This review focuses on the dose-response of serotonin reuptake inhibitor (SRI) antidepressants for efficacy and for adverse drug events (ADEs). Dose-response is identified by placebo-controlled, double-blind, fixed-dose clinical trials comparing various doses for efficacy and for ADEs. Reports from the great majority of clinical trials have consistently found that the minimum SRI effective dose is usually optimal for efficacy in the treatment of depression disorders, even though most American medical practitioners raise the dose when early antidepressant treatment results are negative or partial. To better understand this issue, the medical literature was comprehensively reviewed to ascertain the degree to which SRI medications resulted in a flat dose response for efficacy and then to identify specific ADEs that are dose-dependent. Strong evidence from fixed-dose trial data for the efficacy of nonascendant, minimum effective doses of SRIs was found for the treatment of both major depression and anxiety disorders. Particularly important was the finding that most SRI ADEs have an ascending dose-response curve. These ADEs include sexual dysfunction, hypertension, cardiac conduction risks, hyperglycemia, decreased bone density, sweating, withdrawal symptoms, and agitation. Thus, routinely raising the SRI dose above the minimum effective dose for efficacy can be counter-productive.