July 2007

As Depression Becomes More Treatment-Resistant…
For patients who do not respond to initial antidepressant therapy, augmentation, or switch strategies, further augmentation or switching with different agents can bring about remission—but at a lower rate.

New Studies on GAD
Pregabalin and duloxetine (Cymbalta) may be efficacious for adults and venlafaxine (Effexor) for children with generalized anxiety disorder.

Methadone Prolongs QTc Interval
Long-term, high-dose methadone treatment is linked to prolonged QTc intervals.

In Brief
Augmentation for Clozapine Nonresponders; Quetiapine Ineffective for Psychosis/Agitation in Dementia

Effects of Antidepressants on 2D6 Enzymes
Duloxetine (Cymbalta) has substantial and escitalopram (Lexapro) and sertraline (Zoloft and others) more modest inhibiting effects on CYP 2D6.

Effects of Antidepressants on 2D6 Enzymes

July 2007

Many drugs of varying categories are broken down by the 2D6 isoform of the cytochrome P450 (CYP) enzyme system in preparation for elimination from the body. Administering other drugs that inhibit CYP 2D6 activity elevates levels of drugs that rely on 2D6 for their metabolism. Preskorn and others studied the effects of 17 days of treatment with three antidepressants on 2D6 activity by using single-dose pharmacokinetics of the 2D6 substrate metoprolol (Lopressor and others).1 They learned that the area under the plasma concentration-time curve (ie, the effective increase in the substrate drug metabolized via 2D6) increased 180% with duloxetine (Cymbalta), 60 mg daily; 86% with escitalopram (Lexapro), 20 mg/day; and 48% to 67% for sertraline (Zoloft and others), 100 mg/day. Thus, duloxetine had substantial and escitalopram and sertraline more modest inhibiting effects on 2D6.

Sertraline's inhibition of 2D6 increases with increasing doses over the usual clinical range. The authors point out that the amount of 2D6 inhibition (and concomitant elevation of other drugs' blood levels) with these three drugs is much less than that produced by the antidepressants fluoxetine (Prozac and others) or paroxetine (Paxil and others). Knowing which drugs inhibit which enzymes can help predict interactions with clinical consequences.

1Preskorn SH, Greenblatt DJ, Flockhart D, Luo Y, Perloff ES, Harmatz JS, Baker B, Klick-Davis A, Desta Z, Burt T: Comparison of duloxetine, escitalopram, and sertraline effects on cytochrome P450 2D6 function in healthy volunteers. J Clin Psychopharmacol 2007;27:28-34.