Review

Obsessive–compulsive disorder: an integrative genetic and neurobiological perspective

Published online:

Abstract

Obsessive–compulsive disorder (OCD) is characterized by repetitive thoughts and behaviours that are experienced as unwanted. Family and twin studies have demonstrated that OCD is a multifactorial familial condition that involves both polygenic and environmental risk factors. Neuroimaging studies have implicated the cortico–striato–thalamo–cortical circuit in the pathophysiology of the disorder, which is supported by the observation of specific neuropsychological impairments in patients with OCD, mainly in executive functions. Genetic studies indicate that genes affecting the serotonergic, dopaminergic and glutamatergic systems, and the interaction between them, play a crucial part in the functioning of this circuit. Environmental factors such as adverse perinatal events, psychological trauma and neurological trauma may modify the expression of risk genes and, hence, trigger the manifestation of obsessive–compulsive behaviours.

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References

  1. 1.

    Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA 292, 1969–1976 (2004).

  2. 2.

    , , & The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol. Psychiatry 15, 53–63 (2010).

  3. 3.

    The epidemiology of obsessive-compulsive disorder in children and adolescents. Child Adolesc. Psychiatr. Clin. N. Am. 8, 445–460 (1999).

  4. 4.

    et al. Is juvenile obsessive-compulsive disorder a developmental subtype of the disorder? A review of the pediatric literature. J. Am. Acad. Child Adolesc. Psychiatry 37, 420–427 (1998).

  5. 5.

    et al. Children with very early onset obsessive-compulsive disorder: clinical features and treatment outcome. J. Child Psychol. Psychiatry 52, 1261–1268 (2011).

  6. 6.

    et al. Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder. Am. J. Psychiatry 160, 1919–1928 (2003).

  7. 7.

    , & Cognitive-behavioral family treatment of childhood obsessive-compulsive disorder: a controlled trial. J. Am. Acad. Child Adolesc. Psychiatry 43, 46–62 (2004).

  8. 8.

    , & Obsessive-compulsive disorder. Handb. Clin. Neurol. 106, 375–390 (2012).

  9. 9.

    , & Dopaminergic control of cognitive flexibility in humans and animals. Front. Neurosci. 7, 201 (2013).

  10. 10.

    et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch. Gen. Psychiatry 46, 1006–1011 (1989).

  11. 11.

    Factor analysis of symptom subtypes of obsessive compulsive disorder and their relation to personality and tic disorders. J. Clin. Psychiatry 55 (Suppl.), 18–23 (1994).

  12. 12.

    & [Modern typology of symptoms and obsessive-compulsive syndromes: results of a large French study of 615 patients]. Encephale 22, 9–21 (in French) (1996).

  13. 13.

    et al. Symptoms of obsessive-compulsive disorder. Am. J. Psychiatry 154, 911–917 (1997).

  14. 14.

    , , , & Use of factor-analyzed symptom dimensions to predict outcome with serotonin reuptake inhibitors and placebo in the treatment of obsessive-compulsive disorder. Am. J. Psychiatry 156, 1409–1416 (1999).

  15. 15.

    & Phenomenology of obsessive compulsive disorder: a factor analytic approach. Indian J. Psychiatry 43, 306–316 (2001).

  16. 16.

    & Religiosity and religious obsessions in obsessive-compulsive disorder. Psychiatry Res. 104, 99–108 (2001).

  17. 17.

    , , , & Exploratory factor analysis of obsessive-compulsive patients and association with 5-HTTLPR polymorphism. Am. J. Med. Genet. 114, 347–353 (2002).

  18. 18.

    et al. Symptom stability in adult obsessive-compulsive disorder: data from a naturalistic two-year follow-up study. Am. J. Psychiatry 159, 263–268 (2002).

  19. 19.

    , , & Item-by-item factor analysis of the Yale-Brown Obsessive Compulsive Scale Symptom Checklist. J. Neuropsychiatry Clin. Neurosci. 15, 187–193 (2003).

  20. 20.

    , , & Use of factor analysis to detect potential phenotypes in obsessive-compulsive disorder. Psychiatry Res. 128, 273–280 (2004).

  21. 21.

    et al. Obsessive-compulsive disorder symptom dimensions show specific relationships to psychiatric comorbidity. Psychiatry Res. 135, 121–132 (2005).

  22. 22.

    , & Obsessive-compulsive disorder, factor-analyzed symptom dimensions and serotonin transporter polymorphism. Neuropsychobiology 52, 176–182 (2005).

  23. 23.

    et al. Exploratory analysis of obsessive compulsive symptom dimensions in children and adolescents: a prospective follow-up study. BMC Psychiatry 6, 1 (2006).

  24. 24.

    et al. The structure of childhood obsessions and compulsions: dimensions in an outpatient sample. Behav. Res. Ther. 44, 137–146 (2006).

  25. 25.

    et al. Factor analysis of the Yale-Brown Obsessive Compulsive Scale in a family study of obsessive-compulsive disorder. Depress. Anxiety 24, 130–138 (2007).

  26. 26.

    et al. Familiality of factor analysis-derived YBOCS dimensions in OCD-affected sibling pairs from the OCD Collaborative Genetics Study. Biol. Psychiatry 61, 617–625 (2007).

  27. 27.

    et al. Taboo thoughts and doubt/checking: a refinement of the factor structure for obsessive-compulsive disorder symptoms. Psychiatry Res. 151, 255–258 (2007).

  28. 28.

    , & Response of symptom dimensions in obsessive-compulsive disorder to treatment with citalopram or placebo. Rev. Bras. Psiquiatr. 29, 303–307 (2007).

  29. 29.

    et al. Principal components analysis of obsessive-compulsive disorder symptoms in children and adolescents. Biol. Psychiatry 61, 285–291 (2007).

  30. 30.

    , , & Structure of obsessive-compulsive symptoms in pediatric OCD. J. Am. Acad. Child Adolesc. Psychiatry 47, 773–778 (2008).

  31. 31.

    et al. Symptom structure in Japanese patients with obsessive-compulsive disorder. Am. J. Psychiatry 165, 251–253 (2008).

  32. 32.

    , , , & Meta-analysis of the symptom structure of obsessive-compulsive disorder. Am. J. Psychiatry 165, 1532–1542 (2008).

  33. 33.

    , , , & Obsessive-compulsive symptom dimensions as predictors of compliance with and response to behaviour therapy: results from a controlled trial. Psychother. Psychosom. 71, 255–262 (2002).

  34. 34.

    et al. Dimensional predictors of response to SRI pharmacotherapy in obsessive-compulsive disorder. J. Affect. Disord. 121, 175–179 (2010).

  35. 35.

    et al. Distinct neural correlates of washing, checking, and hoarding symptom dimensions in obsessive-compulsive disorder. Arch. Gen. Psychiatry 61, 564–576 (2004).

  36. 36.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Association, 2013).

  37. 37.

    , & A multidimensional model of obsessive-compulsive disorder. Am. J. Psychiatry 162, 228–238 (2005).

  38. 38.

    The genetics of obsessive-compulsive disorder: a review. Dialogues Clin. Neurosci. 12, 149–163 (2010).

  39. 39.

    Heredität und Familientypus der Zwangsneurotiker. Arch. Psychiatry 91, 590–594 (in German) (1930).

  40. 40.

    Problems of obsessional illness (section of psychiatry). Proc. R. Soc. Med. 29, 325–336 (1936).

  41. 41.

    Heredity in the psychoneuroses (summary). Proc. R. Soc. Med. 35, 785–790 (1942).

  42. 42.

    [On the problem of compulsive disease with special reference to its hereditary relations]. Arch. Psychiatr. Nervenkr Z. Gesamte Neurol. Psychiatr. 191, 14–54 (1953).

  43. 43.

    Obsessional neurotics: a long-term follow-up. Br. J. Psychiatry 111, 709–722 (1965).

  44. 44.

    Familial aspects of obsessional neurosis. Br. J. Psychiatry 113, 405–413 (1967).

  45. 45.

    , & Parents of patients with obsessive-compulsive disorder. Psychol. Med. 13, 807–811 (1983).

  46. 46.

    & Clinical characteristics and family history in DSM-III obsessive-compulsive disorder. Am. J. Psychiatry 143, 317–322 (1986).

  47. 47.

    & Familial aspects of obsessive-compulsive neurosis. Br. J. Psychiatry 151, 528–534 (1987).

  48. 48.

    , , , & Psychiatric disorders in the families of patients with obsessive-compulsive disorder. Psychiatry Res. 42, 111–120 (1992).

  49. 49.

    , , & A family study of obsessive-compulsive disorder. Arch. Gen. Psychiatry 49, 362–368 (1992).

  50. 50.

    , , & Family study of obsessive-compulsive disorder in a Mexican population. Arch. Med. Res. 24, 193–198 (1993).

  51. 51.

    , , , & A family study of obsessive-compulsive disorder. Am. J. Psychiatry 152, 76–84 (1995).

  52. 52.

    et al. A family study of obsessive-compulsive disorder. Arch. Gen. Psychiatry 57, 358–363 (2000).

  53. 53.

    , , & An exploratory study on obsessive-compulsive disorder with and without a familial component: are there any phenomenological differences? Psychopathology 35, 8–16 (2002).

  54. 54.

    , , , & A direct interview family study of obsessive–compulsive disorder. I. Psychol. Med. 35, 1611–1621 (2005).

  55. 55.

    et al. A direct interview family study of obsessive–compulsive disorder. II. Contribution of proband informant information. Psychol. Med. 35, 1623–1631 (2005).

  56. 56.

    et al. Familiality of obsessive-compulsive disorder in nonclinical and clinical subjects. Am. J. Psychiatry 163, 1986–1992 (2006).

  57. 57.

    et al. A blind re-analysis of the Iowa family study of obsessive-compulsive disorder. Psychiatry Res. 209, 202–206 (2013).

  58. 58.

    et al. Psychiatric disorders in first degree relatives of children and adolescents with obsessive compulsive disorder. J. Am. Acad. Child Adolesc. Psychiatry 29, 407–412 (1990).

  59. 59.

    et al. Obsessive compulsive disorder in children and adolescents: phenomenology and family history. J. Am. Acad. Child Adolesc. Psychiatry 29, 766–772 (1990).

  60. 60.

    et al. Tics and Tourette's disorder: a 2- to 7-year follow-up of 54 obsessive-compulsive children. Am. J. Psychiatry 149, 1244–1251 (1992).

  61. 61.

    et al. A family study of juvenile obsessive-compulsive disorder. Can. J. Psychiatry 46, 346–351 (2001).

  62. 62.

    et al. A family study of early-onset obsessive-compulsive disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 136B, 92–97 (2005).

  63. 63.

    , , & A family study of obsessive-compulsive disorder with pediatric probands. Am. J. Med. Genet. B Neuropsychiatr. Genet. 134B, 13–19 (2005).

  64. 64.

    et al. Early-onset obsessive-compulsive disorder: a subgroup with a specific clinical and familial pattern? J. Child Psychol. Psychiatry 46, 881–887 (2005).

  65. 65.

    Obsessive-compulsive and spectrum disorders in children and adolescents. Psychiatr. Clin. North Am. 29, 353–370 (2006).

  66. 66.

    & Update on childhood-onset schizophrenia. Curr. Psychiatry Rep. 2, 410–415 (2000).

  67. 67.

    & Family and genetic association studies of bipolar disorder in children. Child Adolesc. Psychiatr. Clin. N. Am. 18, 441–453 (2009).

  68. 68.

    The genetics of Tourette syndrome. Curr. Psychiatry Rep. 3, 152–157 (2001).

  69. 69.

    , , , & Multivariate genetic analysis of twin-family data on fears: Mx models. Behav. Genet. 24, 119–139 (1994).

  70. 70.

    Etiology of obsessions and compulsions: a meta-analysis and narrative review of twin studies. Clin. Psychol. Rev. 31, 1361–1372 (2011).

  71. 71.

    et al. Normative childhood repetitive routines and obsessive compulsive symptomatology in 6-year-old twins. J. Child Psychol. Psychiatry 50, 1139–1146 (2009).

  72. 72.

    et al. Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 310, 317–320 (2005).

  73. 73.

    et al. Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol. Psychiatry 11, 763–770 (2006).

  74. 74.

    et al. Significant linkage to compulsive hoarding on chromosome 14 in families with obsessive-compulsive disorder: results from the OCD Collaborative Genetics Study. Am. J. Psychiatry 164, 493–499 (2007).

  75. 75.

    et al. Hoarding disorder: a new diagnosis for DSM-V? Depress. Anxiety 27, 556–572 (2010).

  76. 76.

    et al. Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands. Am. J. Med. Genet. 114, 541–552 (2002).

  77. 77.

    et al. Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder. Am. J. Hum. Genet. 75, 508–513 (2004).

  78. 78.

    et al. Evidence for a susceptibility locus on chromosome 10p15 in early-onset obsessive-compulsive disorder. Biol. Psychiatry 62, 856–862 (2007).

  79. 79.

    et al. Genomewide linkage analysis in Costa Rican families implicates chromosome 15q14 as a candidate region for OCD. Hum. Genet. 130, 795–805 (2011).

  80. 80.

    et al. Genome-wide linkage analysis of obsessive-compulsive disorder implicates chromosome 1p36. Biol. Psychiatry 72, 629–636 (2012).

  81. 81.

    et al. Partitioning the heritability of tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genet. 9, e1003864 (2013).

  82. 82.

    et al. Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Arch. Gen. Psychiatry 63, 778–785 (2006).

  83. 83.

    , , , & Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arch. Gen. Psychiatry 63, 769–776 (2006).

  84. 84.

    et al. Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 144B, 1027–1033 (2007).

  85. 85.

    et al. A family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder in 378 families. Am. J. Med. Genet. B Neuropsychiatr. Genet. 150B, 886–892 (2009).

  86. 86.

    et al. A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder. Arch. Gen. Psychiatry 66, 408–416 (2009).

  87. 87.

    et al. Comprehensive family-based association study of the glutamate transporter gene SLC1A1 in obsessive-compulsive disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 472–477 (2011).

  88. 88.

    et al. Association between SLC1A1 gene and early-onset OCD in the Han Chinese population: a case-control study. J. Mol. Neurosci. 50, 353–359 (2013).

  89. 89.

    et al. Association of the candidate gene SLC1A1 and obsessive-compulsive disorder in Han Chinese population. Psychiatry Res. 209, 737–739 (2013).

  90. 90.

    et al. Meta-analysis of association between obsessive-compulsive disorder and the 3′ region of neuronal glutamate transporter gene SLC1A1. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162B, 367–379 (2013).

  91. 91.

    et al. Beyond the serotonin hypothesis: a role for dopamine in some forms of obsessive compulsive disorder? J. Clin. Psychiatry 51 (Suppl.), 36–43 (1990).

  92. 92.

    , , & The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder. Pharmacol. Biochem. Behav. 100, 726–735 (2012).

  93. 93.

    et al. Changes in gray matter volume and white matter microstructure in adolescents with obsessive-compulsive disorder. Biol. Psychiatry 70, 1083–1090 (2011).

  94. 94.

    Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies. Mol. Psychiatry 18, 799–805 (2013).

  95. 95.

    et al. Genome-wide association study of obsessive-compulsive disorder. Mol. Psychiatry 18, 788–798 (2013). The first GWAS of OCD.

  96. 96.

    et al. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS. Mol. Psychiatry, (2014). The second GWAS of OCD.

  97. 97.

    , & Neural membrane protein 35/Lifeguard is localized at postsynaptic sites and in dendrites. Brain Res. Mol. Brain Res. 107, 47–56 (2002).

  98. 98.

    et al. Temporal and regional regulation of gene expression by calcium-stimulated adenylyl cyclase activity during fear memory. PLoS ONE 5, e13385 (2010).

  99. 99.

    , & Born to bind: the BTB protein–protein interaction domain. Bioessays 28, 1194–1202 (2006).

  100. 100.

    et al. Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs. Bipolar Disord. 12, 786–792 (2010).

  101. 101.

    , & Functional significance of the LAR receptor protein tyrosine phosphatase family in development and diseases. Biochem. Cell Biol. 82, 664–675 (2004).

  102. 102.

    et al. LAR receptor protein tyrosine phosphatases in the development and maintenance of excitatory synapses. Nature Neurosci. 8, 458–467 (2005).

  103. 103.

    et al. Trans-synaptic adhesion between NGL-3 and LAR regulates the formation of excitatory synapses. Nature Neurosci. 12, 428–437 (2009).

  104. 104.

    , , , & Trans-synaptic adhesions between netrin-G ligand-3 (NGL-3) and receptor tyrosine phosphatases LAR, protein-tyrosine phosphatase δ (PTPδ), and PTPσ via specific domains regulate excitatory synapse formation. J. Biol. Chem. 285, 13966–13978 (2010).

  105. 105.

    et al. Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex. Neuron 69, 287–303 (2011).

  106. 106.

    et al. Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction. Nature Neurosci. 15, 389–398 (2012).

  107. 107.

    et al. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nature Med. 16, 598–602 (2010).

  108. 108.

    et al. Impaired learning with enhanced hippocampal long-term potentiation in PTPδ-deficient mice. EMBO J. 19, 2775–2785 (2000).

  109. 109.

    et al. Forgetting what you have checked: a link between working memory impairment and checking behaviors in obsessive-compulsive disorder. Eur. Psychiatry 28, 87–93 (2013).

  110. 110.

    & Translational research in OCD: circuitry and mechanisms. Neuropsychopharmacology 38, 252–253 (2013).

  111. 111.

    The psychiatric GWAS consortium: big science comes to psychiatry. Neuron 68, 182–186 (2010).

  112. 112.

    , , , & The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers. Neurosci. Behav. Rev. 29, 399–419 (2005).

  113. 113.

    & Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatr. Clin. North Am. 23, 563–586 (2000). The authors provide the first comprehensive neuroanatomical model of OCD.

  114. 114.

    & Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn. Sci. 16, 43–51 (2012).

  115. 115.

    et al. Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neurosci. Biobehav Rev. 32, 525–549 (2008).

  116. 116.

    et al. Developmental alterations of frontal-striatal-thalamic connectivity in obsessive-compulsive disorder. J. Am. Acad. Child Adolesc. Psychiatry 50, 938–948.e3 (2011).

  117. 117.

    et al. Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder. Am. J. Psychiatry 145, 1560–1563 (1988).

  118. 118.

    , & A meta-analysis of functional neuroimaging in obsessive-compulsive disorder. Psychiatry Res. 132, 69–79 (2004).

  119. 119.

    , , & Neuroimaging and neuropsychological findings in pediatric obsessive-compulsive disorder: a review and developmental considerations. Neuropsychiatry 2, 313–329 (2012).

  120. 120.

    et al. Functional magnetic resonance imaging of symptom provocation in obsessive-compulsive disorder. Arch. Gen. Psychiatry 53, 595–606 (1996).

  121. 121.

    et al. Aberrant anterior cingulate activation in obsessive-compulsive disorder is related to task complexity. Neuropsychologia 50, 958–964 (2012).

  122. 122.

    et al. [18F]FDG PET study in obsessive-compulsive disorder. A clinical/metabolic correlation study after treatment. Br. J. Psychiatry 166, 244–250 (1995).

  123. 123.

    et al. Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Arch. Gen. Psychiatry 46, 518–523 (1989).

  124. 124.

    et al. Prospective long-term follow-up of 44 patients who received cingulotomy for treatment-refractory obsessive-compulsive disorder. Am. J. Psychiatry 159, 269–275 (2002).

  125. 125.

    , & in Kaplan and Sadock's Comprehensive Textbook of Psychiatry (eds Sadock, B. J., Sadock, V. A., & Ruiz, P.) 3314–3322 (Lippincott Williams and Wilkins, 2011).

  126. 126.

    et al. Working memory dysfunction in obsessive-compulsive disorder: a neuropsychological and functional MRI study. J. Psychiatr. Res. 43, 784–791 (2009).

  127. 127.

    et al. Altered corticostriatal functional connectivity in obsessive-compulsive disorder. Arch. Gen. Psychiatry 66, 1189–1200 (2009).

  128. 128.

    et al. To discard or not to discard: the neural basis of hoarding symptoms in obsessive-compulsive disorder. Mol. Psychiatry 14, 318–331 (2009).

  129. 129.

    et al. Neural correlates of symptom dimensions in pediatric obsessive-compulsive disorder: a functional magnetic resonance imaging study. J. Am. Acad. Child Adolesc. Psychiatry 48, 936–944 (2009).

  130. 130.

    et al. White matter structure and symptom dimensions in obsessive-compulsive disorder. J. Psychiatr. Res. 46, 264–270 (2012).

  131. 131.

    et al. The major symptom dimensions of obsessive-compulsive disorder are mediated by partially distinct neural systems. Brain 132, 853–868 (2009).

  132. 132.

    , , & A critical review of magnetic resonance spectroscopy studies of obsessive-compulsive disorder. Biol. Psychiatry 73, 24–31 (2013).

  133. 133.

    et al. Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine. J. Am. Acad. Child Adolesc. Psychiatry 39, 1096–1103 (2000).

  134. 134.

    & Neuroscience. Illuminating the neural circuitry of compulsive behaviors. Science 340, 1174–1175 (2013). This perspective paper outlines the utilization of optogenetics research in the context of compulsive behaviours and introduces two groundbreaking optogenetic studies in OCD.

  135. 135.

    et al. Repeated cortico-striatal stimulation generates persistent OCD-like behavior. Science 340, 1234–1239 (2013).

  136. 136.

    , , & Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science 340, 1243–1246 (2013).

  137. 137.

    , , , & Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am. J. Psychiatry 164, 5–53 (2007).

  138. 138.

    et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - first revision. World J. Biol. Psychiatry 9, 248–312 (2008).

  139. 139.

    et al. Caudate glucose metabolic-rate changes with both drug and behavior-therapy for obsessive-compulsive disorder. Arch. Gen. Psychiatry 49, 681–689 (1992).

  140. 140.

    et al. Localized orbitofrontal and subcortical metabolic changes and predictors of response to paroxetine treatment in obsessive-compulsive disorder. Neuropsychopharmacology 21, 683–693 (1999).

  141. 141.

    et al. Systematic changes in cerebral glucose metabolic rate after successful behavior modification treatment of obsessive-compulsive disorder. Arch. Gen. Psychiatry 53, 109–113 (1996).

  142. 142.

    et al. Frontostriatal activation in patients with obsessive-compulsive disorder before and after cognitive behavioral therapy. Psychol. Med. 41, 207–216 (2011).

  143. 143.

    et al. Differential cerebral metabolic changes with paroxetine treatment of obsessive-compulsive disorder versus major depression. Arch. Gen. Psychiatry 59, 250–261 (2002).

  144. 144.

    et al. Rapid effects of brief intensive cognitive-behavioral therapy on brain glucose metabolism in obsessive-compulsive disorder. Mol. Psychiatry 14, 197–205 (2009).

  145. 145.

    , , , & Current status of deep brain stimulation for obsessive-compulsive disorder: a clinical review of different targets. Curr. Psychiatry Rep. 13, 274–282 (2011).

  146. 146.

    , & A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposure therapy. Biol. Psychiatry 63, 1118–1126 (2008).

  147. 147.

    , & The neuropsychology of adult obsessive-compulsive disorder: a meta-analysis. Clin. Psychol. Rev. 33, 1163–1171 (2013).

  148. 148.

    , & Neuropsychological performance in obsessive-compulsive disorder: a critical review. Biol. Psychol. 65, 185–236 (2004).

  149. 149.

    , , & Neuropsychological impairments and their association with obsessive-compulsive symptom severity in obsessive-compulsive disorder. Arch. Clin. Neuropsychol. 26, 364–376 (2011).

  150. 150.

    et al. Impaired response inhibition in obsessive compulsive disorder. Eur. Psychiatry 22, 404–410 (2007).

  151. 151.

    et al. Neuropsychological characteristics of nondepressed adults with obsessive-compulsive disorder. Cogn. Behav. Neurol. 4, 96–109 (1991).

  152. 152.

    , , , & Are neuropsychological deficits trait markers in OCD? Prog. Neuropsychopharmacol. Biol. Psychiatry 32, 1574–1579 (2008).

  153. 153.

    et al. Obsessive-compulsive disorder: a clinical, neuropsychological and positron emission tomography study. Acta Psychiatr. Scand. 82, 233–242 (1990).

  154. 154.

    et al. Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. Arch. Gen. Psychiatry 62, 922–933 (2005).

  155. 155.

    et al. Neurocognitive endophenotypes of obsessive-compulsive disorder. Brain 130, 3223–3236 (2007).

  156. 156.

    et al. Dysfunctional reward circuitry in obsessive-compulsive disorder. Biol. Psychiatry 69, 867–874 (2011).

  157. 157.

    et al. Aberrant ventral striatal responses during incentive processing in unmedicated patients with obsessive-compulsive disorder. Acta Psychiatr. Scand. 123, 376–386 (2011).

  158. 158.

    , , , & Executive dysfunctions in obsessive-compulsive patients and unaffected relatives: searching for a new intermediate phenotype. Biol. Psychiatry 67, 1178–1184 (2010).

  159. 159.

    et al. Cognitive dysfunction in obsessive-compulsive disorder. Acta Psychiatr. Scand. 101, 281–285 (2000).

  160. 160.

    et al. Wisconsin Card Sorting Task (WCST) errors and cerebral blood flow in obsessive-compulsive disorder (OCD). Br. J. Med. Psychol. 70, 403–411 (1997).

  161. 161.

    et al. Cognitive behavior therapy augmentation of pharmacotherapy in pediatric obsessive-compulsive disorder: the Pediatric OCD Treatment Study II (POTS II) randomized controlled trial. JAMA 306, 1224–1232 (2011).

  162. 162.

    , , & Neuropsychological function in obsessive-compulsive disorder: effects of comorbid conditions on task performance. Eur. Psychiatry 18, 241–248 (2003).

  163. 163.

    , , , & Motor inhibition and cognitive flexibility in obsessive-compulsive disorder and trichotillomania. Am. J. Psychiatry 163, 1282–1284 (2006).

  164. 164.

    , , & Specific cognitive deficits in tests sensitive to frontal lobe dysfunction in obsessive-compulsive disorder. Psychol. Med. 26, 1261–1269 (1996).

  165. 165.

    et al. Executive function in Tourette's syndrome and obsessive-compulsive disorder. Psychol. Med. 35, 571–582 (2005).

  166. 166.

    et al. Decision-making heterogeneity in obsessive-compulsive disorder: ventromedial prefrontal cortex function predicts different treatment outcomes. Neuropsychologia 40, 205–211 (2002).

  167. 167.

    et al. Distinct neuropsychological profiles of three major symptom dimensions in obsessive-compulsive disorder. Psychiatry Res. 187, 166–173 (2011).

  168. 168.

    et al. Neural correlates of clinical symptoms and cognitive dysfunctions in obsessive-compulsive disorder. Psychiatry Res. 122, 37–47 (2003).

  169. 169.

    Le test de copie d'une figure complexe; contribution à l'étude de la perception et de la mémoire. Arch. Psychol. 30, 206–356 (in French) (1944).

  170. 170.

    et al. Organizational strategies mediate nonverbal memory impairment in obsessive-compulsive disorder. Biol. Psychiatry 45, 905–916 (1999). The authors demonstrate how non-verbal memory impairments in OCD are mediated by executive function impairments and conclude that poor encoding strategies hinder memory retrieval.

  171. 171.

    , , , & Executive function and nonverbal memory in obsessive-compulsive disorder. Psychiatry Res. 133, 81–90 (2005).

  172. 172.

    et al. Cognitive retraining for organizational impairment in obsessive-compulsive disorder. Psychiatry Res. 144, 109–116 (2006).

  173. 173.

    et al. Decision making and set shifting impairments are associated with distinct symptom dimensions in obsessive-compulsive disorder. Neuropsychology 20, 409–419 (2006).

  174. 174.

    et al. Neuropsychological performance across symptom dimensions in pediatric obsessive compulsive disorder. Depress. Anxiety, (2014).

  175. 175.

    et al. Nonverbal memory and organizational dysfunctions are related with distinct symptom dimensions in obsessive-compulsive disorder. Psychiatry Res. 180, 93–98 (2010).

  176. 176.

    et al. Nonverbal memory dysfunction in obsessive-compulsive disorder patients with checking compulsions. Depress. Anxiety 25, E115–E120 (2008).

  177. 177.

    et al. The differential impact of executive attention dysfunction on episodic memory in obsessive-compulsive disorder patients with checking symptoms versus those with washing symptoms. J. Psychiatr. Res. 41, 776–784 (2007).

  178. 178.

    , & Neuropsychological and neural correlates of hoarding: a practice-friendly review. J. Clin. Psychol. 67, 467–476 (2011).

  179. 179.

    et al. Neuropsychological performance and regional cerebral blood flow in obsessive-compulsive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 657–665 (2003).

  180. 180.

    et al. Verbal and nonverbal memory processing in patients with obsessive-compulsive disorder: its relationship to clinical variables. Neuropsychology 22, 262–272 (2008).

  181. 181.

    , & Obsessive compulsive disorder, checking, and non-verbal memory: a neuropsychological investigation. Behav. Res. Ther. 37, 161–166 (1999).

  182. 182.

    & The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 160, 636–645 (2003).

  183. 183.

    et al. Presupplementary motor area hyperactivity during response inhibition: a candidate endophenotype of obsessive-compulsive disorder. Am. J. Psychiatry 169, 1100–1108 (2012).

  184. 184.

    , , & Overactive error-related brain activity as a candidate endophenotype for obsessive-compulsive disorder: evidence from unaffected first-degree relatives. Am. J. Psychiatry 168, 317–324 (2011).

  185. 185.

    et al. Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective. Psychol. Med. 42, 1–13 (2012).

  186. 186.

    et al. Impaired cognitive flexibility and motor inhibition in unaffected first-degree relatives of patients with obsessive-compulsive disorder. Am. J. Psychiatry 164, 335–338 (2007).

  187. 187.

    et al. Study of neurocognitive endophenotypes in drug-naive obsessive-compulsive disorder patients, their first-degree relatives and healthy controls. Acta Psychiatr. Scand. 124, 152–161 (2011).

  188. 188.

    , & Obsessive compulsive disorder and the glutamatergic system. Curr. Opin. Psychiatry 27, 32–37 (2014).

  189. 189.

    et al. Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity. Phil. Trans. R. Soc. B 368, 20120435 (2013).

  190. 190.

    , , , & Serotonergic responsivity in obsessive-compulsive disorder. Effects of chronic clomipramine treatment. Arch. Gen. Psychiatry 45, 167–172 (1988).

  191. 191.

    , , , & Low level of dopaminergic D2 receptor binding in obsessive-compulsive disorder. Biol. Psychiatry 55, 1041–1045 (2004).

  192. 192.

    et al. Fluvoxamine treatment and D2 receptors: a pet study on OCD drug-naive patients. Neuropsychopharmacology 32, 197–205 (2007).

  193. 193.

    et al. In vivo PET study of 5HT2A serotonin and D2 dopamine dysfunction in drug-naive obsessive-compulsive disorder. Neuroimage 42, 306–314 (2008).

  194. 194.

    , , , & A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch. Gen. Psychiatry 57, 794–801 (2000).

  195. 195.

    et al. Dorsal striatal D2-like receptor availability covaries with sensitivity to positive reinforcement during discrimination learning. J. Neurosci. 31, 7291–7299 (2011).

  196. 196.

    & Current animal models of obsessive compulsive disorder: an update. Neuroscience 211, 83–106 (2012).

  197. 197.

    & Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics. Curr. Opin. Neurobiol. 21, 842–848 (2011).

  198. 198.

    et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448, 894–900 (2007).

  199. 199.

    et al. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nature Neurosci. 9, 119–126 (2006).

  200. 200.

    et al. Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J. Clin. Invest. 121, 446–453 (2011).

  201. 201.

    et al. Perinatal factors affecting expression of obsessive compulsive disorder in children and adolescents. J. Child Adolesc. Psychopharmacol. 18, 373–379 (2008).

  202. 202.

    et al. Traumatic events and obsessive compulsive disorder in children and adolescents: is there a link? J. Anxiety Disord. 25, 513–519 (2011).

  203. 203.

    , & The immunobiology of Tourette's disorder, pediatric autoimmune neuropsychiatric disorders associated with Streptococcus, and related disorders: a way forward. J. Child Adolesc. Psychopharmacol. 20, 317–331 (2010).

  204. 204.

    Serotonin as a modulator of glutamate- and GABA-mediated neurotransmission: implications in physiological functions and in pathology. Curr. Neuropharmacol. 4, 101–114 (2006).

  205. 205.

    & Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J. Neurosci. 24, 5131–5139 (2004).

  206. 206.

    When the serotonin transporter gene meets adversity: the contribution of animal models to understanding epigenetic mechanisms in affective disorders and resilience. Curr. Top. Behav. Neurosci. 7, 251–280 (2011).

  207. 207.

    et al. A genome wide survey supports the involvement of large copy number variants in schizophrenia with and without intellectual disability. Am. J. Med. Genet. B Neuropsychiatr. Genet. 162, 847–854 (2013).

  208. 208.

    The genetics of obsessive compulsive disorder: a review of the evidence. Am. J. Med. Genet. C Semin. Med. Genet. 148C, 133–139 (2008).

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Acknowledgements

This work was supported in part by US National Institutes of Health (NIH) grants NS16648 (to D.L.P.), NS40024 (to D.L.P.) and MH079489 (to D.L.P.).

Author information

Affiliations

  1. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115 USA.

    • David L. Pauls
    • , Amitai Abramovitch
    • , Scott L. Rauch
    •  & Daniel A. Geller
  2. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • David L. Pauls
    • , Amitai Abramovitch
    • , Scott L. Rauch
    •  & Daniel A. Geller
  3. Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • David L. Pauls
  4. McLean Hospital, Belmont, Massachusetts 02478, USA.

    • Scott L. Rauch

Authors

  1. Search for David L. Pauls in:

  2. Search for Amitai Abramovitch in:

  3. Search for Scott L. Rauch in:

  4. Search for Daniel A. Geller in:

Competing interests

D.L.P., S.L.R. and D.A.G have received funds from US National Institutes of Health (NIH) grants. D.A.G. has received funds for lectures at the American Association of Child and Adolescent Psychiatry and at the Massachusetts General Hospital Psychiatry Academy. S.L.R. has received research funding from Cyberonics and Medtronic. A.A. declares no competing interests.

Corresponding authors

Correspondence to David L. Pauls or Daniel A. Geller.

Glossary

Exposure and response prevention

The first-line behavioural therapeutic technique for the treatment of obsessive–compulsive disorder, anxiety disorders and phobias. This technique involves exposing the patient to stimuli that the patient perceives as threatening, anxiety-provoking or dangerous. This gradual exposure accompanies the prevention of responses that the patient usually undertakes in order to avoid or decrease anxiety. This technique is theoretically anchored in the Pavlovian extinction of conditioned fear.

Probands

People who serve as the starting point of a genetic study.

Enuresis

Involuntary control of urination, such as bed-wetting.

Odds ratios

Measures of effect size, defined as the ratio of the odds of an event occurring in one group to the odds of it occurring in another group. In the context of a genetic-association study, this might be the odds of obsessive–compulsive disorder occurring in one genotype group against the odds of it occurring in another genotype group.

Genetic linkage studies

Studies that explore the possibility that a risk gene for a particular disorder is located near a gene or DNA marker localized to a specific chromosomal region and is thus inherited together with that locus during meiosis. These studies are based on the observation that genes that are close to each other on the same chromosome are less likely to be separated during chromosomal crossover and are therefore said to be genetically linked.

Single-nucleotide polymorphisms

(SNPs). DNA sequence variations that occur when a single nucleotide at a specific site in the genome differs between paired chromosomes.

Candidate gene studies

Studies that assess whether specific 'candidate' genes are involved in the variation observed for a particular trait based on prior knowledge, such as the function of the gene and polymorphisms in the gene that are known to alter its function.

Genome-wide association studies

(GWASs). Studies in which many common genetic variants are examined to determine whether they are associated with a trait. These studies typically focus on associations between single-nucleotide polymorphism and commonly occurring disorders.

Genome-wide significance

A statistical threshold (P = 5 × 10−8) based on the testing of one million single-nucleotide polymorphisms in a genome-wide association study and on the use of a Bonferroni correction for multiple testing (that is, 0.05/1,000,000).

Cingulotomy

A form of a neurosurgical procedure, usually performed in psychiatric patients, that involves surgical severing of the anterior cingulum.

Optogenetics

A novel technique that combines genetics and optics to enable manipulation of specific cells in living organisms, utilizing light to activate genetically sensitized neurons.

Endophenotype

(Also known as an intermediate phenotype). A quantifiable construct that mediates low-level genetic variability and high-level phenotypic expression.

Go–no-go task

A task of response inhibition in which stimuli (for example, coloured squares) are continuously presented and the individual is asked to respond as fast as possible to all coloured squares (that is, go stimuli) except for one type of no-go stimulus (for example, a red square). Responding to a no-go stimulus is considered to be a commission error — a strong indicator for response inhibition impairments.

Stroop task

A task in which participants are presented with colour names printed in different font colour. In one trial block, the colour name and font colour are incongruent. The difference in performance or reaction time between congruent and incongruent blocks is defined as the Stroop effect.

Stop signal task

A response-inhibition task in which participants are asked to respond as fast as possible to a certain feature of a specific stimulus. On some trials, the go stimulus is followed by a signal indicating that the response should be withheld.

Iowa gambling task

A decision-making task in which the goal is to earn as much money as possible. Participants are faced with four decks of cards. Each card may earn or lose the participant a monetary reward. The decks vary in the percentage of non-rewarding cards. Healthy controls will tend to quickly focus on a 'good' deck, whereas patients with orbitofrontal dysfunction will tend to persevere on 'bad' decks.

Monetary incentive delayed task

A reward task in which participants are required to respond within a time window and be potentially rewarded depending on their response time.

Wisconsin card sorting test

A test in which participants are presented with stimulus cards that differ in the number, form and colour of shapes they show. Participants are required match each card to one of four target cards according to a dimensional rule that is not explicitly articulated. Participants may understand the rule only by either a 'correct' or 'wrong' feedback from the experimenter, who changes the sorting rules throughout the task. The participant is required to discover the rules in order to succeed in this task.

Object alternation test

A test in which participants are presented with two objects, and a target stimulus that may be located under one of the objects. The examiner covers the objects and changes the location of the target stimulus. This task assesses working memory and set shifting.

Set-shifting task

In set-shifting tasks, participants are required to alternate between two judgements within a set of stimuli, as fast as and as accurately as possible.

Trail-making test

In the first part of this test, which assesses psychomotor functioning and processing speed, participants are asked to connect the dots between numbered circles as fast as possible. In the second part, which assesses set shifting, participants are asked to connect the dots according to an ascending order of a series of letters and numbers.

Tower of London test

A task that assesses planning. It consists of three coloured discs placed on pegs. Participants are required to arrange the discs according to specific models using the fewest possible moves. The number of excess moves is an indicator for deficient planning ability.

Wechsler memory scale logical memory

A subtest of the Wechsler memory scale test battery in which participants are asked to remember a short, detailed story.

Rey auditory verbal learning test

A verbal memory test in which participants are asked to memorize a list of words read aloud by the examiner.

Copy number variants

Copy number variants correspond to regions of the genome that have been deleted or duplicated on certain chromosomes. The deletions and/or duplications can result in gene expression changes that can elucidate specific aetiological pathways.