Obsessive-compuîsive disorder (OCD) is a chronic and disabling illness associated with substantial morbidity, with a lifetime prevalence reported to be as high as 3%.! It is characterized by intrusive obsessions (such as contamination fears, thoughts of harming others, horrific sexual or religious images, concerns about order and symmetry, and pathologic doubt), compulsions (such as washing, checking, ordering, repeating, hoarding, and counting), or both. Most patients require long-term pharmacologic treatment, psychosocial treatment, or both.2
Although the definitive pathophysiologic substrate for OCD has yet to be identified, hypotheses regarding how treatments, both pharmacologic and psychosocial, reduce OCD symptoms have been posited.3-4 With well-established pharmacologic agents, such as clomipramine, and the selective serotonin reuptake inhibitors (SSRIs), the clinician has several potentially useful drugs. In addition, cognitive-behavioral therapy (CBT) using exposure and response (or ritual) prevention is a potent treatment for OCD and may be the best initial treatment for certain patients.
This article reviews the pharmacologic and psychosocial treatment of adult patients with OCD. Topics that are discussed include selecting an initial treatment and subsequent options for acute treatment, managing the treatmentresistant patient, choosing between CBT and drugs, and handling long-term maintenance treatment.
Approximately 65% to 70% of patients who receive medication for the first time will show at least a moderate response.5 Despite these treatments, a significant number of patients will be insufficiently responsive or completely refractory to all therapies, including alternative monotherapies, augmenting medications, and CBT.6
Currently, clomipramine and four SSRIs - fluvox amine, fluoxetine, sertraline, and paroxetine - have received approval from the Food and Drug Administration for the treatment of adults with OCD; dorniprarnine, fiuvoxamine, and sertraline are approved by the Food and Drug Administration for use in children. Citalopram, another SSRI that has recently been introduced in the United States, has been used in Europe for depression and OCD. The different pharmacologic strategies are briefly summarized, including monotherapies, combination treatment, augmentation strategies, and approaches for the treatment-refractory patient.
Clomipramine. Clomipramine is the oldest and best-studied medication for OCD. Numerous placebo-controlled studies of clomipramine for OCD show that clomipramine is superior to placebo and results in a mean reduction in OCD symptoms ranging from 36% to 46% 7 The usual starting dose is 50 mg, with increases of 50 mg every 4 to 5 days, and a target dose of 250 mg. Trials of less than 200 mg/d are considered to be inadequate. Monitoring of plasma level can be helpful to determine whether a patient is not responding because of rapid hepatic metabolization of clomipramine, to check whether concomitant medications are resulting in dangerous elevations of clomipramine-desmethylclomipramine levels, or both. Szegedi et al.8 found that when fluvoxamine (50 to 200 mg/d) and clomipramine (37.5 to 225 mg/d) were combined, the dosage that was best tolerated and safe resulted in a desmethylclomipramine-clomipramine ratio of no greater than 0.3 and a combined serum clomipramine and desmethyldomipramine level of less than 450 ng/mL.
Medications That Are Well Established as Effective for Obsessive-Compulsive Disorder Based on Double-Blind Studies
Although effective, clomipramine has several troublesome anticholinergic and anti-adrenergic side effects, such as sedation, dry mouth, blurred vision, orthostasis, and weight gain. Overall, however, it is well tolerated, with approximately 10% of patients in large multicenter studies discontinuing the medication prematurely because of side effects. An electrocardiogram (EKG) is required before beginning treatment, and periodic EKG monitoring should be performed for pediatric patients. Caution should be used when prescribing clomipramine for the suicidal patient because of its lethality in overdose. In addition, there is a dose-related lowering of the seizure threshold such that doses oí more than 250 mg/d are not recommended.
SSRIs. Four selective serotonin inhibitors - fluoxetine, sertraline, paroxetine, and fluvoxamine - have been shown in separate multicenter, placebo-controlled studies to be effective in the treatment of OCD.2 All of the SSRIs studied appear to have a greater magnitude of response at the higher dose ranges, the exception being sertraline, which was equally effective at 50 and 200 mg.9 Although fluoxetine has not been systematically examined, clinical experience suggests that fluoxetine at dosages of 80 mg or higher might be necessary for certain patients (Table 1). Experience with Citalopram in the United States is more limited, but preliminary results from a placebo-controlled study suggest efficacy, which also may be greater at higher dosages.10
Although the SSRIs are generally well tolerated, particularly in comparison with clomipramine, they have several notable side effects, such as gastrointestinal distress, agitation, anxiety, sleep disturbance, headache, and sexual dysfunction. The likelihood of side effects from SSRIs is increased in patients with OCD due to the general need for high doses, which have been associated with an increased rate of side effects.
Selection of an Initial Drug (Table 2\ When initiating pharmacotherapy for OCD, how does the clinician select among the serotonin reuptake inhibitors (ie, clorm^ramine and the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline) that have been approved by the Food and Drug Administration for the treatment of OCD? Differential efficacy plays little role in choosing among these drugs. Instead, the decision to use one of these medications over another is usually based on side effect profile, cost, and safety considerations. Other variables such as medical and psychiatric comorbidity, family history, and past treatment success also factor into the decision.
Direct comparisons of dormpramine with an SSRI generally suggest comparable efficacy, whereas meta-analytic studies suggest that clomipramine is more effective than the SSRIs. In clinical practice, however, most psychiatrists start with one of the SSRIs because they are often better tolerated than domipramine and are not lethal in overdose. Clorrdpramine is generally reserved for patients who have had an insufficient response to one or two SSRIs at a maximum dose for an adequate length of time (ie, approximately 3 months).
An important consideration in choosing among the available first-line agents is the potential for drug interactions, as many patients who have OCD require medications for other medical and psychiatric illnesses concurrently. Two important mechanisms of drug interactions involve the induction or inhibition of hepatic cytochrome P450 enzymes.11 For example, if an asthmatic patient who was taking theophylline, which is a substrate for the CYP1A2 enzyme, were also taking fluvoxamine, an inhibitor of this enzyme, there would be the potential for theophylline to be elevated to unacceptably high levels.12
Comparative pharmacokinetic activity is also important in the initial selection of an agent. Of the SSRIs, only fluoxetine and sertraline have active metabolites, which may provide greater protection against the SSRI discontinuation syndrome associated with abrupt withdrawal or noncompliance with medication. Fluoxetine, with its active metabolite norfluoxetine, has the longest elimination half-life at 4 to 16 days, whereas the elimination half -Hf e of sertraline's metabolite, desmethylsertraline, is 66 hours. Of clinical significance is fluvoxamine' s short halflife of 15 hours, which necessitates twice-a-day dosing and which could lead to poor compliance.
Guidelines for Selection of an Initial Drug
In conclusion, no single first-line drug is more efficacious than another in OCD. In practice, the clinician should try a serotonin reuptake inhibitor at a high dosage for approximately 3 months before switching to another agent (Table 1).
Other Single-Agent Oral Strategies. Although the efficacy of agents beyond the first-line monotherapies has yet to be determined in randomized, double-blind, placebo-controlled trials, several other drugs may have promise. In a 10week, double-blind, placebo-controlled trial of phenelzine (60 mg), a monoamine oxidase inhibitor (MAOI), versus fluoxetine (80 mg), the patients who received fluoxetine improved significantly more than did the patients who received placebo or phenelzine. However, a subgroup of patients with symmetry obsessions responded to phenelzine.13 Currently, however, recent reviews and the available data suggest that the MAOIs should be reserved as a distant second-line approach for OCD.6 Several open studies of venlafaxine using doses up to 375 mg/d have shown modest benefit, although venlafaxine was not significantly better than placebo in a double-blind trial of 30 patients with OCD.14 Although controlled studies of clonazepam, inositol, and buspirone have shown them to have promising results as monotherapy, these studies were of insufficient duration to draw definitive conclusions about the role of these drugs.
Although many patients improve dramatically with the serotonin reuptake inhibitors (ie, clomipramine and the SSRIs), approximately 40% to 60% of patients experience minimal or only partial improvement after an adequate trial with one of these agents.6 Of those patients who "respond" by the criterion employed in most clinical trials (a mean reduction of symptoms of 20% to 40% as scored on the Yale-Brown Obsessive-Compulsive Scale), many are left with troubling residual symptoms.6
If a patient has not responded well to an initial trial of 3 months at an adequate dose of medication, the clinician has several options. CBT could be started (see below), the patient could be switched to another SSRI (or to clomipramine), or, for patients with comorbidities, another medication or CBT directed toward the comorbidity could be added to the treatment regimen. There are several strategies available for treatment-resistant patients, which are summarized below.
Many medications have been tested as augmentors of serotonin, reuptake inhibitors for OCD; however, to date, only the neuroleptic haloperidol and the atypical neuroleptic risperidone have been found to be effective in doubleblind, controlled studies. McDougle et al.35 found that adjunctive haloperidol (mean dose 6.2 ± 3.0 mg/d) was better than adjunctive placebo in reducing residual OCD symptoms in patients receiving fluvoxamine; however, haloperidol was effective only for those patients with OCD who had a comorbid chronic tic disorder. This group subsequently reported that, based on their clinical experience, haloperidol at 0.5 mg/d with increases every 4 to 7 days to a maximum of 2 to 4 mg/ d is helpful16 (Table 1). A recent double-blind, placebo-controlled trial suggested that adjunctive risperidone (mean dose 2.2 ± 0.7 mg) improved OCD symptoms refractory to an SSRI alone, even in the absence of comorbid tics.17 In a large open-label series, Saxena et al.18 found that patients with horrific mental imagery had a particularly fast and robust response to risperidone, whereas patients with comorbid psychotic disorders (schizophrenia, schizoaffective disorder) improved gradually during 2 to 3 weeks. Finally, a recent open trial of olanzapine augmentation of ongoing SSRI treatment has shown promise.19
Other pharmacologic augmentation strategies employed in clinical practice, but with uncertain benefit, include adding clomipramine to an SSRI.8 Negative results with lithium,20 clonazepam,21 desipramine,22 and buspirone23 augmentation of SSRIs for OCD have been observed in controlled studies, whereas open studies of gabapentin24 and donepezil25 augmentation are encouraging. For patients who are refractory to trials of all available medications with suggested efficacy and CBT, final options include intravenous clomipramine and, as a last resort in carefully selected patients, neurosurgery.
In conclusion, the management of treatmentresistant patients is particularly challenging and involves close attention to comorbidities, associated symptoms, and prior treatment response. If a patient has not responded well to monotherapy with a serotonin reuptake inhibitor, and does not have a comorbid tic disorder, switching to another serotonin reuptake inhibitor or CBT alone is recommended. If tics are present, a trial of adjunctive haloperidol or risperidone should be attempted for a few weeks; if no improvement occurs, discontinuation of the neuroleptic is recommended because of the risk of tardive dyskinesia. Alternate augmentation strategies, as reviewed above, may reduce associated symptoms (such as general anxiety), but have not yet been demonstrated to exert a significant therapeutic effect on the primary symptoms of OCD. Given the risks of long-term neuroleptic treatment, the best way to augment a partial serotonin reuptake inhibitor response may be CBT using exposure and response (or ritual) prevention, given the safety and efficacy of this treatment for OCD (see below).
Special Case of PANDAS
In children who meet criteria for pediatric autoimmune neuropsychiatrie disorders associated with streptococcal infections (PANDAS), which includes the presence of OCD, a tic disorder, or both, prepubertal symptom onset, an episodic course, associated group Abeta-hemolytic streptococcal infections, and associated neurologic abnormalities,26 effective treatment might include plasmapheresis, intravenous gamma globulin, maintenance antibiotics, or all of these.27
Although there are numerous psychotherapeutic approaches for OCD, only CBT using exposure and response prevention has been demonstrated in multiple randomized, controlled trials to be a potent treatment for OCD. 28·29 Thus, exposure and response prevention is considered the "gold standard" of psychosocial treatment. For those receiving exposure and response prevention, the response rate is approximately 80%,28-30 and the mean percent reduction in symptoms following exposure and response prevention is almost 50% (range 26.7% to 66. 7%).29 Given the safety and demonstrated efficacy of exposure and response prevention, many clinicians recommend that all patients with OCD willing to participate receive a trial of exposure and response prevention, regardless of whether medications are used.
The structure and format, methodology, and limitations of exposure and response prevention, and its use as an adjunctive treatment for those with a partial response to serotonin reuptake inhibitor medication, are now discussed. A brief discussion of the role of CBT using cognitive therapy techniques in OCD is included as well. For a more comprehensive overview of the role of cognitive therapy in OCD, the reader is referred to a recent review by Simpson and Kozak.31
Structure and Format
Exposure and response prevention involves three major components: (1) actual (ie, in vivo) exposure to feared situations; (2) imaginai exposure to feared consequences; and (3) ritual (or response) prevention, in which patients refrain from compulsive rituals. Exposure employs behavioral conditioning principles such as habituation, in which a patient's anxiety diminishes after sufficient contact with the feared stimulus. For example, a patient with contamination obsessions would be coached to confront feared contaminants (such as public rest rooms) and to imagine touching feared contaminants (such as sewage) and becoming ill, until contact with the feared stimuli no longer generated severe anxiety. Ritual (or response) prevention requires that the patient stop performing all rituals voluntarily and tolerate the often tremendous anxiety associated with not ritualizing. For example, the patient with contamination obsessions and washing rituals would be asked to curtail washing during the treatment, and any ritualized washing would be proscribed.
The format of exposure and response prevention typically includes 15 to 25 individual sessions, each lasting 1 to 2 hours, with sessions scheduled from 1 to 5 times per week. Between sessions, patients are also expected to complete homework assignments for up to 2 hours per day. Although the optimal frequency of sessions has not been determined, there is some evidence that more frequent sessions of therapist-supervised exposure lead to a greater reduction of symptoms.29,32 Thus, patients who have not responded to gradual CBT or who have extremely severe symptoms may profit from a 1 -month intensive course with sessions up to 5 times per week. Although the focus in exposure and response prevention is on individual treatment, some patients might benefit from group CBT or behaviorally focused family therapy.33,34
Procedure and Technique
The technique of exposure and response prevention has been previously described.35 The treatment can be divided into three phases. In the initial sessions, the therapist identifies the patient's primary obsessions and compulsions and generates a list of feared situations. The identification of specific fears is necessary to tailor the exposure exercises to the individual patient. In the next phase, the patient is instructed to abstain from ritualizing and to expose himself or herself to feared situations both in the treatment sessions and between sessions as homework. Both in vivo and imaginai exposure are used. Exposure occurs gradually, so that stimuli causing the most distress are confronted only after less fearful stimuli are confronted and mastered. In addition to office sessions, therapists often conduct home visits to help patients generalize the principles of exposure and response prevention to their home environment. Final sessions focus on consolidating gains made in the treatment and instructing the patient in techniques of relapse prevention; the power of continued self-exposure and ritual prevention in preventing relapse is emphasized. Exposure and response prevention also routinely includes some informal cognitive therapy techniques (eg, a discussion of fear-related thoughts and beliefs); the contribution these informal cognitive therapy techniques make to the outcome of exposure and response prevention is not clear.
Determining the Adequacy of Prior Cognitive-Behavioral Therapy: Questions to Ask the Patient
Limitations of Exposure and Response Prevention
Despite the success rate, there are several notable limitations with exposure and response prevention. Most importantly, up to 30% of patients cannot complete the therapy or refuse this treatment for a variety of reasons, including fear of the exposure exercises, unwillingness to abstain from rituals, and difficulty making the necessary time commitment. In addition, although the mean symptom reduction for those receiving exposure and response prevention is almost 50% (as compared with a 20% to 40% mean reduction in OCD symptoms from serotonin reuptake inhibitor pharmacotherapy),2 the average patient treated with exposure and response prevention is still left with residual OCD.29'36 Other limitations include the lack of qualified therapists formally trained in exposure and response prevention, the paucity of data demonstrating its efficacy for OCD in patients with comorbid mental illnesses,37 and the suggestion that it may be less effective for certain clinical subtypes of OCD (such as patients with hoarding obsessions and compulsions).38
Because psychiatrists often are referred patients with OCD who have already had unsuccessful trials of medications, psychotherapy, or both, it is imperative that they determine whether the previous trials were adequate. This determination is important in developing future treatment plans and in adequately gauging the patient's potential for improvement with the recommended modality. Table 3 contains guidelines for determining the adequacy of prior CBT using exposure and response prevention.
Combining Exposure and Response Prevention and Pharmacotherapy
Is there an added advantage of combining drugs with exposure and response prevention? Based on preliminary results from the first direct comparison of exposure and response prevention, clomipramine, the combination, and a pill placebo, exposure and response prevention was more effective than clomipramine, and the combination of exposure and response prevention and domipramine was superior to pill placebo; however, the combination of exposure and response prevention and clomipramine was not superior to exposure and response prevention alone.30 On the other hand, there might be certain situations in which the combination is warranted, such as for patients with severe comorbid depression,39 or for patients who might try exposure and response prevention if their OCD symptoms were first partially reduced by serotonin reuptake inhibitor pharmacotherapy. In addition, exposure and response prevention may be one of the best ways to augment a partial serotonin reuptake inhibitor response. Simpson et al.40 found that 6 of 6 patients who remained symptomatic despite some benefit from an adequate serotonin reuptake inhibitor trial benefited further from adjunctive exposure and response prevention; the degree of additional benefit was as great as or greater than that reported for medication augmentation strategies (mean symptom reduction of 49%, range 26% to 61%).
Other Psychosocial Approaches to OCD
CBT that relies primarily on cognitive therapy techniques (eg, identifying, challenging, and modifying faulty beliefs)41,42 has also been used in OCD. However, the evidence supporting its use in OCD is less convincing and more controversial than that for exposure and response prevention.29'31 Some have suggested that exposure and response prevention may be enhanced by the addition of cognitive procedures with specific efficacy for either certain subtypes of OCD (eg, hoarding43) or comorbid conditions such as depression. In addition, specific cognitive procedures might prove helpful if patients refuse exposure and response prevention or if patients have a relapse following exposure and response prevention.44 However, whether the addition of specific cognitive procedures to exposure and response prevention can improve the efficacy of optimal exposure and response prevention alone has not yet been established.36 Psychodynamic or psychoanalyticalIy oriented psychotherapy has no utility in the primary treatment of OCD.
CHOICE OF TREATMENT: THERAPY. DRUGS, OR BOTH?
Once the diagnosis of OCD is established, a decision must be made regarding appropriate initial treatment. Given the favorable risk-benefit ratio of CBT using exposure and response prevention, it makes sense for every patient to be offered this modality; however, practical considerations often factor into the decision to medicate initially. Relevant considerations include the availability of qualified therapists specializing in this particular treatment for OCD, cost and insurance status, time available for the patient, patient preferences, psychiatric and medical comorbidity, and prior treatment response. Trie discussion that follows focuses on the impact of psychiatric and medical factors on the choice of treatment modalities.
The treatment of OCD complicated by comorbid psychiatric illness poses special challenges. Clinical experience suggests that the combination of pharmacotherapy and psychotherapy targeting OCD plus the comorbid condition is the best strategy. Some patients with OCD who have comorbid tic disorder, schizotypal personality, psychotic disorders (eg, delusional disorder, schizoaffective disorder, or schizophrenia), or all three are likely to benefit from neuroleptic treatment that can both augment a partial serotonin reuptake inhibitor response and treat the comorbid disorder. If comorbid major depressive disorder or panic disorder is present, CBT plus an SSRI or CBT alone, with elements of the therapy that are appropriate for both OCD and the comorbid disorder, should be considered. In the patient with OCD who has comorbid bipolar illness, CBT plus a mood stabilizer with or without a serotonin reuptake inhibitor is recommended.45
For the pregnant patient, most clinicians recommend an initial trial of CBT alone, as the safety of serotonin reuptake inhibitors in pregnancy is still uncertain. However, when the risk of OCD potentially rivals the risk of medication use in pregnancy (eg, a pregnant mother starves herself because of contamination fears), combined CBT and medication may become necessary.45
For those with medical complications such as heart disease, CBT alone, or in combination with an SSRI, would be the first choice of treatment. Because of the increased risk of cardiovascular side effects with clomipramine versus the negligible risk with the SSRIs, serial SSRI trials should be conducted in patients with heart disease, and clornipramine should be used only with extreme caution.
A CHRONIC ILLNESS WITH LONG-TERM TREATMENT
OCD is best conceptualized as a chronic and probably lifelong illness that will require ongoing treatment.46 A review of 16 exposure and response prevention studies found that patients who respond to exposure and response prevention can experience a relapse during extended follow-up. Depending on the study, the relapse rates ranged from 0% to 46% of the patients observed.28 The relapse rates following discontinuation of medication may be even higher. A double-blind trial of discontinuation of clomipramine found a relapse rate of 89% within 7 weeks47; the relapse rates for the SSRIs studied appear to be less (eg, a 37.7% relapse rate within 63 days for paroxetine).48 Given the risks of relapse, vigilant maintenance treatment is generally necessary, as relatively few patients with OCD are "cured" and most remain in complete remission.
The key elements of maintenance treatment for OCD are only beginning to be studied. In clinical practice, it is often recommended that medications be maintained for at least 1 to 2 years before considering a taper. While medication is being tapered, monthly "booster" exposure and response prevention sessions for 3 to 6 months for the patient who has already undergone a trial of exposure and response prevention may be helpful in reducing the risk of relapse.40,49
In the maintenance phase, medication dosages should generally be the same as those that were effective in the acute phase. Consensus treatment guidelines for OCD45 suggest the use of longterm medication (ie, lifelong prophylaxis) after 3 to 4 mild-moderate relapses or 2 to 4 severe relapses despite adequate CBT. For CBT maintenance, monthly booster sessions for 3 to 6 months are often recommended in clinical practice, although their efficacy in preventing relapse following successful exposure and response prevention treatment has not been established.
As demonstrated in multiple randomized, controlled trials, two treatments are efficacious for the initial treatment of OCD: (1) pharmacotherapy with serotonin reuptake inhibitors (ie, clomipramine and the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline); and (2) CBT using exposure and response prevention. Nevertheless, some patients do not respond to either treatment, and others respond to treatment but are left with significant residual symptoms. Numerous other pharmacologic and psychosocial treatments have been tried in OCD, including augmenting strategies; however, with the exception of using haloperidol or risperidone for patients to augment a partial serotonin reuptake inhibitor response, the evidence supporting these treatments is much less convincing. Thus, in most patients, OCD can be managed with treatment, but not eliminated. Much work remains to be done to develop more effective pharmacologic and psychosocial treatments for patients suffering from this complex and disabling neuropsychiatrie disorder.
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Medications That Are Well Established as Effective for Obsessive-Compulsive Disorder Based on Double-Blind Studies
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