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Neurobiology of Obsessive-Compulsive Disorder: Serotonin and Beyond

  • Herman G.M. Westenberg, Naomi A. Fineberg and Damiaan Denys


The evidence for the involvement of the serotonergic system in the pathogenesis of obsessive-compulsive disorder (OCD) is circumstantial at best, despite being the focus for most pathophysiological research over the last 2 decades. This hypothesis was initially motivated by the observed differential efficacy of selective serotonin reuptake inhibitors in alleviating OCD symptoms. Direct evidence that serotonergic perturbations are implicated in the pathophysiology of OCD is still sparse. There is growing evidence, from both preclinical and clinical studies, that the dopamine system may also be involved in the pathogenesis of OCD, and that dopaminergic and serotonergic pathways play a role in the genesis and maintenance of obsessive-compulsive symptoms. The complex interactions between both systems, the phenotypic heterogeneity of the disorder, and the limitations of the available tests to probe both systems, make it as yet impossible to draw firm conclusions as to how these systems are implicated. Further studies with more selective pharmacologic agents and neurocognitive probes in humans, studies using deep brain stimulation in combination with neuroimaging, and the development of better animal models for OCD may further our understanding of this disabling condition.


Corresponding author

Please direct all correspondence to: Herman G. M. Westenberg, PhD, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Department of Psychiatry, PO Box 85500, 3508 GA Utrecht, The Netherlands. Tel: +31-30-250-9019; Fax: +31-30-212-9205; E-mail


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1. Denys, D, Zohar, J, Westenberg, HG. The role of dopamine in obsessive-compulsive disorder: preclinical and clinical evidence. J Clin Psychiatry. 2004;65(suppl 14):1117.
2. Chou-Green, JM, Holscher, TD, Dallman, MF, et al. Compulsive behavior in the 5-HT2C receptor knockout mouse. Physiol Behav. 2003:78:641649.
3. Tsaltas, E, Kontis, D, Chrysikakou, S, et al. Reinforced spatial alternation as an animal model of obsessive-compulsive disorder (OCD): investigation of 5-HT2C and 5-HT1D receptor involvement in OCD pathophysiology. Biol Psychiatry. 2005:57:11761185.
4. Joel, D, Doljansky, J, Schiller, D. ‘Compulsive’ lever pressing in rats is enhanced following lesions to the orbital cortex, but not to the basolateral nucleus of the amygdala or to the dorsal medial prefrontal cortex. Eur J Neurosci. 2005:21:22522262.
5. Joel, D, Doljansky, J. Selective alleviation of compulsive lever-pressing in rats by D,1 but not D2, blockade: possible implications for the involvement of D1, receptors in obsessive-compulsive disorder. Neuropsychopharmacology. 2003:28:7785.
6. Campbell, KM, de Lecea, L, Severynse, DM, et al. OCD-Like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D1+ neurons. J Neurosci. 1999;19:50445053.
7. Eilam, D, Szechtman, H. Psychostimulant-induced behavior as an animal model of obsessive-compulsive disorder: an ethological approach to the form of compulsive rituals. CNS Spectr. 2005:10:191202.
8. Sullivan, RM, Talangbayan, H, Einat, H, et al. Effects of quinpirole on central dopamine systems in sensitized and non-sensitized rats. Neuroscience. 1998:83:781789.
9. Thoren, P, Asberg, M, Bertilsson, L, et al. Clomipramine treatment of obsessive-compulsive disorder. II. Biochemical aspects. Arch Gen Psychiatry. 1980;37:12891294.
10. Insel, TR, Mueller, EA, Alterman, I, et al. Obsessive-compulsive disorder and serotonin: is there a connection? Biol Psychiatry. 1985;20:11741188.
11. Leckman, JF, Goodman, WK, Anderson, GM, et al. Cerebrospinal fluid biogenic amines in obsessive compulsive disorder, Tourette's syndrome, and healthy controls. Neuropsychopharmacology. 1995:12:7386.
12. Bornstein, RA, Baker, GB. Urinary indoleamines in Tourette syndrome patients with obsessive-compulsive characteristics. Psychiatry Res. 1992;41:267274.
13. de Groot, CM, Bornstein, RA, Baker, GB. Obsessive-compulsive symptom clusters and urinary amine correlates in Tourette syndrome. J Nerv Ment Dis. 1995;183:224230.
14. Cath, DC, Spinhoven, P, Landman, AD, et al. Psychopathology and personality characteristics in relation to blood serotonin in Tourette's syndrome and obsessive-compulsive disorder. J Psychopharmacol. 2001;15:111119.
15. Delorme, R, Betancur, C, Callebert, J, et al. Platelet serotonergic markers as endophenotypes for obsessive-compulsive disorder. Neuropsychopharmacology. 2005;30:15391547.
16. Delorme, R, Chabane, N, Callebert, J, et al. Platelet serotonergic predictors of clinical improvement in obsessive compulsive disorder. J Clin Psychopharmacol. 2004;24:1823.
17. Brewerton, TD, Flament, MF, Rapoport, JL, et al. Seasonal effects on platelet 5-HT content in patients with OCD and controls. Arch Gen Psychiatry. 1993:50:409.
18. Flament, MF, Rapoport, JL, Murphy, DL, et al. Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder. Arch Gen Psychiatry. 1987;44:219225.
19. Hanna, GL, Yuwiler, A, Cantwell, DP. Whole blood serotonin in juvenile obsessive-compulsive disorder. Biol Psychiatry. 1991;29:738744.
20. Hanna, GL, Yuwiler, A, Coates, JK. Whole blood serotonin and disruptive behaviors in juve-nile obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 1995;34:2835.
21. Sallee, FR, Richman, H, Beach, K, et al. Platelet serotonin transporter in children and adolescents with obsessive-compulsive disorder or Tourette's syndrome. J Am Acad Child Adolesc Psychiatry. 1996;35:16471656.
22. Weizman, A, Mandel, A, Barber, Y, et al. Decreased platelet imipramine binding in Tourette syndrome children with obsessive-compulsive disorder. Biol Psychiatry. 1992;31:705711.
23. Marazziti, D, Rossi, A, Gemignani, A, et al. Decreased platelet 3H-paroxetine binding in obsessive-compulsive patients. Neuropsychobiology 1996;34:184187
24. Marazziti, D, Hollander, E, Lensi, P, et al. Peripheral markers of serotonin and dopamine function in obsessive-compulsive disorder. Psychiatry Res. 1992;42:4151.
25. Benkelfat, C, Mefford, IN, Masters, CF, et al. Plasma catecholamines and their metabolites in obsessive-compulsive disorder. Psychiatry Res. 1991;37:321331.
26. Swedo, SE, Leonard, HL, Kruesi, MJ, et al. Cerebrospinal fluid neurochemistry in children and adolescents with obsessive-compulsive disorder. Arch Gen Psychiatry. 1992;49:2936.
27. Hollander, E, Stein, DJ, Saoud, JB, et al. Effects of fenfluramine on plasma HVA in OCD. Psychiatry Res. 1992;42:185188.
28. Zahn, TP, Kruesi, MJ, Swedo, SE, et al. Autonomic activity in relation to cerebro-spinal fluid neurochemistry in obsessive and disruptive children and adolescents. Psychophysiology. 1996;33:731739.
29. Zohar, J, Mueller, EA, Insel, TR, et al. Serotonergic responsivity in obsessive-compulsive disorder. Comparison of patients and healthy controls. Arch Gen Psychiatry. 1987;44:946951.
30. Zohar, J, Insel, TR, Zohar-Kadouch, RC, et al. Serotonergic responsivity in obsessive-compulsive disorder. Effects of chronic clomipramine treatment. Arch Gen Psychiatry. 1988;45:167172.
31. Hollander, E, DeCaria, CM, Nitescu, A, et al. Serotonergic function in obsessive-compulsive disorder. Behavioral and neuroendocrine responses to oral m-chlorophenylpiperazine and fenfluramine in patients and healthy volunteers. Arch Gen Psychiatry. 1992;49:2128.
32. Chamey, DS, Goodman, WK, Price, LH, et al. Serotonin function in obsessive-compulsive disorder. A comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects. Arch Gen Psychiatry. 1988;45:177185.
33. Goodman, WK, McDougle, CJ, Price, LH, et al. m-Chlorophenylpiperazine in patients with obsessive-compulsive disorder: absence of symptom exacerbation. Biol Psychiatry. 1995;38:138149.
34. Gross-lsseroff, R, Cohen, R, Sasson, Y, et al. Serotonergic dissection of obsessive compulsive symptoms: a challenge study with m-chlorophenylpiperazine and sumatriptan. Neuropsychobiology. 2004;50:200205.
35. Ho Pian, KL, Westenberg, HG, den Boer, JA, et al. Effects of meta-chlorophenylpiperazine on cerebral blood flow in obsessive-compulsive disorder and controls. Biol Psychiatry. 1998;44:367370.
36. Lesch, KP, Hoh, A, Schulte, HM, et al. Long-term fluoxetine treatment decreases 5-HT1A receptor responsivity in obsessive-compulsive disorder. Psychopharmacology (Berl). 1991;105:415420.
37. Ho Pian, KL, Westenberg, HG, van Megen, HJ, et al. Sumatriptan (5-HT1D receptor agonist) does not exacerbate symptoms in obsessive compulsive disorder. Psychopharmacology (Berl). 1998;140:365370.
38. Stein, DJ, Van Heerden, B, Wessels, CJ, et al. Single photon emission computed tomography of the brain with Tc-99m HMPAO during sumatriptan challenge in obsessive-compulsive disorder: investigating the functional role of the serotonin auto-receptor. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23:10791099.
39. Boshuisen, ML, den Boer, JA. Zolmitriptan (a 5-HT1B/1D receptor agonist with central action) does not increase symptoms in obsessive compulsive disorder. Psychopharmacology (Berl). 2000;152:7479.
40. McBride, PA, DeMeo, MD, Sweeney, JA, et al. Neuroendocrine and behavioral responses to challenge with the indirect serotonin agonist dl-fenfluramine in adults with obsessive-compulsive disorder. Biol Psychiatry. 1992;31:1934.
41. Hewlett, WA, Vinogradov, S, Martin, K, et al. Fenfluramine stimulation of prolactin in obsessive-compulsive disorder. Psychiatry Res. 1992;42:8192.
42. Lucey, JV, O'Keane, V, Butcher, G, et al. Cortisol and prolactin responses to d-fenfluramine in non-depressed patients with obsessive-compulsive disorder: a comparison with depressed and healthy controls. Br J Psychiatry. 1992;161:517521.
43. Little, KY, Zhang, L, Desmond, T, et al. Striatal dopaminergic abnormalities in human cocaine users. Am J Psychiatry. 1999;156:238245.
44. McDougle, CJ, Goodman, WK, Delgado, PL, et al. Pathophysiology of obsessive-compulsive disorder. Am J Psychiatry. 1989;146:3501351.
45. Rosse, RB, Fay-McCarthy, M, Collins, JP Jr., et al. The relationship between cocaine-induced paranoia and compulsive foraging: a preliminary report. Addiction. 1994;89:10971104.
46. Rosse, RB, Fay-McCarthy, M, Collins, JP Jr., et al. Transient compulsive foraging behavior associated with crack cocaine use. Am J Psychiatry. 1993;150:155156.
47. Koizumi, HM. Obsessive-compulsive symptoms following stimulants. Biol Psychiatry. 1985;20:13321333.
48. Satel, SL, McDougle, CJ. Obsessions and compulsions associated with cocaine abuse. Am J Psychiatry. 1991;148:947.
49. Rosse, RB, McCarthy, MF, Alim, TN, et al. Saccadic distractibility in cocaine dependent patients: a preliminary laboratory exploration of the cocaine-OCD hypothesis. Drug Alcohol Depend. 1994;35:2530.
50. Kouris, S. Methylphenidate-induced obsessive-compulsiveness. J Am Acad Child Adolesc Psychiatry. 1998;37:135.
51. Kotsopoulos, S, Spivak, M. Obsessive-compulsive symptoms secondary to methylpheni-date treatment. Can J Psychiatry. 2001;46:89.
52. Frye, PE, Arnold, LE. Persistent amphetamine-induced compulsive rituals: response to pyridoxine(B6). Biol Psychiatry. 1981;16:583587.
53. Iyo, M, Sekine, Y, Matsunaga, T, et al. Methamphetamine-associated obsessional symptoms and effective risperidone treatment: a case report. J Clin Psychiatry. 1999;60:337338.
54. Lemus, CZ, Robinson, DG, Kronig, M, et al. Behavioral responses to a dopaminergic challenge in obsessive-compulsive disorder. J Anxiety Disorders. 1991;5:369–273.
55. Pitchot, W, Hansenne, M, Moreno, AG, et al. Growth hormone response to apomorphine in obsessive-compulsive disorder. J Psychiatry Neurosci. 1996;21:343345.
56. Brambilla, F, Perna, G, Bussi, R, et al. Dopamine function in obsessive compulsive disorder: cortisol response to acute apomorphine stimulation. Psychoneuroendocrinology. 2000;25:301310.
57. Brambilla, F, Bellodi, L, Perna, G, et al. Dopamine function in obsessive-compulsive disorder: growth hormone response to apomorphine stimulation. Biol Psychiatry. 1997;42:889897.
58. Longhurst, JG, Carpenter, LL, Epperson, CM, et al. Effects of catecholamine depletion with AMPT (alpha-methyl-para-tyrosine) in obsessive-compulsive disorder. Biol Psychiatry. 1999;46:573576.
59. Ceccherini-Nelli, A, Guazzelli, M. Treatment of refractory OCD with the dopamine agonist bromocriptine. J Clin Psychiatry. 1994;55:415416.
60. Goodman, WK, Price, LH, Delgado, PL, et al. Specificity of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder. Comparison of fluvoxamine and desipramine. Arch Gen Psychiatry. 1990;47:577585.
61. Zohar, J, Insel, TR. Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment, and pathophysiology. Biol Psychiatry. 1987;22:667687.
62. Leonard, HL, Swedo, SE, Rapoport, JL, et al. Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents. A double-blind cross-over comparison. Arch Gen Psychiatry. 1989;46:10881092.
63. Hoehn-Saric, R, Ninan, P, Black, DW, et al. Multicenter double-blind comparison of sertraline and desipramine for concurrent obsessive-compulsive and major depressive disorders. Arch Gen Psychiatry. 2000;57:7682.
64. Denys, D, van der, WN, van Megen, HJ, et al. A double blind comparison of venlafaxine and paroxetine in obsessive-compulsive disorder. J Clin Psychopharmacol. 2003;23:568575
65. Denys, D, van Megen, H, Westenberg, H. The adequacy of pharmacotherapy in outpatients with obsessive-compulsive disorder. Int Clin Psychopharmacol. 2002;17:109114.
66. Denys, D, de Geus, F, van Megen, HJ, et al. Use of factor analysis to detect potential phenotypes in obsessive-compulsive disorder. Psychiatry Res. 2004;128:273280.
67. Kent, JM, Coplan, JD, Lombardo, I, et al. Occupancy of brain serotonin transporters during treatment with paroxetine in patients with social phobia: a positron emission tomography study with 11C McN 5652. Psychopharmacology (Berl). 2002;164:341348.
68. Neumeister, A. Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull. 2003;37:99115.
69. Berney, A, Sookman, D, Leyton, M, et al. Lack of effects on core obsessive-compulsive symptoms of tryptophan depletion during symptom provocation in remitted obsessive-compulsive disorder patients. Biol Psychiatry. 2006;59:853857.
70. El Mansari, M, Blier, P. Mechanisms of action of current and potential pharmacothera-pies of obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:362373.
71. Dannon, PN, Sasson, Y, Hirschmann, S, et al. Pindolol augmentation in treatment-resistant obsessive compulsive disorder: a double-blind placebo controlled trial. Eur Neuropsychopharmacol. 2000;10:165169.
72. Pallanti, S, Quercioli, L, Bruscoli, M. Response acceleration with mirtazapine augmentation of citalopram in obsessive-compulsive disorder patients without comorbid depression: a pilot study. J Clin Psychiatry. 2004;65:13941399
73. Bloch, MH, Landeros-Weisenberger, A, Kelmendi, B, et al. A systematic review: anti-psychotic augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry. 2006;11:622632.
74. McDougle, CJ, Barr, LC, Goodman, WK, et al. Lack of efficacy of clozapine monotherapy in refractory obsessive-compulsive disorder. Am J Psychiatry. 1995;152:18121814.
75. Lykouras, L, Alevizos, B, Michalopoulou, P, et al. Obsessive-compulsive symptoms induced by atypical antipsychotics. A review of the reported cases. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:333346.
76. McDougle, CJ, Goodman, WK, Price, LH, et al. Neuroleptic addition in fluvoxamine-refractory obsessive-compulsive disorder. Am J Psychiatry. 1990;147:652654.
77. Shapira, NA, Ward, HE, Mandoki, M, et al. A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder. Biol Psychiatry. 2004;55:553555.
78. Sevincok, L, Topuz, A. Lack of efficacy of low doses of quetiapine addition in refractory obsessive-compulsive disorder. J Clin Psychopharmacol. 2003;23:448450.
79. Fineberg, NA, Sivakumaran, T, Roberts, A, et al. Adding quetiapine to SRI in treatment-resistant obsessive-compulsive disorder: a randomized controlled treatment study. Int Clin Psychopharmacol. 2005;20:223226.
80. Carey, PD, Vythilingum, B, Seedat, S, et al. Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebo-controlled study [ISRCTN83050762]. BMC Psychiatry. 2005;5:5.
81. Fineberg, NA, Stein, DJ, Premkumar, P, et al. Adjunctive quetiapine for serotonin reuptake inhibitor-resistant obsessive-compulsive disorder: a meta-analysis of randomized controlled treatment trials. Int Clin Psychopharmacol. 2006;21:337343.
82. Metin, O, Yazici, K, Tot, S, et al. Amisulpiride augmentation in treatment resistant obsessive-compulsive disorder: an open trial. Hum Psychopharmacol. 2003;18:463467.
83. Ramasubbu, R, Ravindran, A, Lapierre, Y. Serotonin and dopamine antagonism in obsessive-compulsive disorder: effect of atypical antipsychotic drugs. PharmacoPsychiatry. 2000;33:236238.
84. Kuroki, T, Meltzer, HY, Ichikawa, J. 5-HT2A receptor stimulation by DOI, a 5-HT2A/2c receptor agonist, potentiates amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Brain Res. 2003;972:216221.
85. Zhang, W, Bymaster, FP. The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5HT2A and muscarinic receptors. Psychopharmacology (Berl). 1999;141:267278,
86. Zhang, W, Perry, KW, Wong, DT, et al. Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology. 2000;23:250262.
87. Denys, D, Klompmakers, AA, Westenberg, HG. Synergistic dopamine increase in the rat prefrontal cortex with the combination of quetiapine and fluvoxamine. Psychopharmacology (Berl). 2004;176:195203.
88. Ryding, E, Lindstrom, M, Bradvik, B, et al. A new model for separation between brain dopamine and serotonin transporters in 123l-beta-CIT SPECT measurements: normal values and sex and age dependence. Eur J Nucl Med Mol Imaging. 2004;31:11141118.
89. Pogarell, O, Hamann, C, Popped, G, et al. Elevated brain serotonin transporter availability in patients with obsessive-compulsive disorder. Biol Psychiatry. 2003;54:14061413.
90. Hesse, S, Muller, U, Lincke, T, et al. Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder. Psychiatry Res. 2005;140:6372.
91. Stengler-Wenzke, K, Muller, U, Angermeyer, MC, et al. Reduced serotonin transporter-availability in obsessive-compulsive disorder (OCD). Eur Arch Psychiatry Clin Neurosci. 2004;254:252255.
92. Muller-Vahl, KR, Meyer, GJ, Knapp, WH, et al. Serotonin transporter binding in Tourette Syndrome. Neurosci Lett. 2005;385:120125.
93. van der Wee, NJ, Stevens, H, Hardeman, JA, et al. Enhanced dopamine transporter density in psychotropic-naive patients with obsessive-compulsive disorder shown by [123∣]{beta}-CIT SPECT. Am J Psychiatry. 2004;161:22012206.
94. Simpson, HB, Lombardo, I, Slifstein, M, et al. Serotonin transporters in obsessive-compulsive disorder: a positron emission tomography study with [(11)C]McN 5652. Biol Psychiatry. 2003;54:14141421.
95. Adams, KH, Hansen, ES, Pinborg, LH, et al. Patients with obsessive-compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei. Int J Neuropsychopharmacol. 2005;8:391401.
96. Kim, CH, Koo, MS, Cheon, KA, et al. Dopamine transporter density of basal ganglia assessed with [123∣)IPT SPET in obsessive-compulsive disorder. Eur J Nucl Med Mol Imaging. 2003;30:16371643.
97. Pogarell, O, Poepperl, G, Mulert, C, et al. SERT and DAT availabilities under citalopram treatment in obsessive-compulsive disorder (OCD). Eur Neuropsychopharmacol. 2005;15:521524.
98. Sawle, GV, Hymas, NF, Lees, AJ, et al. Obsessional slowness. Functional studies with positron emission tomography. Brain. 1991:114(Pt 5):21912202.
99. Denys, D, van der, WN, Janssen, J, et al. Low level of dopaminergic D2 receptor binding in obsessive-compulsive disorder. Biol Psychiatry. 2004;55:10411045.
100. Denys, D, Van Nieuwerburgh, F, Deforce, D, et al. Association between serotonergic candidate genes and specific phenotypes of obsessive compulsive disorder. J Affect Disord 2006;91:3944.
101. Kim, SJ, Lee, HS, Kim, CH. Obsessive-compulsive disorder, factor-analyzed symptom dimensions and serotonin transporter polymorphism. Neuropsychobiology. 2005;52:176182.
102. Cavallini, MC, Di Bella, D, Siliprandi, F, et al. Exploratory factor analysis of obsessive-compulsive patients and association with 5-HTTLPR polymorphism. Am J Med Genet. 2002;114:347353.
103. Mundo, E, Richter, MA, Zai, G, et al. 5HT1Dbeta Receptor gene implicated in the pathogenesis of obsessive-compulsive disorder: further evidence from a family-based association study. Mol Psychiatry. 2002;7:805809.
104. Enoch, MA, Kaye, WH, Rotondo, A, et al. 5-HT2A promoter polymorphism -1438G/A, anorexia nervosa, and obsessive-compulsive disorder. Lancet 1998;351:17851786.
105. Walitza, S, Wewetzer, C, Warnke, A, et al. 5-HT2A promoter polymorphism -1438G/A in children and adolescents with obsessive-compulsive disorders. Mol Psychiatry. 2002;7:10541057.
106. Camarena, B, Cruz, C de LF Jr., et al. A higher frequency of a low activity-related allele of the MAO-A gene in females with obsessive-compulsive disorder. Psychiatr Genet. 1998;8:255257.
107. Frisch, A, Michaelovsky, E, Rockah, R, et al. Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways. Eur Neuropsychopharmacol. 2000;10:205209.
108. Hemmings, SM, Kinnear, CJ, Niehaus, DJ, et al. Investigating the role of dopaminergic and serotonergic candidate genes in obsessive-compulsive disorder. Eur Neuropsychopharmacol. 2000;13:9398.
109. Nicolini, H, Cruz, C, Camarena, B, et al. DRD2, DRD3 and 5HT2A receptor genes polymorphisms in obsessive-compulsive disorder. Mol Psychiatry. 1996;1:461465.
110. Catalano, M, Sciuto, G, Di Bella, D, et al. Lack of association between obsessive-compulsive disorder and the dopamine D3 receptor gene: some preliminary considerations. Am J Med Genet. 1994;54:253255.
111. Denys, D, Van Nieuwerburgh, F, Deforce, D, et al. Association between the dopamine D2 receptor Taql A2 allele and low activity COMT allele with obsessive-compulsive disorder in males. Eur Neuropsychopharmacol. 2006;16:446450.
112. Novelli, E, Nobile, M, Diaferia, G, et al. A molecular investigation suggests no relationship between obsessive-compulsive disorder and the dopamine D2 receptor. Neuropsychobiology. 1994;29:6163.
113. Billett, EA, Richter, MA, Sam, F, et al. Investigation of dopamine system genes in obsessive-compulsive disorder. Psychiatr Genet 1998;8:163169.
114. Cruz, C, Camarena, B, King, N, et al. Increased prevalence of the seven-repeat variant of the dopamine D4 receptor gene in patients with obsessive-compulsive disorder with tics. Neurosci Lett. 1997;231:14.
115. Millet, B, Chabane, N, Delorme, R, et al. Association between the dopamine receptor D4 (DRD4) gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet. 2003;116:5559.
116. Di Bella, D, Catalano, M, Cichon, S, et al. Association study of a null mutation in the dopa-mine D4 receptor gene in Italian patients with obsessive-compulsive disorder, bipolar mood disorder and schizophrenia. Psychiatr Genet. 1996;6:119121.
117. Karayiorgou, M, Altemus, M, Galke, BL, et al. Genotype determining low catechol-Omethyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci USA. 1997;94:45724575.
118. Karayiorgou, M, Sobin, C, Blundell, ML, et al. Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry. 1999;45:11781189.
119. Alsobrook, JP, Zohar, AH, Leboyer, M, et al. Association between the COMT locus and obsessive-compulsive disorder in females but not males. Am J Med Genet. 2002;114:116120.
120. Niehaus, DJ, Kinnear, CJ, Corfield, VA, et al. Association between a catechol-o-methyltransferase polymorphism and obsessive-compulsive disorder in the Afrikaner population. J Affect Disord. 2001;65:6165.
121. Schindler, KM, Richter, MA, Kennedy, JL, et al. Association between homozygosity at the COMT gene locus and obsessive compulsive disorder. Am J Med Genet. 2000;96:721724.
122. Ohara, K, Nagai, M, Suzuki, Y, et al. No association between anxiety disorders and catechol-O-methyltransferase polymorphism. Psychiatry Res. 1998;80:145148.
123. Erdal, ME, Tot, S, Yazici, K, et al. Lack of association of catechol-O-methyltransferase gene polymorphism in obsessive-compulsive disorder. Depress Anxiety. 2003;18:4145.
124. Azzam, A, Mathews, CA. Meta-analysis of the association between the catecholamineO-methyl-transferase gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet. 2003;123:6469.
125. Kang, DH, Kim, JJ, Choi, JS, et al. Volumetric investigation of the frontal-subcortical circuitry in patients with obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 2004;16:342349.
126. Szeszko, PR, Robinson, D, Alvir, JM, et al. Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder. Arch Gen Psychiatry. 1999;56:913919.
127. Robinson, D, Wu, H, Munne, RA, et al. Reduced caudate nucleus volume in obsessive-compulsive disorder. Arch Gen Psychiatry. 1995;52:393398.
128. Friedlander, L, Desrocher, M. Neuroimaging studies of obsessive-compulsive disorder in adults and children. Clin Psychol Rev. 2006;26:3249.
129. Modell, JG, Mountz, JM, Curtis, GC, et al. Neurophysiologic dysfunction in basal ganglia/limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 1989;1:2736.
130. Aouizerate, B, Guehl, D, Cuny, E, et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog Neurobiol. 2004;72:195221.
131. Schwartz, JM. Neuroanatomical aspects of cognitive-behavioural therapy response in obsessive-compulsive disorder. An evolving perspective on brain and behaviour. Br J Psychiatry Suppl. 1998;131:3844.
132. Albin, RL, Young, AB, Penney, JB. The functional anatomy of disorders of the basal ganglia. Trends Neurosci. 1995;18:6364.
133. Alexander, GE, DeLong, MR, Strick, PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357381.
134. Krawczyk, DC. Contributions of the prefrontal cortex to the neural basis of human decision making. Neurosci Biobehav Rev. 2002;26:631664.
135. Elliott, R, Dolan, RJ, Frith, CD. Dissociable functions in the medial and lateral orbitofrontal cortex: evidence from human neuroimaging studies. Cereb Cortex. 2000; 10:308317.
136. Devinsky, O, Morrell, MJ, Vogt, BA. Contributions of anterior cingulate cortex to behaviour. Brain. 1995;118(Pt 1):279306.
137. Goldman-Rakic, PS. Working memory and the mind. Sci Am. 1992;267:110117.
138. Dubois, B, Verin, M, Teixeira-Ferreira, C, et al. Ho to study frontal lobe functions in humans. In: A-M, Thierry, Glowinsky, J, Goldman-Rakic, PS, et al. , eds. Motor and Cognitive Functions of the Prefrontal Cortex. Berlin: Springer-Verlag; 1994:116.
139. Garber, HJ, Ananth, JV, Chiu, LC, et al. Nuclear magnetic resonance study of obsessive-compulsive disorder. Am J Psychiatry. 1989;146:10011005.
140. Baxter, LR Jr., Schwartz, JM, Mazziotta, JC, et al. Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder. Am J Psychiatry. 1988;145:15601563.
141. Saxena, S, Brody, AL, Schwartz, JM, et al. Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl. 1998;35:2637.
142. Swedo, SE, Schapiro, MB, Grady, CL, et al. Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Arch Gen Psychiatry. 1989;46:518523.
143. Nordahl, TE, Benkelfat, C, Semple, WE, et al. Cerebral glucose metabolic rates in obsessive compulsive disorder. Neuropsychopharmacology. 1989;2:2328.
144. Martinot, JL, Allilaire, JF, Mazoyer, BM, et al. Obsessive-compulsive disorder: a clinical, neuropsychological and positron emission tomography study. Acta Psychiatr Scand. 1990;82:233242.
145. Rauch, SL, Jenike, MA, Alpert, NM, et al. Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. Arch Gen Psychiatry. 1994;51:6270.
146. Breiter, HC, Rauch, SL. Functional MRI and the study of OCD: from symptom provocation to cognitive-behavioral probes of cortico-striatal systems and the amygdala. Neuroimage. 1996;4(suppl):S127–S138.
147. Sachdev, PS, Malhi, GS. Obsessive-compulsive behaviour: a disorder of decision-making. AustNZJ Psychiatry. 2005;39:757763.
148. Critchley, HD, Mathias, CJ, Dolan, RJ. Neural activity in the human brain relating to uncertainty and arousal during anticipation. Neuron. 2001;29:537545.
149. Rolls, ET. The orbitofrontal cortex and reward. Cereb Cortex. 2000;10:284294.
150. Schnider, A, Treyer, V, Buck, A. The human orbitofrontal cortex monitors outcomes even when no reward is at stake. Neuropsychologia. 2005;43:316323.
151. Prabhakaran, V, Narayanan, K, Zhao, Z, et al. Integration of diverse information in working memory within the frontal lobe. NatNeurosci. 2000;3:8590.
152. Schultz, W. Behavioral theories and the neurophysiology of reward. Annu Rev Psychol. 2006;57:87115.
153. Chamberlain, SR, Blackwell, AD, Fineberg, NA, et al. The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers. Neurosci BiobehavBev. 2005;29:399419.
154. Chamberlain, SR, Blackwell, AD, Fineberg, NA, et al. Strategy implementation in obsessive-compulsive disorder and trichotillomania. Psychol Med. 2006;36:9197.
155. Chamberlain, SR, Fineberg, NA, Menzies, LA, et al. Impaired cognitive flexibility and motor inhibition in unaffected first-degree relatives of OCD patients: on the trail of endophenotypes. Am J Psychiatry. 2007. In press.
155. Cavedini, P, Riboldi, G, D'Annucci, A, et al. Decision-making heterogeneity in obsessive-compulsive disorder: ventromedial prefrontal cortex function predicts different treatment outcomes. Neuropsychologia. 2002;40:205211.
156. Cavallaro, R, Cavedini, P, Mistretta, P, et al. Basal-corticofrontal circuits in schizophrenia and obsessive-compulsive disorder: a controlled, double dissociation study. Biol Psychiatry. 2003;54:437443.
157. Nielen, MM, den Boer, JA. Neuropsychological performance of OCD patients before and after treatment with fluoxetine: evidence for persistent cognitive deficits. Psychol Med. 2003;33:917925.
158. Watkins, LH, Sahakian, BJ, Robertson, MM, et al. Executive function in Tourette's syndrome and obsessive-compulsive disorder. Psychol Med. 2005;35:571582.
159. Lawrence, NS, Wooderson, S, Mataix-Cols, D, et al. Decision making and set shifting impairments are associated with distinct symptom dimensions in obsessive-compulsive disorder. Neuropsychology. 2006;20:409419.
160. Remijnse, PL, Nielen, MM, van Balkom, AJ, et al. Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder. Arch Gen Psychiatry. 2006;63:12251236.
161. Cavedini, P, Riboldi, G, Keller, R, et al. Frontal lobe dysfunction in pathological gambling patients. Biol Psychiatry. 2002;51:334341.
162. Cavedini, P, Zorzi, C, Bassi, T, et al. Decision-making functioning as a predictor of treatment outcome in anorexia nervosa. Psychiatry Res. 2006:7(145 suppl 2-3):179187.
163. Cavedini, P, Bassi, T, Zorzi, C, et al. The advantages of choosing antiobsessive therapy according to decision-making functioning. J Clin Psychopharmacol. 2004;24:628631.
164. Fontenelle, L, Marques, C, Engelhardt, E, et al. Impaired set-shifting ability and therapeutic response in obsessive-compulsive disorder. J Neumpsychiatry Clin Neurosci. 2001;13:508510.
165. Moritz, S, Kloss, M, Jacobsen, D, et al. Neurocognitive impairment does not predict treatment outcome in obsessive-compulsive disorder. Behav Res Ther. 2005;43:811819.
166. Bolton, D, Raven, P, Madronal-Luque, R, et al. Neurological and neuropsychological signs in obsessive compulsive disorder: interaction with behavioural treatment. Behav Res Ther. 2000;38:695708.
167. Abbruzzese, M, Ferri, S, Scarone, S. Wisconsin Card Sorting Test performance in obsessive-compulsive disorder: no evidence for involvement of dorsolateral prefrontal cortex. Psychiatry Res. 1995;58:3743.
168. Mataix-Cols, D, Alonso, P, Pifarre, J, et al. Neuropsychological performance in medicated vs. unmedicated patients with obsessive-compulsive disorder. Psychiatry Res. 2002;109:255264.
169. Chamberlain, SR, Fineberg, NA, Blackwell, AD, et al. Motor inhibition and cognitive flexibility in obsessive-compulsive disorder and trichotillomania. Am J Psychiatry. 2006;163:12821284.
170. Watkins, LH, Rogers, RD, Lawrence, AD, et al. Impaired planning but intact decision making in early Huntington's disease: implications for specific fronto-striatal pathology. Neuropsychologia. 2000;38:11121125.
171. Fiorillo, CD, Tobler, PN, Schultz, W. Discrete coding of reward probability and uncertainty by dopamine neurons. Science. 2003;299:18981902.
172. Horvitz, JC. Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience. 2000;96:651656.
173. Kapur, S, Remington, G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry. 1996;153:466476.
174. Amargos-Bosch, M, Bortolozzi, A, Puig, MV, et al. Co-expression and in vivo interaction of serotonin 1A and serotonin 2A receptors in pyramidal neurons of prefrontal cortex. Cereb Cortex. 2004;14:281299.
175. Seeman, P. Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002;47:2738.
176. Marek, GJ, Carpenter, LL, McDougle, CJ, et al. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology. 2003;28:402412.
177. Bortolozzi, A, Diaz-Mataix, L, Scorza, MC, et al. The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem. 2005;95:15971607.
178. Ichikawa, J, Ishii, H, Bonaccorso, S, et al. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem. 2001;76:15211531.
179. Hallbus, M, Magnusson, T, Magnusson, O. Influence of 5-HT1B/1D receptors on dopa-mine release in the guinea pig nucleus accumbens: a microdialysis study. Neurosci Lett 1997;225:5760.
180. O'Dell, LE, Parsons, LH. Serotonin 1B receptors in the ventral tegmental area modulate cocaine-induced increases in nucleus accumbens dopamine levels. J Pharmacol Exp Ther. 2004;311:711719.
181. Neumaier, JF, Vincow, ES, Arvanitogiannis, A, et al. Elevated expression of 5-HT1B receptors in nucleus accumbens efferents sensitizes animals to cocaine. J Neurosci. 2002;22:1085610863.
182. De Deurwaerdere, P, Navailles, S, Berg, KA, et al. Constitutive activity of the serotonin 2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J Neurosci. 2004;24:32353241.
183. Zhou, FC, Lesch, KP, Murphy, DL. Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative. Brain Res. 2002;942:109119.
184. Zhou, FM, Liang, Y, Salas, R, et al. Corelease of dopamine and serotonin from striatal dopamine terminals. Neuron. 2005;46:6574.
185. Potenza, MN. The neurobiology of pathological gambling. Semin Clin Neumpsychiatry. 2001;6:217226.
186. Rosenkranz, JA, Grace, AA. Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning. Nature. 2002;417:282287.
187. Holden, C. ‘Behavioral’ addictions: do they exist? Science. 2001;294:980982.
188. Manes, F, Sahakian, B, Clark, L, et al. Decision-making processes following damage to the prefrontal cortex. Brain. 2002;125:624639.
189. van V, V, Carter, CS. The anterior cingulate as a conflict monitor: fMRI and ERP studies. Physiol Behav. 2002;77:477482.
190. Fitzgerald, KD, Welsh, RC, Gehring, WJ, et al. Error-related hyperactivity of the anterior cingulate cortex in obsessive-compulsive disorder. Biol Psychiatry. 2005;57:287294.
191. Hajcak, G, Simons, RF. Error-related brain activity in obsessive-compulsive undergraduates. Psychiatry Res. 2002;110:6372.
192. Jung, HH, Kim, CH, Chang, JH, et al. Bilateral anterior cingulotomy for refractory obsessive-compulsive disorder: Long-term follow-up results. Stereotact Fund Neurosurg. 2006;84:184189.
193. Kim, CH, Chang, JW, Koo, MS, et al. Anterior cingulotomy for refractory obsessive-compulsive disorder. Acta Psychiatr Scand. 2003;107:283290.
194. Nieuwenhuis, S, Ridderinkhof, KR, Talsma, D, et al. A computational account of altered error processing in older age: dopamine and the error-related negativity. Cogn Affect Behav Neurosci. 2002;2:1936.
195. Talbot, PS, Watson, DR, Barrett, SL, et al. Rapid tryptophan depletion improves decision-making cognition in healthy humans without affecting reversal learning or set shifting. Neuropsychopharmacology. 2006;31:15191525.
196. Rogers, RD, Tunbridge, EM, Bhagwagar, Z, et al. Tryptophan depletion alters the decision-making of healthy volunteers through altered processing of reward cues. Neuropsychopharmacology. 2003;28:153162.
197. Pessiglione, M, Czernecki, V, Pillon, B, et al. An effect of dopamine depletion on decision-making: the temporal coupling of deliberation and execution. J Cogn Neurosci. 2005;17:18861896.

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Neurobiology of Obsessive-Compulsive Disorder: Serotonin and Beyond

  • Herman G.M. Westenberg, Naomi A. Fineberg and Damiaan Denys


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