Trajectory and Predictors of Depression and Anxiety Disorders in Mothers With the FMR1 Premutation



      Although the FMR1 premutation is associated with elevated prevalence of psychiatric disorders, the longitudinal course of symptoms has not been established. The present study followed a sample of women with the FMR1 premutation to characterize the incidence, stability, and predictors of mood and anxiety disorders across a 3-year period.


      Participants included 83 women with the FMR1 premutation (mean age = 38.35) who completed the Structured Clinical Interview for DSM-IV Axis I Disorders at two time points, 3 years apart. Additional information was obtained regarding demographic, child, and biomedical (e.g., medication, menopause, CGG repeats) factors.


      We found increased prevalence of major depressive disorder (MDD) and anxiety disorders over time, with adverse outcomes predicted by complex interactions among biological, behavioral, and environmental risk factors. Lifetime MDD increased from 46% to 54% and lifetime anxiety disorders increased from 28% to 35%. Midrange CGG repeats, elevated child problem behaviors, and divorced marital status conveyed elevated risk for psychiatric diagnoses. Primary ovarian insufficiency was highly prevalent (41%) but did not account for elevated rates of psychiatric diagnoses. Medication use was highly reported (41%), particularly in women with MDD or anxiety, with selective serotonin reuptake inhibitors reported as the most commonly used medication across diagnostic groups.


      The elevated prevalence of depression and anxiety in women with the FMR1 premutation is a clear and pressing concern given the frequent occurrence of the FMR1 premutation in the general community and the adverse outcomes—at both individual and systems levels—associated with psychiatric disorders in this population.


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        • Tassone F.
        • Hagerman R.J.
        • Taylor a.K.
        • Gane L.W.
        • Godfrey T.E.
        • Hagerman P.J.
        Elevated levels of FMR1 mRNA in carrier males: A new mechanism of involvement in the fragile-X syndrome.
        Am J Hum Genet. 2000; 66: 6-15
        • Hessl D.
        • Tassone F.
        • Loesch D.Z.
        • Berry-Kravis E.
        • Leehey M.A.
        • Gane L.W.
        • et al.
        Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation.
        Am J Med Genet B Neuropsychiatr Genet. 2005; 139B: 115-121
        • Roberts J.E.
        • Bailey D.B.
        • Mankowski J.
        • Ford A.
        • Sideris J.
        • Weisenfeld L.A.
        • et al.
        Mood and anxiety disorders in females with the FMR1 premutation.
        Am J Med Genet B Neuropsychiatr Genet. 2009; 150B: 130-139
        • Bailey D.B.
        • Sideris J.
        • Roberts J.
        • Hatton D.
        Child and genetic variables associated with maternal adaptation to fragile X syndrome: A multidimensional analysis.
        Am J Med Genet A. 2008; 146A: 720-729
        • Wheeler A.C.
        • Skinner D.G.
        • Bailey D.B.
        Perceived quality of life in mothers of children with fragile X syndrome.
        Am J Ment Retard. 2008; 113: 159-177
        • Allingham-Hawkins D.J.
        • Babul-Hirji R.
        • Chitayat D.
        • Holden J.J.
        • Yang K.T.
        • Lee C.
        • et al.
        Fragile X premutation is a significant risk factor for premature ovarian failure: The International Collaborative POF in Fragile X study--preliminary data.
        Am J Med Genet. 1999; 83: 322-325
        • Rodriguez-Revenga L.
        • Madrigal I.
        • Alegret M.
        • Santos M.
        • Milà M.
        Evidence of depressive symptoms in fragile-X syndrome premutated females.
        Psychiatr Genet. 2008; 18: 153-155
        • Rodriguez-Revenga L.
        • Madrigal I.
        • Pagonabarraga J.
        • Xunclà M.
        • Badenas C.
        • Kulisevsky J.
        • et al.
        Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families.
        Eur J Hum Genet. 2009; 17: 1359-1362
        • Hagerman R.J.
        • Leavitt B.R.
        • Farzin F.
        • Jacquemont S.
        • Greco C.M.
        • Brunberg J.A.
        • et al.
        Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.
        Am J Hum Genet. 2004; 74: 1051-1056
        • Jacquemont S.
        • Hagerman R.J.
        • Leehey M.A.
        • Hall D.A.
        • Levine R.A.
        • Brunberg J.A.
        • et al.
        Penetrance of the fragile X–associated tremor/ataxia syndrome in a premutation carrier population.
        JAMA. 2004; 291: 460-469
        • Kraan C.M.
        • Hocking D.R.
        • Georgiou-Karistianis N.
        • Metcalfe S.a.
        • Archibald A.D.
        • Fielding J.
        • et al.
        Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers.
        Am J Med Genet B Neuropsychiatr Genet. 2014; 165B: 41-51
        • Cornish K.M.
        • Li L.
        • Kogan C.S.
        • Jacquemont S.
        • Turk J.
        • Dalton A.
        • et al.
        Age-dependent cognitive changes in carriers of the fragile X syndrome.
        Cortex. 2008; 44: 628-636
        • Lachiewicz A.
        • Dawson D.
        • Spiridigliozzi G.
        • McConkie-Rosell A.
        Arithmetic difficulties in females with the fragile X premutation.
        Am J Med Genet A. 2006; 140: 665-672
        • Hantash F.M.
        • Goos D.M.
        • Crossley B.
        • Anderson B.
        • Zhang K.
        • Sun W.
        • Strom C.M.
        FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: Insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States.
        Genet Med. 2011; 13: 39-45
        • Tassone F.
        • Iong K.P.
        • Tong T.-H.
        • Lo J.
        • Gane L.W.
        • Berry-Kravis E.
        • et al.
        FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States.
        Genome Med. 2012; 4: 100
        • Kenna H.A.
        • Tartter M.
        • Hall S.S.
        • Lightbody A.A.
        • Nguyen Q.
        • de Los Angeles C.P.
        • et al.
        High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene.
        Am J Med Genet B Neuropsychiatr Genet. 2013; 162B: 872-878
        • Hunter J.E.
        • Leslie M.
        • Novak G.
        • Hamilton D.
        • Shubeck L.
        • Charen K.
        • et al.
        Depression and anxiety symptoms among women who carry the FMR1 premutation: Impact of raising a child with fragile X syndrome is moderated by CRHR1 polymorphisms.
        Am J Med Genet B Neuropsychiatr Genet. 2012; 159B: 549-559
        • Shelton A.L.
        • Cornish K.
        • Kraan C.
        • Georgiou-Karistianis N.
        • Metcalfe S.A.
        • Bradshaw J.L.
        • et al.
        Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: Through eye movements.
        Brain Cogn. 2014; 85: 201-208
        • Seltzer M.
        • Barker E.
        • Greenberg J.
        • Hong J.
        • Coe C.
        • Almeida D.
        Differential sensitivity to life stress in FMR1 premutation carrier mothers of children with fragile X syndrome.
        Health Psychol. 2012; 31: 612-622
        • Sobesky W.E.
        • Pennington B.F.
        • Porter D.
        • Hull C.E.
        • Hagerman R.J.
        Emotional and neurocognitive deficits in fragile X.
        Am J Med Genet. 1994; 51: 378-385
        • Thompson N.M.
        • Gulley M.L.
        • Rogeness G.A.
        • Clayton R.J.
        • Johnson C.
        • Hazelton B.
        • et al.
        Neurobehavioral characteristics of CGG amplification status in fragile X females.
        Am J Med Genet. 1994; 54: 378-383
        • Reiss A.
        • Freund L.
        • Abrams M.T.
        • Boehm C.
        • Kazazian H.
        Neurobehavioral effects of the fragile X premutation in adult women: A controlled study.
        Am J Hum Genet. 1993; 52: 884-894
        • Franke P.
        • Leboyer M.
        • Gänsicke M.
        • Weiffenbach O.
        • Biancalana V.
        • Cornillet-Lefebre P.
        • et al.
        Genotype-phenotype relationship in female carriers of the premutation and full mutation of FMR-1.
        Psychiatry Res. 1998; 80: 113-127
        • Lachiewicz A.
        • Dawson D.
        • Spiridigliozzi G.
        • Cuccaro M.
        • Lachiewicz M.
        • McConkie-Rosell A.
        Indicators of anxiety and depression in women with the fragile X premutation: Assessment of a clinical sample.
        J Intellect Disabil Res. 2010; 54: 597-610
        • Johnston C.
        • Eliez S.
        • Dyer-Friedman J.
        • Hessl D.
        • Glaser B.
        • Blasey C.
        • et al.
        Neurobehavioral phenotype in carriers of the fragile X premutation.
        Am J Med Genet. 2001; 319: 314-319
        • Loesch D.Z.
        • Bui M.Q.
        • Hammersley E.
        • Schneider A.
        • Storey E.
        • Stimpson P.
        • et al.
        Psychological status in female carriers of premutation FMR1 allele showing a complex relationship with the size of CGG expansion.
        Clin Genet. 2015; 87: 173-178
        • First M.B.
        • Spitzer R.L.
        • Gibbon M
        • William JBW
        Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I).
        American Psychiatric Press, Inc, Washington, DC1996
        • Achenbach T.
        Manual for the Child Behavior Checklist/4-18 and 1991 Profile.
        University of Vermont Department of Psychiatry, Burlington, VT1991
        • Mailick M.
        • Hong J.
        • Greenberg J.
        • Smith L.
        • Sherman S.
        Curvilinear association of CGG repeats and age at menopause in women with FMR1 premutation expansions.
        Am J Med Genet B Neuropsychiatr Genet. 2014; 165: 705-711
        • Boyle L.
        • Kaufmann W.E.
        The behavioral phenotype of FMR1 mutations.
        Am J Med Genet Part C Semin Med Genet. 2010; 154C: 469-476
        • Bailey D.B.
        • Raspa M.
        • Olmsted M.
        • Holiday D.B.
        Co-occurring conditions associated with FMR1 gene variations: Findings from a national parent survey.
        Am J Med Genet A. 2008; 146A: 2060-2069
        • Tonnsen B.L.
        • Cornish K.M.
        • Wheeler A.C.
        • Roberts J.E.
        Maternal predictors of anxiety risk in young males with fragile X.
        Am J Med Genet B Neuropsychiatr Genet. 2014; 165B: 399-409
        • Cornish K.
        • Kraan C.
        • Bui Q.
        • Bellgrove M.A.
        • Metcalfe S.A.
        • Trollor J.N.
        • et al.
        Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women.
        Neurology. 2015; 84: 1631-1638
        • Seritan A.L.
        • Ortigas M.
        • Seritan S.
        • Bourgeois O.D.
        • Hagerman R.J.
        Psychiatric disorders associated with FXTAS.
        Curr Psychiatry Rev. 2013; 9: 59-64
        • Kessler R.
        • Berglund P.
        • Demler O.
        • Jin R.
        The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R).
        JAMA. 2003; 289: 3095-3105
        • Bailey D.B.
        • Skinner D.
        • Sparkman K.L.
        Discovering Fragile X syndrome: Family experiences and perceptions.
        Pediatrics. 2003; 111: 407-416
        • Bourgeois J.
        • Seritan A.
        • Casillas E.M.
        • Hessl D.
        • Schneider A.
        • Yang Y.
        • et al.
        Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers.
        J Clin Psychiatry. 2011; 72: 175-182
        • Beesdo-Baum K.
        • Knappe S.
        Developmental epidemiology of anxiety disorders.
        Child Adolesc Psychiatr Clin N Am. 2012; 21: 457-478
        • Kessler R.C.
        • Bromet E.J.
        The epidemiology of depression across cultures.
        Annu Rev Public Health. 2013; 34: 119-138

      Linked Article

      • Psychopathology Increases With Age in Fragile X Carrier Mothers
        Biological PsychiatryVol. 79Issue 10
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          The saga of psychiatric problems in FMR1 premutation carriers (55–200 CGG repeats) has come a long way over the last 15 years, informed by advances in molecular biology, neuroimaging, and detailed phenotypic assessments within psychiatric and neuropsychological studies. Initially, in the 1990s, female premutation carriers were considered unaffected by psychiatric problems, although epidemiologic studies demonstrated an increased rate of early menopause in carriers compared with the general population.
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