Citalopram for treatment-resistant obsessive-compulsive disorder

Eur Psychiatry 1999 ; 14 : 101-6 © Elsevier, Paris

ORIGINAL ARTICLE

Citalopram for treatment-resistant obsessive-compulsive disorder S. Pallanti1, L. Quercioli2, R.S. Paiva2, L.M. Koran3 Istituto di Neuroscienze and University of Florence Medical School Florence, Italy; 2 Istituto di Neuroscienze Florence Florence, Italy; 3 Department of Psychiatry and Behavioral Sciences, Stanford Medical Center Stanford CA, USA

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(Received 4 November 1997; final version 17 December 1998; accepted 18 December 1998)

Summary – We investigated the comparative efficacy of citalopram vs. citalopram administered with clomipramine, in treatment-resistant obsessive-compulsive disorder (OCD). Sixteen adult outpatients participated in a 90-day, randomized, open-label trial. Eligible patients were aged 18 to 45 years, had moderate to severe DSM-III-R OCD of ≥ one year’s duration, a baseline Yale-Brown scale (Y-BOCS) score of ≥ 25 and no other active axis I diagnosis, and had failed adequate clomipramine and fluoxetine trials. The citalopram-plus-clomipramine group (n = 9) experienced a significantly larger percent decrease in mean Y-BOCS score by day 90 than the citalopram alone group (n = 7). Only one citalopram patient decreased her score by ≥ 35%, and two by ≥ 25%. All nine citalopram-plus-clomipramine patients experienced decreases of ≥ 35%. Side effects were mild to moderate in both groups. We also treated with citalopram six OCD patients who had not tolerated fluoxetine alone and clomipramine alone; three achieved Y-BOCS score decreases of ≥ 35% at 90 days. Since citalopram does not significantly affect clomipramine metabolism, the improvement in the combined drug group is unlikely to have resulted from increased plasma clomipramine levels. Double-blind controlled trials are needed of citalopram in OCD, and of combining citalopram with clomipramine in treatment-resistant OCD. © 1999 Elsevier, Paris citalopram / combined treatment / obsessive-compulsive disorder / treatment-resistant

INTRODUCTION Obsessive-compulsive disorder (OCD) responds to selective serotonin re-uptake inhibitors (SSRIs; fluvoxamine, fluoxetine, sertraline, paroxetine) and to serotonin/norepinephrine re-uptake inhibitors (SNRIs; clomipramine and venlafaxine) [10, 15, 34, 46]. About 40% to 60% of OCD patients experience moderate to marked improvement in response to drug treatment [7]. The proportion who respond to a second medication after failing an initial adequate trial has not been established. For patients who have failed several drug trials, a number of treatment strategies have been reported in case reports or small, uncontrolled series [8,

20, 21, 35]. The only treatment whose efficacy has been established in a double-blind trial is combining a neuroleptic with an SSRI in OCD patients who have a comorbid tic disorder [28]. A good treatment outcome has been reported from combining clomipramine with an SSRI in patients unresponsive to or intolerant of one or both drugs given separately. Six adolescent patients with either a limited response or intolerable side effects to clomipramine responded well when fluoxetine 20–40 mg/d was added to clomipramine 25–50 mg/d [36]. Adding fluoxetine to clomipramine was beneficial in a series of three cases [5]. The authors note that the benefit in two cases may have been related to increased serum levels of

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clomipramine. Seven patients responded to a clomipramine-SSRI combination after not responding to one drug alone [6]. We report the results of a random assignment, openlabel trial of the SSRI, citalopram vs. citalopram plus clomipramine in OCD patients unresponsive to separate adequate trials of both clomipramine and fluoxetine. To our knowledge, this is the first trial of citalopram in OCD patients who have failed two generally effective anti-OCD medications. In Italy, where the trial was conducted, only clomipramine and fluoxetine are approved for the treatment of OCD; citalopram is an experimental drug. Serotonin re-uptake blockade is thought to be critical for efficacy of anti-OCD medications [25]. Citalopram is the most selective SSRI yet discovered, about 240 times more selective than clomipramine and four times more selective than sertraline [17]. Citalopram’s serotonergic re-uptake inhibition is due almost entirely to the S-enantiomer [18]. The metabolites of citalopram are also selective 5-HT re-uptake inhibitors, but are less potent and less able to cross the blood-brain barrier [14, 19]. After oral administration, citalopram is 80% bioavailable and reaches maximum plasma concentration at about 3 h [30]. The half-life in nonelderly adults is about 35 h [31]. Steady-state plasma levels are reached in one to two weeks at doses of 20 mg/d or 40 mg/d [32]. An open-label pilot study, published after we completed our trial, reported that citalopram was effective in OCD patients who were not treatment-resistant [22]. SUBJECTS AND METHODS We recruited adult outpatients meeting DSM-III-R criteria for OCD from among patients treated at our clinic in Florence, Italy. The diagnosis of OCD, present for at least a year, was established by means of a structured clinical interview for DSM-III-R (SCID) [39] conducted by one of us. We also utilized the structured clinical interview for DSM-III-R personality disorders (SCID-II) [38]. We rated patients’ symptoms with the yale-brown obsessive-compulsive scale [9] (Y-BOCS), and the 21-item Hamilton rating scale for depression (HRSD) [13]. All patients were assessed for possible tic disorder using the Yale global tics severity scale (YGTS) [24]. We randomized a pre-planned total of 16 patients. The seven patients randomly assigned to citalopram alone did not differ from the nine randomly assigned to

citalopram-plus-clomipramine in age, baseline HRSD, baseline Y-BOCS or mean dose of clomipramine or fluoxetine received in the treatment trials they had previously failed (table I). All patients had a baseline Y-BOCS score of ≥ 25, no other active axis I diagnosis, and no medical disorder that would contraindicate the use of clomipramine. The distribution of predominant OCD symptoms was similar in the two groups, although the combined treatment group contained more patients with checking rituals (table I). All study patients had failed an adequate trial of clomipramine (≥ 150 mg/d for ≥ 12 weeks) and of fluoxetine (≥ 20 mg/d for ≥ 12 weeks). ‘Failure’ was defined as experiencing less than a 35% decrease from baseline in Y-BOCS score, and a score of ‘minimal improvement’ or less on the clinical global improvement scale (CGI) [12]. The mean length of these failed trials was 16.5 weeks, during which each patient had been pushed to the maximum tolerated medication dose. No patient had behavior therapy during the failed or current medication trials. After receiving an explanation of the potential risks and benefits of the trial and of alternative treatments, each patient gave written informed consent in accordance with the Declaration of Helsinki. Following a four-week washout period, patients were randomly assigned to receive either open-label citalopram alone or citalopram plus clomipramine for 90 days. Patients receiving citalopram alone began at 20 mg/d, increased after two weeks to 40 mg/d. Patients receiving combination treatment began citalopram at 20 mg/d and were increased to 40 mg/d after four weeks. They simultaneously began clomipramine at 25 mg/d, which was increased by 25 mg/d every third day to 150 mg/d, this dose being reached after two weeks. Patients were seen at days 15, 30, 45, 60, 75 and 90, at which times symptom ratings were repeated. Patients’ side effects were evaluated at each visit with a four-point side effects scale (absent, mild, moderate, severe) and pulse rate and blood pressure were obtained. ‘Response’ was prospectively defined as a decrease in Y-BOCS score of ≥ 35%. RESULTS All patients tolerated their assigned dose regimens of study drug and reached full doses on schedule. Pill counts at each visit indicated that patients in both treatment groups complied with their dosing regimens.

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scores first became significantly greater in the combined treatment group at day 60 (figure 1). In the citalopramalone group, only one patient decreased her score by > 35% (from 29 to 16) and two others by > 25% (36 to 26, and 31 to 23). In the citalopram-plusclomipramine group, all nine patients experienced decreases of > 35%. Seven of these patients experienced a ≥ 25% decrease in Y-BOCS score by day 45, but none had improved this much by day 30. In the citalopram-alone group, HRSD scores fell from 12.6 (SD = 2.6) to 6.4 (SD = 1.8), and in the combined drug group from 12.6 (SD = 2.5) to 5.6 (SD = 2.6) (independent samples t-test t = 0.28, df = 14, P > 0.70, two-tailed, pooled variances). There was no statistically significant or large correlation in either group between the percent decreases in the Y-BOCS and HRSD scores (Spearman rank order correlation, rs = 0.31 in the citalopram group, rs = 0.34 in the citalopram-plus-clomipramine group). At baseline, the two treatment groups did not differ in YGTS tic scores: citalopram mean 5.1 (SD = 6.5, range 0–14); combined treatment group mean 6.2 (SD = 6.0, range 0–18). At day 90, YGTS tic scores of treatment responders and non-responders did not differ significantly. Side effects were mild to moderate in both groups, and no patient discontinued treatment because of them (table II). No sexual side effects were reported in the citalopram-alone group. In contrast, when treated with clomipramine, four of these patients had experienced delayed orgasm; during fluoxetine treatment, two had had delayed orgasm, two decreased

Figure 1. Treatment response to citalopram vs. citalopram + clomipramine in treatment resistant OCD.

As can be seen in figure 1, the citalopram-plusclomipramine group experienced a significantly larger percent decrease than the citalopram alone group in mean Y-BOCS score by day 90 (54.2% (SD = 9.4%) vs. 20.1% (SD = 14.4%), independent samples t = 5.73, df = 14, P < 0.001, pooled variance, two-tailed). In absolute terms, the combined drug group’s mean Y-BOCS score decreased from 34.4 (SD = 2.8) at baseline to 15.9 (SD = 3.8), while the citalopram alone group’s score decreased from 32.0 (SD = 2.6) to 25.6 (SD = 4.8) (independent samples t = 4.51, df = 14, P = 0.001, pooled variance, two-tailed). The fall in Y-BOCS

Table I. Demographic and clinical characteristics of OCD patients receiving citalopram or citalopram plus clomipramine. Gender Age (years, SD) HRSD (mean, SD)b Y-BOCS (mean, SD)c Personality disorder Predominant symptoms contamination/cleaning checking counting doubting/fear of harming others Failed trials clomipramine fluoxetine

Citalopram (n = 7)

Citalopram + clomipramine (n = 9)

2F / 5M 24.6 (4.0) 12.6 (2.6) 32.0 (2.6) avoidant (1)

4F / 5M 25.1 (4.8)a 12.6 (2.5)a 34.4 (2.8)a avoidant (1) dependent (1)

2 2 1 2

1 4 1 3

171.4 ± 30.4 mg/d (150–225 mg/d) 52.9 ± 9.5 mg/d (40–60 mg/d)

175.0 ± 37.5 mg/d (150–250 mg/d) 53.3 ± 10.0 mg/d (40–70 mg/d)

P > 0.05, two-tailed, independent samples t-test, pooled variances; df: 14; Yale-Brown obsessive-compulsive rating scale.

a

b

HRSD: Hamilton rating scale for depression; c Y-BOCS:

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Table II. Side effects in obsessive-compulsive patients treated with citalopram or citalopram plus clomipramine.

Nausea Headache Insomnia Anxiety Dry mouth Constipation Delayed orgasm Delayed orgasm and decreased libido Blurred vision Somnolence

Citalopram (n = 7)

Citalopram + clomipramine (n = 9)

1 mild 1 mild, 1 moderate 1 mild 1 mild – – –

2 mild – – – 1 mild, 7 moderate 3 mild, 2 moderate –, 3 moderate –, 1 moderate 2 mild, 1 moderate 2 mild

libido, and one had suffered both symptoms. In the combined treatment group, the same patients who experienced sexual dysfunction from clomipramine alone and fluoxetine alone experienced them with combined clomipramine and citalopram. DISCUSSION This study is limited by the absence of blind ratings and of a placebo control group. In addition, our citalopram dose, 40 mg/d, may have been less than optimal; higher doses of SSRIs are often needed to treat OCD than to treat depression [43, 46]. On the other hand, citalopram 40 mg/d has been reported effective in case reports and open trials with OCD patients [22, 42]. Moreover, three of six additional OCD patients, who had been intolerant of fluoxetine (40 mg/d) and clomipramine (150 mg/d), responded when we treated them with citalopram 40 mg/d; each achieved a 90 day Y-BOCS score of ≤ 18 and a decrease in score of ≥ 35%. The possibility remains, however, that a higher dose of citalopram alone would have been more effective in our treatment-resistant patients than the 40 mg/d dose we utilized [2, 22, 45]. The modest response rate in our citalopram-alone treatment group may reflect their having already failed two SSRI trials. Patients who have failed one or more SSRI trials have a lower response rate than SRI-naive patients. For example, slightly more than 50% of SRInaive, but only slightly more than 30% of SRIexperienced OCD patients responded to sertraline in a series of multicenter trials (Rasmussen S.A., Baer L., Eisen J., Shera D. Previous SRI treatment and efficacy of sertraline for OCD: Combined analysis of four multicenter trials. Presented at the 150th Annual Meeting,

– –

American Psychiatric Association, San Diego, CA, May 17-22, 1997). The limitations of our study notwithstanding, combining 40 mg/d of citalopram with clomipramine seemed more effective than citalopram alone in OCD patients who had failed adequate trials of both clomipramine and fluoxetine. All nine combined treatment patients responded, and six achieved day 90 Y-BOCS scores of ≤ 18, compared to only one of the seven citalopram-alone patients. Only one citalopram-alone patient experienced a > 35% decrease in Y-BOCS score (although three experienced a ≥ 25% decrease). The significant separation of the treatment groups at day 60 occurred because eight of the nine combined-treatment patients had Y-BOCS score decreases of ≥ 25% at this point vs. only two of the seven citalopram patients. Perhaps the early improvement in both treatment groups (from baseline to day 30) reflected the nonspecific effects of hope and attention along with a small amount of drug effect. A gradually increasing, substantial drug effect then took hold in all patients in the combined treatment group but in only one citalopramalone patient (whose Y-BOCS decreased from 24 at day 30 to 16 at day 90). The recommendation of experts that an adequate SRI trial in OCD requires eight to 12 weeks [27] is consistent with the separation of our treatment groups at day 60. Data describing individual OCD patients’ time course of response are scarce, but most patients apparently do not achieve a ≥ 35% decrease in Y-BOCS score until sometime after 42 days of treatment [29]. During continued pharmacotherapy for OCD after response to an acute trial of eight to 12 weeks, responders continue to improve for many months, albeit usually to a modest degree [11, 43].

Citalopram and obsessive-compulsive disorder

Could our results mean that the combined treatment group was simply responding to clomipramine? We do not believe so. First, all nine patients in this group had failed a previous adequate trial of clomipramine at their maximum tolerated dose (table I). Second, although we did not obtain plasma clomipramine levels, citalopram is unlikely to have raised these substantially and to have thereby produced a greater therapeutic response. Clomipramine’s metabolism to desmethylclomipramine, a noradrenaline re-uptake inhibitor, appears to be catalyzed by three hepatic isoenzymes: CYP2C19 [26], CYP1A2, and CYP3A4 [3]. Citalopram is not a strong inhibitor of CYP2C19 [37], CYP1A2 [3] or CYP3A4 [4]. Citalopram could slow the metabolism of clomipramine to 8-OH clomipramine [33], but since 8-OH clomipramine is also 5-HT re-uptake inhibitor [1], the net effect of this slowing would be minimal. No patient treated with citalopram alone in our randomized or open trials (n = 13) experienced any sexual dysfunction. This may be due to citalopram’s extreme selectivity for 5-HT re-uptake blockade, even in contrast to other SSRIs. In particular, citalopram is at least 10 times less active in blocking norepinephrine re-uptake than any other SSRI and 290 times less active than clomipramine [16]. Clomipramine and citalopram are approximately equally potent in 5-HT reuptake blockade; their IC50 values are 1.5 nM and 1.8 nM respectively [16]. However, citalopram has been associated with delayed ejaculation in normal volunteers [37], and with anorgasmia in about 10% of patients with panic disorder [44]. Since complaints of sexual dysfunction can lead OCD patients to discontinue their medication, citalopram’s effect on sexual functioning in OCD patients deserves further study. The addition of citalopram did not appear to increase the frequency or severity of side effects that patients had experienced when treated with clomipramine alone (table II). Thus, in patients for whom a trial of combined SSRI/SNRI is a clinically reasonable option, citalopram may offer some advantage over SSRIs that raise plasma clomipramine levels. Fluvoxamine, for example, in doses of 100–200 mg/d raises plasma clomipramine levels four-fold, while diminishing plasma desmethylclomipramine levels by 40% [14]. On the other hand, the higher plasma clomipramine levels may be beneficial in some OCD patients [23]. Still, given the possibility of cardiovascular side effects [40], or changes in intracardiac conduction [41] induced by high plasma levels of clomipramine or its metabolites, we recommend screening electrocardiograms, moni-

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toring vital signs and obtaining plasma clomipramine and desmethylclomipramine levels in future studies of combining citalopram and clomipramine. CONCLUSIONS Notwithstanding the limited size of our study and its lack of blinding, our results suggest that nonresponders to adequate trials of both an SSRI and an SNRI may benefit from a combined SSRI/SNRI trial. Our open-label case series of six patients intolerant of clomipramine and fluoxetine, three of whom responded to citalopram alone, is consistent with earlier open-label series suggesting that citalopram is effective in the treatment of OCD. Large-scale, randomized, double-blind, placebocontrolled, fixed dose studies are needed to evaluate the efficacy of different doses of citalopram in OCD and to compare treatment with citalopram or clomipramine alone to treatment with the combination for patients who have failed to respond to both drugs. These studies should include assays of plasma drug and metabolite levels as well as both patient-rated and clinician-rated outcome measures. ACKNOWLEDGEMENTS We would like to acknowledge the assistance of Sue Thiemann, M.S., who performed the statistical analyses. REFERENCES 1 Baettig D, Bondolfi G, Montaldi S, Amey M, Baumann P. Tricyclic antidepressant plasma levels after augmentation with citalopram: a case study. Eur J Clin Pharmacol 1993 ; 44 : 403-5. 2 Bejerot S, Humble M. Citalopram treatment of OCD: a pilot study of anti-obsessive efficacy. Biol Psychiatry 1991 ; 29 : 443-7. 3 Brøsen K. The pharmacogenetics of the selective serotonin re-uptake inhibitors. Clin Invest 1993 ; 71 : 1002-9. 4 Brøsen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993 ; 45 : 1211-4. 5 Browne M, Hornm E, Jones TT. The benefits of clomipraminefluoxetine combination in obsessive compulsive disorder. Can J Psychiatry 1993 ; 38 : 242-3. 6 Figueroa Y, Rosenberg DR, Birmaher B, Keshavan MS. Combination treatment with clomipramine and selective serotonin reuptake inhibitors for obsessive-compulsive disorder in children and adolescents. J Child Adolescent Psychopharmacol 1998 ; 8: 61-7. 7 Goodman WK, McDougle CJ, Price LH. Pharmacotherapy of obsessive compulsive disorder. J Clin Psychiatry 1992 ; 53 : Suppl 4 : 29-37.

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