Obsessive-Compulsive Disorder: Etiology, Pathophysiology, Factors

Etiology and Pathophysiology

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.

Genetic Factors

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.

Neurobiological Factors

Neuroanatomical Aspects

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.

Neurochemical Aspects

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

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.