Biology of obsessive–compulsive disorder

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Brain Structure[edit]

The biology of obsessive–compulsive disorder primarily involves[vague] the brain regions of the striatum, the orbitofrontal cortex and the cingulate cortex. People with OCD evince increased grey matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei, while decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate gyri.[1][2] These findings contrast with those in people with other anxiety disorders, who evince decreased (rather than increased) grey matter volumes in bilateral lenticular / caudate nuclei, while also decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate gyri.[2] OCD involves several different receptors, mostly H2, M4, NK1, NMDA, and non-NMDA glutamate receptors.[3] The receptors 5-HT1D, 5-HT2C, and the μ opioid receptor exert a secondary effect.[clarification needed] The H2, M4, NK1, and non-NMDA glutamate receptors are active in the striatum, whereas the NMDA receptors are active in the cingulate cortex.

Receptors[edit]

The activity of certain receptors is positively correlated to the severity of OCD, whereas the activity of certain other receptors is negatively correlated to the severity of OCD. Activity of the histamine receptor (H2); the Muscarinic acetylcholine receptor(M4); the Tachykinin receptor (NK1); and non-NMDA glutamate receptors are positively correlated with symptom severity in OCD. Associations for which activity is negatively correlated with severity include the NMDA receptor (NMDA); the Mu opioid receptor (μ opioid); and two types of 5-HT receptors (5-HT1D and 5-HT2C). The central dysfunction[clarification needed] of OCD may involve the receptors nk1, non-NMDA glutamate receptors, and NMDA, whereas the other receptors could simply exert secondary modulatory effects.

Brain-Derived Neurotrophic Factor[edit]

There is an association between brain-derived neurotrophic factor (BDNF) and OCD.[4] Hormonal dysregulation and a delayed sleep phase in patients with OCD point to a possible role of abnormal circadian rhythms in the pathophysiology of the disorder.[5]

Estrogen and OCD[edit]

Aromatase is an enzyme expressed in several gonadic tissue sites. It is the rate limiting step in the conversion of androgens to estrogen. This conversion can significantly impact estrogen levels in brain areas. Low estrogen levels in turn lead to behavioral changes that have been displayed in Obsessive Compulsive Disorders (ODC) in humans.[6] These OCD-linked effects have been demonstrated by Aromatase knockout mice (ArKO), who lack a functional enzyme to convert androgens to estrogen. This ArKO knockout strategy has provided a model to examine the physiological impact of lower than normal amounts of estrogen.[7]

Studies with ArKO mice have been used to show that varying levels of estrogen affect the onset of Obsessive Compulsive Disorder (OCD) behaviors. Interestingly enough, lower amounts of estrogen increase of OCD behaviors in males more than females.[8] Male ArKO mice increase repetitive behaviors such as wheel running and grooming, in comparison to normally developed mice. These repetitive and obsessive-like behaviors revert back to typical levels with 17beta-estradiol replacement therapy, providing even more evidence that low levels of estrogen increases risk for OCD behaviors in males.[9] Male ArKO mice also showed a decrease in levels of catechol-O-methyl transferase (COMT) protein.[10] Low levels of COMT protein are associated with susceptibility to OCD, especially within human males.[11] While a decrease in estrogen levels in males shows an increase in OCD behaviors, females show the opposite effect.

Variation in estrogen can lead to increased levels of OCD symptoms within women as well. The disorder itself has a later onset in women, and tends to show two distinct peaks of onset. The first peak occurs around puberty and the second around the age of childbearing. These peaks correlate with time periods where estrogen levels are highest in women.[12] Studies within rats further investigated this correlation, finding that OCD behavior varied during the estrous cycle, being highest at late diestrus and proestrus when estrogen levels are highest, and lowest after estrogen has decreased.[13] in addition, women with OCD have reported changes in the intensity and occurrences of their symptoms during their premenstrual and menstrual period, after pregnancy, and following menopause.[14] Research found that the absence of estrogen in ArKO female mice decreased [[barbering[[ (cleaning), wheel running, and grooming tendencies associated with OCD behavior.[15] This correlates with other findings that increased levels of estrogen increase OCD behaviors in females.

Pharmaceuticals[edit]

Pharmaceuticals that may directly counteract the core mechanisms are aprepitant (nk1 antagonist), riluzole (glutamate release inhibitor), and tautomycin (NMDA receptor sensitizer). Also, the anti-Alzheimer's drug memantine is being studied by the International OCD Foundation in its efficacy in reducing OCD symptoms due to it being an NMDA antagonist.[16] One case study published in The American Journal of Psychiatry suggests that "memantine may be an option for treatment-resistant OCD, but controlled studies are needed to substantiate this observation."[17] The drugs that are popularly used to fight OCD may be limited by their inaction upon what are believed to be the core mechanisms. Many trials are currently underway to investigate the efficacy of a variety of agents that affect these 'core' neurotransmitters, particularly glutamatergic agents.[1] Other genes and receptors under investigation for possible links to OCD include GABBR1, SLC1A1, GRIN2B, TPH2, DRD2, DRD3, DRD4, COMT, and MAO-A.

Group A Streptococcal Infections[edit]

Growing evidence indicates that OCD with rapid onset in children and adolescents may be caused by a syndrome connected to Group A streptococcal infections (PANDAS)[18][19][20] or caused by immunologic reactions to other pathogens (PANS).[21]

See also[edit]

References[edit]

  1. ^ Radua, Joaquim; Mataix-Cols, David (November 2009). "Voxel-wise meta-analysis of grey matter changes in obsessive–compulsive disorder". British Journal of Psychiatry 195 (5): 393–402. doi:10.1192/bjp.bp.108.055046. PMID 19880927. 
  2. ^ a b Radua, Joaquim; van den Heuvel, Odile A.; Surguladze, Simon; Mataix-Cols, David (5 July 2010). "Meta-analytical comparison of voxel-based morphometry studies in obsessive-compulsive disorder vs other anxiety disorders". Archives of General Psychiatry 67 (7): 701–711. doi:10.1001/archgenpsychiatry.2010.70. PMID 20603451. 
  3. ^ Paul, Sean (August 2013). "Serotonin System Dysfunction in OCD" 9. p. 1. 
  4. ^ Hall, D.; Dhilla, A.; Charalambous, A.; Gogos, A.; Karayiorgou, M. (Aug 2003). "Sequence Variants of the Brain-Derived Neurotrophic Factor (BDNF) Gene Are Strongly Associated with Obsessive-Compulsive Disorder". The American Journal of Human Genetics 73 (2): 370–376. doi:10.1086/377003. ISSN 0002-9297. PMC 1180373. PMID 12836135.  edit
  5. ^ Lange KW, Lange KM, Hauser J, Tucha L, Tucha O (October 2012). "Circadian rhythms in obsessive-compulsive disorder". J Neural Transm 119 (10): 1077–83. doi:10.1007/s00702-012-0805-z. PMID 22543530. 
  6. ^ Alonso, P., Gratacòs, M., Segalàs, C., Escaramís, G., Real, E., Bayés, M., & Menchón, J. M. (2011). "Variants in estrogen receptor alpha gene are associated with phenotypical expression of obsessive-compulsive disorder". Psychoneuroendocrinology 36 (4): 473–483. 
  7. ^ Boon, W. C., & Horne, M. K. (2011). "Aromatase and its inhibition in behaviour, obsessive compulsive disorder and parkinsonism". Steroids 76 (8): 816–819. 
  8. ^ Lochner, C., Hemmings, S. M. J., Kinnear, C. J., Moolman-Smook, J. C., Corfield, V. A., Knowles, J. A., & Stein, D. J. (2004). "Gender in obsessive-compulsive disorder: clinical and genetic findings". European Neuropsychopharmacology 14 (2): 105–113. 
  9. ^ Hill, R. A., McInnes, K. J., Gong, E. C. H., Jones, M. E. E., Simpson, E. R., & Boon, W. C. (2007). "Estrogen deficient male mice develop compulsive behavior". Biological Psychiatry 61 (3): 359–366. 
  10. ^ Hill, R. A., McInnes, K. J., Gong, E. C. H., Jones, M. E. E., Simpson, E. R., & Boon, W. C. (2007). "Estrogen deficient male mice develop compulsive behavior". Biological Psychiatry 61 (3): 359–366. 
  11. ^ Hill, R. A., McInnes, K. J., Gong, E. C. H., Jones, M. E. E., Simpson, E. R., & Boon, W. C. (2007). "Estrogen deficient male mice develop compulsive behavior". Biological Psychiatry 61 (3): 359–366. 
  12. ^ Brandes, M., Soares, C. N., & Cohen, L. S. (2004). "Postpartum onset obsessive-compulsive disorder: diagnosis and management". Archives of Women's Mental Health 7 (2): 99–110. 
  13. ^ Flaisher-Grinberg, S., Albelda, N., Gitter, L., Weltman, K., Arad, M., & Joel, D. (2009). "Ovarian hormones modulate 'compulsive' lever-pressing in female rats". Hormones and Behavior 55 (2): 356–365. 
  14. ^ Boon, W. C., & Horne, M. K. (2011). "Aromatase and its inhibition in behaviour, obsessive compulsive disorder and parkinsonism". Steroids 76 (8): 816–819. 
  15. ^ Flaisher-Grinberg, S., Albelda, N., Gitter, L., Weltman, K., Arad, M., & Joel, D. (2009). "Ovarian hormones modulate 'compulsive' lever-pressing in female rats". Hormones and Behavior 55 (2): 356–365. 
  16. ^ Bloch, M. H., Coric, V., & Pittenger, C. "New Horizons in OCD Research and the Potential Importance of Glutamate: Can We Develop Treatments That Work Better and Faster?". International OCD Foundation. Retrieved 24 January 2012. 
  17. ^ Poyurovsky M, Weizman R, Weizman A, Koran L (2005). "Memantine for treatment-resistant OCD". The American Journal of Psychiatry 162 (11): 2191–2. doi:10.1176/appi.ajp.162.11.2191-a. PMID 16263867. 
  18. ^ Moretto, Germana, Pasquini Massimo, et al.: "What every psychiatrist should know about PANDAS: a review". Department of Psychiatric Sciences and Psychological Medicine, "Sapienza" University of Rome. In: Clinical Practice and Epidemiology in Mental Health 2008.
  19. ^ NIMH PANS/PANDAS Information Page: http://intramural.nimh.nih.gov/pdn/web.htm
  20. ^ "PANDAS studies are no longer recruiting patients". Bethesda, MD: National Institute of Mental Health, Pediatrics and Developmental Neuroscience Branch. 24 February 2009. Retrieved 13 December 2009. 
  21. ^ ↑ Swedo SE, Leckman JF, Rose NR: From Research Subgroup to Clinical Syndrome: Modifying the PANDAS Criteria to Describe PANS; Pediatr Therapeut 2012, 2:2; doi:10.4172/2161-0665.1000113