Since a substantial proportion of smokers have comorbid
mood disorders, the smoking cessation aid
varenicline might occasionally be prescribed to patients who are simultaneously treated with
antidepressants. Given that
varenicline is a selective
nicotinic acetylcholine receptor partial agonist and not a substrate or inhibitor of
drug metabolizing
enzymes, pharmacokinetic interactions with various classes of
antidepressants are highly unlikely. It is, however, conceivable that
varenicline may have a pharmacodynamic effect on
antidepressant-evoked increases in central monoamine release. Interactions resulting in excessive transmitter release could cause adverse events such as
serotonin syndrome, while attenuation of monoamine release could impact the clinical efficacy of
antidepressants. To investigate this we examined whether
varenicline administration modulates the effects of the
selective serotonin reuptake inhibitor sertraline and the
monoamine oxidase inhibitor clorgyline, given alone and combined, on extracellular concentrations of the monoamines
serotonin,
dopamine, and
norepinephrine in rat brain by microdialysis. Given the important role attributed to cortical monoamine release in
serotonin syndrome as well as
antidepressant activity, the effects on extracellular monoamine concentrations were measured in the medial prefrontal cortex. Responses to maximally effective doses of
sertraline or
clorgyline and of
sertraline plus
clorgyline were the same in the absence as in the presence of a relatively high dose of
varenicline, which by itself had no significant effect on cortical monoamine release. This is consistent with the binding profile of
varenicline that has insufficient affinity for receptors,
enzymes, or transporters to inhibit or potentiate the pharmacologic effects of
antidepressants. Since
varenicline neither diminished nor potentiated
sertraline- or
clorgyline-induced increases in
neurotransmitter levels, combining
varenicline with serotonergic
antidepressants is unlikely to cause excessive
serotonin release or to attenuate
antidepressant efficacy via effects on cortical
serotonin,
dopamine or
norepinephrine release.