Relapse or recurrence in depression: why has the cutoff been set at 6 months?




Hans-Jürgen MÖLLER, MD, PhD
Michael RIEDEL, MD
Florian SEEMÜLLER, MD
Department of Psychiatry and Psychotherapy
Ludwig-Maximilian-University
Munich, GERMANY

Relapse or recurrence in depression: why has the cutoff been set at 6 months?


by H. J . Möller, M. Riedel , and F. Seemüller, Germany

Classification into relapse or recurrence of a newly occurring depressive episode has important therapeutic implications. In the past, diverse outcome measures with arbitrary definitions have been used in antidepressant treatment trials. In an attempt to harmonize and standardize these definitions, a task force was set up by the MacArthur Foundation. This article summarizes the currently used definitions for response, remission, relapse, recurrence, continuation, and maintenance treatment, and discusses whether relapse is the consequence of incomplete remission. The two most important outcomes that are important in order to distinguish relapse from recurrence are the threshold for remission and the time spent in remission before recovery can be ascribed to a patient. For remission a 17-item Hamilton Depression Rating Scale (HAMD-17) threshold of below 7, and for recovery a time span of 6 months in remission seem to be now accepted by the research community. Recent research on remission thresholds, together with the role of unrecognized residual symptoms in the development of depressive disorder, are discussed. The “6-month” period for determining the end of an episode is explained and justified by two different approaches involving the length of the depressive episode and data from antidepressant discontinuation trials. To conclude, the limitations and pitfalls of both methods are discussed.

Medicographia. 2011;33:125-131 (see French abstract on page 131)

Defining relapse or recurrence is directly dependent on the definition of the healthy, illness-free state commonly referred to as remission or recovery. Remission derives from the Latin word remittere (remisi, remissum), which literally translates as “to abate” or “to remit,” “to send back.” Clearly, in medical terms, the term remission relates to the former meaning, describing the “abatement” or the “decrease” of symptoms.

So from a linguistic point of view this would not necessarily imply absolute freeness of symptoms, but would rather describe an improvement in the course of illness. In the early days of depression research this has contributed to quite a few difficulties and much confusion regarding definitions of outcome terms like response, remission, and partial remission. This ultimately led to the paradox that one researcher’s definition of “remission” equaled another researcher’s definition of “response.”1 In 1988, in an attempt to overcome these controversies, the MacArthur Foundation set up a task force led by Ellen Frank with the goal of achieving a con- sensus in defining outcomes of clinical studies.2 This led to the current definition of “remission,” which, in its narrow medical sense, refers to the virtual absence of depressive symptoms. Terms like “recovery,” “relapse,” and “recurrence” were also precisely defined. Important therapeutic concepts relating to these outcomes, are “response,” and “acute, continuation, and maintenance therapy.” These terms have often been used quite arbitrarily in the past. After the publication of the consensus paper by Ellen Frank in 1991,2 the American College of Neuropsychopharmacology (ACNP) updated these recommendations by introducing small changes.3 In the wake of the MacArthur Foundation, several other groups were set up to standardize the definition of psychiatric terms such as bipolar disorder4 or schizophrenia.5,6 In the following, we briefly summarize the current concepts underlying the terms response, remission, recovery, relapse, and maintenance, before discussing in more detail some important aspects closely related to relapse and recurrence, as well as the why the time span of 6 months was agreed upon. Figure 12,4 shows the important periods in depression treatment and the corresponding terminology for the illness phases in relation to these treatment periods.

Response

Response describes a gradual improvement during depression treatment and usually implies a treatment effect.7 Response is usually defined as a 50% improvement from baseline to end point on depression rating scales such as the 17-item Hamilton Depression Rating Scale (HAMD-17) or the Montgomery-Åsberg Depression Rating Scale (MADRS). Response tends to occur early on during the course of treatment (eg, after 2 weeks8) and usually precedes remission as a precondition. It is the main categorical outcome parameter of short-term antidepressant trials. Thus, response occurs during the acute treatment phase of major depression.

Figure 1
Figure 1. Overview of response, remission, recurrence, and relapse in relation to the
treatment phase.

Modified after reference 4: Tohen et al. Bipolar Disord. 2009;11: 453-473. © 2009, Blackwell Munksgaard.

Remission

As stated before, remission refers to a relatively short symptom- free period.7 Usually, remission is defined by a threshold on a depression rating scale. In contrast to response, remission is not necessarily related to any treatment. It can also occur spontaneously in patients without treatment. Michael Thase has shown that a threshold of equal to or below 7 on the HAMD-17 best distinguished healthy control persons from patients with major depression (Figure 2).9 Recently, this threshold was replicated in a large sample of naturalistically treated patients with major depression.10 In contrast to response, remission can occur with or without treatment. From a therapist’s perspective, remission is the starting point of continuation therapy with the primary goal of sustaining remission until recovery is achieved.

Recovery

The concept of recovery implies a prolonged period of remission. This period should be long enough so that a major depressive episode (MDE) is unlikely to occur in the near future.3 In other words, once a patient achieves recovery, many months of remission can be anticipated.3 In accordance with remission, recovery can be ascribed while the patient is either on or off treatment. From a theoretical point of view, recovery implies that the illness activity of the MDE is no longer present, but it is important to keep in mind that the underlying vulnerability may still be present. This also means that recovery refers only to the last episode and not to the affective disorder as a whole.

Thus, recovery is only lost if recurrence occurs. The ACNP Task Force recommends a time span of 4 months, while others have repeatedly used a 6-month duration to define recovery.11 The fact that a patient has recovered also raises the possibility for the treating clinician to consider discontinuing treatment, which is of course one of the most important clinical implications of recovery.

Relapse and recurrence

Both terms refer to the reappearance of a full-blown MDE. The essential distinction between both terms is the time at which each event occurs. According to the description by Frank et al, “relapse” is “a return of symptoms satisfying full syndrome criteria for an episode that occurs during a period of remission, but before recovery.”2 This again points to how critical the time criterion of recovery and the symptomatic threshold of remission are, as all other definitions are based upon them. As for “recurrence,” this is defined as “the appearance of a new episode of MDE, occurring during recovery.”2

In summary, we not only discriminate remission and recovery, but also relapse as an early return or “fall back” into the initial MDE, and recurrence as a late return of the illness and as a development of a new depressive episode, unrelated to the prior, “cured” episode, respectively.

Continuation and maintenance therapy

These terms are closely connected with the terms relapse and recurrence. The goal of continuation therapy is to preserve the therapeutic success of the acute phase until recovery is achieved (Figure 1). In addition, clinicians should try to eliminate residual symptoms, restore social functioning, and prevent relapse of depression during continuation. The time span of the continuation therapy should have the length of the “natural course” of an MDE and is exactly the same time span that is used to define recovery.

In practice, patients mostly stay on the same medication regimen that led to the remitted state with only small changes in dosage, mostly to optimize tolerability. Once recovery is achieved, maintenance therapy starts, with the primary goal of prevention of recurrences. Clearly, the indication of maintenance therapy has to be reviewed for each single patient based on individual factors.

With respect to the above-described concepts relative to outcomes in major depression and corresponding therapeutic phases, it is obvious that two variables are crucial for longterm outcome:
– The threshold and definition of remission.
– Determining when recovery has set in, ie, the 6-month cutoff period.

Threshold and definition of remission

There is still no consensus regarding the best way of determining when the remitted state has been reached. As explained above, the HAMD rating scale, now in use for almost 50 years,12 has been widely used to assess symptomatic severity, response, and remission in clinical trials. Despite recent criticism,13 it remains the “gold standard” in academic and regulatory clinical trials.14 Other depression rating scales include the MADRS15 with its hypothesized better sensitivity to change, or the Inventory of Depressive Symptomatology (IDS),16,17 which reflect more contemporary definitions of depression, and are also used to define remission.

Figure 2
Figure 2. HAMD severity distribution for healthy controls (blue shade, left) and depressed outpatients (orange shade, right).

Abbreviations: HAMD, Hamilton depression rating scale; sdu, standard deviation unit.
Modified from reference 9: Thase. J Clin Psychiatry. 2003;64(suppl 13)18-25. © 2003, Physicians

Postgraduate Press, Inc.

The most widely used criterion for remission is a HAMD-17 score of ≤7, which corresponds to a HAMD-7 score of ≤3.18 The recommendation of the ACNP Task Force is to use a score of ≤7 or even ≤5 on the HAMD-17 scale as criterion for remission.3 For the MADRS, scale cutoff scores of ≤8 or ≤9,19 <10,20 ≤10,21 ≤11,22 were suggested. However, there is recent evidence to support the use of more stringent scores on both the HAMD and MADRS scales. Patients with HAMD-17 scores ≤2 (or MADRS scores ≤4) show better psychosocial functioning than those with scores of 3 to 7 (or MADRS scores of 5 to 9).21 On the other hand, a problem with the use of very stringent definitions of remission is that healthy, nondepressed individuals may be labeled depressive. A literature review of control groups in clinical depression trials reported a mean HAMD-17 score of 3.2±3.2 (SD) among healthy control individuals. 21 As already noted above, Michael Thase was able to separate depressed subjects form healthy controls and thus validate the HAMD-17 threshold of below 7 (Figure 2).9 In addition, in an analysis by our own group, a Hamilton-17 score ≤7 best corresponded to a Clinical Global Impression (CGI) score of 1 (corresponding to “normal, not ill”) in a large sample of naturalistically treated inpatients with MDE.10 However, Nierenbergvery recentlydemonstrated for theSequenced Treatment Alternatives to Relieve Depression (STAR*D) study sample that the number of residual symptom domains was significantly associated with relapse even in patients meeting criteria for full remission (Figure 3).22 This is of high clinical relevance as recent clinical studies indicate that 21% to 35% of patients in remission from an MDE had residual symptoms.24,25 In a recent analysis by our own group on 1014 naturalistically treated inpatients with MDE, patients meeting symptomatic criteria for full remission still showed an identical symptom pattern to that of patients meeting criteria for response, only at a much lower degree of severity.26

Figure 3
Figure 3. STAR*D sample: Kaplan-Meier survival curve of major depressive disorder relapse with the number of residual symptom domains in the year following acute remission with citalopram.

Abbreviations: QIDS-IVR, Quick Inventory of Depressive Symptomatology–Interactive Voice Response (System).
Modified from reference 22: Nierenberg et al. Psychol Med. 2010;40:41-50. © 2009, Cambridge University Press.

Both analyses indicate that residual symptoms in remitted patients resemble still-present illness activity more than anything else (eg, personality traits) and that the definitions we use are still in need of improvement. Two major options are currently under discussion. The first is to expand symptomatic remission criteria to areas of psychosocial functioning. The second option would be to also add a short time criterion for “sustained remission” as proposed by the ACNP Task Force (eg, 3 consecutive weeks). Clearly, a combination of both would probably be the most stringent and accurate method for defining remission. How long the time period of remission should last in order to declare a patient recovered will be reviewed in the next paragraph.

Why has the cutoff for recovery been set at 6 months?

_ Approach based on estimation of the duration of an MDE
The crucial question is: what is the mean duration of an MDE? So far there are only few long-term observational studies available. Based on data from a 10-year follow-up study, Solomon et al calculated an average duration of depressive episodes of 20 weeks, with a median duration of 5 consecutive episodes of 22, 20, 21, 19, and 19 weeks.27 Similarly, Angst et al reported a median length of depressive episodes of 5.4 months in a 5-year follow-up of hospitalized patients with major depressive disorder.28

The sampling method used in these studies has been much criticized, and the recruitment of more chronic and more severe patient samples in such clinical follow-up studies has been dubbed “clinician’s illusion” or “Neyman bias.”29,30 Many individuals do not experience recurrences, and only those who do end up in clinical trials and thus represent the more chronic and severe cases. In other words, hospital-based clinical samples tend to be mostly “prevalence samples,” whereas epidemiological prospective follow-ups of patients with a first episode tend to be mostly “incidence samples.” This is why the natural history of major depressive disorder is usually best studied in prospective follow-up studies of individuals from their first lifetime episode onward,30 such as the NEtherlands MEntal health Survey and Incidence Study (NEMESIS)31 and the Baltimore Epidemiologic Catchment Area (ECA) Follow-up Study.30

The NEMESIS study followed a sample of 273 individuals with first lifetime major depressive episode over a period of more than 2 years.31 The approximated duration of depressive episodes was 3 months. The methodologically most elaborate trial was the ECA, reported on by Eaton et al in 2008.30 Starting with a probability sample of 3481 household residents in 1981, 92 patients with a first lifetime episode of major depression were followed-up for at least 13 years. In this study, the median length of the depressive episode was also 3 months. Of note, about 50% of first-episode patients did not experience a second episode during follow up.

An important finding of this study was that there seemed to be a relationship between the total number of experienced episodes and the median episode duration. The first episode had a median duration of 20 weeks, patients with 3 or more episodes also had a median episode duration of 20 weeks, patients with 4 or more episodes had a median duration of 24 weeks, patients with 5 or more episodes had a median episode duration of 12 weeks, and patients with 9 or more episodes had a median duration of 6 weeks. Interestingly, once the total number of episodes was adjusted, there was neither a strong nor even a significant tendency for episodes earlier in the course to be shorter or longer than the episode occurring later in the course. In summary, this signals a preexisting heterogeneity among patients with major depressive disorder with respect to the duration of episodes.30

_Approach based on discontinuation trials
Beyond the abovementioned descriptive pragmatic definition of recovery based on estimations of median episode duration, is an approach that is based on discontinuation trials. The theoretical backbone here is the assumption that once a patient has recovered, the underlying biological illness activity has stopped and hence treatment can be safely discontinued. Probably one of the best prospective discontinuation studies from a methodological point of view addressing this question was published by Reimherr et al in 1998.32 In this prospective double-blind, controlled, four-arm crossover design trial, 395 patients meeting criteria for remission after 12 or 14 weeks of open-label acute fluoxetine therapy were randomized to either: (i) receive 50 weeks of placebo; (ii) 14 weeks of continuation fluoxetine and then 36 weeks placebo; (iii) 32 weeks fluoxetine continuation and then 12 weeks of placebo; or (iv) 50 weeks of fluoxetine continuation. Relapse rates were lower for patients who continued fluoxetine treatment (FLU) compared with placebo (PLA) for the first interval after 24 weeks of total treatment (FLU: 26%, PLA 49%) and the second interval after 38 total weeks of fluoxetine treatment (FLU: 9%, PLA 23%), but there was no difference for the third time interval after 62 total weeks of fluoxetine treatment (FLU: 11%, PLA 16%). In summary, this report suggests that continuation treatment should be expanded to at least an additional 26 weeks to minimize the risk for relapse.32

A very recent trial on continuation and maintenance treatment giving an estimate of outcome of 6-month continuation is the Prevention of Recurrent Episodes with VENlafaxine for Two years (PREVENT) study. In this trial, 1096 outpatients with recurrent unipolar depression were randomly assigned in a 1:3 ratio to 10 weeks of treatment with venlafaxine ER or fluoxetine. All responders on the HAMD-17 scale (>50% baseline reduction) entered a 6-month double blind continuation phase on the same medication. Continuation phase responders were then enrolled into maintenance treatment consisting of 2 consecutive 12-month phases. At the start of each maintenance phase, venlafaxine ER responders were randomly assigned to receive double-blind treatment with either placebo or venlafaxine, whereas fluoxetine responders continued treatment.

Among remitters of the acute phase, 81% in the venlafaxine and 81%in the fluoxetine group remained remitters at the end of continuation treatment.33 Among patients who were remitters at maintenance baseline, 69% of those taking venlafaxine and 55% of those taking placebo were still remitters after 1 year.34 Certainly it has to be kept in mind that the patient sample suffered from recurrent depression with a mean current episode duration of 6 to 7 months, thus representing a more chronic study population.34 Nevertheless, this study gives fresh evidence for the efficacy of antidepressants during continuation over 6 months and during maintenance.

_ Limitations and pitfalls of these two approaches
Using discontinuation data to estimate the duration of time in remission for a patient to be declared as recovered has 3 important pitfalls:
_ Despite having achieved recovery after a period of 6 months in remission, patients can still experience a new MDE immediately thereafter.
_ Achievement of recovery after 6 months does not necessarily exclude still-present biological illness activity of the affective disorder.
_ Our knowledge of specific antidepressant action is still limited. So far we cannot distinguish whether symptoms are only “suppressed” by the medication or whether the MDE has really abated.

However, to sum up, most data suggest a median duration of depressive episodes varying between 12 and 20 months. But since it can nowadays be assumed that at least a substantial proportion of depressive episodes are under treatment, we currently have no clear idea of how long episodes would last without treatment. Posternak et al have tried to address this issue and estimate the duration of MDEs in the absence of any somatic treatment.35 Out of 318 patients enrolled in the collaborative depression study, 130 patients experienced a recurrence over a 15-year follow-up period that initially went untreated for at least 4 weeks. Of those, 46 subjects received treatment, whereas the other 84 remained entirely untreated. In this study, recovery was defined as time to the first of 8 consecutive weeks with no or minimal symptoms. The total sample consisting of the 130 patients had a median time to recovery of 23 weeks. But surprisingly the subgroup of untreated patients had a much shorter median time to recovery of 13 weeks.35 This example nicely illustrates the methodological difficulties in that research area. As the authors correctly state, the major reason for the shorter time period to recovery in the untreated sample is most probably the general difference between a treatment-seeking and a nontreatment-seeking depressed patient sample.35 As this was a nonrandomized trial, the results rather support prior studies showing that nontreatment-seeking patients have an inherently better prognosis than treatment-seeking patients.36 One possible methodological approach could be to meta-analyze placebo arms of controlled antidepressant trials in order to estimate the median time of a depressive episode in a treatment-seeking patient sample.

So far, we must assume, at least in case of treatment-seeking patients, that the depressive episode without treatment would last longer as discussed in the above-cited trials. In addition, since we have only one prospective study regarding the optimum length of continuation treatment, the 6-month duration still seems defensible. It could also well turn out that recovery should only be ascribed after 1 year, as suggested by Reimherr et al.32 With that definition it might also take longer to reach recovery. Reimherr et al showed that the mean time to recovery (defined as a 1-year period free of any episode) was 2 or 3 years for both men and women. However, periods of 4 months as suggested by the ACNP task force seem to be far too short.3 The main argument used here were reports that demonstrate that the highest chance for any relapse is within the first 4 months. But considering a wider range of trials on relapse rates, the highest risk indeed seems to be in the first or even 2 years after acute treatment.27-30

Summary

To conclude, we should constantly remember the high heterogeneity of the disease major depressive disorder. With that in mind, an individualized approach is always preferable in good daily clinical practice. In this respect we should try to give the best estimate possible of each individual’s mean episode duration. Often patients remember earlier episodes, free of any treatment. With that information clinicians have a perfect estimate of how long continuation treatment should at least last in the individual patient. For research purposes and rougher guideline recommendations the 6-month threshold is still justifiable. Remission should still remain the main treatment goal in treating major depression. However, current criteria maybe need reconsideration, as residual symptoms, even in remitted patients, still seem to be associated with relapse. _

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Keywords: depression; relapse; recurrence; response; remission; recovery; continuation treatment; maintenance treatment; antidepressant