Abstract
Treatment response in obsessive–compulsive disorder (OCD) is heterogeneous and the neurobiological underpinnings of such variability are unknown. To investigate this issue, we looked for differences in brain structures possibly associated with treatment response in children with OCD. 29 children with OCD (7–17 years) and 28 age-matched controls underwent structural magnetic resonance imaging. Patients then received treatment with fluoxetine or group cognitive-behavioral therapy during 14 weeks, and were classified as treatment responders or non-responders. The caudate nucleus, thalamus and orbitofrontal cortex were selected a priori, according to previous evidence of their association with OCD and its treatment. Gray matter (GM) volume comparisons between responders, non-responders and controls were performed, controlling for total GM volume. 17 patients were classified as responders. Differences among responders, non-responders and controls were found in both caudate nuclei (both p-values = 0.041), but after Bonferroni correction for multiple comparisons, these findings were non-significant. However, after excluding the effect of an outlier, findings were significant for the right caudate (p = 0.004). Pairwise comparisons showed larger caudate GM volume in responders versus non-responders and controls, bilaterally. The right caudate accounted for 20.2% of the variance in Y-BOCS changes after treatment in a linear regression model, with a positive correlation (p = 0.016). We present a possible neural substrate for treatment response in pediatric OCD, which is in line with previous evidence regarding the caudate nucleus. Considering the limitations, further research is needed to replicate this finding and elucidate the heterogeneity of treatment response in children with OCD (National Clinical Trials Registration Number: NCT01148316).
Similar content being viewed by others
References
Rapoport JL, Inoff-Germain G, Weissman MM, Greenwald S, Narrow WE, Jensen PS et al (2000) Childhood obsessive–compulsive disorder in the NIMH MECA Study: parent versus child identification of cases. J Anxiety Disord 14(6):535–548
Paula CS, Coutinho ES, Mari JJ, Rohde LA, Miguel EC, Bordin IA (2015) Prevalence of psychiatric disorders among children and adolescents from four Brazilian regions. Rev Bras Psiquiatr 37(2):178–179
Taylor S (2011) Early versus late onset obsessive–compulsive disorder: evidence for distinct subtypes. Clin Psychol Rev 31(7):1083–1100
Abramowitz JS, Whiteside SP, Deacon BJ (2006) The effectiveness of treatment for pediatric obsessive–compulsive disorder: a meta-analysis. Behav Ther 36(1):55–63
Watson HJ, Rees CS (2008) Meta-analysis of randomized, controlled treatment trials for pediatric obsessive–compulsive disorder. J Child Psychol Psychiatry 49(5):489–498
The POTS Team (2004) 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(16):1969
McGuire JF, Piacentini J, Lewin AB, Brennan EA, Murphy TK, Storch EA (2015) A meta-analysis of cognitive behavior therapy and medication for child obsessive–compulsive disorder: moderators of treatment efficacy, response, and remission. Depress Anxiety 32(8):580–593
Friedlander L, Desrocher M (2006) Neuroimaging studies of obsessive–compulsive disorder in adults and children. Clin Psychol Rev 26(1):32–49
Kalra SK, Swedo SE (2009) Children with obsessive–compulsive disorder: are they just “little adults”? J Clin Invest 119(4):737
Boedhoe PS, Schmaal L, Abe Y, Alonso P, Ameis SH, Anticevic A et al (2017) Cortical abnormalities associated with pediatric and adult obsessive–compulsive disorder: findings from the ENIGMA obsessive–compulsive disorder working group. Am J Psychiatry 175(5):453–462. https://doi.org/10.1176/appi.ajp.2017.17050485
Boedhoe PS, Schmaal L, Abe Y, Ameis SH, Arnold PD, Batistuzzo MC et al (2016) Distinct subcortical volume alterations in pediatric and adult OCD: a worldwide meta-and mega-analysis. Am J Psychiatry 174(1):60–69
Harrison BJ, Soriano-Mas C, Pujol J, Ortiz H, López-Solà M, Hernández-Ribas R et al (2009) Altered corticostriatal functional connectivity in obsessive–compulsive disorder. Arch Gen Psychiatry 66(11):1189–1200
Benkelfat C, Nordahl TE, Semple WE, King AC, Murphy DL, Cohen RM (1990) Local cerebral glucose metabolic rates in obsessive–compulsive disorder: patients treated with clomipramine. Arch Gen Psychiatry 47(9):840–848
Saxena S, Brody AL, Maidment KM, Dunkin JJ, Colgan M, Alborzian S et al (1999) Localized orbitofrontal and subcortical metabolic changes and predictors of response to paroxetine treatment in obsessive–compulsive disorder. Neuropsychopharmacology 21(6):683–693
Schwartz JM, Stoessel PW, Baxter LR, Martin KM, Phelps ME (1996) Systematic changes in cerebral glucose metabolic rate after successful behavior modification treatment of obsessive–compulsive disorder. Arch Gen Psychiatry 53(2):109–113
Baxter LR Jr, Schwartz JM, Bergman KS et al (1992) Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive–compulsive disorder. Arch Gen Psychiatry 49(9):681–689
Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ (2000) Decrease in caudate glutamatergic concentrations in pediatric obsessive–compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry 39(9):1096–1103
Gilbert AR, Moore GJ, Keshavan MS, Paulson LAD, Narula V, Mac Master FP et al (2000) Decrease in thalamic volumes of pediatric patients with obsessive–compulsive disorder who are taking paroxetine. Arch Gen Psychiatry 57(5):449–456
O’Neill J, Piacentini JC, Chang S, Levitt JG, Rozenman M, Bergman L et al (2012) MRSI correlates of cognitive–behavioral therapy in pediatric obsessive–compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 36(1):161–168
Huyser C, van den Heuvel OA, Wolters L, de Haan E, Lindauer R, Veltman DJ (2014) A longitudinal VBM study in paediatric obsessive–compulsive disorder at 2-year follow-up after cognitive behavioural therapy. World J Biol Psychiatry 15(6):443–452
Huyser C, van den Heuvel OA, Wolters LH, de Haan E, Boer F, Veltman DJ (2013) Increased orbital frontal gray matter volume after cognitive behavioural therapy in paediatric obsessive compulsive disorder. World J Biol Psychiatry 14(4):319–331
Huyser C, Veltman DJ, Wolters LH, de Haan E, Boer F (2010) Functional magnetic resonance imaging during planning before and after cognitive-behavioral therapy in pediatric obsessive–compulsive disorder. J Am Acad Child Adolesc Psychiatry 49(12):1238–1248
Swedo SE, Schapiro MB, Grady CL, Cheslow DL, Leonard HL, Kumar A et al (1989) Cerebral glucose metabolism in childhood-onset obsessive–compulsive disorder. Arch Gen Psychiatry 46(6):518–523
Hendler T, Goshen E, Zwas ST, Sasson Y, Gal G, Zohar J (2003) Brain reactivity to specific symptom provocation indicates prospective therapeutic outcome in OCD. Psychiatry Res Neuroimaging 124(2):87–103
Pian KLH, van Megen HJ, Ramsey NF, Mandl R, van Rijk PP, Wynne H et al (2005) Decreased thalamic blood flow in obsessive–compulsive disorder patients responding to fluvoxamine. Psychiatry Res Neuroimaging 138(2):89–97
Hoexter MQ, Diniz JB, Lopes AC, Batistuzzo MC, Shavitt RG, Dougherty DD et al (2015) Orbitofrontal thickness as a measure for treatment response prediction in obsessive–compulsive disorder. Depress Anxiety 32(12):900–908
Fullana M, Cardoner N, Alonso P, Subirà M, López-Solà C, Pujol J et al (2014) Brain regions related to fear extinction in obsessive–compulsive disorder and its relation to exposure therapy outcome: a morphometric study. Psychol Med 44(04):845–856
Saxena S, Brody AL, Ho ML, Zohrabi N, Maidment KM, Baxter LR Jr (2003) Differential brain metabolic predictors of response to paroxetine in obsessive–compulsive disorder versus major depression. Am J Psychiatry 160(3):522–532
Rauch SL, Shin LM, Dougherty DD, Alpert NM, Fischman AJ, Jenike MA (2002) Predictors of fluvoxamine response in contamination-related obsessive compulsive disorder: a PET symptom provocation study. Neuropsychopharmacology 27(5):782–791
Sanematsu H, Nakao T, Yoshiura T, Nabeyama M, Togao O, Tomita M et al (2010) Predictors of treatment response to fluvoxamine in obsessive–compulsive disorder: an fMRI study. J Psychiatr Res 44(4):193–200
Brody AL, Saxena S, Schwartz JM, Stoessel PW, Maidment K, Phelps ME et al (1998) FDG-PET predictors of response to behavioral therapy and pharmacotherapy in obsessive compulsive disorder. Psychiatry Res Neuroimaging 84(1):1–6
Hoexter MQ, Dougherty DD, Shavitt RG, D’Alcante CC, Duran FL, Lopes AC et al (2013) Differential prefrontal gray matter correlates of treatment response to fluoxetine or cognitive-behavioral therapy in obsessive–compulsive disorder. Eur Neuropsychopharmacol 23(7):569–580
O’Neill J, Gorbis E, Feusner JD, Yip JC, Chang S, Maidment KM et al (2013) Effects of intensive cognitive-behavioral therapy on cingulate neurochemistry in obsessive–compulsive disorder. J Psychiatr Res 47(4):494–504
Zurowski B, Kordon A, Weber-Fahr W, Voderholzer U, Kuelz AK, Freyer T et al (2012) Relevance of orbitofrontal neurochemistry for the outcome of cognitive-behavioural therapy in patients with obsessive–compulsive disorder. Eur Arch Psychiatry Clin Neurosci 262(7):617–624
De Wit SJ, Alonso P, Schweren L, Mataix-Cols D, Lochner C, Menchón JM et al (2014) Multicenter voxel-based morphometry mega-analysis of structural brain scans in obsessive–compulsive disorder. Am J Psychiatry 171(3):340–349
O’Neill J, Piacentini J, Chang S, Ly R, Lai TM, Armstrong CC et al (2017) Glutamate in pediatric obsessive–compulsive disorder and response to cognitive-behavioral therapy: randomized clinical trial. Neuropsychopharmacology 42(12):2414
Diler RS, Kibar M, Avci A (2004) Pharmacotherapy and regional cerebral blood flow in children with obsessive compulsive disorder. Yonsei Med J 45(1):90–99
Fatori D, de Bragança Pereira CA, Asbahr FR, Requena G, Alvarenga PG, de Mathis MA et al (2018) Adaptive treatment strategies for children and adolescents with obsessive–compulsive disorder: a sequential multiple assignment randomized trial. J Anxiety Disord 58:42–50
Batistuzzo MC, Balardin JB, Martin MdGM, Hoexter MQ, Bernardes ET, Borcato S et al (2015) Reduced prefrontal activation in pediatric patients with obsessive–compulsive disorder during verbal episodic memory encoding. J Am Acad Child Adolesc Psychiatry 54(10):849–858
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P et al (1997) Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36(7):980–988
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(11):1006–1011
Poznanski E, Freeman L, Mokros H (1985) Children’s Depression Rating Scale-Revisited (1984). Psychopharmacol Bull 21(4):979–989
Birmaher B, Khetarpal S, Brent D, Cully M, Balach L, Kaufman J et al (1997) The Screen for Child Anxiety Related Emotional Disorders (SCARED): scale construction and psychometric characteristics. J Am Acad Child Adolesc Psychiatry 36(4):545–553
Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA, Goodman WK et al (1997) Children’s Yale-Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry 36(6):844–852
Miguel EC, Ferrão YA, Rosário MCd, Mathis MAd, Torres AR, Fontenelle LF et al (2008) The Brazilian Research Consortium on Obsessive–compulsive Spectrum Disorders: recruitment, assessment instruments, methods for the development of multicenter collaborative studies and preliminary results. Rev Bras Psiquiatr 30(3):185–196
Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D et al (2006) An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31(3):968–980
Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C et al (2002) Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33(3):341–355
Fossaluza V, Diniz JB, Pereira BdB, Miguel EC, Pereira CAB (2009) Sequential allocation to balance prognostic factors in a psychiatric clinical trial. Clinics (Sao Paulo) 64(6):511–518
Mataix-Cols D, de la Cruz LF, Nordsletten AE, Lenhard F, Isomura K, Simpson HB (2016) Towards an international expert consensus for defining treatment response, remission, recovery and relapse in obsessive–compulsive disorder. World Psychiatry 15(1):80–81
Tukey JW (1977) Exploratory data analysis, vol 2. Addison-Wesley, Boston
Gillan CM, Apergis-Schoute AM, Morein-Zamir S, Urcelay GP, Sule A, Fineberg NA et al (2015) Functional neuroimaging of avoidance habits in obsessive–compulsive disorder. Am J Psychiatry 172(3):284–293
Huyser C, Veltman DJ, de Haan E, Boer F (2009) Paediatric obsessive–compulsive disorder, a neurodevelopmental disorder?: evidence from neuroimaging. Neurosci Biobehav Rev 33(6):818–830
Britton JC, Rauch SL, Rosso IM, Killgore WD, Price LM, Ragan J et al (2010) Cognitive inflexibility and frontal-cortical activation in pediatric obsessive–compulsive disorder. J Am Acad Child Adolesc Psychiatry 49(9):944–953
Rotge J-Y, Guehl D, Dilharreguy B, Tignol J, Bioulac B, Allard M et al (2009) Meta-analysis of brain volume changes in obsessive–compulsive disorder. Biol Psychiatry 65(1):75–83
Radua J, Mataix-Cols D (2009) Voxel-wise meta-analysis of grey matter changes in obsessive–compulsive disorder. Br J Psychiatry 195(5):393–402
den Braber A, van’t Ent D, Cath DC, Wagner J, Boomsma DI, de Geus EJ (2010) Brain activation during cognitive planning in twins discordant or concordant for obsessive–compulsive symptoms. Brain 133(10):3123–3140
van den Heuvel OA, Remijnse PL, Mataix-Cols D, Vrenken H, Groenewegen HJ, Uylings HB et al (2009) The major symptom dimensions of obsessive–compulsive disorder are mediated by partially distinct neural systems. Brain 132(4):853–868
Yu D, Mathews CA, Scharf JM, Neale BM, Davis LK, Gamazon ER et al (2014) Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette’s syndrome and OCD. Am J Psychiatry 172(1):82–93
Peterson BS, Thomas P, Kane MJ, Scahill L, Zhang H, Bronen R et al (2003) Basal ganglia volumes in patients with Gilles de la Tourette syndrome. Arch Gen Psychiatry 60(4):415–424
Shaw P, Sharp W, Sudre G, Wharton A, Greenstein D, Raznahan A et al (2015) Subcortical and cortical morphological anomalies as an endophenotype in obsessive–compulsive disorder. Mol Psychiatry 20(2):224–231
Giedd JN, Rapoport JL, Leonard HL, Richter D, Swedo SE (1996) Case study: acute basal ganglia enlargement and obsessive–compulsive symptoms in an adolescent boy. J Am Acad Child Adolesc Psychiatry 35(7):913–915
Pavone P, Bianchini R, Parano E, Incorpora G, Rizzo R, Mazzone L et al (2004) Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatr Neurol 30(2):107–110
Vidal-Ribas P, Stringaris A, Rück C, Serlachius E, Lichtenstein P, Mataix-Cols D (2015) Are stressful life events causally related to the severity of obsessive–compulsive symptoms? A monozygotic twin difference study. Eur Psychiatry 30(2):309–316
Benedetti F, Poletti S, Radaelli D, Pozzi E, Giacosa C, Ruffini C et al (2012) Caudate gray matter volume in obsessive–compulsive disorder is influenced by adverse childhood experiences and ongoing drug treatment. J Clin Psychopharmacol 32(4):544–547
Hansen ES, Hasselbalch S, Law I, Bolwig TG (2002) The caudate nucleus in obsessive–compulsive disorder. Reduced metabolism following treatment with paroxetine: a PET study. Int J Neuropsychopharmacol 5(1):1–10
Nakatani E, Nakgawa A, Ohara Y, Goto S, Uozumi N, Iwakiri M et al (2003) Effects of behavior therapy on regional cerebral blood flow in obsessive–compulsive disorder. Psychiatry Res Neuroimaging 124(2):113–120
Moore GJ, MacMaster FP, Stewart C, Rosenberg DR (1998) Case Study: caudate glutamatergic changes with paroxetine therapy for pediatric obsessive–compulsive disorder. J Am Acad Child Adolesc Psychiatry 37(6):663–667
Bolton J, Moore GJ, MacMillan S, Stewart CM, Rosenberg DR (2001) Case study: caudate glutamatergic changes with paroxetine persist after medication discontinuation in pediatric OCD. J Am Acad Child Adolesc Psychiatry 40(8):903–906
Valente AA, Miguel EC, Castro CC, Amaro E, Duran FL, Buchpiguel CA et al (2005) Regional gray matter abnormalities in obsessive–compulsive disorder: a voxel-based morphometry study. Biol Psychiatry 58(6):479–487
Saxena S, Brody AL, Ho ML, Alborzian S, Maidment KM, Zohrabi N et al (2002) Differential cerebral metabolic changes with paroxetine treatment of obsessive–compulsive disorder vs major depression. Arch Gen Psychiatry 59(3):250–261
Burgund ED, Kang HC, Kelly JE, Buckner RL, Snyder AZ, Petersen SE et al (2002) The feasibility of a common stereotactic space for children and adults in fMRI studies of development. Neuroimage 17(1):184–200
Lenroot RK, Giedd JN (2006) Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev 30(6):718–729
Maia TV, Cooney RE, Peterson BS (2008) The neural bases of obsessive–compulsive disorder in children and adults. Dev Psychopathol 20(4):1251–1283
Acknowledgements
Supported by the National Institute of Developmental Psychiatry for Children and Adolescents, the São Paulo Research Foundation (FAPESP Grants n# 2009/09949-8; 2013/08531-5; 2014/50917-0) and the Brazilian National Council for Scientific and Technological Development (CNPq—465550/2014-2). Dr. João R. Sato was supported by FAPESP grants n# 2018/04654-9 and 2018/21934-5. The dataset of this study was used in the following studies for other purposes and objectives, with consent of all authors: Fatori et al. [38] and Batistuzzo et al. [39].
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors report no potential conflicts of interest. Dr. Vattimo confirms he had full access to all the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Vattimo, E.F.Q., Barros, V.B., Requena, G. et al. Caudate volume differences among treatment responders, non-responders and controls in children with obsessive–compulsive disorder. Eur Child Adolesc Psychiatry 28, 1607–1617 (2019). https://doi.org/10.1007/s00787-019-01320-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00787-019-01320-w