Nicotinic Antagonist Augmentation of Selective Serotonin Reuptake Inhibitor-Refractory Major Depressive Disorder: A Preliminary Study
Abstract
BACKGROUND: There is evidence for nicotinic hypercholinergic mechanisms in depression. Clinical relationships between tobacco use and depression suggest important effects of nicotine in major depressive disorder (MDD). It has been hypothesized that cigarette smoking may exert antidepressant effects, presumably mediated through stimulation of nicotinic acetylcholine receptor systems. We compared the nicotinic antagonist, mecamylamine hydrochloride (MEC), with placebo as an augmentation strategy for patients with MDD who were refractory to selective serotonin reuptake inhibitor (SSRI) treatment. METHODS: Twenty-one SSRI-treated subjects with MDD were randomized to MEC (up to 10 mg/d; n = 11) or placebo (PLO group; n = 10) during an 8-week trial. The primary outcome measure was the change in depressive symptoms assessed using the 17-item Hamilton Depression Rating Scale during the 8-week trial. RESULTS: There was a significant reduction in 17-item Hamilton Depression Rating Scale scores in the MEC versus PLO groups, as evidenced by a significant medication x time interaction (F1,19 = 6.47, P < 0.05). Five (45.5%) of 11 subjects in the active study medication group demonstrated a 50% or more decrease in depressive symptoms from baseline as compared with 1 (10%) of 10 subjects assigned to placebo medication, but this difference was not significant (P = 0.15; Fisher exact test). The primary side effects of MEC were constipation and orthostatic hypotension. CONCLUSIONS: These preliminary findings suggest that the nicotinic acetylcholine receptor antagonist, MEC, may have utility as an augmentation strategy for patients with SSRI-refractory MDD.
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Mecamylamine is effective as an add-on medication in depressed human subjects who are nonresponsive to an SSRI.
“is effective as an add-on medication in depressed human subjects who are nonresponsive to a selective serotonin reuptake inhibitor (SSRI) (George et al. 2008)”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as George et al. 2008
Clinical trials have suggested that blockade of either mAChRs or nAChRs can decrease symptoms of depression.
“clinical trials have suggested that blockade of either mAChRs (Furey and Drevets, 2006; Furey et al., 2010) or nAChRs (George et al., 2008; Shytle et al., 2002) can decrease symptoms of depression.”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as George et al., 2008
Similar compounds have shown promising effects in smaller clinical trials, and enhanced the effects of SSRIs in human depressed subjects.
“similar compounds have shown promising effects in smaller clinical trials, and enhanced the effects of SSRIs in human depressed subjects (George et al., 2008; Philip et al., 2009)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as George et al., 2008
Recent clinical studies have demonstrated that mecamylamine has an antidepressant-enhancing effect upon co-administration with SSRIs.
“Recent clinical studies (Dunbar et al, 2007; George et al., 2008) have demonstrated that mecamylamine has an antidepressant-enhancing effect upon co-administration with selective serotonin reuptake inhibitors (SSRIs).”
From Varenicline has antidepressant-like activity in the forced swim test and augments sertraline's effect (2009) · cites this paper as George et al., 2008
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- Authors
- George, T. P., Sacco, K. A., Vessicchio, J. C., Weinberger, A. H., & Shytle, R. D.
- Affiliations
- Centre for Addiction and Mental Health (CA)
- Yale University (US)
- University of South Florida (US)
- Corresponding author
- George, Tony P.
- Sacco, Kristi A.
- Vessicchio, Jennifer C.
- Weinberger, Andrea H.
- Venue
- Journal of Clinical Psychopharmacology
- Published
- 2008-06
- Volume
- 28
- Issue
- 3
- Pages
- 340-344
- ISSN
- 0271-0749 (ISSN-L)
- OpenAlex
- W1985905713
- Cited by
- 128
- References
- 17
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 8 · 2014: 10 · 2013: 11 · 2012: 13
- FWCI
- 10.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Pfizer
- University of South Florida
- Ministerio de Economía y Competitividad
- National Institute on Drug Abuse (5K02 DA 16611, K02DA016611)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Keywords
- major depressive disorder, mecamylamine, nicotinic acetylcholine receptor antagonism, antidepressant augmentation, nicotine, depressive symptoms
- MeSH terms
- Adult, Depressive Disorder, Major, Major Depressive Disorder, Drug Resistance, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Mecamylamine, Middle Aged, Personality Inventory, Psychometrics, Selective Serotonin Reuptake Inhibitors, Nicotinic Antagonists
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