Khan and Macaluso effects for duloxetine when compared to placebo (p = 0.007). Male anorgasmia was the main effect noted. However, after 6 months the treatment group showed no statistically signiﬁcant increase in sexual side effects compared with the placebo group (p = 0.677).17 Urinary retention or hesitancy was rarely reported in clinical trials. Less than 2% of patients encountered this side effect, and no patient was catheterized.18 Clinical trials showed no evidence of QT prolongation, effect on glucose metabolism, hematologic abnormalities or difﬁculties with other organ systems.13 There were no reported cases of mania in patients taking duloxetine, compared with 2% of placebo controls. As with SSRIs and venlafaxine, patients taking duloxetine should be carefully monitored for treatment-emergent mania. Concomitant use of a mood-stabilizing medication should be considered in such cases.10 Sudden discontinuation can result in withdrawal symptoms, including but not limited to dizziness, anxiety, nausea, and headache. Because of possible discontinuation syndrome, duloxetine should be tapered rather than stopped abruptly.14 Patients should be made aware of the discontinue syndrome at the start of treatment with duloxetine. However, the above clinical trials showed that “discontinu- ation-emergent adverse events” for duloxetine were statistically significant comparable to placebo.13,14 The venlafaxine comparator arm of study 3 also showed statistically signiﬁcant “discontinuation-emergent adverse events” compared with placebo.14 In May of 2007 the FDA expanded its black box warning regarding antidepressant medication and suicidality to include young adults aged 18 to 24 years. A case series by Parikh et al showed a close relationship between suicidality and duloxetine use. In the cases presented, suicidal ideation was linked to an increase in duloxetine dose.19 In all cases presented, patients were no longer suicidal upon discontinu- ation of duloxetine. All patients prescribed antidepressant medication should provide appropriate informed consent on the risk of suicidality prior to the start of treatment. Having reviewed the basic pharmacology and safety data on duloxetine, we will now look at the bedrock studies that led to FDA approval for the treatment of GAD. Efﬁcacy in GAD We will discuss data from clinical trials that were designed to assess the efﬁcacy of duloxetine in treating patient’s meeting DSM-IV-TR criteria for GAD.3,13,14 Each study utilized the Hamilton Rating Scale for Anxiety (HAM-A) 26 score as the primary efﬁcacy measure. Secondary efﬁcacy measures included HAM-A items for tension and anxious mood, HAM-A Psychic and Somatic Factors, Hospital Anxiety and Depression Scale (HADS), Clinical Global Impressions Improvement scale (CGI-I) scores, and Patient Global Impression-Improvement Scale (PGI-I).3,13,14 The ﬁrst study was a 9-week, double-blind, placebo controlled trial of 513 patients meeting DSM-IV-TR criteria for GAD.3 Inclusion criteria included age 18 years, and a primary diagnosis of GAD as obtained using the Mini Neuropsychiatric Interview for DSM-IV-TR.3 Patients were recruited from 42 outpatient treatment centers in 7 countries including the United States and parts of Europe. The mean age of study participants was 43.8 years of age, with 67.8% females.3 Patients were screened including medical history and physical examination with EKG, renal function tests, thyroid function tests, and urine drug screens. Patients were required to score at least 4 on the Clincical Global Impressions-Severity of Illness scale (CGI-SI). Patients were also required to score at least 10 on the Hospital Anxiety and Depression (HAD) anxiety subscale and at least 9 on the COVI anxiety scale.3 Unlike previous efﬁcacy studies involving venlafaxine, the patients were evaluated using the HAM-A, but were not selected based on a minimum HAM-A score. Patients were also evaluated using the Sheehan Disability Scale (SDS). Response, remission and sustained improvement rates were also documented.3 Exclusion criteria for the study included a diagnosis of MDD (patients could not score 3 on any item of the Raskin Depression Scale) or substance use disorder within the past six months. Exclusion criteria also included a past year diag- nosis of post-traumatic stress disorder, panic disorder, eating disorder, any prior history of a psychotic disorder, obsessive compulsive disorder, and bipolar disorder. Patients under- going psychotherapy within 6 weeks of the study were also excluded from participation in the study.3 Patients were also excluded if they underwent 2 previous unresponsive trials of antidepressant or benzodiazepine medication for GAD. Patients were required to be free of all psychotropic medi- cations for 2 to 4 weeks prior to randomization, depending on the psychotropic medication in question.3 Altogether 126 patients were excluded from the study based on these criteria.3 All patients received single-blinded placebo treatment for 1 week before being randomized to receive placebo, 60 mg/day of duloxetine, or 120 mg/day of duloxetine. Neuropsychiatric Disease and Treatment 2009:5