Sidney H. KENNEDY, MD, FRCPC
Department of Psychiatry
University Health Network
Department of Psychiatry
University of Toronto
Toronto, Ontario, CANADA
Franca M. PLACENZA, PhD
Department of Psychiatry
University Health Network
Toronto, Ontario, CANADA
by S. H. Kennedy and F. M. Placenza,Canada
There is strong evidence to support relapse prevention strategies in the intermediate and long-termmanagement of patients with a history of recurrent Major Depressive Episodes. Most placebo-controlled relapse prevention trials have evaluated the benefits of different antidepressant therapies (tricyclic, selective serotonin reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, and agomelatine) over 6-month to 3-year durations. Evidence-based psychotherapy studies, mainly cognitive behavioral therapy (CBT), mindfulness-based cognitive therapy (MBCT), and interpersonal psychotherapy (IPT), with and without pharmacotherapy, have also been carried out. Although there are considerable variations inmethodologies,metaanalyses and guidelines support maintenance treatments with both antidepressants and psychotherapies. In general, patients with risk factors for recurrent episodes of depression should remain at the same dose of antidepressant medication for at least 2 years. Patients require frequent monitoring with an emphasis onmodifiable risk factors for relapse, including comorbid disorders and treatment adherence. Those who relapse despite adequate medication therapy may benefit from additional CBT or MBCT. Discontinuation of medications requires gradual tapering. It is important to address individual patient factors in the long-term management of Major Depressive Disorder.
Relapse and recurrence
The definitions of relapse and recurrence of a major depressive episode (MDE) proposed by the MacArthur Foundation Task Force1 have been more or less universally accepted. Relapse implies the loss of either response or remission and may be operationalized as the return of sufficient symptoms to meet criteria for an MDE for at least 2 weeks2 or an increase in Hamilton Rating Scale for Depression (HRSD) scores above a predetermined threshold for a minimum duration (eg, HRSD ≥16 for 2 weeks or more).3 Recurrence implies the emergence of a new episode of depression some time after the risk period for relapse within an identified episode, although the distinction between relapse and recurrence is probably more theoretical than pragmatic. These definitions provide a basis for comparative studies to examine relapse prevention across different treatment modalities (eg, pharmacotherapy, electroconvulsive therapy, or cognitive therapy) or within one modality (eg, selective serotonin reuptake inhibitor (SSRI) vs serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants).
Guideline recommendations for relapse prevention
The evidence to support continuation and maintenance antidepressant therapies in the long-term management of MDD is among the most robust in the mood disorders literature.4 Among guidelines developed for the treatment of Major Depressive Disorder (MDD), those of the British Association for Psychopharmacology (BAP),5 the Canadian Network for Mood and Anxiety Treatments (CANMAT),6 the National Institute for Health and Clinical Excellence (NICE),7 the Texas Medication Algorithm Project (TMAP),8 and the World Federation of Societies of Biological Psychiatry (WFSBP)9 are among the most current.10
There is a consensus that maintenance treatment should continue for a minimum of 6 months after achieving symptomatic remission and that the medication dose that was effective during acute treatment should not be reduced. Maintenance treatment for 6 to 9 months is acceptable for patients with one or two episodes who do not have additional risk factors for relapse.5 The presence of risk factors in patients who have had two episodes supports an extended period of maintenance therapy.8 These risk factors are summarized in the CANMAT guidelines (Table I).6 While the WFSBP guidelines concur with the general recommendations to maintain antidepressants at the same dose as the acute phase, these guidelines offer more support for lithium in preventing recurrence of unipolar depressive illness. They also emphasize the benefits of lithium prophylaxis in reducing the risk of suicide.9
Most guidelines also recommend that patients with three or more MDEs should be maintained on antidepressants for at least 1 year and up to lifetime, with duration of maintenance therapy depending upon risk factors for recurrence and patient preference.8 According to the NICE guidelines, patients should continue antidepressants for at least 2 years if they are at risk of relapse.7 Recommendations from the BAP guidelines are that, for patients with more than five lifetime episodes and/or two episodes in the last few years, medication should be continued for at least 2 years.5
Table I. Risk factors supporting long-term (2 years to lifetime) antidepressant
Maintenance treatment beyond 2 years should be considered when factors such as older age, comorbid conditions, and other risk factors are present.7 There is also agreement that when the decision is made to discontinue an antidepressant, it should be done gradually to avoid discontinuation emergent symptoms. High-risk patients should be monitored regularly for early signs of recurrence after discontinuation of antidepressants. According to the CANMAT guidelines, evidence to support maintenance therapy for longer than 2 years has a less established evidence base, but certain risk factors, including earlier onset of depression, continuing psychosocial adversity, older age, and comorbid medical or psychiatric conditions, are indicators for extended maintenance treatment.6 In the NICE guidelines, patients who have relapsed despite adequate antidepressant maintenance treatment are considered candidates for combined medication and psychological interventions, particularly cognitive behavioral therapy (CBT) or mindfulness-based cognitive therapy (MBCT). MBCT is also recommended for people who are currently well, but have experienced three or more prior episodes of depression.7 Similar conclusions are reached in the BAP guidelines, which suggest the addition of CBT to medication for patients with residual symptoms or those with additional risk factors for relapse. The same group also concludes that interpersonal therapy (IPT) is not recommended as a sole maintenance treatment, although it may be a useful adjunct to antidepressants in patients with recurrent depression.5 Psychotherapy is not recommended as a sole treatment to prevent recurrence in the WFSBP guidelines,9 although these guidelines are considerably older than others and did not have access to literature in the past decade. The same is true overall for the guidelines from the American Psychiatric Association (APA).11
Evidence to support relapse prevention strategies in major depressive disorder
_ Pharmacotherapy studies
Support for these guidelines on relapse prevention has steadily emerged over several decades. In a landmark relapse prevention trial, the Pittsburgh group evaluated the benefits of a tricyclic antidepressant (TCA) or IPT alone or in various combinations.12 Results of the survival analysis demonstrated a robust effect for imipramine at an average dose of 200 mg daily and a modest effect for IPT. The mean survival time for both imipramine-treated groups was approximately 2.5 years compared to 1.5 years for IPT and just under 1 year for the placebo control group.12 In the final phase of this project, 20 subjects who had remained in recovery up to 3 years were randomized to continue on imipramine (n=11) or to receive placebo (n=9) for a further 2 years. At the end of 5 years, 5 out of 9 receiving placebo had a recurrence of depressive episodes with a mean survival time of 54 weeks, while only 1 out of 11 receiving imipramine had a recurrence and the mean survival time was 99 weeks.13
One of the first relapse prevention trials with a second-generation antidepressant compared responders to paroxetine who remained on the active treatment for 1 year to those who switched to placebo. There was a significantly lower rate of relapse and longer survival time in the paroxetine group.14 This was followed by a large systematic review of relapse prevention in which Geddes and colleagues (2003)4 identified 31 randomized trials (published or unpublished up to August 2000) involving patients who had responded to an antidepressant during acute treatment and were randomized to continue on the drug or switch to placebo. Although this analysis included trials out to 36 months, most (58%) lasted 6 or 12 months and the majority (81%) involved TCAs or SSRIs. The authors concluded that continuing treatment with an antidepressant reduced the odds of relapse by 70%, with an average of 41% of patients receiving placebo and 18% on antidepressant experiencing a relapse. The relative reduction in year 1 was 20%, corresponding to a number needed to treat of 5 patients.4
Prevention of Recurrent Episodes of depression with VENlafaxine for Two years (PREVENT) was the first large trial to assess relapse prevention with an SNRI in patients with recurrent depression (defined as three or more prior episodes, two occurring within the past 5 years).15,16 The study employed a three-phase, double-blind, placebo-controlled methodology to examine two consecutive 1-year maintenance phases in which responders to venlafaxine ER were randomly assigned to remain on the medication or switch to placebo. At the end of each maintenance phase, patients receiving venlafaxine ER had a significantly longer time to recurrence and lower likelihood of recurrence compared with those who were switched to placebo (Year 1: 23% vs 42%; Year 2: 8% vs 45%).15,16
In a subsequent meta-analysis involving SSRIs, SNRIs, and other second-generation antidepressants, Hansen and colleagues (2008) evaluated 23 placebo-controlled and 4 comparative trials. There were no differences in relapse and recurrence rates in the 4 head-to-head comparative trials. Among the placebo-controlled trials, the duration of randomized follow up in 12 studies was less than 1 year, and 1 year or longer in the remaining 11 trials. The number of patients needed to treat to prevent 1 additional relapse was 5.17 In a recent update on the long-termtreatment of depression with SSRIs and newer antidepressants, Reid and Barbui (2010) reaffirmed the benefit of continuing antidepressant treatment for at least 12 months following the treatment of an acute episode.18
Agomelatine is a new antidepressant with a novel mode of action19 that has also been evaluated under relapse prevention conditions. Like the trials previously reviewed, agomelatine demonstrated similar efficacy in relapse prevention with a cumulative relapse rate of 21.7% for agomelatine compared with 46.6% for placebo over 24 weeks of maintenance therapy.3
_ Psychotherapy studies
In parallel with the pharmacotherapy evidence for relapse prevention, a number of studies have demonstrated the benefits of evidence-based psychotherapies, particularly CBT20 and MBCT.21 While there is some support for IPT as a maintenance therapy, the evidence is less robust. For example, Schramm and colleagues (2007) reported a short-term (3- month) advantage for IPT over clinical management for relapse prevention in hospitalized depressed patients with MDD. However, this difference was not maintained at 1 year.22 Frank and colleagues (2007) also evaluated the potential preventative role of IPT at different frequencies in a large sample of women with recurrent unipolar depression who achieved remission with either IPT alone or in combination with an SSRI. Oncemonthly IPT proved to be a good method of prophylaxis for the subpopulation of women who achieved remission with IPT alone, but was less helpful in the group who required SSRIs in the initial phase of treatment.23 A summary of recommendations for evidence-based psychotherapies in maintenance treatment from the CANMAT guidelines are shown in Table II.24
Despite the impressive evidence from these various controlled trials, adherence to relapse prevention strategies in natural practice trials is considerably less impressive.25,26 The investigators monitored, but did not control, the use of antidepressants during a 2-year follow up of remitted patients who had a history of recurrent depression and were candidates for maintenance antidepressant therapy. Only 42% maintained continuous antidepressant treatment, 38% received antidepressants intermittently, and 20% were without maintenance antidepressant therapy throughout the trial. Overall, based on a standardized minimum effective dose criterion, only 26% of patients received an antidepressant at or above the recommended guideline doses. In this study, there was no difference in rates of relapse between intermittent and continuous antidepressant groups, but those patients who received additional preventive cognitive therapy had the lowest relapse rates.25
Table II. Relapse prevention: recommendations for individual psychotherapies.
S15-S25. © 2009, Elsevier BV.
In a subsequent report involving the same cohort of patients, Bockting and colleagues (2009) compared relapse rates after 5.5 years in “treatment as usual” (TAU) versus TAU augmented with a course of modified cognitive therapy.While the overall relapse rate was high (79%), there was a significantly lower rate in the augmented group (75%) compared with the TAU group (95%).26
_ Neurostimulation studies
Among the neurostimulation therapies, only electroconvulsive therapy (ECT) has an adequate evidence base to provide guidelines for its use in relapse prevention.27 The main clinical dilemma following successful treatment of an acute depressive episode with ECT is the selection of optimal maintenance therapy. In general, antidepressant treatments that failed prior to the use of ECT are not effective in subsequent relapse prevention. However, results from two large collaborative studies, the Consortium for Research in ECT (CORE)28 and the Columbia University Consortium,29 support a combination of nortriptyline and lithium for relapse prevention. In the CORE study, maintenance ECT was as effective as the combination therapy during the first 6 months.28 However, there is insufficient evidence to recommend an optimal frequency for maintenance ECT and only modest evidence to support continuation of ECT in the long term.30
From guidelines to personalized medicine
There are several reasons why it is difficult to compare outcomes for individual antidepressants across the studies and meta-analyses discussed here. Aside from differences in duration of various studies, there is a lack of consensus on what constitutes a relapse. This is well illustrated in the systematic review of 31 trials reported by Geddes and others (2003)4 where virtually every trial employed different criteria for “relapse.” These varied from: (i) poorly defined clinical criteria such as “change in treatment is indicated” or “increase in symptoms sufficient to warrant admission to hospital”; to (ii) increased scores on various symptom scales (eg, Montgomery- Åsberg Depression Rating Scale (MADRS) ≥22; ≥25 or HRSD ≥16, ≥17, ≥18); to (iii) recurrence of a MDE; to (iv) several of these criteria combined.4
Apart from differences in trial methodology, patient variables have also been shown to influence relapse. These include the number of prior episodes, medical and psychiatric comorbidity, and the presence of residual symptoms.31 In addition to clinical and demographic factors, certain biological (eg, short allele of serotonin transporter gene promoter region polymorphism) and psychological (eg, neuroticism, cognitive vulnerability) markers have been identified as risk factors for recurrence of MDD in the context of stress.32,33 Longitudinal controlled studies are needed to establish the role of these markers in optimizing the duration of antidepressant treatment and predicting relapse. _
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Keywords: serotonin reuptake inhibitor; serotonin and norepinephrine reuptake inhibitor; agomelatine; cognitive behavioral therapy; electroconvulsive therapy