Khan and Macaluso and Diabetic peripheral neuropathic pain (DPNP) in 2004.7 Preclinical studies of duloxetine indicated an anxiolytic effect based on reduction in animal anxiety behaviors.7,8 Finally, duloxetine received FDA approval for the treatment of GAD in February of 2007.7 According to Eli Lilly (the manufac- turer of duloxetine), GAD patients treated with duloxetine in clinical trials showed a 46% improvement in anxiety symptoms when compared with placebo.8 This article will review the pharmacologic proﬁle and seminal clinical trials associated with the FDA indication of duloxetine for GAD. Conﬁdence in the predictability of safety, tolerability and efﬁcacy of a medication is directly proportional to the magnitude and quality of its published trials. The goal of this paper is to assess the amount of information from well- controlled systematic trials. This information forms the basis for evidence-based medical practice and helps clinicians to make the most appropriate decisions. Materials and methods A literature search was performed using PubMed with keywords “duloxetine,” “gad,” “generalized anxiety disorder,” and “venlafaxine XR.” The search yielded 27 articles. We included large, multi-center studies and focused on the seminal papers that led to the FDA approval for duloxetine in GAD. We also focused on papers that pooled data from these seminal studies. Data on ﬁle from Eli Lilly was also reviewed, including data from the Eli Lilly website. We also included information available in the duloxetine package insert, as well as the Physicians Desk Reference (PDR). Before we examine data on the efﬁcacy of duloxetine as a treatment for GAD, we review the basic pharmacology of duloxetine. Pharmacodynamics of duloxetine The ratio of duloxetine`s afﬁnity constants for serotonin (5HT) and norepinephrine (NE) reuptake pumps is closer to 1, meaning it is a more balanced and potent inhibitor for these two reuptake pumps than venlafaxine.9 Duloxetine has a Ki of 0.8 nM for NE and 7.5 nM for 5HT, whereas venlafaxine’s Ki for NE and 5HT are 2480 nM and 82 nM respectively.9 Hence, duloxetine has greater afﬁnity for both 5HT and NE.10 Like venlafaxine and milnacipran, duloxetine has minimal afﬁnity for dopamine, histamine (H1), adrenergic, muscurinic, opiate, gamma amino butyric acid (GABA), and substance P receptors.9 Pharmacokinetics of duloxetine Compared with most antidepressants, duloxetine exhibits some unusual absorption properties. Duloxetine is rapidly 24 hydrolyzed in acidic media to naphthol, which has no antidepressant activity.10 To overcome this issue, the pellets inside the duloxetine capsule are enteric coated, but the capsule is not. This enteric coating of the pellets resists dissolution until pellets reach a segment of the gastrointestinal tract where the pH is favorable. This explains why the maximal plasma concentration (Cmax) of duloxetine usually does not occur until 6 hours post dose.10 Duloxetine has a mean plasma half-life of 12 hours, but it can be dosed once daily as the central nervous system half-life may be very different from the plasma half-life. In one reported study, duloxetine dosed at 20 to 40 mg twice daily in 12 healthy male volunteers exhibited linear pharmacokinetics with steady state plasma concentrations typically reached within 3 days of stable dosing.9 Duloxetine is highly protein bound (96%), primarily to albumin and alpha-1-acid glycoprotein.10 Duloxetine is metabolized by CYP-2D6 and 1A2 isoenzymes with no active metabolites.10 Because of CYP-1A2 metabolism, duloxetine use in smokers results in a one third reduction in bioavailability compared with non-smokers.10 However, there is no clinical recommendation for a dosage adjustment based on smoking status.10 Duloxetine should not be used with CYP-1A2 inhibitors such as ﬂuvoxamine.9 Based on in vitro studies, duloxetine is a more potent inhibitor of CYP 2D6 than CYP 1A2. Concomitant use of duloxetine at a dose of 120 mg/day increased levels of desipramine 3-fold, a model CYP 2D6 substrate, indicating substantial inhibition of CYP 2D6.11 However, the recommended dose of duloxetine for the treatment of MDD is 40 to 60 mg/day. At these recommended doses, the increase in plasma levels of CYP 2D6 substrates drugs like desipramine would be expected to be one third to one half that seen with the 120 mg/day dose (ie, 1 to 1.5 fold increase). This is consistent with the linear pharmacokinetics of duloxetine over this dose range, meaning it has no effect on its own CYP 2D6 mediated clearance.11 The effect of duloxetine on CYP 2D6 is signiﬁcantly less than as seen with fluoxetine or paroxetine at their lowest effective antidepressant doses and approximately the same as seen with escitalopram and citalopram.9 Thus duloxetine should be used with caution when combined with potent inhibitors of CYP-2D6 such as paroxetine and drugs using CYP 2D6 for their own clearance, particularly those with narrow therapeutic indexes, as signiﬁcantly high concentrations of duloxetine may result.10 Duloxetine is excreted in urine (70%) and feces (20%), with less than 1% excreted unchanged (urine).12 Neuropsychiatric Disease and Treatment 2009:5