Antidepressants may have an impact on the course of eye dryness. The aim of this study was to investigate the effects of commonly used new antidepressants on eye wetting. Fifty-four patients using new antidepressants and 57 controls were recruited. The Beck Depression Scale and Beck Anxiety Scale questionnaires were completed by the patients, and drug use time and dosages were recorded. The Schirmer test was performed without prior instillation of topical anesthesia to the ocular surface, and the wetting result was recorded for each eye. Escitalopram, duloxetine, and venlafaxine were used by 27, 13, and 14 patients, respectively. The Schirmer test results in the patients were significantly lower than in the controls (P < 0.001). The patients using selective serotonin reuptake inhibitors (SSRIs) displayed lower wetting measurements (≤5 mm) compared with those using serotonin-norepinephrine reuptake inhibitors, which was independent of the duration of antidepressant usage (P < 0.05). Although SSRIs do not have anticholinergic adverse effects except paroxetine, we found that both SSRIs and serotonin-norepinephrine reuptake inhibitors increased the risk for eye dryness. The lower Schirmer test results of the SSRIs may be associated with a mechanism other than the anticholinergic system. An awareness of the drugs that contribute to dry eye will allow ophthalmologists, optometrists, and other physicians to better manage patients who have this problem.