Abstract
Although compelling evidence has shown that obsessive-compulsive disorder (OCD) has a strong genetic component, its genetic basis remains to be elucidated. Identifying biological abnormalities in nonaffected relatives is one of the strategies advocated to isolate genetic vulnerability factors in complex disorders. Since peripheral serotonergic disturbances are frequently observed in OCD patients, the aim of this study was to investigate if they could represent endophenotypes, by searching for similar abnormalities in the unaffected parents of OCD patients. We assessed whole blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor-binding characteristics, and platelet inositol trisphosphate (IP3) content in a sample of OCD probands (n=48) and their unaffected parents (n=65), and compared them with sex- and age-matched controls (n=113). Lower whole blood 5-HT concentration, fewer platelet 5-HTT-binding sites, and higher platelet IP3 content were found in OCD probands and their unaffected parents compared to controls. Whole blood 5-HT concentration showed a strong correlation within families (p<0.001). The only parameter that appeared to discriminate affected and unaffected subjects was 5-HT2A receptor-binding characteristics, with increased receptor number and affinity in parents and no change in OCD probands. The presence of peripheral serotonergic abnormalities in OCD patients and their unaffected parents supports a familial origin of these disturbances. These alterations may serve as endophenotypic markers in OCD, and could contribute to the study of the biological mechanisms and genetic underpinnings of the disorder.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Alsobrook IJ, Leckman JF, Goodman WK, Rasmussen SA, Pauls DL (1999). Segregation analysis of obsessive-compulsive disorder using symptom-based factor scores. Am J Med Genet 88: 669–675.
Alvarez JC, Gluck N, Arnulf I, Quintin P, Leboyer M, Pecquery R et al (1999). Decreased platelet serotonin transporter sites and increased platelet inositol triphosphate levels in patients with unipolar depression: effects of clomipramine and fluoxetine. Clin Pharmacol Ther 66: 617–624.
Arolt V, Lencer R, Nolte A, Muller-Myhsok B, Purmann S, Schurmann M et al (1996). Eye tracking dysfunction is a putative phenotypic susceptibility marker of schizophrenia and maps to a locus on chromosome 6p in families with multiple occurrence of the disease. Am J Med Genet 67: 564–579.
Barr LC, Goodman WK, Price LH, McDougle CJ, Charney DS (1992). The serotonin hypothesis of obsessive compulsive disorder: implications of pharmacologic challenge studies. J Clin Psychiatry 53(Suppl): 17–28.
Bastani B, Arora RC, Meltzer HY (1991). Serotonin uptake and imipramine binding in the blood platelets of obsessive-compulsive disorder patients. Biol Psychiatry 30: 131–139.
Betancur C, Corbex M, Spielewoy C, Philippe A, Laplanche JL, Launay JM et al (2002). Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder. Mol Psychiatry 7: 67–71.
Black DW, Kelly M, Myers C, Noyes Jr R (1990). Tritiated imipramine binding in obsessive-compulsive volunteers and psychiatrically normal controls. Biol Psychiatry 27: 319–327.
Blier P, de Montigny C (1999). Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology 21: 91S–98S.
Brewerton TD, Flament MF, Rapoport JL, Murphy DL (1993). Seasonal effects on platelet 5-HT content in patients with OCD and controls. Arch Gen Psychiatry 50: 409.
Cath DC, Spinhoven P, Landman AD, van Kempen GM (2001). Psychopathology and personality characteristics in relation to blood serotonin in Tourette's syndrome and obsessive-compulsive disorder. J Psychopharmacol 15: 111–119.
Cleare AJ (1997). Reduced whole blood serotonin in major depression. Depress Anxiety 5: 108–111.
Da Prada M, Cesura AM, Launay JM, Richards JG (1988). Platelets as a model for neurones? Experientia 44: 115–126.
Delorme R, Chabane N, Callebert J, Falissard B, Mouren-Simeoni MC, Rouillon F et al (2004). Platelet serotonergic predictors of clinical improvement in obsessive compulsive disorder. J Clin Psychopharmacol 24: 1–6.
Flament MF, Rapoport JL, Murphy DL, Berg CJ, Lake CR (1987). Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder. Arch Gen Psychiatry 44: 219–225.
Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A et al (1997). Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 94: 587–592.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL et al (1989). The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 46: 1006–1011.
Gottesman II, Gould TD (2003). The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160: 636–645.
Greenberg BD, McMahon FJ, Murphy DL (1998). Serotonin transporter candidate gene studies in affective disorders and personality: promises and potential pitfalls. Mol Psychiatry 3: 186–189.
Hanna GL, Veenstra-VanderWeele J, Cox NJ, Boehnke M, Himle JA, Curtis GC et al (2002). Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands. Am J Med Genet 114: 541–552.
Hanna GL, Yuwiler A, Cantwell DP (1991). Whole blood serotonin in juvenile obsessive-compulsive disorder. Biol Psychiatry 29: 738–744.
Hanna GL, Yuwiler A, Cantwell DP (1993). Whole blood serotonin during clomipramine treatment of juvenile obsessive-compulsive disorder. J Child Adolesc Psychopharmacol 3: 223–229.
Hanna GL, Yuwiler A, Coates JK (1995). Whole blood serotonin and disruptive behaviors in juvenile obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry 34: 28–35.
Insel TR, Winslow JT (1992). Neurobiology of obsessive compulsive disorder. Psychiatr Clin North Am 15: 813–824.
Jonnal AH, Gardner CO, Prescott CA, Kendler KS (2000). Obsessive and compulsive symptoms in a general population sample of female twins. Am J Med Genet 96: 791–796.
Keating MT, Sanguinetti MC (2001). Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104: 569–580.
Kilic F, Murphy DL, Rudnick G (2003). A human serotonin transporter mutation causes constitutive activation of transport activity. Mol Pharmacol 64: 440–446.
Leboyer M (2003). Searching for alternative phenotypes in psychiatric genetics. Methods Mol Med 77: 145–161.
Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J (1998). Psychiatric genetics: search for phenotypes. Trends Neurosci 21: 102–105.
Leboyer M, Quintin P, Manivet P, Varoquaux O, Allilaire JF, Launay JM (1999). Decreased serotonin transporter binding in unaffected relatives of manic depressive patients. Biol Psychiatry 46: 1703–1706.
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274: 1527–1531.
Marazziti D, Akiskal HS, Rossi A, Cassano GB (1999). Alteration of the platelet serotonin transporter in romantic love. Psychol Med 29: 741–745.
Marazziti D, Hollander E, Lensi P, Ravagli S, Cassano GB (1992). Peripheral markers of serotonin and dopamine function in obsessive-compulsive disorder. Psychiatry Res 42: 41–51.
Marazziti D, Masala I, Rossi A, Hollander E, Presta S, Giannaccini G et al (2000). Increased inhibitory activity of protein kinase C on the serotonin transporter in OCD. Neuropsychobiology 41: 171–177.
Marazziti D, Pfanner C, Palego L, Gemignani A, Milanfranchi A, Ravagli S et al (1997). Changes in platelet markers of obsessive-compulsive patients during a double-blind trial of fluvoxamine versus clomipramine. Pharmacopsychiatry 30: 245–249.
Marek GJ, Carpenter LL, McDougle CJ, Price LH (2003). Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28: 402–412.
Matuchansky C, Launay JM (1995). Serotonin, catecholamines, and spontaneous midgut carcinoid flush: plasma studies from flushing and nonflushing sites. Gastroenterology 108: 743–751.
McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH (2000). A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 57: 794–801.
McKenzie A, Quinn J (1999). A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA 96: 15251–15255.
Nestadt G, Addington A, Samuels J, Liang KY, Bienvenu OJ, Riddle M et al (2003). The identification of OCD-related subgroups based on comorbidity. Biol Psychiatry 53: 914–920.
Nestadt G, Lan T, Samuels J, Riddle M, Bienvenu III OJ, Liang KY et al (2000a). Complex segregation analysis provides compelling evidence for a major gene underlying obsessive-compulsive disorder and for heterogeneity by sex. Am J Hum Genet 67: 1611–1616.
Nestadt G, Samuels J, Riddle M, Bienvenu III OJ, Liang KY, LaBuda M et al (2000b). A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 57: 358–363.
Nurnberger Jr JI, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J et al (1994). Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 51: 849–859; discussion 863–864.
Ober C, Abney M, McPeek MS (2001). The genetic dissection of complex traits in a founder population. Am J Hum Genet 69: 1068–1079.
Orvaschel H, Puig-Antich J, Chambers W, Tabrizi MA, Johnson R (1982). Retrospective assessment of prepubertal major depression with the Kiddie-SADS-e. J Am Acad Child Psychiatry 21: 392–397.
Ozaki N, Goldman D, Kaye WH, Plotnicov K, Greenberg BD, Lappalainen J et al (2003). Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Mol Psychiatry 8: 933–936.
Pauls DL, Alsobrook II JP, Goodman W, Rasmussen S, Leckman JF (1995). A family study of obsessive-compulsive disorder. Am J Psychiatry 152: 76–84.
Ramamoorthy S, Blakely RD (1999). Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science 285: 763–766.
Sallee FR, Richman H, Beach K, Sethuraman G, Nesbitt L (1996). Platelet serotonin transporter in children and adolescents with obsessive-compulsive disorder or Tourette's syndrome. J Am Acad Child Adolesc Psychiatry 35: 1647–1656.
Stoltenberg SF, Twitchell GR, Hanna GL, Cook EH, Fitzgerald HE, Zucker RA et al (2002). Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism. Am J Med Genet 114: 230–234.
Weiss LA, Veenstra-Vanderweele J, Newman DL, Kim SJ, Dytch H, McPeek MS et al (2004). Genome-wide association study identifies ITGB3 as a QTL for whole blood serotonin. Eur J Hum Genet 12: 949–954.
Weissman MM, Bland RC, Canino GJ, Greenwald S, Hwu HG, Lee CK et al (1994). The cross national epidemiology of obsessive compulsive disorder. The Cross National Collaborative Group. J Clin Psychiatry 55(Suppl): 5–10.
Weizman A, Mandel A, Barber Y, Weitz R, Cohen A, Mester R, Rehavi M (1992). Decreased platelet imipramine binding in Tourette syndrome children with obsessive-compulsive disorder. Biol Psychiatry 31: 705–711.
Willour VL, Yao Shugart Y, Samuels J, Grados M, Cullen B, Bienvenu III OJ et al (2004). Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder. Am J Hum Genet 75: 508–513.
Yaryura-Tobias JA, Neziroglu F, Bhagavan HN (1979). Obsessive-compulsive disorders: a serotonergic hypothesis. In: Saletu B, Berner P, Hollister L (eds). Neuropsychopharmacology: Proceedings of the 11th Congress of the CNIP. Pergamon: Oxford, UK. pp 117–125.
Yuwiler A, Plotkin S, Geller E, Ritvo ER (1970). A rapid accurate procedure for the determination of serotonin in whole human blood. Biochem Med 3: 426–431.
Acknowledgements
We thank the patients and their families who made this research possible. We declare no conflicts of interest. This research was supported by INSERM (National Institute of Health and Medical Research). RD was supported by a fellowship from Fondation pour la Recherche Médicale and NC by a fellowship from INSERM.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Delorme, R., Betancur, C., Callebert, J. et al. Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder. Neuropsychopharmacol 30, 1539–1547 (2005). https://doi.org/10.1038/sj.npp.1300752
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1300752
Keywords
This article is cited by
-
Indirect Genetic Effects for Growth in Pigs Affect Behaviour and Weight Around Weaning
Behavior Genetics (2018)
-
Relevance of orbitofrontal neurochemistry for the outcome of cognitive-behavioural therapy in patients with obsessive–compulsive disorder
European Archives of Psychiatry and Clinical Neuroscience (2012)
-
Intrafamilial Correspondences on Platelet [3H-]Paroxetine-Binding Indices in Bulimic Probands and their Unaffected First-Degree Relatives
Neuropsychopharmacology (2006)
