Background and Purpose—In some studies, late life depression is associated with white matter lesions on MRI. The effect of different classes of antidepressants on progression of white matter lesions is unknown. Selective serotonergic reuptake inhibitors (SSRIs) may decrease platelet aggregation. We hypothesized that Cardiovascular Health Study participants taking SSRIs would less often have worsening white matter on serial MRI than participants not on antidepressants.

Methods—Among 1826 participants who were not using an antidepressant at initial MRI scan, we examined the association of worsening in white matter grade from initial to follow-up MRI scans, 5 years apart on average, and antidepressant use between the scans. Logistic regression models were used, controlling for a variety of potential confounding variables.

Results—Use of any antidepressant during the period of study was associated with worsening white matter. In a multivariable model, risk was slightly increased, not reduced, with use of serotonergic agents (OR 1.36, 95% CI 0.87 to 2.12) and was significantly increased with the use of tricyclic antidepressants (OR 1.77, 95% CI 1.07 to 2.94).

Conclusions—The association between worsening white matter and use of tricyclic antidepressants was an unexpected finding that may relate to indications for use other than depression or to side effects such as hypotension. Protection against worsening was not seen with use of serotonergic agents.