Psychopharmacology Research Tutorial

Consultant, Worldwide Drug Development

It is widely accepted that antidepressants have a delayed therapeutic effect^1-3 despite having immediate neurochemical actions. However, there is growing evidence that antidepressants at effective doses produce discernible clinical improvement in responding patients within 1-2 weeks.^4,5 This alleged delay in therapeutic benefit, which has been attributed to all antidepressants, is assumed to result from an indirect effect on “downstream” neuronal pathways, despite drugs having differences in pharmacologic mechanisms of action.

The oft-cited time lag in onset of therapeutic effect of antidepressants is now being questioned based on findings of several recent studies. Investigations have included both efficacy trials of adequate sample size specifically designed to assess early onset of antidepressant effect and meta-analyses of published placebo-controlled trials to look at the time course of the drug-placebo treatment difference.^6-8 According to one placebo-controlled study assessing the behavioral effects of two prototypical antidepressants, measurable clinical improvement of depressive symptomatology occurs within a few days of initiating treatment.⁵

Meta-Analysis of Depression Trials

Brown University investigators conducted a comprehensive meta-analysis of all placebo-controlled efficacy trials in depression with weekly symptom ratings published between 1981 and 2001.⁸ The patient population involved more than 5,100 depressed patients treated with an approved antidepressant compared with 3,400 control subjects randomly assigned to placebo treatment. Data from 47 double-blind, placebo-controlled trials were included in the analysis, with comparison of mean change from baseline in weekly 17-item Hamilton Rating Scale for Depression (HAM-D) ratings for drug and placebo treatment. Mean pretreatment HAM-D scores were 25.6 and 25.3, respectively, for the medication and placebo groups, ratings consistent with depressive disorder of at least moderate severity.

Over the course of 6 weeks, mean reductions in HAM-D scores were 13.5 for active medication and 9.0 for placebo, representing 51.1% and 35.4% decreases in symptom severity, respectively. With both drug and placebo treatment, it was found that the largest decrease in HAM-D mean severity score occurred during the first week of treatment, with continuing but lesser reductions each week thereafter. Fifty-seven percent of the end-of-treatment drug-placebo difference (indicative of antidepressant effect) occurred within the first 2 weeks of treatment. Rather than a delayed response pattern, the antidepressant versus placebo separation exhibited early onset, with additional benefits of ongoing treatment gradually diminishing. A meta-analysis of Clinical Global Impression ratings as measure of clinical response yielded similar findings. For both outcome analyses, approximately two-thirds of the ultimate therapeutic benefit of active medication (drug versus placebo difference) occurred during the first 2 weeks of the 6-week course of treatment.

Individual Studies of Early Therapeutic Benefit

Because meta-analyses of published studies of placebo-controlled efficacy trials involve trials of varying and often limited sample size,⁸ the argument for early onset would be strengthened by data from individual trials of adequate sample size with more frequent ratings of clinical response. Two such studies involving larger samples of depressed patients have been conducted and have yielded findings similar to the Brown University study. A group of investigators in Zurich, Switzerland studied nearly 1,300 patients using daily depression self-ratings and found measurable antidepressant effects as early as day 5 of treatment. Furthermore, it was found that 90% of those patients who experienced any improvement by week 3 went on to become full responders.⁶ Another study of 370 depressed patients using self-reported symptoms every 3 days found a significant improvement in depression (and anxiety) symptoms for drug versus placebo within the first 3 days of treatment. As for the previous study, early improvement at 1 week was a strong predictor of ultimate treatment response.⁷

Early Onset of Behavioral Effects of Antidepressants

For definitive evidence of a drug’s clinical action as an antidepressant, a study should include both a comparator drug (active control) and a placebo control. Using a placebo-controlled study design with two active comparators, the behavioral effects of both the prototypical serotonin reuptake inhibitor paroxetine and the norepinephrine reuptake inhibitor desipramine were compared with placebo treatment of depressed inpatients.^5,9 Behavioral changes were assessed twice weekly during the first 3 weeks of treatment, beginning at day 3. Time of onset and the temporal profile of behavioral changes were compared across treatment groups at each assessment point, using a mixed-model analysis of variance. Overall change over time was assessed using slope analysis as well as rate of change of HAM-D ratings during the first 3 weeks, adjusting for baseline severity. Analyses of symptom change using a survival analysis procedure¹⁰ was also carried out, yielding similar results.

The study showed that early clinical effects of these two antidepressants were apparent by at least 7 days for desipramine and 10 days for paroxetine treatment.⁵ The initial behavioral actions of the two drugs proved to be somewhat different. With desipramine treatment, significant initial improvement compared with placebo was apparent for motor retardation and depressed mood, while anxiety and hostility symptoms improved early with paroxetine. Treatment with both drugs was associated with significantly more rapid reduction in hostility during the first 2 weeks compared with placebo treatment. For both of these antidepressants, HAM-D total severity score and the depressed mood/motor retardation factor showed significant clinical improvement compared with placebo treatment at week 1.

Conclusion

Meta-analysis of published placebo-controlled efficacy studies, as well as individual trials in depression designed to assess onset of antidepressant effect, have examined the issue of the purported time lag in therapeutic benefit. Contrary to common belief that there is delayed onset of antidepressant benefit, these studies provide compelling evidence that antidepressants at effective doses have nearly immediate effects and demonstrate significant improvement within the first weeks of treatment. In addition to a consistent finding of early onset of therapeutic benefit of antidepressants, behavioral differences have been reported in the clinical actions of desipramine and paroxetine during initial treatment. Desipramine treatment was associated with early improvement in motor retardation and depressed mood, while anxiety and hostility symptoms showed early response to paroxetine. The fact that significant clinical effects occur close in time to the almost immediate neuropharmacologic actions of antidepressants suggests that antidepressant efficacy results from direct enhancement of neuronal transmission at monoaminergic synapses, rather than a purported indirect and delayed “downstream” effect on neuronal pathways.

References

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2.  Anderson IM, Nutt DJ, Deakin JF. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association of Psychopharmacology guidelines. J Psychopharmacol. 2000;14(1):3-20.

3.  Schatzberg AF, Cole JO, DeBattista C, et al. Antidepressants: Manual of Clinical Psychopharmacology. 4th ed. Washington, DC: American Psychiatric Publishing; 2003:137-157.

4.  Mitchell AJ. Two-week delay in onset of action of antidepressants: new evidence. Br J Psychiatry. 2006;188:105-106.

5.  Katz MM, Bowden CL, Berman N, Frazer A. Resolving the onset of antidepressants’ clinical actions: critical for clinical practice and new drug development. J Clin Psychopharmacol. 2006;26(6):549-553.

6.  Stassen HH, Angst J, Delini-Stula A. Delayed onset of action of antidepressant drugs? Survey of results of Zurich meta-analyses. Pharmacopsychiatry. 1996;29(3):87-96.

7.  Parker G, Roy K, Menkes DB, et al. How long does it take for antidepressant therapies to act? Aust N Z J Psychiatry. 2000;34(1):65-70.

8.  Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry. 2005;66(2):148-148.

9.  Katz MM, Tekell JL, Bowden CL, et al. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology. 2004;29(3):566-579.

10.  Stassen HH, Delini-Stula, Angst J. Time course of improvement under antidepressant treatment: a survival-analytical approach. Eur Neuropsychopharmacol. 1993;3(2):127-135.