Dosing Clinical trials studying the efﬁcacy of duloxetine in the treatment of GAD utilized doses ranging from 60 mg to 120 mg daily.3,13,14 Duloxetine is available in capsules of 20 mg, 30 mg, and 60 mg strengths. According to the manufacturer, the recommended dose of duloxetine in GAD is 60 mg/day.7 The manufacturer states: “There is no evidence that doses greater than 60 mg/day confers additional beneﬁt, while adverse reactions such as dizziness, fatigue, somnolence, constipation, and decreased appetite were observed to be dose-dependent.”7 Safety Pooled data from clinical trials involved four cases of over- dose ingesting up to 1400 mg of duloxetine, with no reported fatalities. For the purposes of the studies, overdose was deﬁned as dose 240 mg. Cardiovascular adverse events and toxicity in overdose associated with venlafaxine do not seem to be a concern with duloxetine.14 Duloxetine is not recommended for patients with end stage renal disease (ESRD), because following a single dose of 60 mg of duloxetine, the elimination half-life remains the same, but the Cmax and AUC (area under the curve used to estimate bioavailability) values are approximately 100% greater compared with individuals with normal renal function.15 Because hepatic insufficiency impairs duloxetine metabolism, some researchers have suggested that such patients not be prescribed duloxetine.13 After a single dose of 20 mg, the half-life of duloxetine was 3 times longer, the mean AUC was 5 times greater, and the plasma clearance was 6 to 7 times less in 6 cirrhotic patients with moderate liver impairment versus what was seen in age and gender matched healthy controls.9 Preclinical studies demonstrated the potential for substantial central pharmacodynamic drug-drug interactions when duloxetine as well as other 5HT and NE uptake inhibitors are coadministered with drugs having speciﬁc effects on central 5HT, NE, and DA mechanisms.9 Such 5HT and NE reuptake pump inhibitors include tertiary and secondary amine tricyclic antidepressants (TCAs), selective 5HT uptake inhibitors (SSRIs), selective NE uptake pump inhibitors (eg, reboxetine), and other dual 5HT and NE uptake pump inhibitors (eg, venlafaxine and milnacipran). For simi- lar reasons, the duloxetine package insert includes a warning against using duloxetine in combination with monoamine oxidase inhibitors (MAOIs).7 Such a combination has the potential to cause both a serotonin syndrome, as can occur with simultaneous administration of an SSRI and a MAOI, Neuropsychiatric Disease and Treatment 2009:5 Duloxetine for GAD and a hypertensive crisis, as can occur with the combined administration of an selective NE reuptake pump inhibitor (eg, desipramine or reboxetine) and a MAOI.7 Duloxetine is currently pregnancy category C and possible effects on labor, delivery, and a developing fetus are unknown at this time.10 Use of duloxetine during pregnancy should be supervised by an expert, only after careful assessment of risk, patient education, and informed consent.10 Data from 4 randomized, double-blind, placebo controlled trials of duloxetine in patients 65 years of age showed it to be a safe treatment modality in elderly with GAD. The study showed a high rate of discontinuation (22.2%) due to adverse effects.16 Adverse effects Patients should be made aware of the risks, beneﬁts, possible side effects and alternatives associated with any medication prior to treatment. Pooled data from 3 clinical trials revealed a 16% discontinuation rate for patients treated with duloxetine compared with only 4% for placebo.8 The venlafaxine comparator arm of one study showed only an 11% discontinu- ation rate, which was lower than the 23% discontinuation rate shown in previous pooled data.14 The most common adverse effects included nausea, fatigue, dry mouth, somnolence, vomiting, insomnia, and sexual side effects.8 Side effects commonly associated with duloxetine are similar to those seen with venlafaxine or SSRIs. Nausea and insomnia are common side effects of duloxetine, although nausea seems to be less common than with SSRIs. After the ﬁrst week of treatment, nausea rates associated with duloxetine are comparable to placebo.13 PDR indicates a nausea rate of 31% with venlafaxine, compared to 22% with duloxetine, at 75 to 225 mg and 40 to 120 mg respectively.12 Eight- to nine-week clinical trials studying duloxetine use in depression resulted in a 1.1 lb (1 lb = 0.45 kg) weight loss in the treatment group compared to a 0.5 lb weight gain in the placebo group.3,13,14 One year follow-up data showed a weight gain of 2.46 lb for patients in the treatment group, but no placebo group data were available.10 Clinical trial data showed clinically insigniﬁcant elevations in liver function tests in some patients, with most experts recommending that duloxetine not be used in those with a history of severe liver abnormalities. On follow-up, abnormalities in liver function tests were noted to decrease, regardless of whether or not the patient stopped using duloxetine.3 Sexual side effects were measured prospectively utilizing the Arizona Sexual Experience Scale (ASEX). Short-term clinical trials showed statistically signiﬁcant sexual side 25