and Polkhinghorn 2005). A statistically signiﬁcant effect size (Cohen’s d = 0.38 ± 0.15; p 0.0001) was noted for the ben- zodiazepines compared to placebo in the treatment of GAD using meta-analysis (Hidalgo et al 2007). However, concerns about their long term use, particularly issues of tolerance and dependence, have seen a general reluctance to use benzodi- azepines in clinical practice (Schweizer and Rickels 1998). Antidepressant medications have been extensively used in the treatment of various anxiety disorders and the evidence for their efﬁcacy in panic disorder, obsessive compulsive disorder and to a lesser extent in social anxiety disorder is well documented (Gorman 2002). More recently the effectiveness of antidepressants in GAD has been evaluated in a number of double-blind, placebo controlled clinical trials. The efﬁcacy of the selective serotonin reuptake inhibitors (SSRIs) in GAD has been frequently canvassed (Baldwin and Polkinghorn 2005). Beyond the SSRIs interest has been shown in so called “dual acting” antidepressants, most recently duloxetine. Pharmacolgy of duloxetine Mechanism of action Duloxetine ((+)-(S)-N-methyl-γ-(1-naphthalenyloxy)- 2-thiophene-propanamine) inhibits serotonin (5HT) and noradrenaline (NE) reuptake into nerve endings or slice preparations with the NE/5HT ratio between 2 and 9 both in vivo and in vitro (Kasamo et al 1996; Wong 1998). The drug has a high afﬁnity for human cloned serotonin and noradrena- line transporters in vitro and is more potent than venlafaxine (Bymaster et al 2001). Duloxetine has low afﬁnity for a range of other serotonin, muscarinic, adrenergic and histaminer- gic receptors and does not signiﬁcantly inhibit monoamine oxidase A or B activity (Bymaster et al 2001). Microdialysis studies of acute doses showed that duloxetine signiﬁcantly enhanced the release of extra-cellular levels of both serotonin and noradrenaline in the pre-frontal cortex and hypothalamus of drug naïve rats (Engelman et al 1995). On the other hand, an in vitro study in healthy volunteers are at odds with the animal data and suggest that at doses of 20 and 60 mg/day duloxetine was selective for serotonin reuptake inhibition (Turcotte et al 2001). At higher doses (80 and 120 mg/day) an effect on noradrenaline reuptake was evident (Vincent et al 2004). The pharmacology of duloxetine implies that it is the effect on both serotonin and noradrenaline reuptake which may account for the antidepressant activity of the drug. Pharmacokinetics Duloxetine pharmacokinetics was determined after single and multiple oral doses in healthy volunteers. Duloxetine is Neuropsychiatric Disease and Treatment 2008:4(6) Duloxetine for GAD administered as an enteric coated pellet formulation due to its acid lability (Bymaster et al 2005). The drug exhibited linear pharmacokinetics in healthy male volunteers who received 20 mg twice daily with a dose escalation at weekly intervals to 30 and 40 mg twice daily (Sharma et al 2000). Steady state plasma concentrations were attained within 3 days for each dosing regimen in this study. The effect of food on the rate of absorption of duloxetine was investigated in 12 healthy female volunteers following a single oral dose of 40 mg (Skinner et al 2000). The subjects received the drug on 4 sepa- rate occasions separated by one week: after an overnight fast; 15 minutes after a high fat meal; at bedtime and again after an overnight fast. Both food and night time administration delayed the time to maximum concentration (by a mean of 4 hours) but only bedtime administration reduced the extent of absorption (AUC decreased ∼18%). The effects of food were considered to be relatively modest. A median 2-hour lag time was apparent until absorption began (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring about 6 hours after the dose. The apparent volume of distribution of duloxetine is large. On repeated dosing the mean apparent volume of distribution for duloxetine was 1943 L with a range of 803 to 3531 L (Sharma et al 2000). In this study the mean apparent oral clearance was 114 L/h with a range of 44 to 218 L/h (Sharma et al 2000). The data in young and elderly females after a single oral dose of 40 mg agree reasonably well with the data obtained for males (Skinner et al 2003). Thus the mean apparent clearance was 70.3 L/h and the mean apparent volume of distribution was 962 L in younger women (32–50 years). Age had no statistically signiﬁcant effect on these parameters in elderly women (65–77 years) with a mean clearance 52.9 L/h and mean volume of distribution 1077.9 L (Skinner et al 2003). Duloxetine is highly bound ( 90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evalu- ated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment. The mean elimination half-life of duloxetine is about 12 hours (range 7–27 hours) (Sharma et al 2000; Skinner et al 2003). Following single oral doses of 20, 40 or 60 mg and multiple oral doses of 20 or 40 mg for 5 days there were no clinically signiﬁcant differences in the pharmacokinetics of Japanese and Caucasian subjects (Chan et al 2007). Similarly a retrospective comparison of phar- macokinetic parameters obtained after single and multiple oral dosing with 60 mg in healthy Chinese volunteers were consistent with the data obtained for Japanese and Caucasian subjects (Tianmei et al 2007). 1171