Pharmacotherapy for Treatment-Resistant Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a disabling illness affecting approximately 2%-3% individuals worldwide that is marked by recurrent, distressing intrusive thoughts (obsessions) and repetitive behaviors (compulsions). The underlying pathophysiology is incompletely understood, but OCD symptoms are thought to emerge partly from aberrant functionality in cortico-striato-thalamo-cortical neural circuits. 3 Though OCD is a major cause of functional disability and impairment, 4 the only medications currently approved by the US Food and Drug Administration (FDA) are serotonin reuptake inhibitors (SRIs, ie, the selective SRIs SSRIs and clomipramine). 5 Extensive evidence supports that SRIs are effective for treating OCD symptoms, and with a favorable side effect profile relative to clomipramine, SSRIs are currently the first-line pharmacotherapy. 6 However, around half of patients will respond incompletely to SSRIs, 7 and at least 8 weeks of sustained treatment are typically needed before meaningful clinical improvement is seen. 6 SSRI treatment is associated with dose-dependent side effects including gastrointestinal upset and sexual dysfunction, which may be particularly problematic given that patients with OCD tend to require treatment with higher doses to achieve symptomatic relief compared to those with anxiety and depressive disorders. 8 When patients do not respond to or cannot tolerate SSRIs, the evidence supports several next steps. Here, I briefly review options for pharmacologic management of treatmentresistant OCD, summarizing the evidence supporting each. What constitutes "responsiveness" to OCD treatment remains controversial, though improvement from baseline of 25%-35% on the Yale-Brown Obsessive Compulsive Scale is a commonly used definition. Experts similarly disagree on the definition of "treatment resistance, " but have generally quantified it based on the number of failed treatment trials. 9 A comprehensive review of this topic, including a review of psychotherapeutic and somatic treatment approaches, is beyond the scope of this article; for more detailed discussions, see references 6, 9, 10, and 11.