In this article, it is posited that major depression involves an underfunctioning dopamine system resulting from hypersensitive inhibitory 5-HT2 receptors located on dopaminergic neurons. After a few weeks, treatment with most antidepressant drugs leads to a downregulation of the 5-HT2 receptors that allows for increased dopaminergic firing, which is proposed to be decisive for the antidepressant effect. However, serotonin reuptake inhibitors (SRIs) therapeutic mechanisms probably differ between different therapeutic outcomes. It is hypothesized, that in women, the use of female sex steroids leads to a downregulation of 5-HT2C receptors that contributes to atypical depressive symptoms and premenstrual dysphoria. Consequently, these conditions can be assumed to benefit from the acute increase of serotonergic neurotransmission following ingestion of an SRI rather than the secondary receptor changes, which would explain why there is a therapeutic lag time when SRIs are used to treat depression but not premenstrual dysphoric disorder. The clinical predictions derived from this hypothesis are that 5-HT2 antagonists would be an effective treatment in melancholic depression, have a fast onset of action, speed the onset of SRIs, and can be an effective augmentation for SRI-refractory patients. In contrast, in atypical depression and premenstrual dysphoria a 5-HT2 antagonist would counteract the therapeutic effect of an SRI, while 5-HT2 agonists have a therapeutic potential. It is suggested that therapeutic response to 5-HT2 antagonists/agonists may be used as a diagnostic tool to dissect subgroups of depression.