Antidepressant activity dual inhibitors

With this caveat in mind, each side of the debate has evidence to support its position. The evidence is first summarized supporting the position that SSRIs are less effective than are some other antidepressants (particularly those with dual effects on both serotonin and NE CNS systems) in patients with more severe depression or who are hospitalized. Danish investigators in two double-blind, active-controlled studies found that clomipramine produced a superior response with either paroxetine or citalopram in the treatment of patients hospitalized for major depression (116, 117). Two double-blind studies also have shown that venlafaxine and mirtazapine were more effective than fluoxetine in patients hospitalized with depression ( 114,118). Finally, there are studies showing that the addition of desipramine (one of the most selective NE reuptake inhibitors) to an SSRI can convert nonresponders or pamal responders to full response ( 119, 119a, 120). 

When they occur, depressive symptoms should be treated actively using a combination of cognitive-behavioral therapy and an antidepressant drug. Of the available antidepressants, selective serotonin reuptake inhibitors (SSRIs) have the most favourable combination of efficacy and side-effect profile for the elderly, regardless of the presence of medical co-morbidities. Although the dual agent venlafaxine has been proposed as an alternative agent for older patients who are either non-responders or partial responders to SSRIs, the frail elderly may be particularly vulnerable to its side effects (Hayes 2004). 

Venlafaxine and its active metabolite, 0-desmethylvenlafaxine (ODV), have dual mechanisms of action, with preferential affinity for 5-HT reuptake and weak inhibition of NE and dopamine reuptake. Venlafaxine is approximately 30 times more potent as an inhibitor of SERT than of NET (68). Because of the 30 times difference in transporter affinities, increasing the dose of venlafaxine from 75 to 375 mg/day can sequentially inhibit SERT and NERT. Thus, venlafaxine displays an ascending dose-dependent antidepressant response in contrast to the flat dose-antidepressant response curve observed with the SSRIs. This sequential action for venlafaxine also is consistent with its dose-dependent adverse-effect profile. Its mechanism of action is similar to imipramine. 

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