Obsessive Compulsive Disorder

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Obsessive Compulsive Disorder

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1. Obsessive Compulsive Disorder Abby Suelflow November 20th, 2009

2. Definition Unreasonable thoughts and fears (obsessions) that lead to repetitive behaviors (compulsions). Clinical presentation is remarkably diverse, and can vary both within and across patients May realize obsessions arenít reasonable, may try to ignore them or stop them. This only increases anxiety/stress and feel driven to perform the compulsive acts in order to ease the distress. With OCD, you may have a low quality of life because the condition rules most of your days. You may be very distressed but feel powerless to stop your urges. Most adults can recognize that their obsessions and compulsions don't make sense. Children, however, may not understand what's wrong. 2. Important to identify valid subgroups of patients in order to predict treatment response and resistanceMay realize obsessions arenít reasonable, may try to ignore them or stop them. This only increases anxiety/stress and feel driven to perform the compulsive acts in order to ease the distress. With OCD, you may have a low quality of life because the condition rules most of your days. You may be very distressed but feel powerless to stop your urges. Most adults can recognize that their obsessions and compulsions don't make sense. Children, however, may not understand what's wrong. 2. Important to identify valid subgroups of patients in order to predict treatment response and resistance

3. Alternative phenotypes Early onset OCD-PANDAS Neuropsychology Deficits in cognitive flexibility and motor inhibition Structural variations related to motor inhibitory control Gender Different clinical presentations Drug response Symptoms respond differently to treatments OCD is a spectrum disorder phenotype with many alternate forms.. There is variability in the phenotypic expression and this means that OCD is a heterogeneous disorder and this complicates the search for vulnerable genes. Pediatric autoimmune neuropsychiatric disorders associated with strep Neuropsychology- reduced grey matter in orbitofrontal and right inferior frontal regions and increased gray matter in cingulate, parietal, and striatal regions. Structural variations in large-scale brain systems related to motor inhibitory control may mediate genetic risk for OCDOCD is a spectrum disorder phenotype with many alternate forms.. There is variability in the phenotypic expression and this means that OCD is a heterogeneous disorder and this complicates the search for vulnerable genes. Pediatric autoimmune neuropsychiatric disorders associated with strep Neuropsychology- reduced grey matter in orbitofrontal and right inferior frontal regions and increased gray matter in cingulate, parietal, and striatal regions. Structural variations in large-scale brain systems related to motor inhibitory control may mediate genetic risk for OCD

4. Prevalence 3.3 million Americans (NIMH) 2 in every 50 adults have had incidents of OCD sometime in their life. † Often begins during early childhood or adolescence, usually around age 10. (1/3) In adults, OCD typically occurs around age 21 One of the most common mental illnesses.One of the most common mental illnesses.

5. Complications Suicidal thoughts (1%) Alcohol/substance abuse Other anxiety disorders (co-morbidity) Depression Eating disorders Inability to attend work/school Overall poor quality of life Troubled relationships

6. Centered around themes Contaminated by germs Repeated doubting Ordering Religious Sexual thoughts Aggression . In order to relieve these obsessions, they engage in compulsive acts such as cleaning/washing hands, showering, bathing, brushing teeth, detailed bathroom routines, checking, ordering, and hoarding. The compulsive acts donít relieve the obsessions entirely and it results in a vicious cycle that doesnít end. Results in dermatitis, skin lesions, hair loss. . In order to relieve these obsessions, they engage in compulsive acts such as cleaning/washing hands, showering, bathing, brushing teeth, detailed bathroom routines, checking, ordering, and hoarding. The compulsive acts donít relieve the obsessions entirely and it results in a vicious cycle that doesnít end. Results in dermatitis, skin lesions, hair loss.

7. OCD v. OCPD The biggest difference between OCD and OCPD is the presence of true obsessions and compulsions. Obsessions and compulsions are not present in OCPD. Individuals with OCD use these tasks to reduce anxiety caused by obsessional thoughts, are usually distressed by having to carry out these tasks or rituals. In contrast, people with OCPD view activities such as excessive list making or organization of items around the home as necessary and even beneficial, spend a much greater amount of time engaged in these tasks or rituals than people with OCPD. If the obsessions and compulsions are affecting your life, it is important to see a doctor. The biggest difference between OCD and OCPD is the presence of true obsessions and compulsions. Obsessions and compulsions are not present in OCPD. Individuals with OCD use these tasks to reduce anxiety caused by obsessional thoughts, are usually distressed by having to carry out these tasks or rituals. In contrast, people with OCPD view activities such as excessive list making or organization of items around the home as necessary and even beneficial, spend a much greater amount of time engaged in these tasks or rituals than people with OCPD. If the obsessions and compulsions are affecting your life, it is important to see a doctor.

8. Diagnosis Initially must meet these 3 criteria: You must have either obsessions or compulsions. You must realize that your obsessions and compulsions are excessive or unreasonable. Obsessions and compulsions significantly interfere with your daily routine.

9. Diagnosis cont. Obsessions must meet these specific criteria: Recurrent and persistent thoughts, impulses or images that are disturbing and cause distress. The thoughts aren't simply excessive worries about real problems in your life. You try to ignore or suppress these thoughts, images or impulses. You know that these thoughts, images and impulses are a product of your own mind.

10. Diagnosis cont. Compulsions must these specific criteria: Repetitive behavior that you feel driven to perform, such as hand washing, or repetitive mental acts, such as counting silently. These behaviors or mental acts are meant to prevent or reduce distress about unrealistic obsessions.

11. Causes Family studies- heredity seems to play a role (45-65% genetics in children) 12% prevalence of OCD in 1st degree relatives compared to 2% in relatives of normal controls. Higher rates of GAD, SAD, panic, and agoraphobia in 1st degree relatives with OCD Twin studies- support presence of significant genetic influence (only a few studies) SAD- separation anxiety disorderSAD- separation anxiety disorder

12. Environment Abuse Changes in living situation Illness Death of a loved one Relationship concerns Labor complications, edema during pregnancy, excessive consumption of caffeine/alcohol by mother, and maternal smoking Labor complicationsLabor complications

13. Gene studies Catechol-O-methyltransferase Val158met polymorphism 3-4 fold reduction in enzyme activity Microdeletions of 22q11 region Monoamine oxidase A (MAO-A) Treatment option: MAO Inhibitors Inactivation of catecholamine NT (DA, EP, NEP) Val158met-substitution of valine for methionine. Link between met allele and OCD. Research needs to be done to definitively rule in or out the role of COMT and how this polymorphism may/may not increase susceptibility of OCD. MAO-A- encodes monoamine oxidase A, an enzyme that degrades amine neurotransmitters, such as dopamine, norepinephrine, and serotonin MAO-A low enzymatic activity allele in OCD, MAOI have been used Dopamine System Dopamine transporter gene and dopamine receptors have been studied but no conclusively identified markers Dopamine receptor blocking agents reduce some symptoms Researchers deciding if dopamine antagonists can be combined w/ antidepressants for better results Glutamate system Glutamate transporter gene (SLC1A1) and OCD association. The gene encodes protein called EAAC1 that regulates glutamate flow in and out of brain cells. Brain imaging and spinal fluid studies have shown differences in glutamate system of OCD v. control. the altered glutamate activity may contribute to obsessions and compulsions. Serotonin System Selective serotonin reuptake inhibitors have been used in the treatment of OCD. Inactivation of catecholamine NT (DA, EP, NEP) Val158met-substitution of valine for methionine. Link between met allele and OCD. Research needs to be done to definitively rule in or out the role of COMT and how this polymorphism may/may not increase susceptibility of OCD. MAO-A- encodes monoamine oxidase A, an enzyme that degrades amine neurotransmitters, such as dopamine, norepinephrine, and serotonin MAO-A low enzymatic activity allele in OCD, MAOI have been used Dopamine System Dopamine transporter gene and dopamine receptors have been studied but no conclusively identified markers Dopamine receptor blocking agents reduce some symptoms Researchers deciding if dopamine antagonists can be combined w/ antidepressants for better results Glutamate system Glutamate transporter gene (SLC1A1) and OCD association. The gene encodes protein called EAAC1 that regulates glutamate flow in and out of brain cells. Brain imaging and spinal fluid studies have shown differences in glutamate system of OCD v. control. the altered glutamate activity may contribute to obsessions and compulsions. Serotonin System Selective serotonin reuptake inhibitors have been used in the treatment of OCD.

14. Dopamine system Dopamine receptor blocking agents Glutamate system Elevated levels in several brain regions Transporter gene (SLC1A1) encodes protein called EAAC1 Serotonin system

15. Cortical glutamatergic toxicity as a consequence of the dysfunction of the glutamate transporter EAAC-1 and BDV infection. The glutamate transporter EAAC-1, localized in the postsynaptic membrane, contributes to the clearance of extracellular and intrasynaptic glutamate, and thereby to the regulation of the activation of NMDA and AMPA receptors (A). Variations in the functional gene SLC1A1 may contribute to the loss of functional properties of EAAC-1. This may promote excitoxicity by facilitating prolonged activation of glutamatergic receptors (B). BDV infection is associated with an enhanced level of glutamate, which may lead to a thalamo-cortical overactivation. Subsequently, the glutamatergic intrasynaptic release is elevated, and leads to a prolonged activation of glutamatergic receptors (C). Prolonged activation of these glutamatergic receptors may result in excitotoxicity, leading to the neuronal cell death, and then to the cortical atrophy observed in OCD. BDV, Borna disease virus; NMDA, N-methyl-d-aspartatic acid; EAAC-1, excitatory amino-acid carrier 1; SLC1A1, solute carrier family 1 memberCortical glutamatergic toxicity as a consequence of the dysfunction of the glutamate transporter EAAC-1 and BDV infection. The glutamate transporter EAAC-1, localized in the postsynaptic membrane, contributes to the clearance of extracellular and intrasynaptic glutamate, and thereby to the regulation of the activation of NMDA and AMPA receptors (A). Variations in the functional gene SLC1A1 may contribute to the loss of functional properties of EAAC-1. This may promote excitoxicity by facilitating prolonged activation of glutamatergic receptors (B). BDV infection is associated with an enhanced level of glutamate, which may lead to a thalamo-cortical overactivation. Subsequently, the glutamatergic intrasynaptic release is elevated, and leads to a prolonged activation of glutamatergic receptors (C). Prolonged activation of these glutamatergic receptors may result in excitotoxicity, leading to the neuronal cell death, and then to the cortical atrophy observed in OCD. BDV, Borna disease virus; NMDA, N-methyl-d-aspartatic acid; EAAC-1, excitatory amino-acid carrier 1; SLC1A1, solute carrier family 1 member

16. Serotonergic system SERT-serotonin transporter gene 5-HTT plays important role in maintaining presynaptic homeostasis. 5-HTTLPR- polymorphism in promotor region; 44 bp insertion (L allele) or deletion (S allele). Possible association between L-allele and OCD 5-HTT variant, Ile425Val- linked to treatment-resistance OCD, anorexia nervosa, Aspergers Antidepressants such as SSRI have shown to be efficacious in treating OCD 5-HTT-transport serotonin back into the cell after its message has been delivered. 5-HTT transports serotonin from the synaptic space back into the presynaptic neuron. located on chromosome 17 and has a common polymorphism located in the promoter region (5-HTTLPR-linked polymorphic region) that consists of either the insertion or deletion of 44 bp. The long variant has been reported to generate more gene expression than the short variant (2-3 times higher basal transcriptional activity), and has been associated w/ higher levels of 5-HTT in platelets and brain. The S allele found to reduce transcription efficiency for the 5-HTT gene, resulting in decreased 5-HTT expression and serotonin uptake. 5-HTT-transport serotonin back into the cell after its message has been delivered. 5-HTT transports serotonin from the synaptic space back into the presynaptic neuron. located on chromosome 17 and has a common polymorphism located in the promoter region (5-HTTLPR-linked polymorphic region) that consists of either the insertion or deletion of 44 bp. The long variant has been reported to generate more gene expression than the short variant (2-3 times higher basal transcriptional activity), and has been associated w/ higher levels of 5-HTT in platelets and brain. The S allele found to reduce transcription efficiency for the 5-HTT gene, resulting in decreased 5-HTT expression and serotonin uptake.

17. Illustration 1 shows how this works in a healthy nerve transmission process †Illustration 2 shows the process when Major Depression is present. Note that fewer Serotonin molecules are present in the synaptic cleft and hence fewer make it to the next neuron to make it "fire." Illustration 3 shows how an SSRI drug blocks the reuptake of Serotonin thus causing the concentration in the synaptic cleft to be increased. Consequently more serotonin makes it to the receptor sites on the next nerve cell and the functioning returns to normal. Illustration 1 shows how this works in a healthy nerve transmission process †Illustration 2 shows the process when Major Depression is present. Note that fewer Serotonin molecules are present in the synaptic cleft and hence fewer make it to the next neuron to make it "fire." Illustration 3 shows how an SSRI drug blocks the reuptake of Serotonin thus causing the concentration in the synaptic cleft to be increased. Consequently more serotonin makes it to the receptor sites on the next nerve cell and the functioning returns to normal.

18. The short (S) 5-HTTLPR variant (purple) of the 5-HTT gene (SLC6A4) produces significantly less 5-HTT mRNA and protein, as indicated by the green arrow, than the long (L) variant (red), leading to higher concentrations of serotonin in the synaptic cleft. The short variant is associated with anxiety-related personality traits such as neuroticism, which are risk factors for affective spectrum disorders. MAOA, monoamine oxidase A; SSRI, selective serotonin reuptake inhibitor. The short (S) 5-HTTLPR variant (purple) of the 5-HTT gene (SLC6A4) produces significantly less 5-HTT mRNA and protein, as indicated by the green arrow, than the long (L) variant (red), leading to higher concentrations of serotonin in the synaptic cleft. The short variant is associated with anxiety-related personality traits such as neuroticism, which are risk factors for affective spectrum disorders. MAOA, monoamine oxidase A; SSRI, selective serotonin reuptake inhibitor.

19. Main paper Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene (Baca-Garcia et al. 2007)

20. Introduction A polymorphism in intron 2 of 5-HTT gene consisting of a VNTR 3 alleles have been described, containing: 9, 10, and 12 copies of repetitive element. 9-unipolar depression & bipolar disorder 12- schizophrenia, bipolar, & OCD 9/10- anxiety disorders Possible combined effect of 5-HTTLPR and VNTR polymorphisms on 5-HTT gene expression Multiple repeated copies of a 16-17 bp element Studies have examined relationship b/t the number of repeats of the VNTR polymorphism and susceptibility to psychiatric disorders. Some have reported link b/t Stin2.9 allele and unipolar depression and bipolar disorder, and Stin2.12 allele and schizophrenia, and an association b/t anxiety and the short alleles in patients with self-harming behaviors. Different alleles of the VNTR have been shown to have different regulatory effect on transcription Multiple repeated copies of a 16-17 bp element Studies have examined relationship b/t the number of repeats of the VNTR polymorphism and susceptibility to psychiatric disorders. Some have reported link b/t Stin2.9 allele and unipolar depression and bipolar disorder, and Stin2.12 allele and schizophrenia, and an association b/t anxiety and the short alleles in patients with self-harming behaviors. Different alleles of the VNTR have been shown to have different regulatory effect on transcription

21. PUrpose To assess the association between OCD and the serotonin transporter intro 2 polymorphism.

22. methods Subjects 97 OCD patients (Y-BOCS) 578 psychiatric controls 406 healthy blood donors (controls) Genotyping Genomic DNA extracted and PCR amplification of the VNTR polymorphism Data analysis OCD patients v. psychiatric controls v. healthy controls Allele 12 carriers (12/12, 12/10, 12/9) v. non-carriers (9/9, 9/10, 10/10) Psychiatric controls- other diagnoses excluding OCD (27.7% substance abuse, 30.7% psychoses, 42.5% unipolar depression, 7.5% eating disorders, 23.4% anxiety disorders, 13.3% personality disorders. Yale Brown Obsessive Compulsive Scale (Y-BOCS) assessed severity, General Health Questionnaire-12 used to screen for psychopathology in controls. Genotype frequencies of the VNTR polymorphism of intron-2 of the 5 HTT-gene Psychiatric controls- other diagnoses excluding OCD (27.7% substance abuse, 30.7% psychoses, 42.5% unipolar depression, 7.5% eating disorders, 23.4% anxiety disorders, 13.3% personality disorders. Yale Brown Obsessive Compulsive Scale (Y-BOCS) assessed severity, General Health Questionnaire-12 used to screen for psychopathology in controls. Genotype frequencies of the VNTR polymorphism of intron-2 of the 5 HTT-gene

23. Y-BOCS

24. results

25. Results Genotype frequencies for the VNTR polymorphism in intron 2 of the 5-HTT gene was significantly different in OCD patients compared to psychiatric patients and in OCD patients compared to controls. Genotype frequencies were not significantly different in psychiatric patients compared to controls. OCD patients had an excess of the 12/12 and 12/10 genotypes. Two subgroups- differences were significant when comparing OCD patients (93/97 allele 12 carriers (95.9%)) versus healthy controls (351/406 allele 12 carriers (86.5%)) and OCD patients versus psychiatric patients (498/578) allele 12 carriers (86.2%)) Genotype frequencies for the VNTR polymorphism in intron 2 of the 5-HTT gene was significantly different in OCD patients compared to psychiatric patients and in OCD patients compared to controls. Genotype frequencies were not significantly different in psychiatric patients compared to controls. OCD patients had an excess of the 12/12 and 12/10 genotypes. Two subgroups- differences were significant when comparing OCD patients (93/97 allele 12 carriers (95.9%)) versus healthy controls (351/406 allele 12 carriers (86.5%)) and OCD patients versus psychiatric patients (498/578) allele 12 carriers (86.2%))

27. Discussion Ethnic variations in genotype and allele frequencies of this polymorphism Gene-based approach would be less susceptible to genetic differences between populations. VNTR polymorphism may act in a synergistic way with other polymorphisms Combined effect of 5-HTTLPR and VNTR polymorphisms on 5-HTT gene expression. Higher rates of Stin2.12 alleles in Japanese compared to Caucasian samples SNP-based approach and haplotype based approaches have been criticized. Combined effect of serotonin transporter promotor Higher rates of Stin2.12 alleles in Japanese compared to Caucasian samples SNP-based approach and haplotype based approaches have been criticized. Combined effect of serotonin transporter promotor

28. Conclusion Significant excess of allele 12 in OCD patients Many studies have failed to replicate these results and more research is necessary to determine the exact relationship b/t VNTR polymorphism in intron 2 of the 5-HTT gene and anxiety disorders. Some studies have shown an associated between 9 and 10 alleles and symptoms of anxiety. Some studies have shown an associated between 9 and 10 alleles and symptoms of anxiety.

29. Stars and their obsessions Cameron Diaz Doorknobs Jessica Alba Perfectionism Billy Bob Thornton Repetition David Beckham Symmetry Alec Baldwin Cleaning Jennifer Love Hewitt Closed Doors Leonardo Dicaprio Cracks in pavement

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