Purpose: In clinical molecular imaging the interaction between antidepressant medication and SPECT ligands is a significant potential confound. This study measured nAChR availability, as determined by SPECT imaging, on and off selective serotonin reuptake inhibitors in first episode depressed patients. Methods: Five patients in their first episode of major depressive disorder (MDD) on a single SSRI underwent [I-123]5-I-A85380- SPECT neuroimaging prior to stopping their medication and again 6 weeks following medication cessation. Autoradiography of post mortem brain tissue with [I-125]5-I-A85380 in the presence or absence of flour commonly prescribed antidepressants was also assessed. Results: SSRI antidepressants did not affect the relative binding availability of alpha 4 beta 2 nicotinic acetylcholine receptors for the [I-123]5-I-A85380 ligand in vivo. Radioligand binding in vitro was unaffected by a single, high pharmacological concentration of antidepressants. Conclusion: SPECT imaging studies using [I-123]5-I-A85380 to measure alpha 4 beta 2 nAChR availability in depressed patients are unlikely to be confounded to a major degree by concurrent antidepressant medication. Synapse 64:111-116, 2010. (C) 2009 Wiley-Liss, Inc.