Norman and Olver Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP1A2. Biotransformation and disposition of dulox- etine has been determined following oral administration of 14C-labeled duloxetine (Lantz et al 2003). Unchanged duloxetine comprised about 3% of the total radio-labeled material in plasma, indicating that it underwent extensive metabolism to numerous metabolites. The major biotrans- formation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulphate. Many additional metabolites have been identiﬁed in urine, some representing only minor pathways of elimination. Only trace ( 1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabo- lites of duloxetine; about 20% is excreted in the feces (Lantz et al 2003). As would be expected for a drug extensively metabolized by the liver, patients with hepatic impairment arising in the context of cirrhosis show alterations in single dose pharmacokinetics (Suri et al 2005). Following a single oral dose of 20 mg apparent plasma clearance was lower (24 versus 160 L/h) and systemic exposure (as measured by AUC values) was higher (775 versus 268 ng/h/mL) in the cirrhotic patients compared to healthy controls. For these same subjects mean elimination half life was 3 times longer (47.8 versus 13.5 h) in cirrhotic patients compared to healthy volunteers. Use of duloxetine in generalized anxiety disorder Pre-clinical data Evidence for the use of antidepressants in the treatment of anxiety disorders, at least based on the available animal models, is not well supported (Borsini et al 2002). Many of the models are established on their ability to detect the activity of the benzodiazepines and may not be representative for other classes of agents. In the case of antidepressants two factors may mitigate against the chances of positive results: clinical effects are often observed with chronic administra- tion whereas the animal models for the most part rely on acute effects; many antidepressants, at least initially, are anxiogenic. Pre-clinical evidence for the anxiolytic effect of duloxetine has been observed after chronic administra- tion in one animal model of anxiety (Troelsen et al 2005). The effects of 21 days treatment with 10 mg/kg twice daily 1172 of duloxetine, citalopram, reboxetine and amitriptyline in the zero maze were compared to their effects after acute admin- istration. None of the agents was anxiolytic in this test after acute doses and indeed there was evidence for anxiogenic effects of reboxetine, duloxetine and amitriptyline. Only chronic duloxetine administration produced an anxiolytic response dissociable from non-speciﬁc motor effects in this task. The anxiolytic effect was attributed to the reduction in the serotonin transporter protein in the cortex of mice treated with duloxetine. Clinical data Duloxetine was approved for the treatment of GAD by both the US Federal Drug Administration and the British authorities early in 2007. Despite this approval there are relatively little published data to support its use in this con- dition, although a priori it would be expected to be effective given similar data for other “dual acting” compounds such as venlafaxine. It has been speculated that all SNRI anti- depressants (venlafaxine, duloxetine, milnacipran) might have similar efﬁcacy across a range of conditions including depression, chronic pain, PTSD, panic disorder and social anxiety disorder (Stahl et al 2005; Baldwin 2006). Among the ﬁrst indications that duloxetine might be suit- able for the treatment of anxiety symptoms was an analysis of its effect in trials of major depressive disorder (Dunner et al 2003). Four placebo controlled trials were evaluated and its potential anxiolytic effect assessed from the changes on the anxiety/somatization factor and psychic anxiety (item 10) of the Hamilton Depression Rating Scale (HAM-D). In two of the studies (Goldstein et al 2002; Goldstein et al 2004), data from the Hamilton Anxiety Rating Scale (HAM-A) were also available. Within the limitations of the data set (exclusion of patients with primary anxiety disorder in past 12 months) duloxetine was more effective than placebo in alleviating anxiety symptoms in these depressed patients. The dose of duloxetine ranged from 40 to 120 mg/day. The study could not assess whether the effect on anxiety symptoms occurred independently of the effect on the symptoms of depression. In this pooled comparison duloxetine was also noted to be more effective than either of the comparator agents, paroxetine and ﬂuoxetine. For both comparator agents the dose was ﬁxed and the number of patients was smaller than the total number of patients treated with either duloxetine or placebo. The possibility that the result arises because of a statistical artefact cannot be overlooked. Recent clinical trials have investigated the efﬁcacy of duloxetine for the treatment of patients with GAD. Each of the Neuropsychiatric Disease and Treatment 2008:4(6)