Current mood:

complacent

Duloxetine for the treating generalized panic disorder: an assessment
Copyright © 2009 Khan and Macaluso, publisher and licensee Dove Medical Press Ltd. It is deemed an Open Access article which permits unrestricted noncommercial use, provided the initial work is properly cited. Duloxetine for the management of generalized anxiety: an appraisal
Ahsan Y Khan and Matthew Macaluso
Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine-Wichita, Wichita, KS, USA
Correspondence: Ahsan Y Khan, MD, Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine-Wichita, 1010 N. Kansas Street, Wichita, KS 67214, USA, Email akhan/at/kumc. edu

• Other Sections
  • Abstract
  • Introduction
  • Materials and methods
  • Pharmacodynamics of duloxetine
  • Pharmacokinetics of duloxetine
  • Dosing
  • Safety
  • Adverse effects
  • Efficacy in GAD
  • Chronic pain
  • Venlafaxine XR
  • Future studies
  • Conclusion
  • References

Abstract
Approximately 16 million people in the usa have problems with anxiety attacks alone, while another 12 million experience both anxiety and a minimum of another psychiatric condition. Generalized panic attacks (GAD) has lifetime prevalence rates between 5% and 6%. Treating GAD is aimed primarily at symptom reduction. Duloxetine, a serotonin norepinephrine reuptake inhibitor (SNRI), received Federal drug administration (FDA) approval with the therapy for GAD in 2007. This informative article reviews the pharmacologic profile and seminal many studies from the FDA indication of duloxetine for GAD. A literature search performed using PubMed together with the keywords “duloxetine”, “gad”, “generalized anxiety disorder”, and “venlafaxine XR” yielded 27 articles. We dedicated to papers that pooled data on the market seminal studies. Data on file from Eli Lilly were also reviewed, including data from the Eli Lilly website. Determined by this search, duloxetine was discovered to become an FDA-approved treatment selection for GAD which has been studied in several double-blind, placebo-controlled numerous studies. This report on duloxetine can help physicians to interpret studies properly plus make them to create the best decision about which patients will be the best suited candidates for a trial of duloxetine. Keywords: duloxetine, generalized anxiety disorder, clinical trials, serotonin norepinephrine reuptake inhibitor (SNRI)

• Other Sections
  • Abstract
  • Introduction
  • Materials and methods
  • Pharmacodynamics of duloxetine
  • Pharmacokinetics of duloxetine
  • Dosing
  • Safety
  • Adverse effects
  • Efficacy in GAD
  • Chronic pain
  • Venlafaxine XR
  • Future studies
  • Conclusion
  • References

Introduction
Panic disorders were classified as neurotic disorders till the establishment from the DSM-III in 1980. Approximately 16 million people in the states are afflicted by anxiety conditions alone, while another 12 million experience both anxiety and at least an added psychiatric disorder. 1
Generalized anxiety (GAD) involves excessive bother about everyday activity events, on more days absolutely nothing, to get a period of at least Six months. 2 According to DSM-IV-TR, patients must determine it “tricky to control the worry” and should present with 3 with the following 6 criteria: restlessness or feeling keyed up, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance. 2 Patients with GAD often present hyper-vigilant, with somatic complaints for example musculoskeletal pain or gastrointestinal disturbance. 3 GAD has lifetime prevalence rates between 5% and 6%, and a male to female ratio of a single:2. 4
Treatments for GAD is targeted at symptom reduction, often utilizing selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), buspirone, benzodiazepines and/or psychotherapy. In 1991, Butler et al published evidence supporting using cognitive behavioral therapy (CBT) inside management of GAD. 5 Both venlafaxine and duloxetine have already been Food (FDA) approved for the treatments for GAD. Another SNRI, milnacipran, isn't yet for sale in north america, but is used clinically to deal with major depressive disorder (MDD) and chronic pain in other regions around the globe including Europe. 6 Duloxetine, an SNRI, received FDA approval for MDD and Diabetic peripheral neuropathic pain (DPNP) in 2004. 7 Preclinical studies of duloxetine indicated an anxiolytic effect according to decline in animal anxiety behaviors. 7,8 Finally, duloxetine received FDA approval for your treatment of GAD in February of 2007. 7 As outlined by Eli Lilly (the manufacturer of duloxetine), GAD patients treated with duloxetine in clinical studies showed a 46% improvement in anxiety symptoms as compared to placebo. 8
This information will look at the pharmacologic profile and seminal numerous studies from the FDA indication of duloxetine for GAD. Confidence inside the predictability of safety, tolerability and efficacy of a medicine is directly proportional to your magnitude and excellence of its published trials. The goal of this paper is usually to appraise the quantity of information from well-controlled systematic trials. These records forms the idea for evidence-based medical practice helping clinicians to create the most likely decisions.

• Other Sections
  • Abstract
  • Introduction
  • Materials and methods
  • Pharmacodynamics of duloxetine
  • Pharmacokinetics of duloxetine
  • Dosing
  • Safety
  • Adverse effects
  • Efficacy in GAD
  • Chronic pain
  • Venlafaxine XR
  • Future studies
  • Conclusion
  • References

Materials and techniques
A literature search was performed using PubMed with keywords “duloxetine,” “gad,” “generalized panic disorder,” and “venlafaxine XR. ” The search yielded 27 articles. We included large, multi-center studies and aimed at the seminal papers that resulted in the FDA approval for duloxetine in GAD. We also dedicated to papers that pooled data from all of these seminal studies. Data on file from Eli Lilly had also been reviewed, including data in the Eli Lilly website. We also included information obtainable in the duloxetine package insert, in addition to the Physicians Desk Reference (PDR). Before we examine data about the efficacy of duloxetine to be a treatment for GAD, we assess the basic pharmacology of duloxetine. Pharmacodynamics of duloxetine
Exactely duloxetine’s affinity constants for serotonin (5HT) and norepinephrine (NE) reuptake pumps is nearer to 1, meaning it is a more balanced and potent inhibitor for these particular two reuptake pumps than venlafaxine. 9 Duloxetine has a Ki of 0. 8 nM for NE and 7. 5 nM for 5HT, whereas venlafaxine’s Ki for NE and 5HT are 2480 nM and 82 nM respectively. 9 Hence, duloxetine has greater affinity for both 5HT and NE. 10 Like venlafaxine and milnacipran, duloxetine has minimal affinity for dopamine, histamine (H1), adrenergic, muscurinic, opiate, gamma amino butyric acid (GABA), and substance P receptors. 9

• Other Sections
  • Abstract
  • Introduction
  • Materials and methods
  • Pharmacodynamics of duloxetine
  • Pharmacokinetics of duloxetine
  • Dosing
  • Safety
  • Adverse effects
  • Efficacy in GAD
  • Chronic pain
  • Venlafaxine XR
  • Future studies
  • Conclusion
  • References

Pharmacokinetics of duloxetine
Weighed against most antidepressants, duloxetine exhibits some unusual absorption properties. Duloxetine is rapidly hydrolyzed in acidic media to naphthol, with no antidepressant activity. 10 To get over this matter, the pellets from the duloxetine capsule are enteric coated, nevertheless the capsule will not be. This enteric coating from the pellets resists dissolution until pellets reach a segment in the gastrointestinal tract in which the pH is favorable. This explains why the maximal plasma concentration (Cmax) of duloxetine usually does not occur until 6 hours post dose. 10
Duloxetine incorporates a mean plasma half-life of 12 hours, but it really is usually dosed once daily because the nerves inside the body half-life is quite not the same as the plasma half-life. In a single reported study, duloxetine dosed at 20 to 40 mg two times a day in 12 healthy male volunteers exhibited linear pharmacokinetics with steady state plasma concentrations typically reached within 72 hours of stable dosing. 9 Duloxetine is tremendously protein bound (96%), primarily to albumin and alpha-1-acid glycoprotein. 10
Duloxetine is metabolized by CYP-2D6 and 1A2 isoenzymes with no active metabolites. 10 On account of CYP-1A2 metabolism, duloxetine used in smokers generates a a third decline in bioavailability compared to non-smokers. 10 However, there is absolutely no clinical recommendation for any dosage adjustment according to smoking status. 10 Duloxetine should not be combined with CYP-1A2 inhibitors like fluvoxamine. 9
Dependant on in vitro studies, duloxetine is a more potent inhibitor of CYP 2D6 than CYP 1A2. Concomitant usage of duloxetine at a dose of 120 mg/day increased levels of desipramine 3-fold, a model CYP 2D6 substrate, indicating substantial inhibition of CYP 2D6. 11 However, the recommended dose of duloxetine for the therapy for MDD is 40 to 60 mg/day. At these recommended doses, the rise in plasma degrees of CYP 2D6 substrates drugs like desipramine can be expected to be one third to one half that seen with the 120 mg/day dose (ie, One to one. 5 fold increase). This is consistent with the linear pharmacokinetics of duloxetine over this dose range, meaning they have no affect on a unique CYP 2D6 mediated clearance. 11 The issue of duloxetine on CYP 2D6 is quite a bit lower than as seen with fluoxetine or paroxetine at their lowest effective antidepressant doses and approximately much like seen with escitalopram and citalopram. 9 Thus duloxetine should be in combination with caution when coupled with potent inhibitors of CYP-2D6 such as paroxetine and drugs using CYP 2D6 for his or her own clearance, in particular those with narrow therapeutic indexes, as significantly high concentrations of duloxetine may result. 10
Duloxetine is excreted in urine (70%) and feces (20%), with lower than 1% excreted unchanged (urine). 12
Dosing
Clinical trials staring at the efficacy of duloxetine inside the therapy for GAD utilized doses including 60 mg to 120 mg daily. 3,13,14 Duloxetine will come in capsules of 20 mg, 30 mg, and 60 mg strengths. Based on the manufacturer, the recommended dose of duloxetine in GAD is 60 mg/day. 7 The producer states: “There's no evidence that doses in excess of 60 mg/day confers additional benefit, while adverse reactions such as dizziness, fatigue, somnolence, constipation, and decreased appetite were observed to get dose-dependent. ”7

• Other Sections
  • Abstract
  • Introduction
  • Materials and methods
  • Pharmacodynamics of duloxetine
  • Pharmacokinetics of duloxetine
  • Dosing
  • Safety
  • Adverse effects
  • Efficacy in GAD
  • Chronic pain
  • Venlafaxine XR
  • Future studies
  • Conclusion
  • References

Safety
Pooled data from numerous studies involved four cases of overdose ingesting nearly 1400 mg of duloxetine, without reported fatalities. With the reasons like the studies, overdose was thought as dose >240 mg. Cardiovascular adverse events and toxicity in overdose associated with venlafaxine do not look like very important with duloxetine. 14
Duloxetine is just not appropriate for patients with end stage renal disease (ESRD), because after a single dose of 60 mg of duloxetine, the elimination half-life remains the same, even so the Cmax and AUC (area beneath the curve used to estimate bioavailability) values are approximately 100% greater in contrast to those with normal renal function. 15
Because hepatic insufficiency impairs duloxetine metabolism, some scientific study has suggested that such patients cease prescribed duloxetine. 13 After the single dose of 20 mg, the half-life of duloxetine was Triple longer, the mean AUC was 5 times greater, along with the plasma clearance was 6 times less in 6 cirrhotic patients with moderate liver impairment versus that which was seen in age and gender matched healthy controls. 9
Preclinical studies demonstrated the chance of substantial central pharmacodynamic drug-drug interactions when duloxetine along with 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 similar reasons, the duloxetine package insert includes a warning against using duloxetine in conjunction with monoamine oxidase inhibitors (MAOIs). 7 This sort of combination gets the possibility to cause both a serotonin syndrome, just like occur with simultaneous administration of an SSRI and a MAOI, and a hypertensive crisis, as can occur using the combined administration connected with an selective NE reuptake pump inhibitor (eg, desipramine or reboxetine) and a MAOI. 7
Duloxetine is pregnancy category C and possible effects on labor, delivery, and also a developing fetus are unknown at this time. 10 Use of duloxetine when pregnant ought to be supervised by a professional, 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 showed that it is a safe treatment modality in elderly with GAD. The study showed a high rate of discontinuation (22. 2%) caused by adverse reactions. 16

• Other Sections
  • Abstract
  • Introduction
  • Materials and methods
  • Pharmacodynamics of duloxetine
  • Pharmacokinetics of duloxetine
  • Dosing
  • Safety
  • Adverse effects
  • Efficacy in GAD
  • Chronic pain
  • Venlafaxine XR
  • Future studies
  • Conclusion
  • References

Negative effects
Patients must be made conscious of the health risks, benefits, possible side effects and alternatives associated with any medication previous to treatment. Pooled data from 3 numerous studies revealed a 16% discontinuation rate for patients cured with duloxetine in contrast to only 4% for placebo. 8 The venlafaxine comparator arm of merely one study showed only an 11% discontinuation rate, which had been under the 23% discontinuation rate shown in the past pooled data. 14 The commonest adverse reactions included nausea, fatigue, dry mouth, somnolence, vomiting, insomnia, and sexual unwanted side effects. 8
Unwanted side effects often related to duloxetine can be like those seen with venlafaxine or SSRIs. Nausea and insomnia are typical negative effects of duloxetine, although nausea is very much less frequent compared to SSRIs. Following the first week of treatment, nausea rates associated with duloxetine are just like placebo. 13 PDR indicates a nausea rate of 31% with venlafaxine, when compared with 22% with duloxetine, at 75 to 225 mg and 40 to 120 mg respectively. 12
Eight- to nine-week clinical trials studying duloxetine use within depression led to a 1 hour. 1 lb (1 lb = 0. 45 kg) weight reduction within the treatment group over a 0. 5 lb excess weight from the placebo group. 3,13,14 12 months follow-up data showed a gain of two. 46 lb for patients in the treatment group, but no placebo group data were available. 10
Medical study data showed clinically insignificant elevations in liver function tests in many patients, with most experts recommending that duloxetine not utilised in individuals with a record of severe liver abnormalities. On follow-up, abnormalities in liver function tests were noted to diminish, no matter whether or otherwise not the patient stopped using duloxetine. 3
Sexual side effects were measured prospectively making use of the Arizona Sex Scale (ASEX). Short-term clinical trials showed statistically significant sexual uncomfortable side effects for duloxetine in comparison with placebo (p = 0. 007). Male anorgasmia was the main effect noted. However, after 6 months the therapy group showed no statistically significant surge in sexual unwanted side effects weighed against the placebo group (p = 0. 677). 17
Urinary retention or hesitancy was rarely reported in numerous studies. Under 2% of patients encountered this side effect, with out patient was catheterized. 18 Numerous studies showed no proof of QT prolongation, affect on glucose metabolism, hematologic abnormalities or complaints about other organ systems. 13
There have been no reported cases of mania in patients taking duloxetine, weighed against 2% of placebo controls. Just like SSRIs and venlafaxine, patients taking duloxetine needs to be carefully monitored for treatment-emergent mania. Concomitant using a mood-stabilizing medication is highly recommended in such instances. 10
Sudden discontinuation may result in withdrawal symptoms, including yet not tied to dizziness, anxiety, nausea, and headache. As a consequence of possible discontinuation syndrome, duloxetine ought to be tapered instead of stopped abruptly. 14 Patients ought to be made mindful of the discontinue syndrome at the beginning of treatment with duloxetine. However, the above mentined numerous studies showed that “discontinuation-emergent adverse events” for duloxetine were statistically significant just like 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 add in teenagers aged 18 to 24 years. A claim series by Parikh et al showed a relationship between suicidality and duloxetine use. From the cases presented, suicidal ideation was linked to a rise in duloxetine dose. 19 In all cases presented, patients were no more suicidal upon discontinuation of duloxetine. All patients prescribed antidepressant medication usually supplies appropriate informed consent about the chance suicidality prior to the beginning of treatment. buy lexapro without a prescription Having reviewed the standard pharmacology and safety data on duloxetine, we will now look at the bedrock studies that led to FDA approval for that management of GAD.

• Other Sections
  • Abstract
  • Introduction
  • Materials and methods
  • Pharmacodynamics of duloxetine
  • Pharmacokinetics of duloxetine
  • Dosing
  • Safety
  • Adverse effects
  • Efficacy in GAD
  • Chronic pain
  • Venlafaxine XR
  • Future studies
  • Conclusion
  • References

Efficacy in GAD
We are going to discuss data from many studies that had been built to measure the efficacy of duloxetine for patient’s meeting DSM-IV-TR criteria for GAD. 3,13,14 Each study utilized the Hamilton Rating Scale for Anxiety (HAM-A) score because 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 1st study became 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 decides GAD as obtained with all the Mini Neuropsychiatric Interview for DSM-IV-TR. 3 Patients were recruited from 42 outpatient hospitals in 7 countries like the Usa and elements of Europe. The mean day of study participants was 43. 8 years of age, with 67. 8% females. 3
Patients were screened including health background and physical examination with EKG, renal function tests, thyroid function tests, and urine drug screens. Patients was required to score at the very least 4 around the Clincical Global Impressions-Severity of Illness scale (CGI-SI). Patients were also needed to score at the very least 10 around the Hospital Anxiety and Depression (HAD) anxiety subscale and a minimum of 9 about the COVI anxiety scale. 3
Unlike previous efficacy studies involving venlafaxine, the patients were evaluated with all 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 that study included a diagnosis of MDD (patients could hardly score > 3 on something of the Raskin Depression Scale) or substance use disorder in the past six months. Exclusion criteria also included a past year diagnosing post-traumatic stress disorder, panic disorder, eating disorder, any prior reputation of a psychotic disorder, excessive compulsive disorder, and bpd. Patients undergoing psychotherapy within About six weeks on the study were also excluded from participation from the study. 3 Patients were also excluded when they underwent 2 previous unresponsive trials of antidepressant or benzodiazepine medication for GAD. Patients was required to be clear of all psychotropic medications for just two to 4 weeks previous to randomization, depending on the psychotropic medication involved. 3 Altogether 126 patients were excluded in the study determined by 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. A patient’s dose could possibly be decreased to 30 mg/day of duloxetine should they were not able tolerate the starting dose. All patients who remained inside the study were gradually increased with their randomly assigned dose spanning a two week period. The patients inside the duloxetine groups were randomly allotted to either abrupt discontinuation or gradual (2 week) taper at the end of the research. 3
The effects with the first study yielded a statistically significant (p < 0. 001) improvement in HAM-A scores with duloxetine in comparison with placebo (see Table 1). At 60 mg/day of duloxetine the mean decrease in HAM-A score was 12. 8 in contrast to only 8. 4 for placebo. At 120 mg/day the mean lowering of HAM-A score was 12. 5. 3.