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.