Obsessivecompulsive disorder

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Obsessive-compulsive disorder

• Symptoms
• Neuropathology
• Treatments
• Causes

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OCD

• Obsessions persistent thoughts
• Compulsions persistent behaviors
• Individual is aware that the behavior or
  obsession is unreasonable or excessive

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Heterogeneity

• folie du doute (madness of doubt) and delire
  du toucher (delusion of touch) (Flaret, 1869)
• Checkers vs. washers
• Continuing challenge

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OCD

• ONSET
• males, childhood, often associated with tic
  disorders
• Females, puberty and early adulthood
• 3.3 million adults in the United States (2-3 )
• Cross-cultural studies find symptoms are similar
  in various racial and ethnic groups

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Associated Disorders

• Associated Disorders
• Trichotillomania
• Onychophagia
• Co-morbidity
• Depression
• Tourettes
• body dysmorphic disorder
• Eating disorders

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Neuropathology

• Imaging studies
• Structural increases or decreases in size of the
  orbitofrontal cortex, striatum, or thalamus
• Increased activity in caudate, orbitofrontal
  cortex, cingulate cortex
• Dysfunction of cortical/basal ganglia loop
• Huntingtons, Tourettes, maybe Parkinsons,
  Sydenhams chorea also exhibit OCD
• Remember craving and compulsive drug-taking?

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Structural alterations
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Reduced left orbitofrontal cortex in OCD patients
correlates with severity of symptoms
Kang, et al., 2004, J Neuropsychiatry Clin
Neurosci
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Alterations in the anterior cingulate and globus
pallidus
Drug-naïve patients
Szeszko et al., Am J Psychiatry 2004
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Altered white matter in the anterior cingulate
cortex
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Altered function of the cortico-striatal-thalamo-c
ortical loop
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Overactivity of prefrontal-basal ganglia loops
Baxter et al., 1998
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Increased activity in the thalamus
Saxena et al., Biol Psychiatry, 2001
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At rest

• Increased activity of the orbitofrontal cortex
• Increased activity of the cingulate cortex
• Increased activity in the caudate nucleus
• Increased activity in the thalamus

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Hyperactivity is exacerbated during symptom
provocation

• fMRI
• Contaminated items vs neutral items
• Handling of contaminated items exacerbated
  activity in the prefrontal cortical areas
  (anterior cingulate, orbitofrontal), the basal
  ganglia, and the amygdala

Breiter et al (1996)
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Activation in the orbitofrontal cortex and
amygdala during symptom provocation
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Subtypes of OCD

• Symmetry/ordering
• Hoarding
• Contamination/cleaning
• Obsessions/checking

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Mataix-Cols et al., 2004
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Washing
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Checking
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Hoarding
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There may be distinct neural pathological
patterns associated with different symptom
dimensions

• Cleaning may be more related to emotional
  processing
• Checking may be more related to dysfunction in
  attention and inhibitory control

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Injury-induced OCD
12-year-old female, struck by car Max et al. 1995
Chako et al., 2004
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Overactivity of cortico-basal ganglia

• Baseline
• During provocation of symptoms
• Specific pattern may depend on OCD type
• OCD can be caused by damage to the basal ganglia
• OCD occurs in other prefrontal-basal ganglia
  disorders

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Alterations in other cognitive/emotional processes
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Activation of the anterior cingulate when errors
are committed on a cognitive task in OCD patients
Ursu et al., Psychol Sci, 2003
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Cognitive Alterations

• Memory (working, etc)
• Set shifting
• Response inhibition (more errors of commission)

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Dysfunction of inhibitory processing
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Altered Direct/Indirect Pathway Balance

• Overactivity of the DIRECT LOOP

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Dysfunction of habit formation?
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Neurochemical alterations
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Serotonin hypothesis

• OCD is related to serotonin dysfunction
• Pharmacological treatments for OCD
• Clomipramine
• Fluoxetine (Prozac)
• Paroxetine (Paxil)
• Serotonin Antagonists exacerbate symptoms
• Data on serotonergic measures in OCD patients
  have been conflicting

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Serotonin modulates the prefrontal cortex,
striatum, and thalamus
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Symptoms can be exacerbated by increasing 5-HT
function

• Zohar et al (1987)
• Double-blind, placebo-controlled, random
  assignment study.
• Twelve patients and 20 controls were given a
  single dose of 0.5 mg of mcPP, a serotonergic
  agonist that binds 5-HT receptors.
• Following mCPP, patients with OCD experienced a
  transient but marked excaberation of OCD
  symptoms.
• No significant change in OCD patients who
  received placebo.
• Compared with healthy controls, patients
  exhibited greater behavioral changes after mCPP.

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• Bell et. al. (2001)
• Fourteen patients with OCD ingested a tryptophan
  drink to lower the serotonin level in their
  brains.
• Patients were subjected to stressful situations
  specific to their answers on a survey asking what
  types of situations they typically try to avoid
  in every day life.
• Compared to the control drink, the tryptophan
  drink led to a significant increase in the
  subjective unit of distress, as well as
  compulsive urges and rituals.
• The results of this study suggest that Acute
  Tryptophan Depletion may reverse the
  effectiveness of anti-OCD treatments, leading to
  a transient worsening of OCD symptoms, especially
  when patients have to face specific challenging
  situations they would rather avoid.
• Not always replicated (Barr, 2003)

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Evidence of 5-HT dysfunction

• Increased 5-HT2A receptors in caudate which are
  normalized after SSRI treatment (Adams et al.,
  2005, Int J Neuropsychopharmacol)
• Alterations in serotonin transporters

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Increased midbrain serotonin transporter binding
sites
Limitations Type of marker used Previous use of
psychotropic drugs Age and sex (menstrual
cycle) Co-morbidity What dysfunction does this
reflect?
Pogarell et al. 2003
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No difference in serotonin transporter binding
No depression co-morbidity
Simpson et al., Biol Psychiatr. 2003
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Reduced 5-HT transporters in midbrain
Stengler-Wenzke et al., Eur Arch Psychiatr Clin
Neurosci, 2004
No depression No psychotropic drug use for 6
months
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Dopamine

• Up to 40 of OCD patients do not respond to
  SSRIs.
• Dopamine agonists induce stereotyped movement in
  humans and animals
• Dopamine agonists can exacerbate OCD symptoms
• Co-morbidity of Tourettes and OCD (up to 90 of
  individuals with Tourettes have OCD)
• Adjunctive therapy with conventional
  antipsychotics add to reduction of OCD symptoms
  in individuals treated with SSRIs

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Increases in striatal dopamine transporter
binding in OCD patients
Kim et al, 2003
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Increased striatal DA transporters in
psychotropic-naïve OCD patients
Van der Wee, et al., Am J Psychiatry 2004
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Alterations in striatal D2 receptors
Denys, et al. 2004 Biol Psychaitry
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Treatments
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Treatments

• SSRIs
• Adjunctive antipsychotics (dopamine antagonists)
• Behavior therapy
• Psychosurgery
• Effective treatment, pharmacologic or behavioral
  therapy, normalizes activity

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Normalization of striatal activity with SSRI
treatment

Paroxetine

Saxena et al., 2002
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Normalization of orbitofrontal cortex activation
Saxena et al., 1999
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Behavioral treatment is effective
Limitations no controls
Nakatani, et al. 2003
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PET scans of OCD patients
OCD, pre-behavior therapy
OCD, pre-drug treatment
OCD, post-behavior therapy
OCD, post-drug treatment
Behavior- or drug therapy produce similar
reductions in the activity of the basal ganglia
From Baxter, et al., 1992, Arch Gen Psychiat, 49
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Either drug treatment or behavioral treatment
normalizes brain activity

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Surgical treatments

• Destroy connections between the frontal lobe and
  basal ganglia/limbic structures
• Cingulotomy

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Psychosurgeries
Cingulotomy
Probes are inserted through the skull
into cingulum.
By leading the tips of probes, the tissue is
burned.
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Psychosurgery Success

• 27 definite improvement, 27 probably
  improvement, 46 no improvement (Baer et al,
  1995)
• 32 definite improvement, 14 partial
  improvement, 54 no improvement (Dougherty et al,
  2002)

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Psychosurgeries
Deep Brain Stimulation
1. The surgeon inserts wires through the skull
and into capsule. 2. Wires are permanent and
attached to battery pack implanted in chest. 3.
Battery produces adjustable freq. that has same
effect as the other Surgeries. this has been used
on PD patients.
http//www.erworld.com/sjh_images/OCD.gif
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Can imaging help predict treatment efficacy?
Overactivation of right caudate predicts
Effectiveness of SSRIS
Overactivation of right orbitofrontal cortex and
bilateral thalamus predicts Effectiveness of
adjunctive neuroleptics
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Causes

• Genetics
• Concordance rates are higher among monozygotic
  twins compared to dizygotic twins
• First-degree relatives are 3-12 times more likely
  to develop OCD
• Streptococcal infection immune reaction

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Genetic targets

• Polymorphism in the promoter region for the
  serotonergic reuptake transporter
• 5-HT 1D receptor gene
• DRD4 receptor mutations

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PANDAs

• Pediatric autoimmune neuropsychiatric disorders
  associated with streptococcal infection

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Case of Frances
Perlmutter et al. 1998
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Summary

• OCD is related to dysfunction of prefrontal-basal
  ganglia loops that lead to repetitive thoughts
  and actions
• Effective treatments normalize this activity
• Treatments include SSRIs, behavioral therapies
  and psychosurgery
• Causes include genetic factors and possible
  autoimmune reactions