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National Collaborating Centre for Mental Health (UK). Obsessive-Compulsive Disorder: Core Interventions in the Treatment of Obsessive-Compulsive Disorder and Body Dysmorphic Disorder. Leicester (UK): British Psychological Society; 2006. (NICE Clinical Guidelines, No. 31.)

6PHARMACOLOGICAL INTERVENTIONS

6.1. CURRENT PRACTICE

The guidelines of the Expert Consensus Panel for OCD present specific judgements on a comprehensive range of issues relating to pharmacological and psychological treatments (March et al., 1997). Although the guidelines did not distinguish between clomipramine and SSRIs, improved tolerability of the latter was acknowledged. Combined CBT and medication was preferred by experts in terms of speed, efficacy, durability, tolerability and acceptability, and was thought the best approach for most patients. More recently a smaller group of members of the World Council on Anxiety met to agree recommendations for long-term treatment. They emphasised the importance of continuing treatment long-term from the outset and recommended 1–2 years continuation in treatment-responsive individuals (Greist et al., 2003).

OCD responds to drug treatment in a characteristically slow, gradual way and improvements can take many weeks and months to develop. Patients often need to be encouraged to persevere in the early stages when progress can seem frustratingly slow. Dose titration is usually recommended, with patients remaining at the lowest effective dose levels for several weeks and reassessed before gradually increasing up to the maximum licensed doses according to observed efficacy and tolerability.

There remains a paucity of data on long-term outcome, but the studies that have been performed suggest that the SRIs remain effective for as long as they are continued, and continuation protects against relapse. There is no convincing evidence supporting dose reduction in the longer-term, and the adage ‘the dose that gets you well keeps you well’ probably applies.

6.2. SSRIs

6.2.1. Treatments included

The following treatments were included:

All the above compounds with the exception of citalopram have Marketing Authorisation for the treatment of OCD in the UK.

6.2.2. Studies considered7

The review team conducted a new systematic search for RCTs that assessed the efficacy and tolerability of SSRIs among adults with OCD. Fifty-five studies were identified, of which 20 did not meet the inclusion criteria of the GDG. The 33 published trials plus one unpublished trial (Burnham) provided efficacy data from 4102 participants and tolerability data from 4907 participants.

Of the included studies, 18 compared SSRIs with placebo (BEASLEY1992; BURNHAM, CHOUINARD1990; GOODMAN1989; GOODMAN1996; GREIST1995A; HOLLANDER2003B; HOLLANDER2003D; JENIKE1990A; JENIKE1990B; JENIKE1997; KAMIJIMA2004; KRONIG1999; MALLYA1992; MONTGOMERY1993; MONTGOMERY2001; PERSE1987; ZOHAR1996A), with two of these studies (BEASLEY1992; MONTGOMERY1993) featuring an extension phase involving participants classified as responders on completion of the acute phase of treatment.

Six studies examined the effects of different doses of SSRI (BEASLEY1992; BOGETTO2002; GREIST1995A; HOLLANDER2003D; MONTGOMERY1993; MONTGOMERY2001), with two of these studies (BEASLEY1992; MONTGOMERY1993) featuring an extension phase involving participants classified as responders on completion of the acute phase of treatment.

Two studies compared SSRIs with other SSRIs (BERGERON2002; MUNDO1997a), 10 with clomipramine (ASKIN1999; BISSERBE1997; BURNHAM, FREEMAN1994; KORAN1996A; LOPEZ-IBOR1996; MILANFRANCHI1997; MUNDO2001; SMERALDI1992; ZOHAR1996A) and four with other drugs including desipramine (GOODMAN1990a; HOEHN-SARIC2000), phenelzine (JENIKE1997) and venlafaxine (DENYS2003a).

All 32 acute phase studies (ASKIN1999; BEASLEY1992; BERGERON2002; BISSERBE1997; BOGETTO2002; BURNHAM, CHOUINARD1990; DENYS2003A; FREEMAN1994; GOODMAN1989; GOODMAN1990A; GOODMAN1996; GREIST1995A; HOEHN-SARIC2000; HOLLANDER2003B; HOLLANDER2003D; JENIKE1990A; JENIKE1990B; JENIKE1997; KAMIJIMA2004; KORAN1996A; KRONIG1999; LOPEZ-IBOR1996; MALLYA1992; MILANFRANCHI1997; MONTGOMERY1993; MONTGOMERY2001; MUNDO1997A; MUNDO2001; PERSE1987; SMERALDI1992; ZOHAR1996A) were between 8 and 16 weeks long (mean length = 10.96 weeks). Where the treatment duration was greater than 16 weeks (BERGERON2002), efficacy data was extracted at the 12-week time-point. Participants were classified as outpatient in 18 studies, inpatient in one study and unclear in 13 studies. The average age of the patients in the acute phase studies was 36 years. The average duration of illness in 20 studies was 13.72 years. Although ten studies included patients with comorbid depression, the remaining two-thirds of the studies excluded individuals with comorbid depression, so the trials were testing the effect specifically for obsessive-compulsive symptoms. Ten studies were multi-centre trials, of which three were conducted in the US and six in Europe. Fourteen other studies were conducted in the US, three in Italy, one each in Austria, Canada, Japan, the Netherlands and the UK.

Full details of the studies included in the guideline and the reasons for excluding studies are given in Appendix 16.

6.2.3. SSRIs versus placebo

6.2.3.1. Clinical evidence statements8

Efficacy9Included studies
There is evidence suggesting a difference favouring SSRIs over placebo on the likelihood of treatment response, defined as a 25% + or 35% + reduction on the clinician-rated Y-BOCS and/or CGI ‘much improved’ or ‘very much improved’ (K = 10; N = 2588; RR = 0.77; 95% CI, 0.73 to 0.82). IBEASLEY1992
BURNHAM

GREIST1995A
HOLLANDER2003B
HOLLANDER2003D
KAMIJIMA2004
MALLYA1992
MONTGOMERY1993
MONTGOMERY2001
ZOHAR1996A
There is limited evidence suggesting a difference favouring fluvoxamine over placebo on the likelihood of remission, defined as a score of 8 or less on the clinician-rated Y-BOCS (K = 1; N = 253; RR = 0.90; 95% CI, 0.82 to 0.98). IHOLLANDER2003B
There is limited evidence suggesting a difference favouring SSRIs over placebo on reducing obsessive-compulsive symptoms as measured by the clinician-rated Y-BOCS (K = 12; N = 1629; SMD = −0.42; 95% CI, −0.53 to −0.31). IBEASLEY1992
BURNHAM
GOODMAN1989
GOODMAN1996
HOLLANDER2003B
JENIKE1990A
JENIKE1990B
JENIKE1997
KAMIJIMA2004
MONTGOMERY1993
MONTGOMERY2001
ZOHAR1996A
There is limited evidence suggesting a difference favouring SSRIs over placebo on reducing depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (K = 3; N = 608; SMD = −0.28; 95% CI, −0.44 to −0.11). IMONTGOMERY1993
MONTGOMERY2001
ZOHAR1996A
There is limited evidence suggesting a difference favouring paroxetine over placebo on reducing the severity of illness as measured by the CGI Severity of Illness subscale (K = 1; N = 293; SMD = −0.36; 95% CI, −0.61 to −0.06). IZOHAR1996A
There is limited evidence suggesting a difference favouring citalopram over placebo on reducing impairment of family life as measured by the Sheehan Disability Scale family subscale (K = 1; N = 203; SMD = −0.33; 95% CI, −0.61 to −0.06). IMONTGOMERY2001
There is limited evidence suggesting a difference favouring citalopram over placebo on reducing impairment of social life as measured by the Sheehan Disability Scale social subscale (K = 1; N = 203; SMD = −0.33; 95% CI, −0.61 to −0.05). IMONTGOMERY2001
There is limited evidence suggesting a difference favouring citalopram over placebo on reducing impairment of work as measured by the Sheehan Disability Scale work subscale (K = 1; N = 203; SMD = −0.35; 95% CI, −0.63 to −0.08). IMONTGOMERY2001
There is limited evidence suggesting a difference favouring SSRIs over placebo on the likelihood of treatment response, defined as a 25% + or 35% + reduction on the clinician-rated Y-BOCS and/or CGI ‘much improved’ or ‘very much improved’ in patients with comorbid depression (K = 3; N = 763; SMD = −0.42; 95% CI, −0.53 to −0.31). IBEASLEY1992
KAMIJIMA2004
MONTGOMERY1993
There is limited evidence suggesting a difference favouring SSRIs over placebo on reducing obsessive-compulsive symptoms as measured by the clinician-rated Y-BOCS in patients with comorbid depression (K = 4; N = 489; SMD = −0.58; 95% CI, −0.76 to −0.4). IBEASLEY1992
GOODMAN1989
KAMIJIMA2004
MONTGOMERY1993
Tolerability
There is limited evidence suggesting that SSRIs when compared with placebo increase the risk of reporting adverse effects (K = 10; N = 1786; RR = 1.16; 95% CI, 1.1 to 1.23). IBURNHAM
GOODMAN1996
GREIST1995A
JENIKE1990A
JENIKE1990B
KAMIJIMA2004
KRONIG1999
MALLYA1992
MONTGOMERY2001
ZOHAR1996A
There is evidence suggesting that there is unlikely to be a clinically important difference between SSRIs and placebo on the likelihood of leaving the study early (K = 16; N = 2623; RR = 0.98; 95% CI, 0.85 to 1.13). IBURNHAM
CHOUINARD1990
GOODMAN1989
GOODMAN1996
GREIST1995A
HOLLANDER2003B
HOLLANDER2003D
JENIKE1990A
JENIKE1990B
JENIKE1997
KRONIG1999
MALLYA1992
MONTGOMERY1993
MONTGOMERY2001
PERSE1987
ZOHAR1996A
There is evidence suggesting that SSRIs when compared with placebo increase the risk of leaving the study early due to adverse effects (K = 13; N = 3009; RR = 2.15; 95% CI, 1.62 to 2.86). IBEASLEY1992
BURNHAM
CHOUINARD1990
GOODMAN1989
GOODMAN1996
GREIST1995A
HOLLANDER2003B
HOLLANDER2003D
KAMIJIMA2004
KRONIG1999
MONTGOMERY1993
MONTGOMERY2001
ZOHAR1996A

6.2.4. Different doses of SSRIs

6.2.4.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring 20 mg of an SSRI (citalopram/fluoxetine/paroxetine) over placebo on treatment response (K = 4; N = 666; RR = 0.82; 95% CI, 0.75 to 0.91). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
There is limited evidence suggesting a difference favouring 40 mg of an SSRI (citalopram/fluoxetine/paroxetine) over placebo on treatment response (K = 4; N = 661; RR = 0.79; 95% CI, 0.71 to 0.87). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
There is evidence suggesting a difference favouring 60 mg of an SSRI (citalopram/fluoxetine/paroxetine) over placebo on treatment response (K = 4; N = 666; RR = 0.71; 95% CI, 0.64 to 0.8). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
There is evidence suggesting there is unlikely to be a clinically important difference between 40 mg of an SSRI (citalopram/fluoxetine/paroxetine) and 20 mg of an SSRI on treatment response (K = 4; N = 655; RR = 0.96; 95% CI, 0.85 to 1.08). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
There is limited evidence suggesting a difference favouring 60 mg of an SSRI (citalopram/fluoxetine/paroxetine) over 20 mg of an SSRI on treatment response (K = 4; N = 660; RR = 0.87; 95% CI, 0.76 to 0.98). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
There is evidence suggesting there is unlikely to be a clinically important difference between 60 mg of an SSRI (citalopram/fluoxetine/paroxetine) and 40 mg of an SSRI on treatment response (K = 4; N = 655; RR = 0.90; 95% CI, 0.8 to 1.03). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
Tolerability
There is evidence suggesting that 20 mg of an SSRI (citalopram/fluoxetine/paroxetine) when compared with placebo increases the risk of leaving the study early because of adverse events (K = 4; N = 666; RR = 3.69; 95% CI, 2.03 to 6.7). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
There is limited evidence suggesting that 40 mg of an SSRI (citalopram/fluoxetine/paroxetine) when compared with placebo increases the risk of leaving the study early because of adverse events (K = 4; N = 661; RR = 2.22; 95% CI, 1.17 to 4.22). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
There is limited evidence suggesting that 60 mg of an SSRI (citalopram/fluoxetine/paroxetine) when compared with placebo increases the risk of leaving the study early because of adverse events (K = 4; N = 666; RR = 2.67; 95% CI, 1.44 to 4.98). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
There is limited evidence suggesting a difference favouring 40 mg of an SSRI (citalopram/fluoxetine/paroxetine) over 20 mg of an SSRI on leaving the study early because of adverse events (K = 4; N = 655; RR = 0.60; 95% CI, 0.39 to 0.92). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
There is limited evidence suggesting a difference favouring 60 mg of an SSRI (citalopram/fluoxetine/paroxetine) over 20 mg of an SSRI on leaving the study early because of adverse events (K = 4; N = 660; RR = 0.72; 95% CI, 0.48 to 1.07). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between 60 mg of an SSRI (citalopram/fluoxetine/paroxetine) and 40 mg of an SSRI on leaving the study early because of adverse events (K = 4; N = 655; RR = 1.21; 95% CI, 0.75 to 1.93). IBEASLEY1992
HOLLANDER2003D
MONTGOMERY1993
MONTGOMERY2001

6.2.5. SSRIs versus other SSRIs

6.2.5.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring sertraline over fluoxetine on reducing obsessive-compulsive symptoms as measured by the clinician-rated Y-BOCS at 12 weeks (K = 1; N = 148; SMD = 0.39; 95% CI, 0.07 to 0.72). IBERGERON2002
There is limited evidence suggesting a difference favouring fluvoxamine over citalopram on reducing obsessive-compulsive symptoms as measured by the National Institute of Mental Health Obsessive-Compulsive Global Scale (NIMH-OC) (K = 1; N = 21; SMD = 21.22; 95% CI, −2.17 to −0.27). IMUNDO1997a
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between different SSRIs on the tolerability of treatment.BERGERON2002
MUNDO1997a

6.2.6. SSRIs versus clomipramine

6.2.6.1. Clinical evidence statements

EfficacyIncluded studies
There is evidence suggesting there that is unlikely to be a clinically important difference between SSRIs and clomipramine on treatment response (OCD) (K = 8; N = 1019; RR = 1.02; 95% CI, 0.89 to 1.17). IBISSERBE1997
BURNHAM
LOPEZ-IBOR1996
KORAN1996A
MILANFRANCHI1997
MUNDO2001
ZOHAR1996A
There is evidence suggesting that there is unlikely to be a clinically important difference between SSRIs and clomipramine on OCD symptoms (Y-BOCS) (K = 7; N = 739; SMD = 0.14; 95% CI, −0.01 to 0.29). ILOPEZ-IBOR1996
KORAN1996A
MILANFRANCHI1997
MUNDO2001
SMERALDI1992
ZOHAR1996A
There is evidence suggesting that there is unlikely to be a clinically important difference between SSRIs and clomipramine on OCD symptoms (NIMH-OC) (K = 3; N = 666; SMD = 0.08; 95% CI, −0.08 to 0.23). IBURNHAM
MUNDO2001
ZOHAR1996A
There is evidence suggesting that there is unlikely to be a clinically important difference between SSRIs and clomipramine on OCD symptoms (Y-BOCS) in patients with comorbid depression (K = 3; N = 192; SMD = 0.22; 95% CI, −0.06 to 0.51). ILOPEZ-IBOR1996
MUNDO2001
SMERALDI1992
Tolerability
There is evidence suggesting that there is unlikely to be a clinically important difference between SSRIs and clomipramine on adverse effects (K = 7; N = 1037; RR = 0.95; 95% CI, 0.89 to 1). IASKIN1999
BISSERBE1997
BURNHAM
FREEMAN1994
KORAN1996A
MUNDO2001
ZOHAR1996A
There is limited evidence suggesting that clomipramine when compared with SSRIs increases the risk of leaving the study early (K = 10; N = 1139; RR = 0.72; 95% CI, 0.59 to 0.88). IASKIN1999
BISSERBE1997
BURNHAM
FREEMAN1994
KORAN1996A
LOPEZ-IBOR1996
MILANFRANCHI1997
MUNDO2001
SMERALDI1992
ZOHAR1996A
There is limited evidence suggesting that clomipramine when compared with SSRIs increase the risk of leaving the study early due to adverse effects (K = 8; N = 1095; RR = 0.62; 95% CI, 0.46 to 0.84). IBISSERBE1997
BURNHAM
FREEMAN1994
KORAN1996A
LOPEZ-IBOR1996
MILANFRANCHI1997
MUNDO2001
SMERALDI1992
ZOHAR1996A

6.2.7. SSRIs versus placebo or clomipramine: continuation treatment

6.2.7.1. Descriptive review

Five trials examined the continuation of treatment in patients with OCD (ANSSEAU; LOPEZ-IBOR1996; MONTGOMERY1993; BEASLEY1992; GREIST1995A).

In MONTGOMERY1993, treatment responders (N = 173) continued their blinded treatment for an additional 16 weeks (after an 8-week, double-blind, placebo-controlled trial of three fixed doses of fluoxetine; total N = 217).

Response was maintained during the extension phase. The mean improvement of Y-BOCS scores was fluoxetine 20 mg (−1.3, N = 18); fluoxetine 40 mg (−1.6, N = 20); fluoxetine 60 mg (−1.7, N = 23); placebo (−1.8, N = 12). However, there was no significant difference between fluoxetine and placebo on mean improvement on the Y-BOCS.

ANSSEAU was an unpublished 30-week extension phase trial of a 12-week acute-phase RCT (ZOHAR1996a) that compared the maintenance of efficacy in patients who had responded to paroxetine, clomipramine or placebo. Patients (N = 83) continued on the drug they received during the acute phase.

Ninety per cent of patients in the paroxetine group had maintained a response to treatment (defined as a reduction of at least 25% in the total Y-BOCS scores), compared with 89.5% of patients in the clomipramine group and 75% of patients in the placebo group. However, there was no significant difference between the continuation of paroxetine and placebo (N = 63; SMD = −0.51; 95% CI, −1.15 to 0.12) or between the continuation of paroxetine and clomipramine (N = 71; SMD = −0.01; 95% CI, −0.53 to 0.5) on reducing obsessive-compulsive symptoms as measured by the Y-BOCS. There was also no significant difference between treatment groups on the likelihood of reporting adverse events, paroxetine versus placebo (82% versus 66%, N = 63; RR = 1.24; 95% CI, 0.81 to 1.88), paroxetine versus clomipramine (82% versus 75%, N = 71; RR = 1.1; 95% CI, 0.83 to 1.46).

In a continuation study of BEASLEY1992 (Tollefson et al., 1994), treatment responders (N = 76) continued their blinded treatment for an additional 6 months after a 13-week, double-blind, placebo-controlled trial of three fixed doses of fluoxetine (N = 355).

Sixty-seven per cent of placebo-treated patients improved on the Y-BOCS at the end of the responder extension phase, as did 69.6% of fluoxetine 20 mg-treated patients, 76.2% of fluoxetine 40 mg-treated patients, and 76.9% of fluoxetine 60 mg-treated patients. Combining the fluoxetine-treated groups, 74.3% of patients experienced improvement beyond that seen during the 13-week acute phase. In terms of the number of patients who achieved ≥25% improvement in their Y-BOCS score, there was no difference between any dose of fluoxetine and placebo and between different doses of fluoxetine, 40 mg versus 20 mg (RR = 0.94; 95% CI; 0.57 to 1.54), 60 mg versus 20 mg (RR = 0.7; 95% CI, 0.4 to 1.21) and 60 mg versus 40 mg (RR = 0.74, 95% CI, 0.41 to 1.32).

In GREIST1995a, responders to a 12-week randomised trial of one of three fixed doses of sertraline (50, 100 or 200 mg) or placebo were continued on their treatment. Responders to the acute phase, defined as ‘marked’ or ‘moderate’ improvement on the CGI Efficacy Index were offered an additional 40 weeks of double-blind treatment at their assigned doses. Three hundred and twenty-five patients entered the acute phase, of which 125 patients were classified as responders. One-hundred-and -eighteen patients entered the continuation phase.

Overall, the pooled sertraline group exhibited greater improvement on measures of efficacy over the 48-week treatment period, Y-BOCS mean change scores (SDs): sertraline −5.7 (7.4) versus placebo −2.8 (5.8), F (1,289) = 7.06, p = 0.001. When changes from week 12 to endpoint were examined on efficacy, no differences were seen among any of the individual treatment groups or between the pooled sertraline group and placebo. Patients in the sertraline groups were more likely to report adverse events compared with patients in the placebo group, sertraline 50 mg 94%, sertraline 100 mg 91%, sertraline 200 mg 96%, placebo 79%. Two patients in the sertraline group and none in the placebo group attempted suicide.

LOPEZ-IBOR1996 continued patients for 12 weeks on the same double-blind fluoxetine versus clomipramine treatment received during an 8-week acute phase. Responders (fluoxetine, n = 11; clomipramine, n = 13) received a lower dose of the drug (20 mg fluoxetine and 100 mg clomipramine), while non-responders (fluoxetine, n = 14; clomipramine, n = 8) received a higher dose of the same acute-phase drug (60 mg fluoxetine and 200 mg clomipramine).

No formal statistical analysis took place due to the small size of the treatment arms. However, among responders to fluoxetine the mean endpoint Y-BOCS score was lower (8.8, SD 5.79) compared with baseline (9.6, SD 5.35), whereas among responders to clomipramine the mean endpoint score was higher (13.7, SD 11.79) compared with baseline (11.4, SD 6.13). Among non-responders, there was a decrease in the mean Y-BOCS score from baseline in patients receiving fluoxetine (mean baseline score 26.7, SD 6.38, mean endpoint score 24, SD 7.54), and similarly in patients receiving clomipramine (mean baseline score 21.5, SD 8.62, mean endpoint score 15, SD 9.32).

6.2.8. SSRIs versus placebo or clomipramine: relapse prevention

6.2.8.1. Descriptive review

Five trials were included in the review that examined relapse prevention in patients with OCD (ANSSEAU, BAILER, HOLLANDER2003; KORAN2002; ROMANO2001). A further trial (RAVIZZA1996A) was conducted open-label and therefore excluded from the review.

In BAILER, following a 6-month acute phase RCT of paroxetine versus placebo (BURNHAM) and a 6-month open label phase with flexible dosing of paroxetine (N = 154), non-responders (N = 44) were randomised to a 6-month double-blind relapse prevention phase of fixed dose paroxetine versus placebo.

For the percentage of patients with partial relapses (defined as a Y-BOCS score increase from the acute phase baseline score and an increase of one or more points on the CGI Severity of Illness subscale from the last open label score), the treatment effect was not significant (p = 0.22), although the percentage of partial relapses in the placebo group (63.6%) was greater than the percentage of partial relapses in the paroxetine group (42.1%). There was a significant difference favouring paroxetine over placebo on the Y-BOCS (N = 20; SMD = −1.17; 95% CI, −2.15 to −0.19).

In HOLLANDER2003, treatment responders (N = 105) were randomised to 6-month double-blind, fixed dose, parallel paroxetine/placebo treatment (after completing both a 12-week RCT of paroxetine/placebo [total N = 348] and 6 months of open-label paroxetine treatment [total N = 263].

The results indicated that more of the patients randomised to receive placebo (N = 52) experienced a relapse than those who continued to receive paroxetine (N = 53) when the criteria included an increase of one point or more on the CGI Severity of Illness subscale (38% versus 60%; RR = 0.63; 95% CI, 0.42 to 0.96). With a stricter criterion of a return to baseline of patients' Y-BOCS scores, the effect was stronger, but the difference was not statistically significant (9% versus 23%; RR = 0.41; 95% CI, 0.15 to 1.08). The mean time it took for patients continuing with paroxetine to relapse was 62.9 days compared with 28.5 days for those who relapsed after switching to placebo. Statistically significant differences favouring paroxetine over placebo on mean Y-BOCS scores were found as early as week 2 (F = 5.25; df = 1.68; p = 0.02) and up until 5 months. However, no difference was found between the groups at the end of 6 months. Significantly more patients receiving placebo left the study early because of adverse events compared with those receiving paroxetine (38% versus 5%; N = 105; RR = 0.15; 95% CI, 0.05 to 0.47).

In ANSSEAU, following an acute phase RCT of paroxetine versus clomipramine versus placebo (ZOHAR1996a) and an 8-week maintenance phase, patients were re-randomised within group to the drug or placebo (paroxetine/paroxetine versus paroxetine/placebo, clomipramine/clomipramine versus clomipramine/placebo, and placebo).

There was no significant difference between paroxetine and placebo on the rate of partial relapse (defined as an increase on the Y-BOCS from the baseline score or an increase in CGI severity by one or more points from the last observation), paroxetine 1/10 (10%) versus placebo 2/8 (25%). Based on a 25% response criterion on the Y-BOCS, the rate of response was lower in paroxetine (18.2%) compared with placebo (33.3%), but this was not statistically significant (p = 0.45). There was also no significant difference between paroxetine and placebo on the likelihood of reporting adverse effects, 57% versus 50%, respectively.

In ROMANO2001, treatment responders (N = 71) were randomised to 52 weeks double-blind, fixed dose fluoxetine or placebo treatment (after completing a 20-week single-blind treatment of fluoxetine [total N = 130]). People who continued to receive fluoxetine had a lower estimated 1-year relapse rate compared with those randomised to placebo, though this difference was not statistically different (20.6% versus 31.9%, p = 0.14). Among patients who responded to acute phase treatment with fluoxetine 60 mg/day, a subset of those who continued to receive fluoxetine, the 1-year estimated rate of relapse was lower compared with patients randomised to placebo (17.5% versus 38%, p = 0.04). This estimate was not significantly different for people who responded to acute phase treatment with fluoxetine 20 or 40 mg/day and who continued to receive fluoxetine for a year compared with patients randomised to placebo (28.6% versus 21.3%, p = 0.79). Change on the Y-BOCS from randomisation to endpoint was not statistically different between fluoxetine and placebo (p = 0.54).

In KORAN2002, treatment responders (N = 223) were randomised to 28 weeks double-blind sertraline or placebo treatment (after completing a 52-week single-blind treatment of sertraline [total N initially enrolled = 649]). Patients assigned to sertraline continued on the same dose of sertraline as during the 52-week phase, while patients assigned to placebo were blindly discontinued from sertraline. Mean Y-BOCS scores increased in both groups (mean change at end-point, −1.3 and −3.1 in sertraline and placebo groups respectively). However, patients continuing with sertraline had a lower mean score at endpoint than those receiving placebo (N = 221; SMD = −0.37; 95% CI, −0.63 to −0.10). When a strict criteria for relapse (increase in Y-BOCS >=5, Y-BOCS score >=20 and CGI Global Improvement >=1 continuing for a month) was applied, there was no difference between sertraline and placebo (3.6% versus 5.2%; N = 223; RR = 0.7; 95% CI, 0.2 to 2.4). However, more patients receiving placebo experienced a relapse or insufficient clinical response compared with sertraline (RR = 0.39; 95% CI, 0.20 to 0.76) and more patients experienced an acute exacerbation of OCD (RR = 0.34; 95% CI, 0.19 to 0.60).

6.2.9. Clinical summary

There is evidence from ten studies involving 2,588 patients for the efficacy of SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) for adults with OCD from placebo-controlled trials. The tolerability data indicate that they are generally well tolerated as the likelihood of leaving the study is unlikely to be greater for active treatment than for placebo. However there is limited evidence for more adverse events reported in the active arms and a greater chance of leaving the study because of adverse effects. In addition, there is some evidence that higher doses may be more efficacious than lower doses for citalopram, fluoxetine and paroxetine, and that higher doses may be associated with relatively fewer premature withdrawals because of adverse effects than lower doses. This may be due to the greater response at higher doses encouraging people to stay in the study whether they experience adverse effects or not. There is yet very little evidence suggesting that any one SSRI is more effective than another.

There is evidence from eight studies involving 1,019 patients that there is unlikely to be any clinically important differences between SSRIs and clomipramine either for efficacy or for adverse effects, but there is a greater likelihood of people discontinuing clomipramine based on those leaving the studies early and leaving early due to adverse effects. Thus, although SSRIs and clomipramine are both efficacious treatments (see also 6.4 below), SSRIs may be better tolerated. The continuation studies have investigated long-term treatment with SRIs for up to 48 weeks and the results suggest that patients who have responded to acute-phase treatment continue to respond in the longer term. The relapse prevention studies have used survival analysis to investigate patients for up to 12 months. The results suggest that SSRI treatment continued over the longer term protects against relapse of OCD.

6.3. CLOMIPRAMINE

6.3.1. Introduction

Clomipramine was the first pharmacotherapeutic agent found to have efficacy in OCD (Marks et al., 1980; Montgomery, 1980). The drug shares the pharmacological properties of the tricyclic group of antidepressants from which it is derived, but can be distinguished from other tricyclics by its potent effects at inhibiting the synaptic reuptake of the neurotransmitter serotonin. However, its effects are not selectively mediated by serotonin mechanisms. As a tricyclic, clomipramine is associated with the adverse effects and toxicity in overdose that typifies this group of drugs. For this reason it is usually considered second-line after SSRIs for patients whose symptoms have failed to respond to SSRIs or who are unable to tolerate them.

The following treatments were included:

6.3.2. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy and tolerability of clomipramine. Sixty-four studies were identified, of which 36 did not meet the inclusion criteria of the GDG. The 27 included studies provided efficacy data from 2121 participants and tolerability data from 2208 participants.

Of the included studies, seven compared clomipramine with placebo (BURNHAM; CCSG1991; KATZ1990; MONTGOMERY1990; STEIN1992; THOREN1980A; ZOHAR1996A), five with other tricyclic antidepressants (ANANTH1981; KHANNA1988; THOREN1980A; VOLAVKA1985; ZOHAR1987A), ten with SSRIs10 (ASKIN1999; BISSERBE1997; BURNHAM; FREEMAN1994; KORAN1996A; LOPEZ-IBOR1996; MILANFRANCHI1997; MUNDO2001; SMERALDI1992; ZOHAR1996A), and five with other drugs (ALBERT2002; HEWLETT1992; INSEL1983B; PATO1991; VALLEJO1992). Other comparisons included intravenous clomipramine versus placebo (FALLON1998) and oral clomipramine (KORAN1997).

All included acute phase studies (N = 25) were between 2 and 16 weeks long (mean length = 9.13 weeks). Patients were classified as outpatient in 11 studies, inpatient in 3 studies and mixed in 3 studies. Eight studies did not report patient setting. The average age of the patients was 33.65 years. The average duration of illness based on 10 studies was 10.94 years. Six studies were multi-centre studies, of which two were conducted in the US, two in Europe, one in France and Spain and the other in France and Belgium. Nine other studies were conducted in the US, three in Italy, three in the UK and one each in Austria, Canada, India and Sweden.

Two cross-over trials comparing clomipramine with SSRIs (KHANNA1988, ZOHAR1987a) are summarised in narrative form, as it was not possible to extract data at the point of cross-over. The other two cross-over trials, INSEL1983b and HEWLETT1992, are considered narratively in the sections on MAOIs and anxiolytics respectively.

Full details of the studies included in the guideline and the reasons for excluding studies are given in Appendix 16.

6.3.3. Clomipramine versus placebo

6.3.3.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring clomipramine over placebo on the likelihood of treatment response, defined as a 25% or greater reduction on the clinician-rated Y-BOCS, or CGI ‘much improved/very much improved’ (K = 3; N = 401; RR = 0.81; 95% CI, 0.68 to 0.96). IBURNHAM
STEIN1992
ZOHAR1996A
There is evidence suggesting a difference favouring clomipramine over placebo on the likelihood of remission, defined as a score of 1 to 6 on the NIMH-OC scale (K = 1; N = 520; RR = 0.54; 95% CI, 0.48 to 0.61). ICCSG1991
There is evidence suggesting a difference favouring clomipramine over placebo on reducing obsessive-compulsive symptoms as measured by the clinician-rated Y-BOCS (K = 3; N = 694; random effects SMD = −1.04; 95% CI, −1.72 to −0.36). ICCSG1991 (1)
CCSG1991 (2)
ZOHAR1996A
There is evidence suggesting a difference favouring clomipramine over placebo on reducing obsessive-compulsive symptoms as measured by the Comprehensive Psychopathological Rating Scale (CPRS) or 6-item OCD scale (K = 2; N = 30; SMD = −1.12; 95% CI, −1.92 to −0.32). IMONTGOMERY1990
THOREN1980A
There is evidence suggesting a difference favouring clomipramine over placebo on reducing obsessive-compulsive symptoms as measured by the NIMH-OC scale (K = 4; N = 847; random effects SMD = −0.87; 95% CI, −1.37 to −0.38). IBURNHAM
CCSG1991 (1)
CCSG1991 (2)
ZOHAR1996A
There is limited evidence suggesting a difference favouring clomipramine over placebo on reducing the severity of illness as measured by the CGI Severity of Illness subscale (K = 1; N = 193; SMD = −0.32; 95% CI, −0.60 to −0.03). IZOHAR1996a
There is limited evidence suggesting a difference favouring clomipramine over placebo on reducing psychological distress as measured by the Symptom Checklist-90 (K = 1; N = 151; SMD = −0.32; 95% CI, −0.64 to 0.00). IZOHAR1996a
Tolerability
There is evidence suggesting that clomipramine when compared with placebo increases the risk of reporting adverse effects (K = 3; N = 877; random effects RR = 1.25; 95% CI, 0.96 to 1.62). IBURNHAM
CCSG1991
ZOHAR1996A
There is evidence suggesting that clomipramine when compared with placebo increases the risk of leaving the study early due to adverse effects (K = 2; N = 357; RR = 2.35; 95% CI, 1.31 to 4.22). IBURNHAM
ZOHAR1996A

6.3.4. Clomipramine versus other TCAs

6.3.4.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring clomipramine over imipramine on reducingobsessive-compulsive symptoms as measured by the Self-Rating Obsessional Neurotic Scale (K = 1; N = 16; SMD = −1.17; 95% CI, −2.26 to −0.09). IVOLAVKA1985
There is limited evidence suggesting a difference favouring clomipramine over imipramine on improving global efficacy as measured by the Global Evaluation of Efficacy (K = 1; N = 16; SMD = −1.05; 95% CI, −2.12 to 0.02). IVOLAVKA1985
There is limited evidence suggesting a difference favouring clomipramine over imipramine on reducing depression as measured by the Hamilton Depression Rating Scale (K = 1; N = 16; SMD = −1.04; 95% CI, −2.11 to 0.02). IVOLAVKA1985
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between clomipramine and imipramine on leaving the study early because of adverse effects (K = 1; N = 23; RR = 1.09; 95% CI, 0.18 to 6.48). IVOLAVKA1985

6.3.4.2. Results summary from additional cross-over trials

In KHANNA1988, patients received double-blind clomipramine or nortriptyline in a randomised fashion for 6 weeks and then crossed over to the other drug after a 4-week drug-free interval. Out of the 18 patients who entered the trial, eight completed the full cross-over sequence.

There was no significant difference between pre- and post-trial scores on the Leyton Obsessional Inventory and the Maudsley Obsessive-Compulsive Inventory. There was also no difference between clomipramine and nortriptyline on obsessive-compulsive symptoms.

In ZOHAR1987a, after a 2–4 week placebo-phase, patients were randomly assigned to clomipramine or desipramine. After a 4-week placebo interval, patients were crossed-over to the other drug. The duration of each active treatment was 6 weeks. Fourteen patients entered the trial, of which 10 patients completed the entire cross-over sequence.

The reduction in obsessive-compulsive symptoms as measured by the Comprehensive Psychopathological Rating Scale – Obsessive-Compulsive subscale (CPRS-OC) and the NIMH-OC scale was greater in clomipramine than desipramine (CPRS-OC-5: F1,8 = 8.03, p = 0.02; NIMH-OC: F1,8 = 7, p = 0.03). Using the CPRS-OC subscale, the mean (±SD) improvement during the 6 weeks for clomipramine was 28.4% ± 20.1% compared with 4.2% ± 11.4% for desipramine.

6.3.5. Intravenous clomipramine + placebo pills versus oral clomipramine + placebo IV

6.3.5.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring intravenous clomipramine + placebo pills over oral clomipramine + placebo IV on the likelihood of treatment response, defined as a 25% or greater reduction on the clinician-rated Y-BOCS from baseline (K = 1; N = 15; RR = 0.16; 95% CI, 0.03 to 1.02). IKORAN1997
There is limited evidence suggesting a difference favouring intravenous clomipramine + placebo pills over oral clomipramine + placebo IV on reducing obsessive-compulsive symptoms as measured by the clinician-rated Y-BOCS (K = 1; N = 15; SMD = −1.26; 95% CI, −2.40 to −0.12). IKORAN1997
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between intravenous clomipramine + placebo pills over oral clomipramine + placebo IV on the tolerability of treatment.KORAN1997

6.3.6. Clomipramine versus placebo or SSRIs: continuation or discontinuation of treatment

There were 3 trials that examined the continuation or discontinuation of clomipramine (KATZ1990; LOPEZ-IBOR1996; RAVIZZA1996A). RAVIZZA1996A was an open-label trial and therefore excluded from the review.

In KATZ1990, outpatients received an initial 10-week double-blind treatment of clomipramine or placebo. Patients who responded to the 10-week acute phase (response being defined as response to treatment on at least three occasions during the 10 weeks as judged by the treating physician) entered a double-blind 1-year extension. Two hundred and eighty-six patients entered the study, of which 124 patients with a baseline Hamilton Depression Rating Scale score ≤17 and responding to the acute phase treatment entered the 1-year extension.

Patients from both groups showed improvement over the course of the extension phase compared with baseline as measured by the NIMH-OC scale, clomipramine −4.7 (SD 2.7) and placebo −1.7 (SD 2.5). The improvement was greater in clomipramine compared with placebo (p <0.001). Ninety-eight percent of the clomipramine patients and 65% of the placebo patients reported one or more adverse events. Twenty-five patients taking clomipramine discontinued the extension trial because of medical problems, whereas no placebo patients discontinued the study because of medical problems. Twelve clomipramine patients had serious adverse events. However, the authors suggest that the small sample size, small entry cohort and discontinuation patterns argue against any general or long-term efficacy of placebo, and also against any conclusive interpretations of the data for this highly selected group.

LOPEZ-IBOR1996 continued patients for 12 weeks on the same double-blind fluoxetine versus clomipramine treatment received during an 8-week acute phase. Responders (fluoxetine, n = 11; clomipramine, n = 13) received a lower dose of the drug (20 mg fluoxetine and 100 mg clomipramine), while non-responders (fluoxetine, n = 14; clomipramine, n = 8) received a higher dose of the same acute-phase drug (60 mg fluoxetine and 200 mg clomipramine).

No formal statistical analysis took place due to the small size of the treatment arms. However, among responders to fluoxetine the mean endpoint Y-BOCS score was lower (8.8, SD 5.79) compared with baseline (9.6, SD 5.35), whereas among responders to clomipramine the mean endpoint score was higher (13.7, SD 11.79) compared with baseline (11.4, SD 6.13). Among non-responders, there was a decrease on the mean Y-BOCS score from baseline in patients receiving fluoxetine (mean baseline score 26.7, SD 6.38, mean endpoint score 24, SD 7.54), and similarly in patients receiving clomipramine (mean baseline score 21.5, SD 8.62, mean endpoint score 15, SD 9.32).

6.3.7. Clinical summary

The results of these studies show that clomipramine is effective in the acute treatment of OCD. There have been no ‘dose-finding’ studies for clomipramine so we cannot judge the most effective dose for OCD. There is evidence from one study that intravenous clomipramine may be more effective than oral in partially responsive individuals. The evidence supporting the ongoing efficacy in continuation studies is limited by the shortage of studies in this area.

6.4. OTHER TRICYCLIC ANTIDEPRESSANTS

6.4.1. Introduction

Unlike SSRIs and clomipramine, other antidepressants that have been investigated in OCD so far, for example, tricyclic antidepressants (apart from clomipramine), tricyclic-related antidepressants, serotonin and noradrenaline re-uptake inhibitors (SNRIs) and monoamine-oxidase inhibitors (MAOIs) have not been shown to have convincing anti-obsessional efficacy (see below).

6.4.2. Treatments included

The following treatments were included:

6.4.3. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy and tolerability of TCAs other than clomipramine. Twelve studies were identified, of which five did not meet the inclusion criteria of the GDG. The seven included studies provided efficacy data from 258 participants and tolerability data from 259 participants.

Of the included studies, five compared TCAs with clomipramine (ANANTH1981; KHANNA1988; THOREN1980A; VOLAVKA1985; ZOHAR1987A) and two with SSRIs (GOODMAN1990A; HOEHN-SARIC2000). One study featured an additional placebo comparison (THOREN1980a).

All included studies were between 5 and 28 weeks long (mean length = 12.4 weeks). Patients were classified as outpatient in three studies, inpatient in one study and mixed in one study. One study did not report patient setting. The mean age of the patients was 36.6 years and the mean duration of illness in two studies was 18 years. Four studies were conducted in the US and one each in Canada, India and Sweden.

The results of two cross-over studies (KHANNA1988; ZOHAR1987A) are summarised in narrative form, as it was not possible to extract data at the point of cross-over.

Full details of the studies included in the guideline and the reasons for excluding studies are given in Appendix 16.

6.4.4. Tricyclic antidepressants versus placebo

6.4.4.1. Clinical evidence statements

EfficacyIncluded studies
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between nortriptyline and placebo on the efficacy of treatment in adults with OCD (K = 1; N = 16).THOREN1980a

6.4.4.2. Results summary from additional cross-over trials

In KHANNA1988, patients received double-blind clomipramine or nortriptyline in a randomised fashion for 6 weeks and then crossed-over to the other drug after a 4-week drug-free interval. Out of the 18 patients who entered the trial, 8 completed the full cross-over sequence.

There was no significant difference between pre- and post-trial scores on the Leyton Obsessional Inventory and the Maudsley Obsessive-Compulsive Inventory. There was also no difference between clomipramine and nortriptyline on obsessive-compulsive symptoms.

In ZOHAR1987A, after a 2–4 week placebo-phase, patients were randomly assigned to clomipramine or desipramine. After a 4-week placebo interval, patients were crossed-over to the other drug. The duration of each active treatment was 6 weeks. Fourteen patients entered the trial, of which 10 patients completed the entire cross-over sequence.

The reduction in obsessive-compulsive symptoms as measured by the CPRS-OC subscale and the NIMH-OC scale was greater in clomipramine than desipramine (CPRS-OC-5: F1,8 = 8.03; p = 0.02; NIMH-OC: F1,8 = 7; p = 0.03). Using the CPRS-OC subscale, the mean (±SD) improvement during the 6 weeks for clomipramine was 28.4% ± 20.1% compared with 4.2% ± 11.4% for desipramine.

6.4.5. Clinical summary

The results of these studies do not support the efficacy of tricyclic antidepressants (apart from clomipramine) for OCD.

6.5. TRICYCLIC-RELATED ANTIDEPRESSANTS

6.5.1. Treatments included

The following treatments were included:

6.5.2. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy and tolerability of tricyclic-related antidepressants. Two studies were identified, one of which did not meet the inclusion criteria of the GDG (ANTONELLI1973). The included study (PIGOTT1992) compared trazodone with placebo in a 10-week outpatient trial that provided efficacy data from 17 participants. Participants were begun on a fixed oral dosage regimen of 50 mg/day and were gradually increased, as tolerated, to a maximum of 300 mg/day.

Full details of the studies included in the guideline and the reasons for excluding studies are given in Appendix 16.

6.5.3. Descriptive review

In PIGOTT1992, patients received 10 weeks of either trazodone or placebo in a randomised fashion. There were no treatment differences between trazodone and placebo in patients completing the 10-week trial. Mean maximum decreases from baseline on the Y-BOCS was 2.7, SD 1.87; t = −1.44; p = 0.18, in patients receiving trazodone and −2.83; SD 1.19; t = −2.37; p = 0.06, in patients receiving placebo.

6.5.4. Clinical summary

There is no evidence supporting the efficacy of tricyclic-related drugs in OCD.

6.6. SEROTONIN AND NORADRENALINE REUPTAKE INHIBITORs (SNRIs)

6.6.1. Treatments included

The following treatments were included:

6.6.2. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy and tolerability of SNRIs. Five studies were identified, of which three did not meet the inclusion criteria of the GDG (DENYS2002; TENNEY2003; YARYURATOBIAS1996). The two included studies provided efficacy data from 218 participants and tolerability data from 223 participants, and compared venlafaxine with clomipramine (ALBERT2002) and paroxetine (DENYS2003A).

Both studies were 12 weeks long. Patients were classified as outpatient in both studies. The duration of OCD was 5.15 and 15 years in ALBERT2002 and DENYS2003A respectively. ALBERT2002 was conducted in Italy and DENYS2003A was conducted in the Netherlands.

Full details of the studies included in the guideline and the reasons for excluding studies are given in Appendix 16.

6.6.3. Venlafaxine versus other antidepressants

6.6.3.1. Clinical evidence statements

EfficacyIncluded studies
There is evidence suggesting there is unlikely to be a clinically important difference between venlafaxine and other SRIs on treatment response (OCD) (K = 2; N = 223; RR = 1.13; 95% CI, 0.91 to 1.40). IALBERT2002
DENYS2003A
There is evidence suggesting there is unlikely to be a clinically important difference between venlafaxine and other SRIs on OCD symptoms (K = 2; N = 218; SMD = 0.11; 95% CI, 20.16 to 0.38). IALBERT2002
DENYS2003A
Tolerability
There is limited evidence suggesting a difference favouring venlafaxine over clomipramine on the likelihood of reporting adverse effects in adults with OCD (K = 1; N = 73; RR = 0.67; 95% CI, 0.49 to 0.92). IALBERT2002

6.6.4. Clinical summary

There is no placebo-controlled evidence to support the efficacy of SNRIs in OCD. Although two studies showed similar levels of improvement on venlafaxine that have been found with drugs known to have shown efficacy in previous OCD, the absence of a placebo for comparison in these studies prevents us from concluding that in these studies the drug was actually effective. However, the results are suggestive of efficacy and point to further systematic investigation of SNRIs as a potential treatment for OCD.

6.7. MONOAMINE-OXIDASE INHIBITORs (MAOIs)

6.7.1. Treatments included

The following treatments were included:

6.7.2. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy and tolerability of MAOIs. Five studies were identified, of which two did not meet the inclusion criteria of the GDG (INSEL1982; ZAHN1984). The three included studies provided efficacy data from 67 participants and tolerability data from 94 participants.

One study compared phenelzine with placebo (JENIKE1997) and all three studies compared MAOIs with other drugs, including fluoxetine (JENIKE1997) and clomipramine (INSEL1983B; VALLEJO1992).

The included studies were between 6 and 12 weeks long (mean length = 9.3 weeks). Patients were classified as outpatient in two studies and mixed in one study. The average age of the patients was 33 years. The duration of illness was 6.7 and 11 years in INSEL1983b and VALLEJO1992 respectively. Two studies were conducted in the US and one in the UK.

The results of one cross-over study (INSEL1983b) are summarised in narrative form, as it was not possible to extract data at the point of cross-over.

Full details of the studies included in the guideline and the reasons for excluding studies are given in Appendix 16.

6.7.3. MAOIs versus placebo

6.7.3.1. Clinical evidence statements

EfficacyIncluded studies
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between phenelzine and placebo on the efficacy of treatment in adults with OCD.JENIKE1997
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between phenelzine and placebo on the likelihood of leaving the study early (K = 1; N = 41; RR = 1.05; 95% CI, 0.24 to 4.61). IJENIKE1997

6.7.4. MAOIs versus other drugs

6.7.4.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring phenelzine over clomipramine on reducing anxiety as measured by the Hamilton Anxiety Scale (K = 1; N = 26; SMD = 20.88; 95% CI, 21.69 to −0.07). IVALLEJO1992
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between MAOIs and other drugs on the tolerability of treatment.JENIKE1997
VALLEJO1992

6.7.4.2. Results summary from additional cross-over trials

In INSEL1983B, 24 patients with OCD were randomised to placebo-clorgyline-placebo or placebo-clomipramine-placebo sequences and then crossed over to the other treatment over a 6-month period. The duration of each active treatment was 6 weeks. Ten patients completed the entire cross-over sequence.

Neither clorgyline nor clomipramine were effective in reducing symptom severity as measured by the Leyton Interference score, though clomipramine was effective in ameliorating scores on 13 of 19 measures while clorgyline showed no improvement on all 19 measures. When the 10 patients who completed the entire cross-over sequence were compared, improvement with clomipramine surpassed that seen with clorgyline on the CPRS-OC subscale, the Global Obsessive-Compulsive scale and the Obsessive-Compulsive rating scale. Only one patient displayed more improvement with clorgyline than with clomipramine on obsessive-compulsive symptoms. Side effects were prevalent on placebo, clorgyline and clomipramine.

6.7.5. Clinical summary

There is no convincing evidence supporting the efficacy of MAOIs in OCD.

6.8. ANXIOLYTICS

6.8.1. Introduction

OCD is classified in some diagnostic systems, such as DSM-IV, together with the anxiety disorders. However, anxiolytics (excluding SSRIs) are not considered effective for the treatment of the core symptoms of OCD. The dependence producing effects of benzodiazepines argue against their use as long-term treatments.

6.8.2. Treatments included

The following treatments were included:

6.8.3. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy and tolerability of anxiolytics. Seven studies were identified, of which four did not meet the inclusion criteria of the GDG (KIM1997; LIN1979; ORVIN1967; WAXMAN1977). The three included studies provided efficacy data from 70 participants and tolerability data from 47 participants.

One study compared clonazepam with placebo (HOLLANDER2003C) and two with other drugs (HEWLETT1992; PATO1991).

The included studies were between 6 and 26 weeks long. Patients were classified as outpatient in one study. The average age of the patients was 35 years. All three studies were conducted in the US.

The results of one cross-over study (HEWLETT1992) are summarised in narrative form, as it was not possible to extract data at the point of cross-over.

Full details of the studies included in the guideline and the reasons for excluding studies are given in Appendix 16.

6.8.4. Anxiolytics versus placebo

6.8.4.1. Clinical evidence statements

EfficacyIncluded studies
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between clonazepam and placebo on the efficacy of treatment.HOLLANDER2003C
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between clonazepam and placebo on the tolerability of treatment.HOLLANDER2003C

6.8.5. Anxiolytics versus other drugs

6.8.5.1. Clinical evidence statements

EfficacyIncluded studies
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between buspirone and clomipramine on the efficacy of treatment in adults with OCD.PATO1991
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between buspirone and clomipramine on the tolerability of treatment in adults with OCD.PATO1991

6.8.5.2. Results summary from additional cross-over trial

In HEWLETT1992, 28 patients were initially randomly assigned to clomipramine, clonazepam, clonidine or diphenhydramine as control and then crossed-over to each of the other treatments. The study took place over 26 months, with 6 weeks in each treatment. Sixteen patients completed the entire cross-over sequence. Eight patients discontinued because of adverse side effects.

Clonazepam and clomipramine produced significantly lower Y-BOCS scores than did diphenhydramine and clonidine. In turn, Y-BOCS scores in diphenhydramine were significantly lower than baseline, whereas there was no difference between ratings for clonidine treatment and baseline. While the response rate for diphenhydramine and clonidine was 27% and 20% respectively, the response rates for clonazepam and clomipramine was higher at 48% and 54% respectively. Patients who responded to clonazepam tended to respond to clomipramine, the cross-response rate being 73% and patients who responded to clomipramine tended to respond to clonazepam, cross-response rate 80%.

6.8.6. Clinical summary

Although there is some evidence suggesting potential efficacy for clonazepam, the dependence-producing effects known to occur with benzodiazepines argues against the routine use of the drug for OCD.

6.9. SSRIs/CLOMIPRAMINE VERSUS NON-SRIs

6.9.1. Introduction

There is a body of opinion that SSRIs and clomipramine are superior to non-SRIs. This is based on the evidence that SRIs have been found to be effective compared with placebo, whereas non-SRIS have not. Thus prescribers may well be more likely to choose an SRI for treating OCD. Head-to-head trials comparing SRIs with non-SRIs may influence the confidence with which treatment preferences are made.

6.9.2. Treatments included

The following treatments were included:

Venlafaxine was excluded because it has the properties of both SRIs and TCAs.

6.9.3. Studies considered

Trials which performed head-to-head comparisons of a SSRI or clomipramine with a non-SRI were considered. Six studies were included: GOODMAN1990A; HOEHN-SARIC2000; JENIKE1997; PATO1991; VALLEJO1992; VOLAVKA1985. The studies provided efficacy data on 278 patients and tolerability data on 343 patients. The duration of treatment ranged between 6 and 12 weeks. Patients were classified as outpatient in 4 studies, patient setting was not reported in 2 studies. The average age of the patients was 35 years. Five studies were conducted in the US and one study was conducted in the UK. Two studies included patients with comorbid depression.

6.9.3.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring SSRIs/clomipramine over non-SRIs on reducing obsessive-compulsive symptoms, as measured by the clinician-rated Y-BOCS in adults with OCD (K = 4; N = 258; SMD = 20.3; 95% CI, 20.54 to −0.05). IGOODMAN1990A
HOEHN-SARIC2000
JENIKE1997
PATO1991
Tolerability
There is limited evidence suggesting a difference favouring SSRIs/clomipramine over non-SRIs on the likelihood of leaving the study early due to adverse events in adults with OCD (K = 5; N = 279; RR = 0.51; 95% CI, 0.28 to 0.95). IGOODMAN1990A
HOEHN-SARIC2000
PATO1991
VALLEJO1992
VOLAVKA1985

6.9.4. Clinical summary

There is some evidence that SRIs, not considering venlafaxine, are better than non-SRIs such as TCAs, MAOIs and anxiolytics on efficacy and tolerability, but this is limited by the small number of studies in this comparison. This evidence is supported by the fact that SRIs are better than placebo, whereas TCAs are not better than placebo.

6.10. OTHER PHARMACOLOGICAL INTERVENTIONS

6.10.1. Introduction

In the search for alternative treatment for OCD, a wide range of other pharmacological treatments have been investigated. However, each has been subjected to only very limited study and the results have not supported further systematic exploration. This section considers alternative treatments in patients who were not yet considered as refractory to treatment.

6.10.2. Treatments included

The following treatments were included:

6.10.3. Studies considered

A systematic search was conducted for reports on the above treatments in patients with OCD or BDD. The search yielded 704 records, of which 2 studies (DENBOER1992, FUX1996) were RCTs and 9 studies were non-RCTs. Full details of the search strategy are given in Appendix 6.

6.10.4. Inositol versus placebo

6.10.4.1. Clinical evidence statements

EfficacyIncluded studies
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between inositol and placebo on the efficacy of treatment.FUX1996

6.10.5. Oxytocin versus placebo

6.10.5.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring placebo over oxytocin on the likelihood of reporting adverse effects in adults with OCD (K = 1; N = 12; RR = 6.00; 95% CI, 1.00 to 35.91). IDENBOER1992

6.10.6. Descriptive review

The quality of the evidence was poor, since most studies were case reports (Ansseau et al., 1987; Casas et al., 1986; Eriksson, 2000; Feldman et al., 1988; Knesevich, 1982) or had very small sample sizes (Hewlett et al., 2003; Salzberg & Swedo, 1992; Taylor & Kobak, 2000; Yaryura Tobias & Bhagavan, 1977).

Ansseau and colleagues (1987) reported the treatment of a patient with OCD with intranasal oxytocin or placebo in a double-blind cross-over manner, each randomised period lasting 4 weeks. While no significant changes in obsessive-compulsive symptoms were present during the placebo period, intranasal oxytocin induced a clear improvement on the CPRS-OC. However, the patient also complained of gross memory disturbances during oxytocin therapy and increased psychotic symptoms. In contrast, Salzberg and Swedo (1992) failed to find any discernible effects of oxytocin or vasopressin on obsessive-compulsive symptoms in 3 patients randomised in a blinded fashion to intranasal oxytocin, intranasal vasopressin or normal saline.

Casas and colleagues (1986) studied the anti-obsessional effect of the anti-androgen, Cyproterone acetate. In patients with OCD, during the 10 days of treatment there was a notable improvement in obsessive symptoms and a decrease in compulsive rituals. After the third month of treatment, there was a gradual reappearance of obsessive symptoms, in particular anxiety and the need to perform compulsive rituals. Feldman and colleagues (1988) failed to find improvement in obsessive-compulsive symptoms after treating a patient with OCD with cyproterone acetate for 5 months. Eriksson (2000) studied the effect of a long-acting gonadotropin-releasing hormone analogue, triptorelin. After 4 months of treatment, the patient experienced fewer obsessive-compulsive symptoms and further improvement after 3 more months of treatment.

Hewlett and colleagues (2003) studied the anti-obsessional properties of 5-HT3 receptor antagonist, ondansetron, in 8 patients with OCD. Over the course of the trial, 8 patients experienced an average of 28% reduction on the Y-BOCS from baseline, while 3 patients achieved a clinically significant response (≥35% reduction in Y-BOCS score). Moreover, at 2 weeks' follow-up of the 6 completers, there was a 45% worsening of symptoms associated with discontinuing treatment.

Taylor and colleagues (2000) conducted a 12-week open-label trial of St. John's Wort in 12 patients. Treatment consisted of a fixed dose of 450 mg of 0.3% hypericin twice daily. At the end of treatment, five out of 12 patients were rated as ‘much improved’ or ‘very much improved’ on the CGI Global Improvement scale. A significant improvement similar to that found in clinical trials was found on the Y-BOCS, with a mean change of 7.4 points.

Knesevich (1982) reported improvement on compulsions following a 2-week trial with clonidine (0.1 mg t.i.d.) in a patient with OCD. Increasing the dose to 0.1 mg q.i.d. caused ritualistic behaviour to return, but the symptoms diminished after dosage was brought back to 0.1 mg t.i.d.

Yaryura-Tobais and Bhagavan (1977) reported improvement among seven patients with OCD after treatment with L-tryptophan (3 to 9 g daily) for 1 month. The patients' conditions were stabilised after 6 months to 1 year of treatment.

6.10.7. Clinical summary

In conclusion, the paucity of clinical evidence on other pharmacological treatments for OCD limits our confidence in the efficacy of these alternative pharmacological treatments.

6.11. TREATMENT STRATEGIES FOR PATIENTS SHOWING AN INCOMPLETE RESPONSE TO SRIs

6.11.1. Introduction

Although most individuals with OCD experience substantial improvements on first-line treatment with SRI drugs, for many the treatment response is not complete. In about 30% cases residual symptoms remain in spite of prolonged treatment. The clinical management of ‘incomplete responders’ is an area that has not yet been thoroughly investigated, although there is much interest in the area and treatment-studies indicating promising strategies are already entering the scientific literature.

Research into the area of treatment-resistant OCD has been bedevilled by the lack of universally accepted definitions of treatment-response and treatment-failure. Many of the published studies have used different criteria, making it rather difficult to draw generalised conclusions from them. For example, some studies included only extremely refractory cases whose symptoms had failed to respond to successive treatments with more than one SRI, whereas others included those who had made a partial response to treatment with a single SRI drug. Pallanti and colleagues (2002a) recently proposed criteria based on expert consensus opinion. Specifically, they argued an improvement of ≥35% in baseline Y-BOCS score, or ‘much’ or ‘very much improved’ on the CGI Global Improvement, represented a meaningful clinical response, while ‘remission’ required a total Y-BOCS score of less than 16. Those showing between 25–35% improvement in Y-BOCS scores were considered partial responders. Relapse was defined as a 25% worsening in Y-BOCS (or a CGI score of 6), after a period of remission, and the term ‘treatment-refractory’ was reserved for those who do not respond to ‘all available treatments’. Levels of non-response, according to the numbers of failed treatments, were also defined. It remains to be seen whether these criteria will be universally accepted by the scientific community.

This section reviews research on the pharmacological treatment of individuals who have symptoms failing to completely respond to SRI medication. First there will be a description of current practice, including predictors of treatment failure and definitions of incomplete response. Then the drugs and the studies will be considered, followed by a narrative review of the studies and a clinical summary encapsulating practice points and areas for further research.

6.11.2. Current practice

In contrast to the large amount of data for first-line treatments for OCD, the evidence base for the treatment of individuals whose symptoms have failed to respond adequately to first-line treatments is rather slim. Indeed, we do not understand clearly which clinical factors might predict a better or worse outcome after pharmacological treatment; few pharmacological studies provide information on response status at outcome and the literature on pharmacological response predictors is sparse and inconsistent. The factor analysis by Mataix-Cols and colleagues (1999) suggested that adults with compulsive rituals, early-onset age, longer duration, chronic course, comorbid tics and personality disorders (especially schizotypal), responded poorly to clomipramine and SSRIs. Additional analyses of large databases for clomipramine and fluoxetine reported better responses for previously SRI-naïve individuals, and poorer responses for those with sub-clinical depression. Those with an earlier age of onset responded poorly to clomipramine, but not to fluoxetine (Ackerman & Greenland, 2002). The more recent analysis of data from a large trial of citalopram also reported that patients with a longer duration of illness or previous SSRI treatment, as well as greater illness severity, were less likely to respond well to drug-treatment (Stein et al., 2001). One small study identified better responses in females (Mundo et al., 1999) but children with comorbid attention deficit hyperactivity disorder, tic disorder and oppositional defiant disorder showed a less favourable response (Geller et al., 2003).

OCD responds to treatment gradually with some patients responding more slowly than others, therefore it is important not to anticipate treatment-failure prematurely. There is no agreed consensus on what constitutes an adequate period of treatment, but published expert consensus guidelines suggest at least 12 weeks (Greist et al., 2003; March et al., 1997) and possibly longer may be required in some cases.

In the UK, a number of strategies are currently employed for individuals who have symptoms that are failing to respond adequately to first-line treatment with SRI drugs. Sometimes the individual is treated for longer on the original drug to see if a delayed response occurs. Alternatively the individual may be switched to an alternative SRI, or the SRI continued with the introduction of a drug of either the same class (that is, two SRIs given together) or a drug of another class added in combination (see below). Sometimes the dose of SRI is increased beyond usual recommended daily-dosage limits, or the mode of delivery is changed, for example to intravenous as opposed to oral delivery. Sometimes the individual is switched to a drug of another class used as a monotherapy. These strategies are usually managed under the guidance of a consultant psychiatrist or his/her team. The evidence for these strategies will be reviewed below. The evidence for those involving only SRIs will be reviewed first, and those involving drugs of other classes will be reviewed later.

6.11.3. Descriptive review of strategies involving SRIs

The studies considered in this section were based on a literature review on the pharmacotherapy of OCD (Fineberg & Gale, 2004).

6.11.3.1. Switching SRI

Given the limitations of data supporting alternative strategies, and the acceptability of switching from one SSRI to another, this remains the preferred option for many clinicians. Sometimes, however, it is appropriate to persist for longer with a particular SRI even in patients who show little sign of improvement, since a delayed response may occur after 6 months or more. A panel of international OCD experts made recommendations on switching (Expert Consensus Guideline, March et al., 1997) and they suggested changing the SRI after 8–12 weeks on the maximal dose if the clinical effect was incomplete. They proposed a 40% chance of responding to a second SRI, and a lesser response to a third and suggested switching to clomipramine after 2–3 failed trials on SSRIs. Since that time, a limited evidence-base supporting switching has accrued, but the data remains sparse and inconclusive. In a placebo-controlled sertraline trial, one third of patients benefited from a switch to a second SSRI (Koran et al., 2002). Denys and colleagues (2004) took 43 non-responders to 12 weeks treatment with either paroxetine or venlafaxine and switched them under double-blind conditions to the alternate treatment, whereupon 18 (43%) showed a clinical response. A single-blind study in 29 cases of SRI-resistant OCD showed encouraging results for venlafaxine (37.5–375 mg) as a monotherapy (Hollander et al., 2003b).

These results intimate that patients whose symptoms have failed to respond to an SSRI may benefit from switching agent, but fail to control for the effect of prolongation of treatment per se. RCTs comparing continuation of the original drug with switching are required to properly evaluate the role of switching in OCD.

6.11.3.2. Increasing dose

Results from uncontrolled case studies suggest that, for some patients, increasing SSRI doses above formulary limits may procure a better effect (Bejerot & Bodlund, 1998; Byerly et al., 1996). Although doses of clomipramine up to 300 mg have been systematically investigated and found to be acceptable, the risk of seizures and cardiotoxicity associated with this drug suggest that doses exceeding this should be generally avoided, and if attempted, ECG and clomipramine plasma-level monitoring should be considered.

6.11.3.3. Changing mode of drug-delivery

Changing mode of administration may be considered though this is not practical in many cases. Intravenous clomipramine has been shown to be more effective than placebo in a single double-blind study investigating refractory OCD, with 6 out of 29 patients randomised to clomipramine classed as responders after 14 daily infusions, compared with none receiving placebo infusions (Fallon et al., 1998). A positive open study showing benefit for 21 days intravenous citalopram has also been reported (Pallanti et al., 2002b) but requires confirmation using a controlled study design.

6.11.4. Intravenous clomipramine versus intravenous placebo (for treatment resistant patients)

6.11.4.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring intravenous clomipramine over intravenous placebo on the likelihood of treatment response, defined as CGI ‘much improved’ or ‘very much improved’ (K = 1; N = 54; RR = 0.79; 95% CI, 0.66 to 0.96). IFALLON1998
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between intravenous clomipramine and intravenous placebo on the likelihood of leaving the study early (K = 1; N = 54; RR = 0.43; 95% CI, 0.04 to 4.48). IFALLON1998

6.11.4.2. Combining two SRIs

If a patient has symptoms that fail to respond to successive SRI trials, augmented with CBT, the Expert Consensus Guideline (March et al., 1997) recommends adding another agent to the SRI. The evidence is acknowledged to be limited, based on the results of small RCTs and open case series.

Combining clomipramine with an SSRI has been proposed for adults or children unresponsive to, or intolerant of, SRI monotherapy. This strategy should be approached with caution since the pharmacokinetic interactions on the hepatic cytochrome P 450 isoenzymes may lead to a build-up of clomipramine that could be dangerous, and ECG and clomipramine plasma-level monitoring is advisable. Positive results have been reported from small, uncontrolled case series (Szegedi et al., 1996), although the fluoxetine–clomipramine combination resulted in ECG changes in some cases. Pallanti et al. (1999) compared 9 treatment-refractory patients given citalopram plus clomipramine with 7 given citalopram alone, in a randomised open-label trial. They reported a significantly larger improvement in Y-BOCS ratings for those given the combination, all of whom experienced decreases ≥35% from baseline. This combination is advantageous in not altering the metabolism of clomipramine, and was well tolerated. No controlled studies of the co-administration of different SSRIs have been published.

6.11.5. Augmentation strategies with drugs of other classes

The following drugs, given in order to improve clinical outcome in individuals who have symptoms that are failing to completely respond to SRI monotherapy, were included:

6.11.5.2. Combining SRIs and drugs exerting antidepressant or anxiolytic properties

Controlled studies have found no evidence for the efficacy of lithium augmentation in OCD (McDougle et al., 1991; Pigott et al., 1991). Similarly, three double-blind placebo controlled studies have demonstrated that combining buspirone with an SRI is not helpful (Grady et al., 1993; McDougle et al., 1993; Pigott et al., 1992a). Clonazepam, a benzodiazepine with putative effects on serotonin neurotransmission, failed to impact on the core symptoms of OCD as a monotherapy in one study (Hollander et al., 2003c), but produced some evidence of anti-obsessional effect in another (Hewlett et al., 1992). Pigott and colleagues (1992b) reported limited efficacy for clonazepam given together with fluoxetine or clomipramine in a placebo-controlled study. Pindolol is a beta-blocker which also acts as an antagonist at presynaptic 5HT1A autoreceptors. Dannon and colleagues (2000) demonstrated efficacy for pindolol when combined with paroxetine in a double-blind placebo-controlled study of 14 treatment resistant cases, but another study combining it with fluvoxamine did not (Mundo et al., 1998). Blier and Bergeron (1996) found a beneficial effect for pindolol only when l-tryptophan was openly added to the combination.

The limitations of adding drugs acting on serotonin led investigators to re-examine the role of noradrenergic agents for OCD. While not evidently effective as a monotherapy, nortryptyline (50 mg) administered in combination with 150 mg clomipramine was found to be more effective than clomipramine plus placebo in a small 8-week study looking at 30 individuals with non-refractory OCD (Noorbala et al., 1998). However, Barr and colleagues (1997) investigated the addition of another noradrenergic antidepressant, desipramine, to 20 patients whose symptoms had failed to respond to SSRI monotherapy, in a double-blind placebo-controlled study, and found no added benefit.

6.11.5.3. Combining SRIs and drugs with antipsychotic properties

No positive studies of antipsychotic monotherapy in OCD meet today's standards, and OCD is not recognised as responding to these drugs individually. McDougle and colleagues (1990) reported a benefit from adding open-label pimozide (6.5 mg) in 17 patients unresponsive to fluvoxamine. Patients with comorbid chronic tics or schizotypal disorder were most responsive. A subsequent double-blind placebo-controlled study by the same author demonstrated a significant Y-BOCS improvement for low-dose haloperidol (6.2 mg) added to fluvoxamine. Eleven of 17 patients receiving the active drug achieved ‘responder’ status by as early as 4 weeks, compared with none on placebo. Again, a preferential response was seen in patients with comorbid tics (McDougle et al., 1994). Antipsychotics such as haloperidol and sulpiride are first-line treatments for Tourette's syndrome, so this finding supports a theoretical link between these disorders. This combination increases the side-effect burden, including extra-pyramidal effects. It is therefore recommended to start treatment with very low doses, and increase cautiously subject to tolerability (for example, 0.25–0.5 mg haloperidol, titrated slowly to 2–4 mg (McDougle & Walsh, 2001).

Newer second-generation antipsychotics that modulate serotonin and dopamine neurotransmission also offer promise and are associated with a lower risk of side effects, although they may cause dysregulation of endocrine and metabolic functions and weight gain. Positive reports from open case series were confirmed by McDougle and colleagues (2000a) in the first reported double-blind placebo-controlled study showing efficacy for risperidone augmentation in 36 patients unresponsive to 12 weeks on an SRI. Risperidone (2.2 mg) was superior to placebo in reducing Y-BOCS scores as well as anxiety and depression, was well-tolerated and there was no difference between those with and without comorbid tics or schizotypy. A smaller double-blind study by Hollander and colleagues (2003a) examined patients who had symptoms that were failing to respond to at least two trials of SRIs. Four of 16 patients randomised to risperidone (0.5–3 mg) turned out to be responders, defined as a CGI Global Improvement score of 1 or 2 and Y-BOCS decrease of >25% at the 8-week end-point, compared with none of the six patients randomised to placebo. However, the results, which were limited by the small sample size, did not reach statistical significance.

Quetiapine has also been the subject of recent controlled investigation. There have been contradictory results from open studies (Denys et al., 2002a; Mohr et al., 2002; Sevincok & Topuz, 2003). However, a placebo-controlled single-blind study looking at 27 cases of SRI-resistant OCD showed a significant advantage from adding quetiapine in doses up to 200 mg daily to ongoing SRI (Atmaca et al., 2002). Moreover, the recent double-blind placebo-controlled study by Denys and colleagues (2004) showed evidence of efficacy for 8 weeks quetiapine (<300 mg) augmentation in 20 patients whose symptoms had failed to respond to at least two SRIs, showing a mean decrease of 31% on baseline Y-BOCS, compared with 20 placebo-treated controls whose symptoms showed only 7% improvement (p < 0.001). Eight out of twenty (40%) patients responded to quetiapine therapy, compared with two out of 20 (10%) on placebo.

Encouraging results from a small number of open-label studies of olanzapine (Bogetto et al., 2000; Crocq, 2002; D'Amico et al., 2003; Francobandiera, 2001; Koran et al., 2000; Weiss et al., 1999) were not, however, supported by the double-blind placebo-controlled study by Shapira and colleagues (2004), which investigated 44 partial or non-responders to 8 weeks of fluoxetine. Both groups improved over the 6-week study period, with no additional advantage for the olanzapine-treated patients compared with extending the duration of fluoxetine monotherapy. Differences in entry criteria between studies may partly explain differences in the results.

There has been a positive open-label study of amisulpride (Metin et al., 2003).

Augmentation with clozapine has not been systematically investigated. The results for clozapine monotherapy in OCD have not been encouraging (McDougle et al., 1995a). Some authors have reported emergent obsessions during treatment with atypical antipsychotics, which may be related to their mixed receptor antagonist properties.

Altogether, these results favour the use of second generation antipsychotics such as risperidone and quetiapine as the first-line strategy for augmentation in resistant OCD. It remains uncertain as to how long patients need to remain on augmented treatment. A small retrospective study by Maina and colleagues (2003) showed that the vast majority of patients who had responded to the addition of an antipsychotic to their SRI, subsequently relapsed when the antipsychotic was withdrawn.

6.11.5.4. Other strategies for refractory OCD

Inositol (18 g/day) is an experimental compound that acts through intracellular messenger systems. It was thought to have mild anti-obsessional efficacy but results from a placebo-controlled augmentation study by Fux and colleagues (1999) refute this. Sumatriptan is a 5HT1D agonist used to treat migraine. A small open case series suggested improvement over 4 weeks of treatment but, in a double-blind placebo-controlled study of 10 patients, 5-day treatment was associated with a worsening of OCD (Koran et al., 2001).

6.11.6. Clinical summary

Treatment-resistant OCD is now receiving systematic evaluation. The first step to managing resistant OCD is to check adherence to the original treatment. In the case of resistance, augmentation with second generation antipsychotic agents appears a promising strategy for which there is some supportive evidence from controlled clinical trials. Other techniques for resistant cases, such as increasing the dose above SPC limits, changing to another SSRI or clomipramine, combining SRIs or changing the mode of drug-delivery are under evaluation. Important questions requiring further investigation include identification of clinically relevant predictors relating to treatment–response and relapse, the clarification of optimal duration of treatment and the evaluation of anti-obsessional treatment in comorbid disorders such as schizophrenia with OCD. Agreed definitions for response, relapse, resistance and refractoriness will improve research in this area.

6.12. PHARMACOLOGICAL INTERVENTIONS FOR CHILDREN AND YOUNG PEOPLE WITH OCD

6.12.1. Treatments included

The following treatments were included:

6.12.2. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy of pharmacological interventions among children and young people with OCD. Eighteen published trials were identified, of which four did not meet the inclusion criteria of the GDG. One unpublished trial (Carpenter) was identified. The 14 included studies provided efficacy data from 1034 participants and tolerability data from 1068 participants.

Of the included studies, seven compared acute-phase SSRI treatment with placebo (GELLER2001; GELLER2004; LIEBOWITZ2002; MARCH1998; POTS2004; RIDDLE1992; RIDDLE2001), four compared clomipramine with placebo (DEVEAUGHGEISS1992; FLAMENT1985; MARCH1990; RAPOPORT1980), three compared clomipramine with desipramine (LEONARD1989A; LEONARD1991A; RAPOPORT1980), two examined continuation treatment of SSRIs (CARPENTER; LIEBOWITZ2002), and one study compared continuation of clomipramine treatment with desipramine substitution (LEONARD1991A). Of the seven studies comparing SSRIs with placebo, three examined fluoxetine (GELLER2001; LIEBOWITZ2002; RIDDLE1992), one fluvoxamine (RIDDLE2001), two sertraline (MARCH1998; POTS2004), and one paroxetine (GELLER2004).

All included acute-phase randomised studies were between 8 and 20 weeks long (mean length = 12 weeks). Patients were classified as outpatient in 7 studies, mixed in 3 studies and unclear in four studies. The average age of the patients was 13.2 years. The average duration of illness based on 7 studies was 3.6 years. All studies were conducted in the US, including three studies which were multi-centre studies and one study which was conducted in the US and Canada.

Additional data on suicidal behaviour/ideation was obtained from a review made public by the FDA (Hammad, 2004). The review came about after the FDA commissioned a re-classification of the original patient-level data by experts in suicidality at Columbia University (Iyasu, 2004). The FDA concluded that this blinded classification process identified and corrected many misclassification errors, providing more accurate risk estimates (Hammad, 2004). Four studies were included in the review (GELLER2001; GELLER2004; MARCH1998; RIDDLE2001) providing data on 616 participants.

The results of three cross-over studies (FLAMENT1985; LEONARD1989A; RAPOPORT1980) are summarised in narrative form, as it was not possible to extract data at the point of cross-over.

6.12.3. SSRIs versus placebo

6.12.3.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring SSRIs over placebo on the likelihood of treatment response, defined as a 25% + 40% + reduction on the Children's Y-BOCS (K = 3; N = 430; RR = 0.70; 95% CI, 0.59 to 0.83). IGELLER2001
GELLER2004
RIDDLE2001
There is limited evidence suggesting a difference favouring SSRIs over placebo on reducing obsessive-compulsive symptoms as measured on the Children's Y-BOCS (K = 7; N = 718; SMD = 20.43; 95% CI, 20.58 to 20.28). IGELLER2001
GELLER2004
LIEBOWITZ2002
MARCH1998
POTS2004
RIDDLE1992
RIDDLE2001
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between SSRIs and placebo on the risk of suicidal behaviour/ideation (K = 4; N = 616; RR = 1.81; 95% CI, 0.46 to 7.13). I11GELLER2001
GELLER2004
MARCH1998
RIDDLE2001
There is evidence suggesting that SSRIs when compared with placebo increase the risk of leaving the study early due to adverse effects (K = 6; N = 732; RR = 2.74; 95% CI, 1.46 to 5.14). IGELLER2001
GELLER2004
LIEBOWITZ2002
MARCH1998
POTS2004
RIDDLE1992
RIDDLE2001

6.12.4. Clomipramine versus placebo

6.12.4.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring clomipramine over placebo on reducing obsessive-compulsive symptoms as measured by the Children's Y-BOCS (K = 1; N = 16; SMD = 20.94; 95% CI, 21.99 to 0.11). IMARCH1990
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between clomipramine and placebo on the tolerability of treatment.DEVEAUGHGEISS1992
MARCH1990

6.12.4.2. Results summary from additional cross-over trials

In FLAMENT1985, following a 1-week evaluation period, patients were randomised to 5 weeks of clomipramine or placebo and then crossed-over to 5 weeks of the other treatment. Twenty-three patients entered the drug study and 19 completed the entire cross-over sequence.

Compared with placebo, clomipramine was significantly more effective in relieving obsessional symptoms, as measured on Leyton Obsessional Inventory – Child Version (LOI-CV) symptom (t = 2.19, p = 0.04), resistance (t = 2.12, p = 0.05) and interference scores (t = 2.24, p = v0.04), the OCR scale (t = 3.05, p = 0.007), and the NIMH-OC scale (t = 2.83, p = 0.02). Side-effects scores increased markedly during the first week with clomipramine and by week 5 they were significantly higher than with placebo (t = −2.52, p = 0.02). One patient experienced a grand mal seizure during clomipramine treatment.

In RAPOPORT1980, patients were randomised to 3–5 week consecutive periods of treatment with clomipramine, desipramine or placebo and then crossed-over to each of the other 2 treatments over 16 weeks. Nine patients entered the study and eight completed the entire cross-over sequence.

At the end of treatment, symptom severity as measured by the Leyton Interference and Resistance subscales was comparable across clomipramine, desipramine and placebo. Side effects did not differ between treatment periods.

6.12.5. Clomipramine versus desipramine substitution

6.12.5.1. Clinical evidence statements

EfficacyIncluded studies
There is limited evidence suggesting a difference favouring clomipramine continuation over desipramine substitution on the likelihood of relapse as defined by the Physician's Relapse Scale (K = 1; N = 20; RR = 4.89; 95% CI, 1.37 to 17.49). ILEONARD1991A
Tolerability
The evidence is inconclusive and so it is not possible to determine if there is a clinically important difference between clomipramine continuation and desipramine substitution on the likelihood of leaving the study early (K = 1; N = 21; RR = 3.27; 95% CI, 0.15 to 72.23). ILEONARD1991A

6.12.5.2. Results summary from additional cross-over trials

In LEONARD1989a, following a 2-week single-blind placebo phase patients were randomised to 5-week consecutive periods of treatment with clomipramine or desipramine and then crossed-over to the other treatment. Forty-nine patients participated in the trial.

At the end of treatment, symptom severity was decreased to a greater extent by clomipramine than desipramine based on the NIMH-OC scale (F = 16.62; p = 0.002), Ward OCD Rating scale (F = 21.16; p = 0.00001) and CPRS-OC subscale (F = 10.34; p = 0.003). There was a significant effect of order of drug, whereby the rate of relapse was greater in the clomipramine-to-desipramine cross-over sequence than the desipramine-to-clomipramine cross-over sequence.

In RAPOPORT1980, patients were randomised to 3–5 week consecutive periods of treatment with clomipramine, desipramine or placebo and then crossed-over to each of the other 2 treatments over 16 weeks. Nine patients entered the study and eight completed the entire cross-over sequence.

At the end of treatment, symptom severity as measured by the Leyton Interference and Resistance subscales was comparable across clomipramine, desipramine and placebo. Side effects did not differ between treatment periods.

6.12.6. SSRI versus placebo: continuation/discontinuation

6.12.6.1. Descriptive review

Two studies examined the continuation of SSRIs in children, CARPENTER and LIEBOWITZ2002.

CARPENTER was an unpublished 32-week two-phase trial of paroxetine. In the first phase, patients received open-label paroxetine for 16 weeks. In the second phase, patients who responded to the first phase were either continued with paroxetine at the final daily dose achieved during the first phase or discontinued from paroxetine onto placebo in a double-blind randomised fashion. The duration of the second phase was 16 weeks. Three hundred and thirty-five patients participated in the phase I trial, of which 194 entered the second phase.

The results indicated that the rate of relapse, defined as (a) an increase in CGI Global Improvement score by 1 point for 2 consecutive visits, (b) an increase in CGI Global Improvement score by 2 or more points at any single visit, and (c) a CGI Global Improvement score of 5 or more points at any time, was not significantly different between patients continuing with paroxetine (34.7%) and patients discontinuing from paroxetine (43.9%). Comparing the response rates between the two groups based on a 25% or greater reduction of CY-BOCS from baseline favoured paroxetine continuation over discontinuation (25% versus 13.3%; RR = 0.86; 95% CI, 0.75 to 0.99). Symptom severity increased in both groups during the continuation phase as measured by the CY-BOCS, though this increase was lower in the paroxetine continuation group than the discontinuation group (SMD = −3.3; 95% CI, −5.77 to −0.83).

In LIEBOWITZ2002, patients who responded to an 8-week acute phase of fluoxetine or placebo were entered into an 8-week maintenance phase. Response was defined as ‘much improved’ or ‘very much improved’ on the CGI Global Improvement scale. Patients continued to receive the same drug as during the acute phase and were maintained on the final dose achieved during the acute phase.

Of the 43 patients who entered the acute phase, 18 entered the maintenance phase. At the end of the 8-week maintenance phase, fluoxetine patients had lower CY-BOCS scores than did placebo patients, mean (SD) was 5.64 (5.41) and 11.43 (11.12) respectively, F (1,14) = 9.22; p = 0.009. None of the fluoxetine patients relapsed, while one placebo patient relapsed. There were significantly more fluoxetine than placebo responders (57% versus 27%; χ2 = 3.94; p = 0.05). Twenty-seven percent of the fluoxetine patients reported at least one adverse event, compared with none among the placebo patients.

6.12.7. Clinical summary

There is evidence supporting the treatment of OCD in children and young people with SSRIs. The literature is not extensive, but it is consistent in showing beneficial effects in terms of symptom remission and improvements in global functioning. There are always concerns about the use of drugs in young people, particularly medications which act on the developing central nervous system. These potential risks have to be weighed against the known risks of untreated OCD on emotional, educational and social development, and the impact of chronic OCD on adult adaptation. More research is needed in children and young people in the acute phase, in long-term follow-up, and on educational and cognitive progress.

Although the evidence-base is small for psychological treatment, clinical consensus recommends the use of psychological treatment as first-line in young people with OCD. However, in severe or chronic cases, where CBT has been ineffective or is unavailable, or where the patient chooses medication, this is an effective treatment option, either alone or ideally with, CBT.

For OCD, clinical trial evidence, although not extensive, suggests that CBT and SSRI/SRI treatment have similar efficacy. Clinical trial evidence, observational data and yellow card data all show that SSRIs have a range of side effects related to activation syndromes that have not yet been observed or systematically studied in studies of psychological treatments. At the time of writing this guideline, there is concern about the use of SSRIs in children and young people with major depression, because, with the exception of fluoxetine, they show no evidence of clinically significant efficacy whilst being associated with an increased risk of adverse events, particularly suicidal thought and behaviours. In contrast, in children and young people with OCD clinical trials have shown limited evidence for efficacy, although there is insufficient evidence to determine whether or not SSRIs are associated with an increased risk of suicidal thought and behaviours.

6.13. PHARMACOLOGICAL INTERVENTIONS FOR PEOPLE WITH BDD

6.13.1. Introduction

This topic is of interest because of the lack of experience by psychiatrists in treating BDD and the paucity of evidence concerning pharmacotherapy in this area.

6.13.2. Current practice

There are no surveys of how BDD is currently treated or managed in the UK. Our clinical impression is that following an influential case series of pimozide in delusional disorder (Riding & Munro, 1975) many patients are treated with antipsychotic drugs. The popularity of pimozide itself has since dwindled probably because of concerns about its toxicity and the need to perform an ECG prior to its administration. However, this does not seem to have stopped the prescribing of antipsychotic drugs for BDD.

Current practice is not underpinned by a strong evidence base, for example, there are few studies upon which to base clinical decisions, and there are concerns about the generalisability of patient samples.

6.13.3. Treatments included

The following treatments were included:

6.13.4. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy of pharmacotherapy in BDD.

Two trials met the eligibility criteria set by the GDG. Phillips and colleagues (2002) entered 74 participants with BDD (including those with beliefs of delusional intensity) into the study. Sixty seven were randomised to either fluoxetine or a placebo for 12 weeks. The range of the dose of fluoxetine was between 40 and 80 mg a day. Fluoxetine was significantly more effective than placebo on the Y-BOCS modified for BDD after 12 weeks of treatment (N = 77; SMD = −0.60; 95% CI, −1.09 to −0.11). The baseline for the fluoxetine group was 31.5 (SD 5.6) reducing to 21.0 (SD 9.8) at 12 weeks, which represented a 33% reduction on the main outcome measure. The rate of response, defined as a 30% or greater decrease from baseline on the Y-BOCS, was greater in fluoxetine than placebo at 12 weeks (N = 77; RR = 0.58; 95% CI, 0.39 to 0.85). Patients with delusional beliefs were as likely as those without delusional beliefs to respond to fluoxetine, and no patients with delusional beliefs responded to the placebo. The effect was independent of comorbid diagnoses of OCD or depression.

There has been one double-blind randomised crossover trial comparing clomipramine with desipramine (Hollander et al., 1999). Forty participants with BDD (including those with beliefs of delusional intensity) were enrolled and 29 were randomised into a 2-week, single-blind run-in, followed by 8 weeks of either clomipramine or 8 weeks of desipramine which was then crossed over. Clomipramine is a potent serotonergic reuptake inhibitor and a tricyclic antidepressant. Desipramine is a potent noradrenergic reuptake inhibitor and another tricyclic. Both clomipramine and desipramine led to a reduction in the severity of obsessive-compulsive symptoms from baseline to endpoint as indicated by the BDD-YBOCS scores, baseline BDD-YBOCS was 25.4 (SD 7.2), BDD-YBOCS following clomipramine treatment was 16.2 (SD 8.5) and following desipramine treatment was 20.7 (SD 7.7). The reduction in symptom severity was significantly greater following clomipramine treatment than following desipramine treatment (F 1, 21 = 11.03; p = 0.003). Response rates were 65% for clomipramine and 35% for desipramine, based on 25% improvement on the BDD-YBOCS (p = 0.09). Treatment efficacy was not influenced by comorbidity of OCD, depression or social phobia.

There are limitations to this trial, including a lack of a placebo arm, a maintenance phase after the crossover and potential carry over effects, which are inherent in crossover designs. There is some evidence that the response may have been greater if a higher dose of clomipramine (mean 138 mg/day) was used and for a longer duration (at least 12 to 16 weeks).

6.13.5. SSRI augmentation

Phillips (2005) has conducted an RCT of pimozide augmentation of fluoxetine. Twenty-eight people with BDD (including those with beliefs of delusional intensity) whose symptoms had failed to respond to fluoxetine participated in an 8-week double-blind study of up to 10 mg pimozide or placebo augmentation of fluoxetine. Pimozide was no more effective than placebo; 18.2% of subjects responded to pimozide and 17.6% to placebo. There was no significant effect of baseline delusionality on endpoint BDD severity. Delusionality did not decrease significantly more with pimozide than placebo. Possible explanations of the lack of efficacy include the study's low power and the modest mean pimozide dose. In OCD, augmentation of an SSRI with pimozide and haloperidol has found higher response rates in patients with a tic disorder or schizotypal personality disorder. No BDD subject in this study had either additional diagnosis.

6.13.6. Descriptive review

6.13.6.1. Antidepressants

SRIs other than fluoxetine or clomipramine may be of benefit both theoretically and from the evidence of four case series. There are similar modest benefits from four open label trials. There are two open label case series of fluvoxamine (Perugi et al., 1996; Phillips et al., 1998), one of citalopram (Phillips & Najjar, 2003) and one case series of clomipramine (Hollander et al., 1989).

Phillips and colleagues (1998) entered 30 participants with BDD who received fluvoxamine over 16 weeks. The average dose was 238.8 mg and the range was 50 to 300 mg. The Y-BOCS modified for BDD decreased from 31.1 (SD 5.4) at baseline to 16.9 (SD 11.8) at 16 weeks. This represents a 45% reduction on the main outcome measure. Sixty-three per cent of participants responded based on a criterion of a 30% decrease or more on the Y-BOCS modified for BDD. Fluvoxamine was as effective in participants with an additional diagnosis of delusional disorder as without.

Perugi and colleagues (1996) entered 15 participants with BDD in an open label trial. The duration was for 10 weeks. The average dose was 208 mg and the range of dose was 100 to 300 mg. They did not use the modified Y-BOCS as an outcome measure but reported a 60% reduction over 12 weeks on symptom scores and 10 out of the 15 participants responding on the CGI.

Phillips and Najjar (2003) entered 15 participants with BDD (including those with beliefs of delusional intensity) in an open label study of citalopram over 12 weeks. The average dose was 51.3 mg and the range was 10 to 60 mg. The Y-BOCS modified for BDD decreased from 30.7 (S.D 4.9) at baseline to 15.3 (SD 10.6) at 12 weeks. This represents a 50% reduction on the main outcome measure. 73.3% of participants responded defined as a 30% decrease or more on the Y-BOCS modified for BDD. Citalopram was as effective in participants with an additional diagnosis of delusional disorder as without.

Hollander and colleagues (1989) reported on a case series of five participants with BDD who all responded to either clomipramine or fluoxetine. Four of the five patients' symptoms had failed to respond previously to drugs that had some serotonergic action including tricyclics, trazodone and lithium.

Phillips (1996b) conducted a retrospective case review of 130 patients who had 316 treatment trials of which 42% of 65 SRI trials had led to an improvement on the CGI, compared with 30% of 23 trials with a monoamine-oxidase inhibitor and 15% of 48 trials with a non-SRI tricyclic drug.

No continuation, maintenance or discontinuation studies of an SRI have been reported. Expert opinion and clinical experience suggest that, like OCD, there may be small further gains with an SRI after 12–16 weeks treatment. Furthermore, like OCD, there is a high rate of relapse on discontinuation on a SRI (Phillips et al., 2001).

Lastly there are case reports on the benefit of sertraline (El-Khatib & Dickey, 1995) and two cases with intravenous clomipramine (Pallanti & Koran, 1996). There are two case reports of the benefit of an MAOI, tranlcypromine (Jenike, 1984) and one with a combination of phenelzine, trimipramine and perphenazine (Phillips, 1991).

6.13.6.2. Antipsychotic drugs as a monotherapy

Antipsychotic drugs were prescribed for BDD following a case series describing the benefit of pimozide in individuals with delusional disorder (Riding & Munro, 1975). However the case series included cases of delusions of infestation, delusions of body odour and dysmorphic delusions.

Phillips and colleagues (1996b), in a retrospective survey of medication trials, reported that only 3% of 83 trials of an antipsychotic were of any benefit in BDD. Grant (2001) has described one case report of olanzapine for BDD without delusional disorder. The individual however fulfilled diagnostic criteria for BDD, alcohol dependence and bipolar II disorder. At the end of 3 weeks, she reported no preoccupation with her appearance and no longer met criteria for BDD.

6.13.6.3. SSRI switching or augmentation studies

In individuals with BDD whose symptoms have failed to respond to an SSRI, or who have a partial response to an SSRI, then switching to another SSRI or augmentation with another drug has been tried.

Phillips and colleagues (2001) reported that in those subjects whose symptoms failed to respond to an adequate SRI trial, 42.9% (n = 6) responded to at least one subsequent SRI trial and 43.5% (n = 10) of subsequent SRI trials received by these subjects were effective.

Phillips and colleagues (2001) reported on an open label series of buspirone (extended from Phillips, 1996a) in a chart review of patients whose symptoms failed to respond to an SRI alone or have had only a partial response. In 12 participants, buspirone was added after an adequate does of an SRI; 33.3% of trials were successful. The mean dose was 56.5 mg (range 30–80 mg daily) and was as effective in delusional as non-delusional cases.

6.13.6.4. Young people with BDD

Albertini and Phillips (1999) reported on 33 children and young people with BDD of whom 10 out 19 (53%) treated with an SRI improved on the CGI. No non-SRI medications in 8 trials were effective.

There is one case report on clomipramine in an adolescent with BDD with delusional disorder (Sondheimer, 1988) and one case report of doxepine and behaviour therapy in an adolescent with BDD (Sobanski & Schmidt, 2000).

6.13.7. Clinical summary

The only placebo-controlled RCT in BDD suggested benefit from fluoxetine or clomipramine in BDD. There are also several case series of other SRIs that support this finding.

No evidence exists on the optimal dose of an SRI in BDD but expert opinion is that SRIs in BDD may have a dose response relationship similar to OCD and that the maximum tolerated dose should be tried.

No evidence exists on the optimal duration of a trial of an SRI but expert opinion suggests that at least 12 weeks is required. An SRI is however associated with a high rate of relapse on discontinuation (similar to the treatment of OCD) although this has not been formally evaluated.

There is no evidence for the efficacy of an antipsychotic in BDD as a monotherapy or as augmentation strategy with an SRI. However, an antipsychotic may still be useful for the symptomatic treatment of individuals with BDD who are highly agitated.

There is no evidence for the benefit of MAOIs, non-SRI tricyclics, or atypical SRIs as a monotherapy for BDD. There is no evidence for the benefit or electroconvulsive therapy (ECT) or psychosurgery in BDD.

No studies have yet compared a SRI with CBT or a combination of the two treatments. Expert opinion suggests that the combination of CBT with an SRI is helpful in moderate to severe BDD.

Limited evidence suggests that SSRIs can be effective in children and young people with BDD with a similar response to adults with BDD and young people with OCD. However no evidence exists for the safety of SSRIs in children and young people with BDD.

6.14. CLINICAL PRACTICE RECOMMENDATIONS

6.14.1. Initial treatment options

Children and young people

6.14.1.1.

If psychological treatment is declined by children or young people with OCD or BDD and their families or carers, or they are unable to engage in treatment, an SSRI may be considered with specific arrangements for careful monitoring for adverse events. [B]

6.14.2. How to use pharmacological interventions for adults

Current published evidence suggests that SSRIs are effective in treating people with OCD and BDD, although evidence for the latter is limited and less certain. However, SSRIs may increase the risk of suicidal ideas and self-harm in people with depression and in younger people. It is currently unclear whether there is an increased risk for people with OCD or BDD. Regulatory authorities recommend careful monitoring, especially when initiating treatment and around dose changes. Patients should also be warned about, and monitored for, relapse and discontinuation/withdrawal symptoms when stopping or reducing SSRIs.

Starting the treatment

6.14.2.1.

Common concerns about taking medication for OCD or BDD should be addressed. Patients should be advised, both verbally and with written material, that:

  • craving and tolerance do not occur [C]
  • there is a risk of discontinuation/withdrawal symptoms on stopping, missing doses, or reducing the dose [C]
  • there is a range of potential side effects, including worsening anxiety, suicidal thoughts and self-harm, which need to be carefully monitored, especially in the first few weeks of treatment [C]
  • there is commonly a delay in the onset of effect of up to 12 weeks, although depressive symptoms improve more quickly [C]
  • taking medication should not be seen as a weakness. [GPP]

Monitoring risk

6.14.2.2.

Adults with OCD or BDD started on SSRIs who are not considered to be at increased risk of suicide or self-harm should be monitored closely and seen on an appropriate and regular basis. The arrangements for monitoring should be agreed by the patient and the healthcare professional, and recorded in the notes. [GPP]

6.14.2.3.

Because of the potential increased risk of suicidal thoughts and self-harm associated with the early stages of SSRI treatment, younger adults (younger than age 30 years) with OCD or BDD, or people with OCD or BDD with comorbid depression, or who are considered to be at an increased risk of suicide, should be carefully and frequently monitored by healthcare professionals. Where appropriate, other carers – as agreed by the patient and the healthcare professional – may also contribute to the monitoring until the risk is no longer considered significant. The arrangements for monitoring should be agreed by the patient and the healthcare professional, and recorded in the notes. [C]

6.14.2.4.

For adults with OCD or BDD at a high risk of suicide, a limited quantity of medication should be prescribed. [C]

6.14.2.5.

When adults with OCD or BDD, especially with comorbid depression, are assessed to be at a high risk of suicide, the use of additional support such as more frequent direct contacts with primary care staff or telephone contacts should be considered, particularly during the first weeks of treatment. [C]

6.14.2.6.

For adults with OCD or BDD, particularly in the initial stages of SSRI treatment, healthcare professionals should actively seek out signs of akathisia or restlessness, suicidal ideation and increased anxiety and agitation. They should also advise patients to seek help promptly if symptoms are at all distressing. [C]

6.14.2.7.

Adults with OCD or BDD should be monitored around the time of dose changes for any new symptoms or worsening of their condition. [C]

Choice of drug treatment

Selective serotonin reuptake inhibitors (SSRIs)

6.14.2.8.

For adults with OCD, the initial pharmacological treatment should be one of the following SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, or citalopram. [A]

6.14.2.9.

For adults with BDD (including those with beliefs of delusional intensity), the initial pharmacological treatment should be fluoxetine because there is more evidence for its effectiveness in BDD than there is for other SSRIs. [B]

6.14.2.10.

In the event that an adult with OCD or BDD develops marked and/or prolonged akathisia, restlessness or agitation while taking an SSRI, the use of the drug should be reviewed. If the patient prefers, the drug should be changed to a different SSRI. [C]

6.14.2.11.

Healthcare professionals should be aware of the increased risk of drug interactions when prescribing an SSRI to adults with OCD or BDD who are taking other medications. [GPP]

6.14.2.12.

For adults with OCD or BDD, if there has been no response to a full course of treatment with an SSRI, healthcare professionals should check that the patient has taken the drug regularly and in the prescribed dose and that there is no interference from alcohol or substance use. [GPP]

6.14.2.13.

For adults with OCD or BDD, if there has not been an adequate response to a standard dose of an SSRI, and there are no significant side effects after 4–6 weeks, a gradual increase in dose should be considered in line with the schedule suggested by the Summary of Product Characteristics. [C]

6.14.2.14.

For people with OCD or BDD, the rate at which the dose of an SSRI should be increased should take into account therapeutic response, adverse effects and patient preference. Patients should be warned about, and monitored for, the emergence of side effects during dose increases. [GPP]

6.14.2.15.

If treatment for OCD or BDD with an SSRI is effective, it should be continued for at least 12 months to prevent relapse and allow for further improvements. [C]

6.14.2.16.

When an adult with OCD or BDD has taken an SSRI for 12 months after remission (symptoms are not clinically significant and the person is fully functioning for at least 12 weeks), healthcare professionals should review with the patient the need for continued treatment. This review should consider the severity and duration of the initial illness, the number of previous episodes, the presence of residual symptoms, and concurrent psychosocial difficulties. [GPP]

6.14.2.17.

If treatment for OCD or BDD with an SSRI is continued for an extended period beyond 12 months after remission (symptoms are not clinically significant and the person is fully functioning for at least 12 weeks), the need for continuation should be reviewed at regular intervals, agreed between the patient and the prescriber, and written in the notes. [GPP]

6.14.2.18.

For adults with OCD or BDD, to minimise discontinuation/withdrawal symptoms when reducing or stopping SSRIs, the dose should be tapered gradually over several weeks according to the person's need. The rate of reduction should take into account the starting dose, the drug half-life and particular profiles of adverse effects. [C]

6.14.2.19.

Healthcare professionals should encourage adults with OCD or BDD who are discontinuing SSRI treatment to seek advice if they experience significant discontinuation/withdrawal symptoms. [C]

Other drugs

With the exception of clomipramine, other antidepressants should not normally be used in the treatment of OCD or BDD. Most other drugs have limited or no use in this context.

6.14.2.20.

The following drugs should not normally be used to treat OCD or BDD without comorbidity:

6.14.2.21.

Antipsychotics as a monotherapy should not normally be used for treating OCD. [C]

6.14.2.22.

Antipsychotics as a monotherapy should not normally be used for treating BDD (including beliefs of delusional intensity). [C]

6.14.3. How to use clomipramine for adults

Clomipramine can be offered as a second line drug for OCD/BDD. Always do an ECG and check blood pressure before starting treatment if there is significant risk of cardiovascular disease. Dose changes should be gradual.

6.14.3.1.

For adults with OCD or BDD who are at a significant risk of suicide, healthcare professionals should only prescribe small amounts of clomipramine at a time because of its toxicity in overdose. The patient should be monitored regularly until the risk of suicide has subsided. [GPP]

6.14.3.2.

An electrocardiogram (ECG) should be carried out and a blood pressure measurement taken before prescribing clomipramine for adults with OCD or BDD at significant risk of cardiovascular disease. [C]

6.14.3.3.

For adults with OCD or BDD, if there has not been an adequate response to the standard dose of clomipramine, and there are no significant side effects, a gradual increase in dose should be considered in line with the schedule suggested by the Summary of Product Characteristics. [C]

6.14.3.4.

For adults with OCD or BDD, treatment with clomipramine should be continued for at least 12 months if it appears to be effective and because there may be further improvement. [B]

6.14.3.5.

For adults with OCD or BDD, when discontinuing clomipramine, doses should be reduced gradually in order to minimise potential discontinuation/withdrawal symptoms. [C]

6.14.4. How to use pharmacological treatments in children and young people

In adults with OCD treated by medication, there is clinical trial evidence that supports practice on the onset of therapeutic response, dose needed, rate of increase of dose, duration of treatment, likelihood of relapse on discontinuation. Trials of these aspects have not been done in children and/or young people, but the following good practice for prescribing SSRIs or clomipramine is based on adult trials and clinical experience.

How to use SSRIs in children and young people

6.14.4.1.

When an SSRI is prescribed to children and young people with OCD or BDD, it should be in combination with concurrent CBT (including ERP). If children and young people are unable to engage with concurrent CBT, specific arrangements should be made for careful monitoring of adverse events and these arrangements should be recorded in the notes. [C]

6.14.4.2.

Children and young people with OCD or BDD starting treatment with SSRIs should be carefully and frequently monitored and seen at an appropriate and regular basis. This should be agreed by the patient, his or her family or carers and the healthcare professional, and recorded in the notes. [GPP]

6.14.4.3.

An SSRI should only be prescribed to children and young people with OCD or BDD following assessment and diagnosis by a child and adolescent psychiatrist who should also be involved in decisions about dose changes and discontinuation. [GPP]

6.14.4.4.

A licensed medication (sertraline or fluvoxamine) should be used when an SSRI is prescribed to children and young people with OCD, except in patients with significant comorbid depression when fluoxetine should be used, because of current regulatory requirements. [A]

6.14.4.5.

Fluoxetine should be used when an SSRI is prescribed to children or young people with BDD. [C]

6.14.4.6.

For children and young people with OCD or BDD who also have significant depression, the NICE recommendations for the treatment of childhood depression12 should be followed and there should be specific monitoring for suicidal thoughts or behaviours. [GPP]

6.14.4.7.

Children and young people with OCD or BDD starting treatment with SSRIs should be informed about the rationale for the drug treatment, the delay in onset of therapeutic response (up to 12 weeks), the time course of treatment, the possible side effects and the need to take the medication as prescribed. Discussion of these issues should be supplemented by written information appropriate to the needs of the child or young person and their family or carers. [GPP]

6.14.4.8.

The starting dose of medication for children and young people with OCD or BDD should be low, especially in younger children. A half or quarter of the normal starting dose may be considered for the first week. [C]

6.14.4.9.

If a lower dose of medication for children and young people with OCD or BDD is ineffective, the dose should be increased until a therapeutic response is obtained, with careful and close monitoring for adverse events. The rate of increase should be gradual and should take into account the delay in therapeutic response (up to 12 weeks) and the age of the patient. Maximum recommended doses for children and young people should not be exceeded. [C]

6.14.4.10.

Children and young people prescribed an SSRI and their families or carers, should be informed by the prescribing doctor about the possible appearance of suicidal behaviour, self-harm or hostility, particularly at the beginning of treatment. They should be advised that if there is any sign of new symptoms of these kinds, they should make urgent contact with their medical practitioner. [GPP]

6.14.4.11.

Where children or young people with OCD or BDD respond to treatment with an SSRI, medication should be continued for at least 6 months post-remission (i.e. symptoms are not clinically significant and the child or young person is fully functioning for at least 12 weeks). [C]

How to use clomipramine in young people

6.14.4.12.

Children and young people with OCD or BDD and their families or carers should be advised about the possible side effects of clomipramine, including toxicity in overdose. [C]

6.14.4.13.

Before starting treatment with clomipramine in children and young people with OCD or BDD, an ECG should be carried out to exclude cardiac conduction abnormalities. [C]

6.14.4.14.

For a child or young person with OCD or BDD, if there has not been an adequate response to the standard dose of clomipramine, and there are no significant side effects, a gradual increase in dose may be cautiously considered. [C]

6.14.4.15.

Treatment of a child or young person with OCD or BDD with clomipramine should be continued for at least 6 months if the treatment appears to be effective, because there may be further improvement in symptoms. [B]

Stopping or reducing SSRIs and clomipramine in children and young people

6.14.4.16.

In children and young people with OCD or BDD, an attempt should be made to withdraw medication if remission has been achieved (i.e. symptoms are no longer clinically significant and the child or young person is fully functioning) and maintained for at least 6 months, and if this is their wish. Patients and their family or carers should be warned that relapse and/or discontinuation/withdrawal symptoms may occur. They should be advised to contact their medical practitioner should symptoms of discontinuation/withdrawal arise. [C]

6.14.4.17.

For children and young people with OCD or BDD, to minimise discontinuation/withdrawal reactions on reducing or stopping antidepressants, particularly SSRIs, the dose should be tapered gradually over several weeks according to the individual's need. The rate of reduction should take into account the starting dose, the drug half-life and particular profiles of adverse effects. [C]

6.14.4.18.

Children and young people with OCD or BDD should continue with psychological treatment throughout the period of drug discontinuation because this may reduce the risk of relapse. [C]

Other drugs

6.14.4.19.

Tricyclic antidepressants other than clomipramine should not be used to treat OCD or BDD in children and young people. [C]

6.14.4.20.

Other antidepressants (MAOIs, SNRIs) should not be used to treat OCD or BDD in children and young people. [C]

6.14.4.21.

Antipsychotics should not be used alone in the routine treatment of OCD or BDD in children or young people, but may be considered as an augmentation strategy. [C]

Footnotes

7

Here and elsewhere in the guideline, each study considered for review is referred to by a study ID (primary author and date of study publication in capital letters, except where a study is in press or unpublished, then a date is not used).

8

The full list of all evidence statements generated from meta-analyses (and the associated forest plots) are on the CD-ROM that accompanies the guideline (see Appendix 17 and Appendix 18).

9

In the case of SMDs, negative effect sizes favour the treatment group.

10

The results of the analysis of these studies are considered in the earlier section on SSRIs versus Clomipramine.

11

Given the size of the RR and the upper limit of the CI, an increased risk of suicidal behaviour/ideation can not be ruled out.

12

Depression in children: identification and management of depression in children and young people in primary care and specialist services’ (NICE, September 2005).

Copyright © 2006, The British Psychological Society & The Royal College of Psychiatrists.

All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Enquiries in this regard should be directed to the British Psychological Society.

Cover of Obsessive-Compulsive Disorder
Obsessive-Compulsive Disorder: Core Interventions in the Treatment of Obsessive-Compulsive Disorder and Body Dysmorphic Disorder.
NICE Clinical Guidelines, No. 31.
National Collaborating Centre for Mental Health (UK).
Leicester (UK): British Psychological Society; 2006.

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