Is Onset of Action of Antidepressants Really Delayed?

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Time to Query Whether the Onset of Action of Antidepressants is Really Delayed?

Introduction

The onset of action of antidepressants has generally been considered to be delayed, with no effect being seen until after at least 3 weeks of treatment. However, new evidence suggests that this may not in fact be the case, and that most patients who are going to respond will show some response to antidepressant treatment within the first 1 to 3 weeks of depression medication therapy. This has opened up discussion on how these agents work and how to better predict which patients will respond and benefit from antidepressant treatment.

Depression Still to Be Unravelled

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As little is known about the aetiology of depression, it is hardly surprising that only incomplete treatments are available and that, for most patients, there is not a cure.[1] Newer treatments, although better tolerated, are generally no more effective in treating depression than the original tricyclic antidepressants.[1] What is puzzling is that antidepressants that differ greatly in their biochemical and pharmacological actions have virtually the same efficacy in terms of the proportion of patients in whom they induce a therapeutic response.[1]

Overall, the proportion of patients estimated to be true drug responders is low; on average, about 20 to 25% of patients who present with major depression. Furthermore, 35 to 45% of patients have depression which is resistant to all drug treatment modalities.[1]

Standard Trial Design Confuses the Issue

Where has the concept of a delayed onset of action of antidepressants come from? The original report of the efficacy of imipramine suggested that rather than a delay there was in fact an early onset of improvement.[2] However, most of the current understanding of the course of recovery from depression comes from standard drug trials involving only weekly assessments of efficacy measurements, and these suggest a somewhat different story.[1]

3 Weeks to Show Statistical Differences

When comparing antidepressants with placebo in standard drug trials, a period of 3 weeks is usually required before formal statistical significance between treatments is achieved.[1,3] Moreover, repeat measurements analysis of variance/covariance appear to support the 'delayed onset of action' hypothesis. Results from these analyses suggest that:[1]

response to antidepressants is slow
differences between antidepressants and placebo do not normally reach significance until the third or fourth week of treatment.

This delay has often been interpreted as indicating a delayed onset of action of antidepressants. However, the statistical 'response' lag and onset of action represent 2 principally different concepts that relate to different aspects of efficacy of antidepressant drug therapy.[1]

Withdrawal and Non-response

Efficacy of treatment in clinical studies is generally analysed based on the decision to treat. Thus, patients who withdraw from treatment or whose disease fails to respond are included in the analysis of time of onset of action.[1] If patients do not respond to treatment then the time of onset of effect will be equivalent to the time of the study (i.e. usually 4 to 6 weeks). The effect of this will be to skew the overall perceived time to onset of action.

Placebo Responders: A Confounding Factor

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Placebo response is a major factor in the treatment of depression, and if placebo treatment can trigger a response in some patients, how can true drug responders be distinguished from placebo responders? One suggestion is that abrupt and fluctuating improvement may be an indicator of placebo response,[4] and those with a more gradual steady improvement are responding to drug treatment. However, placebo response may not be uniform for all types of depression (e.g. melancholic compared with non-melancholic depression).[5]

Data Not Convincing

Despite the lack of frequent response measurements in the initial stages of clinical trials, it is possible to get some indication of the distribution of time spans to the onset of response to treatment. This is because the actual rating dates typically fall within 2 days either side of the prespecified 'design' dates of the study protocol. Thus, if there was a delayed onset of therapeutic effect of antidepressants, there should be no response in the initial treatment period and then a clear-cut frequency peak starting to appear somewhere after day 14 in the time spans to the onset of improvement.[1] However, the available data would appear to suggest that there is a continuous distribution of time spans to onset of improvement with a maximum around day 10.[6,7]

Some Response in Early Weeks

Some study results suggest that patients who are going to respond to drug treatment do so within the first 1 to 3 weeks of therapy.[1,7,8] In 1 study, over 70% of patients receiving either moclobemide or fluoxetine who were classified as responding to treatment, showed some improvement within the first 14 days, irrespective of which drug they received.[1]

However, it should be remembered that the time to onset of action of antidepressants may vary between patients with different types of depression. Thus, trials which include a heterogeneous group of patients with major depression may obscure any differences in the time to onset of action of drug therapy.[1]

Not Suppression but a Trigger?

The fact that antidepressants, irrespective of class, seem to be effective, together with the large placebo response seen in patients with major depression, has led to the suggestion that the time course of improvement among responders is actually independent of the treatment modality.[1] The suggestion has been made that, once triggered, the recovery follows its natural course identical to that of spontaneous remission.[1] This hypothesis would then mean that the differences between the efficacy of active drugs and placebo are reflected only by the total number of responders and the number and time distribution of premature withdrawals.[1] Thus, the therapeutic qualities of antidepressants may be triggering and maintaining the conditions necessary for improvement rather than suppressing symptoms.[1]

Time to Clear the Muddy Waters

No studies have been specifically designed to address the timing issues of antidepressant treatment.[1] The lack of this type of study means there are a large number of unanswered questions (see table 1). The answers to these questions may improve the quality of care of patients with depression. Furthermore, the economic implications of identifying signs of early improvement are self-evident.[3]

Any Action Required in the Meantime?

If the above hypothesis is correct and most antidepressant drugs do not have a substantially delayed onset of action then there are some clinical implications. Stassen, et al.[1] suggest that antidepressant treatment should be continued if a slight response (a 20% decrease on a depression rating scale) to drug treatment is seen in the first 2 weeks of treatment. Moreover, until it can be established whether or not switching between the various classes of antidepressant can alter patient response, it has been suggested that if after 3 weeks no improvement is seen, then antidepressant treatment should be changed to a drug from a different class of antidepressants.[1]