Nearly 1 in 5 adults in the United States will experience major depressive disorder (MDD) in their lifetime.1 MDD is an enormous contributor to disability worldwide and within the US. MDD is the fifth leading cause of “disability adjusted life years” and is second only to low back pain in causing “years lived with disability.”2 Antidepressants are often prescribed as first-line treatment, but one-third of patients will not successfully respond to 2 or more adequate medication trials.3 Many of those with treatment-resistant depression (TRD) unfortunately undergo numerous subsequent antidepressant medication treatment trials that fail to result in adequate improvement.3
For those with MDD who respond well to an antidepressant trial, current guidelines recommend continuation pharmacotherapy (C-pharm) with the same agent to prevent relapse.4 For patients who don't respond well to a series of antidepressant medications, electroconvulsive therapy (ECT) is very effective, with response rates of 50% to 60%.5 Given the diminished returns observed with subsequent medications trials,6 ECT is several times more effective for TRD than antidepressants. However, these same guidelines are notably less specific regarding the recommended continuation treatment in patients who respond well to ECT.4 Without continuation ECT treatment, relapse rates after successful ECT treatment approach 80%,7 with even greater risk observed in patients with a history of treatment resistance.8 Fortunately, there are several options available for continuation therapy for patients with MDD successfully treated with ECT.
The most commonly employed strategy for relapse prevention after successful ECT treatment is pharmacotherapy.9,10 A randomized placebo-controlled trial examining the effects of C-pharm in people with depression who remitted after open-label ECT found that the addition of nortriptyline substantially reduced relapse risk compared to placebo over 6 months.7 Unlike prior research examining the effects of C-pharm with tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors, Sackeim et al.7 introduced placebo to control for the potential added benefit of concurrent pharmacotherapy and ECT (eg, 84% of patients treated with placebo after discontinuation of ECT had relapsed by 6 months). The addition of nortriptyline (serum levels 75–125 ng/mL) reduced the relapse risk to 60%.7
Of those in the above study that ended up relapsing by 6 months, more than one-half did so within the first 8 weeks after discontinuation of ECT. It has been postulated that this could be due to the delayed onset of the therapeutic effects of antidepressant medication.11 Because of this, Prudic et al.11 tested whether the initiation of pharmacotherapy at the beginning of a course of ECT would confer greater protective effects after ECT. They compared relapse rates between patients who started antidepressant pharmacotherapy with either venlafaxine or nortriptyline after ECT with those who received the same pharmacotherapy at the initiation of ECT. All patients received open continuation treatment with lithium dosed to steady state levels of 0.5 to 0.7 mEq/L. The rate and timing of relapse observed in each study group did not differ, indicating that starting an antidepressant with initiation of ECT did not confer any additional protective effect against depression relapse.
The beneficial role of lithium in relapse prevention after ECT has long been recognized.12,13 However, methodological problems limit the quality of evidence from these earlier studies. Sackeim et al.7 also studied whether the addition of lithium to nortriptyline improved outcomes after discontinuation of ECT vis-à-vis continuation treatment with nortriptyline alone. In this randomized, placebo-controlled trial, lithium was dosed to serum levels between 0.5 and 0.9 mEq/L. Patients treated with both lithium and nortriptyline showed a relapse rate of only 39%, significantly lower than both the nortriptyline-only group (60% relapse rate at 6 months), as well as the placebo group. The mean lithium level was 0.59 mEq/L, although there was no association between lithium level and relapse rate. Subsequent studies have replicated these findings—concomitant continuation therapy with lithium and an antidepressant reduced relapse to approximately 40% at 6 months.14
Overall, C-pharm is reasonable in patients with MDD successfully treated with ECT and is certainly more effective than no continuation therapy. Along these same lines, it is imperative that treating psychiatrists continue active antidepressant pharmacotherapy management in patients referred for ECT. In fact, to date there is no evidence to support that continuing a previously established ineffective antidepressant regimen (in place prior to the initiation of ECT) improves relapse prevention. There are additional clinical considerations as well when evaluating the appropriateness of C-pharm. ECT is typically recommended only after several failed antidepressant trials,3 and several studies have supported an increased risk of relapse with C-pharm after ECT in patients with a history of treatment resistance.7,8,14 Additionally, although the addition of lithium to antidepressant treatment can substantially decrease risk of relapse, it is important to be aware of contraindicating comorbidities and drug-drug interactions that make it inappropriate for some patients. Antidepressant agents with novel mechanisms of action such as ketamine have not yet been studied as continuation treatment after ECT, although one study is currently under way.15
The use of ECT for continuation of psychiatric illness stabilization precedes development of effective psychiatric medications.16 Nonetheless, relatively few randomized, controlled clinical trials have been published on the efficacy of continuation ECT (C-ECT) as monotherapy. One of the first studies to examine the efficacy of C-ECT monotherapy in patients diagnosed with MDD (using the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III)17 criteria) employed a naturalistic, prospective study design to observe 27 patients who remitted with ECT.18 After remission, participants underwent a protocolized taper of ECT treatments in a fashion that closely resembles modern recommendations, with weekly treatments given over a 1-month period, followed by a taper to every other week for another month, before transitioning to monthly treatments.19 Adherence to the C-ECT protocol significantly reduced the risk of relapse defined as the return of depressive symptoms requiring rehospitalization.
A subsequent randomized, controlled clinical trial conducted by the Consortium for Research in ECT (CORE) compared the effects of C-ECT monotherapy to C-pharm with nortriptyline and lithium in patients with MDD who remitted after a course of ECT. This study determined that both C-ECT and the combined C-pharm strategy were similarly effective in reducing the depression relapse risk.20 In both treatment groups, reported relapse rates were about 40% at 6 months, although the mean time for relapse in the C-ECT group tended to be longer than that for the C-pharm group. Notably, C-ECT was at least as tolerable as medication treatment.
C-ECT is both effective and well-tolerated in the prevention of depressive relapse. It is ideally considered for patients who have remitted, but current professional guidelines don't specify remission as a necessary indication.4 However, it is nonetheless important to reserve the treatment for those patients who have demonstrated a definitive, maximal positive response to ECT.19 Although C-ECT monotherapy has not been shown to be consistently more effective overall than combination C-pharm with adjunctive lithium, it may be particularly advantageous in patients with a high degree of medication resistance and/or a history of intolerance to psychotropic medications.
Combination C-ECT and C-pharm
Unfortunately, there are few randomized controlled clinical trials examining the efficacy of C-ECT plus C-pharm.21 Much of this literature includes observation periods extending beyond the arbitrary 6-month cut-off that distinguishes the continuation and maintenance phases treatment.22 For the purposes of this article, the term “continuation” will be used to refer to both continuation and maintenance.
A single-blind randomized controlled trial examined the effects of C-ECT plus C-pharm versus C-pharm alone in older adults with remitted psychotic depression after acute treatment with nortriptyline and ECT over 2 years.23 For both groups, nortriptyline was flexibly dosed to maintain blood levels between 80 and 120 ng/mL. The combination (C-ECT plus C-pharm) was more effective in preventing relapse than C-pharm alone, with relapse defined as meeting The Diagnostic and Statistical Manual of Mental Disorders, fourth edition,24 criteria for a major depressive episode and a Hamilton Depression Rating Scale (HAM-D) score of greater than or equal to 16. Including participants who dropped out, only 1 of 16 receiving combination treatment relapsed within the study period compared to 8 of 17 receiving C-pharm alone. Just as importantly, there was no indication of reduced tolerability of the combination treatment compared to C-pharm alone. It is particularly noteworthy that in a sample of older adults (mean age ∼70 years) there were no observed differences between groups in cognitive function (as measured using the Folstein Mini-Mental Status Examination). The lack of cognitive impairment due to C-ECT is consistent with other research examining cognitive outcomes in long-term ECT treatment.25
One of the more challenging aspects of managing patients undergoing C-ECT, with or without continuation medications, is determining how to address signs of depressive relapse in the setting of a fixed schedule of treatments. One strategy that has been explored in the literature is adjusting the frequency of ECT treatments in response to early signs of relapse.26,27 One study found beneficial antidepressant effects of an individualized C-ECT schedule with medication treatment by conducting a chart review of 41 patients who had received combination C-ECT and C-pharm treatment for at least 4 months.26 The individualized protocol used in that study involved increasing the frequency of treatments to 2 or 3 times per week until remission was re-achieved, followed by a gradual taper to the frequency when the patient was last stable.
The second phase of the Prolonging Remission in Depressed Elderly study is perhaps the most innovative and well-designed study of flexible C-ECT administration.27 Patients who remitted after an index course of ECT plus open-label venlafaxine were randomized to receive either C-pharm alone or C-pharm plus C-ECT given according to the algorithm developed by the study authors.28 Both groups received C-pharm consisting of venlafaxine and open-label lithium dosed to achieve target levels of 0.4 to 0.6 mEq/L. Those receiving C-ECT were initially run through a fixed taper consisting of four ECTs over a 4-week period. Subsequently, ECT was administered 0, 1, or 2 times per week depending on the patients level of risk for relapse as determined by the results of weekly HAM-D screenings. Overall, both groups performed well with the reported relapse rate for the combination group and C-pharm group at 13.1% and 20.3%, respectively. Unfortunately, this study was not powered to allow valid comparisons between groups, undermining the comparability of the study findings to prior work done by CORE. The group that received combination treatment demonstrated a lower mean HAM-D score at the end of the 6-month study period than the C-pharm group. However, the mean HAM-D score for both groups fell below 10, the typical threshold that defines remission. Only one-third of patients in the combination arm received any symptom-triggered ECT treatments after the fixed taper. Those who did receive additional ECT's relapsed at about the same rate as those who did not. Assuming the method for stratification of risk for relapse used by the study investigators was valid, this would suggest that the algorithm did an effective job at managing moderate and high-risk patients.
Based on the limited high-quality evidence that is available, the combination of C-ECT with C-pharm is safe, well-tolerated, and appears to be more effective than C-pharm alone.23,29,30 However, additional research in this area is needed. Questions regarding the optimal schedule of C-ECT and how to best manage relapse during the continuation phase of treatment remain. Additionally, although there is some evidence for the comparative efficacy of C-pharm to C-ECT plus C-Pharm, there are no adequate studies that compare C-ECT monotherapy to the combination.
Given the high prevalence and enormous disability associated with MDD, effective treatments for both the acute episode and the prevention of recurrence are important. ECT has consistently shown greater efficacy for treatment-resistant forms of the illness, although it is usually considered only after numerous failed antidepressant trials, if at all. Unfortunately, relapse rates after successful treatment with ECT are extremely high. Continuation treatment with antidepressants initiated during the course of ECT or immediately after has been shown to decrease rates of relapse, although the depression relapse risk still remains high. The addition of lithium to continuation antidepressant treatment has been reliably shown to improve outcomes after ECT relative to antidepressants alone. C-ECT monotherapy represents another safe and effective strategy for relapse prevention. As monotherapy, it is as effective as aggressive C-pharm, and is at least as well tolerated. The combination of C-ECT and C-pharm has been shown to be more effective than C-pharm alone. The management of relapse in the setting of C-ECT remains a challenge, and recent work has explored various ways to individualize the scheduled administration of ECT to manage symptom recurrence, although no definitive algorithm has emerged thus far. 26, 27
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