V. Review and Synthesis of Available Evidence

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A. Medications

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.

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.

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).

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.

2. Efficacy of SSRIs
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).

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).

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.

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).

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).

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.

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).

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.

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
4. Other Antidepressants
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.

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.

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).

5. Antipsychotics
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.

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).

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.

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).

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.

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.

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.

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).

6. Other Agents
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).

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.

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).

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.

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).

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.

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.


B. Other Somatic Therapies

Somatic therapies used in the treatment of OCD include deep brain stimulation and other forms of neurosurgery, transcranial magnetic stimulation, and electroconvulsive therapy. Plasmapheresis has been investigated only in childhood OCD. None of these therapies are considered first-line treatments for OCD, and their use is limited to patients with treatment-resistant OCD.

Specific descriptions of the criteria used to establish treatment resistance and to determine eligibility for surgical treatments (stereotactic lesion procedures and DBS) in OCD patients have been published elsewhere (152, 502504).

Data regarding treatment of OCD with these somatic therapies are quite limited, and there is an understandable absence or paucity of double-blind trials; as a result, no definitive conclusions can be drawn. The majority of available reports are case series and open-label trials. Although stereotactic lesion procedures have a more abundant database (197) than the other somatic therapies in patients with treatment-resistant or intractable OCD, the cost, irreversibility, and lack of a clear relationship between specific anatomic lesions and successful outcomes continue to limit their use.

1. Transcranial Magnetic Stimulation

Findings of the four published trials of repetitive TMS (rTMS) are inconsistent, perhaps because the studies differed in design, stimulation sites, duration, and stimulation parameters. The available results and the technique's non-invasiveness and good tolerability should encourage future research, but the need for daily treatment may limit the use of TMS in practice.

In a TMS study of possible frontal lobe involvement in OCD (505), 12 OCD patients (6 patients with past or current major depression) were randomly assigned to receive one session of active right-side or left-side or sham (occipital) rTMS. Blinded raters made ratings during the stimulation and 30 minutes and 8 hours after the session. Compulsive urges, but not obsessions, decreased significantly, and positive mood increased moderately, with right lateral prefrontal rTMS (during stimulation and 30 minutes and 8 hours after stimulation), but not after left rTMS or occipital rTMS. Stimulation was well tolerated, with two patients reporting mild headache after stimulation. Although the report was not intended as a treatment study (only one administration per anatomical site was used), methodological limitations include the treatment duration, lack of Y-BOCS outcome measures, small sample size, and the lack of a control group. Another non-treatment TMS study reported altered cortical excitability in subjects with OCD compared with controls (506).

A 6-week trial (three sessions per week) (507) found no advantage for low-frequency right rTMS (n = 10) over sham stimulation (n = 8). No dropouts were reported, and side effects, consisting of headache and cognitive difficulties, were modest and transient. The use of a relatively nonfocal, teardrop-shaped coil limits the interpretation of the results.

In a 10-session, single-blind, 2-week trial (508), 12 patients with treatment-resistant OCD were randomly assigned to receive active right-side or left-side rTMS. Ten subjects taking medications were maintained on a constant dose for 8 weeks prior to and during the study. Evaluations after 2 weeks of stimulation and 4 weeks later showed significant reduction in obsessions and compulsions in both groups, with no significant difference between right and left stimulation. Four patients (two receiving left and two receiving right rTMS) had a clinically significant improvement (Y-BOCS reduction >40%); one patient relapsed but responded somewhat to repeat treatment. No dropouts were reported, and stimulation was well tolerated, with three patients reporting headache. However, interpretation is limited by the absence of a placebo control group and the presence of concurrent pharmacotherapy.

In an open-label trial (509), 10 treatment-resistant patients (5 with OCD, 3 with Tourette's syndrome, and two with both) received low-frequency rTMS for 2 weeks. Medication doses were stable for at least 12 weeks before and throughout rTMS and the follow-up period. Eight patients completed the study; no dropouts due to side effects were reported. CGI scores decreased significantly at the end of the first and second weeks of treatment, with benefit maintained at the 1-month and 3-month follow-ups. Three of the five patients with pure OCD had a clinically significant improvement, with a > 40% reduction in Y-BOCS scores, and two Tourette's patients had a complete remission at the second week. Six subjects (60%) had clinical improvement that persisted at 3-month follow-up. The study was limited by the open design and small sample size.

2. Electroconvulsive Therapy

The literature on ECT in treatment-resistant OCD includes a case series and several individual cases, with some reported degree of effectiveness. However, the frequent Axis I comorbidity among subjects, lack of standard outcome measures, absence of blinded trials, need for repeated anesthesia, and the side effects of ECT preclude it from being considered for treatment-resistant OCD uncomplicated by co-occurring conditions (191).

The case series (190) describes a retrospective study of 32 patients with DSM-III-R treatment-resistant OCD (19 not depressed and 13 depressed; 14 with primarily checking rituals, 13 with primarily cleaning rituals, and four with both) who received ECT between 1979 and 1991. The patients were treated with bilateral frontotemporal ECT (average three to five seizures per session over 2–3 weeks) and were evaluated 2 days before treatment and at 5 days and 6 and 12 months after the end of treatment. Comparison of baseline scores (Beck Hopelessness Scale, Maudsley Obsessional-Compulsive Inventory) with data 5 days after treatment yielded highly significant pre-post paired t test results (P < 0.001) that were still significant at 6 months posttreatment. However, by 12 months only the MOCI scores remained significantly different from those prior to ECT. In addition, methodological limitations include the absence of blinded ratings and standard outcome measures, the use of medications during the long-term follow-up, and the presence of co-occurring depression in a significant proportion of patients (13/32). Furthermore, the number of seizures per session is not considered standard ECT treatment (191).

In addition, several single case reports (510514) suggest possible efficacy of ECT in treatment-resistant OCD. However, the unblinded ratings, frequent Axis I comorbidity (schizophrenia, depression, Tourette's disorder), and differing ECT parameters limit the confidence that can be placed in the findings.

3. Deep Brain Stimulation

Two small, double-blind trials and several case reports have investigated the efficacy of DBS in OCD. Given the preliminary promising results in treatment-resistant OCD, the procedure's reversibility and adjustability in comparison with ablative neurosurgery, and the absence to date of serious adverse events, DBS deserves investigation in severe, treatment-resistant OCD. Nonetheless, DBS is an invasive procedure, and the risks of brain hemorrhage, infection, and new onset of seizures must be kept in mind (195).

The first report (515, 516) concerns six subjects with OCD refractory to various antiobsessional treatments and to CBT (Y-BOCS 30, GAF 45, both for a minimum of 5 years) who were treated with DBS. Quadripolar electrodes were implanted bilaterally in the anterior limbs of the internal capsules with a double-blind stimulation-off condition representing the placebo condition throughout the 21 months of evaluation. Four patients completed a blinded crossover trial (i.e., stimulator on for 3 months and stimulator off for 3 months, or vice versa, in random order). Three were YBOCS-35% responders during the stimulation-on condition, with CGI-I scores much improved. Responders reported clinically meaningful improvement in the first week of stimulation. Side effects included fatigue and memory disturbances. The persistence of the effect for at least 21 months argues against a placebo effect. Patient 5 received a different electrode placement, one in each dorsomedial thalamic nucleus and one in each internal capsule (517). The dorsomedial thalamic nucleus did not seem as effective a target for this patient, who was also considered a nonresponder with longer-term internal capsule stimulation. Patient 6 experienced a major improvement (more than 50% decrease in postoperative tests) in his aggressive, intrusive thoughts and mood when stimulation was turned on.

One small trial enrolled four subjects with DSM-IV OCD who did not respond to at least four antiobsessional medications and CBT (Y-BOCS 25; GAF 44) (518). The patients, who had been following stable medication regimens for at least 6 weeks before surgery and during the blinded phase of the study, received DBS with quadripolar electrodes placed stereotactically in the anterior limb of each internal capsule; stimulation-off was the control. The double-blind study consisted of four consecutive 3-week periods (in an alternating on-off design), followed by an open phase in which stimulation, medication, and CBT were adjusted to optimize response for up to 1 year. During the double-blind phase, two of the four patients showed clinically meaningful responses but one of these patients also responded during periods without stimulation. One subject experienced mood elevation in response to stimulation. Positron emission tomography (PET) scans showed orbitofrontal deactivation only in the two patients with a positive clinical response. Side effects included tingling, nausea, and diarrhea. Beneficial effects appeared over variable times, ranging from 3 weeks to several months.

In addition, four recent case reports of open-label DBS (519522) suggest the efficacy of DBS in treatment-resistant patients with OCD. In a recent case-series report (523), three of four patients with severe OCD and anxiety disorders who received DBS in the shell of the right nucleus accumbens experienced significant reduction in severity of symptoms.

4. Neurosurgical Stereotactic Lesion Procedures

Neurosurgical treatment for psychiatric disorders has a long and controversial history. Today this approach—including cingulotomy, capsulotomy (also performed via radiosurgery and known as "gamma-knife" capsulotomy), subcaudate tractotomy, limbic leucotomy, central lateral thalamotomy/anterior medial pallidotomy—is a highly selective treatment performed for relatively few patients with severe, treatment-refractory affective, anxiety, or obsessive-compulsive disorders (197). The availability of reversible and adjustable DBS may lead to a decrease in the use of ablative neurosurgical procedures. However, these procedures still represent a potentially efficacious alternative for a few carefully selected patients with very severe OCD.

In view of the changes in neurosurgical techniques in the last decade, only trials using these advanced techniques with adequate numbers of patients and specified inclusion criteria and outcome measures are reviewed.

A prospective unblinded study of bilateral anterior capsulotomy in 15 subjects with treatment-refractory OCD (mean duration = 18.1 ± 5.6 years; mean total Y-BOCS score = 29.7) observed positive results at 1 and 12 months postsurgery: at 12 months, the mean Y-BOCS score decrease was 39%, with 53%, 29%, and 17% of the patients experiencing a 33% decrease, 50% decrease, and 66% decrease in Y-BOCS score, respectively (524). No cognitive deficit was evident in neuropsychological screening tests. Complications were observed in three case subjects: one with transitory hallucinations, one with a single epileptic seizure, and one who developed a progressive behavior disorder (not further specified) that became permanent.

In an unblinded study (525) enrolling 44 subjects with DSM-III-R OCD refractory to at least three SRIs trials, at least one SRI augmentation trial, and a trial of CBT (Y-BOCS 25, GAF 60, both for 5 years), one or more cingulotomies (electrodes positioned in each cingulate gyrus with magnetic resonance imaging [MRI] stereotactic guidance) were performed. Follow-up evaluations were carried out a mean of 32 months after neurosurgery. At the first follow-up (a mean of 6.7 months after the first cingulotomy), the mean Y-BOCS score decrease was 20%; 5 patients (11%) met full responder criteria (YBOCS-35% and CGI-I:1,2), and 4 patients (9%) met partial responder criteria (either YBOCS-35% or CGI-I:1,2 or this degree of improvement not attributed to cingulotomy). At the 32-month follow-up, the mean Y-BOCS score decrease was 29%, with 32% of patients classified as responders and 14% as partial responders. At the most recent follow-up for the 18 patients who received multiple cingulotomies, 5 (28%) were responders and 2 (11%) were partial responders. These results suggest that cingulotomy may benefit some patients with severe treatment-refractory OCD. Although 20% of patients reported at least one adverse effect after cingulotomy (e.g., memory disturbances, apathy, urinary disturbances), only 2 patients (5%) reported enduring sequelae (i.e., seizure disorder and hydrocephalus).

Fourteen subjects with treatment-refractory and medically intractable OCD were evaluated up to 12 months after bilateral anterior cingulotomy (526). At the 6- and 12-month follow-ups, the mean Y-BOCS scores decreased 29% and 36%, respectively, with 4 of 14 (29%) and 6 of 14 (43%) having a response (defined as YBOCS-35% and CGI-I:1,2). No significant changes in cognitive functions or memory were reported at the 12-month evaluation compared with preoperative scores. Adverse effects (headache, insomnia, weight-gain/loss) persisted no more than 3 months after cingulotomy.

In a retrospective unblinded study, 15 subjects with treatment-refractory OCD were followed up for approximately 1 year after bilateral cingulotomy (527). Four of the 15 patients were YBOCS-35% responders. However, only one had sustained benefit lasting more than 1 year. Minor postoperative symptoms included headache, nausea/ vomiting, and urinary incontinence, which resolved after several months. Postoperative MRIs revealed no clear relationship between lesion location and significant clinical improvement.

The efficacy of limbic leucotomy was evaluated in a small unblinded study of 21 subjects, of whom 15 had treatment-refractory OCD and 6 had refractory major depression (528). Patients were evaluated after a mean of 26 months. Five of 12 OCD patients (42%) with physician ratings were rated responders (defined as physician-rated CGI-I:1,2), and 8 of the 13 (62%) OCD patients with self-ratings rated themselves as responders (defined as PGI-I:1,2). One OCD patient, who had a history of a suicide attempt, died by suicide after the surgical procedure. Minor postoperative symptoms of headache, low-grade fever, and nausea/vomiting were common but generally lasted less than 48 hours. Among the 21 subjects, transient postoperative somnolence and apathy were noted in 29% and 24% of patients, respectively. These results are comparable to those in the limited previous reports regarding limbic leucotomy in intractable OCD (529).


C. Psychotherapies

1. Exposure and Response Prevention

Historically, CBT for OCD has been divided into two forms: 1) CBT that relies primarily on behavioral techniques, such as ERP (57), and 2) CBT that relies primarily on cognitive therapy techniques, such as identifying, challenging, and modifying faulty beliefs (530, 531). Certain variants of exposure therapy routinely include some informal cognitive therapy techniques (e.g., a discussion of fear-related thoughts and beliefs), and many variants of cognitive therapy include behavioral experiments, which can be similar to exposure techniques. Therefore, these two forms of CBT, as administered in treatment trials, often overlap. In clinical practice, these two forms are often combined.

Studies that have examined CBT consisting of ERP for adults with OCD are reviewed in this section (see also reference 532).

a. Randomized Controlled Trials Comparing ERP With a Nonactive Treatment

Several randomized controlled trials have examined whether ERP is superior to a nonactive treatment. Although the studies used different variants of ERP (e.g., therapist-supervised or self-controlled exposures), different formats (e.g., individual sessions vs. group therapy), different intensity (e.g., frequency and length of sessions per week), and different control groups, all studies concluded that ERP is efficacious for the treatment of adults with OCD.

Several early controlled studies reported that ERP was superior to progressive muscle relaxation (PMR) (e.g., see references 533, 534). These studies were limited by their small samples and the lack of standard diagnostic and outcome measures.

A 12-week trial compared the effectiveness of random-assignment individual ERP (n = 31), group ERP (n = 30), or PMR (n = 32), which was included as an attention control condition (132). Subjects were free of major depression and Axis II disorders and were treatment naive. Individual ERP was delivered in 1-hour sessions two times a week; group ERP consisted of 2-hour sessions two times a week delivered in groups of 10. In both cases, treatment consisted of exposure (imaginal and in vivo) and response prevention. In those subjects who completed treatment, both individual and group ERP were superior to PMR but not to each other in reducing OCD and depressive symptoms (Y-BOCS score reduction in subjects who completed the study: 40% for individual; 46% for group; 9% for PMR). However, group ERP took much less staff time. Patients receiving either individual or group treatment maintained their gains at 6-month follow-up; however, whether patients received additional treatment during follow-up is unclear.

In a 3-week trial in which all patients completed the study, 18 patients were randomly assigned to receive either ERP (n = 9) or anxiety management (n = 9) (535). Both treatments involved about 15 hours of therapy. ERP consisted of graded exposure to feared situations and ritual prevention both in sessions and as homework. Anxiety management consisted of breathing retraining, PMR, and problem solving. ERP was significantly superior to anxiety management for both OCD and depressive symptoms (e.g., Y-BOCS: 62% reduction for ERP; 6% increase for anxiety management). During the study, five patients continued SRIs that had brought "no improvement" for at least 12 months. Study limitations include the small sample, lack of independent raters, and very short-term duration of observation.

In a large multisite trial (139), 218 patients were randomly assigned to 10 weeks of ERP guided by a therapist (n = 69), ERP guided by a computer and workbook (n = 74), or systematic relaxation guided by an audiotape and manual (n = 75). ERP guided by a therapist consisted of 11 weekly 1-hour sessions in which therapists told patients how to conduct exposures at home but did not supervise in-session exposures. ERP guided by computer used BT STEPS, a nine-step computer-driven interactive voice response system that allows patients to telephone from home at any time of day or night and progress through a self-paced workbook that allows the patient to design and implement an individualized plan of behavior therapy. Relaxation therapy consisted of an audiotape and manual that directed the patient to practice PMR 1 hour daily. Of those who entered, 55 (80%) completed ERP, 55 (74%) completed BT STEPS, and 66 (88%) completed PMR. In ITT analyses, ERP was superior to BT STEPS, and both were superior to PMR (Y-BOCS reduction: 32% for ERP; 23% for BT STEPS; 7% for PMR). Significantly more patients receiving ERP were CGI-I:1,2 responders (60%), compared with patients receiving either BT STEPS (38%) or PMR (14%). Patients who adhered to ERP (either guided by clinician or computer) had a larger mean decrease in their symptoms than the overall mean decrease for that condition. Patients were followed for an additional 14 weeks. However, the groups received different follow-up treatment, so overall group comparisons were confounded. Of note, nonresponders to BT STEPS who were switched to clinician-guided ERP had a significant decrease in OCD severity, whereas nonresponders to ERP who were switched to BT STEPS did not. The authors concluded that minimal ERP (i.e., 11 weekly 1-hour sessions in which a therapist provides instructions only) is superior to BT STEPS and that PMR is ineffective for OCD. However, the reduction in OCD symptoms was substantially less than that seen in other studies in which therapists supervised in-session exposures (e.g., compare ITT results in Lindsay et al. [535] and Foa et al. [123]).

In a Brazilian controlled trial of group ERP (134), OCD patients were randomly assigned to 12 weeks of either group ERP (n = 23) or wait-list control (n = 24). Although 45% of patients were taking medications at the time of therapy, they had been taking the medication at a stable dose for at least 3 months. The group ERP was conducted in weekly 2-hour sessions in groups of seven or eight; it included in-session exposure, ritual prevention, and cognitive restructuring. In ITT analyses, group ERP was significantly superior to the wait-list condition (Y-BOCS reduction: group ERP 43%; wait-list 6%); 70% of group ERP patients were YBOCS-35% responders. Twenty-two ERP patients reevaluated after 3 months had maintained their gains. However, whether patients received additional treatment during follow-up was not stated.

A multisite trial (123) compared the efficacy of 12 weeks of ERP, clomipramine, their combination, and pill placebo in adults with OCD and without co-occurring depression. Of 122 entering randomly assigned treatment, 87 (71%) completed the study. ERP was delivered intensively for the first 4 weeks (i.e., five 2-hour sessions per week); it consisted of exposure (imaginal and in vivo), ritual prevention, and relapse prevention. During exposures, feared consequences and dysfunctional beliefs were discussed. For the remaining 8 weeks, patients received 45-minute maintenance sessions in which no in-session exposures were conducted. Patients randomly assigned to receive clomipramine or placebo were seen for 30 minutes weekly by a research psychiatrist. They received clomipramine titrated up to 200 mg/day or placebo in the first 5 weeks, with an optional increase to 250 mg/day if needed. In ITT and completer analyses, all active treatments were superior to placebo. ITT and completer response rates (CGI-I:1,2) were, respectively, 62% and 86% for intensive ERP, 42% and 48% for clomipramine, 70% and 79% for combination treatment, and 8% and 10% for placebo. Post hoc analyses (126) demonstrated that intensive ERP with or without clomipramine produced a significantly higher proportion of patients (> 50%) with minimal symptoms (i.e., Y-BOCS 12) than either placebo (0%) or clomipramine alone (25%). However, high study refusal rates (71% of those meeting entry criteria refused to participate) and dropout rates (18% at randomization and an additional 23% before completion) may limit the widespread applicability of this study's findings.

In a Japanese study (536), 31 OCD outpatients were randomly assigned to 12 weeks of single-blind ERP plus pill placebo; fluvoxamine 150–200 mg/day (dose reached no later than week 5) plus autogenic training (psychotherapy placebo); or autogenic training and placebo. Among the 28 patients (90%) who completed treatment, ERP was significantly more effective than fluvoxamine in reducing Y-BOCS scores. Ten of 10 (100%) patients receiving ERP were Y-BOCS-35% and CGI:1,2 responders compared with 3 of 10 (30%) fluvoxamine patients and 0 of 8 (0%) placebo patients. The study is limited by small sample size, lack of double-blind ratings, and low doses of fluvoxamine.

In addition to these randomized controlled trials, several controlled trials compared ERP and different variants of cognitive therapy with and without SRI medication. These studies are reviewed in the section on cognitive therapy for OCD (Section V.C.2). Overall, these studies also found that ERP significantly reduced OCD symptoms, further supporting its efficacy for OCD. However, most of these studies lacked a placebo or nonactive control condition. Two used a wait-list control, with one (61) reporting that gradual self-controlled ERP was significantly superior to 8 weeks of wait-list control, and the other (133) finding that group ERP was superior to wait-list control.

Open trials of ERP (totaling hundreds of patients) also support the efficacy of ERP for OCD (e.g., see references 229, 537539).

b. Factors That Affect Outcome From ERP

Several factors appear to affect the outcome of ERP. These include patient adherence to the ERP procedures (540, 541), the patient's degree of insight into the irrationality of his or her fears (with poor insight leading to worse outcome in some [208, 542, 543], but not all [209], studies), and certain co-occurring conditions. For example, severe depression and some co-occurring anxiety disorders (e.g., posttraumatic stress disorder, generalized anxiety disorder) (233, 544, 545) may negatively impact outcome. Other predictors of treatment outcome have also been reported, but none is sufficiently accurate to apply in the individual case (532, 546). Because some data suggest that certain subtypes of OCD patients (e.g., patients with severe hoarding behavior, patients without overt compulsions) may not benefit as much from ERP, modifications of standard ERP for these subtypes are being investigated (e.g., see references 121, 150). Whether the addition of formal cognitive therapy elements can improve the outcome from ERP (either for all OCD patients or for patients with co-occurring conditions such as depression) is also under investigation (Sections II.B.1, II.B.3, II.B.4, and V.C.2).

Some data suggest that ERP is most effective when delivered intensively (e.g., five sessions per week [547, 548]). On the other hand, one study found that twice-weekly ERP was comparable to intensive treatment (141), and good results have been achieved with weekly, 1-hour sessions (63). To date, no study has compared once- or twice-weekly treatment with intensive treatment in a randomized controlled design.

Whether the effects of ERP achieved in randomized controlled trials can be reproduced in routine clinical practice remains unclear. However, several large case series found that ERP (even when delivered weekly) can produce robust effects in fee-for-service settings, as long as the therapists are skilled (or supervised by those skilled) in ERP for OCD (537, 539).

c. Long-Term Outcome From ERP

Studies examining the long-term outcome of adult OCD patients after ERP have generally concluded that most patients remain treatment responders at follow-up (67, 132134, 165, 202, 549552). However, these findings are inconclusive for reasons that include design limitations in some studies (e.g., uncontrolled studies and/or naturalistic follow-up), methodological limitations in others (e.g., lack of standardized assessment instruments and/or blind ratings), and/or inconsistencies in whether additional treatment was received during follow-up. Recently, Simpson et al. (67) examined the posttreatment effects of intensive ERP with relapse prevention after sustained treatment discontinuation, using evaluators blind to original treatment assignment. Twelve weeks after treatment discontinuation, the relapse rate was significantly lower, and the time to relapse was significantly longer, for ERP responders (with or without concomitant clomipramine; n = 33; 12% relapse rate) than for responders to clomipramine alone (n = 11; 45% relapse rate). Limitations include the small sample size and short period of observation after treatment discontinuation.

Incorporating relapse prevention procedures into exposure therapy appears to improve the long-term outcome of ERP. A small randomized trial (124) examined whether ERP with (n = 10) or without (n = 10) relapse prevention produced different outcomes. Both groups received 3 weeks of intensive ERP (i.e., 15 daily sessions with 45 minutes devoted to imaginal exposure and 45 minutes to in vivo exposure sessions) followed by four 90-minute sessions of either relapse prevention (i.e., discussion of stressors likely to trigger OCD, meeting with a significant other to discuss maintenance of gains, and cognitive restructuring) or associative therapy (i.e., free association about OCD symptoms) combined with progressive muscle relaxation (AT-PMR). Those subjects receiving relapse prevention also received nine 15-minute phone calls over 12 weeks of follow-up. Outcome was evaluated after intensive ERP with relapse prevention and after 6 months of follow-up. Both groups had dramatic decreases in OCD symptoms after intensive ERP, without a significant difference (Y-BOCS decreases in subjects who completed the study: 66% for relapse prevention; 60% for AT-PMR). However, at 6-month follow-up the relapse prevention group showed significantly lower relapse rates than the AT-PMR group on most measures and a trend in this direction on the Y-BOCS. The authors concluded that relapse prevention helps patients maintain gains from ERP. Relapse prevention techniques are part of some standard ERP protocols (142).

d. Cognitive-Behavioral Therapy as an Augmentor of SRI Response

Data from open trials (i.e., Simpson et al. [161] [n = 6], Tolin et al. [162] [n = 20]) and a completed randomized trial (i.e., Tenneij et al. [163] [n = 96]) indicate that CBT consisting of ERP can successfully augment a partial response to an adequate SRI trial. A small (n = 14) open trial (553) also suggests that the addition of CBT consisting of exposure, response prevention, and cognitive therapy can help SRI nonresponders, although this trial lacked a control group continuing on medication alone. No data are available regarding the effect of adding cognitive therapy elements alone in attempts to augment medication response.

2. Cognitive Therapy

This section reviews studies that have examined the efficacy of cognitive therapy (CT) in the treatment of adults with OCD. For the purposes of this review, CT includes those variants of CBT that rely primarily on cognitive therapy techniques as described in Section V.C.1. The studies address three issues: whether CT without ERP is effective, whether CT is as effective as ERP and/or medication, and whether the addition of cognitive procedures to ERP leads to a better outcome.

a. Efficacy of Cognitive Therapy Without ERP

A small randomized trial involving patients who had previously failed to respond to CBT consisting of ERP compared the efficacy of group cognitive therapy to a wait-list control for OCD patients with contamination concerns (554). Eleven patients received 9 weeks of Danger Ideation Reduction Therapy (DIRT), which consisted of eight 1-hour group therapy sessions and included cognitive restructuring, expert testimony and corrective information, attentional focusing, DIRT proscribed exposure, response prevention, and behavioral experiments. Although DIRT led to significant greater changes than the wait-list control on several self-report OCD and depression measures, the effects were small (e.g., a 20% mean reduction in OCD symptoms on the MOCI). Study limitations include the small sample size, self-report measures, and use of a wait-list control.

An open trial enrolling 15 patients (555) found that individual CT in the absence of prolonged exposure led to significant improvement on several self-report OCD and depression measures (including the Y-BOCS, Obsessional Beliefs Questionnaire, and BDI). CT consisted of 14 weekly 60-minute sessions and included psychoeducation, CT procedures following Beck's method, and relapse prevention. Behavioral experiments were used to test and correct a patient's belief but did not involve prolonged exposure.

In sum, there is limited evidence to support the efficacy of pure CT (i.e., cognitive restructuring without exposure or "behavioral experiments") in the treatment of OCD.

b. Efficacy of Cognitive Therapy Versus ERP

Most direct comparisons of CT and ERP have found that these treatments produce similar results. However, strong conclusions are difficult to reach for a number of reasons. First, some variants of ERP include informal cognitive techniques (e.g., relapse prevention, cognitive restructuring during exposures) and some forms of cognitive therapy include informal exposures (i.e., behavioral experiments [behaviors that test the validity of the patient's obsessional beliefs, e.g., "If I think about a disease, my daughter will get it."]), blurring the distinction between these treatments. Second, the published studies have differed in their designs and treatment procedures (e.g., duration and frequency of treatment sessions). Third, only some studies formally monitored therapist adherence to the treatment protocols. Fourth, some studies had limited power to detect differences. Fifth, no study included a placebo group other than a wait-list control. Therefore, the treatment recommendations gleaned from these studies are necessarily specific to the procedures used and limited by these methodological weaknesses. Together, the data suggest that CT that includes behavioral experiments has similar efficacy to ERP based solely on habituation (i.e., without discussion of feared consequences or dysfunctional beliefs).

Two early studies (556, 557) examined the efficacy of rational-emotive therapy (RET) based on the work of Ellis (558); this CT program included the identification and challenge of irrational beliefs but no behavioral experiments. Both studies found that therapist-administered RET helped OCD patients and was similar in efficacy to self-controlled ERP. One study (557) concluded that RET followed by self-controlled ERP was no better than self-controlled ERP alone. However, both studies had small samples (i.e., n 11 per condition) and used a less than optimal ERP format (e.g., self-controlled as opposed to therapist-guided exposure). Another small open trial in six subjects compared RET with ERP and thought stopping and found that RET was more effective than ERP for purely obsessional patients who had no covert rituals, and that thought stopping was not helpful at all (151).

A larger randomized study by van Oppen et al. (559) compared outcomes in 28 patients who received 16 weeks of CT based on the model of Beck (530) and Salkovskis (531), and 29 patients who received self-controlled ERP. This CT program targeted dysfunctional beliefs considered to be central to OCD (i.e., the overestimation of danger and inflated personal responsibility), and specifically included behavioral experiments. For both conditions, therapy was delivered weekly in 45-minute sessions. Among the subjects who completed the trial, both treatments led to significant and clinically meaningful improvement in OCD. Although there were no significant group differences, CT appeared somewhat superior (Y-BOCS reduction: 45% for CT; 32% for ERP). However, a less than optimal ERP format (i.e., self-controlled exposure) was utilized, and the CT program used behavioral experiments. Half the patients in this study participated in a multicenter trial comparing fluvoxamine, ERP, and CT, described below.

Van Balkom et al. (61) randomly assigned 117 patients to one of five conditions: fluvoxamine plus ERP, ERP, CT, fluvoxamine plus CT, or wait-list control. At baseline, patients on average had mild depressive symptoms. Full results are presented for the 70 patients who completed 16 weeks of active treatment and the 16 patients who completed the 8-week wait-list condition. The mean dose at week 16 in both fluvoxamine conditions was 197 (± 82) mg/day. All therapy sessions were 45 minutes long. CT and ERP were delivered as in the van Oppen study (559) described above. CT targeted dysfunctional OCD beliefs and included behavioral experiments. ERP consisted of gradual self-controlled exposure in vivo with gradual self-imposed response prevention. At week 16, all active treatments led to a significant decrease on all OCD measures, with no significant differences between the treatment groups (Y-BOCS reduction for subjects who completed the trial: 46% for CT [n = 19]; 32% for ERP [n = 19]; 43% for fluvoxamine plus CT [n = 14]; 49% for fluvoxamine plus ERP [n = 18]). The authors concluded there was no reason to combine SRIs and CBT (either CT or ERP) in OCD adults without severe co-occurring mood disorder. However, neither the ERP nor the fluvoxamine treatments were optimized. Moreover, the combination groups received only 10 therapy sessions that started after 8 weeks of fluvoxamine treatment, whereas the groups receiving ERP or CT alone received 16 therapy sessions. Some of these patients were followed naturalistically for 6 months, but the fact that they received varied treatment during this follow-up period precludes strong conclusions (549).

A French multisite randomized trial (62) compared the outcome of patients who received 20 hours of either CT (n = 32) or ERP (n = 33) over 16 weeks. CT treatment consisted of twenty 1-hour individual sessions following the Beck and Salkovskis model (i.e., challenging of dysfunctional beliefs); behavioral experiments to "confront feared situations to modify thoughts" were also used. ERP consisting of therapist-aided exposure with response prevention was delivered in an intensive phase (4 weeks of two 2-hour individual sessions per week) and a maintenance phase (12 weeks of one 40-minute booster session every 2 weeks). In those patients who completed treatment, both treatments led to significant and substantial reductions in OCD symptoms (Y-BOCS reduction: 44% for CT; 42% for ERP), and many patients were YBOCS-25% responders (77% for CT; 70% for ERP). There were no significant group differences. Patients were followed after treatment to week 52, but 26% of the patients were lost to follow-up, and whether those followed received additional treatment is unclear.

In a Canadian randomized trial (133), OCD patients (48% who were taking a stable dose of medication and 50% of whom had a co-occurring Axis I disorder) were randomly assigned to 12 weeks of CT (n = 18), ERP (n = 16), or wait-list control (n = 33). Patients in the wait-list condition were randomly assigned to receive CT or ERP after the 12-week delay, and their data were pooled with the data from those who received active treatment initially. Treatment was delivered in groups and consisted of 2.5-hour sessions delivered once per week. Based on the work of Salkovskis (560), Freeston et al. (64), and van Oppen and Arntz (561), the CT focused on challenging appraisals of intrusive thoughts; behavioral experiments were used to collect evidence for and against alternative appraisals. ERP consisted of in-session and between-session exposure and ritual prevention focused on producing habituation, and relapse prevention; discussion of cognitive beliefs was proscribed. In those patients who completed treatment, both treatments were superior to wait-list control; however, group ERP was superior to group CT in the pooled sample (Y-BOCS decrease: 26% for CT; 39% for ERP). Of the 63 patients who completed treatment, 16% of CT patients and 38% of ERP patients recovered (defined as a Y-BOCS score decrease 6 points and a total score < 12). Of note, 12 of 49 CT and 2 of 44 ERP patients dropped out of the study after learning of their randomization and before starting treatment. Moreover, nearly twice as many patients taking medication received ERP than received CT. At 3-month follow-up, there was still a significant advantage for ERP over CT. However, these data are limited by the fact that patients were not prohibited from obtaining treatment during follow-up.

In another Canadian controlled trial (63), patients were randomly assigned to receive individual CT (n = 37) or ERP (n = 34). Both treatments consisted of 12 weekly 60-minute sessions and followed the same format as in the study of McLean et al. (133) described above. Specifically, the CT focused on challenging dysfunctional beliefs but included behavioral experiments; the ERP included relapse prevention but no cognitive restructuring. In those who completed treatment (n = 59, 83%), OCD severity improved significantly in both treatment groups, with no significant group differences (Y-BOCS score reduction: 56% for CT; 52% for ERP). Of those patients who completed the study, 67% of CT and 59% of ERP patients recovered (defined as a Y-BOCS score decrease 6 points and a total score < 12). Both groups also had a significant decrease in depressive symptoms and in dysfunctional beliefs. The authors concluded that individual ERP utilizing only habituation was similar in efficacy to individual CT that included behavioral experiments, and that both treatments reduce OCD symptoms. Additional CT techniques without exposure are described in case reports (129, 130).

c. Adding Cognitive Therapy to ERP

Some data suggest that ERP is more effective if it includes not only habituation but also discussion of feared consequences and dysfunctional beliefs (120, 121). One small study suggests that the addition of relapse prevention helps patients maintain their gains (124). Whether CT added to ERP helps OCD patients with co-occurring conditions (e.g., depression) is under investigation.

An early study (562) found that both ERP and ERP plus "self-instructional" talk (i.e., emitting more positive statements after imagining being exposed to some feared stimulus) led to clinically significant improvement. However, the small sample (n = 8 vs. n = 7) and the uncertain diagnostic validity of the sample (given the lack of standard criteria at that time) preclude strong conclusions.

A Norwegian randomized trial (122) examined whether the ERP protocol of Kozak and Foa (142), which includes discussion of feared consequences and dysfunctional beliefs during exposures, could be improved by the addition of formal CT elements based on Beck's work (530). Patients were randomly assigned to receive ERP plus CT, ERP plus relaxation training, or wait-list control for 6 weeks. After 6 weeks, those assigned to the wait-list control were randomly assigned to receive one of the active treatments. The final sample consisted of 16 patients who received ERP plus CT and 19 patients who received ERP plus relaxation training; 34% were taking a stable dose of medication during the trial. Therapy consisted of 2-hour sessions twice weekly, for a total of 12 sessions. Each session consisted of 1.5 hours of ERP and 30 minutes of either CT (based on the Beck model and focused on either co-occurring conditions or faulty OCD beliefs) or relaxation training (progressive muscle relaxation). ITT analysis indicated that both active groups did significantly better than wait-list controls, with no differences between the two active conditions (Y-BOCS reduction: 33% for ERP plus CT; 28% for ERP plus relaxation training). However, more patients completed ERP plus CT (15/16) than ERP plus relaxation (12/19). The authors concluded that the addition of CT to ERP (delivered as outlined in Kozak and Foa [142]) may reduce the dropout rate but does not necessarily enhance efficacy. However, the sample was relatively small, and there were other methodological limitations (e.g., wait-list design, many ratings done by the therapist, more exposure time for patients who received ERP plus relaxation training).

Recent studies have also examined whether CT added to ERP can improve outcome (120, 122).

3. Group and Multifamily Behavioral Treatment

A limited number of studies have investigated group and multifamily behavioral treatments for OCD.

A 12-week unblinded random-allocation study (132) compared group (n = 30) and individual ERP (n = 31) with an active control (progressive muscle relaxation; n = 32). Patients with major depression or Axis II disorders were excluded. Both active treatments were superior to the control treatment, as reflected in changes in Y-BOCS, BDI, and Social Adjustment Scale scores. However, response to treatment was faster with individual behavior therapy. The authors concluded that group therapy ERP was useful for less severe OCD. From an efficiency standpoint, the individual treatment consumed 720 staff hours compared with 48 hours in the group therapy condition.

A randomized trial (133) (consisting of 12 weeks of weekly 2.5-hour groups) compared group CT with behavioral experiments (n = 33) and group ERP (n = 40) against a wait-list control. The control subjects were later randomly assigned to either active treatment. Subjects were diagnosed with DSM-IV OCD of greater than 1 year's duration and had been taking medication on a stable regimen for 3 months. Ninety-three subjects entered the trial, 76 (82%) began treatment, and 63 (68%) completed treatment. Both active treatments were significantly superior to the control condition as reflected in change in Y-BOCS scores. The effect sizes (Cohen's d) were 1.62 for ERP (n = 16), and 0.98 for CT (n = 18). For those completing treatment, the difference in the proportions of "recovered" subjects (defined as Y-BOCS score decrease 6 points and final score < 12) was not significant: ERP (38%, n = 32) and CBT (16%, n = 31). At 3-month follow-up, ERP was associated with a significantly greater recovery rate among subjects who completed the treatment: ERP (45%) and CBT (13%). The ERP group included more subjects using medication, but in the analyses this did not affect improvement. This study suggested that group ERP was marginally superior to group CT. Caution in interpreting these results is warranted, because more subjects in the ERP group were taking medication, and because CT was characterized by a higher refusal rate among subjects accepted for treatment.

A single-blind, randomized trial compared 12 weeks of weekly 2-hour group therapy sessions combining ERP with cognitive therapy and homework assignments (group CBT) (n = 23) against a wait-list control (n = 24) (134). The group CBT included exposure, ritual prevention, and cognitive restructuring. Seventy percent of those in group CBT were YBOCS-35% responders compared with 4% of controls. The Y-BOCS score effect sizes (not Cohen's d) in the ITT groups were 1.33 for the group CBT group and 0.43 for the controls. The therapeutic gains were maintained at 3-month follow-up. Group CBT was associated with a significant improvement in the quality of life as measured by the Abbreviated WHOQOL. Nearly half the subjects were maintained on stable medication regimens, but this did not appear to influence the effect of active treatment. These and other reports suggest the utility of group behavioral therapies in the treatment of OCD; however, additional study is warranted.

An uncontrolled, double-blind study without random assignment compared group CBT (including ERP) (n = 17) and multifamily CBT (n = 19) (136). In each treatment there were ten to twelve 2-hour sessions monthly. This small study found that both modalities were effective, with a significant decrement in the Y-BOCS score in both components, and a significant decrease in the Sheehan Disability Inventory in the group CBT component. This study provides support for both group approaches. There are too few studies of multifamily CBT to provide sufficient evidence to recommend its use.

In an unblended, random allocation study in India, patients who had had no prior CBT but who had failed pharmacological treatment were assigned to either a treatment in which family members functioned as co-therapists conducting desensitization and ERP (n = 15) or the same treatment without a family member co-therapist (n = 15) (135). The treatment group with a family member co-therapist showed significantly greater improvement at 12 weeks and at 1-month follow-up on the MOCI and the Global Assessment of Severity scale. This small study suggests the utility of family co-therapists, but the results may not be generalizable to other cultures and are limited by the absence of a control group and the variability to be expected among families.

4. Kundalini Yoga

In a 12-week study (563), subjects with a primary DSM-III-R diagnosis of OCD, a minimum Y-BOCS score of 15, and no medical contraindications to yoga were randomly assigned to 12 weekly 2-hour group sessions of Kundalini yoga (n = 12) or 1-hour group sessions of mental mindfulness and relaxation response management (n = 10). Both groups were instructed to practice at home daily. Seven subjects completed each treatment arm. The subjects in the yoga group who completed the trial experienced a mean Y-BOCS score decrease of 38% (9.4 points), compared with a 14% decrease (2.9 points) for the control group. In the ITT analyses, the yoga group's mean decrease in Y-BOCS score was significant (5.5 points), but the mean decrease for the control group (2.0 points) was not. In both groups, an unspecified but equal number of subjects had been taking stable doses of anti-OCD medications for at least 3 months before randomization. Yoga was apparently well tolerated, but the reasons for dropout are not given. This small study requires replication by an independent group before any conclusion about the effectiveness of yoga can be drawn.


D. Combined Therapy

Only six randomized trials have directly addressed whether the combination of an SRI and CBT consisting of ERP is superior to either treatment alone in adults with OCD, and limitations in their designs and/or procedures prevent definitive conclusions. Some studies also compared SRI monotherapy with ERP monotherapy. Few studies had adequate sample sizes to detect small differences between treatments, even if such differences did exist. Moreover, some studies excluded patients with significant comorbidity even though comorbidity is common in OCD and such patients may be those who would benefit most from combination treatment. Finally, certain design decisions (e.g., how the treatments were delivered) may have prevented the detection of important differences between combination treatment and monotherapy.

Despite these problems, the available data support the idea that combination therapy can be superior to monotherapy in some OCD patients but that it is not necessary for all OCD patients (166, 167). In particular, one study found that combination therapy is superior to ERP monotherapy in OCD patients with co-occurring depression (164). In OCD patients without co-occurring depression, another study found that combination therapy and intensive ERP therapy alone were each superior to SRI monotherapy (123).

Marks et al. (564) compared the outcome of 40 OCD patients randomly assigned to receive oral clomipramine or pill placebo plus 30 sessions of CBT consisting of ERP. The study design was complex: during weeks 0–4, patients received either clomipramine or placebo; during weeks 4–10, patients also received either 30 sessions of ERP or 15 sessions of relaxation training followed by 15 sessions of ERP. A direct comparison of the effects of clomipramine plus ERP, ERP plus placebo, clomipramine plus relaxation training, and placebo plus relaxation training could only be made at week 7. At that time, patients receiving clomipramine plus ERP (n = 10) had more improvement in rituals than patients receiving ERP plus placebo (n = 10) or clomipramine plus relaxation training (n = 10); however, there was no significant interaction of clomipramine and ERP. The complex design, small sample, lack of standard OCD measures, and treatment procedures (e.g., the effects of clomipramine were likely underestimated at week 7) preclude strong conclusions.

A separate study (565) compared the outcome of 49 patients randomly assigned to receive one of four treatments: 6 months of clomipramine and 23 weeks of antiexposure instructions (clomipramine plus antiexposure); 6 months of clomipramine and 23 weeks of self-controlled ERP (clomipramine plus ERP [self]); 6 months of clomipramine and 8 weeks of self-controlled ERP, followed by therapist-aided ERP from weeks 8 to 23 (clomipramine plus ERP [self and therapist]); or 6 months of placebo and 8 weeks of self-controlled ERP, followed by therapist-aided ERP from weeks 8 to 23 (placebo plus ERP [self and therapist]). At week 8, clomipramine plus ERP (self, n = 25) produced significantly more improvement in rituals and depression than placebo plus ERP (self, n = 12). However, at week 23, clomipramine plus ERP (self and therapist, n = 10) showed no superiority over placebo plus ERP (self and therapist) plus placebo (n = 8). At week 8, clomipramine plus ERP (self, n = 13) also produced significantly more improvement than clomipramine plus antiexposure (n = 12) in rituals and depression. Only three of the subjects in the clomipramine plus antiexposure group improved enough to continue, precluding further comparisons. The authors concluded that the combination of clomipramine and ERP therapy had a small transitory additive effect compared with placebo plus ERP therapy. However, the complex design, small sample, lack of standard OCD measures, and treatment procedures (e.g., the clomipramine groups only achieved doses ranging from 127–157 mg/day) preclude strong conclusions.

Cottraux et al. (165) randomly assigned 60 adult patients with OCD to 24 weeks of fluvoxamine with ERP (fluvoxamine plus ERP), fluvoxamine with instructions not to engage in ERP (fluvoxamine plus antiexposure), or placebo plus ERP. Of the 60 patients who entered, 44 (73%) completed all 24 weeks (n = 16, 13, and 15, respectively); of these 44, 19 (43%) entered with a major depressive or dysthymic disorder (mean 17-item Ham-D score = 19). ERP therapy consisted of eight weekly sessions that included imaginal ERP during sessions and self-controlled ERP, followed by 16 weeks of therapist-guided ERP. Among those patients who completed treatment, all groups improved on some measures of rituals and depression, but only the fluvoxamine plus ERP group improved on all measures at week 24. The combined fluvoxamine treatment groups had the largest percent reduction in the duration of rituals per day (fluvoxamine plus ERP = 46%; fluvoxamine plus antiexposure = 42%; placebo plus ERP = 25%) and the largest percentage of patients who, by self-report, had more than a 30% reduction in rituals per day (fluvoxamine plus ERP = 69%; fluvoxamine plus antiexposure = 54%; placebo plus ERP = 40%); however, these group differences were not statistically significant. Study limitations include the small sample, the lack of standard OCD measures, and the limited information about the treatment procedures (e.g., the ERP protocol consisted of weekly sessions of an unspecified duration, and other psychosocial interventions were provided "as needed").

Hohagen et al. (164) randomly assigned 60 adults with OCD to receive fluvoxamine plus CBT or placebo plus CBT. Many patients had co-occurring mood, anxiety, and personality disorders (mean 21-item Ham-D score = 19), and many (92%) had received prior treatment (84% had taken medication, 35% had prior CBT). The mean dose of fluvoxamine was 288 mg/day (range = 250–300 mg/day). CBT was conducted weekly for at least 3 hours and included therapist-aided exposure as well as cognitive restructuring. After 9 weeks of treatment, both groups showed significant reductions in OCD severity. 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 revealed that 1) both groups improved significantly and comparably on compulsions, but the fluvoxamine plus CBT group improved significantly more on obsessions; and 2) patients with co-occurring depression fared better if they received fluvoxamine plus CBT. The authors concluded that combination therapy should be used when obsessions dominate the clinical picture or when a secondary depression is present. Limitations include the lack of data on whether the two groups differed in their response to prior treatment, the fact that only 49 patients entered the final analysis because 9 were removed to equate baseline Y-BOCS scores in the two groups, and the fact that two patients dropped out for clinical reasons.

Van Balkom et al. (61) randomly assigned 117 patients to receive one of five conditions: fluvoxamine plus ERP, ERP, CT, fluvoxamine plus CT, or wait-list control. At baseline, patients on average had mild depressive symptoms. Full results are presented for the 70 patients who completed 16 weeks of active treatment and the 16 patients who completed the 8-week wait-list condition. The mean fluvoxamine dose at week 16 in both fluvoxamine conditions was 197 (± 82) mg/day. All therapy sessions were 45 minutes long. ERP consisted of gradual self-controlled exposure in vivo with gradual self-imposed response prevention. At week 16, all active treatments led to a significant decrease on all OCD measures, with no significant differences between the treatment groups. The authors concluded there was no reason to combine SRIs and CBT (either ERP or CT) in OCD adults without severe co-occurring mood disorder. However, neither the ERP nor the fluvoxamine dosing was optimized. Moreover, the combination group received only 10 ERP sessions, whereas the group receiving ERP alone received 16 sessions.

Foa et al. (123) compared treatment outcome in 122 adult OCD patients randomly assigned to receive intensive ERP, clomipramine, clomipramine plus intensive ERP, or placebo. Patients with major depressive disorder (and a Ham-D 18) were excluded. Mean daily doses of clomipramine during the last study week for all who entered and all who completed the trial, respectively, were 196 and 235 mg/day for clomipramine patients and 163 and 194 mg/ day for clomipramine plus intensive ERP patients. ERP was delivered intensively for the first 4 weeks (i.e., two information-gathering sessions, fifteen 2-hour sessions conducted over 3 weeks, two home visits); this intensive phase was followed by eight 45-minute weekly maintenance sessions over the next 8 weeks. Patients receiving clomipramine plus intensive ERP began both treatments simultaneously. At week 12, all active treatments were superior to placebo at reducing OCD symptoms. In addition, clomipramine plus intensive ERP and ERP did not significantly differ from each other, but each was superior to clomipramine alone. For all who entered treatment and all who completed the 12-week trial, the CGI-I:1,2 response rates were, respectively, 70% and 79% for clomipramine plus intensive ERP, 42% and 48% for clomipramine, 62% and 86% for ERP, and 8% and 10% for placebo. The authors concluded that clomipramine, intensive ERP, and their combination are all efficacious treatments for OCD. In addition, in OCD patients without co-occurring depression, intensive ERP was superior to clomipramine. The authors noted several factors that may have limited their ability to detect a superiority of combination treatment over intensive ERP monotherapy (e.g., the exclusion of patients with co-occurring depression, the potency of intensive ERP, the fact that the combination group did not achieve maximum clomipramine doses). Study limitations include the lack of data on patients who dropped out after randomization but before treatment started and the lack of systematic data on subjects' prior treatment history. Interpretation of these results (123, 126) is also limited by uncertainty as to whether the treatment groups were equally treatment resistant at baseline and by high study refusal rates and dropout rates.

In the absence of definitive data, combination treatment (SRI medication plus CBT consisting of ERP) is appropriate in clinical situations in which there are co-occurring disorders that are SRI responsive or there has been a partial response to monotherapy (163), and in efforts to reduce the chance of relapse when medication is discontinued (67).


E. Discontinuation of Active Treatment

Four double-blind SRI discontinuation studies in adults with OCD have been published. Each concerned a different SRI and used a different design (e.g., length of observation and method of placebo substitution) and a different relapse definition. Each produced different results.

Pato et al. (199) found that 89% of the 18 patients who had responded to clomipramine had "substantial recurrence" (not further defined) of OCD 7 weeks after they were blindly switched (over 4 days) to placebo. Romano et al. (201) found no significant differences in 1-year estimates of relapse rates among patients who had responded after 5 months of fluoxetine treatment between 36 patients who continued to take fluoxetine (21%) and 35 patients who were switched to placebo (32%); relapse was defined as a 50% loss of improvement on the Y-BOCS, a Y-BOCS score of 19, and a CGI-I rating of much or very much worse relative to the end of treatment. Koran et al. (200) found that it was uncommon for patients who responded to sertraline to discontinue the medication because of relapse or insufficient response over 28 weeks, regardless of whether they continued to take sertraline (3% [3/108]) or were switched over 2 weeks to placebo (4% [5/113]); relapse was defined as a Y-BOCS increase of 5 points, a total Y-BOCS score of 20, and a 1-point increase in CGI-I score relative to the end of acute treatment at three consecutive visits at 2-week intervals. Rates of relapse or discontinuation because of insufficient response were 9% for sertraline and 24% for placebo, a significant difference. Finally, Hollander et al. (80) found that patients who had responded to 9 months of paroxetine treatment who continued to take paroxetine for 6 months had a significantly lower relapse rate (37.7%) than those switched immediately to placebo (58.8%) and a longer time to relapse (62.9 days vs. 28.5 days); relapse was defined as a return to the pretreatment Y-BOCS score or a 1-point increase on the CGI-severity (CGI-S) scale (566) relative to the end of treatment. In summary, using different SRIs, different study designs, and different relapse criteria, double-blind discontinuation studies reported SRI relapse rates ranging from a low of 4% over 28 weeks (200) to a high of 89% over 7 weeks (199).

An unblinded study of 130 OCD patients (177), in which drug discontinuation was instituted after response to 6 months of open treatment, reported significantly higher 6-month relapse rates for the patients whose medication was discontinued: 8% (clomipramine 150 mg/day) versus 46% (no drug), 0% (fluoxetine 40 mg/day) versus 40% (no drug), and 8% (fluvoxamine 300 mg/day) versus 62% (no drug) (177). Equally large or larger disparities were present after 1 and 2 years of treatment versus no treatment, and relapse rates were higher. Relapse was defined as a Y-BOCS increase of 25% plus a CGI-I score indicating much or very much worse relative to the end of treatment. These data suggest both that SRIs may not fundamentally differ in the long-term durability of treatment response after treatment discontinuation and that most patients will eventually relapse after stopping SRI treatment.

In a review of 16 CBT studies that used ERP, Foa and Kozak (202) concluded that patients receiving ERP (with and without concomitant medication) did well long-term. Of 376 treated patients, 76% were responders at follow-up (mean = 29 months; range = 6–72 months). Of responders to acute ERP treatment (with or without medication), the proportion losing their response during follow-up was 20% or less in most studies. While suggestive, these findings are inconclusive because of 1) design limitations in some studies (e.g., uncontrolled studies with naturalistic follow-up); 2) methodological limitations in others (e.g., lack of evaluators blind to original treatment assignment); 3) differences in determining "response"; 4) inconsistencies in whether treatment during follow-up was permitted (and reported); and 5) differences in length of follow-up. Further complicating any comparison with SRI relapse rates is the fact that the relapse definition employed in this review (i.e., loss of response) differs from that used in the SRI studies.

A multi-site study that compared the effects of clomipramine and intensive ERP after 12 weeks of treatment (123) and again 12 weeks after treatment discontinuation (67) found that subjects who responded to intensive ERP (with or without concomitant clomipramine) had a significantly lower relapse rate (12%) and longer time to relapse after treatment discontinuation than did subjects who responded to clomipramine alone (45%); relapse was defined as a return to baseline severity on the CGI-S scale. Post hoc analyses of these data generally supported these findings, since most of the relapse criteria examined produced the same outcome—albeit with substantial variability—depending on the specific criteria used for relapse (203). However, high study refusal rates (71% of those meeting entry criteria refused to participate) and dropout rates (18% at randomization and an additional 23% before completion) may limit the widespread applicability of this study's findings.

Together, these data suggest that ERP treatment response may be more durable, at least in the short run, than response to some SRIs after they are discontinued. However, the observed differences could be explained by other factors, including clinical characteristics of the subjects studied, differences in the length of follow-up, the intensity of treatment prior to treatment discontinuation, the rate of medication taper, and the relapse criteria. Because of these differences, no definitive conclusions about the relative durability of SRI and ERP treatment effects can be drawn from these studies.

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)


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