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
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
b. Clomipramine as an Augmentation
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.
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 patientshalf of
whom also had depressive symptomswere 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
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
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
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
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
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
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
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).
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
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 (418–421).
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
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).
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])
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.
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).
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)
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).
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.
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
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.
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).
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
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 8. Results of Second-Generation Antipsychotic Augmentation
in Treatment-Resistant Obsessive-Compulsive Disorder (Double-Blind,
| Add to My POL
Table 8. Results of Second-Generation Antipsychotic Augmentation
in Treatment-Resistant Obsessive-Compulsive Disorder (Double-Blind,
|Medication||Mean Final Dose (mg/day)||Final Dose Range (mg/day)||Active Drug: Respondersa/Total
(N)||Percentage of Responders, Drug/Placebo|
Carey et al. 2005 (458458)b
Fineberg et al. 2005 (459459)
Denys et al. 2004 (158158)
Erzegovesi et al. 2005 (157157)
McDougle et al. 2000 (155155)
Hollander et al. 2003 (156156)
Bystritsky et al. 2004 (159159)
Shapira et al. 2004 (460460)b
Other controlled trials did not find significant differences
between antipsychotic and placebo augmentation (458–460);
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.
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).
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
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.
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
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
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).
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).
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
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).
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.
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).
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.
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.