Etiology of OCD

CHAIRPERSON : DR ANUPAMA
PRESENTER : DR CHANDINI

Introduction
Obsessions:
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

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
Indirect pathway

Etiology
Psychological and Environmental Factors

Learning Theory
Psychoanalytic Theory
Role of Personality & stress

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 .

Heritability estimates of OCD symptoms ranging from

27 to 47%.
Increased rate of OCD in family members of OCD

probands.
1st degree relatives : 312 times ed risk

Genetic Factors

Twin and Family Studies

Genetic factors play an important role particularly in

patients with comorbid tic disorder.

Evidence supporting familial transmission are
higher rates of OCD symptoms among family members

of TS patients
higher rates of Tourettes disorder and tics in first-

degree relatives of children with OCD.

Genetic factors
Linkage and Association Studies
Association studies with candidate genes have focused mostly

on the serotonin and dopamine systems

Genes involved are serotonin transporter, serotonin 1D, 2A, and

2C receptors, tryptophan hydroxylase, dopamine D2, D3, and D4

receptors, dopamine transporter, monoamine oxidase A, and
catechol-o-Methyltransferase.
These studies have been equivocal results, yielding positive as well

as numerous negative results.

Genetic factors
Linkage studies
The first genome-wide study implicated

chromosome 9p24 .
A second study produced evidence supporting

chromosomes 3q, 7p, 1q, 15q, and 6q.

Glutamate transporter gene, SLC1A1.

Neurobiological Factors

Neuroanatomical :
Have implicated abnormalities in the orbitofrontal cortex,

anterior cingulate cortex, and structures of the basal ganglia and

thalamus.
These structures 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 striatopallidal pathways ( Saxena et al. ( 1998 ).

Neuroanatomical :
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.
Successful treatment of OCD symptoms may lead to

normalization of frontal cortical activation.

mical

Indirect evidence implicating a role for basal ganglia

dysfunction in OCD,
lies in the clinical relationship between neurological insults to

the basal ganglia and the subsequent development of

obsessions and compulsions.
There is an association between OCD and Tourettes disorder,

Sydenhams chorea, bilateral necrosis of the globus pallidus,

and postencephalitic parkinsonian symptoms.

Neurochemical factors
Serotonin
Serotonin hypothesis : OCD involves an abnormality in the serotonin

neurotransmitter system.
(1) Therapeutic response of patients to chronic administration of certain

types of medication
(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.

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.
High whole blood SRI levels and improvement in OCD

noted.

Neurochemical factors :
Serotonin
Decreased levels of cerebrospinal 5-hydroxyindoleacetic

acid, 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.

hemical factors
Serotonin
The radioligand [ 18 F]altanserin, increased density of

serotonin 2A receptors in the caudate nuclei of OCD patient

noted.
SPECT : higher occupancy of the serotonin transporter by

[123-beta] citalopram was associated with better citalopram

response.

Pharmacologic challenge studies : role of serotonin in

the pathophysiology of OCD.

The serotonin receptor partial agonist m

-chlorophenylpiperazine, and serotonin 1B agonist

sumatriptan have been 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.
The therapeutic benefit of coadministration of dopamine blockers

and SRIs in a subset of patients with OCD and tic disorders .

Decreased level of platelet [3H]imipramine binding and a increase

in the level of sulphotransferase activity in OCD noted. This further

supports hypothesis of reduced 5-HT activity and increased
dopamine transmission in OCD.

hysiological models
striato thalamocortical circuits
A direct pathway involves 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.

An indirect pathway involves 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.
This in turn causes inhibition of the thalamus, and thereby, decreased

excitation of the prefrontal cortex.

Psychological and Environmental Factors

Learning Theory :
A model based on the psychological concept of conditioning.
Compulsions usually decrease the anxiety caused by
obsessional thoughts.
Compulsion becomes a conditioned response to anxiety.
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.
Learning theory model of OCD has had a major influence on
behavioural therapy used in treatment.

Obsession

Learning theory of OCD

Psychoanalytic Theory
The dynamic aspects of OCD were 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.
According to the psychoanalytical formulation, 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 the onset of Symptoms/ Worsen Symptoms

Phylogenetic Model
Integrates the biological factors with psychological models.
In this model, 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 at a

hierarchically higher level of organization, leading to psychological
disturbances.
This model 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 noted.

Complication of rheumatic fever is accompanied by
obsessivecompulsive symptoms in over 70 per cent of
cases, antibodies directed against the caudate. This is
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
PANDAS : Anti-Basal ganglia abs in serum

imaging studies

Positron emission tomography has demonstrated the

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 magnetic resonance imaging studies

have found decreased sizes of caudates bilaterally.

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 rCMRglucose in OFC & Caudate nucleus

Significant reductions after Rx

SPECT sed rCBF in Caudate

Animal Models

Animal models may provide an important window on treatment

efficacy and the influence of environmental and genetic factors.

Behavioural models : animal models based on naturally

occurring behaviours.
Behavioural animal models comprise barbering and marble

burying in mice, along with signal attenuation in mice

Its based on the 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 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

Tourette's Syndrome
Impulse Control Disorders
Eating Disorders
Autism
Asperger's Syndrome
OCPD
Somatization Disorder
BDD
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!