Obsessive Compulsive Disorder

Clomipramine, a potent inhibitor of both 5-HT and NE reuptake, was observed more than 30 years ago to reduce obsessive-compulsive symptoms (Renynghe de Voxurie 1968). The superior benefit of this potent serotonergic TCA over desipramine represents a cornerstone in the 5-HT hypothesis of OCD (Benkelfat et al. 1989). Fluoxetine has been shown to be effective in OCD independent of a patient's comorbid mood status (Jenike et al. 1989). Patients who have OCD may require higher doses of medication and longer treatment periods than do patients with depression to determine response. Currently, clomipramine and the SSRIs are considered to be the first-line agents for treatment of OCD (Kaplan and Hollander 2003).

A precise explanation of this selective 5-HT advantage in OCD is unknown. A heightened level of metabolic activity in the orbital region and caudate dysfunction have been reported by Baxter et al. (1992) and may be normalized by either somatic (fluoxetine 60-80 mg) or behavioral interventions. Hypersensitivity of the serotonergic system has been theorized. Receptor downregulation associated with long-term SSRI therapy has been offered as a potential explanation of clinical response (Zohar et al. 1988). This hypothetical neuroadaptation is supported by a positive correlation between symptomatic improvement from baseline and cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) (Thorén et al. 1980) or platelet 5-HT concentration (Flament et al. 1985). Chronic administration of fluoxetine attenuates ipsapirone-induced hypothermia and adrenocorticotropic hormone (ACTH) and cortisol release among patients with primary OCD. Although these data support a model of drug-induced 5-HT1A subsensitivity and/or dampened postreceptor signal, the magnitude of change fails to correlate with the degree of clinical improvement (Lesch et al. 1991). An SSRI-mediated decrease in 5-HT responsivity is consistent with the observed latency in symptomatic improvement.

Because OCD is a chronic disorder, prolonged fluoxetine therapy may be necessary. In patients whose symptoms have been minimally or only moderately reduced with SSRI treatment, numerous augmentation strategies have been proposed, including tryptophan, fenfluramine, lithium, buspirone, trazodone, or a neuroleptic (see Goodman et al. 1992). In addition, fluoxetine has shown efficacy in children and adolescents with OCD (Geller et al. 2001). In so-called OCD spectrum disorders, such as skin picking (Bloch et al. 2001) and body dysmorphic disorder (Phillips et al. 2002), controlled trials also indicate efficacy for fluoxetine.

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