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Second-Generation Antidepressants for Treating Adult Depression—An Update

Slide: 25 of 28

Noncomparative Evidence on Adverse Effects: Diabetes, Fractures, and Bleeding

Diabetes Mellitus
In a cohort of 165,958 patients with depression included in the U.K. General Practice Research Database, a total of 2,243 cases of incident diabetes mellitus and 8,963 matched comparison subjects were identified. This nested case-control study showed that recent long-term use (>24 months) of antidepressants in moderate to high daily doses was associated with an increased risk of diabetes (incidence rate ratio (IRR), 1.84; 95-percent confidence interval [95% CI], 1.35 to 2.52). The study investigated tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, and other antidepressants. For users of SSRIs as a group, increased risk was observed only for recent long-term use of moderate to high daily doses (IRR, 2.06; 95% CI, 1.20 to 3.52). When individual antidepressants were analyzed, increased risk estimates only in long-term users were observed for recent use of fluvoxamine, paroxetine, and venlafaxine. Antidepressant treatment for shorter periods or with lower daily doses was not associated with an increased risk.

A large, well-conducted case-control study, including 498,617 subjects (124,655 cases and 373,962 controls) from a Danish national prescription database, reported a significant dose-response relationship for citalopram, fluoxetine, and sertraline with respect to an increase of the risk of fracture. Among SSRIs, high-dose citalopram, fluoxetine, paroxetine, and sertraline were associated with the highest risk for hip fracture (odd ratio [OR], 1.98, 95% CI, 1.82 to 2.16) and other fractures except fractures of the forearms and spine (OR, 1.38; 95% CI, 1.33 to 1.44). Evidence regarding the impact of the duration of use on the risk of fractures was mixed for second-generation antidepressants. A Dutch case-control study that did not meet eligibility criteria reported an increase for nonvertebral fractures for SSRIs as a class.

Increased Risk of Bleeding
Evidence from three case-control studies indicated an increased risk of upper gastrointestinal tract bleeding during SSRI treatment. These studies did not meet eligibility criteria because they provided no information on the comparative risks among individual SSRIs.