title: Safety and tolerability of dexmecamylamine (TC-5214) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to antidepressant therapy: results of a long-term study.
abstract: Safety and tolerability are important considerations when selecting patients' treatment for major depressive disorder. We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine (TC-5214), adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder and who had an inadequate response to antidepressants. This 52-week, double-blind, placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine. Patients were randomized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI. The patient population comprised inadequate responders from 2 Phase III acute dexmecamylamine studies (NCT01157078 [study 002], NCT01153347 [study 004]) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding randomization. Safety and tolerability were assessed by monitoring adverse events, vital signs, and physical and laboratory parameters. Descriptive statistical analyses were performed on most efficacy-related end points. Sustained efficacy was analyzed using logistic regression. Overall, 813 patients were randomized (610 received dexmecamylamine, 203 received placebo). In total, 82.4% and 84.6% of patients, respectively, experienced an adverse event. Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation (19.6% vs 6.0%), dizziness (12.0% vs 7.0%), and dry mouth (9.7% vs 5.0%). Back pain (2.8% vs 8.5%), weight increase (4.4% vs 7.0%), and fatigue (5.6 % vs 7.5%) occurred more frequently in placebo-treated patients. No notable differences were observed between dexmecamylamine and placebo for any secondary end point. In this long-term study, safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine.
authors.affiliation: From *AstraZeneca Pharmaceuticals, Wilmington, DE; and †Targacept Inc, Winston-Salem, NC.
authors.forename: Raj
authors.initials: R
authors.lastname: Tummala
authors.forename: Dhaval
authors.initials: D
authors.lastname: Desai
authors.forename: Johan
authors.initials: J
authors.lastname: Szamosi
authors.forename: Ellis
authors.initials: E
authors.lastname: Wilson
authors.forename: David
authors.initials: D
authors.lastname: Hosford
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Dunbar
authors.forename: Hans
authors.initials: H
authors.lastname: Eriksson
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003248:Constipation / Q000139:chemically induced / Q000175:diagnosis; D003865:Major Depressive Disorder / Q000175:diagnosis* / Q000188:drug therapy* / Q000523:psychology; D004244:Dizziness / Q000139:chemically induced / Q000175:diagnosis; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005221:Fatigue / Q000139:chemically induced / Q000175:diagnosis; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008464:Mecamylamine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D008875:Middle Aged; D011446:Prospective Studies; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D008464:Mecamylamine; D017367:Selective Serotonin Reuptake Inhibitors