| Abstract|| |
Most studies suggest that obsessive-compulsive disorder runs a chronic course. Only 40%–70% of patients respond to first-line treatment with selective serotonin reuptake inhibitors (SSRIs). The most common pharmacological strategy used in clinical practice for partial responders to SSRIs is augmentation with an atypical antipsychotic. This article aims to review the efficacy, tolerability, and comparative efficacy of antipsychotics as augmenting agents in patients who showed inadequate response to SSRIs. In addition to case reports and case series, 15 randomized controls trials, 6 meta-analyses, and 3 expert guidelines have been examined. The findings suggest that one in three SSRI nonresponders improve with antipsychotic augmentation. The presence of comorbid tics and/or schizotypal disorder may predict a better response to antipsychotic augmentation. Among antipsychotics, risperidone, and aripiprazole have the best evidence, with haloperidol being considered second in-line owing to its unfavorable side effect profile. Guidelines recommend that antipsychotics be administered at a low-to-medium dosage for a duration not exceeding 3 months, with mandatory discontinuation if there is no response. Larger studies and head-to-head trials are needed to further explore this treatment strategy.
Keywords: Antipsychotic, augmentation, obsessive-compulsive disorder, treatment resistance
|How to cite this article:|
Thamby A, Jaisoorya T S. Antipsychotic augmentation in the treatment of obsessive-compulsive disorder. Indian J Psychiatry 2019;61, Suppl S1:51-7
| Introduction|| |
Obsessive-compulsive disorder (OCD) is characterized by the presence of obsessions and/or compulsions, with an estimated prevalence of 1%–3%. In many patients, OCD runs a chronic course which may worsen without treatment. The first-line treatments recommended for OCD are pharmacological treatment with selective serotonin reuptake inhibitors (SSRIs) or cognitive behavior therapy (CBT) using exposure and response prevention (ERP) techniques. In most low- and middle-income countries, psychological services are sparse; hence, in practice, pharmacological strategies are often the only available option.
One of the major challenges in the first-line treatment of OCD with SSRIs is that only 40%–70% of patients have an adequate response; the remaining experience either nonresponse or partial response. Switching over to a different SSRI is recommended for those with nonresponse, while augmentation strategies are generally recommended for people with partial response. Augmentation refers to the process of adding treatment with a different mechanism of action to the primary drug to boost its therapeutic efficacy. There is robust evidence to use CBT as an augmenting agent with some experts recommending that CBT is considered as a first-line augmentation strategy in those who do not show the satisfactory response to SSRIs., However, as mentioned earlier, the availability of trained therapists remains an issue of concern world over, developing nations in particular. A multicenter international study that explored the next-step strategies used in clinical practice for patients with OCD who do not respond to first-line treatment reported that augmentation with an antipsychotic is the most commonly used strategy.
This article aims to review the efficacy, tolerability, and comparable efficacy of the use of antipsychotics as an augmenting agent in patients with OCD who demonstrated an inadequate response to an SSRI trial.
| First-Generation Antipsychotics|| |
Haloperidol is the most widely studied first-generation antipsychotics (FGA). Two double-blind, placebo-controlled trials evaluated the efficacy of haloperidol augmentation. The first study demonstrated a significant reduction in the Yale–Brown Obsessive-Compulsive Scale (Y-BOCS) severity score when fluvoxamine was augmented with haloperidol after a 4-week trial. Eleven out of 17 patients (65%) changed to “responders” and a better response was seen in those with comorbid tics. The second study which had a crossover design also found that the augmentation of SSRIs with haloperidol 2 mg/day significantly reduced the severity of obsessions. However, the study had a very small sample size (n = 16) and a short treatment duration (2 weeks). An open-label trial with FGA augmentation of fluvoxamine found that comorbid tics and schizotypal disorder predicted better response to augmentation.
Patients receiving haloperidol in the above-mentioned studies had poor tolerability. Nearly 50% of patients developed extrapyramidal symptoms resulting in dropouts or administration of adjuvant anticholinergics/beta-blockers.,, Hence, the augmentation with FGA may be considered only if there are contraindications to the use of second-generation antipsychotics (SGAs); if employed, FGAs are better initiated at a lower dose with a slow and monitored increase in dosage if required.
| Second-Generation Antipsychotics|| |
Risperidone is the most widely studied augmenting agent in the treatment of OCD. There are multiple randomized controlled trials (RCTs) on the efficacy and tolerability of risperidone augmentation of SSRIs. In the first RCT, 36 OCD patients refractory to SSRI treatment were randomized to 6 weeks of risperidone or placebo augmentation. At the end of the trial, 50% of the risperidone-treated group had responded compared to none in the placebo group. Post RCT, an open-label trial of risperidone augmentation among participants in the placebo group also resulted in 50% response rate. Risperidone was well tolerated and the presence of comorbid tics or schizotypal disorder did not predict response. Similar results were also reported for risperidone augmentation in another RCT with a smaller number of OCD patients who had failed at least two adequate trials of SSRIs. The mean dosage of risperidone across these two studies was 2.2 mg/day., In the third trial, OCD patients who had not responded to the first adequate trial of fluvoxamine were randomized to receive risperidone 0.5 mg/day or placebo. In the risperidone group, 50% responded compared to 20% in the placebo group. In a recent large RCT, 100 partial or nonresponders to SSRIs were randomized into three groups as follows: adjuvant CBT, adjuvant risperidone, and adjuvant pill placebo groups. The study found no significant difference between the risperidone and placebo groups at the end of 8 weeks; however, CBT was clearly superior to risperidone and pill placebo. However, the study had a few limitations, including the lack of a placebo arm for CBT, selection bias, less SSRI refractoriness in the sample, limited therapist contact in the pill groups compared to that in the CBT group, and difficulty in blinding.
In a recent chart review from our center of 92 patients treated with risperidone, we employed “all-cause discontinuation” as a primary outcome measure, and found that 25% continued the use of risperidone. The rest had discontinued risperidone due to adverse effects or lack of efficacy. In those who continued the use of risperidone, the fall in the Y-BOCS total score was considerably greater than in those who discontinued risperidone (42% vs. 4%). Of those who continued risperidone, almost all had a fall in the Y-BOCS score of at least 25% compared to the baseline score.
Only a single RCT has examined paliperidone (9-hydroxyrisperidone, the active metabolite of risperidone). An 8-week placebo-controlled double-blind study of 34 SSRI-resistant OCD patients failed to find any significant difference between paliperidone and placebo. However, there was a numerical trend favoring paliperidone, and the authors suggested a better-powered RCT to conclusively address the issue of efficacy.
Aripiprazole is another well-studied antipsychotic augmenting agent for the treatment of OCD in both youth and adults. A small open-label study and two placebo-controlled trials in adults have demonstrated the efficacy of aripiprazole in SSRI-resistant OCD patients. The open-label study using aripiprazole with a mean daily dose of 11.2 mg found a significant reduction in the Y-BOCS score at the end of 12 weeks. Subsequently, a 16-week double-blind, placebo-controlled trial in 30 SSRI-resistant adult OCD patients showed a significant reduction in the Y-BOCS score with aripiprazole (15 mg/day) augmentation. These findings have been replicated in a 12-week double-blind, placebo-controlled trial wherein the daily dosage of aripiprazole augmentation was 10 mg/day. Aripiprazole was generally well tolerated with the most commonly reported adverse effects being mild, transient restlessness and sedation.,,
Although rigorous trials are lacking in young people, there are case series and open-label trials which have evaluated the efficacy of aripiprazole augmentation. In a case series, assessing the efficacy of aripiprazole augmentation in 39 adolescent OCD patients (mean age 14.6 ± 1.2 years) who had not responded to two initial trials of SSRI monotherapy, more than a half of the patients showed good response and tolerability. In a small open-label trial in 16 children (mean age 10.9 ± 2.9 years) with treatment-resistant OCD, aripiprazole was administered at a mean dosage of 4.75 mg/day. At the end of 12 weeks, there was a significant reduction in the children's Y-BOCS score and improvement in the clinical global impressions–improvement (CGI-I) score. A more recent larger open-label study with 48 children and adolescents who had not responded to at least two SSRIs and CBT also reported similar improvement.
A chart review from our center, using all-cause discontinuation as the primary outcome measure, demonstrated that 7 out of 23 (30%) SSRI-resistant OCD patients continued to use aripiprazole, and the remaining 16 participants discontinued aripiprazole due to adverse effects or lack of efficacy. Six of the participants (26%) had ≥25% reduction in the Y-BOCS total score with aripiprazole augmentation.
A 6-week double-blind, placebo-controlled trial with 26 SSRI-resistant adult OCD patients demonstrated a significant reduction in the Y-BOCS score with olanzapine (11.2 mg/day) augmentation compared to placebo. Nearly 46% in the olanzapine arm had responded compared to none in the placebo group. A similar double-blind, placebo-controlled 6-week trial with 44 OCD patients failed to replicate the above findings. However, many of these patients were on suboptimal anti-obsessional doses of fluoxetine suggesting that the participants may not be truly SSRI resistant. The most common adverse effect and reason for discontinuation noted in both the studies was weight gain.,
Findings have been inconsistent regarding the efficacy of quetiapine. In a 12-week placebo-controlled, double-blind study with 42 OCD patients, quetiapine (mean dose 169 mg/day) failed to demonstrate any significant effects compared to placebo. However, SSRI resistance in these patients had not been well established. In another similar 8-week study with 40 SSRI-resistant OCD patients, quetiapine augmentation (up to 300 mg/day) was found to be effective, with 40% of those on quetiapine showing response compared to 10% on placebo. In both studies, quetiapine was well tolerated with sedation being the most common adverse effect. A small RCT of quetiapine augmentation in highly SSRI-resistant OCD patients found that quetiapine (mean dose of 215 mg/day) was numerically superior to placebo; however, the difference did not reach statistical significance. Another placebo-controlled RCT with quetiapine augmentation of up to 400 mg/day in OCD patients unresponsive to SSRIs failed to demonstrate any efficacy.
| Meta-Analyses|| |
There are 15 RCTs till date on antipsychotic augmentation in treatment-resistant OCD. Most of them have a small sample size limiting the power, homogeneity, and conclusions that can be drawn. Hence, it is important to review the findings of meta-analyses of antipsychotic augmentation in OCD. There are six meta-analyses to date, all of which have included double-blind, randomized, placebo-controlled trials comparing augmentation of SSRIs with antipsychotics to placebo supplementation in treatment-resistant OCD.,,,,, The number of RCTs included in each meta-analysis varies from 9 in the earliest to 14 in the most recent ones., The variance in the number of trials is due to the reporting of newer RCTs during the intervening period. The two recent meta-analyses, for all practical purposes, represent an updated meta-analysis of previous reports., Hence, for brevity and clarity, only the findings of the two meta-analyses are being reported.
The most recent meta-analysis (2015) included 14 double-blind, randomized, placebo-controlled trials (n = 491) investigating quetiapine (N = 4, n = 142), risperidone (N = 4, n = 132), aripiprazole (N = 2, n = 79), olanzapine (N = 2, n = 70), paliperidone (N = 1, n = 34), and haloperidol (N = 1, n = 34). Augmentation with antipsychotics was found to be significantly more efficacious than placebo (pooled response rate of 29.8% vs. 12.5%). Among the individual antipsychotics examined, only aripiprazole, haloperidol, and risperidone significantly outperformed placebo. Another recently published meta-analysis (N = 14, n = 493), which examined SGAs reported similar positive findings with aripiprazole and risperidone. Both the meta-analyses did not find evidence for the effectiveness of quetiapine or olanzapine in comparison to placebo.,
In addition to efficacy, the commonly reported secondary outcomes are the following:
- Antipsychotic augmentation is effective in the management of both obsessions and compulsions
- There was no significant difference between the antipsychotic and the placebo groups with respect to all-cause discontinuation,
- Medium/standard doses of antipsychotics were found to be more effective than lower doses for augmentation with serotonin reuptake inhibitors (SRIs),
- One meta-analysis which used data from nine studies (n = 278 OCD patients), found that the number needed to treat (NNT) for antipsychotic augmentation in OCD patients with comorbid tics was 2.3 (95% confidence interval [CI] = 1.5–5.2) compared to NNT of 5.9 (95% CI = 0.07–0.27) in those without comorbid tics, suggesting that antipsychotic augmentation may have better response in OCD patients with comorbid tics
- Further, another meta-analysis suggested that antipsychotic augmentation in OCD patients without established SSRI resistance is not beneficial; antipsychotic augmentation should be attempted only after SSRIs have been administered at the recommended dose for at least 8 weeks. The absolute risk difference of treatment response in OCD patients who had received <12 weeks of SRI monotherapy was 0.06 (95% CI = 0.13–0.24) compared to 0.22 for those who had received a full trial
- Another possible treatment predictor that has been examined is comorbid schizotypal disorder. Although better response has been noted in some open-label trials, the same has not been demonstrated in controlled trials and there are no meta-analysis findings.,
Mechanism of action of antipsychotic augmentation
Although widely used, the pharmacological mechanism of antipsychotic augmentation is not very well understood. A mixed model meta-regression analysis attempted to address this issue by analyzing data from 13 RCTs and correlating the effectiveness of each antipsychotic with its receptor-binding profile. It showed that the compounds with greater affinity to dopamine receptors (D2R, D3R) positively correlated with clinical efficacy. This might explain why drugs such as risperidone or FGAs have better efficacy compared to drugs with relatively lesser dopamine receptor binding such as olanzapine and quetiapine.
There also have been attempts using genetic and neuroimaging tools to identify the possible neurobiological basis of antipsychotic augmentation. Positron-emission tomography of risperidone augmentation in SSRI-resistant OCD patients (n = 15) demonstrated that a relatively lower metabolic rate in the striatum and a higher rate in the anterior cingulate cortex might predict clinical response to risperidone augmentation. The only genome-wide association study to identify genetic variants associated with response to the combination of an SSRI and an antipsychotic failed to demonstrate any significant findings. However, using pathway-based analysis, five enriched pathways involved in calcium signaling were identified to be associated with response to antipsychotic combination of SSRIs.
Risperidone versus cognitive behavior therapy
A large RCT which compared risperidone, pill placebo, and ERP in patients with moderately severe OCD (Y-BOCS ≥16) despite 12 weeks of SSRI treatment did not show any benefit from risperidone augmentation. At the end of 8 weeks, the ERP group had significant reduction in the Y-BOCS scores compared to both the pill placebo and the risperidone groups, with the risperidone group showing only comparable efficacy to those receiving pill placebo. In an extension of this study, those who did not respond to risperidone (n = 32) were treated with CBT and 53% had responded (≤25% reduction in the Y-BOCS total score) and 34% remitted (Y-BOCS ≤12) at the end of 4 months suggesting the efficacy of CBT in those who do not respond to risperidone augmentation.
Relative efficacy of antipsychotics
There are only three studies that have compared the differential efficacy of antipsychotics as augmenting agents. A double-blind RCT evaluated the efficacy of aripiprazole (n = 22) and quetiapine (n = 22) in OCD patients with established fluvoxamine resistance. At the end of 12 weeks, there were no responders in either arm but there was a significantly higher number of partial responders in the quetiapine group compared to the aripiprazole group.
A single-blind RCT evaluated the efficacy of olanzapine (2.5–10 mg/day) and risperidone (1–3 mg/day) augmentation in 50 OCD patients who had established SSRI resistance for 8 weeks. No significant difference was noted between the two treatment groups. However, risperidone was more commonly associated with amenorrhea, whereas olanzapine was associated with weight gain.
A retrospective study compared 24 SSRI-resistant OCD patients treated with quetiapine (n = 15) and ziprasidone (n = 9) augmentation. About 80% in the quetiapine group had responded compared to 44% in the ziprasidone group. However, the study did not report whether the difference was statistically significant.
Antipsychotic versus clomipramine augmentation
An open-label trial evaluated the efficacy of quetiapine (n = 11) and clomipramine (n = 10) augmentation in SSRI-resistant OCD patients. There was a significant reduction in the Y-BOCS score at the end of 12 weeks in the quetiapine group but not in the clomipramine group. However, there was no significant difference between the groups at the end of the trial. Discontinuation rates were also similar across the groups with one patient in the clomipramine group discontinuing due to serotonin syndrome.
Paroxetine, fluoxetine, and fluvoxamine are potent inhibitors of CYP enzymes; hence, a combination with antipsychotics (especially SGA) is likely to result in up to 40%–75% elevations in the serum levels of antipsychotics. This may lead to an increased propensity for common adverse effects such as sedation and extrapyramidal symptoms. In addition, the combination of SSRIs and SGAs increases the risk of life-threatening adverse effects such as QTc prolongation and Torsades des pointes. The presence of additional risk factors in patients such as history of syncopal attacks, arrhythmias or cardiac conditions, electrolyte imbalance, family history of sudden unexplained death, and age >65 years warrants caution, including frequent electrocardiography monitoring.
Clinical indications for antipsychotic augmentation
Most guidelines recommend that antipsychotics may be tried in the following clinical scenarios:
- Partial response to SSRI: ≥25% but ≤35% reduction in the Y-BOCS total score and a CGI-I rating of at least 3 (“minimally improved”) lasting for at least 1 week
- Incomplete remission with SSRI: Y-BOCS remains >12 and CGI-severity rating of ≥3 (“mildly ill”)
- No response to at least two SSRIs: <25% reduction in the Y-BOCS score and CGI-rating ≥4 (“no change”).
Duration of antipsychotic trial
The trial duration of most RCTs that have examined antipsychotic augmentation in treatment-resistant OCD varies from 4 to 8 weeks. Given the increased propensity of this combination for adverse effects, it may be recommended that trials for the efficacy should not continue more than 12 weeks. In case of no observable response to treatment, the antipsychotic should be stopped.
Duration of antipsychotic augmentation among responders
There are no methodologically robust studies which have examined this issue; however, a retrospective chart review has evaluated the effects of discontinuation of antipsychotics in those OCD patients who had responded to adjunctive antipsychotic (haloperidol, pimozide, olanzapine, and risperidone). Out of 18 patients, 15 (83.3%) relapsed, with most of the relapses occurring within 2 months of discontinuation. Hence, it is recommended that responders may continue the antipsychotics for at least 1 year, after which discontinuation may be considered following due to consideration of all clinical correlates.
Doses of antipsychotic augmentation
Most RCTs have used lower doses of antipsychotics, and the same findings have been replicated in meta-analyses. Recently, the Indian Psychiatric Society published guidelines for the management of OCD. The expert group reviewed the evidence and recommended the following dosage (with strength of recommendation) in the Indian population. These doses are slightly lower than the recommendations in the recently published meta-analysis [Table 1].
|Table 1: Antipsychotic augmentation in obsessive-compulsive disorder (taken with permission from the Indian Psychiatric Society guidelines for the management of obsessive-compulsive disorder, 2017)|
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In pregnancy and lactation, the decision to employ antipsychotics should be individualized, weighing factors such as severity of OCD, response to antipsychotic augmentation, patient preference, and availability/response to nonpharmacological options such as CBT. The risk-benefit should be clearly explained and documented. Considering available evidence, both regarding the efficacy and possible adverse fetal outcomes, risperidone may be considered as the first-line augmenting agent. Risperidone has demonstrated the efficacy in controlled trials, with no clear evidence regarding its association with increased risk of birth defects. Haloperidol may be recommended as the second-line agent. There is lack of safety data during pregnancy for aripiprazole. Hence, it should be avoided until sufficient data are available.
In lactating mothers also, among the antipsychotics with proven efficacy, risperidone may be considered as the preferred augmenting agent. Although it may promote lactation and no abnormalities have been reported in the infant, it is to be noted that risperidone is excreted in breast milk.
Evidence regarding antipsychotic augmentation in pediatric OCD is lacking. Research findings from the adult OCD population demonstrating increased efficacy in adult patients with comorbid tics suggest possible efficacy of antipsychotic augmentation in pediatric OCD patients who also have an increased proportion of comorbid tics. Nonetheless, there are concerns regarding the adverse metabolic effects of antipsychotics. Hence, they should be discontinued if no improvement is observed after 6–12 weeks of administration. Guidelines suggest that antipsychotic augmentation is considered only if the response to multiple SSRIs is poor and adequate trial of CBT fails.
Limitations and future directions
Although antipsychotics are by far the best studied and had the best evidence among available pharmacological augmenting agents for OCD; most studies have very small sample sizes. Some promising antipsychotics with preferentially strong D2 blockade such as amisulpride are yet to be studied in controlled trials. There is a dearth of studies evaluating the long-term efficacy and adverse effects of antipsychotic agents. Methodologically, robust head-to-head studies comparing various antipsychotic agents and other augmenting agents such as those with glutamatergic and serotonergic actions are sparse.
| Conclusions and Recommendations|| |
Antipsychotics are currently the first-line pharmacological augmenting agents for OCD. Current evidence suggests that among patients augmented with antipsychotics, one in three SSRI-resistant OCD patients will show a response. Among antipsychotics, risperidone, and aripiprazole have the best evidence, with haloperidol to be considered as second-line owing to its unfavorable side-effect profile. Antipsychotics should be administered in low-to-medium doses and should be discontinued if there is an unsatisfactory response after an adequate trial not longer than 3 months. Long-term use should be considered only after weighing the risks and benefits.
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Conflicts of interest
There are no conflicts of interest.
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Dr. T S Jaisoorya
Department of Psychiatry, OCD Clinic, NIMHANS, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None