Hedges and Woon pharmacological interventions even after discontinuation (Simpson et al 2004). Until the availability of the tricyclic antidepressant clomipramine, pharmacotherapy resulted in little, if any, improvement in OCD. The efﬁcacy of clomipramine in OCD is now well established (Dell’Osso et al 2006), and its inhibition of serotonin reuptake guided attention to a possible role for serotonin in OCD (Abramowitz 1997). In fact, non-serotonergic antidepressants appear to have little efﬁcacy in OCD (Fallon and Mathew 2000; Dell’Osso et al 2006). Since the introduction of clomipramine, other phar- macological approaches to treat OCD using medication have developed that predominantly include the use of selective serotonin reuptake inhibitors (SSRIs; Starcevic 2005). A 1997 meta-analysis comparing clomipramine with ﬂuoxetine and sertraline found larger effect sizes for clomipramine; however, there were relatively few studies of ﬂuoxetine and sertraline, and a large contrast in side effect proﬁles between clomipramine and placebo may have inﬂated the effect size for clomipramine (Abramowitz 1997). More recently, other work also has found that clomipramine tends to be slightly superior to other SSRIs in OCD (Ackerman and Greenland 2002; Dell’Osso et al 2006). Using meta-regression to control for factors such as clinical-trial length and OCD severity in their meta-analysis of placebo-controlled trials of clomip- ramine, ﬂuvoxamine, sertraline, and paroxetine, Ackerman and Greenland (2002) found superiority for clomipramine. Monoamine oxidase inhibitors may have limited efﬁcacy in OCD and a controlled, 6-week trial of buspirone suggested efﬁcacy in OCD (Fallon and Mathew 2000). In a double- blind, placebo-controlled, multiple-crossover trial compar- ing clomipramine, clonazepam, and clonidine against each other in 6-week-long trials for the treatment of OCD, both clomipramine and clonazepam were effective in reducing symptoms (Hewlett et al 1992). Generally, SSRIs antidepressants tend to be preferred over tricyclic antidepressants in treating anxiety disorders including OCD (Simpson et al 2004), a practice due to, in part, overall fewer side effects from SSRIs (Starcevic 2005). In placebo-controlled trials, citalopram, ﬂuoxetine, ﬂuvox- amine, paroxetine, and sertraline all appear effective in the short-term treatment of OCD (Fallon and Mathew 2000; Eddy et al 2004), and the SSRIs as a class are generally considered to be ﬁrst-line drug treatment for OCD (Kaplan and Hollander 2003; Simpson et al 2004; Stein, Tonnoir et al 2007), despite the slight possible superiority of clomipramine in efﬁcacy studies (Dell’Osso et al 2006). Case reports, open trials, and blinded trials comparing venlafaxine with active comparators 456 preliminarily support the efﬁcacy of venlafaxine (Phelps and Cates 2005), a dual serotonin and norepinephrine reuptake inhibitor, for OCD. However, a placebo-controlled trial of venlafaxine in OCD did not show clear superiority for ven- lafaxine (Phelps and Cates 2005). As such, more controlled trials are required to establish the place of venlafaxine in the treatment of OCD (Dell’Osso et al 2006). Even with the efﬁcacy of behavioral interventions and SSRIs, many patients with OCD continue to have OCD features (Fallon and Mathew 2000; Eddy et al 2004). Furthermore, OCD treatment outcome data for over a year are limited (Eddy et al 2004). To successfully treat OCD, long-term treatment appears to be required due to the chronic nature of OCD. For example, Simpson et al (2004) in a randomized trial investigated relapse rates after treatment discontinuation in patients who had responded to expo- sure and response therapy alone, to exposure and response therapy plus clomipramine, to clomipramine alone, and to placebo. They found a signiﬁcant advantage at 12 weeks after treatment discontinuation for patients who had initially responded to exposure and response prevention alone or with clomipramine compared with clomipramine alone. In other words, successful drug treatment for OCD for many patients may require long-term treatment. Moreover, despite the use of SSRIs and psychotherapy, refractory OCD remains a particular challenge (McDougle et al 1993), resulting in several augmentation strategies. One approach to managing treatment-resistant OCD is adding drugs that increase serotonin transmission to SSRIs (McDougle et al 2000). Clomipramine, for instance, has been combined with SSRIs, although this combination is poorly studied and requires careful monitoring of plasma clomipramine and desmethylclomipramine levels (Fallon and Mathew 2000). Drugs in addition to clomipramine have been added to SSRIs in refractory cases. However, a double-blind trial found little advantage using lithium to augment ﬂuvox- amine in treatment-resistant OCD (McDougle et al 1991). Similarly, McDougle et al (1993) in a placebo-controlled trial found little advantage when buspirone was added to ﬂu- voxamine in patients who had not responded to ﬂuvoxamine alone. Other drugs that have been combined with an SSRI in an attempt to improve response in OCD include donepezil and gabapentin (Fallon and Mathew 2000), although these trials tended to be small and uncontrolled. The double-blind, placebo-controlled addition of the beta blocker pindolol to patients who had not responded to open treatment with paroxetine resulted in improvement as measured by the Yale- Brown Obsessive-Compulsive Scale (Dannon et al 2000). In Neuropsychiatric Disease and Treatment 2007:3(4)