A number of intriguing avenues have been investigated to deter-mine the
etiology and pathophysiology of OCD. Although our un-derstanding of what causes
this disorder has continued to grow, there is still much to learn. It is likely
that OCD is caused by a complex interaction of factors rather than a single
defect. However, for the purpose of clarity, these factors are described
separately.
A number of approaches have been used to evaluate the role of heredity
in OCD. Twin studies have examined rates of concord-ant monozygotic twins
versus discordant monozygotic twins with OCD. A review of this literature
reveals a concordance rate of 63% in monozygotic twins and supports the notion
that genetic factors are implicated in the expression of OCD. Given the
concordance rate of less than 100% in monozygotic twins, it is clear that
envi-ronment also plays a role in OCD’s phenotypic expression.
A second
approach to examining the role of genetics in OCD has been to investigate the
rate of OCD in family members of OCD probands. Evidence supporting familial
transmission of OCD has been obtained by studying the frequency of OCD in
relatives of patients with Gilles de la Tourette’s Syndrome (TS). Available
datasupport familial transmission in some cases of OCD
and suggest that genetic factors play an important role in its etiology,
particu-larly in patients with comorbid tic disorder. Thus, in recent years a
molecular genetics approach has begun to be applied to OCD, although there have
been not significant findings to date.
Brain imaging techniques have advanced the search for abnor-malities in
brain functioning and/or structure in patients with OCD. Numerous studies have
now been done with both struc-tural imaging – CT (computed tomography) and MRI
(magnetic resonance imaging) – and functional imaging – PET (positron emission
tomography), SPECT (single photon emission computed tomography), fMRI
(functional magnetic resonance imaging) and MRS (magnetic resonance
spectroscopy). These techniques have demonstrated abnormalities in OCD
patients. These abnor-malities occur at rest and with symptom provocation and
they are “normalized” with effective treatment.
While not all results are in agreement, a majority of these studies have
implicated abnormalities in the orbitofrontal cor-tex, anterior cingulate
cortex, and structures of the basal gan-glia and thalamus. These structures are
proposed to be linked in neuroanatomical circuits. One well-articulated model
by Saxena and colleagues (1998) proposes that OCD symptoms are medi-ated by
hyperactivity in orbitofrontal–subcortical circuits, which might be due to an
imbalance in tone between direct and indirect striato–pallidal pathways. Some
studies have implicated a prefer-ential role for right anterolateral
orbitofrontal cortex in both OCD symptoms and symptom response. This view has
neurocognitive implications because studies of executive function in OCD
pa-tients have shown that patients have difficulty with alternation tasks and
tasks that involve making choices. A number of treat-ment studies (see later)
with clomipramine, fluoxetine, paroxetine and cognitive–behavioral therapy
(CBT) have shown a decrease in caudate glucose metabolism with successful
treatment.
Further indirect evidence implicating a role for basal gan-glia dysfunction
in OCD lies in the clinical relationship between neurological insults to the
basal ganglia and the subsequent de-velopment of obsessions and compulsions.
There is an association between OCD and Tourette’s disorder, Sydenham’s chorea,
bilat-eral necrosis of the globus pallidus and postencephalitic parkin-sonian
symptoms.
The hypothesis that OCD involves an abnormality in the sero-tonin
neurotransmitter system has been called the serotonin hypothesis. Several
different lines of investigation support this hypothesis: 1) therapeutic
response of patients to chronic ad-ministration of medication; 2) measurements
of central and peripheral neurotransmitter or metabolite concentration; and 3)
pharmacologic challenge paradigms which measure behavioral and neuroendocrine
effects produced by acute administration of selective pharmacologic agents.
All the evidence from treatment studies points to a role for serotonin
and speaks of a need for prolonged administration to see a positive effect. All
of the antidepressants that effectively treat OCD affect serotonin. These
antidepressants are potentinhibitors of the presynaptic reuptake of serotonin
(i.e., SRIs). Those antidepressants that primarily affect the noradrenergic
system have not been found to have antiobsessional properties. Exactly how the
SRIs improve OCD symptoms remains unclear; while the immediate action of these
agents may be to increase serotonin in the synapse, they undoubtably cause a
cascade of changes, both presynaptically and postsynaptically.
The role of the dopamine system in OCD’s pathophysi-ology has also been
investigated. When added to the SRIs, dopamine antagonists (neuroleptic agents)
decrease symptoms of OCD in patients with OCD and comorbid tics, as well as in
pa-tients with OCD and comorbid schizotypal personality disorder. It has been
hypothesized that some forms of OCD, particularly OCD plus Tourette’s disorder,
may involve an imbalance in activ-ity between serotonergic and dopaminergic
systems.
Given the complex interactions and overlap among monoaminergic and other
receptors in the brain, it is likely that a number of neurotransmitters are
involved in OCD’s pathophysi-ology and etiology. The effect of long-term
treatment with SRIs is probably several: to change the ratio of dopamine to
serotonin turnover, alter the gene expression of target neurons to
stress-related neuropeptides, and decrease the sensitivity of subtypes of
presynaptic serotonin auto- and heteroceptors belonging to the 5-HT1 receptor family. Ongoing
research is expected to elucidate further the likely role of serotonin and the
possible role of other neurotransmitters in OCD.
Animal models may provide an important window on treatment efficacy and
the influence of environmental and genetic factors in OCD. Because of the
inherent difficulties in studying cognitive aspects of OCD (such as guilt,
over-responsibility and doubt) in animals, attention has focused on repetitive
motor actions that are similar to compulsions. Ethologists have observed that
when specific, goal-directed actions are thwarted, animals may sub-stitute
unrelated behaviors, known as displacement behaviors, which frequently involve
digging, pecking, or grooming. These motor actions have several elements: they
are triggered by con-flict over territory or by frustration, they continue in a
stereo-typed fashion, and they are excessive and/or inappropriate to the
context in which they are performed. Thus, they are similar to the compulsive
behaviors of OCD. Another animal model for OCD is acral lick disorder, in which
dogs and cats groom themselves ex-cessively, causing cutaneous lesions. As in
OCD, stress increases these excessive grooming behaviors. Of interest is the
positive responsive of acral lick disorder to clomipramine, fluoxetine and
sertraline but not to placebo, which lends support to the hypoth-esis that this
behavior represents an animal model of OCD.
A number of models implicate excessive dopaminergic ac-tivity in
repetitive behaviors. For example, dopamine antagonists such as haloperidol
decrease stereotyped behaviors in animals induced by amphetamine
administration, stimulation, or stress. Animal models offer the advantage of
accessibility and ease of manipulation for controlled trials and as such can play
a valuable role in understanding OCD’s etiology.
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