By-Sadaf SiddiquiModerator-Prof.S.A.Azmi

Etiopathogenesis of Obsessive Compulsive Disorder

Introduction

It is defined as occurring of unwanted and intrusive thoughts or distressing images which

are accompanied by compulsive behaviors to neutralize the obsessive thoughts.

Up to 1980 considered a treatment resistant chronic condition of psychological origin.

The observation that CLOMIPRAMINE (a TCA with serotogenic profile) is effective was a major breakthrough.

HISTORYPrehistoric times-possessed by devil and exorcism as

treatment.

Obsessions and hand-washing rituals resulting from guilt were immortalized in the 17th century in Shakespeare's character, Lady Macbeth.

With time, the explanation of obsessions and compulsions moved from a religious view to a medical one.

OCD was first described in the psychiatric literature by Esquirol in 1838, and by the end of the 19th century, it was generally regarded as a manifestation of melancholy or depression.

By the beginning of the 20th century, theories of obsessive-compulsive neurosis shifted towards psychological explanations.

Pierre Janet reported successful treatment of rituals with behavioral techniques; but with Sigmund Freud's writings on psychoanalysis of the Rat Man, OCD came to be conceptualized as resulting from unconscious conflicts and from the isolation of thoughts and behaviors from their emotional antecedents.

With the rise of behavior therapy in the 1950s, learning theories which had proved useful in dealing with phobias were applied to OCD.

Different theories led to different treatment Phlebotomy.Laxative and purgatives.

Henry Maudsley (1895) - opium and morphine, to be taken three times a day,

Adding low doses of arsenic along with these narcotics could be helpful.

As the twenty-first century begins, advances in pharmacology, neuroanatomy, neurophysiology and learning theory have allowed us to reach a more therapeutically useful conceptualization of OCD.

EPIDEMIOLOGYOnce believed to be rare, OCD was found to have a lifetime

prevalence of 2.5% in the Epidemiological Catchment Area study.[1]

Lifetime prevalence are generally in the range of 1.7-4%.

The incidence of OCD is higher in dermatology patients and cosmetic surgery patients

1.Karno M, Golding JM, Sorenson SB, Burnam MA. The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry. Dec 1988;45(12):1094-9.

Equal across sex and culture.

Prevalence among adult and children same

67% have MADD ,25% have social phobias.

25% chronic schizophrenic have OCD symptoms.(poor prognosis).

British Epidemiology found a gender ratio of 1.4 to 1 (women to men).

Torres et al., 2006

Other co-morbid- panic disorder ,eating disorder ,alcohol use disorder.

Relationship with OCPD is debatable.(OCPD) is not a prominent risk factor for developing OCD

CLINICAL FEATURESCharacterized by obsession, compulsion or both(75%)

Obsessional thoughts are- ideas, images or impulses that enter the individual's mind again & again in a stereotyped form.

Are invariably distressing ( they are violent or obscene, or simply because they are perceived as senseless) .

The sufferer often tries, unsuccessfully, to resist them.

Are, recognized as the individual's own thoughts, even though they are involuntary and often repugnant

Compulsive acts are stereotyped behaviors that are repeated again and again.

Are not inherently enjoyable, nor do they result in the completion of inherently useful tasks

Individual often views them as preventing some objectively unlikely event ,often involving harm to or caused by himself or herself.

Usually, this behaviour is recognized by the individual as pointless or ineffectual and repeated attempts are made to resist it;( in very long-standing cases, resistance may be minimal).

It was classified as anxiety disorder in DSM-4.

BUT

The DSM-5 chapter on anxiety disorder no longer includes obsessive-compulsive disorder (which is included with the obsessive-compulsive and related disorders).

This is also reflected in the ICD 10 classification which lists OCD as a separate entity from anxiety disorder .

Sims textbook of psychopathology states that:

“Certainly OCD is not an anxiety disorder. Isolated obsession or obsessive compulsive disorder may occur with or without anxiety, with or without depression and with or without personality disorder .It is a distinct and separate phenomenon”

ETIOLOGY

CAUSAL FACTORS

Psychosocial Causal factors

Cognitive Causal

factors

Biological Causal factors

Behavioral factors

BIOLOGICAL CAUSAL FACTORS

NEUROTRANSMITTERSSEROTONIN

Dysregulation of serotogenic system

Measurng the level of 5HIAA( a measure of serotonic turn over) in CSF

Affinities of platelet serotonin binding sites to radiolabled imipramine which binds to serotonin reuptake site and reported variable finding of these measures in OCD.

Some study - decreased level of 5HIAA after treatment with clomipramine and normalization of platelet transporter after treatment with clomipramine.

Although research suggests that alteration of brain serotonergic systems may be one mechanism through which SSRIs have their therapeutic effects, there is no evidence of baseline serotonergic dysfunction in OCD patients.

DOPAMINESome forms of OCD are etiologic related to TS. TS appears

to be predominantly dopaminergically mediated, as evidenced by the well-documented clinical response to haloperidol and other dopamine antagonists.

OCD patients with comorbid tic disorder or TS are usually resistant to conventional pharmacotherapy with proserotonergic compounds, and may benefit from adjuvant treatment with dopamine (DA) or DA/5-HT blockers .

This suggests that there is an involvement of DA in at least some OCD patients.

The serotonin and dopamine systems interact extensively, particularly in the basal ganglia, an area that has been implicated in the pathogenesis of obsessive-compulsive phenomenology by several studies.

GLUTAMATEAttention has also been focused on glutamatergic

abnormalities and possible glutamatergic treatments for OCD.[1,2]

Although modulated by serotonin and other neurotransmitters, the synapses in the cortico-striato-thalamo-cortical circuits thought to be centrally involved in the pathology of OCD principally employ the neurotransmitters glutamate and gamma-aminobutyric acid (GABA)

Pittenger C, Krystal JH, Coric V. Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive-compulsive disorder. NeuroRx.

Wu K, Hanna GL, Rosenberg DR, Arnold PD. The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder. Pharmacol Biochem Behav.

CSF glutamate concentration was significantly greater in OCD patients as compared with control subjects

Indeed, glutamate and serotonin interact on a number of levels in the frontal striatal circuit.

However, the persistence of symptoms despite targeting serotonin and glutamate pharmacologically indicates limits of the serotonin and glutamate hypothesis of OCD.

Clearly, a solitary neurochemical hypothesis of a psychiatric disorder is limited, as neurotransmitters do not operate in a vacuum.

COPPER AND OCDElevated copper and corresponding changes in dopamine

may result in increased number or sensitivity of post-synaptic dopamine receptors in certain areas of the brain.

Association between ceruloplasmin and OCD might be examined through ceruloplasmin and copper relationship, since there is now growing evidence that the dopamine system may be involved also in the pathophysiology of OCD

However, association between ceruloplasmin and OCD may be explained via copper and serotonin relationship, too.

High ceruloplasmin levels are associated with obsessive compulsive disorder: a case control study,Behav Brain Funct. 2008; 4: 52

THE AUTOIMMUNE HYPOTHESISAllen, Leonard, and Swedo first proposed the intriguing

autoimmune hypothesis of OCD after a thoughtful review of the literature.

An association was drawn between infection with group A -hemolytic Streptococcus (as well as other agents, including viruses), and the onset or the exacerbation of OCD in some children

10 to 30% of patient of rheumatic fever develop synderham’s chorea and show symptoms of ocd.

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS).

1. PANDAS form of OCD is rapid in onset.

2. Occurs in close association with a strep infection.

3. Usually have involuntary movements of the arms, legs and face

Fewer recent studies reports the herpes simplex virus as the apparent precipitating infectious event.

Increasing evidence linking streptococcal infection to OCD in children suggests that microbiomics may prove an important research area for understanding and treating mental disorders.

GENETIC FACTOR

OCD has significant genetic component .

Three to five times higher probability of OCD in relatives of probands with OCD.

Concordance for OCD in twins is significantly higher for monozygotic twins than for dizygotic twins

Twin studies have supported strong heritability for OCD, with a genetic influence of 45-65% in studies in children and 27-47% in adults.[1]

Monozygotic twins may be strikingly concordant for OCD (80-87%), compared with 47-50% concordance in dizygotic twins.[2]

Several genetic studies have supported linkages to a variety of serotonergic, dopaminergic, and glutamatergic genes

1.van Grootheest DS, Cath DC, Beekman AT, Boomsma DI. Twin studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet. Oct 2005;8(5):450-8.

2. Carey G, Gottesman I. Twin and family studies of anxiety, phobic, and obsessive disorders. In: Klein DF, Rabkin JG. Anxiety: New Research and Changing Concepts. New York: Raven Press; 2000.

BRAIN IMAGING STUDIESCurrent research has gravitated toward structural and

functional neuroimaging

These technological innovations have provided a better understanding of the neuroanatomical risk factors of OCD

DAMAGE IN BASAL GANGLIAScientists proposed that any damage to the basal ganglia

might result in the OCD symptoms.

The significance of identifying the basal ganglia is that it shows that physical damage to a brain structure results in a neuropsychological (mental/emotional) condition.

CHANGES IN BRAIN ACTIVITYModern brain imaging techniques have shown that people

with OCD have more than usual activity in three areas of the brain. These are:

1. orbital frontal cortex,

2. cingulated cortex and

3. caudate nucleus of the basal ganglia

The OFC and ACC are intricately connected to the basal ganglia via the cortico—basal ganglia—thalamocortical (CBGTC) loops.

CT AND MRI have shown decreased size of caudate nucleus bilaterally.

PET scan has shown increased activity in the frontal lobe, caudate nucleus, and the cingulum of patients

1.The caudate nucleus,specific brain cells in basal gangliaThis area of the brain acts as a filter for thoughts coming in

from other areas.

The caudate nucleus is also considered to be important in managing habitual and repetitive behaviors.

2.The prefrontal orbital cortex located in front area of brainThe level of activity in the prefrontal orbital cortex is

believed to affect appropriate social behavior.

Lowered activity or damage in this region is linked to feeling uninhibited, making bad judgments and feeling a lack of guilt.

More activity may therefore cause more worry about social concerns

3.The cingulate gyrus in the centre of brainThe cingulate gyrus is believed to contribute the emotional

response to obsessive thoughts. This area of the brain tells you to perform compulsions to relieve anxiety.

This region is highly interconnected to the prefrontal orbital cortex and the basal ganglia via a number of brain cell pathways

Current theories suggests OCD the result of an imbalance between “direct” & “indirect” pathways.

Direct pathways run from the cortex to the striatum, then to the GPi and SNr, then to the thalamus, and finally back to the cortex.

The indirect pathways are described as running from the cortex to the striatum, then to the GPe, the STN, the GPi and SNr, then thalamus, finally back TO cortex

While the net effect of the direct pathway is excitatory, the net effect of the indirect pathway is inhibitory

OCD may result from excessive neural tone in the direct pathway relative to the indirect pathway results in a positive feedback loop whereby obsessive thoughts are trapped.

There is a broad consensus for widely distributed abnormalities involving fronto-striatal circuits in OCD.[1]

Moreover, reversal of orbitofrontal cortex (OFC) dysfunction after treatment has also been reported.[2]

1. Jenike MA, Rauch SL, Cummings JL, Savage CR, Goodman WK. Recent developments in neurobiology of obsessive-compulsive disorder. J Clin Psychiatry 1996;57:492-503.

2.Swedo SE, Pietrini P, Leonard HL, Schapiro MB, Rettew DC, Goldberger EL, et al. Cerebral glucose metabolism in childhood-onset obsessive compulsive disorder. Revisualization during pharmacotherapy. ‑Arch Gen Psychiatry. 1992;49:690-4.

Organic insult to these regions can produce obsessive and compulsive symptoms.

Results of neurosurgical treatment of OCD strongly support this hypothesis.

Cingulotomy- interrupts this loop at the anterior cingulate cortex.

Anterior capsulotomy -lesions within the anterior limb of the internal capsules.

subcaudate tractotomy (lesions in the substantia innominata, just under the head of the caudate nucleus)

PSYCHOSOCIAL CAUSAL FACTORS

Ego marshalled certain defenses: 1. INTELLECTUALIZATION AND ISOLATION 2. UNDOING 3. REACTION FORMATION.

The imperfect success of these defenses gave rise to OCD symptoms: (anxiety; preoccupation with dirt or germs or moral questions; and, fears of acting on unacceptable impulses.)

Psychoanalytic factor (Freud‘) patient's mind responded mal adaptively to

conflicts between unacceptable, unconscious sexual or aggressive id and the demands of conscience and reality.

It regressed to concerns with control and to modes of

thinking characteristic of the anal-sadistic stage of :

AMBIVALENCE- which produced doubting, MAGICAL THINKING -superstitious compulsive acts

BEHAVIORAL FACTORSMowrer’s two process theory of avoidance learning(1947) :

According to this theory, neutral stimuli become associated with frightening thoughts or experience through classical conditioning and come to elicit anxiety.

EXAMPLE

This model predicts, then, that exposure to feared objects or situations should be useful in treating OCD if the exposure is followed prevention of the rituals, enabling the person to see that the anxiety will subside naturally in time without the ritual.

This indeed the cure of the most effective form of Behavioral therapy for OCD

Classical experiment conducted by Rachman and HodgsonThey found that for most people with OCD, exposure to a

situation that provoked their obsession did indeed produce distress, which would continue for a moderate amount of time and then gradually dissipate.

Obsessive-Compulsive Disorder: Theory, Research, and Treatment edited by Richard P. Swinson, Martin M. Antony, S. Rachman, Margaret A. Richte

Environmental factorA number of environmental factors may contribute to the

onset and maintenance of OCD.

Although some research suggests no link between negative life events and OCD, there are many reports in which childhood OCD has been triggered by a specific, often traumatic, event, including: the death of a loved one; the loss of a pet; a divorce in the family; a change in school etc.

Furthermore, a recent study indicated that one to two years prior to the onset of symptoms, both children and adults who develop OCD experience more negative life events than controls.

Taken together, these results suggest that stress or trauma can play a role in the development of OCD among certain individuals.

Injuries also have been associated with OCD.

The results of one study, in which 80 children and adolescents who suffered a traumatic brain injury were examined, indicated that almost 30% of the young people had new onset obsessive compulsive symptoms within one year after the serious injury

In a study, Berthier and colleagues (2001) assessed 10 referred patients who had developed OCD after TBI and found peculiar symptoms of obsessive slowness in 3 cases and compulsive exercise practice in 3 cases also (1 patient had both symptoms).

Grados states that obsessive-compulsive phenomena following brain injury are probably more common than generally expected,most symptoms have an early onset.(1)

1. Grados M. Obsessive-compulsive disorder after traumatic brain injury. Int Rev Psychiatry 2003;15:350-358

COGNITIVE CAUSAL FACTORS

Many cognitive theorists believe that individuals with OCD have faulty or dysfunctional beliefs, and that it is their misinterpretation of intrusive thoughts that leads to the creation of obsessions and compulsions.

According to the cognitive model of OCD, everyone experiences intrusive thoughts. People with OCD, however, misinterpret these thoughts as being very important, personally significant, revealing about one’s character, or having catastrophic consequences

The Obsessive-Compulsive Cognitions Working Group, an international group of researchers who have proposed that the onset and maintenance of OCD are associated with maladaptive interpretations of cognitive intrusions, has identified six types of dysfunctional beliefs associated with OCD:

1.Inflated sense of Responsibility

A belief that one has the ability to cause and/or is responsible for preventing negative outcomes;

This sense of inflated responsibility for the harm they may cause adds to the “perceived awe fullness of any harmful consequences and may motivate compulsive behaviors like washing and checking to reduce the likelihood of the event.

2. Over importance of thoughts (also known as thought-action fusion): the belief that having a bad thought can influence the probability of the occurrence of a negative event or that having a bad thought (e.g., about doing something) is morally equivalent to actually doing it.

3. Control of thoughts: a belief that it is both essential and possible to have total control over one’s own thoughts

4. Overestimation of threat: a belief that negative events are very probable and that they will be particularly bad;

5. Perfectionism: a belief that one cannot make mistakes and that imperfection is unacceptable; and

6. Intolerance for uncertainty: a belief that it is essential and possible to know, without a doubt, that negative events won’t happen.

People with normal and abnormal obsessions differ primarily in the degree to which the resist their own thoughts.

The factor contributing to the frequency of obsessive thoughts and negative moods is the attempt to suppress them.

CONCLUSIONOCD is a chronic and delibitating condition.

Understanding its aetiology and its pathophysiology will be helpful in designing treatment which are directed towards pathology.

Brain scans of people with OCD have shown that they have different patterns of brain activity than people without OCD and that abnormal functioning of circuitry within a certain part of the brain (striatum) may cause the disorder.

Abnormalities in other parts of the brain and an imbalance of brain chemicals, especially serotonin, may also contribute to OCD.

Some experts believe that a problem related to streptococcal infections, such as streptococcal throat infection and scarlet fever can suddenly bring on the disorder or make its symptoms worse in some children.

In sum, although the definitive cause or causes of OCD have not yet been identified, research continually produces new evidence that hopefully will lead to more answers.

It is likely, however, that a delicate interplay between various risk factors over time is responsible for the onset and maintenance of OCD.

REFERENCES Kaplan and saddocks synopsis of psychiatry-eleventh edition

kaplan and sadock's comprehensive textbook of psychiatry9th edition

Karno M, Golding JM, Sorenson SB, Burnam MA. The epidemiology of obsessive-compulsive disorder in five US communities. Arch Gen Psychiatry. Dec 1988;45(12):1094-9.

Obsessive-Compulsive Disorder: Theory, Research, and Treatment edited by Richard P. Swinson, Martin M. Antony, S. Rachman, Margaret A. Richte

.van Grootheest DS, Cath DC, Beekman AT, Boomsma DI. Twin studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet. Oct 2005;8(5):450-8.

Carey G, Gottesman I. Twin and family studies of anxiety, phobic, and obsessive disorders. In: Klein DF, Rabkin JG. Anxiety: New Research and Changing Concepts. New York: Raven Press; 2000

Thank you