Etiology of OCD

transcript

ETIOLOGY OF OCDPRESENTER : DR. DAVINC/P : DR. ARUNA05/09/2012

IntroductionObsessions:Recurrent, persistent & intrusive ego-

dystonic 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

IntroductionLifetime prevalence = 2-3%Mean age of onset – 20 yrsBimodal distributionAlmost equal distribution in adult

males & femalesAdolescents : M > F40% of childhood onset OCD continue

into adulthood

ObsessionsContaminationPathological doubtSomaticNeed for SymmetryAggressiveSexual Blasphemous

CompulsionsCheckingWashingCountingNeed to ask or

confessOrdering &

ArrangingHoardingMiscellaneous

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 Indirect 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 FactorsTwin 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 FactorsMarkers 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(Pauls’86)

Higher rates of Tourette’s disorder and tics in

first-degree relatives of children with OCD.

(Leonard’92)

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)

Glutamate transporter gene, SLC1A19p24

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

understanding of pathophysiology of disease

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

orbitofrontal–subcortical 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

Tourette’s disorder, Sydenham’s chorea,

bilateral necrosis of the globus pallidus, and

postencephalitic parkinsonian symptoms.

Neuroanatomical factorsMeta 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

◦(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.

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.

Serotonin

Decreased levels of cerebrospinal 5-

hydroxyindoleacetic 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.

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)

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 factorsDopamine

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 modelsCortico 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 modelsHypothesis (Saxena et al,2000)Excessive relative activity in the direct

pathway in OFC/ACC cortico—basal ganglia—thalamocortical(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.

Compulsion becomes a conditioned response to anxiety.

Psychological & Environmental FactorsBecause 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 TheoryDynamic 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 theoryInterpretation 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 disturbances.

Phylogenetic ModelThis might also explain why

neither biological nor psychological treatments alone always lead to complete remission of symptoms

Immune factorsAssociation between OCD and the

autoimmune disease of the basal ganglia, Sydenham's chorea has been studied.

Complication of rheumatic fever is accompanied by obsessive–compulsive 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 immune-modulating treatments (IV IgG and plasmapheresis) have been associated with improvements in OCD patients with suspected PANDAS

Brain imaging studiesPET :

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

cortex–basal 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

• SPECT – ↓sed rCBF in Caudate

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 ModelsTwo 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 dataSleep 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 DisordersModel suggests that many

conditions overlap with OCD in ◦symptomatic profile ◦demographics, family history◦neurobiology, comorbidity◦clinical course and ◦response to various

pharmacotherapies

OC spectrum disordersTourette's SyndromeImpulse Control DisordersEating DisordersAutismAsperger's SyndromeOCPDSomatization DisorderBDD ,Olfactory reference syndromeHypochondriasisParaphilias & 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

Etiology of OCD

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