From The Quarterly, Fall 2012

Patients with depression tend to smoke a lot, which led to the idea that nicotine may ease depressive symptoms. Research has shown how the process works. Nicotine binds to particular receptor molecules on the surface of nerve cells in the brain, first activating the receptors, which actually increases depressive symptoms, but then when the receptors turn off, an antidepressant-like effect does seem to follow.



In their normal role the receptors affected by nicotine are receptors for the neurotransmitter acetylcholine, a chemical involved in nerve-cell communication. In the 1970s, a hypothesis of acetylcholine involvement in depression was explored, but it was overshadowed by the introduction of fluoxetine (Prozac®), a selective serotonin reuptake inhibitor (SSRI) that targets the neurotransmitter serotonin. Based on the observations of how the acetylcholine receptor responds to nicotine, researchers hypothesized that if receptor activity could be blocked, it might have a therapeutic effect for patients with depression.



The drug mecamylamine (Inversine®), developed to treat hypertension, is an acetylcholine receptor blocker. In a clinical trial of mecamylamine for depression, patients who had failed to respond to Prozac® or other SSRIs were given mecamylamine along with an SSRI. The results were positive; the combined treatment had an antidepressant effect. The next trial was with a partial agonist, a drug that does not fully block the receptor. Cytosine is a natural product made from the flowers of the laburnum plant. The first trial of cytosine with mice gave the same effect as the full blocker but without the side effect of mecamylamine of severe constipation. Varenicline (ChantixTM) is a drug on the market that works like cytosine and has also shown positive antidepressant effects used in concert with an SSRI.



Before the drug can be introduced for widespread use, another hurdle must be surmounted. As is the case with SSRIs alone, the combined SSRI and acetylcholine receptor blocker can produce an increase in suicidal ideation in a small subset of patients. Researchers are conducting trials to try to identify the patients for whom this treatment would not be advisable. At the same time, other lines of research are seeking to better understand where and how achetylcholine receptor blockers are working in the brain and how the two neurotransmitter systems work together.

Marina R. Picciotto, Ph.D.

Charles B.G. Murphy Professor of Psychiatry, Neurobiology and Pharmacology

Yale University

1996 NARSAD Young Investigator Grantee

2004 NARSAD Independent Investigator Grantee