Etiology of OCD
Transcript of Etiology of OCD
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
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 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.
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 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.
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