Augmenting Selective Serotonin Reuptake Inhibitors With Clomipramine in Obsessive-Compulsive Disorder: Benefits and Risks

Clinical Problem

A 16-year-old boy was prescribed fluoxetine for obsessive-compulsive disorder (OCD). The dose was stepped up from 20 mg/d to 60 mg/d across 4 weeks. Despite adequate drug compliance, there was only modest improvement, and, therefore, clomipramine (25 mg/d) was added 3 months later to augment the fluoxetine-mediated benefits. Encouraging results led to a stepwise increase in the dose of clomipramine from 25 mg/d to 75 mg/d. What might be the risks associated with the combination of fluoxetine (60 mg/d) with clomipramine (75 mg/d)?

Why Augment an SSRI With Clomipramine?

Clomipramine is generally acknowledged to be the most effective monotherapy for OCD; for example, a meta-regression analysis of 12 randomized controlled trials (RCTs) in pediatric OCD1 found that clomipramine was superior to the selective serotonin reuptake inhibitors (SSRIs), which did not differ significantly among themselves. However, clomipramine is associated with significant anticholinergic and other adverse effects,2 and so SSRIs tend to be chosen as first-line agents for patients with OCD.3 In such situations, the dose of the SSRI is usually stepped up, depending on how well the drug is tolerated, because higher doses are associated with greater anti-OCD efficacy.4

Unfortunately, patients with OCD do not always respond adequately to initial treatment with an SSRI,5 and augmentation strategies therefore become necessary. Whereas drugs such as buspirone, clonazepam, and others have been used for SSRI augmentation, the largest body of evidence supports augmentation with atypical antipsychotic drugs.6-8

Among the atypical antipsychotics, a recent meta-analysis8 of 12 RCTs found that risperidone (3 RCTs) was associated with the best evidence of benefit; neither quetiapine (5 RCTs) nor olanzapine (2 RCTs) was associated with significant efficacy, and the benefits with aripiprazole and haloperidol (1 RCT each) were inconsistent. A problem with risperidone is that it can cause adverse effects such as weight gain, extrapyramidal symptoms, and prolactin elevation.9 Some clinicians therefore offer an SSRI-clomipramine trial before augmenting SSRIs with an atypical antipsychotic drug. Usually in such trials, the SSRI drug is prescribed in its full therapeutic dose, and clomipramine is prescribed in a low dose. The expectation is that the serotonergic effect of the combination will be greater than that with SSRI monotherapy and that clomipramine will be reasonably well tolerated because the dose is low.

Benefits of the SSRI-Clomipramine Combination

There is anecdotal as well as RCT-based evidence for anti-OCD benefits with an SSRI-clomipramine combination. For example, Simeon et al10 reported the use of a fluoxetine-clomipramine combination in 6 adolescents with OCD, all of whom had failed to tolerate or respond to clomipramine monotherapy. Combination treatment duration ranged from 4 to 28 weeks and beyond; doses were 20-40 mg/d for fluoxetine and 25-50 mg/d for clomipramine. All patients responded better to the combination than to clomipramine monotherapy. Furthermore, combination therapy was better tolerated than clomipramine monotherapy. Browne et al11 described 4 patients with severe OCD; 2 improved with the fluoxetine-clomipramine combination after failing trials with these drugs in monotherapy. The other 2 showed further improvement when fluoxetine was added to clomipramine therapy. Doses were 20-60 mg/d for fluoxetine and 50-250 mg/d for clomipramine. Figueroa et al12 reported 7 patients who were effectively treated with a combination of clomipramine and fluvoxamine, paroxetine, or sertraline.

In an open-label comparative study13 (n = 24 evaluated subjects), the addition of sertraline (50 mg/d) to clomipramine (150 mg/d) in OCD patients who had not responded to clomipramine monotherapy (150 mg/d) resulted in better tolerability and greater treatment gains relative to an increase in the clomipramine dose to 250 mg/d. In another open-label RCT,14 the combination of citalopram with clomipramine (n = 9) was associated with greater efficacy than the continuation of citalopram (n = 7) in severely ill patients with OCD, all of whom had previously failed monotherapy trials with clomipramine and fluoxetine. In this RCT, all 9 patients randomly assigned to combination treatment were considered responders.

Marazziti et al15 treated 20 severely ill, clomipramine-refractory OCD patients using a combination of clomipramine (mean dose = 164 mg/d) and citalopram (mean dose = 38 mg/d). OCD ratings dropped by about 20% after 12 weeks and by > 30% at the end of 48 weeks; about half of the sample was considered to have responded to the combination.

In a 12-week RCT,16 54 patients with OCD who had failed fluoxetine monotherapy in the highest recommended or tolerated dose were randomly assigned to receive clomipramine (75 mg/d), quetiapine (200 mg/d), or placebo augmentation of fluoxetine. Clomipramine was dosed at a maximum of 75 mg/d (mean = 56 mg/d), and quetiapine was dosed at a maximum of 200 mg/d. Fluoxetine was dosed at a maximum of 40 mg/d when combined with active medication and at a maximum of 80 mg/d when combined with placebo. OCD ratings decreased by about a quarter with high-dose fluoxetine and with the fluoxetine-clomipramine combination, but there was little improvement in the fluoxetine-quetiapine patients. The response rate in the fluoxetine-clomipramine group was 44%.16

Not all studies found combination therapy effective. For example, Diniz et al17 described a small RCT of 21 evaluable patients with OCD, all of whom had failed to respond adequately to an SSRI. These patients had been randomly assigned to receive SSRI augmentation with either quetiapine (n = 11) or clomipramine (n = 10). Only 1 patient (10%) responded to clomipramine augmentation. In this RCT, most patients received fluoxetine (maximum dose = 40 mg/d) as the SSRI; the target dose of clomipramine was 75 mg/d.

Risks Associated With the SSRI-Clomipramine Combination

SSRI drugs and clomipramine have different adverse effect profiles. What are the adverse effects that have been recorded when clomipramine is combined with an SSRI? Tachycardia (n = 2) and QTc prolongation (n = 2) were described among 7 youths who received an SSRI-clomipramine combination for OCD.12 Two of 22 patients receiving a combination of fluvoxamine (50-200 mg/d) and clomipramine (50-225 mg/d) experienced myoclonic jerks; these 2 patients were receiving fluvoxamine at the doses of 50-100 mg/d and 100-150 mg/d, and clomipramine at the doses of 100-225 mg/d and 37.5-150 mg/d, respectively. The myoclonic jerks remitted when the medication doses were reduced. The combination was otherwise generally well tolerated, with anticholinergic adverse effects and sedation often reported.18

A seizure was reported in a young woman with OCD, 3 months after she attained a fluoxetine dose of 60 mg/d along with a clomipramine dose of 100 mg/d.19 A seizure occurred in a young man treated with fluoxetine (20 mg/d) for OCD, 4 days after his clomipramine dose was increased from 75 mg/d to 100 mg/d.20

In a small RCT,17 5 of 15 patients randomly assigned to clomipramine (target dose, 75 mg/d) augmentation of an SSRI (mostly fluoxetine, dosed at 40 mg/d) dropped out early due to severe constipation. Of the remaining 10 who comprised the sample evaluated in the RCT, an elderly male patient receiving fluoxetine (40 mg/d) with clomipramine (50 mg/d) experienced excessive sweating, tremors, and motor agitation, necessitating treatment discontinuation.

In a study15 of 20 patients, the citalopram-clomipramine combination was associated with a considerable adverse effect burden; problems experienced included anticholinergic symptoms, impairments in sexual functioning, and weight gain. However, these effects were not more than could have been expected given that each drug was used in moderate to high doses (mean citalopram and clomipramine doses of 38 mg/d and 164 mg/d, respectively). In a recent RCT,16 3 of 18 patients receiving a fluoxetine-clomipramine combination developed QTc prolongation and were discontinued from the study.

Mechanisms of Risks Associated With the SSRI-Clomipramine Combination

The SSRI-clomipramine combination may trigger adverse effects through pharmacodynamic and pharmacokinetic mechanisms. The risk of each increases with increasing dose of the drugs in the combination.

When an SSRI and clomipramine are used in low doses, the combination can be expected to be well tolerated. This is because SSRIs are usually associated with a benign adverse effect profile and because low-dose clomipramine is unlikely to cause clinical adverse effects. It is reasonable to assume, however, that adverse effects could be additive; for example, decreased libido or orgasmic dysfunction could be subclinical or mild with the administered dose of each, but could emerge or become more severe when the 2 drugs are combined.15 The risk of QTc prolongation is another example of a possible additive adverse effect, such as when citalopram21 and clomipramine22,23 are combined. It should also be remembered that SSRIs and clomipramine are both serotonergic, and so increasing doses can result in symptoms of serotonergic overstimulation. Examples of such symptoms are anxiety, tremor, akathisia, and insomnia.24 Such symptoms have been described with the fluoxetine-clomipramine combination.17

When the clomipramine dose is moderate to high, the risk of an adverse pharmacokinetic interaction grows. Clomipramine is demethylated by cytochrome P450 (CYP)1A2,25 CYP3A4,25 and CYP2C19,26,27 and clomipramine and its active metabolite desmethylclomipramine are both hydroxylated by CYP2D6.25,28 Therefore, SSRIs that inhibit multiple enzymes could be expected to raise the levels of and hence the risk of adverse effects with clomipramine. In this context, fluoxetine potently inhibits CYP2D6,29 moderately to potently inhibits CYP2C19,29,30 and has a modest to no inhibitory effect on CYP3A4.31-33 Fluvoxamine potently inhibits CYP1A2,29 moderately to potently inhibits CYP2C19,29,30,34,35 modestly inhibits CYP2D6,29 and mildly inhibits CYP3A4, if at all.31,36 Paroxetine strongly inhibits CYP2D6,29 and sertraline inhibits CYP2D6 modestly37 or not at all.38

SSRI inhibitory effects on the CYP enzymes are dose-dependent29 and more apparent in patients who have mutated CYP genes or are extensive metabolizers.34,35 These SSRIs could therefore pharmacokinetically interact with clomipramine to a clinically significant extent, with greater risk of interaction at higher SSRI dosing levels. Citalopram and escitalopram are weak inhibitors of enzymes such as CYP1A2, CYP2C19, and CYP2D637,39 and therefore may not result in clinically significant interactions at usual doses.40

Several pharmacokinetic studies illustrate the interactions between SSRIs and clomipramine. For example, in about half of 22 patients treated with a fluvoxamine-clomipramine combination, clomipramine levels were unacceptably high at 500-1,200 ng/mL, although serious side effects were few.18 Levels were far lower at 11-180 ng/mL with prudent doses of the fluoxetine-clomipramine combination.16 Fluoxetine can treble the level of a coadministered tricyclic antidepressant (TCA).41 A review of literature concluded that fluoxetine, fluvoxamine, and paroxetine can markedly raise blood levels of TCA; sertraline also raises TCA levels, but to a lesser extent, and citalopram probably does not affect TCA levels at all.40

As far as could be ascertained, only 1 study18 has evaluated the effect of clomipramine on blood levels of SSRIs. This study addressed fluvoxamine, a drug the levels of which may not rise with clomipramine (see below). Given that clomipramine modestly to potently inhibits CYP2D642,43 and given that fluoxetine,44 sertraline,45 paroxetine,46 citalopram,47,48 and escitalopram,49 but not fluvoxamine50 are metabolized by this enzyme (CYP2D6), one might expect that clomipramine would dose-dependently increase the levels and hence the adverse effects of these SSRIs. However, most of the SSRIs are metabolized by multiple enzymes,51 and so inhibition of CYP2D6 by clomipramine may not have a substantial impact because SSRI metabolism would continue through metabolic pathways mediated by the other CYP enzyme(s). It should also be remembered that SSRIs are generally well tolerated, and so an increase in SSRI levels may not result in clinically significant consequences.

Pharmacodynamic and pharmacokinetic interactions between SSRIs and clomipramine are summarized in Table 1.

Combining SSRIs With Clomipramine: Suggestions for Practice

As would have been obvious from an earlier section, the risks associated with the SSRI-clomipramine combination are not minor; serotonergic overstimulation, QTc prolongation, myoclonic jerks, and seizures are important concerns. This does not mean that the combination is undesirable; rather, their combination needs to be prudent, and close monitoring is advisable.

What does prudence entail? In simplest terms, both drugs need to be prescribed in lower rather than higher doses, because the risks of pharmacodynamic and pharmacokinetic interactions increase as the doses rise. With the exception of citalopram, which increases the risk of QTc prolongation,21 SSRIs are unlikely to cause serious adverse effects even at higher levels of dosing. However, clomipramine has a narrower therapeutic index, with seizures occurring in 0.48% of patients receiving doses of up to 250 mg/d and 2.1% of patients receiving doses of 300 mg/d and above.52 Given that fluoxetine coadministration, for example, can treble TCA levels,41 a 100-mg/d dose of clomipramine may result in blood levels that could be expected with a 300-mg/d dose if this drug is combined with fluoxetine. The implication, therefore, is that when clomipramine is combined with an SSRI that inhibits clomipramine metabolism (Table 1), doses should ideally be limited to a maximum of 75 mg/d, and, at this dose and higher, blood clomipramine level monitoring is desirable.

Browne et al11 described 2 OCD patients who tolerated and responded to a combination of fluoxetine (60 mg/d) and clomipramine (150-250 mg/d); a third OCD patient tolerated and responded to fluoxetine 20 mg/d and clomipramine 150 mg/d. Amsterdam et al53 described 11 depressed patients in whom fluoxetine (dose not specified) was augmented with clomipramine. The dose of clomipramine was 300 mg/d in 3 patients, 175-250 mg/d in 3 patients, 100-150 mg/d in 3 patients, and 25-50 mg/d in the remaining 2 patients. Only 1 patient had treatment-limiting adverse effects; these were jitteriness and insomnia, and they occurred at a clomipramine dose of 150 mg/d. These findings, combined with the findings of seizures with the fluoxetine-clomipramine combination at lower doses of clomipramine (100 mg/d)19,20 and QTc prolongation at even lower doses (75 mg/d),16 suggest a wide variability in the risk of the interaction across individuals. A reason could be that clomipramine levels at the same dose vary 3- to 14-fold across individuals.54 It could therefore be a good idea to monitor blood clomipramine levels wherever feasible, and to monitor the electrocardiogram (ECG), as well. Clomipramine doses should not exceed 75 mg/d if blood level monitoring is not possible. Finally, all patients receiving the SSRI-clomipramine combination should be carefully monitored for treatment-emergent adverse effects.

These recommendations apply chiefly to situations in which interactions can be expected (Table 1). What about citalopram? Can this drug be safely administered with clomipramine? Citalopram may not have much effect on clomipramine levels,40 although some stray reports on pharmacokinetic interactions have been published.55,56 However, citalopram, especially in higher doses,21 and clomipramine22,23 can each increase the QTc interval. The risk of an additive interaction therefore suggests a need for ECG monitoring when these 2 drugs are combined. Clomipramine can probably be safely administered with escitalopram.

Here are a few final practical suggestions. If higher doses of clomipramine are inevitable, divided dosing or the use of sustained-release formulations will result in lower peak blood levels and hence a lower risk of adverse effects that are related to high levels. Lastly, if the risk of seizures is high because the clomipramine dose or level is high (or because the patient has an epileptic diathesis for any other reason), and if the patient needs to be maintained at the current dosing level lest the treatment benefits are lost, it may make sense to add a low to moderate dose of an anticonvulsant drug. This strategy lacks empirical support but could make sense in the refractory OCD patient who is responding to SSRI-clomipramine combination treatment. A precedent is the similar strategy that is adopted in medication-refractory patients with schizophrenia who are receiving high doses of clozapine.57-60

Notes on Blood Level Monitoring of Clomipramine

If blood level monitoring is desirable in SSRI-treated patients receiving higher doses of clomipramine, what clomipramine levels are safe and appropriate? Unfortunately, there is little consensus on the subject, and standard reference sources do not provide separate ranges for different indications. One study61 in 33 patients with OCD found that average plasma levels were 170 ng/mL for clomipramine and 379 ng/mL for desmethylclomipramine at a mean dose of 239 mg/d; levels were higher in responders than nonresponders after 10 weeks of treatment. In contrast, in depression the threshold for satisfactory response was suggested to be about 160-200 ng/mL for clomipramine and desmethylclomipramine combined.62 Recommendations for clomipramine monitoring could be complicated by the finding that plasma clomipramine levels can vary 3- to 14-fold at a particular dose and schedule of dosing.54

Some authorities cite ranges for clomipramine (30-250 ng/mL) and desmethylclomipramine (150-500 ng/mL) separately,63 whereas others cite levels (150-500 ng/mL) without offering ranges for the drug and its metabolite separately.64 There is also no consensus on whether blood should be drawn 12 hours after the last dose18,63 or at trough level. However, Stein and Fineberg65 suggest that trough levels of clomipramine and desmethylclomipramine combined should usually be kept below 450 ng/mL to minimize toxicity.

Each month in his online column, Dr Andrade considers theoretical and practical ideas in clinical psychopharmacology with a view to update the knowledge and skills of medical practitioners who treat patients with psychiatric conditions.

Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India (candrade@psychiatrist.com).
Financial disclosure and more about Dr Andrade.

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