In terms of tolerability and toxicity, the SSRIs appear to be more acceptable to both patients and their physicians than older antidepressants. Some investigators, however, believe that the TCAs and monoamine oxidase inhibitors (MAOIs) are more effective than the SSRIs in certain subtypes of depression. While the data are mixed, as will be discussed below, most studies indicate that the SSRIs and TCAs are equally efficacious.
Tricyclic Antidepressants (TCAs)
The influential studies from the Danish University Antidepressant Group (DUAG) in 19861 and in 19902 sparked an ongoing debate on the relative efficacy of SSRIs and tricyclic antidepressants: specifically, that the TCAs are superior for endogenous depression. The DUAG group compared clomipramine to citalopram in one study and to paroxetine in another, in inpatients with major depression. The first study of 114 inpatients found that 62% responded to clomipramine and 34% to citalopram. Similarly, in the second study, 46% responded to clomipramine and only 19% responded to paroxetine after 6 weeks of treatment. Of note, the DUAG generalized clomipramine to all TCAs when clomipramine is anything but a prototypical TCA with regard to its mechanism of action and, among the TCAs, its unique efficacy in obsessive-compulsive disorder (OCD). It might be more accurate to conclude that clomipramine is superior to at least two SSRIs in severely depressed inpatients and not to conclude that these data can be generalized to all TCAs and all SSRIs.3,4
Selective Serotonin Reuptake Inhibitors (SSRIs): Past, Present and Future, edited by S. Clare Stanford. ©1999 R.G. Landes Company.
Roose and colleagues5 compared nortriptyline to fluoxetine in geriatric melancholic depressed inpatients in a hybrid design that blended a head-to-head study (nortriptyline compared to fluoxetine) with data from prior studies of nortriptyline at their center, in a non-randomized assignment. They found that, analyzing all randomized patients (i.e., intent-to-treat analysis), 67% responded to nortriptyline and 23% responded to fluoxetine after 7 weeks of treatment.
Despite these often cited studies, there remains a general consensus that SSRIs are equally effective with TCAs for moderate major depressive disorder.6 A meta-analysis by Montgomery et al7 of 42 randomized controlled studies of over 4000 patients found SSRIs to be equivalent in efficacy to imipramine and amitriptyline. No significant differences were found in patients who dropped out due to lack of efficacy, but significantly fewer patients discontinued studies due to side-effects from the SSRIs compared to the TCAs. The higher discontinuation rate with tricyclics, however, may be due to a subtle bias with TCAs being started at high doses rather than using slower and more tolerable dose escalations. Another meta-analysis8 of randomized clinical trials also indicated equal efficacy between SSRIs and TCAs (44 trials with non-clomipramine TCAs and 7 with clomipramine). A large randomized study of 536 depressed patients in a primary care setting provided further evidence for comparable efficacy between SSRIs and TCAs. No differences were found between fluoxetine and desipramine or imipramine in terms of clinical outcomes, treatment costs, or quality of life.9
George and Lydiard10 reviewed 11 double-blind, placebo-controlled trials specifically looking for differences in onset of action between fluoxetine and TCAs but found no differences. A large study of depressed patients comparing paroxetine, imipramine and placebo did find a difference in onset of action between these two antidepressants. Paroxetine was superior to placebo after one week, but imipramine and placebo were not different until week two.11
In summary, head-to-head comparisons between TCAs and SSRIs indicate equal efficacy and onset of action but slightly different side-effects. SSRIs have greater tolerability, less cardiotoxicity, sedation, weight gain, and anticholinergic side-effects.
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Are You Depressed? Heard the horror stories about anti-depressants and how they can just make things worse? Are you sick of being over medicated, glazed over and too fat from taking too many happy pills? Do you hate the dry mouth, the mania and mood swings and sleep disturbances that can come with taking a prescribed mood elevator?