Evidence-Based Reviews

Treatment-resistant OCD: Options beyond first-line medications

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Adjunctive agents, psychotherapy, neuromodulation may help refractory symptoms



Obsessive-compulsive disorder (OCD) is marked by recurrent and persistent anxiety-provoking thoughts (obsessions) accompanied by repetitive behaviors (compulsions) that focus on alleviating distress caused by obsessive thoughts. Although patients recognize the obsessions and compulsions are unreasonable, these thoughts and behaviors remain time-consuming and impair function. Even when they appropriately identify and treat OCD, clinicians often face “treatment-resistant” (or “treatment-refractory”) patients who do not respond adequately to standard therapies (Box).1 Several factors contribute to treatment resistance, including those related to the patient, the environment, the clinician/health system, and pathology (Table 1).2 An estimated 10% to 40% of patients with OCD are treatment-resistant.2

This article discusses the range of options for addressing resistant OCD, including augmenting first-line treatments with pharmacotherapy, psychotherapy, or reversible or irreversible forms of neuromodulation.

Defining treatment resistance in obsessive-compulsive disorder

Treatment resistance generally refers to lack of sufficient improvement despite multiple adequate and appropriate treatment trials. However, there are no universally accepted definitions or metrics of treatment resistance, and often it is operationally defined. For mood disorders, it may be defined by failure to remit or respond clinically (50% reduction in symptoms) despite ≥2 adequate antidepressant trials or failure to respond clinically despite adequate medication trials across several neurotransmitter classes. The terms treatment resistant and treatment refractory are synonymous; they refer to the same phenomenon and are used interchangeably in the literature. Including the terms “remission” and “recovery” when judging treatment efficacy for anxiety disorders can be limiting because of the chronic and often unrelenting nature of these conditions.

One review proposed categorizing obsessive-compulsive disorder treatment response into several stages along a spectrum, ranging from complete recovery (or remission) to full or partial response to non-response (or completely refractory).1 However it is defined, treatment resistance in anxiety disorders likely is characterized by minimal restoration of function despite several appropriate treatment exposures.

Table 1

Factors that contribute to treatment resistance in obsessive-compulsive disorder

Disease severity
Medical comorbidity
Psychiatric comorbidity (mood, personality, and/or substance use disorders)
Treatment nonadherence
Cultural factors
Childhood stressors (trauma, abuse)
Long-term persistent stressors (psychosocial, occupational, financial)
Life stages
Clinician/health system
Lack of knowledge in primary care (brief treatment duration, subtherapeutic dosing)
Lack of psychotherapeutic training
Limited doctor-patient relationship (eg, availability/cost of treatment)
Underlying disease pathophysiology (largely unknown):
  • Multiple neurotransmitter system interactions
  • Polygenetic influences (genetic load)
  • Gene-environment interactions
  • Neural circuits (cortical and subcortical feedback loops)
Diagnostic variance (dimensional vs categorical vs target symptom approach)
Syndromal variation (differing presentations over time)
Treatment limitations (limited empirical studies, nonrepresentative study samples)
Source: Reference 2

First-line pharmacotherapy

Clomipramine or a selective serotonin reuptake inhibitor (SSRI) are considered first-line treatments for OCD. Although some evidence indicates that clomipramine may have greater efficacy than SSRIs, its poor tolerability and potential lethality in overdose make it a less practical first choice in treatment-naïve patients.3,4 SSRIs generally are well tolerated and have a favorable safety profile. Nearly all SSRIs have randomized clinical trials (RCTs) and FDA indications that support their use in OCD. SSRI choice may be guided by patient or prescriber preference because no evidence suggests that 1 SSRI is superior to another for treating OCD.5 In contrast to major depressive disorder, in OCD there is a dose-response relationship for SSRI treatment; higher doses typically are required to achieve response or remission.6,7

Augmentation and other options

Patients who have not responded to at least 2 adequate trials of first-line medications may benefit from an augmentation strategy or treatment with an unconventional agent. Such cases should be managed by a specialist who has experience in treating OCD and with careful consideration of potential risks of these interventions.

Evidence suggests the following pharmacotherapies may effectively treat OCD and may be warranted for treatment-resistant patients.

Serotonergic agents

Supratherapeutic SSRI doses. Evidence suggests that supratherapeutic doses of SSRIs may be effective, which may be a logical first step when treating patients already taking an SSRI who have not responded. In a multi-center, double-blind study comparing sertraline, 200 mg/d, to sertraline, 250 to 400 mg/d, the latter group showed significantly greater symptom improvement.8 Citalopram may not be suitable for this approach because of the recent FDA announcement regarding dose-dependent QTc prolongation associated with this medication.9

Serotonin-norepinephrine reuptake inhibitors (SNRIs). In the only double-blind, placebo-controlled study of venlafaxine for OCD, the drug was not significantly more effective than placebo.10 This study was small (N = 30). There are sufficient positive results from open-label and blinded comparator studies that venlafaxine generally is accepted as an effective and well-tolerated treatment for OCD at doses ≥225 mg/d.11


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