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C U R R E N T A N D E X P E R I M E N T A L
T H E R A P E U T I C S O F O C D
E R I C H O L L A N D E R S T E F A N O P A L L A N T I
UNIQUE ASPECTS OF OCD
PHARMACOTHERAPY
Obsessive-compulsive disorder (OCD) is a chronic disorder with substantial impact on quality of life (1) that affects 2% to 3% of the US population (2,3). Previously believed to be refractory to treatment, the symptoms of OCD are substantially reduced with the use of medications having potent effects on blocking the serotonin (5-HT) transporter. The response to serotonin reuptake inhibitors (SRIs) in OCD is somewhat unique compared to that in other mood and anxiety disorders, in that higher doses and a longer lag- time to therapeutic effect of SSRIs may be required, and a lack of response to other antidepressant/antianxiety agents in OCD is evident. Nevertheless, SRIs do not cure patients, and 30% to 50% remain treatment nonresponders; there- fore, other pharmacologic approaches, augmentation strate- gies, and especially cognitive-behavioral treatments may be- come necessary. Recently, other more invasive treatment options have been studied in the refractory population as well. This chapter highlights the psychopharmacology of OCD, including the current state of the art and future direc- tions. Cognitive behavioral treatments for OCD, which are also highly effective, are not extensively reviewed here.
DIFFERENTIAL DIAGNOSIS AND
COMORBIDITY: IMPLICATIONS FOR
THERAPEUTICS
Although the diagnosis of OCD is usually straightforward, presenting with classic obsessive and compulsive symptoms, sometimes OCD presents with atypical features. Con-
Eric Hollander: Department of Psychiatry, Mount Sinai School of Medi- cine, New York, New York. Stefano Pallanti: Institute for Neurosciences, Florence, Italy.
versely, other disorders may present with symptoms remi- niscent of OCD. For example, the ruminations of depres- sion, intrusive thoughts, or delusions of psychotic disorders, and stereotyped behaviors of developmental disorders, may mimic OCD. Thus, comprehensive clinical evaluation and careful differential diagnosis are essential. Psychiatric comorbidity is the rule rather than the excep- tion in OCD. Up to two-thirds of all patients with OCD have lifetime comorbidities (3,4). These comorbid condi- tions not only serve to cloud the diagnostic picture, but also can influence the selection of optimal treatments. The prevalence of obsessive-compulsive symptoms in schizophrenic patients has been estimated to range from 7.8% to 46.6% (5–7). A recent paper reported that in the early phase of the disorder, 14% of schizophrenic patients fulfilled criteria for a diagnosis of OCD (8). Atypical neuro- leptics have been associated with both new onset and exacer- bation of obsessions and compulsions, with numerous re- ports for clozapine (9) and less for risperidone. Treatment of OCD symptoms in schizophrenic patients may take into account this possible effect of atypical neuroleptics, and dos- age reduction and/or SRI augmentation may be recom- mended (10). The prevalence of OCD in patients with bipolar disorder has been estimated to be around 30% (11–12), half of whom had one or two other associated anxiety disorders (13); therefore, previous manic or hypomanic episodes and subthreshold hyperthymic characteristics should be evalu- ated and treated accordingly (14). Because SRIs may some- times precipitate hypomanic or manic episodes in adults (15–17) and adolescents (18) without previous manic epi- sodes, low initial doses, gradual dose elevation, and addition of mood stabilizers may be required.
IMPACT OF COMORBIDITY/SUBTYPES,
OUTCOME MEASURES, AND RESPONDER
CRITERIA
In evaluating treatment response in OCD, the patient popu- lation under study and measurement of response can signifi-
1648 Neuropsychopharmacology: The Fifth Generation of Progress
cantly impact findings. For example, OCD patients who fail to respond to prior SSRI therapeutic trials may have only a 25% chance to respond to an additional SSRI trial (19). Likewise, patients with comorbid tics (20), delusional symptoms, or schizotypical personality disorder (21) may not respond to SSRIs, and may require neuroleptic augmen- tation strategies. OCD patients with neurological soft-signs may be poorly responsive to SSRIs (22). Also, specific OCD subtypes, such as hoarders, may be poorly responsive to SSRIs. Finally, related or OCD spectrum disorders share important features with OCD and may be comorbid with OCD, influencing treatment outcome (23).
TREATMENT RESPONSE
The degree of symptom resolution in response to treatment determines the need for dosage adjustment, augmentation, or switching to an alternative treatment. Treatment re- sponse may be assessed qualitatively via periodic clinical interviews or the regular use of validated scales such as the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) to quantify the ongoing severity of OCD symptoms. Approxi- mately 60% of patients treated with SRIs experience at least a 25% to 35% decrease in symptoms in Y-BOCS (24), which is typically operationalized as a criterion for response. Although the Y-BOCS score generally is an excellent gauge of symptomatic improvement, the overall change in quality of life also must be considered. The Y-BOCS does not reflect these quality of life issues, and may not be sensi- tive to subtle changes, such as going from 8 to 2 hours per day of rituals. The criteria set for response (i.e., 25% or 35% reduction in Y-BOCS, CGI improvement of 1 or 2, or a combination of the two) may markedly impact percent- age of subjects who are considered responders in various trials, and thus studies that utilize different response criteria might yield very different response rates.
SEROTONIN AND DOPAMINE FUNCTION IN
OCD
Evidence for serotonergic and dopaminergic function in OCD is discussed in detail elsewhere (see Chapter 112). Extensive research documenting the efficacy of SRIs has indicated that the antiobsessional properties of these drugs may be related to their 5-HT reuptake inhibition properties. Peripheral and central marker abnormalities have generally supported a proposed 5-HT hypothesis (25). Of note, in a subgroup of OCD patients, increased levels of CSF 5- hydroxyindoleacetic acid (5-HIAA) have been observed and a correlation has been found between response to treatment and a reduction of both 5-HIAA levels and platelet 5-HT concentration (26-27). The partial serotonin 5-HT2C ago- nist m -chlorophenylpiperazine ( m -CPP) has been found to
acutely exacerbate symptoms in a subgroup of OCD pa- tients in some (28,29) but not all studies (30), and has generally demonstrated neuroendocrine blunting in these patients as compared to normal controls (29,31). Treatment with clomipramine or fluoxetine leads to cessation of this behavioral exacerbation and normalization of the neuroen- docrine findings in response to repeat m -CPP challenge (32, 33). There is some evidence for linkage disequilibrium of the 5-HT1DB receptor gene and OCD, with preferential transmission of the G allele to affected subjects (34). To date, a specific abnormality of the 5-HT system in OCD has not been identified and the strongest evidence in support of the serotonin hypothesis remains the preferential response to SRIs. There is a debate regarding the nature of the SRI-induced changes to the 5-HT system. Administration of the SRIs results in an immediate inhibition of the 5-HT transporter, with the effect of increasing synaptic 5-HT; however, the full clinical response may not be seen for up to 8 to 12 weeks of SRI treatment. An understanding of the neuroadaptive changes that take place with treatment is helpful in clarify- ing the mechanism of action involved. It has been reported that desensitization of 5-HT-2 receptors is implicated in the antiobsessional effect of SRIs (35). Alteration of serotonin release in the orbito-frontal cortex has been found to occur only after 8 weeks of treatment (36). These adaptive changes seem to involve a reduction in the number of receptors and altered responsivity of second messengers (37). There are many subtypes of 5-HT receptors, each having a distinct pattern of brain localization, with those expressed in basal ganglia and orbitofrontal regions of particular interest in the etiology of OCD (38). There are complex structural and functional interactions between dopamine (DA) and 5-HT in the brain. Evidence implicating DA in the neurobiology of OCD is derived from a number of areas. In animal models, amphetamines have been shown to induce stereotypies that are viewed as compulsive behaviors (39). An association of postencepha- litic Parkinson syndrome with obsessive-compulsive symp- toms has been found (40). The comorbidity of Tourette syndrome and OCD is well described (41), as well as the association of a variety of other basal ganglia disorders with OCD. There is also evidence of DRD2 and DRD3 receptor gene polymorphisms in OCD (42).
SEROTONIN REUPTAKE INHIBITORS: ACUTE
TRIALS
SRIs include clomipramine (Anafranil), fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and citalopram (Celexa). Of these, fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram are ‘‘selective sero- tonin-reuptake inhibitors’’ (SSRIs), characterized by mini- mal affinity or pharmacologic action at receptor sites other
1650 Neuropsychopharmacology: The Fifth Generation of Progress
TABLE 114.1. CONTROLLED TRIALS OF SEROTONIN REUPTAKE INHIBITORS THERAPY FOR OBSESSIVE-COMPULSIVE DISORDER IN ADULT PATIENTS
Studies (Ref.) Conditions Results
Clomipramine (CMI) vs Placebo or Non-SRIs Karabanow, 1977 (47) CMI vs placebo CMI superior to placebo Montgomery, 1980 (48) CMI vs placebo crossover CMI superior to placebo Mavissakalin et al, 1985 (49) CMI vs placebo CMI superior to placebo Jenike, 1989 (50) CMI vs placebo 73% improved on CMI Greist et al., 1990 (51) CMI vs placebo 73% improved on CMI 6% improved on placebo CMI collaborative group, 1991 (52) CMI vs placebo 38%–44% decrease Sx with placebo 3%–5% decrease Sx with placebo Thoren et al., 1980 (53) CMI vs nort. vs placebo CMI, but not nort., superior to placebo Ananth et al., 1981 (54) CMI vs amitriptyline CMI superior to amitriptyline Insel et al., 1983 (55) CMI vs clorgyline CMI effective, clorgyline not Zahn et al., 1984 (56) CMI vs clorgyline CMI superior to clorgyline Volavka et al., 1985 (57) CMI vs imipramine CMI superior to imipramine Cui, 1986 (58) CMI vs dosxepin 78% improve on CMI 36% improve on doxepin Lei, 1986 (59) CMI vs imipramine crossover CMI superior to imipramine Zhao, 1991 (60) CMI vs amitriptyline 95% improve on CMI 56% improve on amitriptyline SSRIs vs Placebo or Non-SRIs Perse et al., 1987 (80) Fluvoxamine vs placebo Fluvoxamine superior to placebo Goodman et al., 1989 (81) Fluvoxamine vs placebo Fluvoxamine superior to placebo Goodman et al., 1990 (83) Fluvoxamine vs desipramine Fluvoxamine superior to desipramine Chouinard et al., 1990 (85) Setraline vs placebo Sertraline superior to placebo Jenike et al., 1990 (84) Setraline vs placebo Sertraline superior to placebo Greist et al., 1992 (70) Setraline vs placebo Sertraline superior to placebo Tollefson et al., 1994 (74) Fluoxetine vs placebo Fluoxetine superior to placebo Montgomery et al., 1993 (78) Fluoxetine vs placebo Fluoxetine superior to placebo CMI vs SSRIs Den Boer et al., 1987 (61) CMI vs fluvoxamine Comparable efficacy Freeman et al., 1994 (103) CMI vs fluvoxamine Comparable efficacy Pigott et al., 1990 (62) CMI vs fluoxetine Comparable efficacy Koran et al., 1996 (63) CMI vs fluvoxamine Comparable efficacy Lopez-Ibor et al., 1996 (102) CMI vs fluoxetine Comparable efficacy Zohar et al., 1996 (64) CMI vs paroxetine Comparable efficacy
mine treatment responded after 6 weeks compared to 12% receiving placebo (defining response as much or very much improved on the improvement item of the Clinical Global Impression Scale). Of special interest, Goodman and associ- ates (83) demonstrated the selective efficacy of SSRIs in OCD because fluvoxamine (up to 300 mg per day) was significantly more effective than the norepinephrine reup- take inhibitor desipramine in the reduction of obsessive- compulsive symptoms in an 8-week double-blind trial.
Sertraline
Although one early study did not find sertraline to be supe- rior to placebo in the treatment of OCD (84), several subse- quent studies have demonstrated its efficacy in OCD. Chouinard and associates (85) found sertraline (up to 200 mg per day) to be more effective than placebo on all out-
come measures in an 8-week trial. A large 12-week, multi- center, placebo controlled, double-blind trial of sertraline in three fixed doses (50, 100, or 200 mg per day), found sertraline at 50 and 200 mg per day to be significantly more effective than placebo, but the 100-mg dose was not more effective than placebo. Clinical outcome was not correlated with sertraline plasma levels (86).
Paroxetine A large multicenter placebo controlled study of paroxetine in three fixed doses (20, 40, and 60 mg per day) found that the 40- and 60-mg doses were significantly more effective than placebo, but the lower dose (20 mg) was not more effective than placebo (71). There was a suggestion of a dose–response relationship, and paroxetine was well toler- ated in the acute dose study phase.
Chapter 114: Current and Experimental Therapeutics of OCD 1651
Citalopram
Citalopram, the most selective of the SSRIs, has not been granted FDA approval in OCD. In a 24-week open pilot study of 29 OCD patients treated with citalopram, 76% had reduction in Y-BOCS scores of more than 50% com- pared to baseline, with most doses between 40 and 60 mg per day (87). In a 10-week single-blind study of 30 patients with OCD who underwent randomized treatment with flu- voxamine, paroxetine, or citalopram, there were no signifi- cant differences found between the three treatments, al- though the study was underpowered to detect significant differences between active treatments (88). Recent con- trolled treatment trials suggest efficacy in OCD (89).
Zimeldine
Although early research with zimeldine in OCD was prom- ising, it has been withdrawn from use owing to several re- ports of Guillain-Barre syndrome occurring during treat- ment.
Venlafaxine
Venlafaxine, a serotonin/norepinephrine reuptake inhibi- tor, has not been systematically studied in controlled trials in OCD, but open pilot data suggest potential efficacy and the need for controlled trials (90).
SEROTONIN REUPTAKE INHIBITORS: SIDE
EFFECTS AND DRUG INTERACTIONS
Side Effects
Efficacy must be balanced against side effects in choosing treatment options, and side-effect profile is magnified in OCD because the treatment is likely to be chronic. All SRIs can cause side effects attributable to their serotonergic ac- tion. Clomipramine, a TCA, is most apt to cause anticholin- ergic and antiadrenergic side effects, whereas SSRIs tend to cause fewer side effects mediated via nonserotonergic recep- tor systems (43–45,91–95). TCAs such as clomipramine have a quinidine-like anti- arrhythmic effect that slows intracardiac conduction (95). Although generally an issue only in patients with known cardiac disease, occasional adverse effects may be seen in patients with no documented pre-existing condition. Fur- thermore, in overdose, the cardiac conduction effects of TCAs lead to much greater toxicity than the SSRIs. This is important, because there is an increased rate of suicide attempts in OCD, especially when associated with comor- bid disorders. TCAs have anticholinergic effects that can cause tachycardia, blurred vision, constipation, urinary re- tention, and confusion (44). Orthostatic hypotension may
occur as a result of alpha 1 -adrenergic antagonism (44). Last, clomipramine lowers seizure threshold (94). SSRIs are relatively safe compared to TCAs. Few, if any, deaths have been reported following overdose with SSRIs. Although side effects are generally less severe, one may see agitation, anxiety, nausea, headaches, weight gain (over time), and sexual dysfunction (43). Although any of these side effects can contribute to noncompliance, sexual dys- function is seen in as many as one-third of patients (92) but may not be readily reported unless the clinician specifically inquires about it. There are little systematic data on the treatment of SSRI-induced sexual dysfunction, but case re- ports and clinical practice have shown that effective inter- ventions may include lowering the dose of SSRI or adding yohimbine (an 2 -adrenergic antagonist), amantadine (a dopamine agonist), methylphenidate, cyproheptadine (an antihistaminic/antiserotonergic agent), buspirone, or silde- nafil (69). There also exists a clinically significant discontin- uation syndrome that occurs on abrupt discontinuation of an SSRI with short half-life (71).
Drug Interactions Patients treated for OCD often take concurrent medica- tions; therefore, potential drug interactions should be con- sidered when selecting an antiobsessional agent. In addition to well-established drug interactions known to occur with clomipramine and other TCAs, individuals may also experi- ence idiosyncratic reactions (91,93,95–99). Some medica- tions interact with clomipramine by influencing its plasma concentration, whereas others potentiate clomipramine’s side effects via synergy at relevant receptor sites. The hypo- tensive effects of clomipramine can be exacerbated by - methyldopa, -adrenergic blockers, clonidine, diuretics, and low-potency antipsychotics. Quinidine and other class Ia antiarrhythmics as well as thioridazine, mesoridazine, and pimozide may add to cardiotoxic effects of TCAs. Common medications that have anticholinergic effects can synergize with TCAs to produce anticholinergic toxicity, including antihistamines, antiparkinsonians, low-potency antipsy- chotics, over-the-counter sleeping pills, and antispasmodics or antidiarrheals. Conversely, TCAs such as clomipramine can potentiate the effects of warfarin or block the effects of guanethidine. SSRIs can participate in drug interactions as a conse- quence of effects on the hepatic cytochrome P-450 system (96–98). As each SSRI is metabolized by one or more isoen- zymes of cytochrome P-450, they may either inhibit or in- duce the corresponding enzymatic activity, thereby affecting the metabolism of other drugs. Conversely, other medica- tions can inhibit or induce the P-450 system, thereby modu- lating the metabolism of SRIs. There is tremendous individ- ual variation in P-450 effects. In addition, because SSRIs are highly protein-bound, this can lead to drug interactions
Chapter 114: Current and Experimental Therapeutics of OCD 1653
showed steady improvement throughout the study; no dif- ferences were observed between the groups for any efficacy variable at any time and both clomipramine and fluvoxa- mine were equally effective in reducing OCD symptoms; they displayed differences in the profiles but not severity of the side effects.
LONG-TERM TREATMENT AND
DISCONTINUATION
OCD is a chronic disorder; therefore, long-term treatment is often required. Although this research has methodologic limitations, data on long-term SSRI treatment (fluoxetine, sertraline, and paroxetine) suggests that efficacy is main- tained and sometimes increases over time. Still more infor- mation is needed on the long-term efficacy and safety of SRIs in OCD treatment. SRIs have been proved effective in the acute treatment of OCD; double-blind substitution trials with clomipramine have shown that symptoms fre- quently recur after discontinuation of treatment (108,109). A retrospective follow-up study of 85 patients with OCD reported that most of the patients treated with SSRIs for 1 to 3 years had maintained or increased symptom improvement (110). Two double-blind and/or placebo-controlled long- term SSRI continuation studies have reported continued efficacy and tolerability (74,75). Although valuable, these studies had no effective control group for the maintenance phase: Because only responders to an acute trial continued into long-term maintenance, there were only a handful of placebo patients in maintenance and there was no other control group. To date, no long-term, double-blind substi- tution trials have been published. An open-label discontin- uation trial (111) followed 130 responders to 6 months of acute treatment with an SRI: clomipramine, fluoxetine, or fluvoxamine. This occurred for 2 years of treatment (or until they experienced a recurrence) with the same medication at the same dose, the same medication at half the dose, or no treatment. The study showed a superior therapeutic effect for both medication conditions compared to discontinua- tion of pharmacotherapy. One controlled, long term, dou- ble-blind substitution trial (71) has shown that paroxetine is superior to placebo in preventing OCD relapse during a 6-month discontinuation trial (which followed 12 weeks of acute treatment in a double-blind placebo-controlled pa- roxetine dose finding trial and 6 months of open-label pa- roxetine treatment). In addition, treatment effects appeared to be sustained and may have even increased over the time of the trial. In addition, following the double-blind discon- tinuation phase, subjects switched to placebo had a signifi- cantly greater rate of relapse, and time to relapse was signifi- cantly shorter on placebo versus paroxetine (71). One study suggested that long-term maintenance therapy might be provided with lower dosages of antiobsessional drugs, with a clear advantage for tolerability and compliance (112).
SRI S IN CHILDHOOD AND ADOLESCENT
OCD
The clinical presentation of OCD in children and adoles- cents resembles that observed in adults (113). There has been increasing awareness of the frequency with which chil- dren and adolescents suffer from OCD (114). Clomipra- mine has been well studied in the treatment of OCD in this population. An 8-week multicenter double-blind study (115) found clomipramine to be effective and superior to placebo (mean Y-BOCS scores decreased by 37% versus 8%). These findings led to FDA approval of clomipramine for the treatment of OCD in children and adolescents. The side-effect profile in this sample included anticholinergic, antihistaminic, and -adrenergic effects such as dry mouth, tremor, sedation, dizziness, sweating, and insomnia. No se- rious adverse events were reported; however, some patients were withdrawn owing to hepatic enzyme elevations and cardiac palpitations. Electrocardiographic monitoring should be undertaken because tricyclic antidepressants have the potential for being cardiotoxic (116). Fluvoxamine is an FDA-approved SSRI for the treatment of pediatric OCD. In an 8-week open-label trial of fluvoxa- mine with adolescents (100 to 300 mg per day), the majority of patients showed significant improvement in their OCD symptomatology (117). The side-effect profile was similar to that reported in adults, including hyperactivity, anxiety, sedation, dizziness, headache, tremor, and nausea. A large ( N 120) double-blind placebo-controlled 10-week study of fluvoxamine (50 to 200 mg per day) with children and adolescents (ages 8 to 17) found the drug to be significantly superior to placebo (118). Side effects were described as mild; those that were more commonly reported in the flu- voxamine group included insomnia, agitation, hyperactiv- ity, somnolence, and dyspepsia. There have been four small prospective studies investigat- ing the efficacy of fluoxetine in pediatric OCD. Three of these were open design (119–121). Riddle and co-workers (122) conducted a double-blind crossover trial of fluoxetine ( N 14; mean age 11.8; 20 mg per day, fixed daily dosing) and reported it to be superior to placebo as measured by CGI scores for global improvement. The most commonly reported adverse effects included insomnia, motor activa- tion, fatigue, and nausea. In general, the side effects were reasonably well tolerated and did not result in withdrawal from the study, except for a 13-year-old boy who developed suicidal ideation in the third week of fluoxetine treatment. There were no significant changes in laboratory studies, EKG, weight, pulse, or blood pressure. Major limitations of the study were the small sample size and the fixed dosage. In a retrospective chart review by Geller and colleagues (123), fluoxetine led to moderate to marked improvement in OCD symptoms in 74% of patients ( N 38); mean age 12.3). Relatively high doses of the drug were required, on average 50 mg per day (1.0 mg/kg per day). Long-term
1654 Neuropsychopharmacology: The Fifth Generation of Progress
TABLE 114.2. CONTROLLED TRIALS OF SEROTONIN REUPTAKE INHIBITOR THERAPY FOR OBSESSIVE-COMPULSIVE DISORDER IN CHILDREN AND ADOLESCENTS
Study (Ref.) Conditions Results
Flament et al., 1985 (125) CMI vs placebo CMI superior to placebo Devaugh-Geiss et al., 1992 (115) CMI vs placebo 37% decrease Sx on CMI 8% decrease Sx on placebo Rapoport et al., 1980 (126) CMI vs DMI vs placebo No differences Leonard et al., 1988 (127) CMI vs DMI CMI superior to DMI Leonard et al., 1991 (109) CMI substituted with DMI in 50% 18% on CMI relapsed Riddle et al., 1992 (122) Fluoxetine vs placebo Fluoxetine superior to placebo March et al., 1998 (124) Sertraline vs placebo Sertraline marked improved 42% vs 26% placebo Riddle et al., 2001 (124a)
efficacy was sustained over the follow-up period of, on aver- age, 19 months. Fluoxetine was generally well tolerated and adverse effects were less marked than those associated with clomipramine. Despite this apparent tolerability of high doses, it has been recommended that, for children, an appro- priate starting dose of fluoxetine is 10 mg per day or less (122). The FDA has also approved sertraline for the treatment of child and adolescent OCD, which has been shown to be safe and effective in this population (124). In a randomized, double- blind, placebo-controlled trial, 107 children aged 6 to 12 years and 80 adolescents aged 13 to 17 years were randomized to receive either sertraline titrated to a maxi- mum of 200 mg per day (53 children, 39 adolescent) or placebo (54 children, 41 adolescents). After 12 weeks, 42% of the patients receiving sertraline and 26% of those receiv- ing placebo were very much or much improved on CGI ratings. The incidence of side effects was similar to that reported in adults; sertraline appears to be a safe and effec- tive antiobsessional agent in children and adolescents. In an open-label trial, the adverse effects and potential clinical efficacy of citalopram (10 to 40 mg) were examined in 23 children and adolescents (aged 9 to 18 years). After 10 weeks, over 75% of these youths showed a moderate or marked improvement and adverse effects appeared to be minor and transient, suggesting that citalopram might be well tolerated in children and adolescents (Table 114.2) (128). Recent reviews on the treatment of children and adoles- cents with OCD suggest that adjunctive interventions in- cluding parent case management education and specific cog- nitive-behavioral should be considered in the majority of cases.
BEHAVIOR THERAPY AND
PHARMACOTHERAPY
Prolonged exposure coupled with response prevention is a key element of behavior therapy for OCD. Exposure in-
volves prolonged confrontation with stimuli that provoke obsessional thoughts or compulsive behaviors. Patients agree not to engage in their usual ritualistic behavior or cognitions and to remain in the situation until their discom- fort wanes. Homework is generally prescribed outside the therapist contact. Success rates vary from 50% to 80% (129). Some studies suggest that up to 90% of patients have achieved clinically significant benefits from behavior therapy (130). Generally, 70% to 80% of these patients maintain their acute gains at 1-year follow-up (131). Intensive behavior therapy over 3 weeks has produced promising results, even in a very symptomatic group. Foa and colleagues (132) reported that 51% of patients experi- ence at least a 70% drop in symptoms, with 35% experienc- ing a 31% to 69% reduction. These gains are generally (75%) maintained at 12-month follow-up. It is often diffi- cult to arrange such extensive exposure in an outpatient setting, however. Recent results in one trial suggest that providing this treatment in a group setting may be effective and cost effective (133). Relapse prevention programs have proved beneficial in maintaining the gains of acute treat- ment (134).
Comparisons A metaanalysis comparing behavioral treatments and SSRIs in OCD involved 77 studies in 4,641 patients. Effect sizes for behavior therapy were not significantly different from those of the SSRIs. There were also no significant differences between the SSRIs, although CMI appeared to have some increased efficacy but not sufficient enough to warrant fa- voring it over other SSRIs given its side-effect spectrum and the dangers associated with overdose (135). The choice between these two modalities is often dominated by the relatively limited availability of behavioral therapists and by patient preference. Up to 25% of individuals refuse behav- ioral therapy, whereas others prefer a nonpharmacologic treatment. A computer program offering behavior therapy via 12 computer-controlled interactive phone calls was found effective in over two-thirds of the patients (136).
1656 Neuropsychopharmacology: The Fifth Generation of Progress
Clonazepam
Clonazepam, a benzodiazepine with unique serotonin prop- erties, has been efficacious in augmentation to SRIs in the patients with OCD in case series (154) and in a double- blind, controlled augmentation trial with fluoxetine or clomipramine (155).
Trazodone
Trazodone, a 5-HT2 and -adrenergic blocker with weak 5-HT reuptake properties, which has m -CPP as a minor metabolite, was recently reported effective in augmentation to various SRIs in five cases of refractory OCD (156).
Pindolol
Pindolol is a -adrenergic blocker with 5-HT1B and 5- HT1A receptor antagonist activity. Recent reports indicate that adjunctive pindolol may shorten the latency to antide- pressant response to SRIs (157); however, data in OCD patients are mixed. One study of pindolol augmentation to paroxetine in resistant OCD resulted in mild improvement (158), whereas another report found that pindolol did not shorten the latency of fluvoxamine antiobsessional response (159). Thus, the utility of pindolol in non-depressed OCD patients is in doubt.
Dopaminergic Agents
The dopamine system has also been implicated in the patho- physiology of OCD; therefore, it is potentially useful in augmentation studies. Dopamine antagonist/SRI combina- tions have been reported to be effective in OCD.
Haloperidol
In a double-blind, placebo-controlled study of OCD pa- tients on fluvoxamine monotherapy, haloperidol augmenta- tion was found to be significantly more effective than that of placebo, and 100% of patients with a concurrent chronic tic disorder (8/8) responded to ongoing fluvoxamine-halo- peridol treatment (160).
Pimozide
Open case series have shown the effectiveness of pimozide/ SRI combinations in OCD patients with and without com- orbid tic-related disorders (161).
Risperidone
In an open trial of risperidone/SRI combination treatment, 87% (14/16) of patients with refractory OCD had substan- tial reduction in OC symptoms (162). In another open trial,
after the addition of risperidone, seven out of 14 patients had clinical improvement after failing to respond to SSRI treatment alone (163). Other cases of risperidone augmenta- tion reported effectiveness in reducing OC symptoms in patients who had failed SRI trials (164,165). A chart review, including eight OCD patients treated with the combination of an SRI and risperidone, reported three (37.5%) patients much or very much improved in OCD symptoms (166).
Olanzapine Case series (167,168) and open-label trials (169) have re- ported benefits of adding titrated doses of olanzapine ( or 15 mg per day) to an SSRI in refractory OCD patients. Thus, olanzapine might also be considered in the augmenta- tion of severe forms of OCD, although careful monitoring of the potential interaction with SSRIs is suggested because this combination may produce idiosyncratic effect on plasma levels.
GABA/Second Messenger Systems Gabapentin, a -aminobutyric acid (GABA) analogue, was reported to improve OC symptoms in 5/5 partial responders in a 6-week pilot study of fluoxetine augmentation within 2 weeks of treatment (170). In an open-label augmentation trial of SRIs with inositol, a precursor in the phosphatidyl- inositol cycle, 3/10 refractory OCD patients reported clini- cally significant responses on the CGI improvement scale (171); therefore, agents affecting other neurotransmitter or second messenger systems may play a role in augmentation strategies.
NOVEL PHARMACOTHERAPIES
Some individuals with OCD remain refractory even to aug- mentation strategies. For them, alternate pharmacotherapy may provide relief.
Intravenous Clomipramine Intravenous clomipramine was first reported successful in treating obsessive symptoms in 1967 (46). A review of the literature found over 100 cases of successful treatment with intravenous clomipramine (172). In a double-blind, pla- cebo-controlled trial of intravenous versus oral pulse loading of clomipramine in 15 OCD patients, six of seven patients treated with intravenous clomipramine were responders compared to one of eight patients with oral clomipramine (4.5 days after pulse loading), suggesting greater immediate improvement with intravenous pulses (173). This may be owing to avoidance of the first-pass liver metabolism of clomipramine, resulting in a greater clomipramine/des- methyl clomipramine ratio, more potent central 5-HT ef-
Chapter 114: Current and Experimental Therapeutics of OCD 1657
fects, and fewer side effects. The superiority of the intrave- nous route compared to the oral one has been reported in a placebo-controlled study (174). After 1 month of intrave- nous clomipramine (doses up to 250 mg per day) 58% of 21 patient nonresponders to oral administration randomized to receive intravenous clomipramine showed a marked clinical improvement rated by both CGI and Y-BOCS, without serious adverse events.
Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs), which block the catabolism of serotonin as well as norepinephrine and dopa- mine, have been reported successful for refractory OCD in some but not all studies. Case reports of successful treatment are available for iproniazid (175) and most substantially for phenelzine, which was one of the first pharmacologic agents tried for OCD. These reports primarily combined phenel- zine with other medications (176–178). However, in a 10- week placebo-controlled comparison trial of fluoxetine ver- sus phenelzine in 54 patients with OCD, patients treated with fluoxetine significantly improved more than those in the phenelzine or placebo groups, except for a subgroup of patients with symmetry obsessions who responded to phe- nelzine (179).
Serotonergic Agents
Buspirone monotherapy was reported to be ineffective in an 8-week open trial of 14 OCD patients (180) and Hewlett’s survey found seven reported successes and 21 reported fail- ures (172). Trazodone has been found successful in both cases and open trials of comorbid depression with OCD (181–183); however, it was found ineffective in reducing OC symptoms in a double-blind, placebo-controlled trial (184). The first treatment response to tryptophan was de- scribed in seven patients with OCD (185), with no further controlled studies. The role of other serotonergic agents in treating OCD including 5-HT3 agonists (ondansetron) and 5-HT2 agonists requires further research.
Noradrenergic Agents
The noradrenergic system has also been explored as a novel individual pharmacotherapy in OCD. A case report of clon- idine, an 2-agonist, documented improvement in OCD (186). Intravenous clonidine was reported to markedly re- duce obsessions in six OCD patients (187). However, in a double-blind controlled crossover trial of clomipramine, clonazepam, and clonidine in 28 OCD patients, clonidine was found ineffective in reducing OCD symptoms (188).
Stimulants and Dopamine Releasers
Although most attention has focused on the blockade of dopaminergic receptors in OCD, there are also reports that
agents that release dopamine and dopamine receptor ago- nists may also have efficacy in OCD. Insel and associates (189) reported that two patients treated with amphetamines (10 to 20 mg) achieved a ‘‘persistent benefit’’ for a period of several weeks. He reported an additional two patients treated with ‘‘low-dose’’ amphetamines for several months who reported a decrease in obsessional symptoms. Ceccher- ini-Nelli and Guazzelli (190) described three cases of OCD with concurrent depression responding to the dopaminergic agonist bromocriptine (15 to 30 mg). These reports must be reconciled with reports that chronic administration of methylphenidate and amphetamine may induce ritualized behaviors and other OCD-like symptoms (191,192). There are seven cases of reported improvement and one reported failure on chronic dopaminergic agonists. In a sur- vey by Hewlett (172), five of 28 subjects (19%) achieved a good response with chronic amphetamine. Neither of these two patients treated with bromocriptine had any im- provement. Bupropion, which inhibits dopaminergic reup- take, was associated with 15 failed treatments. The OCD-like behaviors induced by chronic amphet- amine may represent stereotypies, or complex tics, rather than compulsions that are performed to reduce anxiety. Clomipramine is a potent inhibitor of dopamine uptake and is antiobsessional. Conceivably, the response to low- dose neuroleptics in OCD may stem from their effects on blocking presynaptic dopamine D2 receptors, increasing dopamine release (190).
Benzodiazepines Case reports of clonazepam have also shown its efficacy (172,193). In a double-blind crossover trial, 40% of the patients who had failed clomipramine treatment had clini- cally significant responses to clonazepam treatment, and clo- nazepam was significantly more effective than clomipramine during the first 3 weeks of treatment (188). However, a double-blind multicenter placebo-controlled trial of clona- zepam demonstrated no efficacy (194). Other benzodiaze- pines, such as alprazolam, have also not shown efficacy in treating OCD (195).
Anticonvulsants There are three case reports of significant response to non- benzodiazepine-related anticonvulsants (two of whom had clinical epilepsy) all with carbamazepine, and 23 treatment failures (172). Two patients with OCD and clinical epilepsy responded to clonazepam treatment (196); however, clinical experience with anticonvulsants may be more positive. Two of 12 patients (17%) at two sites had successful trials of carbamazepine, and six of 26 patients (23%) at three sites had positive outcomes with sodium valproate (172).
Chapter 114: Current and Experimental Therapeutics of OCD 1659
course of illness, comorbidity, family history, neurobiology, and treatment response (selective efficacy of SSRIs) (25). Three key clusters of disorders have been identified: (a) disorders with preoccupation with body image, body weight, or body sensations; (b) impulsive disorders in which repetitive behaviors are driven by pleasure; and (c) neurolog- ically based disorders with repetitive behaviors. Clusters 2 and 3 are dealt with elsewhere in the volume. Here we focus on one disorder from the first cluster where there exist double-blind controlled pharmacologic data. Body dysmorphic disorder (BDD), the distress of imag- ined ugliness, is a somatoform disorder in which patients are obsessed with an imagined imperfection or deformity in their appearance, and repeatedly check their appearance in mirrors or engage in cosmetic surgery to change their appearance. There is often poor insight or delusional convic- tion, and secondary depression and social phobia. A recent double-blind crossover trial compared the SRI clomipramine to the noradrenergic reuptake inhibitor desi- pramine (DMI) (8 weeks of each phase) in 40 BDD patients (211). Desipramine, the active control, was chosen to con- trol for nonspecific antidepressant and antidepressants, and because it has a similar side-effect profile to CMI, enhancing the blind. The SRI CMI resulted in significantly greater improvement in all primary outcome measures of BDD severity than did DMI, and also improved measures of func- tional impairment to a significantly greater extent than did DMI. Subjects with delusional conviction regarding body defect improved on CMI but not DMI, and severity of delusional conviction improved with CMI. Thus, BDD, like OCD, but in contrast to other mood or anxiety disor- ders, demonstrates a selective efficacy to SRIs, but not to NRI treatment. The delusional conviction in BDD appears secondary to obsessive preoccupation, and also responds to SRI treatment.
CONCLUSION
In summary, SSRIs and the tricyclic antidepressant clomi- pramine are currently the first-line treatment for OCD, with the SSRIs’ side-effect profile being more favorable than that of clomipramine. However, 40% to 60% of patients with OCD may not respond to an adequate treatment trial of an SRI. Furthermore, not all patients tolerate SSRIs, and there is often a time delay in seeing a full therapeutic re- sponse. Thus, other pharmacologic approaches to treating OCD have been investigated, and certainly combinations of pharmacotherapy and cognitive behavioral therapy are considered the treatment of choice. Augmentation and novel monotherapy strategies have been explored in refrac- tory patients, with serotonergic enhancers, dopamine/sero- tonin antagonists, enhancers of second messenger systems, and GABAergic agents, with varying efficacy. Recently, im-
munomodulatory and invasive procedures have been ex- plored as well, but require further study.
ACKNOWLEDGMENTS
The authors acknowledge the support of the PBO Founda- tion. Dr. Hollander has received research support and/or served as a consultant or on a speaker’s bureau for the fol- lowing companies: Solvay, Abbott, SmithKline Beecham, Lilly, Wyeth-Ayerst, and Bristol Myers Squibb.
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