Remission of Depression: How Effective are Antidepressants?
There exist longstanding concerns that antidepressant drugs produce modest clinical improvement, with only a minority of patients achieving full remission of their depressive episodes. Uncertainties about the therapeutic benefits of antidepressant treatment have been heightened by awareness of how difficult it is to demonstrate differences between active drugs and placebo in controlled clinical trials. This was evidenced by an analysis of data for several approved antidepressants submitted to the Food and Drug Administration over the past 2 decades.1-3
Doubts continue to be raised about the inability of antidepressants to fully relieve depressive symptoms and to induce remission of a major depressive episode.4-5 Data from controlled clinical trials infer that response rates with antidepressant treatment differ from placebo by only a small percentage. Recent media reports have emerged claiming that a majority of patients are insufficiently helped by antidepressants.6 Yet, the perception that antidepressants yield poor therapeutic response conflicts with clinical experience. Such experience suggests that most patients benefit from drug treatment when attention is paid to response to the drug and when antidepressant therapy is switched if improvement is insufficient.
Remission Rates in Placebo-Controlled Efficacy Trials
Consensus about what constitutes remission varies among experts. In placebo-controlled efficacy studies, a generally accepted definition of remission is achieving a score of ≤7 on the 17-item Hamilton Rating Scale for Depression (HAM-D), corresponding to minimal symptoms. Using this criterion for pharmaceutical industry efficacy trials, the data suggest remission rates of 35% to 45% for the newer antidepressants, such as venlafaxine and selective serotonin reuptake inhibitors.7 However, one should recognize that efficacy trials are typically short-term studies (6–8 weeks duration). In most short-term trials, group mean severity scores are still trending downward at the end of treatment, suggesting that additional patients would have achieved remission if therapy were continued longer. Consequently, most efficacy trials tend to underestimate the degree of improvement attributable to the study drug as compared with placebo. In addition, patients with an unsatisfactory response to a study drug might very well have achieved remission if switched to another antidepressant.
Remission rates in clinical practice settings are hard to quantify because well-controlled trials that allow longer treatment and switching of drugs for poor response necessitate complex study designs that are difficult to implement. However, a recent study attempted to address the question by examining eventual remission rates for patients who participated in a series of efficacy trials at Columbia University.8 Effectiveness was assessed in patients unimproved after initial treatment who were subsequently switched to a second or third drug using a therapeutic approach analogous to clinical practice.
Remission Rates in Effectiveness Studies
The investigators examined clinical remission in participants involved in three clinical trials of second-generation antidepressants conducted at the depression clinic at New York State Psychiatric Institute and Columbia University, and compared results with remission rates following a previously published study.9 Follow-up therapy after the initial study drug treatment differed among the three studies. In one study, nonresponders received up to two additional courses of the drug of the clinician’s choice; in two other studies, nonresponders were switched to a protocol-specified second antidepressant drug under blinded conditions, and then, if necessary, received a third course of antidepressant of the clinician’s choice. The investigators compared the results of these second-generation drug trials with aftercare of subjects involved in a previous trial of first-generation antidepressants (imipramine, phenelzine, or placebo).9 In this latter study, drug nonresponders received up to two additional courses of antidepressant treatment in order to seek remission.
In these clinical trials, patients were evaluated using the clinician-rated HAM-D and the self-rated Symptom Checklist-90 (SCL-90) scales. In the few instances where no final HAM-D or SCL-90 score was available to make a determination of remission, the clinical chart was reviewed. In such cases, remission only applied if the patient was described as being either euthymic or depression free.
Remission Rates with Second-Generation Antidepressants
A total of 171 patients entered the three second-generation antidepressant trials, and 50% (n=86) of the patients achieved remission during the first course of treatment (8–12 weeks); 73 patients were unimproved, and 44 of these received up to 12 weeks of treatment with a second antidepressant. Twenty-two of the latter group achieved remission. Of 20 unimproved patients following the second course of treatment, 14 were switched to a third drug, with 5 remitting. In total, 66% (n=113) of the 171 original patients ultimately achieved remission of their depressive episode. These findings show that in spite of being treated in a research setting where some constraints on clinical management exist, two-thirds of patients experienced remission of their depressive episodes. An additional 10% (n=17) improved significantly, although without achieving remission.
Remission Rate with First-Generation Antidepressants
These results were compared with clinical management of 420 patients following participation in a previously published double-blind trial of first-generation antidepressants (imipramine or phenelzine versus placebo).9 In this 6-week trial, drug nonresponders were switched to double-blind treatment with the other active drug (either imipramine or phenelzine) for 6 additional weeks, and placebo nonresponders were randomly assigned to either imipramine or phenelzine. If a third course of treatment was necessary, patients were treated open label with the antidepressant of the clinician’s choice for 6 additional weeks.
During initial double-blind treatment, 48% (n=205) of patients met remission criteria by 6 weeks. Of 167 nonresponders, 121 patients were switched to a second course of double-blind treatment, with 58 patients achieving remission. There were 24 nonresponders who underwent a third 6-week course of open-label treatment, with 12 patients remitting. Thus, out of 450 patients initially entering treatment for depression in this study, a total of 65% (n=275) ultimately remitted, while 15% (n=65) additional patients improved significantly but failed to remit.
The Importance of Continuing Treatment
The fact that 66% of patients ultimately achieved remission in a combined sample totaling more than 600 subjects involved in first- and second-generation antidepressant trials suggests that a majority of depressed patients will benefit if they remain in treatment. Since not all patients agreed to switch antidepressants and chose to drop out instead, 66% probably represents an underestimate of the potentially achievable rate of remission with drugs. In fact, in this study >90% of patients remaining in treatment for up to three courses of drugs remitted. It is likely that data in new drug applications inherently underestimate the effectiveness of antidepressants because industry-funded efficacy studies are predominately short-term trials that impose restrictions on dose and duration of drug treatment and do not permit switching therapy.
The overall favorable therapeutic outcome in these Columbia studies infers that the majority of depressed patients will remit if they receive appropriate antidepressant therapy. Good therapeutic management requires closely monitoring patients, with dose titration based on clinical response, and switching drugs if remission is not achieved with an adequate course of treatment. Motivating patients to continue treatment until they experience therapeutic benefit is a key aspect of optimal clinical management.
The perception that antidepressants produce low remission rates derives largely from results of short-term efficacy trials conducted by the pharmaceutical industry during the approval process. These studies tend to underestimate drug effectiveness and the remission rates potentially achievable in the practice setting. Effectiveness studies where patients are switched for reason of unsatisfactory response to another antidepressant drug indicate that the majority of patients will ultimately remit if they remain in treatment. Motivating depressed patients to remain in treatment is therefore a critical part of good clinical management. PP
1. Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the food and drug administration database. Arch Gen Psychiatry. 2000;57(4):311-317.
2. Robinson DS, Rickels K. Concerns about clinical drug trials. J Clin Psychopharmacol. 2000;20(6):593-596.
3. Khan A, Khan SR, Walens G, Kolts R, Giller EL. Frequency of positive studies among fixed and flexible dose antidepressant clinical trials: an analysis of the food and drug administration summary basis of approval reports. Neuropsychopharmacol. 2003;28(3):552-557.
4. Olfson M, Marcus SC, Druss B, Elinson L, Tanielian T, Pincus HA. National trends in the outpatient treatment of depression. JAMA. 2002;287(2):203-209.
5. Schneider LS, Nelson JC, Clary CM, et al. An 8-week multicenter, parallel-group, double-blind, placebo-controlled study of sertraline in elderly outpatients with major depression. Am J Psychiatry. 2003;160(7):1277-1285.
6. Goode E. Antidepressants lift clouds, but lose ‘miracle drug’ label. New York Times. June 30, 2002.
7. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234-241.
8. Quitkin FM, McGrath PJ, Stewart JW, et al. Remission rates with 3 consecutive antidepressant trials: effectiveness for depressed outpatients. J Clin Psychiatry. 2005;66(6):670-676.
9. Quitkin FM, Stewart JW, McGrath PJ, et al. Columbia atypical depression. A subgroup of depressives with better response to MAOI than to tricyclic antidepressants or placebo. Br J Psychiatry Suppl. 1993;(21):30-34.
Dr. Robinson is a consultant with Worldwide Drug Development in Melbourne, Florida.
Disclosure: Dr. Robinson is a consultant to Bristol-Myers Squibb, Genaissance, Organon, Somerset, and Takeda.