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Obsessive-compulsive disorder
Jonathan S Abramowitz, Steven Taylor, Dean McKay
Obsessive-compulsive disorder is a severe and disabling clinical condition that usually arises in late adolescence or Lancet 2009; 374: 491–99
early adulthood and, if left untreated, has a chronic course. Whether this disorder should be classified as an anxiety University of North Carolina,
disorder or in a group of putative obsessive-compulsive-related disorders is still a matter of debate. Biological models Chapel Hill, NC, USA
(Prof J S Abramowitz PhD);
of obsessive-compulsive disorder propose anomalies in the serotonin pathway and dysfunctional circuits in the
University of British Columbia,
orbito-striatal area and dorsolateral prefrontal cortex. Support for these models is mixed and they do not account for Vancouver, BC, Canada
the symptomatic heterogeneity of the disorder. The cognitive-behavioural model of obsessive-compulsive disorder, (Prof S Taylor PhD); and
which has some empirical support but does not fully explain the disorder, emphasises the importance of dysfunctional Fordham University, NY, USA
(D McKay PhD)
beliefs in individuals affected. Both biological and cognitive models have led to empirical treatments for the
Correspondence:
disorder—ie, serotonin-reuptake inhibitors and various forms of cognitive-behavioural therapy. New developments in
Dr Jonathan S Abramowitz,
the treatment of obsessive-compulsive disorder involve medications that work in conjuction with cognitive-behavioural Department of Psychology,
therapy, the most promising of which is D-cycloserine. University of North Carolina,
Chapel Hill, NC 27599, USA
jabramowitz@unc.edu
Introduction • repugnant obsessions concerning sex, violence, and
Obsessive-compulsive disorder is characterised by the religion;
occurrence of either obsessions, compulsive rituals or, • hoarding, which are obsessions about acquiring and
most commonly, both.1 Obsessions have four essential retaining objects, and associated collecting com-
features: they are recurrent and persistent thoughts, pulsions.
impulses, or images that are experienced as intrusive and Recent findings have supported these five dimensions
cause great anxiety; they are not simply excessive worries across ages from childhood through adulthood.3,4 Although
about real life issues; the affected individual attempts to hoarding has traditionally been regarded as a form of
ignore, suppress, or neutralise them with some other obsessive-compulsive disorder, the differences between
thought or action; and the affected individual recognises hoarding and the other obsessive-compulsive symptom
that these thoughts are a product of his or her mind.1 dimensions are compelling enough that some researchers
Examples of obsessions include unwanted thoughts or now think that hoarding is a separate disorder.5
images of harming loved ones, persistent doubts that one No laboratory tests exist for obsessive-compulsive
has not locked doors or switched off electrical appliances, disorder, and the diagnosis is made by clinical interview.
intrusive thoughts of being contaminated, and morally or To diagnose the disorder according to the Diagnostic and
sexually repugnant thoughts (eg, intrusive thoughts of Statistical Manual of Mental Disorders IV (DSM-IV)
behaving in a way that violates one’s morals or runs criteria,1 the affected individual must suffer from either
counter to one’s sexual preferences). obsessions or compulsions that cause great distress, are
Compulsions are repetitive behaviours (eg, repetitive time-consuming (more than 1 h per day), or substantially
hand washing, ordering, or checking) or mental acts (eg, interfere with normal functioning. At some point in the
repetitive praying, counting, or thinking good thoughts course of the disorder, the affected individual must also
to undo or replace bad thoughts) that the affected recognise that the obsessions and compulsions are
individual feels compelled to do in response to an excessive or unreasonable. This criterion does not apply
obsession, or according to rigid rules (eg, checking that a to children because they may not have sufficient cognitive
light switch is turned off by switching it on and off awareness to make this judgment. Also, commonplace
exactly ten times). Compulsions are aimed at preventing childhood rituals (eg, avoiding cracks on the pavement)
or reducing distress, or preventing some dreaded event.1 are not compulsions, they are not distressing or
However, they are excessive or not realistically connected debilitating, and they tend to be transient.
to what they are intended to prevent.
Obsessive-compulsive disorder is a symptomatically
heterogeneous condition, in which various different kinds Search strategy and selection criteria
of obsessions and compulsions exist. However, research We searched Medline and PsychInfo from 2003 to 2008, with
indicates that certain obsessions and compulsions tend to the search terms ˝obsessions˝, ˝compulsions˝, ˝obsessive-
co-occur to form five main dimensions:2 compulsive disorder˝, and ˝OCD˝. Although we focused on
• obsessions about being responsible for causing or publications in the past 5 years, we did not exclude commonly
failing to prevent harm; checking compulsions and referenced and highly regarded older publications. We also
reassurance-seeking; searched the reference lists of articles identified by this search
• symmetry obsessions, and ordering and counting strategy and selected those we judged relevant. Review articles
rituals; and book chapters are cited to provide readers with more
• contamination obsessions, and washing and cleaning details and more references than this Seminar has space for.
rituals;
Obsessive-compulsive disorder would not be diagnosed obsessive-compulsive disorder than in the general
if obsessions and compulsions arose in the context of population.6 20–30% of people with the disorder have a
some other disorder such as schizophrenia. In such current or past history of tics.1
cases, the current diagnostic conventions (ie, International
Classification of Diseases [ICD] and DSM) indicate that Pathophysiology
obsessive-compulsive symptoms are due to some other Neurochemistry and neuroanatomy
disorder (ie, schizophrenia). Here, we focus on obsessive- Obsessive-compulsive disorder has been linked to a
compulsive symptoms as they occur in what is currently disruption in the brain’s serotonin system.18 Serotonin
called obsessive-compulsive disorder. dysregulation, however, has been implicated in many
People with this disorder have varied insights into the other psychological disorders, and whether these
senselessness of their symptoms,1 with most acknow- disorders differ from one another in the type of
ledging that obsessions and compulsions are at least abnormality is unclear. Obsessive-compulsive disorder
somewhat unrealistic and excessive. Insight can be has been associated with hypersensitivity of postsynaptic
assessed by asking the patient how strongly he or she serotonin receptors.19 Individuals with the disorder might
believes that the obsessions are realistic and that the have a specific dysfunction in the genes encoding for the
rituals actually serve to prevent disastrous consequences. serotonin transporter (5-HTT) and serotonin receptor
(5HT2A),20 but these have not been consistently
Prevalence, demographic features, and identified.21 The glutamate system might also be dys-
comorbidity functional in obsessive-compulsive disorder.22 Preliminary
Compared with people with other anxiety or unipolar research has implicated glutamate transporter genes—
mood disorders, those with obsessive-compulsive such as Sapap323,24 and SLC1A1—25–27 in the disorder.
disorder are less likely to be married, more likely to be Furthermore, the dopamine system might be abnormal
unemployed, and more likely to report impaired social in obsessive-compulsive disorder, although results have
and occupational functioning.6 This disorder has a been inconsistent regarding which dopamine genes are
lifetime rate of 2–3% in the general population,7 without associated with the disorder.28
sex differences in distribution, with the exception that in Two common features of obsessive-compulsive
children the disorder is more common in boys than in disorder—excessive doubting and repetitive actions—
girls.8 Onset is usually gradual and, if untreated, the suggest that specific brain regions are involved in the
course is mainly chronic, with symptoms changing over condition. In particular, the frontal orbito-striatal area
time, often in response to life stressors.9,10 The disorder is (including the caudate nucleus) and the dorsolateral
rarely limited to a single episode or to recurrent episodes. prefrontal cortex have been implicated in the inhibition
It usually arises in late adolescence or early adulthood, of responses and in planning, organisation, and
although onset in childhood or late adulthood can occur.11 verification of previous actions.29 Accordingly, a recent
Clinical presentation of the disorder in children and meta-analysis of brain imaging in adults has suggested
adults is generally similar.1 that obsessive-compulsive symptoms might be
Obsessive-compulsive disorder has been identified in implemented within the orbital cortex and the caudate
many different ethnic groups.12 Cross-national differ- nucleus.30 Similar findings have been reported for
ences in prevalence are difficult to interpret because they children.31 Preliminary evidence has shown white matter
could be due to various factors, including culturally anomalies in frontal regions in people with obsessive-
influenced reporting biases such as reluctance to admit compulsive disorder, which is consistent with the
to suffering from a mental disorder. The main features of hypothesis of a dysregulation in this and other brain
the symptoms seem to be consistent over time; for regions.32,33 Figure 1 shows the orbito-subcortical circuits
example, obsessions about violations of social taboos that might connect regions of the brain associated with
concerning sexual behaviour and aggression.13,14 However, obsessive-compulsive symptoms. The direct pathway
cultural background could affect the content of obsessions projects from the cerebral cortex to the ventromedial
and compulsions.15 For example, religious obsessions caudate, to the internal segment of the globus pallidus
and compulsions (eg, blasphemous intrusive thoughts, and substantia nigra, and then to the thalamus and back
compulsive praying, and cleansing compulsions) might to the cortex. The indirect pathway is similar, but projects
be more common in ethnic groups that emphasise the from the ventromedial caudate through various structures
importance of religious observance than in those in in the basal ganglia before returning to the direct pathway.
which religion has a less prominent role.16 Overactivity of the direct pathway is thought to be
Epidemiological surveys suggest that at least 50% of associated with obsessive-compulsive symptoms.
people with the disorder have at least one other
psychological illness—most commonly a comorbid Genetic factors
anxiety disorder (eg, social phobia) or a unipolar mood Probands with obsessive-compulsive disorder are more
disorder (eg, major depressive disorder).6,17 Alcohol abuse likely to have first-degree family members who suffer
or dependence is also more common in people with from the same disorder than are matched controls who
compulsive rituals. For example, a patient who fears the from rituals) over and above the non-specific factors
number 13 because it will bring bad luck would practise (eg, expectations, attention) that are common to all
writing this number and imagining causing bad luck. He psychological treatments.
or she would also refrain from performing any rituals to
reduce anxiety or the chances of bad luck (eg, saying Psychotherapy and pharmacotherapy: D-cycloserine
prayers, checking for reassurance). The aim of exposure Despite the hope that the combination of serotonin
and response prevention is to teach patients with reuptake inhibitors and exposure and response
obsessive-compulsive disorder that his or her obsessional prevention would lead to a more pronounced reduction
anxiety does not persist indefinitely, and that avoidance of symptoms than that achieved with either monotherapy,
behaviour and compulsive rituals are unnecessary for this result has not been obtained. A meta-analysis of
averting harm.71 Although exposure and response randomised controlled trials85 comparing combined
prevention is the only empirically supported psychological treatments with monotherapies of serotonin reuptake
treatment for obsessive-compulsive disorder, additional inhibitors or exposure and response prevention showed
motivational interventions are sometimes necessary for no clear benefit of combined treatment over either
patients with very severe symptoms or for those with a monotherapy alone.
limited ability to perceive that behaviours arising from A novel approach that combines exposure-based
obsessions are senseless.72 treatments with medication involves the search for
The Yale-Brown obsessive-compulsive scale (Y-BOCS)73 pharmacological agents that facilitate fear extinction.
is regarded as the gold standard measure of obsessive- Animal research suggests that the N-methyl-d-aspartate
compulsive symptom severity and is used in most (NMDA) glutamate receptors are important for the
treatment trials. Figure 3 shows the results of randomised expression of conditioned fear responses in the
controlled trials using this measure. These studies74–78 basolateral amygdala and of conditioned fear extinction
consistently demonstrated that exposure and response in the amygdala.86 These findings are consistent with the
prevention was better than other forms of psychotherapy view that fear extinction, similar to fear acquisition, is a
and placebos. Meta-analyses79–81 found large effect sizes, form of learning. Accordingly, NMDA agonists,
ranging from 1·16 to 1·72 in trials of exposure and administered before an exposure task, might facilitate
response prevention with adults79–81 and children.82,83 the extinction of fear responses.
Although often effective, exposure and response One such compound is D-cycloserine, which has been
prevention provokes anxiety in patients, and therefore used for years in humans to treat tuberculosis and is not
approximately 25% of patients drop out of treatment.84 associated with significant side-effects. Animal research
For patients who undergo exposure and response has shown that this compound facilitates fear extinction
prevention, the effects of this treatment often last up to at after either systemic administration or intra-amygdala
least 2 years.70 infusion.86 Research on humans suffering from either
animal phobia or social anxiety disorder has provided
Pharmacotherapy versus exposure and response preliminary evidence that D-cycloserine, administered
prevention shortly before an exposure session, can facilitate (ie,
Researchers have investigated the efficacy of medications speed up) fear extinction.87,88 With regard to obsessive-
versus exposure and response prevention. Foa and compulsive disorder, three studies have compared
colleagues77 compared exposure and response prevention exposure and response prevention (10–12 sessions) with
with clomipramine, the combination of exposure and D-cycloserine (100–250 mg) to exposure and response
response prevention and clomipramine, and placebo. prevention with a placebo.89–91 D-Cycloserine was not
Exposure and response prevention reduced Y-BOCS better than placebo in reducing obsessive-compulsive
scores by 55%, whereas clomipramine alone reduced it symptoms either immediately after treatment or at
by 31%. The combination of exposure and response 1–3-month follow-up. However, in two studies90,91 that
prevention and clomipramine reduced Y-BOCS scores by assessed outcome at the midpoint of exposure,
58%, which was significantly greater than the effect of D-cycloserine was superior to placebo—ie, it improved
clomipramine alone, but not of exposure and response symptoms more rapidly. A limitation of all three trials
prevention alone. All active treatments were superior to was the small number of participants in each treatment
placebo (11% Y-BOCS reduction). group (10–14 per group), which reduces the statistical
Overall, the findings from randomised controlled trials power of these studies.
suggest that exposure and response prevention—whether Overall, preliminary results suggest using D-cycloserine
delivered in daily or weekly sessions—substantially as a method for accelerating the effects of exposure and
improve obsessive-compulsive symptoms, and its effect response prevention, especially in the early phases of
is more than that produced by pharmacotherapy. Evidence treatment. Further research on large samples is needed to
also exists that symptom reduction is due to the specific replicate these findings and to determine the optimal dose
techniques used in exposure and response prevention of D-cycloserine. Research on patients with acrophobia (ie,
(ie, exposure to fear-provoking stimuli while refraining phobia of heights) suggests that as little as 50-mg
D-cycloserine is effective.88 Moreover, animal research understanding of the causes and treatment of this severe,
indicates that high doses of D-cycloserine can desensitise debilitating, and chronic disorder.
NMDA receptors, thereby attenuating the effects of the References
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