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The following sections review evidence on the outcomes of pharmacological treatments for OCD. Unless otherwise indicated, outcomes are given for the intent-to-treat (ITT) sample with the last-observation-carried-forward (LOCF) method. ITT results inform the clinician of what outcome to expect when considering all patients exposed to a treatment. Results reported for patients who completed the study, by contrast, indicate what to expect for those exposed to completed durations of treatment. Finally, visitwise outcome results indicate likely outcomes for patients exposed to those particular durations of treatment. In considering "responder" rates reported in OCD pharmacotherapy studies, it may be helpful to keep in mind the responder rates reported in subjects in the placebo arms of such studies. As noted previously in Section II.B.6, "responders" are variously defined as subjects who experience a 25% or 35% decrease in Y-BOCS score or a CGI-I score of 1 (very much improved) or 2 (much improved), usually after 12 weeks of treatment. In one analysis of studies published before 1997, responder rates in placebo subjects ranged from 0% to 35% (mean 15%), with later studies generally reporting higher placebo response rates (70). In the interest of brevity, the responder criteria specified above are symbolized in this section as follows: YBOCS-25%, YBOCS-35%, and CGI-I:1,2.

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1. Efficacy of Clomipramine

Clomipramine is a mixed serotonin and norepinephrine reuptake inhibitor (and cholinergic and histaminic blocking agent) introduced in Europe in 1966 for treating depression. It was subsequently used for OCD and was approved by the FDA in 1989 for the treatment of OCD in the United States.

Randomized controlled studies have found clomipramine significantly superior to placebo in the treatment of OCD. However, no adequate studies have determined the minimally effective or optimal clomipramine dose. Trials directly comparing clomipramine with certain SSRIs (e.g., fluoxetine, fluvoxamine, and paroxetine) report equal effectiveness. However, in some studies the SSRIs appear to have better tolerability. Sample sizes limited the power of most of these studies to detect differences, and most studies did not include a placebo comparison group. Thus, although clomipramine is recommended for treating OCD, safety and tolerability issues favor the SSRIs.

The Clomipramine Collaborative Study (390), the first large, double-blind, placebo-controlled trial in the United States of a pharmacotherapy for OCD, was a landmark for the treatment of OCD in general, and clomipramine treatment specifically. This 10-week, double-blind, placebo-controlled, multicenter study included 260 subjects in each group. Subjects who had not received prior CBT or clomipramine and scored 16 on the Y-BOCS and 7 on the National Institute of Mental Health Obsessive-Compulsive Scale (NIMH-OC) were included. Subjects took clomipramine at a dose of at least 200 mg/day or matched placebo, with the opportunity to increase the dose to 300 mg/day. The mean Y-BOCS score in the clomipramine group decreased 40% compared with 4% in the placebo group. The YBOCS-35% responder rate in the clomipramine group (55%) far exceeded that in the placebo group (7%). In a 1-year extension (391) in a subsample (n = 134) of participants in the Clomipramine Collaborative Study, OCD symptoms fell to the subclinical range in 50% of the clomipramine group, compared with 4% of the placebo group. CGI-I:1,2 responder rates for clomipramine were 50% versus 7% for placebo. Adverse reactions, however, led 17 of the 129 (13%) subjects taking clomipramine to drop out of the study.

Many additional randomized, double-blind, placebo-controlled studies or active-comparator studies support the effectiveness of clomipramine treatment of OCD (70, 392, 392b). Taken together with the findings of the Clomipramine Collaborative Study, these studies indicate that clomipramine at doses of up to 250 mg/day is an effective treatment for OCD. Adverse effects, especially anticholinergic and cardiovascular effects and weight gain, are common; however, dropout rates are not high except in one study (393). Clomipramine may elevate levels of liver transaminases, and a potential for seizures exists at doses exceeding 250 mg/day.

Several studies have compared clomipramine with other medications (also see Section V.A.2). Pigott et al. (394) compared clomipramine 250 mg/day (n = 5) and fluoxetine 40 mg/day (n = 6) in a small crossover trial of 10 weeks on each drug with a 4-week washout period interposed. The Y-BOCS score decreased significantly in both groups, with no between-group significant difference. Lopez-Ibor et al. (395) found no difference in Y-BOCS score decrease in an 8-week, double-blind comparison of clomipramine 150 mg/day (n = 25) and fluoxetine 40 mg/day (n = 30). The YBOCS-25%, but not the YBOCS-35%, responder rate was significantly higher for clomipramine. The drugs did not differ in dropout rates. This study was, however, small, had no placebo control arm, and used low doses of both medications.

A 10-week, multicenter, randomized controlled trial (396) compared clomipramine (n = 34; maximum dose = 250 mg) and fluvoxamine (n = 30; maximum dose = 250 mg). All patients had a Y-BOCS score 16 at baseline, and half of the patients had had prior treatment. Improvement in Y-BOCS score was equivalent (fluvoxamine mean Y-BOCS score decrease = 8.6; clomipramine decrease = 7.8). Both medications were well tolerated, but the clomipramine group experienced more sexual dysfunction. In a 10-week, multicenter, randomized controlled trial, patients scoring 16 on the Y-BOCS were treated with clomipramine (n = 65; maximum dose = 300 mg, mean = 206 mg) or fluvoxamine (n = 37; maximum dose = 300 mg, mean = 212 mg). The drugs were equally effective (YBOCS-25% responder rates for clomipramine and fluvoxamine were 56% and 54%, respectively). Both medications were well tolerated, with no difference in dropout rates due to adverse events (397). Another 10-week, multicenter, randomized controlled trial enrolling patients scoring 16 on the Y-BOCS compared clomipramine (n = 42; maximum dose = 250 mg, mean = 255 mg) with fluvoxamine (n = 37; maximum dose = 300 mg, mean = 201 mg). The drugs were equally effective, but fluvoxamine was better tolerated; constipation and dry mouth were problematic in the clomipramine group (398).

In a 12-week, double-blind, flexible-dose trial that included a placebo arm, clomipramine (n = 99; 150–250 mg/day, mean = 113 mg/day) and paroxetine (n = 201; 20–60 mg/day, mean = 37 mg/day) produced equal Y-BOCS-25% responder rates (55%), which were significantly higher than that associated with placebo (35%) (393). Paroxetine was significantly better tolerated than clomipramine; withdrawal rates for treatment-emergent adverse events were 17% for clomipramine, 9% for paroxetine, and 6% for placebo. However, the placebo group had more subjects with "serious" treatment-emergent adverse events (6.1%) than did the clomipramine (2.5%) or placebo (2.0%) groups.

At least five meta-analyses have evaluated randomized, double-blind, controlled studies comparing clomipramine with SSRIs. A meta-analysis of studies comparing clomipramine and fluoxetine reported a greater effect size (Cohen's d) for clomipramine (1.84) than for fluoxetine (1.34) (399), but with fewer adverse events for fluoxetine. Dropout rates did not differ. A later meta-analysis (400) found the effect size (Cohen's d) for fluoxetine (3.45) in seven studies to be greater than that for clomipramine (3.24) in 12 studies, with a lower dropout rate for fluoxetine subjects. Using data on subjects who completed the studies, Abramowitz (69) found a modestly greater effect size (Cohen's d) for clomipramine than for certain SSRIs (effects sizes: clomipramine vs. placebo, 1.31/0.66 [clinician rating/patient rating], fluvoxamine vs. placebo, 1.28/0.37; sertraline vs. placebo, 0.37/ 1.09; fluoxetine vs. placebo, 0.68/[no patient rating done]). When the difference in side-effect profiles between clomipramine and placebo was statistically adjusted to zero, the superiority of clomipramine over the SSRIs disappeared. Eddy et al. (59) also found a greater effect size (Cohen's d) for clomipramine in analyzing 32 randomized controlled studies (18 involving clomipramine) published between 1980 and 2001, enrolling 3,500 subjects. The pre-post clomipramine effect size was 1.55; the sertraline effect size (largest among the SSRIs) was 1.36. This result must be viewed with caution because more subjects in the clomipramine trials were treatment naive, one-third of potential subjects were excluded from the studies, and only 80% completed the trials. A meta-analysis using meta-regression (effect-size modeling using least-squares regression) applied to 25 randomized controlled trials published between 1989 and 1997 found that the superiority of clomipramine over fluoxetine, fluvoxamine, and sertraline in placebo-controlled trials persisted after heterogeneity effects were controlled for (70). There was no significant difference among the SSRIs in comparisons with placebo-controlled trial results.

Several explanations have been proposed for this disparity in results between placebo-controlled and clomipramine-SSRI direct comparison studies. Abramowitz (69) suggested that clomipramine's apparent superiority may have resulted from its more obvious side effects, thus diminishing the integrity of the blind in placebo-controlled studies. Further doubt is cast on the larger effect size of clomipramine compared with the effects of the SSRIs by the fact that double-blind trials directly comparing clomipramine with fluvoxamine, fluoxetine, and paroxetine showed no difference (70), and a double-blind comparison with sertraline found sertraline more effective (401). This latter result was strongly influenced, however, by inappropriately high starting doses of clomipramine (50 mg/day), which led to a high dropout rate, and by low maximum clomipramine doses. A meta-analysis using meta-regression (70) found that age at onset, pre-trial OCD severity, date of publication, trial length, and length of single-blind prerandomization each affected the magnitude of the treatment effect; but after these predictive factors were controlled for, clomipramine still appeared superior in comparisons across placebo-controlled trials.

Clomipramine has been compared, albeit in methodologically limited studies, with the MAOIs clorgyline and phenelzine. A small crossover study with 6-week drug treatment periods found a significant effect for clomipramine but not for clorgyline (402). A 12-week randomized trial comparing clomipramine 225 mg/day (n = 16) with phenelzine 75 mg/day (n = 14) found no difference, but the study was very underpowered and used nonstandard outcome measures (403).

Foa et al. (123) compared clomipramine (n = 36), intensive CBT consisting of ERP (n = 29), clomipramine plus intensive ERP (n = 31), and placebo (n = 26). In this 12-week randomized trial enrolling subjects with Y-BOCS 16, no major depression, and no prior adequate treatment with clomipramine or ERP, clomipramine was more effective than placebo. Intensive ERP combined with clomipramine was more effective than clomipramine alone but was not more effective than intensive ERP alone.

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a. Intravenous Clomipramine

A few investigators have studied the effects of intravenously administered clomipramine, which produces higher immediate plasma levels by avoiding first-pass liver metabolism. However, this treatment is not available in the United States. In controlled trials, intravenous clomipramine has been shown to be superior to placebo in treatment-resistant patients (404). Pulse-loaded intravenous clomipramine was more rapidly effective than identical oral doses in a double-blind pilot study (405), but a larger study did not confirm this finding (85). Both studies reported therapeutic effects in some patients with very treatment-resistant OCD, suggesting that rapid escalation of oral doses may help such patients. Pulse-loaded intravenous clomipramine was more effective than gradually increased intravenous clomipramine, and more rapidly so in a study in which intravenous treatment was followed by treatment with orally administered clomipramine (406).

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b. Clomipramine as an Augmentation Agent

The strategy of adding clomipramine to an SSRI or vice versa is supported by expert opinion (140, 175) and several open-label trials. In a randomized, open-label, 90-day trial that compared adding clomipramine or nothing to citalopram in patients who had failed to benefit from adequate 16-week trials of both clomipramine and fluoxetine, nine of nine patients in the clomipramine augmentation group were YBOCS-35% responders, versus only one of seven patients assigned to citalopram alone (176). In patients with an inadequate response to 6 months of clomipramine 150 mg/day, Ravizza et al. (407) reported a better response and fewer side effects when sertraline 50 mg/day was added to clomipramine 150 mg/day than when the clomipramine dose was raised to 250 mg/day.

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2. Efficacy of SSRIs

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a. Fluvoxamine

Double-blind, placebo-controlled, and active-comparator studies indicate that fluvoxamine is significantly more effective than placebo and equal in efficacy to clomipramine and certain SSRIs (citalopram, paroxetine), although the sample size for the latter comparison was small. Compared with clomipramine, fluvoxamine showed fewer anticholinergic side effects and better tolerability. Whether the combination of fluvoxamine and CBT (particularly ERP) is more effective than CBT alone is uncertain because of methodological shortcomings in available studies.

An early double-blind, placebo-controlled trial (408) reported positive findings when 42 OCD patients—half of whom also had depressive symptoms—were randomly assigned to receive fluvoxamine (up to 300 mg/day, mean final dose = 255 mg/day) or placebo for 6–8 weeks. Nine of 21 fluvoxamine patients were CGI-I:1,2 responders (mean Y-BOCS score decrease from baseline = 42%) versus none in the placebo group. The majority of week 6 partial responders became full responders at week 8 of fluvoxamine treatment, suggesting that at least 8 weeks of treatment are needed to detect a full clinical response.

A 10-week, double-blind trial (409) randomly assigned 40 OCD subjects to receive fluvoxamine (up to 300 mg/day, mean maximum dose = 294 mg/day) or placebo and reported a statistically significant greater improvement for fluvoxamine than for placebo on Y-BOCS and NIMH-OC but not CGI measures.

Two pivotal 10-week, multicenter, double-blind, placebo-controlled studies with identical study protocols provide convincing evidence for the therapeutic efficacy of fluvoxamine in OCD (410, 411). Subjects met DSM-III-R criteria for OCD of at least 12 months' duration and had an NIMH-OC scale score of 7 and a 17-item Hamilton Depression Rating Scale (Ham-D) score of 19. Seventy-nine (410) and 78 (411) fluvoxamine-treated subjects and 78 (410) and 80 (411) placebo-treated subjects completed the studies. Fluvoxamine was flexibly titrated to 100–300 mg/day. At week 10, the mean fluvoxamine doses were 245 and 251 mg/day, at which time the mean Y-BOCS score had fallen 21% in the fluvoxamine groups compared with 7% in the placebo groups (among patients who received at least one postbaseline rating). A statistically significant difference between the two groups was first observed at week 6. CGI-I:1,2 response (ITT) was achieved in 33% and 38% of fluvoxamine subjects compared with 9% and 15% of placebo subjects.

In the largest double-blind, placebo-controlled fluvoxamine trial (412), 253 OCD subjects were randomly assigned to receive fluvoxamine controlled release or placebo (efficacy analyses: n = 237, 117 fluvoxamine controlled release, 120 placebo). After 12 weeks, fluvoxamine was significantly more effective than placebo on all efficacy measures, including the Y-BOCS and CGI scales. YBOCS-25% and YBOCS-35% response rates were significantly higher in the fluvoxamine group, as were remission rates (44% vs. 31% and 18% vs. 8%, with Y-BOCS score definitions of 16 and 8, respectively). Therapeutic effects were evident at week 2, which is earlier than reported in other fluvoxamine versus placebo studies, with the earlier onset of effects perhaps attributable to the higher starting dose (100 mg/day). Fluvoxamine, although having more side effects (e.g., insomnia, nausea, somnolence) than placebo, was safe and generally well tolerated.

In double-blind, active-comparator studies, fluvoxamine was superior to desipramine and as efficacious as other SRIs (clomipramine and some SSRIs); however, the lack of placebo control groups prevents calculating the net drug effect (i.e., active drug effect minus placebo effect).

In an 8-week trial (413), OCD subjects were randomly assigned to receive fluvoxamine (up to 300 mg/day, mean final dose = 214 mg/day) or desipramine (up to 300 mg/day, mean final dose = 223 mg/day). Forty subjects completed at least 2 weeks of treatment and were included in the efficacy analysis. The mean Y-BOCS score decreased 29% from baseline in the fluvoxamine group and was virtually unchanged in the desipramine group.

In a 12-week trial (414), 12 OCD subjects were randomly assigned to receive fluvoxamine or clomipramine (both up to 200 mg/day). For the 10 subjects who completed the study, the Y-BOCS score decreases were similar in the treatment groups; however, the small number of subjects limits the power to detect differences.

In a 10-week multicenter trial (396), fluvoxamine (up to 250 mg/day, mean final dose = 200 mg/day) was as effective as clomipramine (up to 250 mg/day, mean final dose = 200 mg/day). Endpoint Y-BOCS scores among the 64 randomly assigned subjects with at least one postbaseline rating did not significantly differ between the two treatment groups. Fluvoxamine produced fewer anticholinergic side effects and less sexual dysfunction than clomipramine. These findings were replicated in a subsequent 10-week study (397) that involved 79 OCD subjects randomly assigned to receive fluvoxamine (up to 300 mg/day, mean final dose = 225 mg/day) or clomipramine (up to 300 mg/day, mean final dose = 201 mg/day). Among the 73 subjects with at least one postbaseline rating, the percentage of Y-BOCS-25% responders in the two groups showed no difference at any time. The mean Y-BOCS score decrease was 30% in both treatment groups. The fluvoxamine group experienced fewer anticholinergic side effects.

In a large, 10-week, multicenter, double-blind trial, 227 OCD subjects were randomly assigned to receive fluvoxamine (up to 300 mg/day) or clomipramine (up to 300 mg/day) (415). Both groups experienced a marked improvement in OCD as evidenced by Y-BOCS, NIMH-OC, and CGI scores. Fluvoxamine was better tolerated primarily because troubling anticholinergic side effects were more common in the clomipramine group. In a small, 10-week, single-blind trial, 30 OCD patients were randomly assigned to receive fluvoxamine (up to 300 mg/day, mean final dose = 290 mg/day), paroxetine (up to 60 mg/day, mean final dose = 53.3 mg/day), or citalopram (up to 60 mg/day, mean final dose = 50.9 mg/day); all patients completed the study (416). At trial endpoint the percentage of responders (with response defined as YBOCS-35% and a CGI-I score 3 [minimally improved]) showed no statistically significant differences, suggesting similar effectiveness. However, the small number of subjects in each group severely limited the power to detect differences between the drugs.

Two double-blind studies compared the efficacy of fluvoxamine combined with different forms of CBT to the efficacy of CBT alone or of CBT combined with placebo. In a combined single- and double-blind trial, 60 patients were randomly assigned to receive fluvoxamine and antiexposure therapy, fluvoxamine and ERP, or placebo and ERP (165). Pharmacotherapy (fluvoxamine up to 300 mg/day, mean dose = 282 mg/day) lasted for 24 weeks. The medication was then tapered over a 4-week period and discontinued, and patients were then free to seek treatment as desired. Evaluations were conducted after 2 months of active treatment (n = 50) and at the end of active treatment (6 months, n = 44). Follow-up evaluations by a blinded rater were done at 1 year (n = 37) and 18 months (n = 33). Fluvoxamine with ERP and fluvoxamine with antiexposure therapy yielded greater reduction in rituals at week 8 than placebo with ERP, but this superiority disappeared at 1 year. By week 24, all treatments had reduced OCD symptoms, with no significant between-group differences. Fluvoxamine plus antiexposure and fluvoxamine plus ERP had more effect on depressive measures than did ERP plus placebo. However, the lack of a standard response measure (Y-BOCS), the small number of subjects in each treatment group, and varying treatments subjects received during follow-up limit interpretation of the results.

Hohagen et al. (164) randomly assigned 60 OCD inpatients to receive 10 weeks of either fluvoxamine (up to 300 mg/day, mean dose = 288 mg/day) plus CBT or placebo plus CBT. The CBT consisted of therapist-aided ERP plus cognitive restructuring. In the 49 patients who completed the study, both treatments significantly reduced OCD symptoms. However, there were significantly more YBOCS-35% responders in the fluvoxamine plus CBT group (87.5%) than in the placebo plus CBT group (60%). Post hoc analyses suggested that patients with OCD and depression benefited more from fluvoxamine plus CBT than from placebo plus CBT. However, this conclusion must be viewed cautiously, as no information was given on the two groups' degree of response to prior treatments, and the analyses excluded nine subjects in order to equalize the two groups' baseline Y-BOCS scores.

Van Balkom et al. (61) randomly assigned 117 outpatients to five treatment conditions: fluvoxamine plus cognitive therapy, fluvoxamine plus self-guided ERP, cognitive therapy alone, self-guided ERP alone, or an 8-week wait-list control. Fluvoxamine was titrated to 300 mg/day, with a mean endpoint dose in the two drug groups of 197 mg/day. Pharmacotherapy lasted 16 weeks, and a naturalistic follow-up measurement was made at 6 months. Completer and ITT analyses posttreatment revealed no differences in effects (Y-BOCS, SCL-90, BDI) between the four active treatment conditions; however, this result may be due to inadequate power. Overall, 36% of subjects who completed the study were responders (Y-BOCS score 12 and 6-point improvement). No evidence was found that the combination of fluvoxamine with cognitive therapy or ERP was superior to the cognitive therapy or ERP alone. However, neither the ERP nor the fluvoxamine dosing was optimized. Moreover, because of the absence of a group treated with fluvoxamine alone and of a control group for the duration of the study, the differential efficacy of fluvoxamine, cognitive therapy, or self-guided ERP at week 16 cannot be determined.

A recent follow-up study (66) assessed 62 OCD subjects who completed controlled trials (23 treated with CBT consisting of ERP alone, 24 with SRI alone [fluvoxamine or clomipramine], 15 with ERP plus medication) and found that most subjects showed long-term improvement following either ERP or medication treatment. The small number of patients in each group, however, limited the power to detect differences between the groups.

One fluvoxamine study supports the hypothesis that OCD with co-occurring chronic tic disorders may be a clinically meaningful subtype. An 8-week open-label trial (223) assessed the efficacy of fluvoxamine in 66 OCD patients, of whom 33 had tic disorders. Of the OCD patients with co-occurring chronic tic disorders, 21% were fluvoxamine YBOCS-35% and CGI-I:1,2 responders compared with 52% of the OCD patients without co-occurring chronic tics. The authors concluded that fluvoxamine monotherapy may be less efficacious in OCD patients with tics than in those free of this condition. A clomipramine study, however, found no reduction in effectiveness in OCD patients with tics (224).

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b. Fluoxetine

Three randomized, double-blind, placebo-controlled studies show that fluoxetine is significantly more effective than placebo. In addition, double-blind active-comparator studies suggest fluoxetine is comparable in efficacy to clomipramine and sertraline and superior in efficacy to phenelzine. Compared with clomipramine, fluoxetine exhibited fewer side effects in one study. In other studies, fluoxetine was well tolerated, with side effects comparable to those of the comparator drugs.

Two large, randomized, double-blind, placebo-controlled studies demonstrated the effectiveness of fluoxetine in the treatment of adults with DSM-III-R OCD. In an 8-week double-blind study (417), 214 subjects were randomly assigned to receive fluoxetine 20, 40, or 60 mg/day or placebo. Fluoxetine response (defined as YBOCS-25% and CGI-I:1,2) rates were significantly higher in the 40 mg/day and 60 mg/day groups (48% and 47%, respectively) than in the placebo group (26%), but the response rate in the 20 mg/day group (36%) was not. In a 16-week extension, subjects who had not responded to 20 mg/day or 40 mg/day and who took fluoxetine 60 mg/day experienced a highly significant decrease in Y-BOCS scores. Fluoxetine and placebo dropout rates did not differ significantly.

A 13-week, randomized, double-blind trial (83) assessed the effects of fluoxetine 20, 40, or 60 mg/day versus placebo in 355 outpatients with OCD. At each dose, fluoxetine was significantly superior to placebo on the Y-BOCS and other efficacy measures, with statistical significance reached by week 5. The fluoxetine groups had YBOCS-35% response rates of 32%, 32%, and 35%, respectively, with a trend for greater improvement in the 60 mg/day group. The YBOCS-35% response rate in the placebo group was 8.5%. The safety and efficacy of fluoxetine in the acute treatment of OCD are further supported by open trials (418421).

Two studies compared fluoxetine with clomipramine in the treatment of DSM-III-R OCD without using a placebo control group (394, 395). In the first study, involving crossover designs with 10 weeks of treatment, 4 weeks of drug washout, and samples of 6 and 20 subjects, fluoxetine up to 80 mg/day was as effective as clomipramine up to 250 mg/day (394). Both drugs produced a significant decrease in the Y-BOCS score, although clomipramine was associated with more adverse events. The second study, an 8-week, double-blind, randomized trial, compared fluoxetine 40 mg/day (n = 30) with clomipramine 150 mg/day (n = 25) (395). The two drugs appeared equally effective over this short treatment period. The YBOCS-25% responder rate, but not the YBOCS-35% responder rate, was higher with clomipramine. The discontinuation rates for adverse events were 3% for fluoxetine and 4% for clomipramine.

A 24-week, randomized, double-blind trial compared the efficacy and tolerability of fluoxetine (mean dose = 57 ± 23 mg/day) and sertraline (mean dose = 140 ± 59 mg/day) in outpatients with DSM-IV OCD (422). Equivalent and significant improvement was found at week 24 in Y-BOCS and NIMH-OC scale scores. Remission rates (defined as Y-BOCS score 11 and CGI-I:1,2) at weeks 12 and 24 were significantly higher for sertraline (36% vs. 22% at week 24). Subjects treated with sertraline showed an earlier improvement on some, but not all, efficacy measures. Both medications were well tolerated; rates of discontinuation due to adverse events were 14% for fluoxetine and 19% for sertraline.

A 10-week randomized trial compared fluoxetine 80 mg/day, phenelzine 60 mg/day (both doses achieved by the end of week 3), and placebo in 64 adults with DMS-III-R OCD (423). Fluoxetine was superior to placebo at weeks 6 and 10 as well as to phenelzine at week 10. Symmetry obsessions and lower baseline Y-BOCS scores were significantly more common in phenelzine responders than in fluoxetine responders; however, this post hoc analysis provides only weak evidence for a phenelzine effect in this subgroup.

The long-term treatment of OCD with fluoxetine has been examined to a limited extent. In a continuation of the 13-week, double-blind, placebo-controlled, fixed-dose fluoxetine study (83), treatment responders continued their blinded treatment, whereas nonresponders began a 24-week open-label trial of maximally tolerated doses up to 80 mg/day (81). Among acute-phase responders, all three doses of fluoxetine (20, 40, and 60 mg/day) were associated with further Y-BOCS improvement. The acute-phase nonresponders benefited from upward dose titration, with two-thirds achieving a YBOCS-35% response. Another study assessed the efficacy and safety of 52 weeks of fluoxetine or placebo treatment in patients with DSM-IV OCD who had responded to single-blind fluoxetine for 20 weeks (201). Patients who received fluoxetine had numerically lower relapse rates compared with those who received placebo, although the difference was not significant (see Section V.E for details).

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c. Paroxetine

Three double-blind placebo-controlled trials show paroxetine to be more effective than placebo acutely; an additional double-blind study shows the superiority of paroxetine relative to placebo in maintaining response over 6 months of continuation treatment. A double-blind active-comparator study suggests that paroxetine is comparable in efficacy to clomipramine. Compared with venlafaxine, the relative efficacy of paroxetine is less clear, as findings vary with the definition of treatment response. Paroxetine's tolerability is comparable to that of other SSRIs. Some evidence (424), but not all (80), suggests paroxetine is more likely to be associated with significant weight gain. Paroxetine is more likely to induce anticholinergic side effects than are other SSRIs (118, 425). It also carries a greater risk of an unpleasant withdrawal syndrome, comparable to the risk associated with venlafaxine (426).

In a 12-week double-blind trial (80), OCD patients without co-occurring major depression, tics, or Tourette's disorder were randomly assigned to receive paroxetine 20 mg/day (n = 88), 40 mg/day (n = 86), 60 mg/day (n = 85), or placebo (n = 89). A little more than half of subjects had had a prior SRI trial. Endpoint response rates (defined as YBOCS-25% or Clinical Global Impression–Severity [CGI-S] score decrease of 2 points) for paroxetine 40 mg/day (25%) and 60 mg/day (29%), but not 20 mg/day (16%), were significantly greater than for placebo (13%). In a 12-week, double-blind, flexible-dose study (427), 191 subjects were randomly assigned to receive placebo or paroxetine, with the dose increasing from 20 mg/day to 40 mg/day by week 3 and up to 50 mg/day from week 8 onward. The CGI-I:1,2 response rate was significantly greater in the paroxetine (50%) than in the placebo group (24%). A significantly greater response rate was similarly observed in subjects randomly assigned to receive 12 weeks of flexibly dosed paroxetine 20–60 mg/day (mean dose = 37 mg/day) (n = 201) or placebo (n = 99) (393). More than half (55%) of the paroxetine subjects were YBOCS-25% responders compared with 35% of placebo subjects. The active comparator, flexibly dosed clomipramine (150–250 mg/day, mean dose = 113 mg/day), produced the same responder rate as paroxetine.

A 12-week, randomized, double-blind, flexible-dose study (172) comparing paroxetine with venlafaxine found no significant difference in YBOCS-35% responder rates for paroxetine at doses up to 60 mg/day (44%) (n = 76) and venlafaxine at doses up to 300 mg/day (37%) (n = 75), although the YBOCS-25% responder rate was higher for paroxetine (66%) than for venlafaxine (49%). When the medication for nonresponders in this study was switched to the alternative medication in a double-blind fashion, a higher YBOCS-25% responder rate was observed for paroxetine (56% [15/27]) than for venlafaxine (19% [3/19]) (171).

Long-term effectiveness of paroxetine has been observed in one study. Responders to paroxetine in a 12-week double-blind study and its 6-month open-label, flexible-dose extension phase (N = 105) were randomly assigned to receive 6 months of double-blind paroxetine or placebo (80). Relapse was defined as a return to the baseline Y-BOCS score or an increase of 1 point in the CGI-S score for more than one visit. Subjects assigned to placebo had a significantly higher relapse rate (59%) than those assigned to paroxetine (38%). The mean time to relapse was 29 days in the placebo group and 63 days in the paroxetine group.

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d. Sertraline

Two double-blind, placebo-controlled trials demonstrated the efficacy of sertraline in treating OCD. In double-blind active-comparator studies, sertraline appeared comparable in efficacy to fluoxetine. Sertraline was superior in efficacy to clomipramine (although methodological shortcomings influenced the latter comparison) and, in subjects with co-occurring depression, was superior to desipramine. Finally, in an open-label trial, subjects who responded to 1 year of treatment with sertraline experienced further small but noticeable decreases in symptoms when treatment was extended to 2 years.

In a 12-week, randomized, fixed-dose trial (82), subjects were assigned to sertraline 50 mg/day (n = 80), 100 mg/day (n = 81), 200 mg/day (n = 80), or placebo (n = 84). Sertraline at doses of 50 mg/day and 200 mg/day was significantly superior to placebo with regard to change in Y-BOCS, NIMH-OC, CGI-S, and CGI-I scores, but at 100 mg/day sertraline was only superior in terms of the NIMH-OC, probably because of the high dropout rate (33%) in this group. At endpoint, CGI:1,2 responder rates were 39% for sertraline and 30% for placebo. A 12-week, double-blind, randomized study of flexibly-dosed sertraline 50–200 mg/day (mean maximum dose at endpoint = 165 ± 55 mg/day) found the drug (n = 86) more effective than placebo (n = 81) with regard to change in Y-BOCS, NIMH-OC, and CGI-S scores (428). The CGI-I:1,2 responder rate was numerically but not significantly higher for sertraline (41%) than for placebo (23%).

In a 24-week, double-blind, randomized, flexible-dose comparison of sertraline 50–200 mg/day (mean endpoint dose = 140 ± 59 mg/day) (n = 77) versus fluoxetine 20–80 mg/day (mean endpoint dose = 57 ± 23 mg/day), the differences in CGI-I:1,2 responder rates (60% and 60%) and remission (defined as CGI-I:1,2 plus Y-BOCS < 12) rates (36% vs. 22%) were not significant (422).

A 16-week double-blind study compared sertraline and clomipramine 50 mg/day for 4 weeks followed by flexible increases in dose to 200 mg/day (mean final dose = 132 mg/day for sertraline and 101 mg/day for clomipramine) (401). The sertraline group had significantly greater improvement as measured by the Y-BOCS, NIMH-OC, and CGI-S. Inappropriately high starting doses of clomipramine (50 mg/day), producing a high dropout rate and low maximum clomipramine dose, strongly influenced the comparative result. Among subjects treated for at least 4 weeks, the two drugs produced equal results, but the mean final clomipramine dose was relatively low. The Y-BOCS-35% responder rates were 72% for sertraline and 65% for clomipramine.

In another double-blind, flexible-dose study (429), OCD patients with co-occurring depression were randomly assigned to receive sertraline 50–200 mg/day (mean endpoint dose = 160 ± 50 mg/day) or desipramine 50–300 mg/day (mean endpoint dose = 194 ± 90 mg/day). Sertraline (n = 79) was more effective than desipramine (n = 85) in bringing about "robust improvement in OCD symptoms" (Y-BOCS score decrease 40%).

A second completed year of continued treatment with open-label sertraline flexibly dosed from 50 mg/day to 200 mg/day was associated with a mean decrease in Y-BOCS scores from about 12 to about 9 in 38 subjects (430) who had been CGI-I:1,2 responders in a 1-year, fixed-dose, double-blind study (431).

Finally, after 1 year of single-blind treatment, sertraline responders rarely relapsed over 28 weeks regardless of whether they were maintained on flexibly dosed sertraline (50–200 mg/day) (3/108, or 3%) or switched over 2 weeks to placebo (5/113, or 4%) (200) (see Section V.E. for details).

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e. Citalopram

A double-blind, placebo-controlled trial showed citalopram to be more effective than placebo, with a trend for greater efficacy and more rapid response at a higher dose. Several open trials suggest efficacy for citalopram in individuals whose OCD has not responded to other SRIs. In addition, several open-label trials suggest comparable efficacy to other SRIs. The active isomer in citalopram, escitalopram, is now marketed as a separate SSRI in the United States.

In the only double-blind, placebo-controlled, randomized trial, 12 weeks of treatment with fixed-dose citalopram 20 mg/day (n = 102), 40 mg/day (n = 98), or 60 mg/day (n = 100) produced higher YBOCS-25% response rates (57%, 52%, and 65%, respectively) than did placebo (n = 101) (37%) (432). There were trends for the highest dose to be associated with a more rapid response.

A small open-label trial suggests that citalopram (n = 11; mean dose = 51 mg/day) and paroxetine (n = 9; mean dose = 53 mg/day) bring about similar YBOCS-35% responder rates (40% and 45%, respectively) in inpatients (416). The response rate to fluvoxamine (n = 10; mean dose = 290 mg/ day) (60%) was numerically but not statistically significantly higher. An open-label, random-assignment, flexible-dose study utilizing a blinded rater found no significant difference in YBOCS-35% responder rates to 12 weeks of citalopram 40–60 mg/day (n = 23) (48%), fluvoxamine 200–300 mg/day (n = 83) (55%), clomipramine 150–250 mg/ day (n = 37) (48%), or paroxetine 40–60 mg/day (n = 16) (50%) (433).

An open-label trial of citalopram flexibly dosed from 20 mg/day to 60 mg/day (mean final dose = 46 mg/day) reported that 22 of 29 (76%) patients who completed 24 weeks of treatment experienced a 50% decrease in Y-BOCS score (434). Among 18 patients who completed 16 weeks of citalopram (20 mg/day for 2 weeks, then 40 mg/day) after nonresponse to two or three adequate, 6-month SRI trials (Y-BOCS decrease < 25% and score 21), 14 (78%) were CGI-I:1 responders (435). A shorter 12-week trial (176), using the YBOCS-35% definition, reported a lower responder rate: only one of seven (14%) subjects who had failed to benefit (Y-BOCS score decrease < 35%) from fluoxetine ( 20 mg/day for 12 weeks) and from clomipramine ( 150 mg/day for 12 weeks) responded to citalopram (20 mg/day for 2 weeks, then 40 mg/day).

A single case report described a patient whose OCD was unresponsive after 3 months of citalopram 80 mg/day but subsequently responded to 160 mg/day, which was well tolerated over several months (436). Intravenous citalopram (unavailable in the United States) was well tolerated in one study at doses of 20–80 mg/day and may have a faster onset of action than oral citalopram (437).

Escitalopram was as effective as paroxetine for OCD in a European multicenter double-blind, active-comparator trial (437a) and was superior to placebo in preventing OCD relapse in a second large European double-blind trial (437b).

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f. Venlafaxine

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) that does not have an FDA indication for OCD. A small, double-blind, placebo-controlled trial with venlafaxine was negative, but several open-label trials showed robust responses in OCD symptoms at doses of at least 225 mg/day. In addition, double-blind active-comparator studies suggest venlafaxine is comparable in efficacy to clomipramine and perhaps to paroxetine. Venlafaxine has been generally well tolerated.

In the only double-blind, placebo-controlled trial (438), 30 OCD patients were randomly assigned to receive placebo or venlafaxine (up to 225 mg/day) for 8 weeks. At endpoint, there were no statistically significant differences in response, although there was a trend for greater response in the venlafaxine group. The study's small sample size, short trial length, low venlafaxine dose, and lack of standard outcome measures (Clinical Global Impression, ratings of avoidance) severely constrain interpretation.

In a 12-week, double-blind, active-comparator study (172), 150 OCD patients were randomly assigned to receive venlafaxine XR (up to 300 mg/day) or paroxetine (up to 60 mg/day). Full response was defined as a Y-BOCS score decrease of 50% and partial response as a decrease of 35%. An ITT LOCF analysis demonstrated no significant differences in responder rates (full response: 24% venlafaxine vs. 22% paroxetine; partial response: 37% venlafaxine vs. 44% paroxetine). Only a small percentage of patients (5%) dropped out because of adverse effects. The study's methodological limitations include the absence of a placebo control group and venlafaxine doses not exceeding 300 mg/day. In addition, the venlafaxine group had undergone more unsuccessful medication trials.

Nonresponders (Y-BOCS decrease < 25%) in this study (n = 43) were treated for 12 additional weeks with the alternative medication (171). A significantly higher proportion of those whose medication was switched to paroxetine (56%, 15/27) were YBOCS-25% responders compared with those whose medication was switched to venlafaxine XR (19%, 3/16). However, the small sample size, the lack of a placebo control group, and a less stringent response criterion are methodological limitations in this second study.

In a 12-week double-blind trial (173), 73 OCD subjects were randomly assigned to receive venlafaxine (225–350 mg/day, mean dose = 265 mg/day) or clomipramine (150–225 mg/day, mean dose = 168 mg/day). Visitwise and LOCF analyses at study end revealed no statistically significant difference between the groups in YBOCS-35% and CGI-I:1,2 responder rates (visitwise responder rates: venlafaxine 36% vs. clomipramine 50%; LOCF responder rates: venlafaxine 35% vs. clomipramine 43%). The investigators concluded that venlafaxine at these doses may be as effective acutely as clomipramine, with fewer side effects. However, confidence in these results is again limited by the lack of a placebo control group, the small size of the study, and by the relatively low mean clomipramine dose.

An open, naturalistic, retrospective study examined treatment results for 39 OCD patients (29 who were "nonresponders" [undefined] to one or more SRI trials) after treatment for a mean of 18 months (range 1–56 months) with venlafaxine up to 450 mg/day (mean final dose = 230 mg/day) (439). At study end, 69% of subjects entering the study were CGI-I:1,2 responders. Of note, 76% of the "nonresponders" to one or more SRI trials, and 82% of the "nonresponders" to two or more SRI trials were sustained responders. Venlafaxine even at the higher end of the dosing range was well tolerated.

An 8-week open-label trial in which 12 OCD patients were treated with venlafaxine 150–300 mg/day reported responder rates of 75% (YBOCS-35%) and 35% (CGI-I:1,2) (440) without substantial side effects. A 12-week open-label trial utilizing venlafaxine 150–350 mg/day in 10 OCD patients reported responder rates of 30% (YBOCS-35%) and 40% (CGI–I:1,2), with a more robust response in treatment-naive patients (441). Marazziti (442) reported five patients whose OCD was resistant to SSRIs who improved (Y-BOCS, Ham-D, and other clinical evaluations) for at least 1 year with venlafaxine 150–225 mg/day.

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3. Implementation of SRIs

Available trial data suggest that higher SSRI doses produce a somewhat higher response rate and somewhat greater magnitude of symptom relief (7982) (Table 5).

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Table Reference Number
Table 5. Effects of Higher Selective Serotonin Reuptake Inhibitor (SSRI) Doses in Fixed-Dose Trials on Obsessive-Compulsive Disorder (OCD)

Among nonresponders, raising the dose of an SSRI is associated with enhanced response (Table 6). The literature does not allow specification of the chance of response as a function of the number of previously failed adequate SRI trials. Attempts to interpret the clinical trial data are limited by differences in the number of failed trials in patients included in a given study, by absence of information about the number of failed adequate trials, by differences in the definition of "failed," and by the small, highly selected samples. However, clinical experience suggests that patients who do not respond to one SRI may still respond well to another (Table 7). With SRIs, response rates to a second trial are close to 50% but may fall off as the number of failed adequate trials increases. A switch to venlafaxine at doses of 225–350 mg/day is also supported by active-comparator trials and open-label studies that suggest its effectiveness in treating OCD.

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Table Reference Number
Table 6. Effects of Raising the Dose of Selected SSRIs in Nonresponders
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Table Reference Number
Table 7. Chance of Responding to the Next Serotonin Reuptake Inhibitor (SRI) After Failure to Benefit From the Previous SRI
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4. Other Antidepressants

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a. Monoamine Oxidase Inhibitors

There is only very weak support for the use of MAOIs in OCD. In one small, double-blind, placebo- and fluoxetine-controlled study, the Y-BOCS score decrease for subjects completing a 10-week trial of phenelzine 60 mg/day (n = 17) was not significantly greater than for those completing placebo treatment (n = 18), in contrast to the Y-BOCS score decrease produced by fluoxetine 80 mg/day (n = 19) (423). In a post hoc analysis, the authors suggested that symmetry obsessions might be a strong predictor of phenelzine "response" (undefined). In a blinded, 12-week, random-assignment, open-label comparison of phenelzine 75 mg/day (n = 12 completers) and clomipramine 225 mg/day (n = 14 completers), with both doses reached by week 5, no significant difference was found on either the Maudsley Obsessional-Compulsive Inventory (MOCI) or a nonstandard scale (403). The absence of a placebo group, use of nonstandard rating scales, and small sample size limit this study's evidentiary weight. A case series (443) and isolated case reports add only minimal evidence of the effectiveness of MAOIs. The presence of severe anxiety or panic attacks or of symmetry obsessions has been a positive predictor in some case reports.

The side-effect burden of MAOIs can be significant and includes cardiovascular problems and weight gain, as well as potentially severe drug-drug interactions and dietary restrictions associated with nonselective MAOIs or high-dose selective MAOIs (444, 445). This burden, combined with the relative lack of evidence for MAOI efficacy, argues against the use of these medications except in severely ill OCD patients who have failed most or all first-line treatments and most second-line treatments.

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b. Tricyclic Antidepressants

Limited investigations of TCAs other than clomipramine have found no evidence for their efficacy in treating OCD.

A randomized controlled trial comparing nortriptyline, clomipramine, and placebo with eight subjects in each treatment group found that clomipramine, but not nortriptyline, was superior to placebo in reducing interview-based ratings of OCD severity (446). However, there was no significant difference in effectiveness between clomipramine and nortriptyline.

In a placebo-controlled trial that divided OCD subjects into a "high depression" group (Beck Depression Inventory [BDI] score 21) and a "low depression" group (BDI score £ 20), imipramine (mean dose = 233/mg/day) reduced depression over 6 weeks in the highly depressed patients (n = 37) but did not affect the obsessive-compulsive symptoms in either depressed group (447).

In another study, 38 patients were divided into moderately and mildly depressed groups according to their Beck Depression Inventory scores (232). One half of each group received imipramine and the other half received placebo for 6 weeks followed by 3 weeks of daily CBT consisting of ERP and then 12 weekly sessions of supportive psychotherapy. Although imipramine improved depressive symptoms in the depressed patients, it did not affect obsessive-compulsive symptom severity. ERP reduced OCD symptom severity, but imipramine did not potentiate ERP effects. Response of OCD to therapy did not differ in moderately depressed versus mildly depressed patients.

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c. Trazodone

Case reports and case series (448) suggest that trazodone at doses of at least 250 mg/day may warrant a trial in OCD patients who have not responded to first- and second-line treatments. In one case series (N = 5), augmentation of an SSRI with trazodone 300–600 mg/day was helpful in alleviating OCD and anxiety as well as sleep disturbance, gastrointestinal distress, and sexual dysfunction (449). However, a 10-week, double-blind, placebo-controlled trial with 11 patients who completed the trazodone trial (mean dose = 235 mg/day) and 6 patients who completed the placebo trial found no evidence of efficacy (450). Nevertheless, the trial may have been too short (6 weeks at 250 mg/day) with too small a sample to allow definitive conclusions. If trazodone is used, sedation is likely to be a limiting side effect, and torsades de pointes has been reported on rare occasions (451). Males must be warned of the risk of priapism, which may occur in from 1/1,000 to 1/10,000 men (451).

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5. Antipsychotics

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a. Monotherapy

Few studies have examined the efficacy of antipsychotics as monotherapy for OCD, and the available evidence does not support such use. An early study (452) examined chlorpromazine in a mixed population of patients (those with "psychoneuroses or personality disorders with some symptoms of an obsessive or compulsive type") and did not use standardized assessment instruments. Case studies using haloperidol were inconclusive (e.g., references 453 and 454), although a case report described an OCD patient who responded well to loxapine (455).

An open 10-week trial involving 12 OCD patients examined the possible efficacy of clozapine 300–600 mg/day (456). The patients had not responded (Y-BOCS score decrease 35% or score < 16 and a CGI-I:1,2) to prior SRI trials. Two patients dropped out because of side effects (i.e., sedation and hypotension). Among the 10 patients who completed the study, none had a response to the trial; the mean Y-BOCS reduction was 10%. The authors concluded that clozapine is ineffective as monotherapy in patients who have not responded to prior SRI treatment.

Most recently, Connor et al. (457) examined the efficacy of aripiprazole in eight OCD patients over 8 weeks. Seven patients took aripiprazole at a dose of 10–30 mg/day, but two dropped out due to side effects (i.e., akathisia, nausea). Among the five completers, three experienced a Y-BOCS decrease of 30%; two subjects were rated much or very much improved. The authors concluded that some patients may benefit from aripiprazole monotherapy. However, the small sample and open-label design preclude strong conclusions.

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b. Augmentation

In the many OCD patients who have either no response or a partial response to SRI treatment, antipsychotic medication has been used to augment treatment with an SRI. Randomized, placebo-controlled augmentation trials of both first-generation (haloperidol) and second-generation (risperidone, olanzapine, quetiapine) antipsychotic medications have yielded response rates in the range of 40% to 55% within 4–6 weeks (Table 8).

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Table Reference Number
Table 8. Results of Second-Generation Antipsychotic Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder (Double-Blind, Placebo-Controlled Trials)

Other controlled trials did not find significant differences between antipsychotic and placebo augmentation (458460); however, methodological limitations in these studies likely contributed to the negative findings. In two of these studies (458, 460), in which SSRI monotherapy was limited to 8 weeks, the failure of active drug to separate from placebo was probably due to a high rate of response to continued SSRI monotherapy in the placebo augmentation group. One 16-week, double-blind, placebo-controlled trial (459) found no significant difference between quetiapine (mean final dose = 50–400 mg/day) and placebo. Again, the dosing may have been low.

The long-term effects of antipsychotic augmentation have not been systematically studied. A retrospective chart review (160) found that 15 of 18 patients (83%) who responded to antipsychotic augmentation relapsed within 1 year after the antipsychotic was discontinued. Thirteen of the 15 who relapsed did so by the eighth week after discontinuation.

Many questions about antipsychotic augmentation in OCD remain unanswered, including the optimal dose for each of the agents, their long-term tolerability, and the reasons some patients benefit but others do not. In addition, the relative efficacy of the different agents remains to be examined.

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c. Haloperidol

In the first double-blind, placebo-controlled study of antipsychotic augmentation (154), 34 patients with OCD resistant to 8 weeks of fluvoxamine (defined as less than a YBOCS-35% decrease or a score 16 and not having a CGI-I:1,2) were randomly assigned to receive 4 weeks of adjunctive haloperidol (n = 17) or placebo (n = 17). Adjunctive haloperidol (initiated at 2 mg and increased to a maximum of 10 mg/day) was significantly more effective than placebo. Eleven of the 17 haloperidol patients responded versus none of the patients receiving placebo, but akathisia requiring propranolol treatment was common. Response was defined as 1) YBOCS-35% and score < 16; 2) CGI-I:1,2; and 3) consensus of the treating clinician and two of the primary investigators. Of the 11 responders, 7 met all three criteria, and 4 met two criteria. All 8 subjects with co-occurring tics responded to haloperidol, versus 3 of 9 without tics. No subject with tics responded to placebo. The authors concluded that OCD patients with a chronic tic disorder might benefit from adjunctive haloperidol but that it should not be used indiscriminately because of the risk of tardive dyskinesia.

A 9-week, double-blind, placebo-controlled, crossover study compared 2 weeks of adjunctive treatments with risperidone 1 mg/day, haloperidol 2 mg/day, or placebo in 16 patients with Y-BOCS scores of 16 after at least 12 weeks of therapeutic SRI doses (461). Haloperidol augmentation, but not risperidone augmentation, reduced the Y-BOCS score significantly more than did placebo augmentation. Both drugs were significantly better than placebo at reducing Y-BOCS obsession scores. Four subjects dropped out of the study before receiving neuroleptic treatment. Of the 12 subjects (75%) who completed the risperidone arm, 5 (42%) discontinued haloperidol for adverse events. The low dose of risperidone that was used constrains interpretation of the study results (see Section V.A.5.d).

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d. Risperidone

Three double-blind, placebo-controlled studies, albeit of modest size, and several open-label studies support the safety and effectiveness of risperidone augmentation of SRI treatment of OCD. McDougle et al. (155) randomly assigned 36 patients whose OCD was resistant to 12 weeks of SRI treatment (< YBOCS-35% decrease or a score 16 and CGI-I:1,2) to 6 weeks of adjunctive risperidone (n = 20) or placebo (n = 16). Risperidone was initiated at 1 mg/day, and the dose was increased by 1 mg weekly. The mean final risperidone dose was only 2.2 mg/day (SD = 0.7 mg/day; range = 1–4). Among patients who completed the trial (risperidone, n = 18; placebo, n = 15), risperidone was significantly superior to placebo (Y-BOCS reduction: 32% for risperidone; 9% for placebo). Nine (50%) of the 18 patients who completed the risperidone trial were responders compared with none of the 15 patients who completed the placebo trial. Response was defined as 1) YBOCS-35% and score < 16; 2) CGI-I:1,2; and 3) consensus of the treating clinician and two of the primary investigators. There was no difference in outcome between OCD patients with and without co-occurring tic disorder or schizotypal personality disorder. Risperidone was well tolerated, with mild transient sedation being the most prominent adverse effect; one risperidone patient dropped out in the first week because of intolerable insomnia.

In a smaller controlled study (156), 16 OCD patients who had "failed" (i.e., no more than minimally improved) at least two 12-week SRI trials were randomly assigned to receive 8 weeks of adjunctive risperidone (n = 10) or placebo (n = 6). Risperidone was started at 0.5 mg/day, and the dose was increased by 0.5 mg weekly to a maximum of 3 mg/day; the mean risperidone dose was 2.25 mg/day (SD = 0.86), with no difference between responders and nonresponders. In the ITT sample, the risperidone group had a numerically larger mean Y-BOCS score decrease (25%) than the placebo group (5%). Four of 10 (40%) risperidone patients and none of six (0%) placebo patients were YBOCS-25% responders. Three subjects discontinued (risperidone, n = 1; placebo, n = 2) because of unsatisfactory clinical response. Risperidone was generally well tolerated; only four risperidone patients experienced side effects (i.e., sedation, dizziness, dry mouth).

A randomized controlled trial (157) examined the efficacy of adding risperidone 0.5 mg/day versus placebo in OCD patients who had either responded or not responded to their first SRI trial (12 weeks of fluvoxamine, maximum dose = 300 mg/day, final doses not provided). Responders (defined as those with YBOCS-35% and CGI-I:1,2) and "nonresponders" were then randomly assigned to receive added risperidone 0.5 mg/day or placebo for 6 weeks. Among the 39 patients completing the trial, added risperidone significantly reduced OCD symptoms in the 10 fluvoxamine nonresponders but not in the 9 fluvoxamine responders (Y-BOCS reduction for fluvoxamine nonresponders: risperidone 26%, placebo 7%; Y-BOCS reduction for fluvoxamine responders: risperidone 4%, placebo 28%). Among the fluvoxamine nonresponders, 5 of 10 (50%) risperidone patients and 2 of 10 (20%) placebo patients became YBOCS-35% responders. The study's limitations include the small sample size, the potential for ceiling effects in the fluvoxamine responders, the low dose of risperidone, and the lack of information about whether the treatment groups received similar fluvoxamine doses prior to augmentation.

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e. Olanzapine

The safety and effectiveness of adjunctive olanzapine in OCD have been examined in two randomized, placebo-controlled trials and several open-label trials. Bystritsky et al. (159) randomly assigned 26 OCD patients who had not "improved" (undefined) after at least two 12-week SRI trials and at least one ERP trial to 6 weeks of adjunctive olanzapine (n = 13) or placebo (n = 13). OCD patients with current co-occurring Axis I disorders were excluded. The mean olanzapine dose was 11.2 mg/day (SD = 6.5; range: 5–20 mg/day). In the ITT sample, adjunctive olanzapine was significantly superior (Y-BOCS reductions: olanzapine 17%; placebo 2%). Six (46%) of 13 olanzapine patients were YBOCS-25% responders compared with none in the placebo group. Two olanzapine patients (15%) discontinued because of the side effects (sedation: n = 1; weight gain: n = 1).

Shapira et al. (460) randomly assigned OCD nonresponders (< 25% decrease) or partial responders (YBOCS-25% but score 16) after 8 weeks of fluoxetine (40 mg/day in 42 subjects, 20 mg/day in 1 subject), to 6 weeks of adjunctive olanzapine (n = 22), or placebo (n = 22). Olanzapine was started at 5 mg/day, and the dose was increased to a maximum of 10 mg/day. Both treatment groups improved significantly, with no significant difference between them; the proportions of responders were similar (YBOCS-25% = 41% for both groups; YBOCS-35% = 23% for olanzapine, 18% for placebo). The authors concluded that adding olanzapine was not superior to extending the 8-week fluoxetine monotherapy trial. However, as they noted, the patients were unlikely to have attained full benefit from the SSRI before the olanzapine trial began, thus obscuring any olanzapine effect. Olanzapine patients gained a mean of 2.8 (± 3.1) kg compared with 0.5 (± 1.8) kg for placebo patients.

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f. Quetiapine

The safety and effectiveness of quetiapine augmentation of SRI treatment in OCD have been evaluated in three randomized, double-blind, placebo-controlled trials; one randomized, single blind, placebo-controlled trial; and several open-label studies.

Denys et al. (158) randomly assigned 40 OCD patients without co-occurring diagnoses who were unresponsive (Y-BOCS decrease < 25%) after at least two SRI trials (at maximum tolerated dose for 8 weeks) to receive adjunctive quetiapine (n = 20) or placebo (n = 20) for 8 weeks. Quetiapine was started at 50 mg/day, and the dose was increased, following a fixed dosing schedule, to a maximum of 300 mg/day. In the ITT sample, adjunctive quetiapine was significantly superior to placebo (Y-BOCS reduction: quetiapine 32%; placebo 7%). Eight (40%) quetiapine patients were responders (defined as YBOCS-35% and CGI-I:1,2), compared with only two (10%) placebo patients. The most common side effects of quetiapine were somnolence (95%), dry mouth (55%), weight gain (30%), and dizziness (30%).

Carey et al. (458) randomly assigned 41 patients who had not responded (defined as not CGI-I:1,2 or not YBOCS-25%) after 12 weeks of SRI treatment to 6 weeks of flexibly dosed adjunctive quetiapine (n = 20) or placebo (n = 21). The mean final quetiapine dose was 169 (± 121) mg/day. Both quetiapine and placebo led to a significant reduction in mean Y-BOCS scores (Y-BOCS reduction: quetiapine 27%; placebo 26%). Responder (defined as CGI-I:1, 2 and YBOCS-25%) rates were 40% and 48% for quetiapine and placebo, respectively. Two quetiapine patients dropped out because of severe sedation, and 75% complained of sedation (vs. 33% of placebo patients). Quetiapine augmentation was no more effective than placebo, but the study was limited in that patients had received their maximum SRI dose for only 6 weeks before randomization.

Fineberg et al. (459) randomly assigned 21 adult OCD patients with minimal response (defined as <25% Y-BOCS decrease) after 12 weeks of an SRI at the maximum tolerated dose, to receive either adjunctive quetiapine (n = 11; mean final dose = 215 mg/day, range = 50–400 mg/day) or placebo (n = 10). After 16 weeks of augmentation, there was no difference in the ITT sample between the two groups (Y-BOCS reduction: quetiapine 14%; placebo 6%). Three of 11 quetiapine-treated patients were YBOCS-25% responders compared with 1 of 10 placebo patients. The authors suggested that exclusion of co-occurring Axis I disorders and tic disorders may have led to their negative findings.

In a single-blind placebo-controlled study (462), 27 OCD patients with no response to at least one 12-week SRI trial (defined as no more than minimal improvement, a Y-BOCS score of 18, and agreement of three of the authors) were randomly assigned to receive adjunctive quetiapine (n = 14) or placebo (n = 13) for 8 weeks. Of the 14 patients randomly assigned to 50–200 mg/day of quetiapine, 10 (71%) experienced improvement (defined as Y-BOCS decrease 30%), in comparison to none of the placebo patients. Nine quetiapine-treated patients reported side effects (nausea, n = 6; sedation, n = 3; dizziness, n = 1). The study's main limitation was the single-blind design.

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g. Other Antipsychotic Agents

Double-blind, placebo-controlled studies are not available for ziprasidone or aripiprazole. Published case reports weakly suggest that ziprasidone augmentation of SRI pharmacotherapy may be effective (463). A small (n = 8), open-label, 8-week, flexible-dose study of aripiprazole (10–30 mg/day) monotherapy reported that three subjects (38%) experienced a 30% or greater decrease in Y-BOCS score (457).

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6. Other Agents

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a. Adrenergic Agents

Pindolol, a beta-blocker and serotonin1A (5-HT1A) presynaptic receptor antagonist, increases serotonergic transmission through its effect on the presynaptic 5-HT1A receptor. It has been suggested that pindolol can be given once or twice daily for augmentation in the treatment of psychiatric disorders (464). In OCD, small studies have produced mixed results regarding its possible efficacy as an augmentation agent. An 8-week, double-blind, placebo-controlled trial examined pindolol augmentation of fluvoxamine in 15 patients (180). No differences between the two treatment groups were noted either in symptomatic response or in the latency of response to fluvoxamine. A double-blind, placebo-controlled trial enrolled 14 patients with DSM-IV OCD who had not responded to paroxetine and at least two other SRIs (179). Augmentation with pindolol 2.5 mg three times daily was associated with significant decrease in the Y-BOCS score after the fourth week of treatment. The greatest improvement was noted in the ability to resist compulsions. No group differences were found in pulse rate or blood pressure. An open-label study found beneficial therapeutic effects from combining pindolol and a serotonergic antidepressant, but only after tryptophan was added (465). Another open-label study found that one of eight patients with treatment-resistant OCD responded to pindolol augmentation (466).

A double-blind crossover comparison trial with 6-week drug periods found clonidine (maximum dose = 1.0 mg/day) ineffective in 28 patients with DSM-III-R OCD (467).

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b. Benzodiazepines

Evidence for beneficial effects of benzodiazepines as monotherapy for OCD is primarily limited to case reports with clonazepam and alprazolam. For clonazepam, negative results from a double-blind, placebo-controlled trial (468) and an open trial (469) cast serious doubt on the positive results of a double-blind, multiple-crossover trial (467). In the latter study, effectiveness seems to have necessitated doses that were poorly tolerated and produced serious adverse events. Modest doses of benzodiazepines may relieve anxiety and distress in OCD without directly diminishing the frequency or duration of obsessions or compulsions. However, case reports have noted an onset of action within 1–3 weeks. Among patients with histories of substance abuse or dependence, benzodiazepine use may aggravate symptoms and should be prescribed cautiously (234, 255). Thus, given their limited evidence for efficacy, benzodiazepines cannot be recommended as monotherapy for OCD, except in those rare individuals who are unable or unwilling to take standard anti-OCD medications.

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c. Buspirone

Small and methodologically limited studies provide inconsistent results regarding the possible effectiveness of buspirone 60 mg/day as monotherapy and no substantial evidence of its effectiveness as an augmenting agent.

A 6-week double-blind comparison of buspirone titrated to 60 mg/day (n = 10) and clomipramine titrated to 250 mg/day (n = 10) suggested equal effectiveness (470). In a 4-week, double-blind, placebo-controlled, crossover trial (n = 13), however, buspirone was no better than placebo (471). In addition, an 8-week open trial of buspirone at a dose of 60 mg/day for the last 5 weeks of the trial resulted in virtually no decrease in the mean Y-BOCS score of the 10 subjects who completed the study (472). However, these trial durations were too short to allow a robust test of buspirone's possible effectiveness.

In a small (n = 14), 10-week, double-blind, placebo-controlled trial, which involved a 2-week placebo lead-in followed by 10 weeks of buspirone augmentation, buspirone did not differ from placebo, although 29% (4/14) of buspirone subjects experienced a YBOCS-25% response (473). A 6-week, double-blind, placebo-controlled trial of buspirone 60 mg/day as an augmentation of fluvoxamine was negative, but this study assessed the efficacy of buspirone augmentation in patients with treatment-resistant OCD (<35% decrease in Y-BOCS score and rated "unimproved" by the investigators) rather than in partial responders for whom further improvement was sought (474).

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d. Inositol

Inositol, a precursor in the phosphatidylinositol cycle, has been studied in two double-blind, placebo-controlled, crossover studies (as monotherapy in one and as an augmenting agent in the other) and an open augmentation trial. Inositol appears to be well tolerated. In addition, the data weakly suggest that inositol may benefit a minority of OCD patients but do not support a recommendation that it be routinely tried.

In a double-blind, crossover study, inositol (18 gm/day) and placebo were administered for 6 weeks in each condition in 13 subjects free of major depression and with variable responses to SSRIs (475). There was a small but significantly greater decrease in the Y-BOCS score in the inositol condition (5.9 points) compared with the placebo condition (2.8 points). A double-blind, placebo-controlled, crossover augmentation study with 6 weeks in each condition and no washout between conditions found no difference in Y-BOCS score decrease between inositol and placebo in the first drug condition, but the study groups were small (six inositol and four placebo) (476). Subjects had been taking a stable SRI dose for at least 8 weeks before randomization but showed greater improvement in the study's first 6 weeks than in its second 6 weeks, regardless of which blinded drug was administered first. In an open study (477), inositol (18 gm/day) was added for 6 weeks in 10 subjects who had been rated minimally improved on the CGI-I after 12 weeks or more of stable SSRI treatment. Mean Y-BOCS scores fell significantly from 23.6 (± 4.4) to 17.6 (± 4.6), but only three subjects (30%) achieved CGI-I scores of much improved.

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e. Lithium

Case reports suggest that lithium monotherapy may deserve further study in trials that utilize an adequate serum level ( 0.6 mEq/L) and an adequate duration of treatment ( 10 weeks). However, findings from an 8-week, double-blind, crossover augmentation study (n = 16) with a mean serum level of 0.54 mEq/L (478) and a 4-week, double-blind, placebo-controlled, augmentation trial (n = 10) with a mean serum level of 0.77 mEq/L (479) were negative. The 4-week lithium treatment period in these studies may have been too short to fully evaluate lithium's potential utility as an augmentation agent in OCD. The utility of lithium in the treatment of co-occurring bipolar disorder is clearly established (193).

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f. Mirtazapine

A study combining an open-label first phase with a double-blind discontinuation phase suggests that mirtazapine may be effective for OCD in patients who have not received SRI treatment or have not responded to only one adequate SRI trial (174). However, the small sample size (15 treatment-naive patients and 15 not responding to exactly one adequate SRI trial) makes these results suggestive rather than strong evidence for mirtazapine's effectiveness. Significant weight gain was observed in more than 30% of patients in the first 12 weeks of treatment. A small pilot study provides slight additional support (480). Additional double-blind, placebo-controlled trials utilizing a parallel groups design are indicated.

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g. Other Medications

A case series (481) and a double-blind, placebo-controlled crossover study (182) suggest that once-weekly oral morphine sulphate 30–45 mg may be useful as an augmentation strategy for resistant OCD. In the double-blind study, 7 of 23 subjects (30%) experienced a YBOCS-25% response to morphine versus none in the placebo condition. In addition, a small (n = 8), 6-week, open-label study found evidence for the effectiveness of tramadol monotherapy 254 ± 119 mg/day in the six patients who completed at least 2 weeks of treatment (183). The dose-limiting side effect was sedation.

Some anticonvulsants (valproate, oxcarbazapine, carbamazepine, gabapentin, topiramate) have been reported to help individual patients either as monotherapy or as augmentation agents. A small (n = 9), 8-week, open-label carbamazepine trial (482) and a small case series (n = 5) (483) each reported only one positive response. A 6-week open-label study of gabapentin augmentation (mean dose = 2520 mg/day) in five patients who had a partial response to fluoxetine suggested some benefit (484), but a 6-week, double-blind, placebo-controlled, crossover trial of gabapentin 3600 mg/day added to fluoxetine found no benefit (485). An open case series reviewing at least 14 weeks of topiramate augmentation (mean daily dose = 253 mg) in 16 patients who had a partial response or no response to SRI treatment reported 11 of 16 (68.8%) CGI-I:1,2 responders. The mean time to response was 9 weeks (486).

l-Tryptophan 3–9 gm/day combined with nicotinic acid 1 gm two times daily and pyridoxine 200 mg two times daily was reported to be beneficial in early case reports that predated modern diagnostic criteria and measurement instruments (487, 488). However, some patients became violent. Adding l-tryptophan at doses exceeding 1–2 gm/day to an SRI can induce the serotonin syndrome.

d-Amphetamine 30 mg, studied in a single-dose, double-blind, placebo-controlled trial, was associated with a significant decrease in self-rated symptoms about 6 hours after the dose, independently of effects on mood (184). d-Amphetamine had an acute anti-OCD effect in 11 of 12 subjects (92%). With placebo, neither the self-ratings nor the blinded observer's ratings decreased significantly. Two patients continued d-amphetamine at a dose of 10–20 mg/day for "several weeks" with continued response. In a small (n = 11), double-blind, placebo-controlled, crossover study of single doses of methylphenidate 40 mg and d-amphetamine 30 mg, both taken orally, the latter drug was associated with a significantly greater reduction in OCD symptom rating than was placebo (185). Five of the 11 subjects (45%) had a 50% decrease in their OCD scores after d-amphetamine, two (18%) after methylphenidate, and only one (9%) after placebo. In both studies, the decrease in OCD symptoms was independent of mood effects. Open-label methylphenidate, 40 mg once orally, produced no significant effect on OCD or mood 4 hours later in a small study (n = 13), although four patients had a 50% decrease in an OCD rating scale score (489). Case reports exist of OCD benefit after treating co-occurring attention-deficit disorder with stimulants. The presence of tics or Tourette's disorder does not contraindicate the use of stimulants to treat ADHD co-occurring with OCD, although methylphenidate appears to be better tolerated in this situation than d-amphetamine (490).

Hallucinogens have been reported to alleviate OCD in individual cases (491, 492). Since hallucinogens are not a practical treatment modality or recommended, studies of safer serotonin2A,C (5-HT2A,C) receptor agonists may be warranted.

Ondansetron 1 mg three times daily was associated with a significant decrease in Y-BOCS scores in a small (n = 8), 8-week, open-label study (493).

St. John's wort (450 mg of 0.3% hypericum two times daily), a weak serotonin-reuptake inhibitor, was associated with CGI-I:1,2 response in 5 of 12 (42%) subjects in a 12-week open-label trial (494). However, a 12-week, flexible-dose, placebo-controlled trial enrolling 60 subjects found St. John's wort to be no better than placebo (181). In addition, St. John's wort predisposes to photosensitivity and interacts with anti-HIV medications (495), cyclosporin (496, 497), and birth control pills (498), among other medications (499).

Bupropion titrated from 150 mg/day to 300 mg/day after 2 weeks had no mean effect on Y-BOCS scores in an open trial involving 12 patients (500). However, 2 patients were YBOCS-25% responders; 4 patients "improved," with a mean Y-BOCS decrease of 31%, but 8 patients experienced a worsening of symptoms, with a mean Y-BOCS increase of 21%.

A 12-week open-label study adding riluzole 50 mg two times a day to SSRIs and other augmenting medications reported that 7 of 13 (54%) patients with treatment-resistant OCD were YBOCS-35% responders (501). However, these results must be viewed cautiously because ratings were not blinded, other augmenting medications were present, and prior treatment regimens were stable for only 4 weeks before riluzole was added. Riluzole was well tolerated, although one patient experienced an asymptomatic increase in liver enzyme (ALT) to a level more than nine times normal, which decreased despite continued treatment.

Table Reference Number
Table 5. Effects of Higher Selective Serotonin Reuptake Inhibitor (SSRI) Doses in Fixed-Dose Trials on Obsessive-Compulsive Disorder (OCD)
Table Reference Number
Table 6. Effects of Raising the Dose of Selected SSRIs in Nonresponders
Table Reference Number
Table 7. Chance of Responding to the Next Serotonin Reuptake Inhibitor (SRI) After Failure to Benefit From the Previous SRI
Table Reference Number
Table 8. Results of Second-Generation Antipsychotic Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder (Double-Blind, Placebo-Controlled Trials)

References

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