Onset of antidepressant activity: Reexamining the structure of depression and multiple actions of drugs

Abstract

The question of when antidepressant drugs (AD) initiate significant clinical actions in depressed patients is still unsettled. Findings from early studies on whether there is a lag in the onset of therapeutic actions were in disagreement. More recent results with the selective serotonin reuptake inhibitors (SSRIs) and other new Ads indicate that clinical actions occur within the first 2 weeks. In this paper, evidence from efficacy studies with the Ads is reviewed and the methodologic and conceptual obstacles to achieving definitive results about the onset issue are analyzed. Depression, formerly viewed as a homogenous disorder, is now seen as heterogenous and multifaceted in structure. Such major structural components as anxiety and disturbed psychomotor functioning can be as significant to the core of the disorder as depressed mood itself. Further, the Ads have been shown to act initially on different facets of the clinical disorder which then result in multiple clinical actions, e.g., an initial reduction in anxiety followed by stimulation of motor activity. Data from the NIMH Collaborative Study of the Psychobiology of Depression are used to illustrate: (1) the componential structure of severe depressive disorder; (2) the sequence of change in the major behavioral components of the disorder associated with the tricyclic drugs; (3) the consequent ‘multiple’ onsets of clinical actions; and (4) measurement of the clinical significance and visibility of the early behavioral changes. Recent results describing new behavioral and methodological approaches, the use of early clinical changes to predict outcome, and strategies for designing sound studies of onset are discussed. Depression and Anxiety 4:257–267, 1996/1997.© 1997 Wiley‐Liss, Inc.

Can the Effects of Antidepressants Be Observed in the First Two Weeks of Treatment?

“…He concluded that the usual response for patients treated with antidepressants appeared to be immediate, "at least immediate in terms of 1 week" and might be attributable to the natural course of the illness. Similar observations have been reported (Coryell et al 1982;Katz et al 1987;Casper et al 1994;Stassen et al 1994;Katz et al 1994). A contrary position, according to which there is at least a delay of several weeks in the onset of true drug effect, has been suggested by others (Quitkin et al 1987).…”

“…They suggest that effect sizes are large, and the implication is that antecedent change could be used to detect ultimate responders. Katz et al (1987Katz et al ( , 1994 estimated effect size at week 1 to vary from .24 to .9 depending on the measure. They used guidelines from Cohen (1988), which suggest that an effect size of .5 is medium and readily detectable to a clinical observer.…”

The Timing of Antidepressant Effects: A Comparison of Diverse Pharmacological and Somatic Treatments

“…Because depression is a multi-faceted disorder, some investigators have suggested that any measure used to evaluate early improvement should include subscales measuring cognitive, vegetative, and emotional dimensions [12,27,28]. In this context, Katz and colleagues identified eleven depressive constructs using several rating scales during treatment with imipramine and amitriptyline [23,29].…”

“…This issue is particularly critical because several studies have demonstrated the influence of early antidepressant effects in predicting long-term outcome [12,28,31,32]. One study that investigated the time course of improvement in patients randomized to different antidepressants (amitriptyline, oxaprotiline, imipramine, moclobemide) found a significant difference between active drug and placebo after five days of treatment, an effect that continued to increase during the first two weeks [33].…”

“…Another study similarly observed that patients showing a sustained antidepressant response after ten days of treatment were more likely to achieve response after one month [35]. The findings by Katz and colleagues described above suggested that early behavioral changes taking place during the first two weeks of treatment could predict subsequent long-term outcome [23,28,30]. Szegedi and colleagues also noted that early improvement in patients receiving mirtazapine or paroxetine in the first two weeks of treatment predicted response after six weeks of treatment [8].…”