Pharmacological treatment for obsessive–compulsive disorder

Obsessive–compulsive disorder

Pharmacological treatment for obsessive–compulsive disorder

The systematic investigation of obsessive–compulsive disorder (OCD) has depended on the introduction of universally accepted diagnostic criteria and comprehensive rating scales that are sensitive enough to measure small treatment-related changes, such as the Yale–Brown Obsessive Compulsive Scale (YBOCS).1 This contribution reviews the key clinical questions relating to pharmacotherapy for OCD (Table 1). After 30 years of intensive pharmacological investigation, it still appears to be the case that OCD responds selectively to drugs that act as powerful inhibitors of the synaptic reuptake of serotonin – clomipramine and the selective serotonin reuptake inhibitors (SSRIs). Drugs lacking potent serotonin reuptake inhibitor (SRI) actions, such as the tricyclic antidepressants amitriptyline, nortriptyline and desipramine, and the monoamine oxidase inhibitors (MAOIs) clorgyline and phenelzine, have not been found to be effective in controlled studies. Nor is there convincing evidence supporting the efficacy of benzodiazepines, lithium or electroconvulsive therapy (ECT) (Table 2). However, symptoms often respond only partially to SRIs and for around one-third of cases the response is poor. Increasing dosages or switching between SRIs are practical next steps. Growing evidence supports the efficacy of adding first- or second-generation antipsychotic agents, but long-term data is lacking.

Naomi A Fineberg Kevin J Craig

Abstract The systematic investigation of obsessive–compulsive disorder (OCD) has depended on the introduction of universally accepted diagnostic criteria and comprehensive rating scales that are sensitive enough to measure small treatment-related changes, such as the Yale–Brown Obsessive Compulsive Scale. This contribution reviews the key clinical questions relating to pharmacotherapy for OCD. After 30 years of intensive pharmacological investigation, it still appears to be the case that OCD responds selectively to drugs that act as powerful inhibitors of the synaptic reuptake of serotonin – clomipramine and the selective serotonin reuptake inhibitors (SSRIs). Drugs lacking potent serotonin reuptake ­inhibitor (SRI) actions, such as the tricyclic antidepressants amitriptyline, nortyiptyline and desipramine, and the monoamine oxidase inhibitors (MAOIs) clorgyline and phenelzine, have not been found to be effective in controlled studies. Nor is there convincing evidence supporting the efficacy of benzodiazepines, lithium or electroconvulsive therapy (ECT). However, symptoms often respond only partially to SRIs and for around one-third of cases the response is poor. Increasing dosages or switching between SRIs are practical next steps. Growing evidence supports the efficacy of adding first- or second-generation antipsychotic agents, but long-term data are lacking.

Clomipramine – the earliest treatment Promising reports from uncontrolled case studies performed in the 1970s were investigated in a large series of double-blind ­placebo-controlled trials that demonstrated conclusive evidence of efficacy for clomipramine in patients suffering with OCD. Some studies specifically excluded comorbid depression, while others demonstrated efficacy for clomipramine in patients with varying amounts of comorbid depression.2–7 Later studies confirmed that clomipramine was also effective in childhood and adolescent OCD, and focused attention on the importance of early recognition and treatment.8 Two large, multicentre, placebo-controlled studies of clomipramine (in doses of up to 300 mg/day) in non-depressed adults showed a gradual, linear improvement in obsessions and compulsions, starting after only 1 week of treatment and continuing to the 10-week endpoint of the study (reviewed in Zohar and Fineberg, 20019). The resulting 40–50% improvement in baseline OCD ratings represented a substantial improvement in emotional and social wellbeing. This gradual improvement characterizes the anti-obsessional effect of SRI treatment (Table 3) and distinguishes OCD from depression, where the clinical response occurs sooner. Extension studies have shown ongoing improvements for

Keywords antipsychotic drugs; obsessive–compulsive disorder; OCD; pharmacotherapy; randomized controlled trials; serotonin reuptake ­inhibitors

Naomi A Fineberg MBBS MRCPsych is Consultant Psychiatrist at Queen Elizabeth II Hospital, Welwyn Garden City, UK, and Honorary Visiting Fellow at the University of Hertfordshire, Hatfield. She qualified from Cambridge University and Guy’s Hospital, and trained in psychiatry at St Mary’s Hospital, London. Her research interests include the investigation and management of obsessive–compulsive disorder and other anxiety disorders. Conflicts of interest: none declared.

Key clinical questions for OCD pharmacotherapy • • • • • •

Kevin J Craig MB MPhil is a clinical research associate at the University of Cambridge and Honorary Consultant Psychiatrist at Addenbrooke’s Hospital, Cambridge, UK. He qualified from University of the Witwatersrand, Johannesburg, and trained in psychiatry in Cambridge. His research interests include compulsive disorders and memory. Conflicts of interest: he has received research grant funding from GlaxoSmithKline Ltd.

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What drug? What daily dose? How long should treatment continue? What are the long-term advantages/disadvantages? What happens when treatment is discontinued? What if the patient fails to respond?

Table 1

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has been concurrent administration of exposure therapy in the placebo-treated group.11 There are few alternatives to SRIs in the treatment of OCD. Studies of venlafaxine, which is predominantly serotonergic at lower doses, have not consistently demonstrated an anti­obsessional effect.12 The development of SSRIs as treatments for OCD has been an important advance, in view of their improved safety and tolerability compared with clomipramine. Yet in approximately 30% of patients the clinical response to drugs is disappointing, and better treatments would be welcome.

Pharmacological specificity of OCD treatment Effective • Potent SRIs such as clomipramine, fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram Ineffective • Tricyclics (apart from clomipramine) • MAOIs • Lithium • Antipsychoticsa • Benzodiazepines • Oxytocin • Naloxone • ECT aHave

What is the most effective dose of SRI? OCD has traditionally been thought to require higher doses of medication than depression and anxiety. In order to examine this, head-to-head studies are needed to compare different fixed doses of the active drug with placebo. (Clomipramine has not been examined in this way.) Whereas single-dose studies showed efficacy for relatively low fixed daily doses of clomipramine (75 mg and 125 mg) compared with placebo,13 most studies used flexible doses titrated toward the upper end of the range (200–300 mg/ day). Similarly, fluvoxamine was found to be effective in doses ranging from 150 mg/day to 300 mg/day.14 Fluoxetine, paroxetine and sertraline have each been investigated using a series of multiple fixed doses. In the case of fluoxetine, all three fixed doses (20 mg, 40 mg and 60 mg/day) were found to be effective, but the greatest response was seen in the patients receiving the highest doses. A meta-analysis of the grouped data showed that the 60 mg dose was significantly more effective than 20 mg. Two fixed-dose comparisons of 20 mg, 40 mg and 60 mg of paroxetine produced similar findings. In both studies the 40 mg and 60 mg doses were effective, but the 20 mg dose did not separate from placebo.15,16 Interestingly, in the fixed-dose study of sertraline the 50 mg and 200 mg doses were superior to placebo, whereas the 100 mg dose was not, but this study may have been underpowered. The data have been interpreted to suggest that the highest dose levels tested in the studies (60 mg paroxetine, fluoxetine and citalopram; 200 mg sertraline) are associated with better anti- obsessional efficacy. Some psychiatrists use even higher doses of SSRIs, particularly in the treatment of resistant OCD, but in the absence of controlled data this practice cannot be recommended without reservation.

a possible adjunctive role, augmenting SRIs.

Table 2

up to 2 years. For this reason, longer treatment periods of at least 12 weeks are advocated, and judgements concerning the degree of clinical response to a given drug should always take account of the duration of treatment.

SSRIs and the development of the therapeutic armamentarium The demonstration in more recent studies that the more highly selective SSRIs are also effective, showing a similar slow, incremental treatment effect, suggests that their anti-obsessional properties are related to the inhibition of neuronal reuptake of serotonin in the central nervous system (CNS). Convincing evidence from large-scale, placebo-controlled studies supports the efficacy of fluvoxamine, fluoxetine, sertraline, paroxetine, escitalopram and citalopram in the acute treatment of OCD (reviewed in Fineberg and Craig, 200610). There is little doubt that SRIs are effective in patients with significant levels of concurrent depression. The improvement in depressive symptoms occurs in parallel with improvements in the OCD, and the presence of moderate levels of comorbid depression does not interfere with the treatment response. The relative strength of the anti-obsessional effect of drug treatment is highlighted by the observation that SRIs still show superiority compared with placebo in studies where there

Dose titration

The anti-obsessional profile of SRIs

Improvements in OCD usually take several weeks to become established, irrespective of the dose, and it is helpful to warn patients about this from the outset. Unlike panic disorder, OCD is not usually associated with an exacerbation of anxiety in the first few days of treatment. Given that higher doses are associated with more adverse effects, it is recommended to start treatment at lower dose levels and, titrating against clinical response, slowly and steadily increase the dose over weeks and months. The clinician needs to strike a delicate balance between speed of response and tolerability. The arguments for slower dose increases are particularly persuasive for children and the elderly. Special care with higher doses is also required for cases

• Early onset of response may be hard to detect • Slow, incremental improvements over weeks and months • Positive dose–response relationship (established for most compounds) • Comprehensive improvement in obsessions, compulsions and mood • Effects sustained as long as treatment continues • Relapses prevented in long-term treatment • Inadequate response in a significant minority of cases Table 3

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with comorbidity. For example, patients with comorbid panic disorder may be particularly sensitive to early anxiogenic effects of SSRIs, and lower than average doses may be required for the first week or two. Those with bipolar affective disorder are susceptible to switching into mania and may require additional mood stabilizers. OCD sufferers are notoriously poor at recognizing their own improvements, and it is useful to enlist the help of friends or relatives to inform on early signs of clinical improvement. The application of specific observer-rated scales (such as the YBOCS) can help detect small improvements in the clinical setting. A substantial proportion of patients show a delayed response, with improvements occurring only after several months. These cases are challenging, and there is often pressure to change treatments or escalate the doses prematurely. As a general rule it is best to wait at least 12 weeks to allow the treatment-effect time to develop (reviewed in March et al., 199717); in some cases even longer periods are required.

relapse. Lack of agreed criteria for defining a relapse has bedevilled the interpretation of relapse-prevention studies in OCD. In the double-blind study, 16 out of 18 patients who had shown sustained improvements on clomipramine showed a substantial worsening of their obsessive–compulsive symptoms within 4 weeks of randomization to placebo.21 The re-emergence of the OCD was gradual and progressive and was not related to the duration of clomipramine pre-treatment, which exceeded 2 years in some cases. In this study, reinstatement of the clomipramine resulted in improvement in all the patients to a level close to that achieved before the discontinuation, but other authors have reported less favourable results. Two large studies investigated subjects who had responded to 6 months’ open-label paroxetine and showed that those who continued on the active drug suffered significantly fewer relapses over the following 6 months than those who were randomized to placebo. In one study, approximately 10% of the paroxetinetreated group showed a full relapse, compared with 18% on placebo.4 The clinical relevance of a partial relapse, as defined in this study, has been questioned since it may represent a transient fluctuation in symptoms rather than a sustained deterioration. YBOCS scores were maintained or slightly improved in the paroxetine group, but deteriorated in the placebo group. A more recent study produced strikingly similar findings: patients randomized to placebo showed a rapid and significant recurrence of their OCD within 2 weeks, while those who continued on paroxetine showed further improvement.16 Using a conservative criterion for relapse – defined as a return to baseline YBOCS scores – 9.4% of the paroxetine-treated patients relapsed over the 6-month follow-up, compared with 21.6% on placebo. A more favourable relapse rate (roughly 32% over the course of 12 months) was shown following double-blind discontinuation of fluoxetine after 20 weeks’ active treatment in a study by Romano et al.20 However, patients remaining on 60 mg fluoxetine still had significantly lower rates of relapse (17.5%) than those switched to placebo. These data suggest that medication confers protection against relapse for as long as it is continued, and argue for the unlimited continuation of treatment, as long as patients can tolerate it. Discontinuation, if necessary, should be gradual to minimize discontinuation effects, and patients should be warned to look out for the early signs of relapse, whereupon reinstatement of the drug may achieve the same level of improvement as before, although this cannot be guaranteed.

Is pharmacological treatment effective in the longer term? OCD is a chronic illness and clinicians need to know whether treatments that have been shown to be effective in short-term studies maintain their efficacy over the longer term. Evidence for long-term efficacy can be derived from a variety of studies. Investigators have taken treatment responders from acute treatment studies and transferred them to uncontrolled treatment with an SSRI, with the result that the response has increased over time with no evidence of tolerance developing. A small number of randomized, double-blind, placebo­controlled extension studies have actively followed up treatment responders from acute efficacy studies. Patients continued to improve for at least 1 year if they remained on the active treatment, whereas patients on placebo did not.18,19 Drop-out rates for SSRIs were markedly lower than for clomipramine. For example, in a double-blind continuation study of sertraline only 13% of patients dropped out of treatment prematurely over the 40-week extension period. Of these, one-third blamed side effects and twothirds blamed unsatisfactory clinical response.7 The completers from this study were followed up for a further year on openlabel sertraline and showed significant additional improvements in their OCD over the course of the second year, with a reduced incidence of side effects compared with the earlier study. It would appear that efficacy is sustained in the longer term, and patients continue to improve for at least 2 years (probably for longer) after the start of their treatment. With continued treatment, side effects abate over time, adding to the therapeutic benefit. There are no controlled data on the best doses for long-term treatment, although the adage ‘the dose that gets you well, keeps you well’ probably applies. The results from a fixed-dose trial with fluoxetine supports the 60 mg dose as being the most effective over a 24-week extension phase.20 Most experts recommend continuing treatment at the higher dose levels.

SSRIs vs. clomipramine Head-to-head studies are needed to test the relative efficacy and tolerability of different treatments. To date three such controlled trials have been carried out in the case of SSRIs, none supporting the superior efficacy of any one compound.22–24 At present, therefore, we must assume equivalent effectiveness for these ­compounds. The selection of a particular SSRI may take account of other factors, such as interactions with other drugs that the patient may be taking. In this respect, fluoxetine, paroxetine and, to a much lesser extent, sertraline inhibit the P450 isoenzyme CYP2D6, which metabolizes tricyclic antidepressants (including clomipramine), antipsychotics and b-blockers. Fluvoxamine inhibits CYP1A2, which metabolizes warfarin, tricyclics, benzodiazepines

How long should pharmacotherapy continue? Once again, the evidence from controlled studies is helping to inform clinical practice. A small number of double-blind studies have evaluated whether prolonged SSRI treatment prevents

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and some anti-arrhythmics. Citalopram and escitalopram do not significantly affect hepatic metabolism. Fluoxetine has a long halflife and fewer discontinuation effects, which can be advantageous for patients who forget to take ­tablets. Several studies have compared clomipramine with one or other SSRI, and on the whole the results have shown ­equivalent efficacy for clomipramine and paroxetine, fluvoxamine and fluoxetine. A study of sertraline found that it outperformed clomipramine on some measures, but the doses of clomipramine may have been too low to allow a fair comparison.22 Meta-­analyses of existing studies, which suggested clinical superiority for clomipramine over the SSRIs, have been criticized for failing to take account of the important differences between the studies under examination.25 Although the comparator studies suggest equivalent efficacy, the SSRIs are associated with a more favourable side-effect profile and are better tolerated than clomipramine. These factors assume paramount importance for OCD sufferers, who are expected to take treatment at high doses for unlimited periods. Compared with clomipramine, which, in high doses, produces serious anticholinergic side effects, a high risk of convulsions (up to 2%) and potentially dangerous cardiotoxicity, the SSRIs are much better tolerated, although they are responsible for more asthenia, insomnia and nausea. All SRIs are associated with impaired sexual performance (30%) and some cause weight gain, but clomipramine appears to be more problematic than the SSRIs in this respect. Sexual function should be carefully monitored and, if necessary, strategies such as dose-reduction and short drug holidays can be considered if the patient is stable.

Double-blind, placebo-controlled pharmacotherapy studies in treatment-refractory OCD Positive results suggesting efficacy • Switching SRI30 • High-dose SRI31 • Adding risperidone21,32–34 • Adding quetiapine35 • Adding haloperidola,36 • Intravenous clomipramineb,37 Negative results suggesting lack of efficacy • Adding lithium38,39 • Adding buspirone40,41 • Adding desipraminec,42 • Adding tri-iodothyronine (liothyronine)39 • Adding inositol43 • Adding clonazepam44 • Adding St. John’s Wort45 aPrimarily

in ‘tic-related’ OCD. in many countries. cSmall numbers and improvements not apparent on all OCD rating scales. bInvestigational

Table 4

delay these strategies until an adequate trial of at least 12 weeks has been attempted. There is a shortage of evidence to support drug-switching compared with extending treatment with the same drug for longer. Nonetheless, 11–33% of patients not responding to the first SRI were reported to show clinically meaningful response to a second drug, with decreasing likelihoods for subsequent changes (reviewed in Zohar and Fineberg, 20019). High dose treatments of up to 400 mg in the case of sertraline and 300 mg in the case of clomipramine have been reported to be effective. Changing the mode of drug delivery may also be tried. Intravenous clomipramine has been found to be effective in a single controlled experiment. Combining clomipramine with an SSRI has been advocated by some experts, but care should be taken in the case of paroxetine and fluoxetine, which inhibit the hepatic cytochrome P450 isoenzymes. The subsequent build-up of clomipramine can be dangerous. Plasma level and ECG monitoring are advisable if this strategy is considered. There is no evidence that antipsychotics are effective in OCD as monotherapy. However, the balance of evidence from a growing number of small randomized controlled studies and meta­analyses suggest that augmentation with haloperidol, risperidone, and quetiapine may be beneficial Three studies have shown that low doses of adjunctive risperidone (1–2 mg) improved responses to SSRIs in resistant patients without tics,32–34 and one controlled study and a meta-analysis has shown efficacy for adjunctive quetiapine (<200 mg/day) in a similar population. The use of atypical antipsychotics in this area is very promising,35 but there have been case reports of clinical worsening associated with SRI–­antipsychotic combinations, possibly related to higher doses of the antipsychotic. A meta-analysis of existing treatment trials suggested patients with comorbid tic disorders and early onset OCD were particularly responsive to adjunctive antipsychotic

First-line treatment The superior tolerability of SSRIs and the lower rate of premature discontinuation, relative to clomipramine, offer considerable benefits in the long-term management of OCD, and indicate that they should be considered the treatment of choice. Clomipramine should be reserved as a second-line treatment for patients who cannot tolerate SSRIs or have failed to respond to them. Although both pharmacotherapy and psychotherapy have been shown to be effective, there is a lack of data regarding the benefits of combining the two. Two small studies compared fluvoxamine plus behaviour therapy with placebo plus behaviour therapy and, in spite of small numbers, demonstrated superior efficacy for the combination over exposure.11,26 Subsequent trials with larger samples have remained unable to confirm the benefit of combining pharmacotherapy with psychotherapy.27 In clinical practice it would seem sensible to encourage patients who are on medication to also understand and adhere to the principles of cognitive–behavioural therapy (CBT), and a number of studies support the value of adding a CBT intervention to OCD patients on medication.28,29

Treatment strategies for incomplete response on SRIs In approximately 30% of cases, residual symptoms remain in spite of prolonged treatment with SRI drugs. The problem of partial responders is an important area that has not yet received adequate controlled investigation. A number of strategies may be considered including changing SRI, high-dose SRI treatment and/ or antipsychotic augmentation (see Table 4). It is advisable to

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medication.46 In view of potential adverse effects, treatment is usually started at low doses, increasing cautiously subject to tolerability. The better side-effect profile associated with secondgeneration agents favours their use over that of haloperidol. Long-term studies are also required to test sustained efficacy, tolerability and relapse prevention. One small study has reported a high level of relapse following open-label discontinuation. The use of standardized instruments to monitor clinical progress in this resistant group of patients is recommended. Promising reports of the effect of augmenting SRIs with buspirone have not stood up to scrutiny under controlled conditions. Nor is there evidence that augmentation with lithium, clonazepam or buspirone has a role in OCD (See Table 4). ECT is ­generally unhelpful. ◆

15 Dunbar GC, Steiner M, Bushnell W. Long-term treatment and prevention of relapse of obsessive–compulsive disorder with paroxetine. Eur Neuropsychopharmacol 1995; 5: 372. 16 Hollander E, Allen A, Steiner M, et al. Acute and long-term treatment and prevention of relapse of obsessive–compulsive disorder with paroxetine. J Clin Psychiatry 2003; 64: 1113–21. 17 March JS, Frances A, Kahn DA, et al. The expert consensus guideline series: treatment of obsessive compulsive disorder. J Clin Psychiatry 1997; 58: 1–72. 18 Greist JH, Jefferson JW, Kobak KA, et al. A 1 year double-blind placebo-controlled fixed dose study of sertraline in the treatment of obsessive–compulsive disorder. Int Clin Psychopharmacol 1995; 10: 57–65. 19 Stein D, Tonnoire B, Andersen EW, et al. Escitalopram in the treatment of obsessive compulsive disorder. Proceedings of the American Psychiatric Association Annual Meeting, 2006. 20 Romano S, Goodman W, Tamura R, et al. Long-term treatment of obsessive–compulsive disorder after an acute response: a comparison of fluoxetine versus placebo. J Clin Psychopharmacol 2001; 21: 46–52. 21 Pato MT, Zohar-Kadouch R, Zohar J, et al. Return of symptoms after discontinuation of clomipramine in patients with obsessive– compulsive disorder. Am J Psychiatry 1988; 145: 1521–25. 22 Flament MF, Bisserbe JC. Pharmacologic treatment of obsessive– compulsive disorder: comparative studies. J Clin Psychiatry 1997; 58(suppl 12): 18–22. 23 Mundo E, Rouillon F, Figuera ML, et al. Fluvoxamine in obsessive– compulsive disorder: similar efficacy but superior tolerability in comparison with clomipramine. Hum Psychopharmacol 2001; 16: 461–68. 24 Zohar J, Judge R. Paroxetine versus clomipramine in the treatment of obsessive–compulsive disorder. OCD Paroxetine Study Investigators. Br J Psychiatry 1996; 169: 468–74. 25 Pigott TA, Seay SM. A review of the efficacy of selective serotonin reuptake inhibitors in obsessive–compulsive disorder. J Clin Psychiatry 1999; 60: 101–106. 26 Hohagen F, Winkelmann G, Rasche-Ruchle H, et al. Combination of behaviour therapy with fluvoxamine in comparison with behaviour therapy and placebo. Results of a multicentre study. Br J Psychiatry Suppl 1998: 71–78. 27 POTS. Cognitive–behavior therapy, sertraline, and their combination for children and adolescents with obsessive–compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA 2004; 292: 1969–76. 28 O’Connor K, Todorov C, Robillard S, et al. Cognitive–behaviour therapy and medication in the treatment of obsessive–compulsive disorder: a controlled study. Can J Psychiatry 1999; 44: 64–71. 29 Simpson HB, Gorfinkle KS, Liebowitz MR. Cognitive–behavioral therapy as an adjunct to serotonin reuptake inhibitors in obsessive– compulsive disorder: an open trial. J Clin Psychiatry 1999; 60: 584–90. 30 Fineberg NA, Nigam N, Sivakumaran T. Pharmacological strategies for treatment-resistant obsessive compulsive disorder. Psychiatric Annals 2006; (in press). 31 Bejerot S, Bodlund O. Response to high doses of citalopram in treatment-resistant obsessive–compulsive disorder. Acta Psychiatr Scand 1998; 98: 423–24. 32 Erzegovesi S, Guglielmo E, Siliprandi F, et al. Low-dose risperidone augmentation of fluvoxamine treatment in obsessive–compulsive

References 1 Goodman WK, Price LH, Rasmussen SA, et al. The Yale–Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 1989; 46: 1006–11. 2 Flament MF, Rapoport JL, Berg CJ, et al. Clomipramine treatment of childhood obsessive–compulsive disorder. A double-blind controlled study. Arch Gen Psychiatry 1985; 42: 977–83. 3 Insel TR, Murphy DL, Cohen RM, et al. Obsessive–compulsive disorder. A double-blind trial of clomipramine and clorgyline. Arch Gen Psychiatry 1983; 40: 605–12. 4 Jenike MA, Baer L, Summergrad P, et al. Obsessive–compulsive disorder: a double-blind, placebo-controlled trial of clomipramine in 27 patients. Am J Psychiatry 1989; 146: 1328–30. 5 Marks IM, Stern RS, Mawson D, et al. Clomipramine and exposure for obsessive–compulsive rituals: i. Br J Psychiatry 1980; 136: 1–25. 6 Mavissakalian M, Hamann MS, Jones B. Correlates of DSM-III personality disorder in obsessive–compulsive disorder. Compr Psychiatry 1990; 31: 481–89. 7 Thoren P, Asberg M, Cronholm B, et al. Clomipramine treatment of obsessive–compulsive disorder. I. A controlled clinical trial. Arch Gen Psychiatry 1980; 37: 1281–85. 8 DeVeaugh-Geiss J, Moroz G, Biederman J, et al. Clomipramine hydrochloride in childhood and adolescent obsessive–compulsive disorder – a multicenter trial. J Am Acad Child Adolesc Psychiatry 1992; 31: 45–49. 9 Zohar J, Fineberg NA. Practical pharmacotherapy. In: Fineberg NA, Marazziti D, Stein D, eds. Obsessive–compulsive disorder: a practical guide. London: Martin Dunitz, 2001. 10 Fineberg NA, Craig KJ. Benefits and limitations of pharmacotherapy in OCD. Clin Neuropsyciatry 2006; 3: 345–63. 11 Cottraux J, Mollard E, Bouvard M, et al. A controlled study of fluvoxamine and exposure in obsessive–compulsive disorder. Int Clin Psychopharmacol 1990; 5: 17–30. 12 Denys D, van Megen HJ, van der Wee N, et al. A double-blind switch study of paroxetine and venlafaxine in obsessive–compulsive disorder. J Clin Psychiatry 2004; 65: 37–43. 13 Montgomery SA. Clomipramine in obsessional neurosis: a placebocontrolled trial. Pharmacological Medicine 1980; 1: 189–92. 14 Hollander E, Koran LM, Goodman WK, et al. A double-blind, placebocontrolled study of the efficacy and safety of controlled-release fluvoxamine in patients with obsessive–compulsive disorder. J Clin Psychiatry 2003; 64: 640–47.

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disorder: a double-blind, placebo-controlled study. Eur Neuropsychopharmacol 2005; 15: 69–74. 33 Hollander E, Baldini Rossi N, Sood E, et al. Risperidone augmentation in treatment-resistant obsessive–compulsive disorder: a double-blind, placebo-controlled study. Int J Neuropsychopharmacol 2003; 6: 397–401. 34 McDougle CJ, Epperson CN, Pelton GH, et al. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive–compulsive disorder. Arch Gen Psychiatry 2000; 57: 794–801. 35 Denys D, de Geus F, van Megen HJ, et al. A double-blind, randomized, placebo-controlled trial of quetiapine addition in patients with obsessive–compulsive disorder refractory to serotonin reuptake inhibitors. J Clin Psychiatry 2004; 65: 1040–48. 36 McDougle CJ, Goodman WK, Leckman JF, et al. Haloperidol addition in fluvoxamine-refractory obsessive–compulsive disorder. A doubleblind, placebo-controlled study in patients with and without tics. Arch Gen Psychiatry 1994; 51: 302–08. 37 Fallon BA, Liebowitz MR, Campeas R, et al. Intravenous clomipramine for obsessive–compulsive disorder refractory to oral clomipramine: a placebo-controlled study. Arch Gen Psychiatry 1998; 55: 918–24. 38 McDougle CJ, Price LH, Goodman WK, et al. A controlled trial of lithium augmentation in fluvoxamine-refractory obsessive– compulsive disorder: lack of efficacy. J Clin Psychopharmacol 1991; 11: 175–84. 39 Pigott TA, Pato MT, L’Heureux F, et al. A controlled comparison of adjuvant lithium carbonate or thyroid hormone in clomipraminetreated patients with obsessive–compulsive disorder. J Clin Psychopharmacol 1991; 11: 242–48. 40 Grady TA, Pigott TA, L’Heureux F, et al. Double-blind study of adjuvant buspirone for fluoxetine-treated patients with obsessive– compulsive disorder. Am J Psychiatry 1993; 150: 819–21. 41 McDougle CJ, Goodman WK, Leckman JF, et al. Limited therapeutic effect of addition of buspirone in fluvoxamine-refractory obsessive– compulsive disorder. Am J Psychiatry 1993; 150: 647–49.

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42 Barr LC, Goodman WK, Anand A, et al. Addition of desipramine to serotonin reuptake inhibitors in treatment-resistant obsessive– compulsive disorder. Am J Psychiatry 1997; 154: 1293–95. 43 Fux M, Benjamin J, Belmaker RH. Inositol versus placebo augmentation of serotonin reuptake inhibitors in the treatment of obsessive–compulsive disorder: a double-blind cross-over study. Int J Neuropsychopharmcol 1999; 2: 193–95. 44 Crockett BA, Churchill E, Davidson JR. A double-blind combination study of clonazepam with sertraline in obsessive–compulsive disorder. Ann Clin Psychiatry 2004; 16: 127–32. 45 Kobak KA, Taylor LV, Bystritsky A, et al. St John’s wort versus placebo in obsessive–compulsive disorder: results from a doubleblind study. Int Clin Psychopharmacol 2005; 20: 299–304. 46 Bloch MH, Landeros-Weisenberger A, Kelmendi B, et al. A systematic review: antipsychotic augmentation with treatment refractory obsessive–compulsive disorder. Mol Psychiatry 2006; 11: 622–32. Further reading Fineberg N, Marazitti D, Stein DJ, eds. Obsessive–compulsive disorder: a practical guide. London: Martin Dunitz, 2001. (A practical account of modern theories on aetiology, assessment and treatment of OCD for the clinician.)

Practice points • SSRIs are the preferred first-line treatment for OCD • Higher doses may be more effective • Gradual dose titration, measuring clinical response and side effects, is usually appropriate • Standardized rating scales (e.g. YBOCS) are helpful to objectify clinical response • Maintenance treatment appears to protect against relapse • Augmentation strategies include switching SRI, increasing the dose of SRI or adding low-dose antipsychotics

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