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Paroxetine + bupropion is a combination of two antidepressant medications used off-label in clinical practice for the treatment of major depressive disorder, particularly in patients who have not responded adequately to monotherapy or who experience intolerable side effects such as sexual dysfunction. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that increases synaptic serotonin levels by inhibiting its reuptake into presynaptic neurons. Bupropion is an aminoketone class antidepressant that acts primarily as a norepinephrine-dopamine reuptake inhibitor (NDRI), increasing the levels of these neurotransmitters in the brain. The combination may be considered for patients with partial response to either agent alone or to mitigate SSRI-induced sexual dysfunction[2][4]. However, this combination carries significant risks due to pharmacokinetic interactions—bupropion inhibits CYP2D6, which metabolizes paroxetine, leading to increased paroxetine plasma concentrations and risk of adverse effects including serotonin syndrome[1][3][5]. This regimen should only be used under close medical supervision.
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