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Bupropion acts as an norepinephrine-dopamine reuptake inhibitor (NDRI).It is an atypical antidepressant, different from most commonly prescribed antidepressants such as selective serotonin reuptake inhibitors (SSRIs).Its effect may also be "considerably less than of the approved agents ...Thus it may be prudent for the clinician to recommend a trial of behavior therapy at this point, before moving to these second-line agents." Similarly, the Texas Department of State Health Services guideline recommends considering bupropion or a tricyclic antidepressant as a fourth-line treatment after trying two different stimulants and atomoxetine. There have also been a few studies suggesting that bupropion can improve sexual function in women who are not depressed, if they have hypoactive sexual desire disorder (HSDD).It was originally called by the generic name amfebutamone, before being renamed in 2000.

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According to a 2014 Cochrane review, while there is an association with suicide it is unclear if bupropion was the cause.

The agency concluded that "in the majority of cases the individual's underlying condition may provide an alternative explanation." Suicidal thoughts and behaviors are rare in clinical trials, and the FDA requires all antidepressants, including bupropion, to carry a boxed warning stating that antidepressants may increase the risk of suicide in persons younger than 25.

This warning is based on a statistical analysis conducted by the FDA which found a 2-fold increase in suicidal thought and behavior in children and adolescents, and 1.5-fold increase in the 18–24 age group.

It should be avoided in individuals who are also taking monoamine oxidase inhibitors (MAOIs).

When switching from MAOIs to bupropion, it is important to include a washout period of about two weeks between the medications.

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