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 aren’t 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
As Good as it Gets

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 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.

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 don’t relieve the obsessions entirely and it results in a vicious cycle that doesn’t end. Results in dermatitis, skin lesions, hair loss.

7. OCD v. OCPD OCD CHARACTERISTICS OCPD CHARACTERISTICS
Thoughts, images, idea that won’t go away and behaviors that you must carry out over and over again
An excessive need for perfectionism and control over all aspects of your environment
Distressing enough to cause you to try to get rid of the obsessions with other thoughts or actions, like compulsions.
Preoccupation with details, rules, lists, order or organization to the extent that you often forget the major point of the activity
Accepted as coming from your own mind, but often feel impossible to control.
An inability to get rid of items that no longer have value
Unrealistic solutions to the problems they are supposed to prevent.
Excessive devotion to work at the expense of time spent with your friends or family
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 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 complications

13. Gene studies Catechol-O-methyltransferase Monoamine oxidase A (MAO-A)
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.

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

15. Glutamergic concentrations increased in CSF, orbitofrontal cortex, and the striatum, but smaller in anterior cingulate cortex
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 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.

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.

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.

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 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 Genotyping Data analysis 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

23. Y-BOCS 0-7 Subclinical 8-15 Mild 16-23 Moderate 24-31 Severe 32-40
Extreme
Y-BOCS
1.Time Spent on Obsessions
0 hr/day
0-1 hrs/day
1-3 hrs/day
3-8 hrs/day
8+ hrs/day
Score 1 2 3 4
2. Interference from Obsessions
None
Mild
Definite, but Manageable
Substantial Impairment
Incapacitating
3. Distress from Obsessions
Severe
Near Constant, Disabling
4. Resistance to Obsessions
Always Resist
Much Resistance
Some resistance
Often Yields
Completely Yields
5. Control Over Obsessions
Complete Control
Much Control
Some Control
Little Control
No Control

24. results Healthy controls Psychiatric controls OCD patients % males
59.1%
40.0%
44.3%
Mean age
36.2
40.3
39.7
Y-BOCS global scale
22.7
Obsession subscale
11.3
Compulsions subscale
11.6

25. Results Genotypesa,b (%) N 9/9 9/10 9/12 10/10 10/12 12/12 Healthy
controls
406 (100.0)
1 (0.2)
4 (1.0)
5 (1.2)
50 (12.3)
170 (41.9)
176 (43.3)
Psychiatric
578 (100.0)
2 (0.3)
6 (1.0)
7 (1.2)
72 (12.5)
240 (41.5)
251 (43.4)
OCD
patients
97 (100.0)
0 (0)
4 (4.1)
46 (47.4)
47 (48.5)
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%))

26. Allele 12 carriers OCD 93/97 (95.9%) Healthy 351/406 (86.5%)
93/ (95.9%)
Healthy
351/406 (86.5%)
Psychiatric
498/578 (86.2%)
Both significantly different

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

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.

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