The majority of available data based on long-term follow-up studies in obsessive-compulsive disorder (OCD) patients indicate that, after the acute phase of treatment (approximately 6 months), drug discontinuation leads to the recurrence of symptoms in most patients (23-89%) (Thorén et al., 1980; Pato et al., 1988; Fontaine and Chouinard, 1989; Leonard et al., 1989; Pato et al., 1991; Ravizza et al., 1996).
Considering the reinstitution of treatment after relapse due to drug discontinuation, several studies concluded that it led to global improvement in all patients, although there is lack of well designed and conducted perspective studies to elucidate this issue. Pato et al. (1988) reinstated clomipramine in 16 patients who had been responders to 10.7 ± 5.5 months of therapy (mean clomipramine dosage 236 mg/day) and had relapsed after drug discontinuation. Following the blinded discontinuation phase of the study, all 16 patients with symptom recurrence chose to have clomipramine readministered. An open assessment after 8 weeks using the NIMH Global Obsessive-Compulsive Scale showed that the patients had generally returned to their prestudy level of improvement. In a group of eight patients who had been 'partial responders' to a clomipramine trial of 17.1 ± 8.3 months (mean clomipramine dosage was 143 mg/day), and had relapsed during a desipramine substitution period, Leonard et al. (1991) found that the substituted group regained its presubstitution clinical status within the first month of clomipramine reinstatement. Orloff et al. (1994) reported on the follow-up of a cohort of 85 OCD patients on various anti-obsessionals. Remarkably, only four patients had stopped medication (three on fluoxetine and one on clomipramine), all after becoming pregnant and all experienced relapse. All four patients restarted medication after delivery and again experienced remission of symptoms.
As the main objective of the three studies was not the evaluation of the efficacy of drug reinstitution, results on this topic are compromised by methodological bias: (I) treatment duration prior to discontinuation varies between patients within the same study; (II) mean scores on rating scales are not reported and in two studies (Leonard et al., 1991; Orloff et al., 1994) it is not clear which is the rating scale used; (III) some of the studies are restricted to samples of children and adolescents; and (IV) the Orloff study is a review of patients' records which reported on the four patients having had recurrences without specifying Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores or the time from reinstitution to response.
The aim of the present study was to determine whether patients whose symptoms recur after drug discontinuation respond again when the same drug at the same daily dosage is reinstituted.
Patients were subjects with a primary diagnosis of OCD who entered a 6-month, open-label, noncomparative, acute treatment phase study with the following serotonin reuptake inhibitors (SRIs): clomipramine, fluoxetine, fluvoxamine and paroxetine. A subgroup of patients participated in a 2-year, open-label follow-up study that has been already published (Ravizza et al., 1996). The other subjects were enrolled specifically for this study.
All patients had to meet DSM-III-R criteria for OCD according to the SCID (Structured Clinical Interview for DSM-III-R) (Spitzer et al., 1990). In addition: (I) obsessive-compulsive symptoms had to have been present for at least 1 year prior to study entry; (II) patients had to have a Y-BOCS total score equal to or greater than 16; and (III) a 17-item Hamilton Rating Scale for Depression (HAM-D) equal to or less than 14 at the baseline evaluation was required. A current diagnosis of major depressive disorder and/or a HAM-D score of 15 or greater, a present or previous diagnosis of schizophrenia or other psychotic disorders, or an organic brain syndrome or medical illness that would contraindicate the use of SRIs excluded potential subjects from the study.
After having provided their informed consent to participate in the study, patients were randomly assigned to one of the four following treatments: clomipramine (given initially in a dosage of 50 mg/day with increases of 50 mg every 2 days to a daily dose of 150 mg), fluoxetine (given initially in a dosage of 20 mg/day and from the fourth day in a daily dose of 40 mg), fluvoxamine (given initially in a dosage of 100 mg/day with increases of 100 mg every 2 days to a daily dose of 300 mg), or paroxetine (given initially in a dosage of 20 mg/day and from the fourth day in a daily dose of 40 mg). No concomitant therapies (drug or psychotherapies) were permitted during this phase of treatment. Patients assigned to these four treatment strategies were then followed up with monthly visits for the next 6 months. At every visit (baseline and follow-up visits), patients were evaluated by means of the Y-BOCS and Clinical Global Improvement (CGI). At the end of the acute phase, patients were considered responders when having had a decrease of 35% or more in their Y-BOCS total score and being rated as 'much improved' or 'very much improved' on the CGI with respect to the condition at baseline. All patients who completed the acute therapy phase and achieved responder status were allowed to continue the study.
The subset of patients who participated in the 2-year, open-label, follow-up study (Ravizza et al., 1996) was allowed to enter this reinstitution study only if, after the acute phase, patients had been assigned to the discontinuation arm of the study. The other OCD patients who participated in the follow-up study and who had been assigned to receive full- or half-doses were not considered for this reinstitution study.
In order to eliminate possible interferring bias, for all patients, the drug discontinuation was performed within 1 week.
During the treatment responder extension (discontinuation) phase, patients were assessed at baseline (T6) and every month thereafter, or until they experienced a worsening of symptoms. The treatment responder extension phase lasted 6 months. During these months the evaluation instruments were the Y-BOCS and the CGI. Clinical condition was considered worsened when, at any time of the long term follow-up, patients were evaluated as 'much worse' or 'very much worse' on the CGI and showed an increase of 25% or more on the Y-BOCS total score in comparison with the end of the acute treatment phase. This was considered as a 'relapse'. After having had the status of 'relapsed' confirmed in a second following visit (interval between visits: one month), patients were enrolled in the reinstitution phase study. Patients then had to meet relapse criteria for two consecutive visits spaced 1 month apart.
Patients who responded to the acute treatment phase, had their treatment discontinued for 6 months, but did not relapse during the discontinuation phase, were excluded from the study and had no treatment reinstated.
A total of 388 patients entered the 6-month, open-label, noncomparative, acute treatment phase with fixed doses of SRIs (Fig. 1). Of these, 281 were drawn from the group who participated to the long term, follow-up study by Ravizza et al. (1996). Three hundred and forty-nine (89.9%) completed the acute treatment phase. Thirty-nine subjects (10.1%) discontinued because of adverse events, inefficacy, protocol violations or noncompliance. A total of 183 patients (52.4% of those who completed the acute phase) met criteria for treatment response at the end of the acute phase and entered the 6-month discontinuation follow-up phase. Forty-two patients were responders to clomipramine, 56 to fluoxetine, 40 to fluvoxamine and 45 to paroxetine. Two subjects were lost during the follow-up (one patient in the group who had been taking clomipramine and one in the group who had been taking paroxetine), yielding a total of 181 patients who completed the discontinuation phase. Of these, 81 (44.8%) met relapse criteria as defined in our study.
These 81 patients who were responders to the 6-month, open-label, noncomparative, acute treatment phase with fixed doses of SRIs and who relapsed within 6 months of drug discontinuation were enrolled in the reinstitution phase. All patients had the drug to which they responded in the acute phase reinstituted at the same daily dose; moreover, this dosage was reached in the same amount of time we used in the acute phase. Similar to the acute treatment phase, no concomitant pharmacotherapy or psychotherapy was accepted. Patients were restarted on medication immediately after meeting relapse criteria.
The reinstitution trial lasted 24 weeks with monthly evaluations. The evaluation instruments were the same we used in the acute phase (the Y-BOCS and the CGI scale). For our purposes, we considered as responders all patients who showed a decrease of 35% or more in their Y-BOCS total score and who were rated as 'much improved' or 'very much improved' on the CGI with respect to the Y-BOCS total score and clinical assessment they showed at the beginning of the reinstitution phase.
The acute phase and the discontinuation phase of the study were performed to obtain a sample of patients who had been responders to SRIs and who had relapsed during the discontinuation phase. This group of patients was retreated with the same drug at the same dose in order to evaluate whether patients whose symptoms recur after drug discontinuation respond again when the same drug treatment is reinstituted.
Data obtained in the reinstitution phase were analysed using Pearson's chi-squared test or Fisher's exact test when appropriate. The cumulative percentages of patients who responded in the second trial were compared to those of patients who responded in the acute treatment phase (for all SRIs together) across all evaluation times.
Of all patients who discontinued drug treatment (n = 181), 81 (44.7%) relapsed within the 6-month observation period and subjects who discontinued fluoxetine relapsed significantly later with a significant delay of 2 months (Fig. 2). In the majority of patients who relapsed (n = 81), the symtoms recurrences occurred within the second month of discontinuation except for subjects who were fluoxetine withdrawn that mainly relapsed after the third month of discontinuation (Fig. 3).
These 81 patients constituted our sample of which 18 had clomipramine reinstated at a dosage of 150 mg/day, 22 fluoxetine at a dosage of 40 mg/day, 21 fluvoxamine at a dosage of 300 mg/day and 20 paroxetine at a dosage of 40 mg/day. Mean Y-BOCS total scores of these 81 patients did not differed significantly between the beginning of the acute treatment phase (I trial) and the beginning of the reinstitution phase (II trial). No differences were detected also when examining separately patients according to the drug used.
Cumulative percentage of responders
The cumulative proportion of responders among patients treated with the four different SRIs during the two trials (acute treatment and drug reinstitution after a relapse due to drug discontinuation) are shown in Fig. 4 (all patients together). When considering all patients together (Fig. 4; n = 81), a difference in the cumulative percentage of responders appeared at month 4 and increased at months 5 and 6 (Pearson chi-squared, P = 0.028, P = 0.009 and P < 0.001, respectively). When considering patients separately according to the SRI used, no differences in percentages of responders were found at any time with respect to the first trial (acute phase).
In order to investigate whether the relapse rates or the relapse latencies were associated with an early or late onset of OCD, we compared patients having an age at onset of up to 17 years (n = 59) with patients having an age of onset at age 20 years or later (n = 107). Fifteen patients were not considered for this statistical analysis because the age at onset of their disorder was between 17 and 20 years. In both trials, no differences in relapse rates and in relapse latencies were found between patients with an early or a late onset of the disorder.
This is the first study specifically performed on drug reinstitution after a relapse due to drug discontinuation in OCD patients.
Our study was aimed at evaluating whether patients whose symptoms recur after drug discontinuation respond again when the same drug used previously is reinstated.
Our results indicate that patients whose symptoms recur after drug discontinuation respond again when the same drug used previously (at the same dosage used in the acute phase) is reinstated, but at a lower degree with respect to the acute treatment: one patient out of five who had responded to the acute treatment and had relapsed on drug discontinuation failed to meet response criteria (as defined in our study) after 6 months from drug reinstitution. The difference in response rate between the acute treatment and the reinstitution treatment emerged after 4 months of therapy and persisted at months 5 and 6. The same pattern of response to the second trial emerged when considering patients separately according to the reinstated drugs. However, the small number of patients assigned to each of the four different treatments prevented us from achieving statistically significant results. Our findings suggest, moreover, that there are no differences between the four drugs considered when examining responders rates.
The important finding of our study is that the cumulative responder rate was lower in the drug reinstitution period (84%) compared to the first time round. This implies that, as a population, our patients were more resistant the second time round and suggest that the increasing resistance is a product of the passage of time in OCD or, alternatively, a product of extra episodes. Further investigations to clarify this are needed.
The findings from our study, together with literature data indicating high relapse rates when discontinuing the treatment after the acute phase, strongly support the idea of continuing the treatment in OCD over the long term. In fact, drug discontinuation leads to the recurrence of symptoms in most patients (23-89%) (Thorén et al., 1980; Pato et al., 1988; Fontaine and Chouinard, 1989; Leonard et al., 1989; Pato et al., 1991; Ravizza et al., 1996) and treatment reinstitution in responders who had relapsed fails to improve symptoms in approximately 20% of patients.
Our data, demonstrating a response latency within 6 weeks in the phase I trial and a response rate of 84% when the drug is re-instituted, imply that a clinician should wait 6 months before concluding that an anti-obsessive drug is not going to work for the patient. We suggest that the observation period before considering strategies for treatment resistant OCD should always be longer than the usually suggested 12 weeks.
The methodological limitations of our study should also be considered. Our study was performed in an open-label manner; thus, our results need to be replicated under double-blind conditions. Another issue that should be considered is the lower response rate on restarting medications, which might reflect patients who were placebo responders in the first trial, and who failed to exhibit a placebo response in the reinstitution phase. Placebo responders means, in this context, that the observed favourable response was due to psychological factors such as participating in a clinical trial and getting attention, and not to the physiological effects of the drug. However, in our opinion, it is unlikely that a placebo response could have lasted for the 6 month duration of the first trial. Moreover, the clinical trial was exactly identical in the two phases, and it is again unlikely (although possible) that a placebo responder to the first trial failed to exhibit a placebo response in the reinstitution phase.
Several questions still need to be answered: are patients who failed to respond again to the same drug different from those who achieved a full therapeutic response? Are there, in other words, predictors that would allow clinicians to identify subjects who do not respond again to the same drug in case of relapse due to drug discontinuation and who would require long-term treatment? Research on drug treatment of OCD is in progress and an answer to these questions will allow clinicians to ameliorate treatment strategies in an effort to control symptomatology of this disabling disorder.
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Keywords:© 2001 Lippincott Williams & Wilkins, Inc.
obsessive-compulsive disorder; drug discontinuation; long-term treatment