ETIOLOGY OF OCD

PRESENTER : DR. DAVIN C/P : DR. ARUNA 05/09/2012

Introduction
Obsessions: Recurrent, persistent & intrusive egodystonic thoughts, impulses or images Compulsions: Repetitive behaviors or mental acts that are executed with the goal of preventing or reducing distress or preventing some dreaded events or situations

Introduction

Lifetime prevalence = 2-3% Mean age of onset 20 yrs Bimodal distribution Almost equal distribution in adult males & females Adolescents : M > F 40% of childhood onset OCD continue into adulthood

Obsessions Contamination Pathological doubt Somatic Need for Symmetry Aggressive Sexual Blasphemous

Compulsions Checking Washing Counting Need to ask or confess Ordering & Arranging Hoarding Miscellaneous rituals

Etiology

Genetic Factors Twin and Family Studies Linkage and Association Studies

Neurobiological Factors Neuroanatomical Aspects : Abnormalities in the orbitofrontal cortex, anterior cingulate cortex, and structures of the basal ganglia and thalamus. Neurochemical Aspects

Serotonin Dopamine
Pathophysiological model :cortico striato thalamocortical
circuits

Direct pathway

Etiology

Psychological and Environmental Factors

Learning Theory Psychoanalytic Theory Role of Personality & stress Cognitive theory

Phylogenetic Model Immune factors Brain imaging studies

Animal Models
Other biological data

Genetic Factors
Twin and Family Studies

Concordance rate in monozygotic twins more than discordant dizygotic twins .(80%MZ vs 50%DZ Inyoue,1965) Heritability estimates of OCD symptoms 27 -

47%.(2005)

Increased rate of OCD in family members of OCD probands 3-5 times increased risk

Hopkins family study Prevalence of OCD in first-degree

relatives was approximately 11.7%, while the occurrence in relatives of controls was around 2.7%3-12 times risk

Genetic Factors

Markers of heterogeneity with respect to familial transmission :

Early onset (<18 yrs) Comorbidity for tics / Tourette's syndrome Hoarding

Genetic Factors

Play an important role particularly in patients with comorbid tic disorders.

Evidence supporting familial transmission :

Higher rates of OCD symptoms among family

members of Tourette Syndrome

patients(Pauls86)

Higher rates of Tourettes disorder and tics in first-degree relatives of children with

Genetic factors
Linkage studies

The first genome-wide study implicated

chromosome 9p24. (Hannah,2002)

A second study produced evidence

supporting chromosomes 3q27-28, 7p,

1q, 15q, and 6q. (2006)Obsessive

Compulsive Genetic Association Study (OCGAS)

Genetic factors
Association Studies

Association studies with candidate genes

have focused mostly on the serotonin & dopamine systems

Genes involved are : serotonin transporter serotonin 1D, 2A, and 2C receptors tryptophan hydroxylase

Genetic factors
Dopamine D2, D3, and D4 receptors, Dopamine transporter, Monoamine oxidase A, and

Catechol-o-Methyltransferase.

Studies have been equivocal, yielding

positive as well as numerous negative

results.

Major drawbackrequires detailed

Neurobiological Factors
Neuroanatomical Factors :

Have implicated abnormalities in the orbitofrontal cortex,

anterior cingulate cortex, and structures of the basal ganglia and thalamus.

These are proposed to be linked in neuroanatomical

circuits OCD symptoms are mediated by hyperactivity in

orbitofrontalsubcortical circuits, which might be due to

an imbalance between direct and indirect striato pallidal pathways .(Saxena,1998,Lacerdo,2003,Szeszko,2005)

Neuroanatomical factors

Role of Right anterolateral orbitofrontal cortex in

both OCD symptoms and symptom response noted.

Neurocognitive implications Studies of executive function in OCD patients have shown that patients have difficulty with alternation tasks and tasks that involve making choices, mediated by inappropriate activation of frontal striatal regions.(Maltby,2005)

Successful treatment of OCD symptoms may lead to normalization of frontal cortical activation.

Neuroanatomical factors

Indirect evidence implicating a role for basal ganglia dysfunction in OCD

1.

The clinical relationship between neurological insults to the basal ganglia & the subsequent development

of obsessions and compulsions.

2.

There is an association between OCD and Tourettes disorder, Sydenhams chorea, bilateral necrosis of the globus pallidus, and postencephalitic parkinsonian symptoms.

Neuroanatomical factors
Meta analysis of functional neuroimaging (Whiteside,2004) In patients with OCD, these areas:

(1) are hyperactive at rest relative to healthy control (2) become increasingly active with symptom provocation (3) no longer exhibit hyperactivity following successful treatment with SRI pharmacotherapy or cognitive-based therapy

Neurochemical factors
Serotonin

Serotonin hypothesis : OCD involves an abnormality

in the serotonin neurotransmitter system.

Supportive investigations (1) Therapeutic response of patients to chronic administration of certain types of medication(SSRIs)

(2) Measurements of central and peripheral

neurotransmitter or metabolite concentration

Neurochemical factors
(3) Pharmacologic challenge paradigms

that measure behavioural and

neuroendocrine effects produced by acute

administration of selective pharmacologic

agents (4) Measurement of receptor binding using radioligands.

Neurochemical factors
Serotonin

Exactly how the SRIs improve OCD symptoms

remains unclear

The immediate action of these agents may be to increase serotonin in the synapse, cause a cascade of changes, both presynaptically and

postsynaptically.

Relationship between high whole blood SRI levels and improvement in OCD has been noted.

Neurochemical factors
Serotonin

Decreased levels of cerebrospinal 5hydroxyindoleacetic acid(5HIAA), have been correlated with clinical improvement after clomipramine treatment.

A decrease in platelet serotonin level an indirect

measure of neuronal reuptake -- has been correlated

with clinical improvement with clomipramine.

Neurochemical factors
Serotonin

The radioligand [ 18 F]altanserin, increased density of serotonin 2A receptors in the caudate nuclei of OCD patient noted.(Adams,2005)

SPECT : Higher occupancy of the serotonin

transporter by [123-beta] citalopram was associated with better citalopram response.(Stengler,2006)

Neurochemical factors

Pharmacologic challenge studies : Role of

serotonin in the pathophysiology of OCD.

The Serotonin receptor partial agonist m chlorophenylpiperazine, and Serotonin 1B,D agonist Sumatriptan shown to increase symptoms of OCD.

The increase in obsessions can be blocked with pretreatment by the serotonin receptor antagonist metergoline or by chronic treatment with clomipramine.

Neurochemical factors
Dopamine

Evidence for dopaminergic involvement has evolved from OCD symptoms noted in basal ganglia disorders, such as Tourette's syndrome, Sydenham's chorea, and postencephalitic parkinsonism.

Therapeutic benefit of coadministration of dopamine blockers and SRIs in a subset of patients with OCD and tic disorders

role for dopamine dysfunction.

Decreased level of platelet [3H]imipramine binding and an increase in the level of sulphotransferase activity in OCD

supports hypothesis of reduced 5-HT activity and increased

dopamine transmission in OCD.

Pathophysiological models Cortico striato thalamocortical circuits

Direct pathway :An inhibitory GABAergic signal from the striatum to the internal part of the globus pallidus, which causes disinhibition of the thalamus, resulting in an excitatory effect on the prefrontal cortex. Indirect pathway :An excitatory signal to the internal part of the globus pallidus resulting from an inhibitory signal from the striatum to the external part of the globus pallidus and subthalamic nucleus causes inhibition of the thalamus, and thereby, decreased excitation of the prefrontal cortex. Net effect of the direct pathway is excitatory, the net effect of

the indirect pathway is inhibitory

Pathophysiological models
Hypothesis (Saxena et al,2000) Excessive relative activity in the direct pathway in OFC/ACC corticobasal gangliathalamocortical(CBGTC) loops may result in a positive feedback loop whereby obsessive thoughts are trapped. Why patients with OCD develop specific obsessions instead of a generalized obsessive behavior towards everything??response bias toward particular stimuli

Psychological & Environmental Factors

Learning Theory : (Hobart Mower's two-factor conditioning theory) A model based on the psychological concept of conditioning. Via classical conditioning, a neutral stimulus (or event) becomes conditioned to elicit distress because of its association with an unrelated aversive (or feared) stimulus. Fear can be conditioned to both mental events (e.g., blasphemous thoughts) and physical stimuli / behaviors (e.g., a contaminated object, items perceived as dangerous, driving, eating). Compulsions usually decrease the anxiety caused by obsessional thoughts.

Psychological & Environmental Factors

Because of the tension reducing aspect of the compulsion, this learned behaviour becomes reinforced and eventually fixed Compulsions, in turn, actually reinforce anxiety because they prevent habituation from occurring. This model has had a major influence on behavioural therapy used in treatment.

Learning Theory of OCD

Psychoanalytic Theory

Dynamic aspects of OCD first described by Sigmund Freud, who coined the term obsessional neurosis'.

The disorder was thought to result from a regression

from the Oedipal phase to the anal phase, with its characteristic ambivalence.

Freud originally suggested that obsessive symptoms result from unconscious impulses of an aggressive

or sexual nature. These impulses cause extreme

anxiety, which is avoided by the defence mechanisms.

Psychoanalytic Theory

Freud described three major psychological defence

mechanisms in OCD: isolation, undoing, and reaction

formation.

Isolation of Affect : separation of the anxiety causing idea and the aroused affect affect attaches to neutral ideas(symbolic associations)become anxiety provokingobsessions Undoing : compulsive acts,performed to prevent/undo feared consequences of obsessions Reaction formation :results in character traits exaggerated,inappropriate

Psychoanalytic Theory

OCD develops when these defences fail to contain the anxiety.

Personality traits : perfectionism, indecisiveness, and rigidity as seen in OCPD

Role of Personality

OC traits are egosyntonic

Unacceptable O & C are absent Same defense mechanisms Only 15-35% of OCD pts had premorbid OC traits

Role of Stress

Precipitate onset of Symptoms/ Worsen Symptoms

Cognitive theory
Interpretation of intrusive thoughts rather than the frequency/content Individual perceives responsibility for causing/ failing to prevent harm,obsessional patterns develop Attempts to neutralize intrusive thoughts (or obsessions) via motor or cognitive rituals, avoidance, and reassurance-seeking behavior facilitate the proliferation of anxiety Eg. Tendency to equate thought with action , exaggerated responsibility for potential untoward consequences of inaction

Phylogenetic Model

Integrates the biological factors with psychological models.

Here, behavioural inhibition and harm-assessment systems, which develop early in human phylogeny, are disrupted.

This disruption can occur at a hierarchically

primary level of biological organization, resulting in

neurobiologic disturbance, OR higher level of organization, leading to psychological

Phylogenetic Model

This might also explain why neither biological nor psychological treatments alone always lead to complete remission of symptoms

Immune factors

Association between OCD and the autoimmune disease of the basal ganglia, Sydenham's chorea has been studied. Complication of rheumatic fever is accompanied by obsessivecompulsive symptoms in over 70% of cases, (antibodies directed against the caudate)consistent with the hypothesis of basal ganglia dysfunction in OCD. A strong connection was reported between OCD/Tourette's syndrome and the B-cell antibody D8/17. Cell-mediated immune-function alterations have been reported in OCD

Immune factors
Pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) : (Leonard,Swedo ,2001) Anti-Basal ganglia Abs in serum following group A beta-hemolytic streptococcal infections (GABHS) Small sample studies of immunemodulating treatments (IV IgG and plasmapheresis) have been associated with improvements in OCD patients with suspected PANDAS

Brain imaging studies

PET : Presence of increased activity in the frontal lobes, the basal ganglia (especially the caudate nucleus), and the cingulum of patients with OCD.

Pharmacological and behavioural treatments reportedly reverse those abnormalities

Both CT and MRI studies have found decreased

sizes of caudates bilaterally.

Brain imaging studies

Brain imaging research suggests a role for the

prefrontal cortexbasal ganglia thalamic circuitry.

An evoked potential study showed enhanced processing negativity in the frontal cortex consistent

with the prefrontal hyperactivity shown in brain imaging

studies

Resting State Functional Studies 18-FDG PET sed regional cerebral metabolic rates of glucose(rCMRglucose ) in OFC & Caudate nucleus
Significant reductions after treatment

Animal Models

May provide an important window on treatment efficacy and

the influence of environmental and genetic factors. Inherent difficulties in studying cognitive aspects of OCDfocus on repetitive motor actions that are similar to compulsions

Behavioural models : based on naturally occurring behaviours. Comprise barbering and marble burying in mice, along with signal attenuation in mice Based on hypothesis that compulsive behaviours result from a deficit in the feedback associated with the performance of normal goal-directed responses.

Animal Models

Two additional animal models in OCD: genetic models & pharmacological models. Genetic model include the induction of excessive grooming by disruption of Hoxb8 ,a transcription factor involved in development; as well as neat repetitive chewing associated with knockout of the 5-HT2c receptor

Pharmacological model include indecision induced by 5-HT agonists, as well as compulsive checking induced by the dopamine D2/D3 agonist

quinpirole.

Other biological data

Sleep electroencephalography and

neuroendocrine studies :

Decreased rapid eye movement latency

Non-suppression on the
dexamethasone suppression test

Decreased growth hormone secretion

with clonidine infusions

OC Spectrum Disorders

Model suggests that many conditions overlap with OCD in

symptomatic profile demographics, family history neurobiology, comorbidity clinical course and response to various pharmacotherapies

OC spectrum disorders

Tourette's Syndrome Impulse Control Disorders Eating Disorders Autism Asperger's Syndrome OCPD Somatization Disorder BDD ,Olfactory reference syndrome Hypochondriasis Paraphilias & non-paraphilic sexual addictions

Conclusion

Ongoing research is expected to elucidate

further role of serotonin and the possible role

of other neurotransmitters in OCD.

Future directions in the genetics of OCD includes whole-genome gene expression analysis using microarrays and analysis of

copy number variation, epigenetic factors

such as DNA methylation.

THANK YOU