Augmenting obsessive-compulsive disorder treatment: from brain to mind.

Thearticle “Cognitive-BehavioralTherapyvsRisperidone for Augmenting Serotonin Reuptake Inhibitors in ObsessiveCompulsive Disorder: A Randomized Clinical Trial” by Simpson et al1 in this issue reports that exposure/ritual prevention (EX/RP) iswithout question more effective than risperidoneorplacebo inaugmentingserotoninreuptake inhibitor (SRI) response in an8-week randomized clinical trialwith 100 participants. Simpson et al call for a change in practice, because augmentation for SRI nonresponders with atypical antipsychotics is recommended in theAmerican Psychiatric Association guidelines.2 This is a well-controlled randomized clinical trial worthy of strong conclusions. Simpson et al have a track record of well-controlled combination studies in obsessive-compulsive disorder (OCD), and the conclusion that EX/RP should be considered first for SRI treatment augmentation is supported by the current data. Wewould like to consider further the implicationsof these findings and to examinewhat thesedatamay suggestwith regardtomechanismofactionofOCDtreatment ingeneral.There isnodiscussionof themechanismsofactionofanyof the treatments within the study, neither the monotherapies nor the combined therapies. Simpson et al hypothesized that risperidone and EX/RPwould each be equally effective for SRI nonresponders, yet it is difficult to explain no augmentation effects of the risperidone vs placebo based on prior studies. If theprior studieswere accurate, thenwhat is unique about the current study that risperidonewasnotmoreeffective thanplacebo?Simpsonet alnotedifferencesbetween their sampleand other studies’ samples, including the potentially less refractory nature of the subjects’ disease and possible past antipsychotic use; however, there are no clear smoking guns to account for the discrepant findings. To our knowledge, no study has found that adding medication to EX/RP achieves better outcome than EX/RP alone for OCD.3 The only exceptionmay be the use of D-cycloserine in addition to EX/RP for OCD.4,5 This is also true for other anxiety disorders, that, in general, adding other medications, typically SRI antidepressants, to cognitive-behavioral therapy does not seem to afford any benefit over the cognitive-behavioral therapy as a monotherapy, other than with D-cycloserine, which is thought to enhance the N-methyl-D-aspartate–dependent emotional learning process.3 Interestingly, a large randomized clinical trial recently found that risperidone was no more effective than placebo in augmenting SRI nonresponders in posttraumatic stress disorder.6 Overall, this collection of studies may imply that mechanisms that enhance the process of synaptic plasticity and emotional learning (such as N-methyl-D-aspartate– acting agents given only at the time of therapy) may enhance behavioral exposure therapy and possibly other forms of psychotherapy. However, monoaminergic-acting medications, such as SRIs and antipsychotics, may act to primarily dampen symptoms of dysregulated neural circuits but not correct the circuit dysfunction per se. We will examine this idea in more detail later. Theprincipal brain regions implicated inOCD include the cortical-striatal-thalamic-cortical circuit that regulates motor control caudally andemotional/cognitive controlmore rostrally (Figure).7 Interestingly, these frontostriatal circuitry connections were recognized more than 20 years ago,8 although at that time, the primary focus was on the striatum. Increased orbitofrontal cortex activity in OCD had previously been identified with positron emission tomography. These findings have since been augmented with a greater understandingof orbitofrontal cortex function andan increased appreciation that other brain areas that regulate emotion exert controlwithin thesepathways, particularly the amygdala. Recentworkhas replicated these early findings that pathophysiological pathwaysamongorbitofrontal-striatal regionsmaybe common to all forms of OCD.9 The efficacy of SRIs for OCD was identified serendipitously initially, in part because of the dearth of effective pharmacotherapeutics for OCD. However, dense serotonergic projections from the dorsal raphe to the orbitofrontal cortex and striatum have led to hypotheses that serotonergic manipulations may have direct effects on the disrupted circuit functioning underlying OCD. The observation that OCD tends to require higher doses of SRIs than depression treatment is consistent with potentially different circuit targets of action. However, as discussed by Simpson et al,1 and well recognized in the field, SRIs are only effective in treating a subset of patients with OCD. Therapeutic strategies for the many patients who do not benefit from SRI treatment are critical for progress. Antipsychotic agents were also applied empirically, initially, as with other psychiatric agents, in the attempt to extend available drugs to refractory OCD. However, these agents were never as effective as SRIs and the rationale followed the lines of targeting the “psychosis-like” symptoms of severe obsessions and ruminations. Subsequently, the subset of patients with tic-like OCD appear to have responded to antidopaminergic antipsychotic therapy, as do Related article page 1190 Opinion