Aripiprazole

Aripiprazole is the first marketed antipsychotic with D2 partial agonist activity. While the earliest published study by Connor and colleagues examined aripiprazole monotherapy in OCD, all the subsequent trials were add-on in treatment-resistant OCD, that is, serotonin-reuptake inhibitor (SRI) resistant [36,37,38,39,40,41,42].

Evidence from Randomized Controlled Trials

Two double-blinded trials, one by Sayyah and colleagues and another by Muscatello and colleagues, differentiated aripiprazole from placebo after 12 weeks of intervention [38, 39]. First, in the study by Sayyah and colleagues, 39 patients were randomized to receive either aripiprazole 10 mg/day or placebo. Any patient with prominent psychiatric comorbidity was excluded from the study. The mean Y-BOCS score at baseline was 22.21 in the aripiprazole group and 24.12 for the placebo group. After 12 weeks of blinded intervention, the resulting Y-BOCS score was 15.42 in the aripiprazole group and 23.12 in the placebo group (p < 0.0001). Sedation was more commonly reported from the patients receiving aripiprazole (four patients in the aripiprazole group and two in the placebo group) [39]. Muscatello and colleagues conducted a double-blind, placebo-controlled trial of aripiprazole augmentation in serotonin reuptake inhibitor (SRI)-refractory OCD (fluvoxamine, fluoxetine, citalopram, paroxetine, or clomipramine). Thirty patients were randomized to receive either aripiprazole (15 mg/day) or placebo. While change in Y-BOCS score was the primary objective, neurocognitive function was measured using various tools as secondary objectives (the Wisconsin Card Sorting Test, the Verbal Fluency Task-Controlled Oral Word Association Test and the Stroop Color-Word Test). Baseline Y-BOCS score was 23.23 in the aripiprazole group and 23.60 in the placebo group. After 12 weeks of blinded intervention, the mean Y-BOCS score in the aripiprazole group was 16.31 while there was no reduction observed in the placebo group (p < 0.0001). As a secondary outcome analysis, there was a clear trend toward improved neurocognitive functioning in the patients receiving aripiprazole. Restlessness (n = 7) and insomnia (n = 2) were frequently reported in the aripiprazole group [38].

Two head-to-head trials have been published for aripiprazole in the management of treatment-resistant OCD. In a study by Selvi and colleagues, aripiprazole was compared with risperidone as augmenting agents for SRI-resistant OCD. In this single-blind, randomized study, patients who did not show a ≥ 35% decrease in the Y-BOCS scores after 12-week monotherapy with an SRI were randomized to an 8-week single-blind additional period in which refractory patients received either risperidone 3 mg daily or aripiprazole 15 mg daily as augmentation to SRI treatment. Of 41 patients, 50% of aripiprazole and 72.2% of risperidone patients met the response criteria of Y-BOCS decrease ≥ 35% at the end of the study. Mean Y-BOCS total scores between the two groups at weeks 12 and 20 were significant and favored risperidone (r(32) = 2.115, p < 0.05; t(32) = 2.675, p < 0.05). Y-BOCS Obsessions subscale results favored risperidone at weeks 12 and 20 (t(32) = 2.417, p < 0.05; t(32) = 2.630, p < 0.05) [43]. The second head-to-head trial was carried out with aripiprazole and quetiapine as augmenting agents to an ongoing SSRI. In total, 44 female patients were randomized and received blinded treatment of quetiapine (maximum 300 mg/day) or aripiprazole (10 mg/day) for 12 weeks. The mean Y-BOCS score reduction in the quetiapine group was 3.31 (from 31.18 to 27.97, p = 0.01) and 2.45 in the aripiprazole group (from 33.17 to 30.72, p = 0.06), of which clinical significance is unclear [44].

Evidence from Uncontrolled Trials

Open-label trials were of moderate size (ranging 10–40) and used an aripiprazole dose of at least 10 mg/day for a maximum of 12 weeks [36, 37, 40]. The reductions in Y-BOCS score were moderate in these trials. Delle Chiaie and colleagues conducted an open-label study to test the efficacy of aripiprazole in patients with refractory OCD. After excluding patients with any major psychiatric comorbidity or laboratory abnormalities, 20 patients were enrolled to receive aripiprazole (mean dose 12.62 mg/day) for 12 weeks. Treatment outcome was measured by Y-BOCS score and Clinical Global Improvement–Severity scale (CGI-S). Full response was defined as ≥ 35% reduction in the Y-BOCS score. After 12 weeks, mean Y-BOCS score was reduced from 28.99 (baseline) to 15.55 (p = 0.0001) and CGI-S was reduced from 5.1 (baseline) to 2.55 (p = 0.0001) [40].

Case Series and Case Reports

Two case series were reported from patients who failed not only one or more SSRI but also one or more augmenting antipsychotic [41, 45]. Aripiprazole augmentation resulted in mean Y-BOCS score reduction of at least 30% (combined, n = 74 completers). These results suggest that aripiprazole may act uniquely as a partial D2 agonist against pathology of severe OCD.

There have been a number of published case reports describing the successful use of adjunctive aripiprazole in the management of severe OCD [46,47,48,49,50,51,52,53,54,55,56,57,58,59,60]. Patients with different comorbidities have been successfully treated, notably comorbid bipolar disorder [47, 55, 60], major depressive disorder [52, 61], Tourette syndrome [62], and ExD [50]. In cases of OCD with comorbid bipolar disorder, the challenge for the clinician is the relative contraindication to antidepressants due to the possible risk of switching to a manic episode. In the three published cases, aripiprazole was added to a high-dose mood-stabilizing medication, such as lithium, and the patients experienced clinical improvement [47, 55, 60]. Aripiprazole monotherapy has also been reported [61, 62]. Successful use of aripiprazole in OCD with poor insight or with delusion may be of clinical interest, as aripiprazole is an SGA that would be indicated for psychotic disorders [48, 56].

Based on the reviewed evidence, aripiprazole is effective in treating SSRI-resistant OCD, though less efficacious than risperidone.

Clozapine

Evidence from an Uncontrolled Trial

McDougle and colleagues illustrated a 10-week, open-label trial of adult patients with refractory OCD treated with clozapine as monotherapy [63]. Twelve patients (6 women, 6 men; mean age 34.8 years) received flexible dosing of clozapine 300–600 mg/day (mean dose 462.5 mg/day) for a minimum of 8 weeks after a 3-week wash-out period of any other psychotropic medications. Patients were included if their OC symptoms were of moderate severity on the CGI scale for at least 2 years and were refractory, defined as a Y-BOCS score of ≥ 16 or < 35% improvement, no better than minimal improvement on Clinical Global Impression–Improvement (CGI-I) scale, and consensus of no improvement by the primary investigators. Additionally, the patient also had to be refractory to a clomipramine dose of at least 200 mg/day, a fluoxetine dose of at least 60 mg/day, or a fluvoxamine dose of at least 200 mg/day for a minimum of 8 weeks, a combination of clomipramine, fluoxetine, or fluvoxamine with a typical neuroleptic for a minimum of 4 weeks, and a trial of behavioral therapy while receiving medication. Response criteria after initiation of clozapine was defined as > 35% improvement on Y-BOCS scale and final score < 16, a final CGI rating of ‘much improved’ or ‘very much improved’, and a consensus of patient improvement by all primary investigators. Ten patients (83%) completed the trial, of which none met criteria for responders. Two patients discontinued the trial early due to adverse events of sedation and hypotension.

Case Reports

Two case reports (n = 2) demonstrated the use of clozapine for treatment of refractory OCD as monotherapy [64, 65]. Case 1 was a 21-year-old White male who was determined to have treatment refractory OCD after 17 medication trials, electroconvulsive therapy, and other procedures that were all unsuccessful at alleviating his compulsions. After years of failure, the patient was started on clozapine and titrated up to 600 mg/day. A reduction in compulsions was noted, as well as a decrease in score on the Y-BOCS from 36 to 19 at 4 months of treatment [64]. Similarly to the previous case in the number of treatment failures, Case 2 represented a 27-year-old female who was treated with 14 different combinations of SRIs and neuroleptics over 9 years without relief of her aggressive and violent compulsions. The patient was started on clozapine and titrated up to 400 mg/day. This case also noted a decrease in compulsions, as well as a decrease in her Y-BOCS score from 35 to 18 after 3 weeks of treatment [65]. No significant side effects were reported in either of the cases.

Mixed results were observed in the data when clozapine was utilized as monotherapy for treatment of refractory OCD. Though McDougle et al. showed no improvement in their patient population, it should be noted that positive results were seen in the case reports, which represented patients who had a longer history of treatment failure [63,64,65].

Olanzapine

Evidence from a Randomized Controlled Trial

Shapira et al. demonstrated a double-blind, placebo-controlled trial of olanzapine added to fluoxetine in patients with refractory OCD [66]. Patients with a diagnosis of OCD for a minimum of 1 year entered the study (n = 74) and initially underwent a trial of fluoxetine titrated to 40 mg daily and maintained over 8 weeks. A total of 44 patients (18 male, 26 female; mean age 36.9 ± 11.1 years) were deemed non-responders or partial responders to fluoxetine therapy and underwent randomization to receive olanzapine treatment (n = 22) or placebo (n = 22) in addition to fluoxetine. Both groups demonstrated a significant improvement in their Y-BOCS scores (mean decrease of olanzapine: 5.1 ± 4.9 and placebo: 3.8 ± 3.8, p < 0.0001) over 6 weeks of treatment. A total of four patients, two in each group, discontinued treatment due to adverse events. Weight gain was observed more in the olanzapine plus fluoxetine group.

Evidence from Uncontrolled Trials

Maina and colleagues conducted a two-phase trial to analyze the efficacy and safety of risperidone and olanzapine augmentation therapy in patients with treatment-resistant OCD [67]. Patients were enrolled in the first phase if they met criteria for OCD with symptoms present for at least 1 year and had a Y-BOCS score ≥ 16. These patients (n = 96) were entered into a 16-week open-label phase where they received treatment with an SSRI for at least 12 weeks. If patients did not show improvement in their Y-BOCS score or score ≤ 2 on the CGI-I scale, they were considered non-responders and entered into the second single-blind, 8-week phase of the trial. Fifty patients (52%) were considered SSRI-resistant after phase 1 and titrated on risperidone 1 mg daily (n = 25; mean daily dose 2.1 ± 0.6 mg/day, max 3 mg/day) or olanzapine 5 mg daily (n = 25; mean daily dose = 5.3 ± 2.6 mg/day, max 10 mg/day). Twenty-two patients (88%) in the risperidone group and 21 patients (84%) in the olanzapine group completed the trial. Patients within each group demonstrated a significant improvement from baseline in the mean total Y-BOCS score (p < 0.001, both), obsession and compulsion subscores (p < 0.001, both) and in the analysis of CGI-S scores (p < 0.001, both). No differences were detected in the efficacy between both treatment groups at any point in time. Adverse events were seen in both groups, 52% (n = 13) with risperidone and 64% (n = 16) with olanzapine, with the only statistically significant event being increased weight gain with olanzapine (mean 2.8 ± 3.10 vs 0.77 ± 2.16 kg; p = 0.10).

Mixed results were seen when augmenting an SSRI with a SGA in SSRI-refractory OCD patients. Matsunaga et al. conducted a trial to assess the long-term safety and efficacy of augmenting an SSRI with an SGA in this patient population [68]. A total of 137 patients with a diagnosis of OCD were initially assigned to receive fluvoxamine or paroxetine for 12 weeks. At 12 weeks, SSRI responders (n = 46) continued treatment with the SSRI and CBT was added, while SSRI-refractory patients (n = 44) were randomly assigned to receive augmentation with an SGA. Patients were initiated on risperidone (n = 7; mean dose 3.1 ± 1.9 mg/day), quetiapine (n = 18; mean dose 60.0 ± 37.3 mg/d) or olanzapine (n = 18; mean dose 5.1 ± 3.2 mg/day) for at least half a year in combination with CBT. At baseline of augmentation initiation, the SSRI plus atypical antipsychotic (SSRI-AAP) group had significantly higher mean total Y-BOCS score compared with responders (29.3 ± 9.9 vs 25.8 ± 11.4, respectively; p < 0.01), as well as significantly more obsessions, ordering, repeating rituals and hoarding symptoms (all p < 0.01). At 1 year, the mean improvement rate in total Y-BOCS score in the responders group was significantly higher versus the SSRI-AAP group (50.0 ± 14.3 vs 40.4 ± 17.9, respectively; p < 0.01); however, there was no significant difference in the percentage of patients whose improvement rate was > 50%. Increased body weight, increased appetite, mean BMI, and mean fasting blood glucose were all significantly more frequent in the SSRI-AAP group versus the responders after 1 year (all p < 0.01). No patient discontinued treatment due to unwanted side effects. No significant differences were seen across individual antipsychotics in the mean reduction on Y-BOCS total score, follow-up mean BMI, fasting blood glucose, triglycerides, or total cholesterol levels. There was, however, a significantly higher difference seen in the mean rate of increased BMI with olanzapine and quetiapine compared with risperidone (15.4 ± 8.8 and 13.8 ± 9.4 vs 6.5 ± 4.4, respectively; p < 0.01).

Several small studies (n = 6) have demonstrated mixed results with olanzapine used as augmentation to an SSRI in patients considered to have SSRI-refractory OCD. Of a total of 97 patients (48 male, 46 female, 3 unknown; mean age 36.1 years) who entered into each of these trials, 94% (n = 91) completed the desired length of each. The majority of trials analyzed olanzapine augmentation to an SSRI over 4–12 weeks, with the exception of one that looked at outcomes up to 1 year and one trial that included a patient that was augmented with venlafaxine. The most common SSRIs used within the trials included fluoxetine, fluvoxamine, and paroxetine augmented with titrated or fixed doses of olanzapine, with daily doses up to 5 mg (n = 2) and 10 mg (n = 4). The majority of patients were considered responders (n = 54) to olanzapine therapy versus non-responders (n = 37). Response was defined within each trial but the majority used a decrease in Y-BOCS score, ranging from > 25% to 50%, followed by a score of ‘2’ or ‘1’ on the CGI-I scale. Olanzapine was well tolerated with few patients stopping therapy due to unwanted side effects. The most commonly reported adverse events were sedation, weight gain, and increased appetite [69,70,71,72,73,74].

Case Reports

A total of 21 patients were observed through the literature by case reports and case series that demonstrated the use of olanzapine for treatment of OCD as both monotherapy (n = 2) and augmentation (n = 19). Overall, 76% (n = 16) of patients experienced improvement in their OC symptoms, 9.5% (n = 2) of patients worsened based on an increase in Y-BOCS score and one (5%) patient’s symptoms remained unchanged. In two patients (9.5%), the Y-BOCS score was not reported [75,76,77,78,79,80,81,82,83]. The majority of patients were males (74%; mean age 37 years) in the olanzapine as augmentation group. Patients received doses of olanzapine ranging from 1.25 mg/day to 20 mg/day over a period of 3 weeks–2 years. Sixteen patients (78%) showed improvement on their Y-BOCS scores after initiation of olanzapine additional to an antidepressant (n = 15) or a mood stabilizer (n = 1) [75,76,77,78,79,80]. Two patients experienced worsened symptoms when olanzapine was added to fluvoxamine 200 mg daily and paroxetine 40 mg daily, while one patient experienced no change in symptoms [79, 83]. Weight gain (n = 2) and sedation (n = 8) were the most commonly reported adverse events [76, 83]. One patient discontinued treatment after 3 weeks due to sedation despite a decrease in Y-BOCS score [83].

Limited results were seen with patients who received olanzapine as monotherapy for treatment of OCD. Only two case reports were documented, with both stating improvements in OC symptoms with olanzapine monotherapy [81, 82]. Although both stated improvement, one patient did not have a documented Y-BOCS score [82]. The other patient experienced a decrease in his Y-BOCS score over 10 weeks from before olanzapine treatment (Y-BOCS 31) to after (Y-BOCS 16) [81].

The majority of the data analyzed proved olanzapine may be considered an option in treating patients with OCD. All trials presented and most of the case reports showed improvement in OCD symptoms when olanzapine was used in combination with an SSRI. Though limited in data, olanzapine also proved to have positive results in treating patients with OCD when used as monotherapy. The adverse event of weight gain may limit its use, as it was observed in each trial and case.

Paliperidone

Evidence from a Randomized Controlled Trial

One published study by Storch and colleagues is available on the use of paliperidone for OCD in adults. A double-blind pilot study evaluating the efficacy and tolerability of paliperidone augmentation in 34 adults with treatment-resistant OCD who met DSM-IV criteria for OCD and were symptomatic following two or more adequate SRI trials. Patients were treated for 8 weeks with either paliperidone (up to 9 mg per day) or matching placebo in addition to SRI. Use of paliperidone showed significant reductions in obsessive–compulsive symptoms based on Y-BOCS (p < 0.01). Placebo administration was associated with medium-sized, trend-level changes in Y-BOCS (p = 0.05). In exploratory analyses, paliperidone superiority compared with placebo was not significant (p = 0.14). Paliperidone was well tolerated and no significant weight gain was reported with its use [84].

Evidence of paliperidone in OCD is limited to one study, which suggests it may be beneficial in treatment-resistant patients.

Quetiapine

Evidence from Randomized Controlled Trials

The evidence in the use of quetiapine for the management of SRI-resistant OCD has been equivocal. Several randomized, placebo-controlled trials have failed to show significant difference for the quetiapine group [85,86,87,88,89]. In one randomized, placebo-controlled, comparison trial of clomipramine and quetiapine, Diniz and colleagues [85] randomized 54 patients who did not respond to fluoxetine monotherapy (at least 8 weeks) to fluoxetine + placebo, fluoxetine + clomipramine, or fluoxetine + quetiapine (maximum 200 mg/day) groups. Baseline Y-BOCS score was 24.98 in the three treatment groups. The mean age of the patients was 33.78 (range 18–64) with mean duration of illness of 18.13 years. Nineteen (35%) patients were comorbid with BDD, four patients with TTM, and 13 (24%) with ExD. There were high rates of current mood episode (32 patients, 59%) and anxiety disorders (42 patients, 78%). Mean dose of fluoxetine was 72.96 mg/day, while the mean for the clomipramine + fluoxetine group was 66.67 mg/day due to pharmacokinetic interaction with clomipramine. Mean dose of quetiapine was 142 mg/day, with sedation and drowsiness being the most intolerable adverse effect. After 12 weeks of blinded treatment, the final Y-BOCS score was 18 in the fluoxetine + placebo, 18 in the fluoxetine + clomipramine and 25 in the fluoxetine + quetiapine group (p < 0.001). The authors attributed quetiapine’s failing to show difference to the frequent psychiatric comorbidities in the patients and the high placebo response rate [85]. It may also be that the duration of SSRI monotherapy treatment was not adequate and patients continued to respond to SSRI monotherapy beyond the screening phase.

Trials that differentiated quetiapine from placebo showed a wide range of therapeutic response [44, 90,91,92,93]. In a placebo-controlled, single-blind study by Atmaca and colleagues, 27 patients were deemed to have treatment-refractory OCD after 3 months of open-label screening phase of a single SRI therapy, and were randomized into quetiapine augmentation or placebo group. There was no significant difference between the groups with respect to current age, number of previous failed SRI treatment, or the baseline Y-BOCS score (23.9). Half of the patients had comorbid Axis I disorder (major depressive disorder, social phobia, hypochondriasis, and panic disorder). After 8 weeks of intervention, the mean Y-BOCS score decreased from 24.1 to 13.4 in the quetiapine group (p < 0.05), with non-significant change in the placebo group (− 2.4) [90]. In a head-to-head trial by Shoja Shafti and Kaviani [44], quetiapine was compared with aripiprazole in the management of fluvoxamine-refractory OCD, resulting in a clinically insignificant outcome (see Sect. 4.1.1).

Case Reports

Adjunctive use of quetiapine in treatment-resistant OCD has been described in three case reports (six patients). Five out of six patients had comorbid mood or anxiety disorder (age range 22–65 years, men and women). Two patients reported partial response to risperidone prior to a trial of quetiapine. Low-dose quetiapine (up to 200 mg/day) was added to ongoing SRI as augmentation. In all cases, the final Y-BOCS scores were at or below 16 [94,95,96].

Quetiapine has shown mixed outcomes in treatment of SRI-resistant OCD. The controlled trials that assessed quetiapine had limitations, which makes it difficult to conclude the true benefit of quetiapine as an augmenting agent for treatment-resistant OCD. All the published case reports had positive outcomes from quetiapine, which suggest a possible benefit of quetiapine, though not conclusive.

Risperidone

Evidence from Randomized Controlled Trials

Studies of exposure and response prevention (EX/RP) compared with risperidone generally show superiority of EX/RP. A trial of 100 patients on therapeutic SRI dose with at least moderate OCD severity was conducted in which patients were randomized to 8 weeks of EX/RP, risperidone, or placebo. Patients who responded entered a 6-month maintenance phase continuing the augmentation strategy received acutely. According to intent-to-treat analyses, EX/RP demonstrated superior OCD outcomes compared with risperidone following the 6-month maintenance treatment based on the Y-BOCS (10.95 vs 18.70; p = 0.009). A greater percentage of patients in the EX/RP group met response criteria (Y-BOCS decrease ≥ 25%: 70 vs 20%; p < 0.001) and achieved minimal symptoms (Y-BOCS ≤ 12: 50 vs 5%; p < 0.001). The authors concluded that OCD patients taking SRIs who responded to EX/RP or risperidone during the acute phase maintained their improvement over the 6-month maintenance phase and EX/RP demonstrated superior outcomes after the 6-month maintenance phase [97]. Simpson and colleagues conducted a randomized clinical trial to compare two SRI augmentation strategies with placebo in adult patients with OCD. Patients included in this study had at least moderate OCD despite therapeutic SRI dose for at least 12 weeks before study entry. One hundred patients were randomized and 86 completed the trial. Patients were randomized to 8 weeks of risperidone 4 mg daily, EX/RP, or pill placebo in addition to SRI therapy. Patients in the EX/RP group had significantly greater reduction in Y-BOCS scores by week 8 (EX/RP vs risperidone: mean [SE] − 9.72 [1.38]; p < 0.001 and EX/RP vs placebo: mean [SE] − 10.10 [1.68]; p < 0.001). A greater percentage of patients receiving EX/RP responded (Y-BOCS score decrease ≥ 25%) compared with risperidone and placebo (80 vs 23% vs 15%, respectively; p < 0.001) and achieved minimal symptoms (Y-BOCS score ≤ 12; 43 vs 13 vs 5%, respectively; p = 0.001). The authors concluded that adding EX/RP was superior to risperidone and placebo as augmentation in OCD patients receiving SRIs [98]. Wheaton and colleagues examined moderators and predictors of these augmentation strategies in a separate analysis. Patients who were on a stable SRI dosage were randomized to EX/RP, risperidone, or placebo. Significant moderators were pretreatment OCD severity, age, and depression. SRI augmentation with EX/RP was more effective than risperidone, and EX/RP superiority increased with baseline OCD severity and younger age [99].

Hegde and colleagues evaluated 92 patients with OCD who were initiated on risperidone augmentation without CBT and who had been receiving stable and adequate doses of SRIs for at least 12 weeks. Twenty-five percent of patients continued risperidone at the time of last follow-up and the remainder of patients discontinued risperidone due to intolerability or ineffectiveness. Patients who continued to take risperidone had significantly greater decrease in Y-BOCS scores compared with patients who did not continue (41.6 vs 3.7%; p < 0.001). Twenty-four percent of patients experienced a reduction of at least 25% in Y-BOCS score [100]. In a double-blind, placebo-controlled trial of risperidone augmentation to SRI therapy in adult, treatment-resistant OCD patients, patients who failed at least two SRI trials received either risperidone 0.5–3 mg daily or placebo for 8 weeks following 12 weeks of SRI treatment. This study included 16 patients. Four patients of ten on risperidone, compared with none in the placebo group, responded with CGI-I score 1 or 2 and a Y-BOCS score decrease ≥ 25% [101]. In another double-blind, placebo-controlled study, McDougle and colleagues evaluated risperidone addition in patients with OCD refractory to SRI treatment. Thirty-six patients were randomized to risperidone or placebo for 6 weeks. Fifty percent of risperidone-treated patients responded compared with no patients in the placebo group (p < 0.005). Risperidone was significantly superior to placebo in decreasing OCD, depressive, and anxiety symptoms. Risperidone was well tolerated [102]. A double-blind, placebo-controlled study of low-dose risperidone augmentation of fluvoxamine treatment in OCD patients was conducted by Erzegovesi and colleagues. Forty-five patients were included and 39 patients completed the study. Five patients (50%) receiving risperidone were responders compared with two (20%) in the placebo group according to Y-BOCS scale reduction by ≥ 35%. Risperidone was generally well tolerated [103]. In an open label study of 20 refractory OCD patients, risperidone was added and titrated to mean dose of 3 mg daily over 8 weeks. All patients had a reduction in OCD symptoms according to decreased Y-BOCS total score. Risperidone was well tolerated [104]. Saxena and colleagues evaluated 21 SRI-refractory OCD patients who received adjunctive risperidone (mean dose 2.75 mg daily). Five patients experienced akathisia and discontinued treatment. Sixteen patients continued combined treatment and 14 experienced significant reductions in OCD symptoms within 3 weeks [105].

Risperidone augmentation has been compared with other antipsychotic drugs as well. In a single-blind, randomized study, risperidone was compared with aripiprazole (see Sect. 4.1.1) [43]. A double-blind, placebo-controlled, crossover study comparing 2-week adjunctive treatment with risperidone, haloperidol, and placebo in patients with OCD with severe symptoms on a stable dose of SRI was conducted by Li and colleagues. Sixteen patients were enrolled but 12 completed the study. Both risperidone and haloperidol significantly decreased obsession according to the Y-BOCS (p < 0.05). A decrease in the Hopkins Symptom Checklist 90–revised (SCL-90R) anxiety scale score was also observed. Risperidone improved depressed mood according to the Hamilton Rating Scale for Depression (HAM-D), the SCL-90R depression scale, and the Profile of Mood States. Five of 12 patients discontinued haloperidol treatment early due to adverse effects. All patients in the risperidone group completed the 2-week treatment [106]. Maina and colleagues conducted an 8-week, single-blind, randomized trial comparing risperidone (1–3 mg daily) with olanzapine (2.5–10 mg daily) in addition to SRI treatment. Patients included in this study were those with OCD who did not demonstrate a ≥ 35% decrease in Y-BOCS score after 16 weeks of SRI treatment. Of 50 patients randomized to risperidone or olanzapine, significant response was observed in both groups, but no difference between the two treatment groups was noted [67]. In another study, 44 OCD patients who failed to respond to SSRIs were randomized to receive olanzapine, quetiapine, or risperidone and were treated with an SSRI plus atypical antipsychotic in combination with CBT for 1 year. Atypical antipsychotic augmentation reduced Y-BOCS total scores in SSRI-refractory patients. Compared with SSRI responders, total Y-BOCS scores for patients who received atypical antipsychotics were initially higher (SSRI-refractory patients 29.3 ± 9.9 vs SSRI responders 25.8 ± 11.4; p < 0.01) and remained higher following 1 year of treatment (19.3 ± 6.8 vs 13.7 ± 4.6; p < 0.01). Patients in the atypical antipsychotic group reported significantly more frequent increased appetite and increased body weight [68].

Case Reports

Several case reports on risperidone use in OCD patients have been published. McDougle and colleagues report on three OCD patients who were unimproved after a minimum of 12 weeks of fluvoxamine treatment. Risperidone 1 mg daily was added to fluvoxamine therapy. All three patients demonstrated significant improvement in Y-BOCS following risperidone addition. Y-BOCS scores decreased by 65, 56 and 43% for the three patients, respectively, within 4 weeks of risperidone treatment. Risperidone was well tolerated with mild to moderate sedation noted [107]. Yoshimura and colleagues reported three OCD patients who were successfully treated with the addition of low-dose risperidone (0.5–1 mg/day) to fluvoxamine with improvement in OCD symptoms and no evidence of extrapyramidal symptoms or other adverse events [108]. The case of a 43-year-old male with OCD treated with clomipramine 200 mg daily, who saw decrease in OCD symptoms and Y-BOCS score with addition of titrated risperidone therapy, is presented by Kawahara and colleagues [109]. Sun and colleagues reported two OCD patients who had poor response to fluoxetine and paroxetine. Neither patient received behavioral therapy or psychotherapy. Both patients demonstrated significant improvement in Y-BOCS scores after addition of risperidone 1 mg daily to paroxetine therapy. Following 4 weeks of risperidone, Y-BOCS scores reduced by 57 and 53% [110]. Ravizza and colleagues evaluated the short-term efficacy and safety of adjunctive risperidone in SSRI-refractory OCD patients. Fourteen patients who were SSRI nonresponders received risperidone augmentation and showed good clinical improvement and drug tolerability [111]. Stein and colleagues reviewed charts of patients treated in an OCD clinic with an SSRI and risperidone combination. Eight OCD patients were refractory to SSRI treatment and had received risperidone augmentation. Three OCD patients reported very much or much improvement in OCD symptoms, one patient minimal to much improvement, and one patient experienced intolerable side effects of increased anxiety and irritability [112]. Agid and Lerer present the case of a 25-year-old White male with severe, treatment-refractory OCD who responded with improved obsessive and compulsive symptoms to the addition of risperidone 0.5 mg daily in addition to paroxetine treatment [113]. In contrast, a case report of a 21-year-old OCD patient with no comorbid disorders receiving fluoxetine therapy whose obsessive–compulsive symptoms rapidly worsened with the addition of risperidone titrated up to 3 mg daily over 3 days has been reported. Following risperidone discontinuation, the patient gradually recovered over the course of 3 months; however, he did not attain pre-risperidone status [114].

Evidence reveals EX/RP is superior to risperidone, and risperidone augmentation is superior when compared with placebo. One study comparing aripiprazole to risperidone showed risperidone augmentation to be superior. When compared with haloperidol or olanzapine, both risperidone and comparator drug decreased OCD symptoms but no difference was seen between the two groups. One study comparing olanzapine, quetiapine, and risperidone showed reduced Y-BOCS scores in all patients who received atypical antipsychotic augmentation. The majority of case reports and series describe improved OCD symptoms with the addition of risperidone.

Ziprasidone

Evidence from Uncontrolled Trials

Published data on ziprasidone for OCD are limited. Bruno and colleagues performed a 12-week, open-label, uncontrolled trial on ziprasidone as add-on therapy in patients with treatment-resistant OCD being treated with SRIs. In 17 patients studied, add-on ziprasidone moderately but significantly reduced compulsive symptoms based on the Y-BOCS score. No patient experienced a full response defined as ≥ 35% reduction in Y-BOCS score [115]. Savas and colleagues conducted a retrospective evaluation of 24 treatment-resistant OCD patients followed for 24 weeks. Patients had OCD without psychotic features according to DSM-IV criteria. Fifteen patients were prescribed quetiapine (100 mg/day titrated up to maximum of 1200 mg/day) and nine patients were prescribed ziprasidone (80 mg/day titrated up to a maximum of 160 mg/day) as adjunctive therapy to high dose SRIs. Patients who did not reach the 6-month follow up, had a history of severe physical illness, alcohol and substance abuse or dependence, comorbid psychiatric conditions, or who were treated with a combination of antidepressants, typical antipsychotics, atypical antipsychotics other than quetiapine and ziprasidone, or mood stabilizers were not included. Clinical improvement was defined as an improvement of ≥ 30% on the Y-BOCS score 2 months after the initial diagnosis. Clinical improvement was observed in 80% of quetiapine-treated patients and 44.4% of ziprasidone-treated patients (p > 0.05). The mean Y-BOCS scores for the ziprasidone group were significantly higher than the quetiapine group at 2-, 3-, and 6-month follow-up (p < 0.05). CGI-S scores were higher in the ziprasidone group at 2-, 3-, and 6-month follow-up (p < 0.05) [93].

Limited evidence with ziprasidone for OCD shows moderate improvement with the drug and that it was less effective than quetiapine in one study.

Review of Available Meta-Analyses and Reviews for the Efficacy of SGAs for OCD

Bloch and colleagues conducted a meta-analysis of nine double-blind, randomized, placebo-controlled trials of antipsychotics as augmentation treatment for treatment-refractory OCD (n = 278; 3 quetiapine, 3 risperidone, 2 olanzapine and 1 haloperidol). Based on response criteria of 35% reduction in Y-BOCS score, haloperidol and risperidone were deemed efficacious while the evidence for olanzapine and quetiapine was inconclusive. Overall, antipsychotic augmentation was efficacious in one third of the patients [116].

The subsequent meta-analysis of randomized controlled trials assessing efficacy of SGAs in treatment-resistant OCD was conducted by Skapinakis and colleagues. In this meta-analysis, ten trials were included (1 haloperidol, 3 risperidone, 2 olanzapine, 4 quetiapine). Criteria for successful treatment was the percent reduction in Y-BOCS set by respective investigators (35% reduction in 5 trials and 25% in the other 5 trials). The authors concluded that antipsychotics were associated with a higher response rate than placebo, though a high level of heterogeneity among the trials was present. The heterogeneity was reduced when moderate-high dose was used and when the duration was > 8 weeks. Treatment-associated adverse effects were not addressed [117].

Komossa and colleagues conducted a review of SGAs in OCD (11 trials, n = 396). Based on treatment response definition of at least 25% reduction in Y-BOCS score, risperidone was more efficacious than placebo in the primary outcome (25% reduction in Y-BOCS score). While olanzapine had some efficacy-related outcomes, it was offset by strong risk of weight gain. Quetiapine was not any more efficacious than placebo [118]. Haloperidol was not included in the review because of its predictable risk of extrapyramidal adverse effects and because the single trial that was conducted with haloperidol was prior to most trials with atypical antipsychotics.

A report by the Agency for Healthcare Research and Quality on the efficacy of SGAs in off-label uses, including OCD, concluded that risperidone and quetiapine may have efficacy, but the adverse effects were common. Risperidone as augmentation of an SSRI had moderate-to-high evidence, while olanzapine as augmentation of an SSRI had low-to-very low evidence. Quetiapine showed low-to-very low evidence as augmentation of citalopram, but this was conflicted with moderate-to-high evidence of inefficacy as augmentation of an SSRI. There was no trial available for asenapine, iloperidone, and paliperidone [119].

Dold and colleagues conducted a review of double-blind, placebo-controlled, randomized trials of 14 studies that comprised of 491 participants with OCD resistant to SRI. The impact size was the greatest with quetiapine (n = 142), followed by risperidone (n = 132), aripiprazole (n = 79), olanzapine (n = 70), paliperidone (n = 34), and haloperidol (n = 34). Mean Y-BOCS score decrease was the primary outcome of the meta-analysis. Statistically significant superiority over placebo was noted in aripiprazole, haloperidol, and risperidone trials, while olanzapine, paliperidone, and quetiapine trials failed to differentiate from placebo. Response rate as defined by Y-BOCS decrease ≥ 35% was 30% overall (compared with 12.5% in placebo). There were overall significantly more adverse effects in the antipsychotic treatment group compared with placebo group, although the discontinuation rate did not differ between the groups [120]. Earlier meta-analysis led by the same author concluded that only risperidone had significant benefit based on absolute Y-BOCS score reduction and a 35% decrease cut-off in Y-BOCS score as response. Aripiprazole and haloperidol were then each supported by a single trial and, thus, were not classified as having strong evidence [121].

According to a systematic review and meta-analysis by Maher and colleagues, the overall evidence of SGAs in the treatment of OCD in patients who were resistant to an SSRI was deemed moderate. Ten placebo-controlled trials with olanzapine, quetiapine, aripiprazole, and risperidone were reviewed against treatment response criteria of change in Y-BOCS score. Two trials with olanzapine did not show significant improvement compared with placebo, and five trials with quetiapine only showed a trend toward improvement with antipsychotic treatment, with no statistical significance. While the three trials with risperidone showed superior outcome with the antipsychotic, the potential for publication bias was present [122].

Veale and colleagues published a meta-analysis of 14 placebo-controlled, randomized clinical trials of SGAs in SRI-resistant OCD (n = 493) [123]. The authors sought to identify the appropriate place of therapy as part of stepped care for patients with SRI-resistant OCD according to UK treatment guidelines. Included trials had one of the following SGAs: risperidone (4 trials), olanzapine (2 trials), quetiapine (5 trials), paliperidone (1 trial) and aripiprazole (2 trials). Efficacy was defined as change in Y-BOCS score after antipsychotic augmentation. Statistically significant superiority was seen only in risperidone and aripiprazole trials. The authors did not report overall adverse effects across the included trials [124].

Table 2 Summary of high evidence studies of second generation antipsychotics for obsessive–compulsive disorder Full size table

Summary Statement for OCD

Based on the review of data, aripiprazole and risperidone may have the most benefit as an augmentation strategy to SRIs in patients with SRI-resistant OCD. Evidence remains inconclusive for quetiapine, while severe metabolic adverse events limit olanzapine use, though the evidence is greater than for quetiapine. Paliperidone seems promising, given that it is a metabolite of risperidone. Table 2 summarizes high-evidence clinical trials in OCD.