To our knowledge, this is the first randomized clinical trial to compare 2 recommended SRI augmentation strategies for adults with OCD. Adding EX/RP to SRIs was superior to risperidone and pill placebo in reducing OCD symptoms and improving insight, functioning, and quality of life. Risperidone was not superior to placebo on any outcome.
That EX/RP was superior to placebo corroborates Tenneij et al,8
who found that adding EX/RP to paroxetine or venlafaxine was superior to continued medication alone in 96 adults with OCD. The findings also confirm our prior study,9
which found augmentation with EX/RP superior to stress management therapy(a control for time and attention) in 108 adults with OCD. That our 2 studies, conducted more than 5 years apart, yielded such similar effects underscores the efficacy of EX/RP as an SRI augmentation strategy for adults with OCD: across both studies, 33% to 43% who began EX/RP and 38% to 46% who completed it achieved minimal symptoms (Y-BOCS score ≤12), which is associated with good quality of life and adaptive functioning.33
Our study also affirms the low placebo response seen in other OCD SRI augmentation studies3,9
: of our patients randomized to pill placebo augmentation, only 15% responded, and 5% achieved minimal symptoms after 8 weeks.
Contrary to our expectations, adding EX/RP to SRIs was superior to adding risperidone on every outcome. These findings are important because antipsychotics are increasingly prescribed to outpatients with OCD,34
and risperidone is recommended as the medication of first choice to augment SRI response.3,4
Our results call for increased use of EX/RP for augmenting unsatisfactory SRI effects.
Adding risperidone to SRIs was not significantly better than placebo on any outcome measure, even though risperidone’s response rates were numerically higher. These findings are at odds with 3 smaller trials.5–7
The most positive6
found risperidone (n = 18) superior to placebo (n = 15), with a mean (SD) Y-BOCS score decrease from 27.4 (5.4) to 18.7 (8.3) and a 50% response rate in treatment completers; their mean (SD) daily risperidone dose (2.2 [0.7] mg/d; median, 2.0 mg/d) was similar to ours (1.9 [1.1] mg/d; median, 2.0 mg/d). That study used a different response definition and analyzed only treatment completers, potentially explaining some of the discrepancy. However, applying a response definition used in meta-analyses (Y-BOCS score decrease ≥ 35%3,4
) to all randomized subjects (assuming drop-outs are non responders), the difference between our risperidone and placebo response rates (17.5% vs 15%) leads to an absolute risk difference of only 0.025. The 3 other controlled trials had absolute risk differences of 0.356
; patients in 1 of these studies5
received only 0.5 mg/d of risperidone.
Several differences between our study and these prior trials may explain the different outcomes. First, the samples differed. We randomized patients with clinically significant symptoms (Y-BOCS score ≥16) despite receiving an SRI at a maximally tolerated dose for 12 weeks or more. All but 2 reported at least minimal improvement while receiving an SRI, which is why they had continued receiving their SRI. The other studies focused on patients with no more than minimal response to an SRI. Thus, the other studies may have had a more SRI-refractory sample. For example, McDougle et al6
treated patients for 8 weeks with an SRI and then randomized only those who met all of the following criteria: (1) less than 35% Y-BOCS score decrease or Y-BOCS score more than 16; (2) no more than minimal improvement; and (3) consensus of 3 clinicians that the patient was unimproved. Importantly, Erzegovesi et al5
found that only SRI nonresponders (not responders) benefit from risperidone augmentation. In contrast, those with and without an SRI response have been shown to benefit from EX/RP augmentation.8,9,35–37
Second, given the increasing use of second-generation antipsychotics in OCD,34
our sample might have had greater prior antipsychotic exposure and therefore be more antipsychotic resistant. Prior antipsychotic exposure is not described in prior studies; 17% of our sample had previously been exposed to an antipsychotic for atleast a week. However, our sensitivity analysis indicated that baseline differences in prior antipsychotic exposure did not explain differences in outcome. Third, patients with OCD have treatment preferences.38
Our study randomized patients to medication or EX/RP; it likely attracted either those without preferences or those with preferences but the willingness to chance being randomized to the other. The other studies randomized patients only to medication, likely attracting those who preferred medication. Treatment preferences like these can affect treatment outcome.39
Finally, to our knowledge, ours is the largest sample (risperidone, n = 40; placebo, n = 20); the absolute risk difference for the other studies was based on only 6 to 20 patients per group.
Risperidone’s adverse effects were expected. However, there were 2 surprises. First, 37% of patients had moderate to severe adverse effects at baseline; assuming these are due to SRIs, this suggests that long-term SRI treatment is not benign. Second, while most patients receiving risperidone (88%) reported treatment-emergent adverse effects, many receiving placebo (72%) or EX/RP (58%) did too. Moreover, both patients receiving risperidone and EX/RP gained weight, although those receiving risperidone were more likely to do so.
Several limitations deserve consideration. First, we recruited patients already receiving SRIs. Consequently, we do not have measures of OCD severity prior to SRI treatment to quantify degree of SRI response. Second, patients receiving EX/RP knew they were receiving therapy, whereas those taking a pill understood they had a one-third chance of receiving placebo; thus, factors like differential expectancy could have contributed to the outcome. In addition, the groups differed in clinician contact: those receiving EX/RP had 2 hours of contact with their psychiatrist and about 26 contact hours with their therapist, whereas those receiving risperidone or placebo had 4 hours of contact with their psychiatrist. However, prior studies have shown that attentional one has minimal effects on OCD symptoms.9
Third, some data suggest that antipsychotic augmentation is most helpful in patients with OCD and tic disorders.3
Because only 5% of our patients reported a lifetime tic disorder, our data cannot address this question. Finally, the study design could not address whether patients with OCD receiving SRIs who fail to respond to EX/RP (or are unwilling to try it) might benefit from risperidone augmentation.
Our study recruited patients like those commonly seen in out-patient practice. We minimized exclusions and permitted co-morbid anxiety and depressive disorders. Thus, our findings likely apply to patients with OCD receiving SRIs who are willing to try medication or psychotherapy and who can adhere to these treatments. We have previously shown that patient adherence to EX/RP is strongly associated with outcome.40,41
With regard to EX/RP’s effectiveness outside academic settings like ours, EX/RP has been successfully disseminated to specialty fee-for-service practices42,43
and nonacademic community clinics44
; it has even been successfully delivered by the Internet.45
Patients with OCD receiving SRIs should be offered EX/RP before antipsychotics given EX/RP’s superior efficacy and less negative adverse effect profile. Identifying who achieves minimal OCD symptoms from adding EX/RP to SRIs and whether such patients can then successfully discontinue their SRI warrants future research. Whether patients with OCD receiving SRIs who fail to respond to EX/RP (or are unwilling to try it) can benefit from risperidone augmentation remains an unanswered question. Alternative medication augmentation strategies for patients with OCD receiving SRIs are needed.