A Double-Blind,Randomized,Placebo-Controlled Trial of Mecamylamine Hydrochloride for the Treatment of SSRI-Refractory Major Depressive Disorder.

Mecamylamine for the Treatment of Depression in SSRI-Treated Partial Responders

A. Purpose

1. To compare the nicotinic receptor antagonist mecamylamine (MEC) to placebo for the treatment of depressive symptoms in nicotine-dependent, cigarette smokers and in non-smokers who are maintained on, and are partial responders to serotonin-selective reuptake inhibitors (SSRIs).
2. To determine the effects of MEC versus placebo on cigarette smoking behavior in SSRI-maintained depressed smokers and non-smokers.

B. Background The co-morbid rates of nicotine dependence in patients with major depression are estimated to be 50-60% [1-3]. Smokers with a history of major depression disorders have great difficulty quitting smoking compared to smokers without a history of major depression [2, 4]. Furthermore, smokers with a history of depression appear to be at substantial risk for the emergence of depressive symptom exacerbation, typically within one month after smoking cessation [2, 5-7], though this phenomenon has been recently questioned [8]. Recent estimates are that nearly 45% of all cigarettes consumed in the USA are by individuals with mental illness [10].

These clinical relationships between tobacco use and depression do suggest some important effects of nicotine and nicotinic receptor mechanisms in major depressive disorder. Thus, it has been postulated that nicotine and cigarette smoking may exert antidepressant effects [4, 5, 11, 12], presumably mediated through stimulation of nicotinic acetylcholine receptor (nAChR) systems. In fact, it has been shown in an open-label trial that nicotine patch could produce substantial antidepressant effects with 3 days of transdermal nicotine administration in non-smoking subjects with major depression [12].