Onset of Clinical Action of Antidepressants

By Martin M. Katz

Time of onset of clinical actions induced by antidepressants (ADs)  is critical for uncovering basic mechanisms underlying their efficacy, for developing further understanding of the nature of the depressive disorder and for predicting early in treatment,whether a drug is likely to be effective. The criticality of the onset issue has been recognized since the discovery of the new drugs.  It was initially observed by Kuhn (1958) that the clinical effect in most responsive patients occurred within the first week. The controversy was then, ignited by the Quitkin et al. (1984) study showing that clinical actions of the antidepressants “lag” several weeks behind the drug’s initial effects on central neurotransmitter systems. The latter study resulted in the “onset lag” becoming a commonly accepted “textbook “notion. Conversely, the National Institute of Mental Health (NIMH) Collaborative Depression Study group (CDS) reported in Katz et al. (1987), based on a large sample of severely depressed, hospitalized patients, that in treatment–responders, significant changes in major components of the disorder occurred within the first two weeks. Neither of the two studies was aimed directly at the “onset” issue; the results on onset were the product of secondary analyses. Neither study was, therefore, able to providea definitive answer to the question of clinical-onset. What the studies did accomplish, however, was to highlight the onset question, critical to determining sequence of drug actions and to uncovering relationships between drug-induced neurochemical and clinical actions. At the practical level, knowledge of timing also determines when the clinician can expect to see the first drug-induced changes, and whether the presence or absence of early changes can predict the nature of the patients’ clinical response to drug treatment.

Following these early reports, technical papers aimed at the methodology required to achieve definitive answers on timing appeared, and a series of independent meta-analyses targeting the problem in large drug trials, were conducted. A body of literature on the issue has been developed since 1990 that many now believe have resolved the issue.

An abbreviated set of references, including papers which analyze this area of the literature, and which report the more definitive results from the meta-analytic studies, is listed below. The list includes the published earlier exchange on the two conflicting views in the journal Neuropsychopharmacology.

The general consensus as it exists today can be summarized in the following statements drawn from several of these recent publications:

1.      “One-third of the total (clinical) effect of selective serotonin re-uptake inhibitors (SSRIs) after six weeks of treatment is seen in the first week” (Taylor et al. 2005, based on literature review and meta-analyses).

2.      “Among responders the onset of improvement occurs in more than 70% of cases within the first three weeks of treatment with an AD “(Stassen et al. 1997,based on analysis from a multihospital study and survey of results).

3.      “Drug specific types of behavioral response in the first one or two weeks of treatment with desipramine or paroxetine are highly predictive of six week outcome” (Katz et al. 2004, based on drug-placebo comparison study).

4.      Absence of behavioral changes during first two to three weeks indicates little chance of positive response at outcome (Szegedi et al. 2009; Katz et al. 2011; Stassen et al. 1997, based on finding that >90% of patients who show no improvement during the first two weeks, show non-response at outcome).

Relevant References:

I. Technical:How to measure onset

1.      Laska EM, Siegel C Characterizing onset in psychopharmacological clinical trials. Psychopharmacolog Bull 1995;  31: 29-35.

2.      Katz MM, Koslow SH, Fraser A. Onset of antidepressant activity: reexamining the structure of depression and multiple actions of drugs. Depression and anxiety 1997; 4: 257-67.

3.      Leon AC, Blier R, Culpepper L et al. An ideal trial to test differential onset of antidepressant effect. J Clin Psychiatry 2001; 62: 34-6

4.      Stassen HH, Angst J, Delini-Stula A. Time course of improvement under antidepressant treatment: a survival–analytic approach. Eur Neuropsychopharmacol 1993; 3: 127-35.


II. Clinical Studies and Reviews

1.      Kuhn R. The treatment of depressive states with G22355 (imipramine hydrochloride). American Journal of Psychiatry 1958; 115: 459-64.

2.      Quitkin F M, Rabkin JG, Ross D, Stewart JW. Identification of true drug response to antidepressant. Arch Gen Psychiatry 1984; 41: 782-6.

3.      Katz MM, Koslow SH, Maas JW, Frazer A, Bowden CL, Casper R, Croughan J, Kocsis J, Redmond E. The timing, specificity, and clinical prediction of tricyclic drug effects in depression. Psychol Med 1987; 17: 297-309.

4.      Stassen HH, Angst J, Delini-Stula A. Delayed onset of action of antidepressant drugs? Survey of recent results. Eur Psychiatry 1997: 12: 166-76.

5.      Katz MM, Tekell J, Bowden CL Brannan S,Houston JP, Berman N, Frazer A. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology 2004; 29: 566-79.

6.      Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z Early onset of SSRI antidepressants: Systematic review and meta-analysis. 2006; 63: 1217-23.

7.      Posternak MA, Zimmerman MD. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry 2005; 66: 148-58.

8.      Papakostas GI, Perlis RH, Scalia MJ. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clinical Psychopharmocol 2006; 26: 56-60.

9.      Robinson DS. Antidepressant drugs: Evidence for onset of therapeutic effect. Primary Psychiatry 2007; 14: 21-3.

10.  Machado–Vieira R, Luckinbaugh DA, Manji HK, Zarate CA. Rapid onset of antidepressant action: a new paradigm in the research and treatment of major depressive disorder. J Clin Psychiatry 2008; 69: 946-58.

11.  Szegedi A, Jansen WT, van Wugenburg AP. Early improvement in the first two weeks as predictors of treatment outcome in patients with major depressive disorder: a meta-analysis including 6,562 patients. J Clin Psychiatry 2009; 70: 344-53.

12.  Katz MM, Berman N, Bowden CL, Frazer A. The componential approach enhances the effectiveness of 2-week trials of new antidepressants. J Clin Psychopharmacology 2011; 37:  193-218.


III. Earlier Controversy: Conflicting Views on the Evidence

Can the effects of antidepressants be observed in the first two weeks of treatment?  

Quitkin et al. Neuropsychopharmacology 1996; 15: 390-4.

Katz MM et al. Neuropsychopharmacology 1997; 17:110-1.


Martin M. Katz
January 9, 2014