Managing rapid metabolizers of antidepressants

Depressed patients who rapidly metabolize antidepressants may be common, and may not respond to even high doses of antidepressants if subtherapeutic plasma levels are produced. Rapid metabolizers (RMs) are identifiable if patients are on tricyclic antidepressants (TCAs), and TCA plasma levels (commonly available) are monitored. Strategies to achieve therapeutic levels in RMs include: (1) megaprescribing, or (2) inhibiting the metabolism of the parent drug. Megaprescribing TCAs runs the risk of markedly elevating levels of potentially toxic hydroxy metabolites. In this study twelve depressed, non-responding RMs were identified while taking the TCA, desipramine. Fluoxetine or paroxetine, selective serotonin re-uptake inhibitors (SSRIs) known to potently inhibit cytochrome P450 2D6 (the isoenzyme responsible for desipramine metabolism), was then added to continuing desipramine. Therapeutic range desipramine levels were achieved in ten patients, and seven of the ten achieved excellent or good sustained responses. The combination SSRI and TCA therapy was well tolerated. Whether response primarily reflected the TCA at therapeutic range levels, or a synergistic serotonin-noradrenaline interaction between the respective antidepressants, requires further clarification. The results of this open study suggest the need for controlled trials of antidepressant metabolism inhibition in RMs.