INTRODUCTION — Obsessive-compulsive disorder (OCD) is characterized by recurrent, intrusive, and distressing thoughts, images, or impulses (ie, obsessions), and repetitive mental or behavioral acts that the individual feels driven to perform (ie, compulsions) to prevent or reduce distress.
OCD can be effectively treated with serotonergic antidepressants as well as cognitive-behavioral therapy. However, patients frequently experience a partial response to treatment. A number of augmentation strategies have been studied.
Pharmacotherapy for OCD in adults is discussed here. The epidemiology, clinical manifestations, and diagnosis of OCD are discussed separately. Psychotherapy for OCD, deep brain stimulation for OCD, and OCD in pregnant and postpartum women are also discussed separately. (See "Obsessive-compulsive disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis" and "Psychotherapy for obsessive-compulsive disorder in adults" and "Obsessive-compulsive disorder in pregnant and postpartum patients" and "Deep brain stimulation for treatment of obsessive-compulsive disorder".)
MONOTHERAPY
Efficacy — Two classes of serotonergic antidepressants are strongly supported by randomized trials for OCD, while evidence for the third is weaker:
●Selective serotonin reuptake inhibitor (SSRI) antidepressants – Fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, and escitalopram.
●Clomipramine – A tricyclic antidepressant that inhibits the reuptake of serotonin and norepinephrine.
●Venlafaxine – A serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant.
Selective serotonin reuptake inhibitors — The SSRIs have been shown to be efficacious for OCD in large, multisite randomized trials. A meta-analysis of 17 randomized trials with a total of 3097 patients with OCD found SSRIs to be more effective than placebo in reducing the symptoms of OCD [1]. No individual SSRI was found to be more efficacious than the other SSRIs for OCD. All of the SSRIs except citalopram and escitalopram have been approved for the treatment of OCD by the US Food and Drug Administration (FDA) in the United States.
Clomipramine — A meta-analysis of seven randomized trials of 392 patients with OCD found clomipramine to reduce symptoms of OCD compared with placebo [2]. A tricyclic antidepressant, clomipramine inhibits the reuptake of serotonin and norepinephrine. Clomipramine is generally less well tolerated than the SSRIs or SNRIs. (See 'Side effects' below.)
Head-to-head comparisons between clomipramine and several of the SSRIs (fluoxetine, fluvoxamine, paroxetine, and sertraline) have not shown either to be superior for OCD [3-9]. Some meta-analyses of randomized trials that did not directly compare clomipramine to SSRIs have suggested that clomipramine has a greater effect size than the SSRIs [10]. However, the studies of SSRIs generally occurred in an era later than the clomipramine trials, and thus likely included more patients who had previously responded inadequately to another agent.
In general, SSRIs and clomipramine lead to improvement in 40 to 60 percent of people with OCD. On average, OCD patients who receive an adequate trial of one of these agents will experience a 20 to 40 percent reduction in their OCD symptoms [11,12]. Thus, they typically offer amelioration rather than elimination of symptoms.
Serotonin-norepinephrine reuptake inhibitors — Based on their mechanism and similarity to the SSRIs, we would expect the SNRIs to effectively treat OCD. There has been limited study of these medications in OCD, however, and they have not been approved by the FDA for OCD [13-18]. As an example, there is only one small, eight-week trial that randomly assigned 30 patients with OCD to either venlafaxine or placebo and found no significant difference in OCD symptom reduction between the two groups [13]. The maximum dose of venlafaxine was limited to 225 mg/day. Two additional randomized trials, which lacked a placebo control, compared higher doses of venlafaxine to SSRIs or clomipramine, finding similar rates of response among the agents [14,15]. Larger, placebo-controlled trials are needed. Duloxetine has not been studied in OCD in randomized trials.
Side effects — Common side effects of serotonergic antidepressants are described briefly below and in more detail separately. Serious adverse events, including serotonin syndrome and suicidality, are described separately. (See "Serotonin syndrome (serotonin toxicity)" and "Effect of antidepressants on suicide risk in adults".)
Selective serotonin reuptake inhibitors — SSRIs are generally well-tolerated. Potential side effects include gastrointestinal problems (eg, nausea or diarrhea), agitation, sleep disturbances (eg, insomnia, vivid dreams), increased tendency to sweat, and sexual side effects (eg, decrease in libido, trouble ejaculating, delayed orgasm). (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)
Clomipramine — Some patients may not be able to tolerate the side effects of clomipramine, which include sedation, dry mouth, constipation, urinary delay, orthostatic hypotension, and cardiac conduction delay. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Clomipramine'.)
Serotonin-norepinephrine reuptake inhibitors — SNRIs are generally well tolerated; the most common side effects include nausea, constipation, dizziness, insomnia, sedation, and sexual side effects. Venlafaxine may cause elevated blood pressure and increases risk for gastrointestinal bleeding. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects".)
Medication selection — When medication is used, we recommend SSRIs as first-line treatment. There is much greater support from randomized trials for SSRIs than for venlafaxine; the SSRIs have a superior side effect profile compared with clomipramine [19]. Because none of the individual SSRIs have shown an advantage in efficacy for OCD, the choice among the SSRIs can be made on the basis of prior treatment response, drug side effects and their acceptability to the patient, and the potential for drug interactions. (See 'Selective serotonin reuptake inhibitors' above and 'Serotonin-norepinephrine reuptake inhibitors' above and 'Clomipramine' above and 'Side effects' above.)
A beneficial aspect of the serotonergic antidepressants for OCD is that these medications can provide effective treatment for several depressive and anxiety disorders that commonly co-occur with OCD. (See 'Comparing pharmacotherapy and psychotherapy' below.)
If an adequate trial of the SSRI results in no response, the patient should be given another trial of monotherapy, either with a different SSRI, clomipramine, or venlafaxine.
It has been estimated that less than one-half of patients will benefit from switching from one SSRI to another, and the likelihood of response diminishes as the number of failed adequate trials increases [19].
If a trial of one of the serotonergic antidepressants results in a partial response, but the patient continues to experience clinically significant symptoms, we suggest augmentation of this agent. (See 'Augmentation' below.)
Administration and course of treatment — Most fixed-dose trials of the serotonergic antidepressants studied in OCD suggest that higher doses led to greater response rates and/or greater mean rates of improvement compared with lower doses [20-24]. A meta-analysis that supported this dose-response relationship also found that higher doses are associated with a higher proportion of dropouts due to side effects [25]. Suggested therapeutic dose ranges for OCD are as follows [19,26] (see 'Augmentation' below):
●SSRIs
•Fluoxetine – 40 to 80 mg/day
•Fluvoxamine – 200 to 300 mg/day
•Paroxetine – 40 to 60 mg/day
•Sertraline – 50 to 200 mg/day
•Citalopram – Up to 40 mg/day (20 mg/day in patients older than 60)
•Escitalopram – 20 to 40 mg/day
●Clomipramine – 100 to 250 mg/day
●Venlafaxine – 225 to 350 mg/day
Patients should be started at a low dose to enhance tolerability (eg, fluoxetine 10 or 20 mg/day). The dose can be increased every week or every other week (as tolerated). The patient should be maintained at a dose within the therapeutic range for at least six weeks before concluding that he or she is resistant to the agent; the treatment response curve appears to follow a logarithmic shape, with the greatest incremental benefits occurring on average by week 6 [27]. An adequate trial of medication for OCD has thus been defined as the maximum dose tolerated for a minimum of six weeks [19]. It is important to explain this to patients, so that they do not prematurely stop the medication before it has a chance to work. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)
Evidence is limited on the efficacy of higher-than-recommended dosing of SSRIs for OCD (eg, fluoxetine 120 mg/day). A trial randomly assigned patients with OCD who had not responded to 16 weeks of sertraline (titrated from 50 mg/day to 200 mg/day) to continue sertraline at 200 mg/day or to continue at an increased dose (averaging 357 mg/day) [28]. After 12 weeks of treatment, the higher dose group showed greater average improvement than the lower dose group. However, the difference was clinically modest. Both groups continued to have clinically significant symptoms and similar rates of adverse events. Thus, increasing SSRIs to higher-than-recommended doses may be effective for certain OCD patients, but this is not a highly effective strategy for all and can lead to more side effects.
Duration of treatment — Although clinical trials of current medications for OCD are mostly short-term, extended trials of SSRIs and clomipramine, which randomly assigned drug responders to continued medication treatment or to placebo, have generally found that patients who continue medication have a lower rate of relapse than patients on placebo [21,29-32]. Relapse rates have varied widely, in part due to methodological differences among studies. As a result, American Psychiatric Association practice guidelines suggest that OCD patients who respond to an adequate trial of a serotonergic antidepressant should stay on that medication for at least one to two years [19]. However, this needs further study. If the medication is discontinued, American Psychiatric Association practice guidelines recommend that it should be slowly tapered (eg, 10 to 25 percent every one to two months).
Other medications as monotherapy — There is a paucity of data supporting the use of other medications as monotherapy for OCD. No other drugs are approved for the disorder by the FDA in the United States. Small, limited trials have suggested possible benefits of several other agents: mirtazapine (an antagonist at presynaptic alpha-2 adrenergic, 5-HT2, and 5-HT3 receptors) [33], tramadol (an agonist at the mu opioid receptor as well as a modulator of noradrenergic and serotonergic systems) [34], and stimulants (eg, D-amphetamine) [35-37]. All require further study with randomized trials to determine efficacy for OCD.
Medications intended to target the glutamatergic system either as monotherapy or as an adjunct to SSRIs or exposure and response prevention (ERP) are also receiving increased attention, but none are supported by empirical data as robust as the support for SSRIs or ERP. Human genetic studies, imaging studies, and animal models of OCD suggest that glutamatergic abnormalities in corticostriatal brain circuits contribute to obsessions and compulsions. Medications thought to modulate the glutamate system have been increasingly tested in patients with OCD. Various agents have shown promise in open-label or small randomized trials either as monotherapy or as adjunct to SSRI or ERP (see 'Other pharmacologic augmentation' below). These agents include: N-acetylcysteine (an amino-acid derivative that has glutamate-modulating properties) [38,39], D-cycloserine [40-43], memantine (a noncompetitive N-methyl-D-aspartate [NMDA] receptor antagonist) [44-49], riluzole (an agent thought to modulate glutamate both by reducing neuronal release and increasing glial reuptake) [50-52], and minocycline (an agent thought to modulate glutamate by enhancing glial glutamate transport) [53,54]. In a small proof-of-concept crossover study, a single dose of intravenous ketamine (an NMDA receptor antagonist) as monotherapy led to the rapid acute resolution of obsessions in unmedicated adults with OCD [55]. This introduces the possibility of developing rapid-acting medications for OCD.
There are no randomized trials of antipsychotic medications as monotherapy for OCD. Small, open trials have shown inconsistent results [56,57].
AUGMENTATION — With many patients experiencing a partial response to a serotonergic antidepressant, there is considerable interest in strategies to augment these medications for OCD. Common approaches to augmentation include adding:
●Cognitive-behavioral therapy (CBT)
●Risperidone or another antipsychotic medication
●A low dose of clomipramine (to a selective serotonin reuptake inhibitor [SSRI] or serotonin-norepinephrine reuptake inhibitor)
Augmentation with CBT — Randomized trials have demonstrated the benefit of adding cognitive-behavioral therapy (CBT), consisting of exposure and response prevention, to the treatment of patients with OCD that have partially responded to a serotonergic antidepressant [58,59]. (See 'Comparing pharmacotherapy and psychotherapy' below and 'Combining pharmacotherapy and psychotherapy' below.)
●Ninety-six patients who completed three months of medication (paroxetine or venlafaxine) for OCD were randomized to a six month continuation of the medication alone or with the addition of exposure and response prevention (18 45-minute sessions over six months [58]). The augmentation of the antidepressant with exposure and response prevention modestly increased the proportion of patients achieving remission compared with continued medication alone. The mean reduction in OCD symptoms did not significantly differ between the two groups.
●One hundred-eight patients who continued to experience clinically significant symptoms of OCD despite 12 weeks of a therapeutic dose of a serotonergic antidepressant were randomly assigned to exposure and response prevention or to stress management therapy (17 90-minute sessions over eight weeks), while continuing the medication [59]. After eight weeks, patients who received exposure and response therapy plus the medication experienced a greater decrease in OCD symptoms, a higher rate of treatment response (74 versus 22 percent), and a greater proportion with mild to minimal symptoms (33 versus 4 percent) compared with patients who received stress management therapy plus the antidepressant [59].
●One hundred OCD patients who had obtained some benefit from at least 12 weeks of serotonergic antidepressant treatment were randomly assigned to receive eight weeks of additional exposure and response prevention, risperidone, or pill placebo. The group receiving exposure and response prevention experienced a greater decrease in OCD symptoms and a higher rate of treatment response compared with patients receiving risperidone or placebo (80 percent versus 23 and 15 percent) [60].
Different factors can affect outcomes from CBT (consisting of exposure and response prevention), including the length and frequency of therapy sessions, the presence of severe comorbidity like severe depression, and the patient’s degree of insight. Patient adherence to practicing exposures and resisting rituals in-between sessions is one of the most robust predictors of both acute and long-term outcomes [61-63].
Antipsychotic augmentation — Antipsychotic drugs have been shown to be efficacious at reducing OCD symptoms in some patients when added to an SSRI or clomipramine. At the same time, none of these agents are approved by the Food and Drug Administration in the United States for the treatment of OCD and thus their use is “off-label.”
Efficacy — Haloperidol, risperidone, quetiapine, olanzapine, and aripiprazole have all be shown in randomized controlled trials to augment serotonin reuptake inhibitor (SRI) response, although there are also negative trials of some of these agents [64-72]. It is unclear whether varying responses found across antipsychotic trials reflect true differences in efficacy or methodologic issues specific to the trials. There have been multiple meta-analyses of these randomized trials [73-76]; the most comprehensive analyzed 14 double-blind randomized placebo controlled trials totaling 491 patients and included four trials of quetiapine (142 patients), four trials of risperidone (132 patients), two trials of aripiprazole (79 patients), two trials of olanzapine (70 patients), and one trial each of haloperidol (34 patients) and paliperidone (34 patients) [75]. Despite some methodologic differences between these meta-analyses, all come to the conclusion that antipsychotic augmentation of SRIs for OCD is supported by the clinical trials and that this strategy will help a subset (about one-third) of OCD patients. The strongest evidence supports the use of risperidone, aripiprazole, and haloperidol (but the results for haloperidol are based on only one trial). Patients experiencing minimal SRI response and/or patients with comorbid tic disorders may be most likely to respond [73,74,76]. Most of these trials used low doses (eg, risperidone 0.5 to 2 mg/day).
Side effects — Side effects were incompletely reported across studies described above, but available data suggested that antipsychotic augmentation was associated with greater weight gain and/or sedation than SSRI or clomipramine monotherapy [73,74]. Side effects of antipsychotic drugs can include metabolic syndrome, extrapyramidal symptoms, tardive dyskinesia, and neuroleptic malignant syndrome [77].
Administration — Given the delayed onset of action of SSRIs or clomipramine, the antipsychotic should be added only after the patient has not responded following a trial of at least 12 weeks at the maximal antidepressant dose tolerated [19]. Low antipsychotic doses appear effective (eg, 0.5 to 3 mg for risperidone or the equivalent). The antipsychotic should be terminated after one month if the patient does not show a clear benefit. This limits exposure to antipsychotics’ known risks. (See 'Side effects' above and "Second-generation antipsychotic medications: Pharmacology, administration, and side effects" and "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects".)
Efficacy trials of antipsychotic augmentation for OCD have generally examined short-term use only. One placebo-controlled trial that randomized 82 OCD patients on SSRIs to the addition of either risperidone, exposure and response prevention, or pill placebo for eight weeks then followed responders for up to six months: those who acutely responded to risperidone and remained on risperidone were likely to maintain their treatment gains out to six months [78]. One small retrospective study suggested a high risk of relapse when the antipsychotic was discontinued; 13 of 15 patients had a return of OCD symptoms when their antipsychotic was stopped [79]. Patients who respond to antipsychotic augmentation are thus advised to continue the medication for up to six months before an attempt is made to gradually discontinue. If symptoms recur or worsen during the taper, then the antipsychotic can be restarted for a longer period provided that the patient is not experiencing long-term adverse effects of the antipsychotic.
Other pharmacologic augmentation — Although not extensively studied, low doses of clomipramine (≤75 mg/day) may be effective, based on open trials and small randomized trials, in augmenting SSRI treatment in adults with OCD [80]. Higher doses can result in markedly increased levels of clomipramine, and should ideally be used in conjunction with monitoring serum levels of the drug and its metabolites [81].
Other medications have been tested in augmentation of serotonergic antidepressants in OCD. Although promising in case reports or open trials, several did not show clear efficacy in small randomized trials, including lithium, buspirone, clonazepam, L-triiodothyronine, pindolol, and desipramine [19]; a large multisite study of ondansetron was negative [82] despite promising data from smaller pilot trials [83-85]. One possible explanation for this pattern of results is that these agents may only help a subset of patients who by chance were more likely to be recruited into the smaller trials.
Other augmentation strategies that have shown some promise but need further study in randomized trials include: D-amphetamine or caffeine [86], lamotrigine [87], celecoxib [88], pregabalin [89], N-acetylcysteine [38,39], memantine [45,46,49], riluzole [50-52], and minocycline [53,54].
COMPARING PHARMACOTHERAPY AND PSYCHOTHERAPY — Available evidence suggests that cognitive-behavioral therapy (CBT) may be more effective than treatment with serotonergic antidepressants for non-comorbid OCD. The type of CBT commonly used for OCD uses exposure and response prevention (ERP), sometimes with adjunctive cognitive restructuring. A 12-week randomized trial compared ERP (provided intensively for 4 weeks followed by 8 weekly maintenance sessions), clomipramine (200 to 250 mg/day), ERP plus clomipramine, and pill placebo in 122 patients with OCD [90]. A greater proportion of patients responded to ERP compared with clomipramine or placebo (62 versus 42 and 8 percent, respectively). Mean OCD symptom reduction was greater in the group receiving ERP compared with patients receiving clomipramine or placebo.
In OCD comorbid with major depression or other anxiety disorders, the serotonergic antidepressants have the additional benefit of being an effective treatment for several of these disorders. (See "Obsessive-compulsive disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis", section on 'Epidemiology'.)
COMBINING PHARMACOTHERAPY AND PSYCHOTHERAPY
CBT and clomipramine or selective serotonin reuptake inhibitors — Combined therapy with medication and cognitive-behavioral therapy (CBT) may be more effective than monotherapy for some, but not all, patients with OCD [91]. How CBT and serotonergic antidepressants are combined (specifically the dose of each treatment and the timing of when they are combined) can influence the effectiveness of this strategy. The presence of comorbid conditions, patient preference, and treatment access can all influence whether to pursue monotherapy or combination treatment.
●In the aforementioned trial, the effects of exposure and response prevention (ERP) did not differ from that of ERP plus clomipramine for OCD [90]. This trial studied OCD patients who were relatively free of comorbid depression, and ERP was delivered in an intensive format (15 two-hour sessions delivered over three weeks followed by two home visits and then weekly 45 minute sessions out to 12 weeks). Moreover, the ERP and clomipramine were started at the same time, such that the full effects of clomipramine were not yet realized during the ERP treatment. (See 'Comparing pharmacotherapy and psychotherapy' above.)
●In contrast, in the three trials discussed above of effective ERP augmentation of serotonergic antidepressants, patients were already stable on a serotonergic antidepressant. In the trial with the smallest benefit, patients also received a low intensity of ERP: 18 ERP sessions were delivered, but each session was only 45 minutes in length, and they were delivered over six months. (See 'Augmentation with CBT' above.)
Cognitive-behavioral therapy and D-cycloserine — There appears to be minimal role for D-cycloserine, a partial agonist at the N-methyl-D-aspartate receptor, in augmenting ERP in patients with OCD. D-cycloserine enhances fear extinction in animal models and thus had been hypothesized to enhance extinction learning in exposure therapy for OCD. However, randomized trials have not demonstrated a clear, lasting benefit of D-cycloserine augmentation [40-43,92]. In the largest trial to date, D-cycloserine did not improve remission rates following ERP compared with placebo [92]. In some trials, D-cycloserine reduced time to response to ERP but did not result in increased overall response by the end of the trials [40,42].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Obsessive-compulsive disorder and related disorders".)
SUMMARY AND RECOMMENDATIONS
●Treatment – We recommend that patients with obsessive-compulsive disorder (OCD) be treated with cognitive-behavioral therapy (CBT) consisting of exposure and response prevention (ERP), a selective serotonin reuptake inhibitor (SSRI) medication, or both (Grade 1A). (See 'Introduction' above.)
For most patients with OCD, we suggest first-line treatment with ERP (a type of CBT) rather than treatment with an SSRI medication (Grade 2B). SSRI medication is a reasonable alternative if CBT is unavailable, not indicated, or if the patient prefers medication. (See 'Comparing pharmacotherapy and psychotherapy' above.)
●Medication selection – For patients with OCD and a severe, co-occurring disorder that is typically responsive to SSRI treatment, we suggest initial treatment of both disorders with an SSRI (Grade 2C). (See 'Monotherapy' above and 'Medication selection' above.)
●Administration – Higher doses of SSRIs or clomipramine have generally been found to be more effective for OCD. As an example, fluoxetine can be gradually titrated to 40 to 80 mg/day. The medication should be continued within the therapeutic range for at least six weeks before concluding that the drug is ineffective. Some patients may respond to doses that are higher than the maximum approved by the US Food and Drug Administration (FDA), although at the risk of greater side effects. (See 'Administration and course of treatment' above.)
If an adequate trial of the SSRI results in no response, we suggest treatment with a different SSRI, clomipramine, or venlafaxine (Grade 2C) if the patient prefers medication or progressing to a trial of ERP if the patient is willing. (See 'Monotherapy' above and 'Medication selection' above.)
●Augmentation – If a trial of an SSRI or serotonin-norepinephrine reuptake inhibitor results in a partial response, but the patient continues to experience clinically significant symptoms, we suggest augmenting the antidepressant with CBT consisting of exposure and response prevention before trying an antipsychotic medication (eg, risperidone 0.5 to 3 mg/day) (Grade 2B). Other approaches with less supporting evidence are increasing the SSRI dose above the maximum approved by the FDA or adding clomipramine (≤75 mg/day). (See 'Augmentation' above.)
●Duration of treatment – SSRIs and clomipramine generally lead to improvement in 40 to 60 percent of people with OCD. When patients have an adequate response, practice guidelines recommend that they be maintained on the medication for at least one to two years, though more research is needed on this issue. (See 'Duration of treatment' above.)
