When Fluvoxamine Treats Only Depression and Clomipramine Treats Only Obsessive-Compulsive Disorder—Combine Them?

SIR: We present a case of a 38-year-old man with a 10-year history of severe obsessive-compulsive disorder (OCD), major depression (MD), and comorbid attention-deficit/hyperactivity disorder (ADHD). This case demonstrates either that fluvoxamine and clomipramine (CMI) can differ greatly in their target of pathology, or that their combination creates a beneficial therapeutic pharmacodynamic environment.¹

Specifically, the patient's 5-year trial of 250 mg (blood level 590 μg/ml) clomipramine treated only OCD. A subsequent, independent 200-mg fluvoxamine trial for 15 months treated only his depression, during which time his OCD remained incapacitating. However, when we combined these drugs at nontoxic doses, both disorders responded well. That is, the comorbid disorders (MD and OCD) were treated successfully with the combination, when full independent trials of each were not effective for both OCD and MD.

Traditionally, most psychiatrists expect patients on selective serotonin reuptake inhibitors (SSRIs) or CMI to get side effects the first week, an antidepressant effect in the following weeks, and finally an anti-OCD benefit. In this case, clomipramine, which targets all three of this patient's conditions, helped only his OCD at a high therapeutic blood level of 590 μg/ml (250 mg/day). During a 5-year trial on this dose, the patient's rituals decreased 70% and his obsessions 50%; this allowed him to be functional in terms of his OCD. However, he remained profoundly depressed, as measured by a Beck Depression Inventory (BDI) score of 43, and showed both passive suicidal ideation and severe anhedonia. Further undermining the traditional view, when he was changed to fluvoxamine monotherapy, his depression fell into the normal range on multiple depression scales, but his OCD was incapacitating, with a score of 39 on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). We could not blame the failure of each antidepressant to treat both OCD and depression on short trials or low doses because his clomipramine had been at a high blood level for 5 years and his fluvoxamine trial was 200 mg/day for 15 months. The failure to treat both OCD and depression did not fit the traditional view that one needs a longer trial or a higher dose. Certainly it would have been possible to prescribe higher, possibly dangerous experimental CMI doses, but we felt it more appropriate to combine both drugs carefully.

When this patient first presented, our initial expectation, from a very brief 4-week study by Szegedi et al.,² was that the combination of the two drugs would cause a significant increase in CMI levels. This useful but limited 4-week study did not answer our questions as to why a therapeutic dose of clomipramine for 5 years would affect only OCD and why a long trial of therapeutic fluvoxamine would treat only major depression. It did, however, alert us to the need for caution in combining these two drugs. Also, although one study has shown that fluvoxamine has the least effect on the CYP2D6 system when compared with other SSRIs,³ there was nevertheless a need for significant caution—specifically, because fluvoxamine is an inhibitor of CYP1A1-2, CYP2C19, CYP3A3-4, and CYP2D6, and clomipramine is a substrate of all four.^4,5

At intake, we discontinued the patient's CMI to allow for a safe fluvoxamine start. As expected from his history, he promptly became severely troubled by his OCD. We then started fluvoxamine, raised it to 200 mg for his depression, and slowly added small doses of clomipramine to create less risk of cardiac arrhythmia or seizure. Over the course of approximately 5 months the patient was finally put on fluvoxamine 100 mg qam and qhs and CMI 25 mg (CMI level 550 mg/ml). Our patient had no side effects and was successfully treated for both depression and OCD. His Y-BOCS total score was only 10, and his Inventory to Diagnose Depression score was 9 (normal range). He resumed full-time work for the first time in 8 years and has stayed well for 16 months.

Because of the tremendous complexity of clomipramine metabolism in the presence of fluvoxamine, we cannot fully determine from this case the reason for our success. It is possible that there is a subgroup of individuals for whom clomipramine and fluvoxamine have different neurochemical targets. Or it may be that clomipramine in the presence of high-dose fluvoxamine, which creates a novel pharmacodynamic environment with different metabolite levels and altered ratios, makes one or both of the drugs more effective. We do believe that this case is useful in proposing two major explanations for our success and calls into question the traditional view that more time and a higher dose are indicated for a treatment-resistant, depressed OCD patient.

It is also of interest that years earlier, the patient had been placed on the combination amphetamine and dextroamphetamine (Adderall) with significant benefit to his ADHD symptoms. When we added this drug again, we saw a marked decreased in his ADHD symptoms, but also an immediate doubling of his Y-BOCS score. When we replaced the Adderall with methylphenidate 15 mg tid, his obsessions virtually ceased and his ADHD symptoms remitted.