Methods and compositions are disclosed for the intravaginal or rectal delivery of selected serotonin reuptake inhibitors (SSRIs) to the systemic circulation. Such methods and compositions are useful in the treatment of depression, migraine headaches, chronic pain, psychoactive substance abuse disorders, pre-menstrual dysphoric disorder (PMDD) and obsessive compulsive disorders. The compositions may be formulated for the immediate release or controlled release of SSRIs over an extended period of time. A preferred SSRI is fluoxetine.