non-cardiogenic pulmonary edema. A series of 4 case reports suggesting a close temporal relationship between duloxetine use and the emergence of suicidal ideation in adult patients has been reported (Parikh et al 2008). In each of the cases suicidal ideation emerged in the context of increasing the dose of duloxetine. These ideas resolved when duloxetine was stopped. Another pooled analysis was performed on the tolerability data for 23,983 patients exposed to duloxetine in 64 studies for any indication, including GAD (Gahimer et al 2007). The most common treatment emergent adverse events were nausea, headache, dizziness, dry mouth, constipation, insom- nia, somnolence, hyperhidrosis, diarrhea and fatigue. These effects were reported to emerge early in treatment and were of mild to moderate severity. Generally they were tolerated with time. Increases in systolic and diastolic blood pressure on average were 1 mmHg. It can be concluded for these analyses that duloxetine at the doses used results in side effects consistent with the known pharmacological proﬁle of the drug. In general the compound is well tolerated by most patients, at least in the short term. Some information on long term safety is avail- able from studies in depression. An open label extension of duloxetine in doses of 60 to 120 mg/day was conducted in 81 patients with major depressive disorder for up to two years of treatment (Wohlreich et al 2007). Treatment emergent side effects included upper respiratory tract infection (13.1%), headache (10.7%), insomnia (10.7%), anxiety (9.5%), weight gain (9.5%), nasopharyngitis (8.3%), constipation (7.1%), hyperhidrosis (7.1%) and abnormal dreams (6.0%). Both diastolic and systolic blood pressure were increased by about 1 mmHg and heart rate was increased by a mean of about 3 bpm. The data suggest that duloxetine is not associated with major side effects on long term administration. Nevertheless the database is relatively small. Further data on the longer term use of the drug and its safety and tolerability in patients with GAD are required. Cardiovascular and electrocardiographic effects Of growing concern in the use of many medications has been the risk of sudden cardiac death associated with prolongation of the corrected QT interval (QTc) (Fermini and Fossa 2003). The effects of supra-therapeutic exposures to duloxetine were evaluated in 117 healthy female volunteers using a random- ized, double-blind, placebo controlled, cross-over study (Zhang et al 2007). Subjects received placebo for 22 days or duloxetine for 20 days with a 14 day washout period between Neuropsychiatric Disease and Treatment 2008:4(6) Duloxetine for GAD regimens. In addition each subject received a single oral dose of 400 mg moxiﬂoxacin before or after the placebo/duloxetine treatment as a positive control. Duloxetine was administered to a maximum dose level of 200 mg twice daily using a step-wise dose escalation procedure. ECG was recorded at four time points (2, 6, 10 and 12 hours) at baseline, fourth day of duloxetine dosing, and at the two highest dose levels (160 mg bd and 200 mg bd). Following moxiﬂoxacin ECG was recorded 2 and 6 hours after dosing. Data were analyzed using 3 QT interval correction methods: mixed effects analysis of covariance with RR interval change from baseline as the covariate, Fridericia’s correction method and an individual QT correction method. The mean QTc interval was not prolonged for any of the three correction methods. On the contrary mean QTc interval decreased from baseline. Moxiﬂoxacin prolonged QTc at all time points regardless of the correction method. Duloxetine at supra-therapeutic doses is unlikely to affect the QT interval in healthy subjects. These ﬁndings are consistent with the data obtained in clinical trials where mean change in the QRS width of the electrocardiogram was judged not likely to be of clinical signiﬁcance (Hudson et al 2005). A further evaluation of the cardiovascular safety of duloxetine was performed based on all patients exposed to the drug in clinical trials up to December 2005 (Wericke et al 2007). A total of 8504 patients from 42 trials were included in the analysis. The safety proﬁle was based on vital signs, ECGs and emergent events potentially related to cardiovascular effects of the drug. Duloxetine treated patients were more likely than placebo treated patients to have increases in heart rate and decreases in QTc (Fridericia’s correction) interval. However none of the changes observed were regarded as clinically signiﬁcant. Only one duloxetine treated patient had a prolongation of the QTc interval to 500 msecs (from 499 msecs at base- line to 514 msecs at maximum post baseline observation). In duloxetine-treated patients mean increase in systolic and diastolic blood pressure was 0.65 mmHg and 0.88 mmHg respectively. There was no evidence for a sustained increase in blood pressure associated with the use of duloxetine. Cardiovascular-related adverse events such as palpitations, tachycardia, orthostatic hypotension, hypertension and peripheral edema occurred in duloxetine treated patients to about the same extent as in placebo treated patients. With the exception of palpitations (1.5% for duloxetine treated patients) these events occurred with a frequency less than 1%. Discontinuation events In the placebo controlled studies evidence for discontinu- ation effects following cessation of duloxetine was sought 1177