Obsessive Compulsive Disorder Pharmacotherapy

Original Author: Vicki Ellingrod, Pharm.D., BCPP
Latest Reviser: Vicki Ellingrod, Pharm.D., BCPP and Janice Worsham
Creation Date: 1996
Last Revision Date: June 2005
Peer Review Status: Internally Peer Reviewed

Obsessive Compulsive Disorder (OCD) is a chronic and sometimes crippling illness that affects 2% to 3% of all Americans sometime during their lifetimes (Karno et al 1988).  This prevalence rate indicates that OCD is more common than schizophrenia or panic.   The annual prevalence rate of OCD ranges from 1.1 to 1.8 patients in 100 (Weissman et al 1994).  Typically, patients with OCD have recurrent obtrusive thoughts (obsessions) which often lead to repetitive behaviors (compulsions) that the person feels compelled to perform.  These patients realize that their thoughts and actions are irrational or excessive, but are unable to prevent or contain their actions.   The Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) classifies OCD as an anxiety disorder since the recurrent obsession and compulsions that make up this illness can be severe enough to be time-consuming, cause marked distress or significant impairment (American Psychiatric Association 1994).  Currently there are over 500 clinical features of obsessive compulsives.  Common obsessions include contamination, pathological doubt, aggressive, sexual, somatic, and the need for symmetry and precision, and common compulsions include rituals for checking, cleaning and counting.

As mentioned previously, OCD is a disease constituted by the presence of obsessions, compulsions, or both.  The obsessions and compulsions are often described as “ego-dystonic” since patients often find them alien, uncontrollable, and unexpected (American Psychiatric Press 1994).  In 1992 Rasmussen and Eisen studied over 500 patients with OCD and characterized the most common clinical features.  These researchers found that the most common obsessions were contamination (50%), pathologic doubt (42%), somatic (33%), need for symmetry (32%), aggressive (31%), sexual (24%), and multiple obsessions (72%).  The most common compulsions were checking (61%), washing (50%), counting (36%), need to ask/confess (34%), symmetry and precision (28%), hoarding (18%), and multiple compulsions (58%).  Some of the common symptoms looked for when screening for OCD are an unusual preoccupation with hygiene, cleanliness, safety, or symmetry or irrational fears concerning germs, life-threatening or sexually transmitted diseases, scarring or hair loss.  Along with these, some of the common physical signs include frequent scrubbing, hair pulling, nail picking, rash on hands, knees, ankle or elbow, gum lacerations from excessive tooth brushing, or chapped hands from excessive washing (Rapoport 1988, Koblenzer 1992).

In a study by Rasmussen and Eisen (1992) the mean age of onset for OCD was 20.9 ± 9.8.   For males this age is 19.5 ± 9.2 and for females, the occurrence of OCD is later at 22.0 ± 9.8 (p<0.003).  Sixty-five percent of patients will develop their symptomatology before the age of 25, and the majority of patients with OCD remember having milder symptoms that did not cause undo stress for years before they develop OCD.  Looking historically at these milder symptoms, many were found to satisfy DSM-III-R criteria for OCD.   The average age of onset for these milder symptoms is 13.4 ± 7.6 with no statistically significant difference between genders (Rasmussen and Eisen 1992).  OCD in general is a relatively chronic disorder that develops quickly (i.e. in less than 30 days) for many patients.  The symptoms of the disease often fluctuate in severity and intensity for many years with an increase in symptomatology during stressful situations and times of depressed mood.  Approximately 10% of patients with OCD have a progressive and deteriorating course.  Rarely does a patient experience periods of remission (Rasmussen and Eisen 1992).  In those patients with a first degree biological relative that has OCD or Tourette’s Disorder, the risk of OCD is higher than the general population’s.  The concordance rate of OCD is also higher for monozygotic twins than it is for dizygotic twins which suggest that there is a genetic component to this disease (American Psychiatric Association 1994).

The psychiatric co-morbidity associated with OCD is high.  The primary Axis I diagnoses often associated with OCD are Major Depressive Disorder, Anxiety Disorders (e.g., Specific Phobia, Panic Disorder, Social Phobia), Eating Disorders, and Obsessive-Compulsive Personality Disorder or those personality disorders in the Cluster C category (Black et al 1993).  In the study by Rasmussen and Eisen (1992), two thirds of the patients examined had experienced a Major Depression sometime in their lives.  Eight-five percent of these patients had a secondary depression due to the OCD and 15% had a concurrent depression.  It is estimated that approximately 35-50% of patients with Tourette’s Syndrome also suffer from OCD and 5-7% of OCD patients also have Tourette’s, although between 20-30% of these patients have reported current or past tics (American Psychiatric Association 1994).  

The true pathophysiology of OCD is unknown at this time, but many theories have surfaced which are based on what we know has been effective to treat this disease and our knowledge of how these medications work.  The role of serotonin (5HT) has been highly questioned and investigated.  Since medications that are serotonin reuptake inhibitors have been shown to be effective in OCD, it is believed that changes in 5HT function are critical for the treatment of this disease, and perhaps also play a role in the pathophysiology of the disease.   The role of serotonin in OCD has been demonstrated in studies using serotonin agonists and antagonists.  M-CPP is a 5-HT 1C receptor agonist that also bind to 5-HT2, 5-HT1A, and 5-HT1B receptors.  Administering this compound causes acute exacerbations of OCD symptoms, while fenfluramine, which is a 5-HT presynaptic agonist, does not exacerbate symptoms (Chouinard 1992). 

In 1997 the results of the Expert Consensus Panel for Obsessive Compulsive Disorder was published as a supplement to the Journal of Clinical Psychiatry.  As a part of this panel 79 physicians, who were considered ‘experts’ in the field of OCD treatment, were asked to complete a survey.  Their responses were then tallied and used to design clinical treatment guidelines.  As part of these guidelines an algorithm for the treatment of OCD in the acute phase was designed.  This algorithm concluded that for more severe OCD the treatment of choice in the adult population is either cognitive behavioral therapy (CBT) plus a serotonin reuptake inhibitor (SRI) or an SRI alone.  For adolescents and children the therapy of choice is CBT with the addition of an SRI if the patient desires.  Despite the use of the SRIs for the treatment of OCD, only 40-60% of patients become clinically improved with adequate medication trials.  Often times, even the patients that do respond to medication are not completely symptom free.  The following is a summary of the clinical studies that have been done investigating the use of medication for the treatment of OCD.  Of the SRIs that are mentioned all but two, venlafaxine and citalopram , have been approved by the Food and Drug Administration (FDA) for the treatment of OCD.

SEROTONIN REUPTAKE INHIBITORS

CLOMIPRAMINE

Clomipramine (CMI) was the first medication approved by the FDA for the treatment of OCD.  Structurally, it differs from the other SRIs in that it is a tricyclic antidepressant (TCA) and thus has many of the side effects associated with tricyclic use.  It also caries with it the same risks as other TCAs do in an overdose situation.  Although CMI is considered the ‘gold standard’ for the treatment of OCD its use has declined as newer medications with less side effects and lower lethality in an overdose have been approved.

CMI has been studied in at least 21 different controlled trials for the treatment of OCD.  In 8 of these trials CMI was tested against placebo alone while in the remainder CMI was tested against other medications such as the SRIs, the TCAs, clonazepam and diphenhydramine.  The majority of these studies are summarized in Table One. 

Placebo Controlled Trials

In the 8 placebo controlled trials that have been done, CMI was found to be more effective than placebo in all of them.  The assessment scales most commonly used include the Yale-Brown Obsessive Compulsive Scale (YBOCS), the Obsessive-Compulsive Neurotic Scale (OCNS), the Obsessive-Compulsive Rating Scale (OCRS), the Comprehensive Psychopathological Rating Scale (CPRS), the National Institute of Mental Health Global Scale (NIMH-OC), and the NIMH Self-rating scale.  Additionally the degree of depression present was assessed using the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI).  The Clinical Global Impressions scale has also been used and oftentimes is used to define response as a score of 1 or 2 on the scale. 

When CMI was first being tested in the treatment of OCD several authors hypothesized that the effect seen with the drug was due to its antidepressant effect and not due to a separate antiobsessional effect.  This was found not be true in a study published by Mavissakalian et al in 1985.  This trial was part of the Ciba-Geigy: “Anafranil: Efficacy and Tolerability Study in Obsessive-Compulsive Disorder - Protocol 55” and consisted of 16 outpatients meeting DSM-III Criteria for OCD.  The mean dose of CMI used in the subjects was 228.5 mg/day.  Response was assessed by the Obsessive-Compulsive Neurotic Scale (OCNS), clinician rated 5-point scales and the HAMD.  Of the 16 patients that started the trial, 12 completed the 12 week trial.  At the endpoint of this study 2/7 (43%) of the CMI patients and 0/5 placebo patients were considered responders, although the exact response criteria was not given in the paper.  From this the authors concluded that CMI is more effective than placebo in the treatment of OCD.  These authors also noted that the patients in the placebo group had a reduction in HAMD score, but not in OCNS.  This suggested that changes in OCD and depression can occur independently from each other. 

The largest CMI versus placebo trial to be published was conducted by The Clomipramine Collaborative Study Group (1991).  This was a multi-center trial that evaluated the efficacy, safety, and tolerability of CMI in 520 patients with OCD (DSM-III) for 10 weeks.    The two principle measures used to assess severity of the disorder were the YBOCS (p< 0.001) and the NIMH-OC (p< 0.001).  CMI was more effective than placebo on both of these measures.  The mean reduction in YBOCS scores at the end of 10 weeks was between 38% and 44% for the CMI patients and was 3% to 5% for the placebo patients.  The mean CMI dosage used was between 218.8 - 234.5 mg/day.  Ninety-eight percent of the CMI treated patients reported experiencing a side effect from the medication.  The majority of these were side effects commonly attributed to TCA use (i.e. dry mouth, dizziness, tremor, fatigue, somnolence, constipation, etc.).  Overall this trial confirmed the results of previous smaller trails in which CMI was shown more effective than placebo in reducing the symptoms of OCD. 

Comparator Studies

The first comparator trial for CMI was conducted by Thoren et al (1980). In this study 24 patients with OCD (RDC criteria) were randomized to either CMI, nortriptyline, or placebo for 5 weeks.  The maximum dose of each was 150 mg/day.  The rating scales used to measure OCD symptoms were the CPRS, LOI, Home Incapacity Scale-Ward Incapacity Scale (HIS-WIS), and Individual Self-rating scale (ISS).  Depression was assessed using the Montgomery-Asberg Depression Scale (MADRS).  At the end of the 5 weeks of treatment, there was a 42% mean reduction in OCD scale scores in the CMI group, a 21% reduction in the nortriptyline group, and a 7% reduction in the placebo group.  The only significant differences seen were between CMI and placebo.  These differences were only seen on the OCD scale (p< 0.05) and not with the LOI, HIS-WIS or ISS.  Additionally CMI was superior to placebo on the MADRS.  The effects of CMI over placebo were not seen until 5 weeks of treatment. 

The second medication that has been compared to CMI is amitriptyline.  In a study by Ananth et al (1981), 20 patients with chronic obsessive compulsive neurosis were randomized to receive either CMI or amitriptyline for 4 weeks at a max dose of 300 mg/day.  The rating scales used were the Psychiatric Questionnaire for OCN and Clinical Global Impressions Scale (CGI). Improvement in the Psychiatric Questionnaire for OCN for the obsessive symptoms and symptom severity was seen only in the CMI group versus the baseline scores (p= 0.05), but overall there were no significant differences in the performance of either group. 

In another comparator trial the efficacy of CMI has been tested against clorgyline, a monoamine oxidase inhibitor available in Europe (Insel et al (1983)).  In this study 13 patients with OCD (DSM-III criteria) were entered into a cross over trial consisting of a 4 week placebo washout followed by 6 weeks of drug with a 4 week placebo washout, and an additional 6 weeks of the comparator drug.  The maximum dose of clorgyline allowed was 30 m/day and the maximum dose of CMI was 300 mg/day.  OCD symptomatology was rated by clinicians using the CPRS, the OCRS, the NIMH-OC,  and the HAMD.  The Patient-rated scales used were the  LOI, the Profile of Mood States, and Compulsion Checklist, the BDI, and the NIMH-side effect questionnaire.  A total of 10 patients completed both sections of the cross over design.  In these patients improvement with CMI was greater than that with clorgyline as assessed by the CPRS and the OCRS (p < 0.05). 

CMI has also been compared to imipramine in a trial published by Volavka et al (1985).  In this study 23 outpatients with OCD (DSM-III criteria) were randomized to receive either CMI or imipramine for 12 weeks at a max dose of 300 mg/day. Assessments were done with the Self-Rating Obsessive-Compulsive Personality Inventory (SROCPI), the Self-Rated Obsessional Neurotic Scale (SRONS), the OCRS, the HAMD and the Global Evaluation of Efficacy (GEE).  Of the 23 subjects that started the trial only 16 completed it.  At week 12 CMI was found to be superior over imipramine as assessed by the GEE and HAMD (p< 0.05).  For all other measures CMI showed a non-significant advantage over imipramine.  When patients were grouped according to the categories “somewhat improved”, “much improved” and “unchanged”, the CMI group showed more improvement on obsessive thoughts (p = 0.039) while the compulsive behavior and interference scores showed no significant differences between the two medications.  The authors of this publication noted several limitations of this study.  First the statistical analysis was only done on those subjects completing the study and thus does not include the patients that dropped out due to lack of drug effect.  Secondly the randomization procedure used did not allow the treatment groups to be balanced at baseline since those in the imipramine treated group were sicker, as assessed by the SROCPI and SRONS, than those assigned to CMI.  Overall their conclusion is that CMI is somewhat superior to imipramine for the treatment of OCD and that this effect is independent of the initial severity of depression.

The next randomized double blind comparator trial was published by Zohar and Insel (1987).  In this trial 14 outpatients with OCD (DSM-III criteria) were randomized to receive CMI or desipramine for two 6 week crossover periods with a 4 week placebo washout period in-between.  Ratings of OCD symptoms were done weekly and consisted of the NIMH-Global Scale, CPRS-OC, and the HAMD.  Only 10 of the 14 patients completed both phases of the crossover.  The mean dose of CMI was 235 ± 76 mg/day and for desipramine was 290 ± 32 mg/day.  At weeks 4 and 6 CMI was found to be more effective than desipramine on the CPRS-OC (p< 0.05) and the NIMH-Global OC (p = 0.03).  Using the CPRS-OC the mean improvement during the 6 weeks for CMI was 28.4% ± 20.1% and for desipramine was 4.2% ± 11.4%.  The authors conclude that not all antidepressants have antiobsessional effects and that CMI’s effects may be distinctive in nature. 

The next study involves the treatment of children with OCD.  In this study by Leonard et al (1988), 21 children (mean [± S.D.] age, 13.7 ± 2.9 years) were randomly assigned to CMI or desipramine for two consecutive 5 weeks period at which time the treatments were crossed over.  The dose of the two medications was increased to 3m/kg maximum.  By week 3 of the study CMI was shown to be statistically superior to desipramine by the Global OCD scale (p = 0.002), the NIMH-OC (p = 0.004) and the global depression scales (p = 0.03).  There were some drug-by-order interaction for the global ratings of obsession.  When desipramine was given first the scores were not affected, but an increase in obsessive compulsive scores was seen when subjects relapsed from the CMI during the desipramine stage.  This relapse was usually seen 2 weeks after CMI was stopped. 

These same authors conducted a larger clinical double-blind crossover trial which was similar trial to the previous one  (Leonard et al 1989).  In this trial 48 children and adolescents with OCD (DSM-III criteria) were randomized to either CMI (mean dose [± S.D.], 150 ± 53 mg/day)  or desipramine (mean dose [± S.D.], 153 ± 55 mg/day) for two consecutive 5 week periods with no washout period.  The rating scales used were the LOI-CV, OCRS, CPRS, NIMH-Global OC, BPRS, and HAMD.  In comparing these rating scores at the end of each 5 week period, CMI was found to be superior over desipramine (p< 0.006) on all rating scales expect the LOI-CV.  A significant drug-by-order effect was also present and is similar to the one explained in the previous study (Leonard et al 1988). 

Pigott et al (1990) was the first to publish a trial comparing CMI to fluoxetine.  In this publication two different studies are reported.  In the first trial 11 patients with OCD (DSM-III-R criteria) were randomized to receive either CMI or fluoxetine for 10 weeks followed by a 4 week placebo washout and an additional 10 weeks of crossover medication.  Patients were rated for their OCD symptoms by using the YBOCS, the NIMH-OC and the HAMD.  The mean dose of CMI in the first trial was 209 ± 13 mg/day and fluoxetine 75 ± 4 mg/day.  At the end of each 10 week time period both medications were found to cause significant reductions in assessment scores compared to baseline for all 3 scales (p< 0.05) but no statistical differences between the two medications groups were found.  The mean (± s.d.) reductions in YBOCS score for the two groups were; CMI: -8.4 ± 1.67 and fluoxetine: -7.6 ± 1.84 and for the NIMH-OC were; CMI: -11.2 ± 2.06 and fluoxetine: -12.2 ± 1.37.  Patients reported more side effects during treatment with CMI than with fluoxetine (p< 0.05).  In the second trial, 21 patients with OCD (DSM-III-R criteria) who had previously been stable on CMI were crossed over to fluoxetine in a double-blind manner.  The rating scales that were used in the first trial were also used in the second.  After 6 weeks of fluoxetine treatment (80 mg/day), patients had statistically significant increases in OCD and HAMD scores over the CMI baseline but by week 10 the scores decreased and 85% of the patients had achieved YBOCS scores within 20% of their pre-crossover scores.  Thus the authors concluded that both CMI and fluoxetine are effective in the treatment of OCD, with fewer side effects being associated with fluoxetine treatment. 

The next controlled trial involving CMI was published by Pato et al (1991).  In this trial 18 outpatients with OCD (DSM-III-R criteria) were randomized to receive either CMI or buspirone for 6 weeks followed by a 4 week placebo washout and then a 6 week medication crossover period.  The rating scales used to assess efficacy were the YBOCS, the YBOCS-severity measure, YBOCS-global measure, the NIMH-OC, and the HAMD.  The mean doses of medications used was CMI 225 ± 49 mg/day and buspirone 58 ± 7 mg/day.  In order for a subject to be ‘improved’ a minimum of a 20% decrease in OCD scores needed to be obtained.  At the end of the first 6 week period both drugs were found to have significant reductions in scores compared to baseline for all assessments (p < 0.05).  Overall 67% of the CMI treated patients and 56% of the buspirone patients were considered ‘improved’.  Statistical analysis of the second 6 week period was not done due to detection of significant cross-over effects. 

CMI has also been compared to phenelzine in a study published by Vallejo et al (1992).  In this trial 30 outpatients with OCD (DSM-III criteria) were treated with either CMI or phenelzine for 12 weeks.  The maximum doses of the medications were 225 mg/day of CMI and 75 mg/day of phenelzine.  Many rating scales were used to assess efficacy and included the LOI, the Obsessive-Compulsive Interview Checklist (OCIC), the MOCI, the Vallejo Obsessional Personality Inventory (VOPI), the Global Evaluation Scale (GES), HAMD, Hamilton Rating Scale for Anxiety (HAMA), and others listed in table one.  Of the 30 patients that entered the trial, 26 completed it.  At the end of the 12 weeks both drugs caused a significant decrease (p< 0.05) in baseline scores on all rating except the LOI and the VPOI.  No differences between drugs were found although the scores in the CMI group were lower than those in the phenelzine group. 

The next controlled trial involving CMI was published by Hewlett et al (1992).  In this study 29 outpatients with OCD (DSM-III-R criteria) were randomly assigned to either CMI, clonazepam, clonidine or diphenhydramine for a 6 week crossover trial with a 2 week washout in-between.  Symptoms were assessed by using the YBOCS, HAMD and HAMA.  Clinical response was defined as a 25% or more decrease in YBOCS score.  The average doses of medication were; CMI 239 mg/day, clonazepam 6.85 mg/day, clonidine 0.83 mg/day and diphenhydramine 237 mg/day.  CMI and clonazepam were both more effective than the control medication, diphenhydramine, as assessed by the YBOCS scale (p< 0.05).  Diphenhydramine itself produced a significant reduction in YBOCS from baseline (p< 0.05) while clonidine slowly increased levels of depression and anxiety (p< 0.05) over baseline.  There was a significant cross-response between CMI and clonazepam in that 40% of patients that failed to respond to CMI, did respond to clonazepam.  Response rates for each medication are as follows: CMI 56%, clonazepam 60%, clonidine 23%, and diphenhydramine 27%.  Clonazepam was found to be more effective than the other treatments during the first three weeks of the trial.  Overall the authors concluded that CMI is effective in the treatment of OCD and that clonazepam may be another useful alternative for patients with this disorder.

Freeman et al (1994) published a study that compares CMI with fluvoxamine in a randomized, double-blind, multicenter study.  Sixty-six outpatients with OCD (DSM-III-R criteria) were given between 100- 250 mg/day of either CMI or fluvoxamine for 10 weeks.  The main efficacy variables were the YBOCS, the NIMH-Global OC scale, the CGI- Improvement scale and the HAMD.  A total of 64 patients were included in the intent to treat analysis since two were immediately lost to follow up and provided no drug data.  Of the 64 patients though, 17 dropped out prematurely.  No differences between the two drugs were found except for a longer obsession-free interval from the YBOCS scale in the fluvoxamine group (p= 0.026).  Both drugs were effective in reducing OCD scores with a mean reduction of 33% in the fluvoxamine group and 31% in the CMI group.  Overall each medication was shown to be effective for the treatment of OCD.  Adverse effects were mostly tolerable and an equal number of patents withdrew from each group due to ADRs; 5 in the fluvoxamine group and 4 in the CMI group.

Another CMI comparator trial was published by Koran et al (1995).  This trial is a comparison of fluvoxamine and CMI for the treatment of OCD (DSM-III-R) without co-existing or secondary depression.   After a 2 week placebo washout, patients were randomized to either drug for a total of 10 weeks.  Patients were evaluated using the YBOCS, NIMH-OC, CGI and HAMD.  Of the 79 patients that started the study, 56 completed it.  The mean dosage of each medication obtained was; CMI 201 mg/day and fluvoxamine 255 mg/day.  Responders were classified as patients that had a ≥ 25% decrease in YBOCS score from baseline.  Overall both groups were significantly changed over baseline with no differences being observed between groups.  The mean reduction in YBOCS score in the CMI group was 30% and in the fluvoxamine group was 30.2%.  At week 10, 56% of the fluvoxamine group and 54% of the CMI group were considered responders.  Forty-four percent of the fluvoxamine treated patients and 38% of CMI treated patients had ≥ a 35% decrease in YBOCS.  Side effects that occurred more frequently (p< 0.05) in the fluvoxamine group were dyspepsia (18.95 v. 2.4%), insomnia (35.1% v. 12.2%) and nervousness (32.4% v. 12.2%).  In the CMI group these were postural hypotension (22% v. 2.7%) and dry mouth (73.2% v. 18.9%).

The final comparator trials mentioned here was done by Albert et al (2002).  This was a randomized, single-blind trial of 73 patients treated with CMI or venlafaxine for 12 weeks.  Response to treatment was based on change in YBOCS and CGI scores from baseline. Responders were considered those with an improvement of ≥35% on the YBOCS and a CGI ≤ 2.  For those that completed the study, the average venlafaxine dose was 265 ± 52.5mg/day and the average CMI dose was 168.1 ± 28.9 mg/day.  One patient in the venlafaxine group and 7 in the CMI group dropped out of the study before it was completed.  The venlafaxine patient and 2 of the CMI patients dropped out because of ineffectiveness and the remaining 5 CMI patients because of adverse effects.  At the end of 12 weeks, patients in both treatment groups that completed the study showed a statistically significant improvement in YBOCS scores from baseline (p<0.001 for both treatments).  Also after 12 weeks 9/25 (36%) patients taking venlafaxine and 20/40 (50%) patients taking CMI were considered responders. Using the last observation carried forward, 9/26 (34.6%) and 20/47 (42.5%) of those taking venlafaxine and CMI, respectively, had responded.  The difference in effect between the two drugs was not statistically significant.  Also important is the fact that 61.5% and 91.5% of those taking venlafaxine and CMI, respectively, experienced some kind of adverse effect.  Statistically significant differences in adverse events occurred with the CMI and involved a higher incidence of constipation and reduced salivation.  This study suggests that venlafaxine may be as effective as CMI in the treatment of OCD and also result in fewer side effects than would treatment with CMI.

FLUOXETINE

Fluoxetine is another SRI that has been investigated for the treatment of OCD.  A total of 3 controlled trials have involved fluoxetine and only one of these trials has compared fluoxetine to another OCD treatment or medication (Pigott et al 1990). This trial was presented earlier under the CMI comparator trial section.

The most recent placebo controlled trial of fluoxetine was published by Tollefson et al (1994).  In this study a total of 355 outpatients with OCD (DSM-III-R criteria) were randomized to receive either placebo or a fixed dose of fluoxetine (20 mg, 40 mg, or 60 mg/day) for 13 weeks.  The YBOCS served as the primary assessment scale.  Other rating scales included HAMD, CGI-Severity and Improvement scale, the CPRS, and the Patient Global Impressions Scale (PGI).  Response was defined as at least a 35% improvement on the YBOCS total score from baseline to the next visit.  All three fluoxetine treated groups showed a significant improvement in YBOCS scores over placebo (p< 0.001) with a significant trend being observed with increasing doses of fluoxetine (p< 0.001).  More than half of the fluoxetine treated groups had an endpoint total YBOCS score of < 20.  Approximately 1 in 3 of the placebo patients had scores this low.  Response rates with fluoxetine and placebo are as follows; 20 mg (32.1%), 40 mg (32.4%), 60 mg ( 35.1%), and placebo (8.5%).  Discontinuation rates due to adverse effects ranged between 1.1% and 2.3%.  The most common side effects associated with fluoxetine use were nausea, dry mouth, and tremor (p< 0.01) with the incidence of these being lower in the 20 mg/day fluoxetine group. 

Placebo Controlled Trials

Fluvoxamine was the first non-TCA SRI to gain FDA approval for the treatment of OCD.  It has shown efficacy over placebo in 5 studies for OCD treatment the latest of which was published by Goodman et al (1996).  In this study 160 patients with OCD (DSM-III-R criteria) were randomized to receive either fluvoxamine or placebo for 10 weeks.  All patients also were required to have a HAMD scores ≤ 19 with a score of 2 or less for item 1 (depressed mood).  The main efficacy measures used were the YBOCS, the NIMH-OC, and the CGI.  Out of the 160 patients that were enrolled in the study 120 completed it, but a total of 156 are included in the endpoint analysis.  The mean dose of fluvoxamine used ranged between 215-245 mg/day from weeks 5-10.  Patients were considered responders if they attained a score of 1 (very much improved) or 2 (much improved) on the CGI.  Overall fluvoxamine was found to be more effective than placebo on all measures (p < 0.05) with these effects being seen at weeks 4 and 6.  At week 10, 43.4% of the fluvoxamine group were considered responders, while only 8.6% of those taking placebo were (p< 0.001).  Those that responded showed a substantial clinical benefit from the medication with decreases in the YBOCS score of 47% and NIMH score of 42.9%.  Non responders only experienced a 5.9% decrease in YBOCS score and a 2.5% decrease in NIMH score.  Adverse events were reported on at least 1 occasion for 95% of the fluvoxamine patients and 83.7% of the placebo patients.  Those ADRs that were more common in the fluvoxamine group include, insomnia (32.5% v. 18.8%), somnolence (31.3% v. 12.5%), asthenia (28.8% v. 11.3%), nausea (26.3% v. 10%), diarrhea (22.5% v. 10%), nervousness (18.8% v. 6.2%), abnormal ejaculation (17.5% v. 0%), anxiety (16.3% v. 7.5%), and constipation (16.3% v. 12.5%). 

Comparator Trials

Fluvoxamine has been studied in two controlled comparator trials.  The first is by Goodman et al (1990) and is detailed below.  The second was conducted by Freeman et al (1994) and was a controlled comparison between fluvoxamine and CMI.  The details of this trial are listed under the CMI comparator trial section above.

In a double blind controlled study by Goodman et al (1990) 40 outpatients with OCD (DSM-III-R criteria) were randomized to either fluvoxamine or desipramine for 8 weeks.  Approximately two thirds of each group were clinically depressed (HAMD>20). In addition to being randomized to an active treatment, patients also attended psychotherapy weekly, and were encouraged to resist their OCD symptomatology, but were not formally instructed in behavioral therapy.  Efficacy rating scales used included YBOCS and HAMD. The mean dose ± s.d. at the end of 8 weeks for fluvoxamine was 223 ± 48 mg/day and for desipramine was 214 ± 55 mg/day.  By week 3 YBOCS scores showed a significant decrease from baseline (P<0.02) in the fluvoxamine group and was significantly better than desipramine starting at week 7 (p<0.02).  By the end of 8 weeks, 11 of the 21 patients treated with fluvoxamine were considered responders compared with 2 of the 19 in the desipramine group (p<0.01).  No significant differences were found in regards to antidepressant efficacy of fluvoxamine or desipramine in the two groups.  Of note is that the response of OCD symptoms to fluvoxamine was not initially related to the initial severity of the depressive symptoms (r=-0.27, p=0.23), but changes in total YBOCS scores from baseline were significantly correlated with changes in HAMD from baseline at week 8 (r=0.51, p<0.02). Six of the desipramine group dropped out (4 due to clinical deterioration and two due to side effects), and two of the fluvoxamine patients dropped out due to clinical deterioration.  The most common side effects seen in the fluvoxamine group were daytime drowsiness, nausea, insomnia, headache, tremors and delayed orgasm. 

Paroxetine is the latest of the SRIs to be approved by the FDA for the treatment of OCD and the literature supporting this indication is relatively sparse.  Only one abstract (Wheadon et al 1993) has been cited in various review papers. The study by Wheadon et al (1993) was presented as an abstract at the American College of Neuropharmacology Meeting in Puerto Rico and thus is not readily available by doing a medline literature search.  In this study 348 outpatients with OCD (DSM-III-R criteria) were randomized to receive either placebo or a fixed dose of paroxetine 20 mg, 40 mg, or 60 mg for 12 weeks.  Assessments were done using the YBOCS, NIMH-OC, and CGI.  Eighty percent (280/348) of patients completed he study.  Both the 40 mg and the 60 mg paroxetine groups were shown to be statistically superior to placebo on the YBOCS (p< 0.017) at week 4 and NIMH-OC (p < 0.017) at week 3.  These two groups were also shown to be more effective than the 20 mg group at week 12 for the YBOCS (p< 0.017) and week 12 for the NIMH-OC (p< 0.017).  For the endpoint CGI Global improvement and severity of illness scale, both the 40 mg and the 60 mg groups were better than placebo (p< 0.017) while only the 60 mg group was better than the 20 mg on Global improvement (p< 0.017).  The authors of this poster concluded that paroxetine is safe and effective for the treatment of OCD.

Recently, a comparator study was published that assessed the effects of changing SRIs in nonresponsive patients taking paroxetine or venlafaxine (Denys et al 2004b).  This was a double-blind, 12 week study looking at 150 patients with primary OCD according to DSM-IV.  They were to receive up to 300 mg/day of venlafaxine or 60 mg/day of paroxetine.  Efficacy was assessed by using the YBOCS and nonresponse was considered <25% reduction in the scale.  In the first phase of the study patients received either drug, and at 12 weeks efficacy was assessed.  Those that did not respond were tapered off of their medication over 4 weeks and then received the alternate antidepressant for 12 weeks.  In the first phase, 63% of patients were considered responders and 37% (51 patients) were considered nonresponders.  In the second phase 43 patients were crossed over to the other SRI, where 16 received venlafaxine and 27 received paroxetine.  After cross-over the YBOCS scores decreased 1.8 ± 3.5 and 6.5 ± 7.1 in the venlafaxine and paroxetine groups respectively.  The decrease from baseline (week 16) was significant in the paroxetine group (p<0.000) but not in the venlafaxine group (p=0.065).  There was a significant difference between the two treatment groups that favored paroxetine (p=0.017).  Using ITT-LOCF and considering the combined, phase 1 and 2, venlafaxine and paroxetine trials throughout the study, there was a significant decrease in YBOCS scores in both groups (p<0.00) but there was no difference between the 2 groups (p=0.13).  There was a significant difference in the number of responders for paroxetine (65%) and venlafaxine (43%) (p=0.002).  Thus, after 2 consecutive treatments with SRIs, more than 70% of all the patients that began the study were considered responders.  This study also demonstrated that paroxetine is more efficacious in cases of non- or partial response and in general had a higher response rate than venlafaxine.  In this study over 40% of patients who were nonresponders found benefit from switching medications, supporting the idea often accepted in the clinical setting that when a patient is nonresponsive to one SRI, switching to another SRI is an effective strategy.

The efficacy of sertraline in the treatment of OCD has been investigated in several placebo-controlled, double-blind, multisite studies.  No comparator trials have been published.  The first of these studies was published by Chouinard et al (1990).  In this study 87 patients diagnosed with OCD (DSM-III criteria) without major depression were randomized to receive 8 weeks of either fluvoxamine (mean dose of 223 ± 48 mg/day) for desipramine (mean dose of 214 ± 55 mg/day).  By week 3 YBOCS scores showed a significant decrease from baseline (P<0.02) in the fluvoxamine group and was significantly better than desipramine starting at week 7 (p<0.02).  By the end of 8 weeks, 11 of the 21 patients treated with fluvoxamine were considered responders compared with 2 of the 19 in the desipramine group (p<0.01).  No significant differences were found in regards to antidepressant efficacy (p=0.025).  Overall, 56% of sertraline patients and 32% of placebo patients showed some improvement during the treatment period (p=0.023).  The authors speculated that the cause of the high placebo response rate may have been due to the studies lack of minimum score on an OCD rating scale for inclusion, in addition to unusually supportive and attentive interaction with investigators.   Adverse reactions in the sertraline group that showed a greater than 10% incidence were nausea (28%), insomnia (24%), dyspepsia (24%), ejaculation failure (24%), diarrhea (16%), dry mouth (16%), headache(12%), fatigue(12%) and dizziness (12%).  

A second trial also studied the effectiveness of sertraline versus placebo in OCD (Jenike et al 1990).  The 19 patients with OCD (DSM-III criteria) with baseline HAMD scores < 15 were randomized to receive sertraline or placebo for 10 weeks.  Efficacy was assessed by using YBOCS, NIMH, MOC, and CGI.  No other medications were allowed during the trial and patients were not permitted to have behavior therapy. All of the 19 patients enrolled finished the study and all 10 patients receiving active drug reached the maximum dose of 200 mg/day.   At the end of 10 weeks no significant differences were seen between the sertraline and placebo groups in any of the efficacy variables.  The study’s authors hypothesized that the non-significant results could be due to three factors: 1) they were outside the therapeutic dosing range and a higher or lower dose would have been more efficacious, 2) the sample was too small to detect a difference between placebo and sertraline, and 3) there is something about sertraline’s pharmacologic action that makes it an ineffective treatment for OCD even though it is similar to other medications that are effective such as fluoxetine, fluvoxamine, and CMI.

The last of these placebo controlled trials was a fixed dose study conducted by Greist et al (1992).  In this 12 week trial the efficacy of fixed once daily doses of 50, 100, and 200 mg  of sertraline were compared to placebo in 325 non-depressed outpatients with DSM-III-R diagnosed OCD.  Efficacy measures included YBOCS, NIMH, and the CGI.  In an intent to treat analysis, the pooled sertraline group showed significant greater improvement over placebo in all of the efficacy parameters (p< 0.02).  By breaking the pooled group down, both the 50 mg/day and the 200 mg/day groups showed significantly greater improvement than placebo on all efficacy measures (p< 0.02), while the 100 mg/day group only showed improvement on the NIMH scale (p = 0.03).  There were no significant differences shown between any of the 3 dosage groups.  Sertraline’s onset of effect was seen at week 2 as measured by the YBOCS, and week 4 for the NIMH and CGI. The YBOCS score decreased a mean of 23.4% in the pooled sertraline group versus 14.6% in the placebo group.  According to the CGI 38.9% of sertraline patients were considered improved, whereas only 30% of placebo patients improved.  At the endpoint analysis 35.4% of the sertraline patients had a NIMH score < 7 while only 24% of placebo patients did.  The most statistically significant adverse effects associated with sertraline over placebo were insomnia (p = 0.008), nausea (p = 0.2), diarrhea (p< 0.001), decreased libido (p < 0.001), and anorexia (p = 0.005).  Overall the authors concluded that sertraline in dosage of 50 mg, 100 mg and 200 mg/day is safe, effective, and well tolerated in the treatment of OCD.

The first double-blind, placebo-controlled study to assess the efficacy of citalopram, the most selective of the SSRIs, was published by Montgomery et al (2001).  The 401 patients were randomized to receive a fixed dose of 20, 40, or 60 mg/day of citalopram or placebo for 12 weeks.  Patients had to have a YBOCS of at least 20 to be included and were excluded if they had moderate to severe depression. Efficacy was assessed using intention-to-treat analysis last-observation-carried-forward.  Response was considered a ≥ 25% improvement in YBOCS score compared to baseline.  There was a significant reduction in the YBOCS score vs. placebo for the citalopram 60 mg group from week 3 (p<0.01) and from week 7 for the citalopram 40 and 60 mg groups (p<0.05).  The response rate after 12 weeks of treatment was 57.4% for citalopram 20 mg (p=0.003 vs. placebo), 52% for citalopram 40 mg (p=0.003 vs. placebo), 65% for citalopram 60 mg (p=0.001 vs. placebo), and 36.6% in the placebo group.  The incidence of ADRs with citalopram was 68%-73% and with placebo was 58%.  Adverse effects resulted in 4% of patients discontinuing the study.  The most common adverse events were nausea (17.3%-25%), headache (15.3%-18.6%), and insomnia (11.8%-19%).  This study showed that although 60mg of citalopram showed the best efficacy, there was no significant difference between doses suggesting that all doses above 20 mg are effective for treating OCD.  Other studies have indicated that the minimum dose used for depression may not be effective in OCD, however this study found citalopram to be effective at 20 mg, the minimum dose considered to be effective in depression.  Based on these results, treatment should begin with 20 mg/day and that the dose should only be increased after several weeks as response in OCD is slow.  There may be an advantage in response and speed of onset at the higher dose.           

The efficacy of venlafaxine has been studied in two published reports, one by Denys et al (2004b) mentioned earlier and an open, retrospective study published in 2003 byHollander et al.  This study evaluated the response of 39 patients with a primary diagnosis of OCD, 29 of who were considered resistant to treatment by other SRIs to venlafaxine.  Efficacy was measured with the CGI-I and response was considered a CGI of 1-2.  Nearly 80% of the patients had a comorbid diagnosis and over 92% were taking concomitant medications.  Prior to and throughout the study the concomitant medications remained at stable doses.  Patients were treated for an average of 18 months (range of 1-56 months) receiving an average final dose of 232 mg/day (range of 37.5-375 mg/day).  Nearly 70% of the patients were rated as sustained treatment responders and more specifically, of those who had previously been resistant to other SRI treatment, over 75% responded to venlafaxine.  Only 3 patients discontinued the medication because of side effects, however, most of the patients were also taking other medications so it is difficult to determine if venlafaxine is really at fault for the side effects.  This study provides some groundwork for a double-blind, randomized-controlled trial to see if the findings from this study, which are that venlafaxine may be effective for treatment of both previously untreated and resistant OCD, can be replicated.

MIRTAZAPINE

Because 30%-50% of patients with OCD do not respond to a trial of a SSRI, Koran et al (2001) conducted a study looking at the efficacy of mirtazapine.  This drug’s primary mechanism of action is antagonism at central pre-synaptic alpha2-receptors thus affecting norepinephrine and also enhancement of 5HT neurotransmission and antagonism of some 5HT receptors.  Ten subjects with OCD were enrolled in this 10 week open-label trial and initiated on 15 mg/day of mirtazapine with an increase to 45 mg/day by the end of the second week.  Response was considered a decrease of > 25% in the YBCOS.  The YBCOS scores fell 2.7 points (s.d. 6.3) and two subjects were considered responders.  In this very small open-label study the response rate was low, 20%, which indicates that mirtazapine is not effective treatment for OCD. There were several unfavorable aspects of this trial so little can be gained from it.  A larger randomized, controlled trial is necessary in order to make any recommendation.   

COMBINATION THERAPY

Foa et al (2005) conducted a study in 2005 testing the efficacy of CMI, exposure and ritual prevention, and the combination in treating OCD.  This was a double-blind, randomized, placebo-controlled trial of 122 patients.  They were randomized to intensive exposure and ritual prevention for 4 weeks, followed by 8 weekly maintenance session, and/or CMI for 12 weeks with a maximum dose of 250 mg/day or placebo.  The outcome measures were scores on the YBOCS, CGI and NIMH-GCODS.  Response was considered a score of 1 (very much improved) or 2 (much improved) on the CGI improvement scale.  Exposure and ritual prevention included 15-2 hour sessions over 3 weeks, and homework lasting up to 2 hours a day.  Therapists visited the patient’s home twice in the fourth week and the remaining 8 weeks involved weekly, 45 minute sessions.  At 12 weeks the scores for those patients receiving active treatment were significantly lower than those receiving placebo (p<0.05).  Exposure and ritual prevention was superior to CMI (p≤0.01), the combination was superior to CMI (p<0.01), and no difference was found between exposure and the combination.  The rates of response for completers using exposure, CMP, and the combo were 86%, 48%, and 79%, respectively, while response rates for all that were treated were 62%, 42%, and 70%, respectively.  The mean daily dose for completers taking CMI was 235 mg/day and 194 mg/day for completers who were receiving exposure therapy and CMI.  No data was collected regarding adverse events in the exposure group, but 78% of those in the CMI alone group experienced an adverse event, while 68% of those in the combination group had an adverse event.  The authors concluded that exposure and ritual prevention can be used first-line fore those that refuse medication, or even to augment therapy or reduce the dose of medication, because, although the addition was not statistically significant, on average, those who received both treatments did experience extra benefit.        

MISCELLANEOUS

Several other drugs in addition to the ones previously mentioned have also been tested for their efficacy in the treatment of OCD.  These medications are different from those previously mentioned in that serotonin is not the primary neurotransmitter they manipulate.  In the first study by Prasad (1984), six patients with Obsessive Compulsive Neurosis were randomized to receive either imipramine or zimeldine for 4 weeks.  Zimeldine is a medication that exerts its effects primarily on the serotonergic system.  Patients were rated using the LOI and the MADRS.   At the end of the study patients in the zimeldine group showed a statistically significant decrease in obsessional symptoms than the imipramine group did.  The mean change in the LOI scores for the imipramine group ranged from - 22.3 to -49 while for the imipramine group these changes ranged from -0 to -2.6.

The second study is by Foa et al (1987).  As part of this study 42 obsessive compulsive ritualizers were assigned to either imipramine or placebo.  The groups were then also split according to depression level.  Those with a BDI score of ≤ 20 were in the low depression group and those ≥ 20 were in the high depression group.  Thus a total of 4 groups were used.  The total time of the trial was 10 week with medication (or placebo) being given for 6 week followed by 4 weeks of intensive behavioral therapy.  Assessments were made using the BDI, and clinician rated obsessions and compulsions for each individual patient.  At the end of the 4 week medication trial the statistical analysis results showed that imipramine was more effective than placebo in treating depressive symptoms (p< 0.04). The only obsessive compulsive symptoms that improved significantly was fear and this improvement was only seen in the imipramine treated patients (p< 0.04).  The authors felt that this change in the severity of the fear was due primarily to improvement in depression. These authors also found a drug by depression interaction which indicated that those patients in the depressed group who received imipramine improved more than any of the other 3 groups (p < 0.05).  When comparing the two groups regardless of baseline depression the authors reported that both the placebo and the imipramine groups improved overall on 2 of the 6 measures of obsessive compulsive symptoms; these were the main fear symptom (p< 0.005) and the main compulsive symptom (p< 0.002).  These findings were different than those reported by Mavissakalian et al (1985) and Volavka et al (1985) which lead the authors of this study to conclude that the reduction in OCD symptoms seen with imipramine may not be due to a specific action of the drug.

The last non SRI trial for OCD compared trazodone to placebo for the treatment of OCD (DSM-III-R criteria) (Pigott et al 1992).  In this study 21 outpatients were entered into a randomized, double-blind, placebo controlled trial of trazodone for 10 weeks.  Symptom assessments were done using the YBOCS, NIMH-OC, the HAMD and a standardized symptoms checklist.  A total of 17 patients completed either 10 weeks of trazodone or placebo.  The mean dose of trazodone was 235 mg ± 10 mg/day.  At the end of 10 weeks there were no significant differences between either the active drug group or the placebo group.  Additionally trazodone only produced a 26% mean reduction in platelet 5-HT production while CMI and fluoxetine have been associated with a > 95% reduction.  Thus the authors speculated that trazodone’s lack of effect was due to its inability to adequately affect serotonin neurotransmission. 

Despite the number of clinical trials done investigating the effects of medicine in the treatment of OCD, many patients experience a partial response or are considered non-responders to medication.  An additional treatment strategy often used to help these patients is augmentation of their current medication regimen.  Some of the medications that have been used as augmenting strategies include low dose CMI, high potency benzodiazepines, neuroleptics, and buspirone (Expert Consensus Panel for Obsessive-Compulsive Disorder (1997)).    

In 2000, McDougle et al published a double-blind, placebo-controlled study examining the effects of adding risperidone to a SRI in refractory OCD, the first of its kind using risperidone.  Seventy patients were treated with an SRI for 12 weeks. The 36 that did not respond after 12 weeks were then randomized to receive either risperidone (N=20) or placebo (N=16) for 6 weeks in addition to their SRI.  Of those that completed the study, 9 of 18 risperidone treated patients (mean dose 2.2 +/- 0.7 mg/day) responded while 0 of 15 patients in the placebo group responded.  Risperidone was found to be superior to placebo in reducing OCD symptoms (p<0.001).  There was no difference in response between patients with and without chronic tic disorder or schizotypal personality disorder, which suggests that risperidone may be a useful adjuvant to SRIs in treatment refractory patients.

Olanzapine has also been used in several studies examining use of antipsychotics in augmenting SRI treatment in treatment refractory OCD patients, however the following is the first placebo-controlled study of olanzapine for that purpose (Bystritsky et al, 2004).  The 26 patients in this study were taking an adequate dose of fluoxetine (n=16), paroxetine n=7), sertraline (n=1), or clomipramine (n=2) for at least 12 weeks. Patients were randomly assigned to receive olanzapine or placebo for 6 weeks while continuing their SRI at a stable dose.  The YBOCS was the primary measure and response was considered an improvement in score by at least 25%.  At the end of the trial the mean dose of olanzapine was 11.2 mg/day (SD=6.5).  The last observation carried forward (LOCF) was used to assess outcome, which was that 6 of 13 (46%) of the olanzapine group responded, while none in the placebo group responded.  The olanzapine group had a mean decrease in YBOCS score of 4.2 (SD=7.9), while the placebo group had a mean increase in score of 0.54 (SD=1.3, p=0.04).  Only 2 subjects (15%) discontinued olanzapine because of side effects, 1 due to sedation and the other weight gain, indicating that the combination of an SSRI and antipsychotic can be safe and effective for treatment refractory OCD. 

Another study was done by Shapira et al (2004) and looked at the addition of olanzapine to regimens of fluoxetine.  Seventy-four subjects were treated with up to 40 mg/day of fluoxetine for 8 weeks and of these, 44 were partial (25% or greater reduction in YBOCS but symptomatic) or nonresponders (<25% reduction in YBOCS from baseline) to fluoxetine. Olanzapine was initiated at a dose of 5 mg/day, titrated up to a maximum of 10 mg/day if needed, and taken for 6 weeks.  The YBOCS scores in the fluoxetine plus olanzapine (-5.1 ± 4.9) and fluoxetine plus placebo (-3.8 ± 3.8) groups improved significantly from baseline during the study (p<0.0001).  Nine patients (46%) in each group were considered responders and 5 in the olanzapine group and 4 in the placebo group had a 35% or greater improvement.  This study suggested that olanzapine offered no advantage when added to a regimen of fluoxetine in a treatment refractory patient.  However, these patients only received monotherapy with an SSRI for 8 weeks, while 12 weeks is the current recommendation, so there may have been effect from fluoxetine that occurred after the olanzapine or placebo was started and could account for the high placebo response.      

The final study assessing augmentation is the first double-blind, placebo-controlled trial to show that the addition of quetiapine to SRIs in treatment refractory patients is more effective than a SRI alone (Denys et al 2004a).  Forty treatment refractory patients were randomized to receive either quetiapine or placebo for 8 weeks, while continuing their SRI treatment.  Responders were considered those with a decrease in YBOCS ≥35% and CGI “very much or much improved”.  The ITT-LOCF analysis showed that quetiapine (maximum dose of 300 mg/day) was superior to placebo with a mean decrease in YBOCS of 9.0 ± 7.0 and 1.8 ± 3.4 (p<0.001), respectively.  Eight of twenty (40%) of those on quetiapine were considered responders, compared to 2 of 20 (10%) in the placebo group (p=0.028).  Each patient reported that they had at least 2 or 3 adverse events during treatment.  Somnolence and dry mouth were the most common adverse events, however changing dosing to four times a day decreased the somnolence in several patients.  These results indicate that the addition of quetiapine to a SRI regimen is a safe and effective option for treatment refractory patients.      

  PREDICTORS OF RESPONSE

Erzegovesi et al (2001) aimed to determine which variables influence patient response to proserotonergic drugs in patients with OCD.  This was a 12 week open label trial looking at 159 patients without previous treatment of their OCD. They received fluvoxamine (200-300mg/day), clomipramine (150-250 mg/day), citalopram (40-60 mg/day), or paroxetine (40-60 mg/day). They found that responders, (≥35% decrease in YBOCS), had a significantly higher frequency of a family history of OCD (p=0.001).  Nonresponders had an earlier age of onset (p=0.024) and higher frequency of the poor insight subtype (p=0.000). 

Stein et al (2001) performed a logistic regression on data from a large randomized placebo-controlled trial of citalopram in OCD (Montgomery et al 2001) to determine were predictors of response.  Those more likely to respond received adequate medication for a sufficient period of time, time while nonresponders generally had a longer duration of OCD, more severe symptoms, or previous SRI use.  This data shows that early diagnosis and subsequent adequate dose and duration of medication are important for successful response to the medication.

In 1997 the Journal of Clinical Psychiatry published the results of the expert consensus guidelines for the treatment of obsessive-compulsive disorder.  As part of these guidelines the panel felt that the SRIs are the most effective for the treatment of OCD and recommend all 5 SRIs (fluvoxamine, fluoxetine, clomipramine, sertraline, and paroxetine) as first line treatment. If the patient fails to respond to the first medication prescribed, the panel recommended gradually increasing the dose to the maximum recommended by the manufacturer within 4-8 weeks from the start of treatment.  If the patient experiences a partial response to the medication the dose should be increased to the maximum by 5-9 weeks from the start of treatment or augment.  Overall the experts felt that a trial of 8-13 weeks of adequate medication treatment is necessary before switching to an additional agent or adding an augmenting agent.  Additionally the panel suggested that cognitive-behavioral therapy (CBT) be offered to every patient with OCD, except for those that are unwilling to participate.  They also recommend using CBT in non-responding or partial-responding patients, patients that are intolerant to medication side effects, or in patients with medical conditions in which the use of medication is controversial (i.e. pregnancy). 

Ackerman & Greenland (2002) performed a meta-analysis of the controlled drug studies for OCD to examine why clomipramine appears to more effective relative to placebo that the SSRIs in placebo-controlled trials, yet when the two are directly compared the difference is less obvious.  It has been suggested that this has occurred because more recent trials have included treatment-resistant patients and there has been an increase in placebo response over this same time.  Factors that the authors found were associated with improved clomipramine response were date of publication, length of trial, and required minimum duration of OCD.  The difference between CMI and placebo has been decreasing since 1991.  There has been less improvement in YBOCS, where the yearly change was 1.22 points less (p=<.0001) than older studies.  Trials lasting 12 weeks vs. 10 weeks also showed 5.78 point lower improvement in YBOCS (p<0.001).  Finally, later age of onset was associated with less improvement with CMI, where average age of onset of 23 years vs. 20 years was associated with 6.41 points less improvement (p=0.01).  Fluoxetine studies done between 1993 and 1997 showed an increased improvement in YBOCS scores each year, -0.88 (p=0.01).  Longer trials of fluoxetine were also associated with more improvement, where each 2 weeks resulted in a change of -0.55 on the YBOCS (p=0.01).  The placebo response has also changed and often times in the opposite direction as the drug response.  In CMI studies, the longer trials show a greater response to placebo: 0.71 points (p<0.001) was the average yearly decline.  Older patients and those with a later age of onset also showed greater decline in scores than their counterparts in the placebo arms.  The placebo arms of fluoxetine trials have shown less improvement in placebo arms.  They also found that there was more improvement in the CMI arms relative to placebo than among all SSRIs [-8.55 (95% CI: -9.90, 7.21)] and that there was no difference among SSRIs.  As seen in other meta-analyses, the authors found that there was no difference between CMI and any SSRI in studies that compared them directly.  One potential reason for CMI’s superiority when compared to placebo may be due to its numerous side effects.  Others have found that drugs with more side effects also have larger effects, and certain early side effects in this study were found to predict response.  Another potential reason for the difference is that early trials were shorter and the patients actually responded to nonspecific study effects such as side effects.  This improvement would not be maintained in the longer studies.  The increased placebo response may be due to patients using self-help guides to aid in treatment or inclusion of patients with less severe and shorter duration of OCD. 

A meta-analysis of OCD treatment in the pediatric population was performed by Geller et al (2003).  The medications involved were CMI, sertraline, fluvoxamine, fluoxetine, and paroxetine.  The studies that were included had to be randomized, double-blind, placebo- or active- comparator controlled, and only include patients less than 19 years of age.  A sensitivity analysis was performed and concluded that no single study was contributing significantly to the difference that was found.  The results of this study were that all medications are significantly more effective than placebo and that clomipramine is more effective than the SSRIs that were studied.  This superiority has not been seen in any head-to-head studies performed in adults.  However, its use is still limited due to the adverse cardiac effects that can be seen and is not considered first line treatment.      

REFERENCES

Ackerman DL and Greenland S (2002).  Multivariate meta-analysis of controlled drug studies for obsessive-compulsivedisorder.  J Clin Psychopharmacol; 22(3): 309-317.

Albert U, Aguglia E, Maina G, et al (2002).  Venlafaxine versus clomipramine in the treatment of obsessive-compulsivedisorder: a preliminary single-blind, 12-week, controlled study.  J Clin Psychiatry; 63(11): 1004-1009. 

American Psychiatric Association (1994): Diagnostic and Statistical Manual of Mental Disorders, Edition 4.  Washington, D.C.: American Psychiatric Association. 

Ananth J, Pecknold JC, Van Den Steen N, and Engelsmann F (1981).  Double-blind comparative study of clomipramine and amitriptyline in obsessive neurosis.  Prog Neuro-Psychopharmcol; 5: 257-262.

Black DW, Goldstein R B et al (1993).  Personality disorder in the obsessive-compulsive volunteers, well comparison subjects, and their first degree relatives.  Am J Psych; 150: 1226-1232.

Bystritsky A, Acherman DL, Rosen RM et al (2004).  Augmentation of serotonin reuptake inhibitors in refractory obsessivecompulsive disorder using adjunctive olanzapine: a placebo-controlled trial.  J Clin Psychiatry; 65(4): 565-568.

Chouinard G, Goodman W, Greist J, Jenike M, Rasmussen S, White K, Hackett E, Gaffney M, and Bick PA (1990).  Results of a double-blind placebo controlled trial of a new serotonin uptake inhibitor, sertraline, in the treatment of obsessive-compulsive disorder.  Psychopharm Bull; 26 (3): 279-284.

Chouinard G (1992).  Sertraline in the treatment of obsessive compulsive disorder: two double-blind, placebo-controlled studies.  Intl Clin Psychopharmacol; 7 (suppl 2): 37-41.

Clomipramine Collaborative Study Group (1991).  Clomipramine in the treatment of patients with obsessive-compulsive disorder.  Arch Gen Psych; 48: 730-738.

Cottraux J, Mollard E, Bouvard M, Marks I, Sluys M, Nury AM, Rouge R, and Cialdella P (1990).  A controlled study of fluvoxamine and exposure in obsessive-compulsive disorder.  Intl Clin Psychopharmacol; 5: 17-30.

DeVeaugh-Geiss J, Moroz G, Biederman J, Cantwell D, Fontaine R, Greist JH, Reichler R, Katz R and Landau P (1992).  Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder - a multicenter trial.  J Am Acad Child Adolesc Psych; 31: 45-49.

Denys  D, de Geus F, van Megen HJ, et al (2004a).  A double-blind, randomized, placebo-controlled trial of quetiapineaddition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors.  J ClinPsychiatry; 65(8): 1040-1048.     

Denys D, van Megen HJ, van der Wee N, Westenberg HG (2004b).  A double-blind switch study of paroxetine andvenlafaxine in obsessive-compulsive disorder.  J Clin Psychiatry; 65(1): 37-43).

Erzegovesi S, Cavallini MC, Cavedini P, et al (2001).  Clinical predictors of drug response in obsessive-compulsive disorder.J Clin Psychopharmacol; 21(5): 488-492.

Expert Consensus Guideline Series (1997).  Treatment of obsessive-compulsive disorder.  J Clin Psych; 58 (suppl 4): 5-72.

Flament MF, Rapoport JL, Berg CJ, Sceery W, Kilts C, Mellstrom B and Linnoila M (1985).  Clomipramine treatment of childhood obsessive-compulsive disorder: a double-blind controlled study.  Arch Gen Psych; 42: 977-983.

Foa EB, Liebowitz MR, Kozak MJ et al (2005).  Randomized, placebo-controlled trial of exposure and ritual prevention,clomipramine, and their combination in the treatment of obsessive-compulsive disorder.  Am J Psychiatry; 162(1):151-161.

Foa EB, Steketee G, Kozak MJ, and Dugger D (1987).  Imipramine and placebo in the treatment of obsessive-compulsives: the effect on depression and on obsessional symptoms.  Psychopharm Bull; 23: 8-11.

Freeman CPL, Timble MR, Deakin JFW, Strokes TM, and Ashford JJ (1994).  Fluvoxamine versus clomipramine in the treatment of obsessive compulsive disorder:  A multicenter, randomized, double-blind, parallel group comparison.  J Clin Psychiatry; 55: 301-305.

Geller DA, Biederman J, Stewart SE, et al (2003).  Which SSRI? A meta-analysis of pharmacotherapy trials in pediatricobsessive-compulsive disorder.  An J Psychiatry; 160(11): 1919-1928.

Goodman WK, Kozak MJ, Liebowitz M, and White KL (1996).  Treatment of obsessive-compulsive disorder with fluvoxamine: a multicenter, double-blind, placebo-controlled trial.  Intl Clin Psychopharmacol; 11: 21-29.

Goodman WK, Price LH, Delgado PL, Palumbo J, Krystal JH, Nagy LM, Rasmussen SA, Heninger GR, and Charney DS (1990).  Specificity of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder.  Arch Gen Psychiatry; 47: 577-585.

Goodman W, Price L, Rasmussen S, et al (1989).  The Yale-Brown obsessive-compulsive scale.  II.  Validity.  Archives Gen Psychiatry; 46: 1012-1016. 

Griest J, Chouinard G, DuBoff E, Halaris A, Won KIM S, Koran L, Liebowitz M, Lydiard RB, Rasmussen S, White K, and Sikes C (1992). Double-blind comparison of three doses of sertraline and placebo in the treatment of outpatients with obsessive compulsive disorder.   Clinical Neuropharmacology; 15 (suppl 1, part B): 316B.

Hewlett WA, Vinogradov S, and Agras S (1992).  Clomipramine, clonazepam, and clonidine treatment of obsessive-compulsive disorder.  J Clin Psychopharmacol; 12: 420-430.

Hollander E, Friedburg J, Wasserman S, et al (2003).  Venlafaxine in treatment-resistant obsessive-compulsive disorder.  JClin Psychistry; 64(5): 546-550.

Insel TR, Murphy DL, Cohen RM, Alterman I, Kilts C, and Linnoila M (1983).  Obsessive-compulsive disorder: a double-blind trial of clomipramine and clorgyline.  Arch Gen Psych; 40: 605-612.

Jenike MA, Baer L, Summergrad P, Minichiello WE, Holland A, and Seymour R (1990).  Sertraline in obsessive-compulsive disorder: a double-blind comparison with placebo.  Am J Psych; 147: 923-928.

Jenike MA, Baer L, Summergrad P, Weilburg JB, Holland A, and Seymour R (1989).  Obsessive-compulsive disorder: a double-blind, placebo-controlled trial of clomipramine in 27 patients.  Am J Psych; 146: 1328-1330.

Jenike MA, Hyman S, Baer L, Holland A, Minichiello WE, Buttollph L, Summergrad P, Seymour R, and Ricciardi J (1990).  A controlled trial of fluvoxamine in obsessive-compulsive disorder: implications for a serotonergic theory.  Am J Psychiatry; 147: 1209-1214.

Karno M, Golding JM et al (1988).  The epidemiology of obsessive-compulsive disorder in five U.S. communities.  Arch Gen Psych; 45: 1094-1099.

Koblenzer CS (1992).  Cutaneous manifestations of psychiatric disease that commonly present to the dermatologist - diagnosis and treatment.  Int J Psych Med; 22: 47-63.

Koran LM, McLeroy SL, Davison JRT, Rasmussen SA, Hollander E, and Jenike MA (1996).  Fluvoxamine versus clomipramine for obsessive-compulsive disorder: a double blind comparison.  J Clin Psychopharmacol; 16: 121-129.

Koran LM, Quirk T, Lorberbaum JP, et al (2001).  Mirtazapine treatment of obsessive-compulsive disorder.  J ClinPsychopharmacol; 21(5): 537-539.

Leonard H, Swedo S, Rapoport JL, Coffey M and Cheslow D (1988).  Treatment of childhood obsessive compulsive disorder with clomipramine and desmethylimipramine: a double-blind crossover comparison.  Psychopharm Bull; 24: 93-95.

Leonard HL, Swedo SE, Rapoport JL, Koby EV, Lenane MC, Ceslow DL, and Hamburger SD (1989).  Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents: a double-blind crossover comparison.  Arch Gen Psych; 46: 1088-1092.

McDougle CJ, Epperson CN, Pelton GH, et al (2000).  A double-blind, placebo-controlled study of risperidone addition inserotonin reuptake inhibitor-refractory obsessive-compulsive disorder.  Arch Gen Psychiatry; 57(8): 794-801.

Marks IM, Lelliott P, Basoglu M, Noshirvani H, Monteiro W, Cohen D, and Kasvikis Y (1988).  Clomipramine, self-exposure and therapist-aided exposure for obsessive-compulsive rituals.  Br J Psych; 152: 522-534.

Marks IM, Stern RS, Mawson D, Cobb J and McDonald J (1980).  Clomipramine and exposure for obsessive-compulsive rituals: I.  Br J Psych; 136: 1-25.

Mavissakalian MR, Jones B, Olson S, and Perel JM (1990).  Clomipramine in obsessive-compulsive disorder: clinical response and plasma levels.  J Clin Psychopharmacology; 10: 261-268.

Mavissakalian M, Turner SM, Michelson L, and Jacob R (1985).  Tricyclic antidepressants in obsessive-compulsive disorder: antiobsessional or antidepressive agents? II.   Am J Psych; 142: 572-576.

Montgomery SA, Kasper S, Stein DJ, et al (2001).  Citalopram 20 mg, 40 mg, and 60 mg are all effective and well toleratedcompared with placebo in obsessive-compulsive disorder.  Int Clin Psychopharmacol; 16(2): 75-86.

Pato MT, Pigott TA, Hill JL, Grove GN, Bernstein S, and Murphy DL (1991).  Controlled comparison of buspirone and clomipramine in obsessive-compulsive disorder.  Am J Psych; 148: 127-129.

Perse TL, Greist JH, Jefferson JW, Rosenfeld R, and Dar R (1987).  Fluvoxamine treatment of obsessive-compulsive disorder.  Am J Psych; 144: 1543-1548.

Pigott TA, L’Heureux F, Rubenstein CS, Bernstein SE, Hill JL, and Murphy DL (1992).  A double-blind, placebo controlled study of trazodone in patients with obsessive-compulsive disorder.  J Clin Psychopharmacol; 12: 156-162.

Pigott TA, Pato MT, Berstein SE, Grover GN, Hill JL. Tolliver TJ, and Murphy DL (1990).  Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder.  Arch Gen Psych; 47: 926-932.

Prasad A (1984).  A double blind study of imipramine versus zimelidine in treatment of obsessive compulsive neurosis.  Pharmacopsychiat; 17: 61-62.

Rapoport JL (1988).  The neurobiology of obsessive-compulsive disorder.  JAMA; 260: 2888-2890.

Rasmussen SA and Eisen JL (1992).  The epidemiology and clinical features of obsessive compulsive disorder.  Psych Clinics of North Amer; 15: 743-758.

Riddle MA, Scahill L, King RA, Hardin MT, Anderson GM, Ort SI, Smith JC, Leckman JF, and Cohen DJ (1992).  Double-blind, crossover trail of fluoxetine and placebo in children and adolescents with obsessive-compulsive disorder.  J Am Acad Child Adolesc Psychiatry; 31: 1062-1069.

Shapira NA, Ward HE, Mandoki M, et al (2004).  A double-blind, placebo-controlled trial of olanzapine addition influoxetine-refractory obsessive-compulsive disorder.  Biol Psychiatry; 550: 553-555.

Stein DJ, Montgomery SA, Ksaper S, et al (2001).  Predictors of response to pharmacotherapy with citalopram in obsessivecompulsive disorder.  Int Clin Psychopharmacol; 16(6): 357-361.

Thorn P, Asberg M, Cronholm B, Jornestedt L and Traskman L (1980).  Clomipramine treatment of obsessive-compulsive disorder: a controlled clinical trial.  Arch Gen Psych; 37: 1281-1285.

Tollefson GD, Rampey AH, Potvin JH, Jenike  MA, Rush AJ, Dominquez RA, Koran LM, Shear MK, Goodman W, and Genduso LA (1994).  A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder.  Arch Gen Psychiatry; 51: 559-567.

Vallejo J, Olivares J, Marcos T, Bulbena A, and Menchon JM (1992).  Clomipramine versus phenelzine in obsessive-compulsive disorder: a controlled clinical trial.  Br J Psych; 161: 665-670.

Volavka J, Neziroglu F, and Yaryura-Tobias JA (1985).  Clomipramine and imipramine in obsessive-compulsive disorder.  Psych Research; 14: 83-91.

Weissman MM, Bland RC et al (1994).  The cross national epidemiology of obsessive compulsive disorder.  J Clin Psychiatry; 55(suppl 3): 5-10.

Wheadon DE, Bushnell W and Steiner M (1993).  A fixed dose comparison of 20, 40, or 60 mg paroxetine to placebo in the treatment of obsessive-compulsive disorder.  Presented at the American College of Neuropharmacology Meeting in Puerto Rico.

Zajecka JM, Fawcett J, and Guy C (1990).  Coexisting major depression and obsessive compulsive disorder treated with venlafaxine.  J Clin Psychopharmacol; 10(2): 152-153.

Zohar J and Insel TR (1987).  Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment and pathophysiology.  Biol Psych; 22: 667-687.

Title Page