuadaE, DotoliD, SmeraldiE: Factors affecting fluvoxamine antidepressant activity: Influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol Psychiatry, 50:323–330, 2001.
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